Clinical Supplement

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Management of Painful Physical Symptoms Associated With Depression and Mood Disorders

Moderator: Thomas N. Wise, MD; Discussants: Lesley M. Arnold, MD, Vladimir Maletic, MD; Section Editor: David L. Ginsberg, MD

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Primary Psychiatry. 2005;12(11 suppl 10):1-16.

Funding for this roundtable monograph supplement has been provided through an unrestricted educational grant by Eli Lilly and Company.

An expert panel review of clinical challenges in psychiatry


 

This CME activity is expired.

Accreditation Statement:

 

Mount Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide Continuing Medical Education for physicians. 

Mount Sinai School of Medicine designates this Continuing Medical Education activity for a maximum of 1.0 Category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity.

It is the policy of Mount Sinai School of Medicine to ensure fair balance, independence, objectivity, and scientific rigor in all its sponsored activities. All faculty participating in sponsored activities are expected to disclose to the audience any real or apparent conflict-of-interest related to the content of their presentation, and any discussion of unlabeled or investigational use of any commercial product or device not yet approved in the United States.

 

This activity has been peer reviewed and approved by Eric Hollander, MD, professor of psychiatry, Mount Sinai School of Medicine. Review date: October 4, 2005. 

 

Statement of Need and Purpose:

 

It is estimated that 121 million people worldwide suffer from depression, a disorder which continues to have a sizable burden on society due in part to underdiagnosis and undertreatment. Depression is increasingly seen as a triad of psychological, somatic, and physical symptoms, all of which need to be treated in order for remission to occur. There is a high correlation between the number of painful physical symptoms reported and the presence of depression. In addition, patients with residual physical and emotional symptoms following treatment of depression appear to be at a higher risk of relapse compared with those who do not have residual symptoms. Patients who fail to achieve full remission have a more recurrent and chronic course, increased medical and psychiatric comorbidities, and greater functional burden.

 
 

Despite the development of newer agents with good safety profiles, the management of patients with depression remains a therapeutic challenge. Better recognition, assessment, and treatment of pain associated with mood disorders may enhance outcomes of depression therapy. Dual-acting agents that have shown efficacy in neuropathic pain and in depression independently, may benefit depressed patients with such painful physical symptoms. Unless otherwise stated, all inferences to studies of pain in this monograph refer to diabetic neuropathy in nondepressed patients.

 

Learning Objectives:

 

• Recognize the physical symptoms associated with depression and the importance of treating both emotional and physical symptoms of the disorder.

• Review the neurobiological factors that may underlie depression, pain, and cardiovascular disease.

• Discuss how dual-acting antidepressants may provide relief in multiple symptom domains and review the efficacy, tolerability, and safety of the dual-acting agent duloxetine. 

 

Disclosure of Off-Label Usage:

 

This continuing medical education activity may contain references to unlabeled or investigational uses of drugs or devices.

Faculty Affiliations and Disclosures:

 

Dr. Arnold is associate professor of psychiatry in the Department of Psychiatry at the University of Cincinnati in Ohio. She is a consultant to Cypress, Eli Lilly, Forest, Pfizer, Sanofi-Synthelabo, and Wyeth; is on the speaker’s bureaus of Eli Lilly, Pfizer, and Wyeth; and receives grant/research support from Boehringer-Ingelheim, Cypress, Eli Lilly, Forest, Pfizer, Sanofi-Synthelabo, and Wyeth.

 
 

Dr. Maletic is associate clinical professor of neuropsychiatry and behavioral science at the University of South Carolina School of Medicine in Columbia. He is a consultant to Cephalon, Eli Lilly, and Shire; is on the speaker’s bureaus of Cephalon and Eli Lilly; and receives grant/research support from Eli Lilly.

 
 

Dr. Wise is chief of psychiatry at Fairfax Hospital in Falls Church, Virginia. He is on the advisory board and speaker’s bureau of Eli Lilly.

 
 

Dr. Ginsberg is director of outpatient services in Tisch Hospital’s Department of Psychiatry at New York University School of Medicine in New York City. He is a speaker for AstraZeneca, Cyberonics, Forest, and GlaxoSmithKline; and has received research grants from Cyberonics.

 

Abstract

 

Depression is a common, recurring illness that continues to be underdiagnosed and undertreated in both psychiatric and primary care settings. It is increasingly being recognized that painful physical symptoms, which commonly exist comorbid with depressive disorders, play a role in complicating diagnosis of depression. Patients tend to discuss physical pain with primary care physicians and emotional pain with psychiatrists, often oblivious to the fact that both may be aspects of one disorder. Those who present with somatic complaints are three times less likely to be accurately diagnosed than patients with psychosocial complaints. However, thorough evaluation of mood and anxiety disorders in primary care is sparse due to the limited time primary care physicians can spend with each patient. Better recognition and treatment of both physical and emotional symptoms associated with mood disorders may increase a patient’s chance of achieving remission, which is the optimum therapeutic goal.

 
 

Abnormalities of serotonin and noradrenaline are strongly associated with depression and are thought to play a role in pain perception. Brain-derived neurotrophic factor, which is increased with antidepressant treatment, appears to influence regulation of mood and perception of pain. Clinical evidence indicates that dual-acting agents may have an advantage in modulating pain over those agents that increase either serotonin or noradrenaline alone. The novel dual-acting agents, such as venlafaxine and duloxetine, are better tolerated than tricyclic antidepressants and monoamine oxidase inhibitors. These agents have demonstrated efficacy in depression and in diabetic neuropathic pain independently. Therefore, unless otherwise stated, all inferences to studies of pain in this monograph refer to neuropathic pain in nondepressed patients.

 

 

 
 

 

 

Thomas N. Wise, MD—Moderator

 
 

Introduction

 
 

Recognizing Painful Physical Symptoms Associated with Depression

 
 

Depressive disorders are common, serious, and recurrent illnesses that are associated with poor outcomes in comorbid medical conditions, reduced quality of life for patients and their families, and an increased financial and social burden on society. Depression is frequently underdiagnosed and undertreated, often due to the common presentation of somatic syndromes associated with the disorder. Patients may present to their physician with symptoms of subjective distress often in the form of vague aches, pains, fatigue, dizziness, and other somatic symptoms. Because of the tendency to focus on physical symptoms, the diagnosis of depression is often missed.

 
 

Diagnosis of depression can be made through examinations, laboratory tests (chemical assays or radiologic imaging), and careful questioning of the patient. Although the current medical climate affords clinicians little time to take careful histories and conduct comprehensive examinations, questioning a patient about depression can be done quickly and efficiently. It is quite easy to ask patients if they are depressed or have been experiencing less interest in their usual activities or hobbies (Patient Health Questionnaire-2). Positive answers to both of these questions have been found to be commonly associated with major mood disorders. In addition, asking patients about their thoughts on depression and antidepressant treatment will often help in assessing their willingness to initiate or adhere to an antidepressant treatment regimen.

 
 
 
 

There are a variety of newer antidepressants that can help patients with depressive disorders achieve remission or at least enhance their euthymic mood state so that they can function to their fullest ability.

In this monograph, Lesley M. Arnold, MD, associate professor of psychiatry at the University of Cincinnati in Ohio, discusses the hidden face of depression and the need for remission of affective disorders following treatment response.

 
 

Next, Vladimir Maletic, MD, clinical associate professor of neuropsychiatry and behavioral science at the University of South Carolina School of Medicine in Columbia, reviews the pathophysiology of pain and depression with an emphasis on the mechanisms of dual-action antidepressants.

 
 
 

Finally, I present an overview of the efficacy, tolerability, and safety of duloxetine, a serotonin norepinephrine reuptake inhibitor approved by the Food and Drug Administration for the treatment of major depression and diabetic peripheral neuropathic pain.
 

 

Lesley M. Arnold, MD

 
 

The Nature of Painful and Somatic Complaints in Depressive Disorders

 
 

The Hidden Face of Depression

 
 

Major depressive disorder (MDD) is a common illness in the United States that afflicts approximately 1 in 6 people over the course of their lives. MDD is also associated with substantial morbidity and mortality worldwide. The Global Burden of Disease study1 estimated that by 2020 MDD will be the second cause of disability in industrialized countries exceeded only by ischemic heart disease.

 
 

MDD may present with a combination of emotional and physical symptoms. The emotional symptoms are well recognized and include depressive symptoms such as sadness, tearfulness, and anhedonia, as well as anxiety symptoms such as nervousness and brooding. Some physical symptoms, such as tiredness/fatigue and appetite and weight disturbances, are listed in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision (DSM-IV-TR)2 criteria for MDD. However, there are other physical symptoms common in patients with depression that are not included in the criteria for MDD, such as body aches and pains, headaches, and gastrointestinal (GI) disturbances. The DSM-IV-TR acknowledges that some depressed patients emphasize somatic complaints, such as bodily aches and pains, rather than reporting feelings of sadness (Slide 1).

 

 

The challenge for physicians is to recognize all of the symptoms of MDD that include both emotional and physical symptoms. Patients may feel it is inappropriate to discuss painful symptoms with psychiatrists, because they do not recognize the potential relevance of their painful symptoms to depression. Therefore, it is important for psychiatrists to explore all of the possible MDD-related emotional and physical symptoms. On the other hand, in primary care settings, patients may focus only on the physical symptoms of depression and minimize or neglect to mention the emotional symptoms. Thus, primary care physicians (PCPs) need to ask about emotional symptoms in those patients they suspect might have MDD.

 
 

Recognition of Major Depression

 
 
 

The importance of recognizing and treating MDD is underscored by the findings from the Medical Outcomes Study,3 which included >11,000 outpatients in three healthcare provider systems—primary care, psychiatry, and non-physician therapist settings. The study findings showed that MDD is associated with considerable functional impairment and decreased health-related quality of life equals or exceeds that associated with chronic general medical conditions such as diabetes. However, MDD is still frequently untreated. For example, the National Comorbidity Survey (NCS) Replication Study,4 which was a nationally representative face-to-face household survey of >9,000 individuals ≥18 years of age, demonstrated that among patients who were diagnosed with MDD in the last 12 months, only 51.6% of them received any treatment. Of those patients, only 41.9% received at least minimally adequate treatment, which was defined as at least four outpatient visits with any type of physician for medication for a minimum of 30 days, or at least eight outpatient visits with any professional in the mental health field. 

 

Barriers to Diagnosis in Primary Care

 
 

The results of the NCS study suggest that there continues to be substantial unmet needs for patients with MDD. In primary care settings, there are several possible barriers to the recognition of MDD. First, primary care visits are typically completed in 15 minutes, which is usually an inadequate amount of time to conduct a thorough evaluation for a mood or anxiety disorder. Second, there continues to be stigmatization of mental illness, which makes it difficult for patients to recognize that they have an illness that is treatable. Finally, patients who present to PCPs often present only with physical symptoms of depression, and they may not volunteer emotional symptoms, making it more difficult to diagnose MDD.

 
 

Approximately 50% to 70% of patients with MDD present to PCPs with physical complaints,5,6 and 80% of patients with MDD or anxiety disorders (panic disorder and/or agoraphobia) present exclusively with physical symptoms.7 In a recent international study8 of 1,146 MDD patients in 15 primary care centers in 14 countries, 69% reported only physical symptoms as the reason for their physician visit. Patients with MDD were significantly more likely to report unexplained physical symptoms (eg, insomnia, hypersomnia, change in weight or appetite, fatigue, psychomotor agitation) than those without MDD, and these physical manifestations of depression were similar in all of the countries studied.

 
 

Physical Symptoms Predict Depression: Clinical Studies

 
 
 
In order to improve the recognition of MDD in primary care settings, Kroenke and colleagues9 conducted a study designed to identify predictors of depression and anxiety disorders in a general medical patient population. Five hundred adults with a chief complaint of physical symptoms were included. The study showed that the greater the number of physical symptoms, the greater the likelihood of a depressive or anxiety disorder. The leading symptom category in this study was musculoskeletal complaints (Slide 2).

 

 

 

Kroenke and colleagues10 conducted another study of 1,000 adult primary care patients to determine how the type and number of physical symptoms reported by primary care patients were related to psychiatric disorders and functional impairment. Common physical symptoms such as headache, chest pain, abdominal pain, joint or limb pain, and back pain, were associated with at least a 2–3-fold increased likelihood of a mood or anxiety disorder (Slide 3), and the number of symptoms was the strongest predictor and was a powerful correlate of functional impairment. Thus, patients who present to PCPs with multiple unexplained physical symptoms should be screened for mood and anxiety disorders.

 
 

Gerber and colleagues11 assessed the relationship of specific patient chief physical complaints to underlying depression, and found that certain complaints discriminated between depressed and non-depressed patients, including sleep disturbance, fatigue, shortness of breath, GI complaints, having three or more symptom complaints, and several pain symptoms such as nonspecific musculoskeletal complaints, back pain, and chest pain (Slide 4). Indeed, pain has been found to be present in 30% to 60% of patients with depression,12,13 and a lifetime history of MDD is reported in about two thirds of patients with persistent pain conditions (eg, fibromyalgia, back pain, pelvic pain, chest pain, irritable bowel syndrome).14,15

 

 
 

The relationship between MDD and pain was explored in a recent study by Ohayon and Schatzberg16 in which the authors surveyed a random general population sample of 18,980 European subjects between 15 and 100 years of age. MDD was present in 4% of the group, and 43.4% of those subjects with MDD had a chronic painful physical condition (eg, limb pain, backache, joint or articular disease, GI disease, headache), which was four times more often than subjects without MDD. Subjects with backaches or headaches had the highest odds of having MDD. Furthermore, the 24-hour presence of pain increased the likelihood of having MDD. In another study of the connection between pain and depression, Wu and colleagues17 followed 1,997 adult patients at a family medicine clinic over 30 months. They found that patients with depression had a significantly higher prevalence of headache, osteoarthritis, and abdominal pain than those without depression. In addition, the self-rated pain scores were two times higher in those with depression, and pain predicted depression and anxiety more than any specific medical illness.

 
 

Remission of Depression

 
 

In the treatment of depression it is important to address the painful physical symptoms and other physical symptoms in addition to the emotional symptoms, in order to increase the likelihood of patients reaching remission of MDD. Remission of depression is defined by minimal to no residual symptoms; a score of ≤7 on the 17-item Hamilton Rating Scale for Depression (HAM-D17) or ≤10 on the Montgomery-Asberg Depression Rating Scale; or complete restoration of functioning.18

 
 

Remission is the goal of the acute phase treatment of MDD. Attainment of initial remission followed by sustained remission is the best way to prevent depression-related morbidity. This was demonstrated in a study by Judd and colleagues19 in which patients who had recovered from MDD were followed naturalistically for 10 years. Patients were divided into two groups—those with residual depressive symptoms and those who were asymptomatic. The patients with residual symptoms relapsed three times as fast as those who were in remission. In addition, almost three times as many patients who were in remission remained well compared to those with residual symptoms.

 
 

Many residual symptoms of MDD are physical. In a small study, Paykel and colleagues20 discovered that among patients who had residual symptoms of MDD, >90% had mild to moderate physical symptoms as measured by the HAM-D17 somatic symptoms item, which includes symptoms such as heaviness in limbs, back, or head; backaches; headaches; muscle aches; loss of energy; and fatigue.

 
 

In a naturalistic study of 573 depressed primary care patients, Bair and colleagues21 showed that depression outcomes were worse in patients with comorbid pain. There was an incremental impact with increasing pain severity (Slide 5).

 

 
 
 

There is emerging evidence that improvement in painful physical symptoms may be associated with higher remission rates as demonstrated in a recent study by Fava and colleagues.22 The study was a post-hoc analysis of two identical but independent 9-week randomized control trials in adult outpatients with MDD comparing duloxetine with placebo. Results showed that the remission rate for depressed patients who had a ≥50% improvement in painful physical symptoms was nearly twice that of depressed patients who had <50% improvement in painful physical symptoms. In addition, a study23 of 100 elderly patients with recurrent MDD who were randomized to receive bupropion or paroxetine for 6 weeks, showed that lower perceived physical functioning before treatment was associated with lower remission rates after treatment. Furthermore, remitters had better physical function than partial responders and nonresponders.

 
 

Conclusion

 
 

Physical symptoms, particularly painful physical symptoms, appear to be commonly associated with MDD. Remission of MDD is the goal of treatment, and improvement in both the physical and emotional symptoms may help more patients achieve remission.

 
 

References

 
 

1. Murray CJL, Lopez AD, eds. The Global Burden of Disease. Boston, MA: Harvard University Press; 1996.

 
 
 

2. Diagnostic and Statistical Manual of Mental Disorders. 4th ed text rev. Washington, DC: American Psychiatric Association; 1999. 

 

3. Wells KB, Stewart A, Hays RD, et al. The functioning and well-being of depressed patients. Results from the Medical Outcomes Study. JAMA. 1989;262(7):914-919.

 
 

4. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289(23):3095-3105.

 
 
 

5. Schurman RA, Kramer PD, Mitchell JB. The hidden mental health network. Treatment of mental illness by nonpsychiatrist physicians. Arch Gen Psychiatry. 1985;42(1):89-94. 

 

6. Bridges KW, Goldberg DP. Somatic presentation of DSM III psychiatric disorders in primary care. J Psychosom Res. 1985;29(6):563-569.

 
 

7. Kirmayer LJ, Robbins JM, Dworkind M, Yaffe MJ. Somatization and the recognition of depression and anxiety in primary care. Am J Psychiatry. 1993;150(5):734-741.

 
 

8. Simon GE, VonKorff M, Piccinelli M, Fullerton C, Ormel J. An international study of the relation between somatic symptoms and depression. N Engl J Med. 1999;341(18):1329-1335.

 
 

9. Kroenke K, Jackson JL, Chamberlin J. Depressive and anxiety disorders in patients presenting with physical complaints: clinical predictors and outcome. Am J Med. 1997;103(5):339-347.

 
 

10. Kroenke K, Spitzer RL, Williams JB, et al. Physical symptoms in primary care. Predictors of psychiatric disorders and functional impairment. Arch Fam Med. 1994;3(9):774-779.

 
 

11. Gerber PD, Barrett JE, Barrett JA, et al. The relationship of presenting physical complaints to depressive symptoms in primary care patients. J Gen Intern Med. 1992;7(2):170-173.

 
 

12. Watts CAH. Depresive Disorders in the Community. Bristol, England: John Wirte and Sons; 1996.

 
 

13. Von Knorring L. The experience of pain in depressed patients: a clinical and experimental study. Neuropsychobiology. 1965;1:155-165.

 
 

14. Katon W, Sullivan MD. Depression and chronic medical illness. J Clin Psychiatry. 1990;51(suppl):3-11; discussion 12-4.

 
 

15. Arnold LM, Hudson JI, Hess EV, et al. Family study of fibromyalgia. Arthritis Rheum. 2004;50(3):944-952.

 
 

16. Ohayon MM, Schatzberg AF. Using chronic pain to predict depressive morbidity in the general population. Arch Gen Psychiatry. 2003;60(1):39-47.

 
 

17. Wu LR, Parkerson GR Jr, Doraiswamy PM. Health perception, pain, and disability as correlates of anxiety and depression symptoms in primary care patients. J Am Board Fam Pract. 2002;15(3):183-190.

 
 

18. Nierenberg AA, DeCecco LM. Definitions of antidepressant treatment response, remission, nonresponse, partial response, and other relevant outcomes: a focus on treatment-resistant depression. J Clin Psychiatry. 2001;62(suppl 16):5-9.

 
 

19. Judd LL, Akiskal HS, Maser JD, et al. Major depressive disorder: a prospective study of residual subthreshold depressive symptoms as predictor of rapid relapse. J Affect Disord. 1998;50(2-3):97-108.

 
 

20. Paykel ES, Ramana R, Cooper Z, Hayhurst H, Kerr J, Barocka A. Residual symptoms after partial remission: an important outcome in depression. Psychol Med. 1995;25(6):1171-1180.

 
 

21. Bair MJ, Robinson RL, Eckert GJ, Stang PE, Croghan TW, Kroenke K. Impact of pain on depression treatment response in primary care. Psychosom Med. 2004;66(1):17-22.

 
 

22. Fava M, Mallinckrodt CH, Detke MJ, Watkin JG, Wohlreich MM. The effect of duloxetine on painful physical symptoms in depressed patients: do improvements in these symptoms result in higher remission rates? J Clin Psychiatry. 2004;65(4):521-530.

 
 

23. Doraiswamy PM, Khan ZM, Donahue RM, Richard NE. Quality of life in geriatric depression: a comparison of remitters, partial responders, and nonresponders. Am J Geriatr Psychiatry. 2001;9(4):423-428.

 

 

 
 
 

 

Vladimir Maletic, MD 

 
 
 
 

Pathophysiology of Pain and Depression: The Role of Dual-Acting Antidepressants

 
 

Introduction

 
 

Painful physical symptoms and other somatic symptoms are common in depressed patients, but the relationship between depression and pain is complex. Depressed patients presenting with somatic symptoms are three times less likely to be accurately diagnosed than patients with psychosocial complaints.1 In addition to being a symptom domain of depression, somatic complaints can also be present as a comorbidity: Depressed patients are twice as likely to experience arthritis, back pain, and migraine compared to nondepressed patients.2 As demonstrated by Bair and colleagues,3 depressed patients who had severe pain were four times less likely to achieve a response within a 3-month period than patients who were pain free.

 
 

Pain and Depression: The Role of Noradrenaline, Serotonin, and BDNF 

 
 

Therapeutic action of currently available antidepressants is thought to be associated with their ability to modulate monoaminergic (serotonin, noradrenaline, and dopamine) transmission in the brain. Serotonin and noradrenaline also have a role in modulation of pain.4,5 Afferent fibers, utilizing substance P and glutamate, carry nociceptive signals from the periphery, which creates the perception of pain. En route to the thalamus, these fibers activate nucleus reticularis gigantocellularis. Activation of this noradrenergic nucleus leads to activation of the periaqueductal grey and thereby the release of endogenous opiates, as well as activation of the descending pain pathway (Slide 6).6 As a part of the descending pain pathway, serotonin and noradrenaline fibers modulate the intensity of the pain by interfacing with ascending pain pathways (via an inhibitory GABAergic interneuron).The final outcome is modified effects of substance P, glutamate, and other pain mediators, as well as increased threshold and decreased sensitivity to pain. Noradrenaline and serotonin fibers, forming the pain-modulating dorsolateral funiculus (descending pain pathway) originate from some of the same nuclei as fibers involved in regulation of mood. If we postulate that monoaminergic dysregulation is one of the causes of mood disorders, it follows that modulation of pain will also be compromised.

 
 

Synergy between noradrenaline and serotonin occurs both at the synaptic and at the intracellular level. A study by Shimizu and colleagues7 suggested that people with depression have decreased levels of neurotrophic factors, specifically, brain-derived neurotrophic factor (BDNF), compared to matched non-depressed controls. After successful treatment with antidepressants, the level of BDNF increased to the point where it equaled the levels in controls.

 
 

Antidepressants increase BDNF via effects on transductional cascades and gene expression (Slide 7). BDNF appears to have a neurotrophic effect that influences regulation of mood, perception of pain, and cardiovascular function. BDNF may be the key mediator of the therapeutic response to antidepressants,8 due to its ability to promote neurogenesis and mediate neuroplasticity in activity dependant manner, effectively reshaping neural networks.9 Duration of depression has been shown to correlate with loss of hippocampal volume,10 and researchers speculate that this may result from suppression of BDNF synthesis in depressed patients. Preclinical studies suggest that central injection of BDNF leads to a long-lasting antidepressant effect11 and that blockade of noradrenergic and serotonergic receptors precipitate inhibition of BDNF synthesis.12 Although simultaneous activation of serotonin and noradrenaline receptors theoretically has a synergistic effect on transduction cascade resulting in enhanced expression of BDNF gene, empirical data only partially supports this view. Monoamine oxidase inhibitor (MAOI) and tricyclic antidepressant (TCA) use is consistently associated with increased expression of BDNF in hippocampus, but reports with serotonin norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs) are more equivocal.13 In a preclinical study,14 electroconvulsive therapy and a dual-acting antidepressant increased BDNF transcription in different parts of a rat brain unlike the SSRI, which did not have a significant effect. Thus, increased synthesis of BDNF and other neurotrophic factors, promoted by the synergistic activation of adrenergic and serotonergic receptors, may be the necessary and sufficient explanation of antidepressant action.

 
 
 

In addition to its role in the regulation of mood, BDNF appears to impact pain regulation. Duric and McCarson15 found that both stress and pain downregulated BDNF gene expression in the hippocampus. 

 

BDNF may also play a role in the relationship between major depression and cardiovascular morbidity. Frasure-Smith and colleagues16 noted that depressed patients (Beck Depression Inventory score ≥10) had 3.5 times greater hazard of cardiac death. Lesperance and colleagues17 found a strong correlation between degree of depression at the time of admission for a cardiovascular event, and 5-year survival rate. In a comprehensive review, Nemeroff and colleagues18 speculated that sympathoadrenal hyperactivity and reduced heart rate variability in depressed patients represent some of the principal risk factors for cardiovascular morbidity and death. Interestingly enough, Yang and colleagues19 noted that BDNF acting through P75 receptor has a key role in shifting from excitatory sympathetic to inhibitory cholinergic tone at cardiac myocyte synapses.

 
 

Use of Dual-Acting Agents in Pain

 
 

Clinical evidence indicates that agents modulating both serotonin and noradrenaline might have an advantage in modulating pain over those agents that increase either serotonin or noradrenaline alone.

 
 

Lynch20 conducted a meta-analysis of controlled trials comparing the efficacy of SSRIs, TCAs, MAOIs, and other dual-acting agents. Approximately 80% of the trials that included TCAs showed positive evidence of dose-related analgesic efficacy. The optimal response was achieved at imipramine and desipramine concentrations of 400–500 nm/L, which is about half of the concentration required for an antidepressant response. Only 35% of the SSRI studies (5/14) demonstrated efficacy in treatment of chronic pain (tension headache, migraine, diabetic neuropathy, fibromyalgia, pelvic pain, and low-back pain).20 The largest study to compare fluoxetine and placebo found no significant difference in their ability to supress pain; however, two smaller, open-label studies showed positive effect of SSRIs.20 Controlled trials of MAOIs in atypical facial pain have shown positive results.20 Several studies of venlafaxine and duloxetine21,22 suggest their efficacy in the treatment of pain as well.

 
 

In a meta-analysis by Fishbain,23 all the trials of dual-acting agents and 89% of the trials with noradrenergic agents in the treatment of pain showed separation between drug and placebo, compared to only 14% of the trials involving SSRIs.

 
 

In a double-blind crossover trial, Vrethem and colleagues24 compared the dual-acting agent amitriptyline (75 mg/day) with the noradrenergic agent maprotiline (75 mg/day). The dual-acting agent was more effective than the noradrenergic agent in treating painful diabetic and nondiabetic polyneuropathy.

 
 

Using an alternative method of examining the efficacy of dual acting agents, Sindrup and Jensen25 demonstrated that the odds of having success are much greater with an optimal dose of dual-acting agents than with SSRIs, gabapentin, or even noradrenergic tricyclics. The study looked at the number needed to treat in order to obtain one patient with >50% relief of neuropathic pain. It took roughly seven trials of SSRIs versus four trials with gabapentin in order to produce one success. With optimal dose of dual-acting TCAs, it took only 1.4 trials to produce one positive outcome.

 
 

Recent trials have evaluated the efficacy of venlafaxine in diabetic neuropathy. In a 6-week study by Kunz and colleagues,26 low-dose venlafaxine (75 mg/day) was no more effective than placebo. On the other hand, venlafaxine 150–225 mg/day, a dosage which would normally produce dual activity, separated not only from placebo at week 3 but also from lower dose venlafaxine from week 5 onward (Slide 8).

 
 

In a 12-week study by Goldstein and colleagues,21 457 nondepressed patients suffering from peripheral diabetic neuropathy were treated with duloxetine 60 mg/day and 120 mg/day. Both doses were robustly more effective than placebo in reducing symptoms of peripheral diabetic neuropathy. A lower dose of duloxetine, 20 mg/day, did not separate from placebo (Slide 9). Pathway analysis revealed that 95% of the ultimate benefit was derived from a direct impact on pain rather than from improvement in depressive symptomatology.

 

 
 
 

Treating all of the symptoms of depression, including painful physical symptoms, increases the chance of remission. A study by Paykel and colleagues27 demonstrated that 94% of patients who had lingering symptoms of depression experienced some degree of physical discomfort. Denninger and colleagues28 found that degree of improvement in physical symptoms through antidepressant treatment directly correlated with ability to achieve remission. Farabaugh and colleagues29 demonstrated high correlation between early improvement on 17-item Hamilton Rating Scale for Depression somatic symptoms subscale and remission. Finally, Fava and colleagues22 studied patients with MDD and coincidental aches and pains. Visual Analog Scale was used to assess severity of overall pain, headache, back and shoulder pain, as well as duration and degree of interference with daily activities. Patients who had ≥50% improvement in their overall pain score had nearly twice the remission rate compared to patients who had <50% improvement. (Slide 10). In addition, regardless of improvement in emotional symptoms, the greater the alleviation of painful physical symptoms, the greater the rate of remission.

 
 

Several meta-analyses suggest that remission rates with dual-acting agents may be somewhat higher than with SSRIs. A study by Anderson30 established that TCAs, especially amitriptyline, were associated with higher remission rates than the SSRIs. In a recent study by Nelson and colleagues,31 dual action was achieved by combining desipramine and fluoxetine. This combination resulted in a greater remission rate than either agent alone. Finally, two meta-analyses32,33 looked at the remission rates of venlafaxine versus SSRIs. Both had similar outcomes suggesting that the dual-acting agent venlafaxine had greater efficacy.

 
 
 
 

Conclusion

 
 

In order to increase the chance of remission, an antidepressant needs to have therapeutic efficacy for both emotional and somatic symptoms of depression. Antidepressants that increase both serotonin and noradrenaline appear to have an advantage over SSRIs, and novel agents such as duloxetine and venlafaxine are better tolerated than TCAs and MAOIs.

 
 

References

 
 

1. Kirmayer LJ, Robbins JM, Dworkind M, Yaffe MJ. Somatization and the recognition of depression and anxiety in primary care. Am J Psychiatry. 1993;150(5):734-741.

 
 

2. McWilliams LA, Goodwin RD, Cox BJ. Depression and anxiety associated with three pain conditions: results from a nationally representative sample. Pain. 2004;111(1-2):77-83.

 
 

3. Bair MJ, Robinson RL, Eckert GJ, Stang PE, Croghan TW, Kroenke K. Impact of pain on depression treatment response in primary care. Psychosom Med. 2004;66(1):17-22.

 
 

4. Gallagher RM, Verma S. Managing pain and comorbid depression: A public health challenge. Semin Clin Neuropsychiatry. 1999;4(3):203-220.

 
 

5. Basbaum AI, Fields HL. Endogenous pain control mechanisms: review and hypothesis. Ann Neurol. 1978;4(5):451-462.

 
 

6. Brose W, Spiegel D. Neuropsychiatric aspects of pain management. In: Yudofsky SC, Hales RE, eds. The American Psychiatric Press Textbook of Neuropsychiatry. Washington, DC: American Psychiatric Press; 1992.

 
 

7. Shimizu E, Hashimoto K, Okamura N, et al. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry. 2003;54(1):70-75.

 
 

8. D’Sa C, Duman RS. Antidepressants and neuroplasticity. Bipolar Disord. 2002;4(3):183-194.

 
 

9. Castren E. Is mood chemistry? Nat Rev Neurosci. 2005;6(3):241-246.

 
 

10. Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A. 1996;93(9):3908-3913.

 
 

11. Hoshaw BA, Malberg JE, Lucki I. Central administration of IGF-I and BDNF leads to long-lasting antidepressant-like effects. Brain Res. 2005;1037(1-2):204-208.

 
 

12. Ivy AS, Rodriguez FG, Garcia C, Chen MJ, Russo-Neustadt AA. Noradrenergic and serotonergic blockade inhibits BDNF mRNA activation following exercise and antidepressant. Pharmacol Biochem Behav. 2003;75(1):81-88.

 
 

13. Duman RS. Role of neurotrophic factors in the etiology and treatment of mood disorders. Neuromolecular Med. 2004;5(1):11-25.

 
 

14. Dias BG, Banerjee SB, Duman RS, Vaidya VA. Differential regulation of brain derived neurotrophic factor transcripts by antidepressant treatments in the adult rat brain. Neuropharmacology. 2003;45(4):553-563.

 
 

15. Duric V, McCarson KE. Hippocampal neurokinin-1 receptor and brain-derived neurotrophic factor gene expression is decreased in rat models of pain and stress. Neuroscience. 2005;133(4):999-1006.

 
 

16. Frasure-Smith N, Lesperance F, Talajic M. Depression and 18-month prognosis after myocardial infarction. Circulation. 1995;91(4):999-1005. Erratum in: Circulation 199824;97(7):708.

 
 

17. Lesperance F, Frasure-Smith N, Talajic M, Bourassa MG. Five-year risk of cardiac mortality in relation to initial severity and one-year changes in depression symptoms after myocardial infarction. Circulation. 2002;105(9):1049-1053.

 
 

18. Nemeroff CB, Musselman DL, Evans DL. Depression and cardiac disease. Depress Anxiety. 1998;8(suppl 1):71-79.

 
 

19. Yang B, Slonimsky JD, Birren SJ. A rapid switch in sympathetic neurotransmitter release properties mediated by the p75 receptor. Nat Neurosci. 2002;5(6):539-545.

 
 

20. Lynch ME. Antidepressants as analgesics: a review of randomized controlled trials. J Psychiatry Neurosci. 2001;26:30-36.

 
 

21. Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S. Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain. 2005;116(1-2):109-118.

 
 

22. Fava M, Mallinckrodt CH, Detke MJ, Watkin JG, Wohlreich MM. The effect of duloxetine on painful physical symptoms in depressed patients: do improvements in these symptoms result in higher remission rates? J Clin Psychiatry. 2004;65(4):521-530.

 
 

23. Fishbain D. Evidence-based data on pain relief with antidepressants. Ann Med. 2000;32(5):305-316.

 
 

24. Vrethem M, Boivie J, Arnqvist H, Holmgren H, Lindstrom T, Thorell LH. A comparison of amitriptyline and maprotiline in the treatment of painful polyneuropathy in diabetics and nondiabetics. Clin J Pain. 1997;13(4):313-323.

 
 

25. Sindrup SH, Jensen TS. Efficacy of pharmacological measurements of neuropathic pain: an update and effect related to mechanism of drug action. Pain. 1999;83:389-400.

 
 

26. Kunz NR, Goli V, Entsuah R, Rudolph R. Diabetic neuropathic pain management with venlafaxine extended release. Eur Neuropsychopharmacol. 2000;10(3):S389.

 
 

27. Paykel ES, Ramana R, Cooper Z, Hayhurst H, Kerr J, Barocka A. Residual symptoms after partial remission: an important outcome in depression. Psychol Med. 1995;25(6):1171-1180.

 
 

28. Denninger JW, Mahal Y, Merens W, et al. The relationship between somatic symptoms and depression. Presented at: 155th Annual Meeting of the American Psychiatric Association; May 18-23, 2002; Philadelphia, Pa.

 
 

29. Farabaugh A, Mischoulon D, Fava M, et al. The relationship between early changes in the HAMD-17 anxiety/somatization factor items and treatment outcome among depressed outpatients. Int Clin Psychopharmacol. 2005;20(2):87-91.

 
 

30. Anderson IM. SSRIS versus tricyclic antidepressants in depressed inpatients: a meta-analysis of efficacy and tolerability. Depress Anxiety. 1998;7(suppl 1):11-7.

 
 

31. Nelson JC, Mazure CM, Jatlow PI, Bowers MB Jr, Price LH. Combining norepinephrine and serotonin reuptake inhibition mechanisms for treatment of depression: a double-blind, randomized study. Biol Psychiatry. 2004;55(3):296-300.

 
 

32. Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry. 2001;178:234-241.

 
 

33. Smith D, Dempster C, Glanville J, Freemantle N, Anderson I. Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants: a meta-analysis. Br J Psychiatry. 2002;180:396-404.

 

 
 
 
 

Thomas N. Wise, MD

 
 
 

Efficacy, Tolerability, and Safety of Duloxetine

 

Duloxetine

 
 

Response and remission rates with the selective serotonin reuptake inhibitors (SSRIs) have not been sufficient and the side-effect profiles of many medications hinder adherence. In addition, somatic symptoms within the depressive syndrome is a clearly demonstrated problem that has shown poor response to current antidepressants. Duloxetine, a dual-reuptake inhibitor of both norepinephrine and serotonin, represents a novel treatment that may address some of these concerns.

 
 

Efficacy

 
 
 

Two double-blind registration trials1,2 were submitted to the Food and Drug Administration which led to the approval of duloxetine 40–60 mg/day for the treatment of depression. The pooled trials included a total of 244 patients given 60 mg duloxetine once daily for 9 weeks and 251 patients given placebo. Results showed a separation from placebo beginning at week 1 on the Maier subscale, which includes the core depressive symptoms from the 17-item Hamilton Rating Scale for Depression (HAM-D17)—depressed mood, feelings of guilt, difficulty in work and activities, psychomotor retardation, agitation, and psychic anxiety. Duloxetine separated from placebo by week 2 on the primary measure of efficacy, the HAM-D17 total score, and continued throughout the study. The study patients who had enrolled with depressive disorders, were concurrently asked various pain questions from the Visual Analog Scale. Duloxetine significantly improved painful physical symptoms associated with depression, including overall pain, back pain, shoulder pain, headache, pain while awake, and interference that pain fosters during daily activities. Remission rates were achieved in the two separate trials with the active agent. 

 

An initial registration trial in Europe showed that paroxetine 20 mg/day (usual starting dose) and duloxetine 80 mg/day and 120 mg/day (doses which exceed the 60-mg/day FDA-approved dosage) were equally efficacious in the treatment of depression.3 In a pooled analysis of two double-blind, head-to-head clinical trials of duloxetine and venlafaxine extended-release (XR), both duloxetine 60 mg (maximum FDA-approved dose) and venlafaxine XR 150 mg (maximum FDA-approved dose=225 mg/day) demonstrated antidepressant efficacy, with a similar reduction in the HAM-D17 total score over 6 weeks; 39% for venlafaxine and 35% for duloxetine.4 Following the acute period, a 6-week extension period allowed for dosage titration to the maximum dose of venlafaxine XR and double the maximum dose of duloxetine. The reduction in the HAM-D17 total score was similar for both treatments during the 12 weeks (P<.05). However, at the 12-week endpoint, venlafaxine XR significantly separated from duloxetine.

 
 

Tolerability

 
 

Sexual dysfunction associated with duloxetine consisted mainly of spontaneous reports of orgasmic delay in males and orgasmic difficulties in women. Pooled data from four duloxetine trials5 reported orgasmic delay in men, but minimal sexual difficulties in women (Slides 11 and 12).

 
 

In pooled studies of depressed patients treated with duloxetine 40–120 mg/day, rates of nausea, dry mouth, and constipation were reported in approximately 20%, 15%, and 14% of patients, respectively. The percentage of patients who discontinued due to adverse events was 10% with duloxetine compared to 4% with placebo (P<.001). In an analysis of pooled data from the registration trials (60 mg/day), duloxetine showed no increase in anxiety as measured by the anxiety subscale of the HAM-D17 (P≤.05).6 In a study of 1,000 patients with variable dosing of 40–120 mg/day, rates of anxiety following the drug were 2.7% in duloxetine-treated patients and 1.9% in placebo-treated patients. Agitation rates were particularly low at 0.9% in both the duloxetine and placebo arm. Self-reported nervousness was also low, at 0.7% and 0.6% in duloxetine and placebo groups, respectively.

 
 

Clinical trials of duloxetine have yielded significantly more reports of nausea and dizziness (Slide 13)1,2 than studies with venlafaxine (Slide 14).7 Pooled data from two 60-mg studies indicated that nausea was the most commonly reported adverse event of duloxetine although most cases were mild (23%) or moderate (13%).8 Severe nausea occurred in 2% of patients, while 62% experienced no nausea. Nausea generally occurred within 1–2 days after treatment initiation, peaked by day 7, and was reduced by week 2 to levels comparable to placebo. Nausea accounted for 0.8% of discontinuations in duloxetine-treated patients versus 0.4% in those taking placebo.

 
 
 

Among individuals who abruptly discontinued their medication, ~12% experienced dizziness, <8% reported nausea, 5% experienced headache, and there was rare occurrence of paresthesia, irritability, and nightmares.

 
 

Safety

 
 

The effect of duloxetine on blood pressure appears to be clinically insignificant. However, there is an elevation of 0.8 mm Hg in systolic blood pressure compared to -1.4 mm Hg on placebo (Slide 15). Therefore, it is recommended that patients have their blood pressure taken at initiation of duloxetine therapy and periodically thereafter. The rates of sustained hypertension in a variety of doses was not significantly different from placebo. The change in heart rate was 1.4 beats/minute elevation compared to -0.6 for placebo.

 

 
 
 

In safety studies up to 52 weeks, duloxetine did not cause QTc prolongation. In addition, in a cohort of >1,000 patient, there were not study withdrawals due to either urinary retention or urinary hesitation and no patient required catheterization. The reason for this might be that duloxetine acts on central nervous system serotonin and norepinephrine and has no affinity for peripheral cholinergic receptors. 

 

Due to the risk of hepatic injury or aggravation of preexisting liver disease, duloxetine should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.10

 

References 

 

1. Detke MJ, Lu Y, Golstein DJ, et al. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry. 2002;63(4):308-315.

 
 

2. Detke MJ, Lu Y, Goldstein DJ, McNamara RK, Demitrack MA. Duloxetine 60 mg once daily dosing versus placebo in the acute treatment of major depression. J Psychiatry Res. 2002;36(6):383-390.

 
 

3. Detke MJ,Wiltse C, Mallinckrodt CH, McNamara RK, Demitrack MA, Bitter I. Duloxetine in the acute and long term treatment of major depressive disorder: a placebo and paroxetine-controlled trial. Eur Neuropsychopharmacol. 2004;14:457-470.

 
 

4. Perahia D, Pritchett YL, Lee TC, Tran PF. Comparing duloxetine and venlafaxine in the treatment of major depressive disorder using a global benefit-risk approach. Presented at: 45th Annual Meeting of the New Clinical Drug Evaluation Unit; 2005. Boca Raton.

 
 

5. Delgado PL, Brannan SK, Mallinckrodt CH, et al. Sexual functioning assessed in 4 double blind placebo and paroxetine controlled trials of duloxetine for major depressive disorder. J Clin Psychiatry. 20005;66:686-692.

 
 

6. Dunner DL, Goldstein DJ, Mallinckrodt C, Lu Y, Detke MJ. Duloxetine in treatment of anxiety symptoms associated with depression. Depress Anxiety. 2003;18(2):53-61.

 
 

7. Thase ME. Efficacy and tolerability of once-daily venlafaxine extended release (XR) in outpatients with major depression. The Venlafaxine XR 209 Study Group. J Clin Psychiatry. 1997;58(9):393-398.

 
 

8. Greist J, McNamara RK, Mallinckrodt CH, Rayamajhi JN, Raskin J. Incidence and Durations of Antidepressant Nausea:Duloxetine Compared with Parosetine and Fluoxetine. Clin Ther. 2004;26:1446-1455.

 
 

9. Thase ME, Tran PV, Wiltse C, et al. Cardiovascular profile of duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine. J Clin Psychopharmacol. 2005;25(2):132-140.

 
 

10. Food and Drug Administration: 2005 Medical Product Safety Alerts. Available at: http://www.fda.gov/medwatch/safety/2005/safety05.htm#Cymbalta. Accessed October 18, 2005.

 

 

 

 

Question-and-Answer Forum

 

Q: How would one switch a patient from another antidepressant to duloxetine?

 
 
 

Dr. Arnold: A recent study1 examined the efficacy and tolerability associated with switching from a selective serotonin reuptake inhibitor (SSRI; citalopram ≤40 mg/day, escitalopram ≤20 mg/day, fluvoxamine ≤150 mg/day, paroxetine ≤40 mg/day, sertraline ≤150 mg/day) or venlafaxine ≤150 mg/day, to duloxetine. Patients with major depressive disorder (MDD) entered this open-label study. Patients who had suboptimal response or poor tolerability to their current antidepressant (n=112) were "switched" to duloxetine 60 mg/day without taper or titration. A comparator group not currently receiving antidepressants were randomized to duloxetine 60 mg/day (n=70). Patients remained on 60 mg/day for 1 week. During the remaining weeks of the study, titration from 60 mg/day to 120 mg/day was possible. The efficacy of duloxetine did not differ significantly between switched and untreated patients. However, the rate of discontinuation due to adverse events among switched patients was significantly lower than that in untreated patients initiating duloxetine. Immediate switching from the SSRIs studied or venlafaxine to duloxetine 60 mg/day was well tolerated. 

 
 
 

Q: Is there any evidence of hypomania or manic switch when a patient is switched to duloxetine?

 
 

Dr. Maletic: In the course of the registration trials the switch to hypomania/mania was at 0.1%, which was equal to the switch rate on placebo (of course, bipolar patients were screened out in registration trials). However, being an effective antidepressant, duloxetine is capable of either aggravating mood or causing a switch to hypomania or mania. I think this is particularly important to underscore, because many of the patients that are now being started on duloxetine are patients who had not had much success on other antidepressants.

 
 

In light of the recent study published by Sharma and colleagues,2 one should be particularly cautious in patients who have not responded to other antidepressants. Sharma and colleagues2 studied several patients who had only one feature in common—lack of response to two adequate antidepressant trials. These patients were evaluated using a structured clinical interview. Approximately 35% of them were initially re-diagnosed as having a bipolar instead of unipolar depression. They continued to follow the entire sample of patients for 1 year. By the conclusion of the year, 59% of the initial sample was reclassified as having bipolar depression.

 
 

In light of these data, I would suggest caution when initiating duloxetine, especially in patients who have not responded to a couple of previous antidepressant trials. These patients require closer monitoring for sudden changes in mood or development of a thought disorder. In that scenario it would be recommended to establish a mood-stabilizing agent first, and then consider an antidepressant if necessary.

 
 
 
 

Dr. Wise: These data also correlate with a results of a recent study by Parker and colleagues3 about treatment-resistant depression. Frequently, bipolarity or severe personality disorder is present and therefore, physicians should be fairly careful when switching patients from one medication to another.

 
 
 
 

Q: What is the best starting dose for duloxetine?

 
 

Dr. Arnold: I have found that starting at 30 mg/day for a week is more tolerable for many patients and causes lower rates of nausea. When I start a patient at 60 mg/day, I have found that tolerability in the first week is improved if the patient takes the medication after a full meal. I inform the patients that most of the time the nausea is mild to moderate and resolves after the first week. The nausea tends to be mild to moderate for most patients even if they start at 60 mg/day. However, it might help to start at a lower dosage (30 mg/day) to decrease the possibility that patients discontinue the treatment prematurely.

 
 
 
 

Dr. Wise: I have found the same thing.

 
 
 
 

Dr. Maletic: Most of my patients have been previously treated with SSRIs. I have noticed that the ones who had gastrointestinal side effects in response to SSRIs were also the ones who were more likely to experience them with duloxetine. In these patients, I usually initiate treatment at the 30-mg dose. Sometimes, in order to minimize the duration of time that the patient spends on a subtherapeutic dose, I provide the patient with a 7-day supply of samples. If they do not experience initial nausea by day 3 or 4, I advise them to increase the dose to 60 mg.

 
 
 
 

Q: Are there less sexual side effects with duloxetine than with SSRIs?

 
 

Dr. Arnold: At this time there are no available head-to-head data that compare duloxetine with SSRIs with regard to sexual side effects. In the duloxetine MDD trials, overall, patients treated with duloxetine experienced significantly more sexual dysfunction than did patients treated with placebo based on changes in the Arizona Sexual Experiences Scale total score. However, when the data were analyzed separately by sex, the male patients on duloxetine reported significantly more sexual dysfunction (related to orgasm) compared to men on placebo, while the female patients in both the duloxetine and placebo groups reported improvement in sexual function with no significant differences between the groups. In my clinical experience, I have seen sexual dysfunction in both male and female patients who are on duloxetine. However, I think that we have to wait for more comparative data about the rates of sexual dysfunction before we can determine whether duloxetine has a lower risk of sexual dysfunction compared to other antidepressants.

 
 

Dr. Wise: Yes, I agree with that.

 
 

Dr. Maletic: In my clinical experience a delay in orgasm was present both in women and in men, maybe a bit more frequently in men, but it is definitely reported by female patients. I have seen fewer complaints of loss of libido with duloxetine than in SSRI-treated patients. However, I cannot say that there is no loss of libido, even though the registration trials found no difference in libido suppression on duloxetine versus placebo.

 
 
 

Q: Is duloxetine safe to use in elderly patients?

 
 

Dr. Wise: At least two trials4,5 have clearly shown that duloxetine is very safe in elderly patients in comparison to other antidepressants. There is not much of a difference between its use in the elderly versus the younger adults. It also seems to improve cognitive symptoms. Cardiovascular problems are not greater in elderly patients treated with duloxetine and urinary problems do not appear to be an issue either.

 
 

Dr. Maletic: In a recent study6 of duloxetine in diabetic peripheral neuropathy in younger patients versus patients >65 years of age, there was no difference observed in the frequency of side effects or overall tolerability.

 
 

References 

 
 

1. Wohlreich MM, Mallinckrodt CH, Greist J, Delgado PL, Watkin JG, Fava M. Immediate switching of antidepressant therapy: Results from a clinical trial of duloxetine. Poster presented at: US Psychiatric Congress; November 20, 2004; San Diego, CA.

 
 

2. Sharma V, Khan M, Smith A. A closer look at treatment resistant depression: is it due to a bipolar diathesis? J Affect Disord. 2005;84(2-3):251-257.

 
 

3. Parker GB, Malhi GS, Crawford JG, Thase ME. Identifying ‘paradigm failures’ contributing to treatment-resistant depression. J Affect Disord. 2005;87:185-191.

 
 

4. Wohlreich MM, Mallinckrodt, Watkin JG, Hay DP. Duloxetine for the long term treatment of major depressive disorder in patients aged 65 and older:an open label study. BMC Geriatr. 2004;4:1-10.

 
 

5. Nelson JC, Wohlreich MM, Mallinckrodt CH, Detke MJ, Watkin JG, Kennedy JS. Duloxetine for the treatment of major depressive disorder in older patients. Am J Geriatri Psychiatry. 2005;13:227-235.

 
 
 
 

6. Robinson MJ, Rosen A, Hardy TA, Prakash A, Shen S, Wernicke J. Duloxetine for the management of diabetic peripheral neuropathic pain: comparison of safety data in older (age≥65) and younger (age≤65) patients. Poster presented at: American Geriatric Society Meeting; May 11-15, 2005; Orlando, Florida.

 

 
 
 

Funding for this roundtable monograph supplement has been provided through an unrestricted educational grant by Eli Lilly. Sponsorship of this supplement does not imply the sponsor’s agreement with the views expressed herein. Although every effort has been made to ensure that the information is presented accurately in this publication, the ultimate responsibility rests with the prescribing physician. Neither the publisher, the sponsor, nor the participants can be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation.

 
 

Copyright ©2005 MBL Communications, Inc. 333 Hudson Street, 7th floor, New York, NY 10013. Printed in the USA.

All rights reserved, including the right of reproduction, in whole or in part, in any form.

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Clinical Supplement

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Depression in the Elderly: The Unique Features Related to Diagnosis and Treatment

Moderator: Katherine Shear, MD; Section editor: David L. Ginsberg, MD; Discussants: Steven P. Roose, MD, Eric J. Lenze, MD, George S. Alexopoulos, MD; CME Reviewer: Eric Hollander, MD

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Primary Psychiatry. 2006;12(8 suppl 7):1-16.

 

 

This CME activity is expired.

 

Funding for this symposium monograph supplement has been provided through an unrestricted educational grant by Forest Pharmaceuticals, Inc.

 

An expert panel review of clinical challenges in psychiatry

 

 

Statement of Need and Purpose:

 

The elderly population is growing at a rapid rate and currently constitutes >12% of the United States population. Depression, a heterogeneous disease often accompanied by significant medical and psychiatric comorbidity, is prevalent and underrecognized among the elderly. Detection of depressive symptoms in the elderly is complicated by high medical comorbidity, frequent use of multiple medications, and a tendency of some older adults to resist psychiatric evaluation. While an episode of depression can first present in late-life, it is more likely to be a recurrence of a disorder that began earlier in life or a continuation of a chronic form of depression.

 

Most older patients can tolerate and respond to acute treatment with serotonergic antidepressants, other psychotropic agents, or manual-based psychotherapy. Antidepressants, particularly serotonergic medications, are considered first-line treatment for major depressive disorder. Psychotherapy has also been found to be efficacious. However, outcomes under usual-care conditions remain poor. Since depression in the elderly often occurs in the context of ongoing medical conditions, treatment is often complicated due to the increased likelihood of drug interactions.

 

Despite the availability of safe and efficacious treatments, depression remains a significant healthcare issue for the elderly and is associated with functional decline, diminished quality of life, mortality from comorbid medical conditions or suicide, demands on caregivers, and increased service utilization. 

 

Learning Objectives:

 

•Recognize and differentiate late-onset depression and its relationship to vascular illness.

 

•Understand and implement an appropriate treatment strategy for comorbid depression and medical illness.

 

•Recognize bereavement-related depression and anxiety, including complicated grief, and understand the data related to treatment efficacy.

 

•Implement appropriate antidepressant and anxiolytic treatment strategies for comorbid depression and anxiety.

 

Target Audience:

 

This activity is designed to meet the educational needs of psychiatrists.

 

Disclosure of Off-Label Usage:

 

This continuing medical education activity may contain references to unlabeled or investigational uses of drugs or devices.

 

Accreditation Statement:

 

Mount Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide Continuing Medical Education for physicians.

 

Mount Sinai School of Medicine designates this Continuing Medical Education activity for a maximum of 1.0 Category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity. Credits will be calculated by the MSSM OCME and provided for the journal upon completion of agenda.

It is the policy of Mount Sinai School of Medicine to ensure fair balance, independence, objectivity, and scientific rigor in all its sponsored activities. All faculty participating in sponsored activities are expected to disclose to the audience any real or apparent conflict-of-interest related to the content of their presentation, and any discussion of unlabeled or investigational use of any commercial product or device not yet approved in the United States.

Faculty Affiliations and Disclosures:

 

Dr. Alexopoulos is professor of psychiatry at Weill Medical College of Cornell University, and director of Weill-Cornell Institute of Geriatric Psychiatry in White Plains, New York. He is a consultant to Forest; on the speaker’s bureaus of Bristol-Myers Squibb, Cephalon, Eli Lilly, Forest, GlaxoSmithKline, Janssen, and Pfizer; and receives grant/research support from Cephalon and Forest.

 
 

Dr. Lenze is assistant professor of psychiatry at the University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, in Pennsylvania. He has received grant/research support from Janssen and Pfizer.

 

Dr. Roose is professor of clinical psychiatry at the College of Physicians and Surgeons at Columbia University in New York City. He is a consultant to Forest and Wyeth; and receives grant/research support from Bristol-Myers Squibb, Forest, and Wyeth.

 
Dr. Shear is professor of Psychiatry at the University of Pittsburgh School of Medicine and director of the Panic, Anxiety, and Traumatic Grief program at Western Psychiatric Institute and Clinic, both in Pittsburgh, Pennsylvania.  She is a consultant to and on the speaker’s bureau of Pfizer; and receives grant/research support from Forest.

 


Abstract

 

Depression affects 6.5 million of the 35 million Americans ≥65 years of age. While depression usually begins earlier in life and recurs periodically, it can present for the first time in people 80–90 years of age as well. Depression throughout the lifespan has a genetic/biological component but is also very much affected by social environmental factors. As people age, demographic factors, social support, and negative life events remain important to overall mental health, while physical illness and disability begin to take on a much more prominent role. Depression in the elderly is associated with impairment, dependency, disability, and significant distress for the individual and their family. This population is likely to present with concomitant cognitive dysfunction and medical illness, which can complicate the identification and treatment of psychiatric conditions. Bereavement is almost universal in late life and is sometimes a deterrent to appropriate diagnosis and treatment of depression. Physical frailty and diminishing social resources further complicate the treatment of depression in the elderly. Elderly individuals respond well to standard pharmacotherapy and psychotherapy treatments for depression. However, due to the high rate of relapse of depression in this population, continuous treatment is often warranted. This monograph will review depression in the elderly in the context of social disruptions, such as bereavement, caregiver strain, interpersonal conflict, role transitions, and social isolation; late-onset vascular depression and cognitive impairment; and physical illness including disability.

 
 

 

 

Katherine Shear, MD—Moderator

Bereavement-Related Depression in the Elderly

 

Recognition and Prevalence of Bereavement

 

 

Bereavement is a profound stressor that leads to some of the most intense psychological pain human beings can experience. Despite the fact that bereavement is very common in the psychiatric population, clinicians and researchers have paid little attention to it. Recognition of complicated grief versus normal grief is difficult because due to inadequate empirical evidence, there is no model to help clinicians distinguish between a pathological grief reaction and a depressive reaction that is normal in the context of loss. Further complicating the diagnosis is the prominent belief that any way grief unfolds is normal.

 

Bereavement is very prevalent in the elderly population: As people get older, more of their close friends and family members die. Widowhood is particularly common in the elderly, especially in women: ~41% of women >65 years of age are widowed (Slide 1).1

 

 

 

 

Common Misconceptions About Grief

 

There are many common misconceptions about grief which have been dispelled by empirical evidence. (A) Effective grief is a process of letting go of the person who died in order to move on. Empirical findings show that effective grief requires accepting the loss; (B) Grief work (experiencing emotional anguish) is necessary in order to move on. It turns out that grief is a natural process that works if it is not impeded; (C) The more intense a person’s pain is, the more effectively they are grieving. Data show that the less intense the initial pain is, the more favorable the outcome is; (D) People who do not grieve early will pay later. In fact, longitudinal studies have shown that delayed grief is very rare and only occurs in 4% to 5% of people who do not grieve early on; (E) Once a person has grieved effectively, they never have to grieve again. Empirical findings indicate that grief is a permanent state that can be reactivated indefinitely; (F) There is some timeframe within which grief should be completed. In actuality, grief is never completed; and (G) Problems with grief are seen primarily in people who have an ambivalent relationship to the person who died. In actuality, complicated grief is seen in people who have a very positive and close relationship with the person who died.

 

Defining Grief

 

 

A study by Boerner and colleagues2 identified four trajectories of grief and depression from pre-loss to 48 months post-loss. The most common group of mourners (40%) were actually “resilient” and did not experience much depression or grief as demonstrated by scores on the Center for Epidemiologic Studies Depression scale. People with “common grief” were those who had increased depression until 6 months after the loss, at which point their depression began to improve until they became resilient at ~18 months. “Chronic depression” occurred in a subset of individuals as did “chronic grief,” which contains the syndrome of complicated grief.

 

Grief is a complex emotional state best defined as the overall psychological reaction to bereavement. It is an evolving mental state that changes as people cope with the different feelings and the new way that they need to live after someone that they love has died. In the model we use for treatment at the University of Pittsburgh, primary grief transitions to integrated grief. Dysphoric emotions of grief include anxiety (eg, about how the surviving person will manage on their own), guilt (eg, about surviving or not having done enough for the person while they were alive), anger (eg, about others not doing or caring enough), and shame (eg, about sense of vulnerability and uncontrollable emotionality). However, there are pleasurable emotions associated with grief as well, including enjoyment in the recall of happy times, amusing anecdotes, pride in honoring the deceased, warmth in recollecting closeness, relief from burden, and pleasure and joy in being alive. Sadness, which is the predominant emotion associated with grief, is the bittersweet feeling of loss of something valuable.

 

Primary Grief

 

 

Primary grief is the form that grief takes immediately following the death of a loved one and is the dominant mental state of the person. It is characterized by a sense of disbelief or difficulty accepting the death; relative disinterest in the rest of the world; a mix of emotions where painful emotions are usually dominant; and preoccupying thoughts and memories of the deceased. These features can last for days or months and may recur transiently for many months or even years.

 

The dual process model of coping with grief focuses on both loss and on restoration of life. The dual processes proceed in tandem with natural oscillation, alternating between attention to loss and attention to restoration. By coping effectively, in an oscillating manner with primary grief and its associated problems, the person moves into a state of integrated grief, in which the death is accepted.

 

Integrated Grief

 

A major characteristic feature of integrated grief is acceptance of the death; there is a mix of emotions, but they transition to a state where more positive emotions are more dominant.2 While the memories of the person who died are accessible, they are not preoccupying and the mourner begins to experience a renewed interest in engagement in life. This state is usually achieved by about 6 months after the death and is permanent.

 

The state of integrated grief has been depicted in several well-written works, notably a short autobiography by Frederick Buechner3—a Presbyterian pastor who’s father committed suicided when he was 10 years old—and a collection of poetry written by Donald Hall4 after his wife’s unexpected illness and death.

 

After the Grieving Process

 

 

When a person has gone through the normal grieving process, there is effective coping and a transition to integrated grief. This includes coping with loss-focused issues such as gaining a satisfying sense of relationship to the deceased; accessible memories; and subsiding of guilt, remorse, and anger. It also includes coping with restoration-focused problems, such as achieving role transition and becoming engaged in satisfying daily activities and relationships. When grief does not work, there can be an onset of major depressive disorder (MDD), and/or complicated grief. A person suffering from complicated grief may have loss-related problems such as difficulty accepting the death, memories which are excessively painful or hard to access, or intrusive images. The mourner may also have restoration-related problems, such as not achieving role transition, finding little pleasure and satisfaction in daily activities, and feeling a sense of estrangement from others.

Major Depression in Bereaved Spouses

 

 

Bereavement-related depression is not a normal reaction to loss. In several studies led by Zisook,5-7 many bereaved spouses met criteria for MDD in the very early stage of the loss. However,  only 24% to 30% of mourners met criteria for MDD 2–6 months after the loss, and only 16% still met criteria for MDD at 1 year. Persistent depression was associated with past history of MDD (24% versus 8%) and family history of MDD (37% versus 24%). Bereaved individuals who are depressed at 2 months have rates of MDD similar to non-bereaved individuals 1 (30%) and 2 (20%) years later. They also have similar duration of time spent in a full-blown episode (38%), time spent with residual symptoms (48%), and depression-free time (24%).

Treatment of Bereavement-Related Depression

Studies suggest that antidepressant medication is efficacious for the treatment of bereavement-related depression. There are open studies in bupropion, escitalopram, and nortriptyline. In the only randomized controlled treatment study of bereavement-related depression, Reynolds and colleagues8 found nortriptyline to be efficacious in the study population of elderly adults (Slide 2). Surprisingly, interpersonal psychotherapy was not as effective as expected.

 

 

 

In a small study by Pasternak and colleagues,9 13 elderly widowed patients treated with nortriptyline showed significant improvement in depression symptoms but only slight improvement in grief symptoms as demonstrated by scores on the Inventory of Complicated Grief. This study was replicated by Zisook and colleagues10 using bupropion (N=22).

 

Complicated Grief Versus Major Depression

 

 

It is important to know the difference between complicated grief and MDD as treating depression does not necessarily improve the symptoms of complicated grief, as demonstrated by the abovementioned studies.6,7 MDD is characterized by pervasive sad mood, guilt related to “I am worthless, a bad person,” pervasive loss of interest or pleasure, and intrusive images which are not prominent. Complicated grief is characterized by painful emotions that occur in pangs triggered by reminders of loss, guilt specific to bereavement and related to having let their loved one down, strong interest in things related to the loved one, prominent intrusive images of the deceased, a yearning for contact with the deceased that persists, and frequently entering a dissociative state where they imagine the deceased is with them.

 

A study by Boerner and colleagues11 showed that 15 weeks after the death of Alzheimer’s care recipients, their caregivers often developed grief, depression, or both. The more positive the relationship with the care recipient was, the more likely the caregiver was to develop complicated grief.

 

Natural Grief

 

 

In a model of natural grief developed at the University of Pittsburgh, bereavement triggers a state of primary grief which is characterized by symptoms of traumatic distress (disbelief; recurrent, almost intrusive images and memories of the person), separation distress (longing and yearning for the person who died), guilt, and social withdrawal. This is a transient dominant state that is painful and preoccupying, but transitions into acceptance, positive emotions, forgiveness, and compassion. After the transition period of ~6 months, the person reaches a state of integrated grief, which is a permanent background state where bittersweet memories are still present, accessible, and changing (Slide 3).

 

 

 

 

Complicated Grief

 

 

In a model of complicated grief developed at the University of Pittsburgh, bereavement triggers primary grief (traumatic distress, separation distress, guilt, and social withdrawal), but instead of being transient it becomes a persistent dominant state that can last for years. This occurs when bereavement triggers secondary emotions and reactions that block the pathway to integrated grief. These secondary emotions include fear of painful emotions, loss of control, losing or betraying the deceased, and loss of sense of self; excessive guilt or anger; moral indignation; and rumination and/or excessive avoidance (Slide 4).

 

 

Core symptoms of complicated grief include experiencing the following >6 months after the death: traumatic distress (recurrent intrusive images of the death, bitter or angry, avoidance of situations, activities, or people); separation distress (intense yearning, longing; urges to reminisce, reveries, seeking proximity to items belonging to the deceased, feeling that life has no meaning without the deceased); guilt (prominent self-blaming thoughts of not helping the person or not preventing the death); and failure to adapt (emotion overwhelming, sense of alienation, feeling that having less grief is a betrayal).

 

A Proposed Treatment for Complicated Grief

 

 

Antidepressant medication has shown no effect and IPT has shown surprisingly little effect, on complicated grief symptoms. In treating patients with complicated grief, posttraumatic stress disorder (PTSD)-like symptoms of distress were the ones that seemed to interfere IPT. Therefore, researchers at the University of Pittsburgh developed a new psychotherapy for complicated grief based on an IPT framework and augmented by a treatment for PTSD. The model of natural grief was used, in which coping occurs in the loss-oriented (imaginal revisiting of the experience of the death, structured behavioral change, structured memories work, imaginal conversation with the deceased) and restoration-oriented (personal goals, meeting with significant other, structured behavioral change) ways.

 

This new complicated grief treatment showed greater response rates (51% compared to 28%) and faster time to response compared to IPT in a recent randomized controlled trial.12 The study included 95 men and women 18–85 years of age who met criteria for complicated grief. Both treatments were administered in 16 sessions during an average interval of 19 weeks per participant. Treatment response was defined as Clinical Global Improvement score of 1 or 2, or as time to a 20-point or better improvement in the self-reported Inventory of Complicated Grief.

 

Summary

 

 

Bereavement is a major life stressor. While most people cope with loss and do not develop bereavement-related depression, there is a significant minority that does. MDD and complicated grief are the two most common problematic clinical sequelae. Bereavement-related depression shows similar response to medication treatment as MDD in other contexts. Complicated grief, however, differs from MDD and requires a targeted treatment. Complicated grief has shown small statistically significant response to selective serotonin reuptake inhibitors and very efficacious response to targeted psychotherapy. Combination treatment may be the best option for patients with complicated grief.

 

References

 

 
1. US Census Bureau Web site. Available at: http://www.census.gov/prod/2003pubs/c2kbr-30.pdf. Accessed July 2, 2005.
 

2. Stroebe M, Schut H. The dual process model of coping with bereavement: rationale and description. Death Stud. 1999;23(3):197-224.

 

3. Buechner F. The Sacred Journey. San Francisco, CA: Harper; 1991.

 

4. Hall D. Without. New York, NY: Houghton Mifflin; 1998.

 

5. Zisook S. Shuchter SR. Depression through the first year after the death of a spouse. Am J Psychiatry. 1991;148:1346-1352.

 

6. Zisook S, Devaul RA. Grief, unresolved grief, and depression. Psychosomatics. 1983;24:247-256.

 

7. Zisoook S, Shuchter SR. Major depression associated with widowhood. Am J Geriatr Psychiatry. 1993;1:316-326.

 

8. Reynolds CF 3rd, Miller MD, Pasternak RE, et al. Treatment of bereavement-related major depressive episodes in later life: a controlled study of acute and continuation treatment with nortriptyline and interpersonal psychotherapy. Am J Psychiatry. 1999;156(2):202-208.

 

9. Pasternak RE, Reynolds CF 3rd, Schlernitzauer M, et al. Acute open-trial nortriptyline therapy of bereavement-related depression in late life. J Clin Psychiatry. 1991;52(7):307-310.

 

10. Zisook S, Shuchter SR, Pedrelli P, Sable J, Deaciuc SC. Bupropion sustained release for bereavement: results of an open trial. J Clin Psychiatry. 2001;62(4):227-230.

 

11. Boerner K, Schulz R, Horowitz A. Positive aspects of caregiving and adaptation to bereavement. Psychol Aging. 2004;19(4):668-675.

 

12. Shear K, Frank E, Houck PR, Reynolds CF 3rd. Treatment of complicated grief: a randomized controlled trial. JAMA. 2005;293(21):2601-2608.

 

 

 

Steven P. Roose, MD

Vascular Depression: A Subtype Specific to Late-Life?

 

Depression Subtypes

 

There is evidence to suggest that vascular depression should be considered a unique subtype of depressive disorder that has particular relevance to late life. Within the unipolar versus bipolar subtype, there are three phenomenologically defined subtypes which are recognized in the DSM-IV. Atypical depression is characterized by oversleeping, overeating, leaden paralysis, and rejection sensitivity. Delusional depression (ie, psychotic depression), is characterized by delusions sometimes accompanied by auditory hallucinations. Melancholic depression is the classic depressive illness first described over 5,000 years ago. Patients within one subtype often have different family histories, psychobiology, and differential treatment response and course of the illness, compared to those within another subtype. Therefore, the establishment of a subtype has both heuristic and clinical importance.

 

The Vascular Depression Subtype

 

In 1991, Figiel and colleagues1 reported that patients with late-onset depression (>60 years of age) had a significantly higher rate of white matter and basal ganglia hyperintensities compared to those with early-onset depression (Slide 5). Bots and colleagues3 demonstrated that severity of the deep white-matter lesions is correlated with the wall thickness of the carotid artery and with prevalence of myocardial infarction (MI).

 

 

The hypothesis that there may exist a vascular depression subtype that is unique to late life was stated by Hickie in 1995,2 which stated that “cerebral vascular insufficiency in elderly people leads to major changes in their subcortical and basal ganglia structure. The resultant late-onset depressive disorders are characterized by deficits in functions that are dependent on intact cortical striatal connections (eg, psychomotor speed and interactiveness), as well as subcortical hyperintense lesions and reduced basal ganglia volumes.” The three criteria associated with vascular depression are late onset; vascular disease and hyperintensities as demonstrated by magnetic resonance imaging (MRI); and interference with cognitive capacities, such as sequencing, planning, organizing, and abstract thinking.

 

The evidence for vascular depression is consistent with the well-established phenomenon of post-stroke depression. Intermittent and progressive ischemia leads to structural damage, which leads to depression (and associated executive dysfunction). Risks for ischemic disease include smoking, hypertension, and a family history. In turn, depression is a risk factor for the development of cardiovascular disease and stroke, and confers a worse mortality rate in patients with ischemic disease and those with congestive heart failure.4


 

The Vascular Depression Model

 

The strong evidence that vascular disease relates to the hyperintensities prominent in late-onset depression contributes to a compelling model of vascular depression. In this model, cardiovascular risk factors lead to cerebral ischemia which leads to frontal and basal ganglia lesions. Depression early in life is a risk factor for the development of both ischemic heart disease and stroke. This risk may be mediated by increased cortisol, insulin resistance, and platelet reactivity, all of which can contribute to vascular damage and ischemia. Vascular damage creates a vulnerability to depression that can be expressed depending on other variables such as psychological factors (eg, low social support), negative life events (eg, death in the family), genetic factors, and social factors (Slide 6).

 

 

Criteria for Vascular Depression

 

Criteria for vascular depression include vascular disease, cognitive impairment, late age of onset, and depression. Definitions of these criteria have vary among studies. For example, some studies of vascular depression include patients with cardiovascular risk factors, while others require MRI lesions. Some studies have assessed impairment of activities of daily living,5 while others have defined executive dysfunction by neuropsychological testing.6 The age defining late onset differs from one study to the next (eg, 40, 50, or  60 years of age). Finally, most studies only include patients who meet criteria for major depressive disorder (MDD); however, many patients with vascular disease have dysthymia or subsyndromal symptoms. According to the post-MI literature, ~20% of patients develop MDD post-MI, and another 20% to 25% develop significant depressive symptomatology.7 The same is true in the post-stroke literature.

 

Treatment Resistance

 

One component of vascular depression is the executive dysfunction syndrome of late-life, and it is hypothesized that depression, executive dysfunction, and treatment resistance are all related to frontostriatal dysfunction. Furthermore, it is believed that dysfunction of the basal ganglia and their frontal connections contributes to poor and unstable treatment response in geriatric depression.

 

Many neuropsychological tests have been used as markers of executive dysfunction, conceptualized as the skills that lead to sequencing, planning, organization, and abstraction. An association has been observed between poor executive functioning and poor response to antidepressants. Kalayam and Alexopoulos8 showed that scores of initiation perseveration on the Dementia Rating Scale are lowest in patients who did not respond to antidepressants. In a study using the Color Word Score, patients who had intact executive dysfunction (high color word score), showed a better antidepressant response rate compared to patients with executive dysfunction.9 Data on relapse in depressed elderly patients receiving nortriptyline showed that those with impaired executive function had a much higher rate of relapse on continuation treatment (Slide 7).10


 


 

Once of the challenges clinicians face is that many depressed patients also present with mild cognitive impairment (MCI). In a study by Pelton and colleagues, 39 patients with depression and amnestic MCI were treated with sertraline up to 200 mg/day for 12 weeks (unpublished data, 2005). Twenty-two were followed for 1 year and showed good response to the antidepressant but very little improvement in cognitive function. At the end of 1 year, 54% had converted to dementia. The expected 1-year conversion rate of a group of nondepressed patients with MCI is about 15%.

 

Thus, patients with depresssion and executive dysfunction have poor treatment response and progressive cognitive decline. Depressed patients who have vascular lesions, regardless of whether or not they have executive dysfunction, seem to be particularly refractory to monotherapy, have a longer time to recovery (measured in months, not weeks), show cognitive decline, and are at risk for stroke.

 

Future Directions for Establishing the Subtype

 

A subtype has external validity and is clinically meaningful if it informs the clinician about treatment response and course of illness. The association of late onset, progressive vascular disease, executive dysfunction, and poor treatment response to antidepressant monotherapy adds compelling support to the notion of a vascular depression subtype. However, vascular depression still requires a definition of the core features of the illness, be it age of onset, executive dysfunction, or vascular lesions, and their relationship to one another. The final determination of criteria (eg, vascular lesion, executive dysfunction, age of onset) and operational criteria (eg, size and location of lesions, what age is considered late onset?) still need to be established.

 

In addition, although there is compelling evidence for vascular depression, important new data has been inconsistent with previous findings. For example, a study from the Duke group shows no significant difference in deep white matter lesion between patients with early-onset depression and those with late-onset depression. However, it does show a significant difference in executive function between early- and late-onset depression on the Trails B. Data from a study of depression in patients >75 years of age showed that late-onset and early-onset patients responded equally well to citalopram treatment. Regarding MRI hyperintensities, the old-old study is consistent with the Duke study, in that the load of hyperintensities was the same in both the late-onset and early-onset patients. Contrary to what the expectation would be, the antidepressant responders in the Duke study had the same degree of MRI hyperintensities as nonresponders.

 

Implications for the Clinician

 

Although more research is needed, there are some useful clinical implications that can be derived from existing data when it comes to evaluating depressed patients >60 years of age. First, it is important to try to establish the age of onset for first episode of MDD, although it is often difficult to have confidence in the reliability of the result. Second, one should assess cardiovascular risk factors, such as smoking, high blood pressure, family history, lipid profiles, and lack of exercise. Third, the clinician must assess cognition and routinely evaluate for cognitive decline; one of the best assessments is the 3/3 object recall at 5 minutes from the Mini Mental Status Exam. Fourth, the clinician must know the patient’s current medication regimen and evaluate anticholinergic load. Most people >65 years of age are on at least five prescription agents in addition to their over-the-counter medication. The psychiatrist and primary care physician must form a relationship so that both are familiar with the patient’s full medical profile and ongoing care. Finally, the clinician must determine whether an MRI is needed. This might be warranted in a depressed patient who has several cardiovascular risk factors and cognitive impairment.

 
 

References

1. Figiel GS, Krishnan KR, Doraiswamy PM, Rao VP, Nemeroff CB, Boyko OB. Subcortical hyperintensities on brain magnetic resonance imaging: a comparison between late age onset and early onset elderly depressed subjects. Neurobiol Aging. 1991;12(3):245-247.

 

2. Hickie I, Scott E, Mitchell P, Wilhelm K, Austin MP, Bennett B. Subcortical hyperintensities on magnetic resonance imaging: clinical correlates and prognostic significance in patients with severe depression. Biol Psychiatry. 1995;37(3):151-160.

 

3. Bots ML, van Swieten JC, Breteler MM, et al. Cerebral white matter lesions and atherosclerosis in the Rotterdam Study. Lancet. 1993;341(8855):1232-1237.

 

4. Alexopoulos GS, Meyers BS, Young RC, Campbell S, Silbersweig D, Charlson M. Vascular depression’ hypothesis. Arch Gen Psychiatry. 1997;54(10):915-922.

 

5. Alexopoulos GS, Meyers BS, Young RC, Kakuma T, Silbersweig D, Charlson M. Clinically defined vascular depression. Am J Psychiatry. 1997;154(4):562-565.

 

6. Krishnan KR, Hays JC, Blazer DG. MRI-defined vascular depression. Am J Psychiatry. 1997;154(4):497-501.

 

7. Schleifer SJ, Macari-Hinson MM, Coyle DA, et al. The nature and course of depression following myocardial infarction. Arch Intern Med. 1989;149:1785-1789.

 

8. Kalayam B, Alexopoulos GS. Prefrontal dysfunction and treatment response in geriatric depression. Arch Gen Psychiatry. 1999;56(8):713-718.

 

9. Baldwin I, Jeffries S, Jackson A, et al. Treatment response in late-onset depression: relationship to neuropsychological, neuroradiological, and vascular risk factors. Pyschol Med. 2004;34:125-136.

 

10. Alexopoulos GS, Meyers BS, Young RC, et al. Executive dysfunction and long-term outcomes of geriatric depression. Arch Gen Psychiatry. 2000;57(3):285-290.

 

 

 

 

Eric J. Lenze, MD

Recognizing Late-Life Depression Comorbid With Medical Illness

 

The Scope of the Problem

 

Practically every medical illness or acute medical event is followed by an increased risk of depression in both young adults and elderly people. Ischemic heart disease, stroke, cancer, endocrine diseases, chronic lung disease, kidney disease, arthritis, hip fracture, and neurodegenerative disease have all been shown to increase ones risk for depression. In a meta-analysis across specialty medical settings, Dew1 observed an increased prevalence of major depressive disorder (MDD) in practically every illness compared to the community rate in the Epidemiologic Catchment Area study. Conversely, elderly people with MDD have a high rate of comorbid medical illness. Descriptive data from a sample of 449 elderly patients at the Western Psychiatric Institute and Clinic in Pittsburgh, showed that most elderly people with depression had 2–4 comorbid medical conditions; >50% had hypertension, and almost 50% had osteoarthritis (R Mantella, PhD, unpublished data, 2005; Slide 8). Hyperlipidemia, diabetes, and hypothyroidism were present in 20% to 35% of patients. These medical conditions are  common in the elderly population in general, but are much more prevalent in the depressed elderly.

 

 

Why is Late-Life Depression Common in Medical Illness?

 

According to standard epidemiology, when two things are associated either A causes B, B causes A, or C causes both A and B. It is thought that all three are the case when it comes to the association between depression and medical illness. Medical conditions increase the risk for depression through several routes. First, neurodegenerative diseases (eg, stroke, Parkinson’s, Alzheimer’s) can cause direct disruption of neurotransmitters or neural circuits involved in mood regulation. Second, cardiac surgery, serious cardiopulmonary event, or hip fracture, can cause severe physiologic stress, which can lead to depression. Finally, the functional disability that occurs with these medical illnesses is a major risk factor for late-life depression. Conversely, depression can increases the risk of several medical conditions in elderly people. Depression can increase the risk for cardiovascular disease, falls and fractures, and possibly cancer. Finally, some theories suggest that there is some shared, perhaps genetic, vulnerability to both depression and medical conditions.2

 

Many studies have shown that the onset of disability in elderly people is a major risk factor for late-life depression.  In the short-term, someone who becomes disabled acutely has to deal with immobility, pain, an extensive hospitalization and rehabilitation period, and anxiety about their situation and their future. Long-term consequences include loss of perceived control, poor self-esteem, demoralization, hopelessness, social or interpersonal activity restriction, and a strain or reduction in one’s interpersonal relationships. Thus, many of the things that keep people resilient to depression are taken away when a person suffers a disabling medical event.3

 

In a study of 115 hip fracture patients, 19% developed MDD over a 6-month period (EJ Lenze, MD, unpublished data, 2005). The greatest period of onset occurred 1–2  weeks after the hip fracture (Slide 9). In contrast, the peak period of risk for depression after a stroke appears to be 3 months. Time to depression may be unique to the type of disabling medical condition.

 

Sequelae of Late-Life Depression

 

In medically ill elderly patients, depression amplifies disability, medical mortality, and healthcare utilization.

Disability

 

The very features of depression, such as apathy, psychomotor retardation, and hopelessness, are disabling. In addition, late-life depression is associated with executive dysfunction, which is the most disabling cognitive deficit. Depression in elderly people also leads to increased medical events, such as heart disease and hip fracture. And finally, depression leads to an impaired ability to recover from disabling medical events; these patients are less likely to participate in medical rehabilitation or adhere to medical recommendations. Despite the fact that studies have shown that depression improves with rehabilitation, disabled depressed elderly are often considered less appropriate candidates for rehabilitation because they are more likely to be amotivated and cognitively impaired. Therefore, it is often the psychiatrist who must advocate for these patients.

 

In a sample of hip fracture patients, both depressed and nondepressed patients who went to a rehabilitation hospital had much better improvement of disability over 2 weeks than those who went to a nursing home, as demonstrated by FIM score—a measure of functional ability commonly used in rehabilitation settings (EJ Lenze, MD, unpublished data). This suggests that depression does not adversely affect these patients’ ability to benefit from rehabilitation.

 

Medical Mortality

 

 

In a study of >2,000 elderly patients with cardiac disease, Penninx and colleagues4 found that those with MDD had a greatly increased risk of cardiac mortality. Frasure-Smith’s5 landmark study of depression and cardiac mortality demonstrated that heart attack patients with elevated depressive symptoms had a greatly increased risk of mortality over 6 months (Slide 10). MDD was actually a greater risk for mortality than other well-known risk factors, such as history of previous heart attack or worsening ventricular function. Depression worsens cardiac outcome because these patients are more likely to have increased sympathetic and decreased vagal or parasympathetic tone, hypothalamic pituitary axis hyperactivity, systemic inflammation, platelet/endothelial activation, poor health behaviors (smoking, physical inactivity), and poor adherence to medical recommendations.6 There is no evidence that treatment of depression actually reduces cardiac mortality; however, the SADHART study found an improved quality of life attributable to depression treatment.

 

Healthcare Utilization

 

 

Some of the signals of depression in both outpatients and inpatients is persistent help-seeking somatic complaints, such as pain, headache, fatigue, insomnia, gastrointestinal symptoms, arthritis, multiple diffuse symptoms, and weight loss. Katon and colleagues7 looked at 6-month healthcare costs in elderly people with MDD or dysthymic disorder compared to controls. Visits to the primary care physician, diagnostic tests, specialty visits, emergency room visits, prescription medications, and inpatient costs were all increased in MDD/dysthymia patients compared to controls.

 

Barriers to Diagnosis

 

All patients with medical disability (eg, cardiac disease, hip fracture) should be assessed for depression. One problem is that medical settings are not optimal for diagnosing MDD in elderly people. Although the onset of depression is very common after disability, MDD is much less common. In addition, symptoms may remit spontaneously and the patient may be in another setting or already suffering the consequences of depression by the time it is recognized. To add to those substantial barriers, other medical conditions can confuse the diagnosis of depression: Many of the symptoms of depression, such as fatigue, insomnia, and loss of appetite, are common in other medical problems as well. In addition, older people are less likely to use the word “depressed,” but will report anhedonia if asked. Many elderly people in medical settings are cognitively impaired which makes them less insightful about their symptoms. They are also commonly delirious, which can be confused with depression.

 

One clue that a medically ill person with depressive symptoms is suffering from an episode of MDD is refusal of treatment. It is not uncommon for patients to be unmotivated for medical rehabilitation for the first couple of days; however, those who persistently refuse rehabilitation and seem depressed require treatment. Finally, prolonged hospitalization is a sign that the patient may have MDD.

 

Barriers to Adequate Treatment

 

Many antidepressants required initiation at a subtherapeutic dose. This becomes a problem in depressed elderly who may be transferred to a different setting before the effective dosage is achieved. Rapid switches between settings makes medication treatment/titration and certainly psychotherapy very difficult. Some data suggest that medication for depression is not as efficacious in medically ill patients. However, many studies do not support this finding. Another barrier to treatment is patient or family refusal for various reasons. Confronting their concerns through psychoeducation can reduce refusal of treatment and help to reduce early discontinuation of treatment. Common reasons for discontinuation include side effects (62%), lack of perceived need (57%), claims that the patient is feeling better (50%), or claims that the medication does not work (32%).8

 

Conclusion

 

Depression is extremely common after a disabling medical event, and many patients require rehabilitation for disability. MDD can interfere with rehabilitation; however, depressed elderly people seem to do well with high-quality rehabilitation, and therefore, treating physicians should not allow providers or practice settings to deny their patients these services. MDD in the context of cardiac disease increases mortality, which reinforces the need to provide treatment in this context. Finally, substantial barriers to diagnosis and treatment can be overcome with good prospective psychoeducation and long-term follow-up. However, given these barriers, new approaches to managing medically ill depressed patients, such as preventive or early intervention approaches, need to be developed.

 
 

References

1. Dew MA. Psychiatric disorder in the context of physical illness. In: Dohrenwend BP, ed. Adversity, Stress, and Psychopathology. London: Oxford University; 1998:177-218.

 

2. Whyte EM, Mulsant BH. Post stroke depression: epidemiology, pathophysiology, and biological treatment. Biol Psychiatry. 2002;52(3):253-264.

 

3. Lenze EJ, Rogers JC, Martire LM, et al. The association of late-life depression and anxiety with physical disability: a review of the literature and prospectus for future research. Am J Geriatr Psychiatry. 2001;9(2):113-135.

 

4. Penninx BW, Beekman AT, Honig A, et al. Depression and cardiac mortality: results from a community-based longitudinal study. Arch Gen Psychiatry. 2001;58(3):221-227.

 

5. Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction. Impact on 6-month survival. JAMA. 1993;270(15):1819-1825.

 

6. Zellweger MJ, Osterwalder RH, Langewitz W, Pfisterer ME. Coronary artery disease and depression. Eur Heart J. 2004;25(1):3-9.

 

7. Katon WJ, Lin E, Russo J, Unutzer J. Increased medical costs of a population-based sample of depressed elderly patients. Arch Gen Psychiatry. 2003;60(9):897-903.

 

8. Lin EH, Von Korff M, Katon W, Bush T, Simon GE, Walker E, Robinson P.  The role of the primary care physician in patients’ adherence to antidepressant therapy. Med Care. 1995;33(1):67-74.

 

 

 

George S. Alexopoulos, MD

Treatment of Late-Life Depression

 

Pathway to Late-Life Depression

 

Imaging studies have shown that aging and disease-related changes in the brain (eg, vascular, inflammatory, endocrine and immune responses) may either directly initiate mechanisms leading to depression (neocortical hypometabolism and limbic hypermetabolism), or create a state of vulnerability to depression (impairment in the function of the frontostriatal, amygdala, and hippocampal abnormalities). Psychosocial adversity acts at all three levels, meaning it can increase aging-induced brain changes; it can directly cause vulnerability to depression; or it can directly initiate mechanisms mediating depression. Many depressed elderly experience disability, which further compromises their ability to cope with the environment. Therefore, in addition to medication, it is important to consider therapies that address the psychosocial adversity these patients experience.

 

Treatment of Late-Life Depression

 

While both mild and severe geriatric depression respond equally well to antidepressants, severe depression is less likely to respond to nonspecific treatments. In studies that include elderly patients with mild depressions, active treatments often do not show separation from placebo because the placebo response rate is very high.1,2 This rather lower remission rate raises the concern that the available drugs are not effective enough.Interestingly, studies that have compared active drugs in geriatric major depressive disorder,3,4 seem to show a higher remission rate than studies comparing drug to placebo.

 

There is good evidence that combining drug therapy with psychotherapy is a more effective way of treating geriatric depression. Almost every psychotherapy treatment that has been tried in the elderly appears to be effective, and seems to have an additive effect to medication therapy. Thompson and colleagues5 demonstrated that cognitive-behavioral therapy (CBT) alone was more effective than desipramine alone. Reynolds and colleagues6 showed that interpersonal therapy (IPT) plus nortriptyline was more effective than IPT plus placebo or nortriptyline plus placebo. Finally, Arean and Cook7 demonstrated that the benefits of psychotherapies are sustained over time.

 

Treatment Recommendations

 

Residual Anxiety

 

 

Remission rates with antidepressants are not very impressive; patients are often left with residual anxiety. When this occurs, the dosage of antidepressant should be increased or alternative pharmacologic methods considered. Benzodiazepines should be avoided or used only short term. Concerns are memory impairment, gait disturbance/falls, disinhibition/agitation, potential habituation, and refusal to stop the medication.

 

When an Antidepressant Fails

 

Clinical data are limited; however, treatment guidelines have been created on the basis of expert opinion. A 2002 guideline developed from a statistical analysis of the opinions of 50 experts in late-life depression, recommended that a patient who fails a trial of a selective serotonin reuptake inhibitor should be switched to venlafaxine or bupropion (Slide 11). If there is no response to velafaxine, the patient should be switched to an SSRI, followed by trials of nortriptyline, bupropion, or mirtazapine. If the patient fails to respond to bupropion, the patient should be switched to an SSRI, followed by trials of venlafaxine, nortriptyline, or mirtazapine. If the patient fails a tricyclic antidepressant, he or she should be switched to venlafaxine. The experts did not strongly endorse augmentation in geriatric patients who have a partial response to an initial antidepressant trial (Slide 12).

 

 

 

Maintenance Treatment

 

The dosages required for continuation/maintenance treatment of late-life depression are the same as those effective in acute treatment. Combination treatment is more likely to prevent relapse than either drug or psychotherapy alone.6 In a multi-centered study by Sackeim and colleagues,8 ECT-treated patients, because of drug resistance, had a lower relapse rate when treated with an antidepressant plus a mood stabilizer than an antidepressant alone.

 

Medical Illness in Late-Life Depression

 

Many medical disorders are associated with a high rate of depression, including autoimmune disorders (cytokine hypothesis), metabolic disorders (hypercorticolemia hypothesis, impaired neurogenesis), vascular disorders (vascular depression hypothesis), neoplasms (leukemia, lymphoma, pancreatic carcinoma), and viral infections (hepatitis, human immunodeficiency virus). In such cases, both the medical and depressive disorders need to be treated simultaneously. For example, if a depressed patient has a high thyroid stimulating hormone (TSH), suppressing the TSH with thyroxin may bring the patient into partial remission. However, if only the depression is treated (eg, with an SSRI), the patient will at best achieve partial remission.

 

In a recent study by Alexopoulos and colleagues,9 vascular risk factors were associated with poor remission rate in elderly patients who were treated with the antidepressant citalopram at 40 mg/day. The value of the vascular depression hypothesis (See pg. 6) is that, if vascular disease contributes to the development of depression, then providing prevention for vascular disease, such as antihypertensive treatment, statins, aspirin, and antioxidants, may protect patients from depression. In addition, if in fact there is such a syndrome as vascular depression, that might influence the choice of antidepressants used. For example, drugs that enhance neurotransmission of norepinephrine (desipramine), dopamine (bromocriptine), or both (amphetamine), may promote behavioral recovery after an ischemic lesion. Other drugs like a-antagonists (trazodone, amitriptyline), benzodiazepines, and dopamine antagonists, inhibit behavioral recovery from ischemic lesions.

 

Several studies have shown that depression is a risk factor for stroke.10 It has also been demonstrated that depression interferes with functional recovery from stroke.11 Finally, studies have shown that antidepressants reduce the incidence of post-stroke depression12 and post-stroke mortality.13

 

Cognitive Impairment in Late-Life Depression

 

Data suggest that cognitive impairment, particularly executive dysfunction, may influence the course of depression. Abnormal initiation perseveration (executive dysfunction), is associated with a high incidence of dementia during long-term follow-up. Another predictor of development of dementia is late age of depression onset. However, it is often difficult to determine the onset of depression. Moreover, early-onset depression predisposes to late-onset depression syndromes because it interferes with the brain’s neuroanatomy and increases vulnerability to late-life syndromes of a different depressive etiology. Nonetheless, late onset of depression has been shown to be a robust predictor of later development of dementia.

 

Alexopoulos and colleagues14 treated 112 depressed elderly patients with citalopram 40 mg/day. Patients who had executive functioning impairment were less likely to achieve remission over a period of 8 weeks (Slide 13). Similarly, the patients who had abnormal response inhibition (inability to select a correct response and suppress a spontaneous response), did not respond well to citalopram. However, depressed patients responded well to problem-solving therapy (PST), which is a simplified form of comorbid behavioral therapy. Disability was also reduced in those who received PST compared to those who received supportive therapy. PST did not improve executive functions, however.

 

 

Conclusion

 

Antidepressants alone may not always be a sufficient treatment for depressed elderly people, and psychotherapies should be considered. Medical comorbidity contributes to depression significantly and it is important to treat both depression and medical diseases contributing to depression simultaneously whenever possible. Cognitive impairment, particularly executive impairment, may require greater clinical vigilance because executive dysfunction may predispose patients to poor response to antidepressants and require additional interventions. Disability is not fully explained by the clinical pathology of the patient and, therefore, requires an individual rehabilitation plan for reestablishing behavioral competence.

 
 

References

1. Schatzberg AF. New indications for antidepressants. J Clin Psychiatry. 2000;61(Suppl 11):9-17.

 

2. Roose SP, Sackeim HA, Krishnan KR, et al; Old-Old Depression Study Group. Antidepressant pharmacotherapy in the treatment of depression in the very old: a randomized, placebo-controlled trial. Am J Psychiatry. 2004;161(11):2050-2059.

 

3. Bondareff W, Alpert M, Friedhoff AJ, et al. Comparison of sertraline and nortriptyline in the treatment of major depressive disorder in late life. Am J Psychiatry. 2000;157(5):729-736.

 

4. Newhouse PA, Krishnan KR, Doraiswamy PM, et al. A double-blind comparison of sertraline and fluoxetine in depressed elderly outpatients. J Clin Psychiatry. 2000;61(8):559-568.

 

5. Thompson LW, Coon DW, Gallagher-Thompson D, Sommer BR, Koin D. Comparison of desipramine and cognitive/behavioral therapy in the treatment of elderly outpatients with mild-to-moderate depression. Am J Geriatr Psychiatry. 2001;9(3):225-240.

 

6. Reynolds CF 3rd, Frank E, Perel JM, et al. Nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression: a randomized controlled trial in patients older than 59 years. JAMA. 1999;281(1):39-45.

 

7. Arean PA, Cook BL. Psychotherapy and combined psychotherapy/pharmacotherapy for late life depression. Biol Psychiatry. 2002;52(3):293-303.

 

8. Sackeim HA, Haskett RF, Mulsant BH, et al. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. JAMA. 2001;285(10):1299-1307.

 

9. Alexopoulos GS, Kiosses DN, Murphy C, Heo M. Executive dysfunction, heart disease burden, and remission of geriatric depression. Neuropsychopharmacology. 2004;29(12):2278-2284.

 

10. Larson SL, Owens PL, Ford D, Eaton W. Depressive disorder, dysthymia, and risk of stroke: thirteen-year follow-up from the Baltimore epidemiologic catchment area study. Stroke. 2001;32(9):1979-1983.

 

11. Gainotti G, Antonucci G, Marra C, Paolucci S. Relation between depression after stroke, antidepressant therapy, and functional recovery. J Neurol Neurosurg Psychiatry. 2001;71(2):258-261.

 

12. Rasmussen A, Lunde M, Poulsen DL, Sorensen K, Qvitzau S, Bech P. A double-blind, placebo-controlled study of sertraline in the prevention of depression in stroke patients. Psychosomatics. 2003;44(3):216-221.

 

13. Jorge RE, Robinson RG, Arndt S, Starkstein S. Mortality and poststroke depression: a placebo-controlled trial of antidepressants. Am J Psychiatry. 2003;160(10):1823-1839.

 

14. Alexopoulos GS, Raue P, Arean P. Problem-solving therapy versus supportive therapy in geriatric major depression with executive dysfunction. Am J Geriatr Psychiatry. 2003;11(1):46-52.

 

 

Question-and-Answer Forum

 

Q: What is the relationship between depression and Alzheimer’s dementia?

 

 

Dr. Roose: Studies have shown that people who have depressive symptomatology at baseline have a much higher rate of developing dementia 4–5 years later. At this point, we know that there is a strong association between depression and developing dementia. We do not know whether depression is a risk factor for developing dementia, or whether depression is a prodromal symptom of dementia.

 

Q: Could the relationship between vascular illness and depression be attributed to reactive depression?

 

 

Dr. Roose: When we were first recognizing post-myocardial infarction (MI) depression, the concept  was that people get depressed after a heart attack. However, when you look at the data, it does not work out that way. In fact, depression precedes the heart attack in 50% of cases. Some data have shown that there is a high rate of intense depressive states 2 hours before the MI, which do not exist in the preceding 24 hours or 6 months prior. Therefore, the concept of reactive depression may apply in some cases, but we should not overlook the fact that the depression may be the precipitating trigger for the ischemic event.

 

Q: Is it possible that vulnerability to depression in later life is related to a decrease in resilience factors?

 

 

Dr. Lenze: To some extent, depression is the absence of resilience or resilience is the absence of depression. Resilience is a concept in psychiatry that comes mostly from studies of children who flourish and do not develop depression even after having been in terrible social, economic, and adverse settings. In elderly people, there is a similar concept. One of the factors that lead to resilience in elderly people is good social support. There is also a basic personality composed of optimism and mastery of one’s life that prevents depression. The onset of a severe disability can cause patients to challenge their optimistic way of thinking and reduce the quality of their social relationships. Although there has not been a lot of research on it, it is certainly a pathway.

 

Q: Is it possible that the reason medical illness is common in late-life depression is because it is common in elderly people rather than due to a strong relationship between depression and medical illness?

 

 

Dr. Lenze: There is a fairly strong association between depression and medical illness. It seems that medical conditions are more common in the depressed population of elderly than they are in the general elderly population. In both elderly and young populations, increased medical illness is associated with increased incidence of depression.

 

Q: Would you wait before starting antidepressants in a bereaved person?

 

 

Dr. Shear: If a  patients meets criteria for major depression 2 weeks after the death of a loved one, it makes sense to treat that person because the higher the distress early on after bereavement, the worse the outcome. Therefore, it is a good idea to mitigate some of that distress if possible.  There is no evidence that selective serotonin reuptake inhibitors blunt the normal emotional reaction. In fact, it is probably the case that very intense emotions interferes more so than the antidepressant medication would.

 

Q: Are there any data relating to reactions to the death of a spouse in an unhappy relationship or after a long illness where death is partly a relief?

 

 

Dr. Shear: The small amount of data we have is quite consistent with the idea that the grief problems do not come from bad or ambivalent relationships. The Longitudinal Follow-up Study of Caregivers of Alzheimer’s Patients study found that caregivers who become depressed have a lessening of depression after the death. We can infer from this, grief proceeds normally with that the death of someone who has been suffering or with whom the caregiver has been suffering. This occurs so long as long as the caregiver is not guilt ridden, and allows themselves to feel  the natural relief that comes from the resolution of a difficult situation.

 

Q: When you referred to depression as a risk factor for stroke or MI, does the prediction pertain to untreated depression, treated depression, or both?

 

 

Dr. Alexopoulos: The studies were done in untreated depression and showed that increased depression increased the likelihood of stroke. I am unaware whether treatment of depression was studied as a predictor of stroke, but clearly proactive treatment of depression, reduces the incidence of stroke and improves mortality after stroke.

 

Q: When we consider the level of evidence in antidepressant therapy in the elderly, why is nortriptyline not rated higher than the other antidepressants?

 

 

Dr. Alexopoulos: My assumption is that nortriptyline is a more difficult drug to use. It requires longer training and has some contraindications. Nortriptyline has side effects such as loss of memory, dry mouth, constipation, tachycardia, and other anticholinergic symptoms that may compromise the patient’s quality of life. These are reasons to worry about nortriptyline. Nonetheless, nortriptyline is highly efficacious.

 

Dr. Roose: I think clinicians are enamored with the therapeutic plasma level of nortriptyline as a treatment for late-life depression. It does not mean that we have the double-blind placebo-controlled trials to support that.  Most of the trials of nortriptyline have been psychotherapy controlled, not necessarily placebo-controlled. And while nortriptyline has shown vast evidence of efficacy, there are safety concerns in terms of cardiovascular risk and other side effects. But certainly the same thing should be said about stimulants, which has become a standard of care in the absence of strong evidence-based medicine.

 

Q: Stimulants are used regularly and extremely effectively in the elderly. What are the effects of these drugs on executive dysfunction?

 

 

Dr. Alexopoulos: Stimulants are becoming the standard of care in rehabilitation after stroke. Patients who have suffered a stroke often have executive dysfunction. Perhaps by enhancing dopamine and norepinephrine neurotransmission, stimulants may improve behavioral recovery after ischemic lesions. Whether stimulants work as antidepressants per se, has not been established. There is not a single well-designed study of stimulants in geriatric depression. At this point, it is unclear whether psychostimulants work as single antidepressants in geriatric major depression, although they may serve as augmentation to antidepressants in patients with depression, executive dysfunction, or vascular depression.

 

Dr. Roose: There is a significant concern about the use of stimulants, particularly in older people, on the basis of its ability to increase QT variability and a vulnerability to arrhythmia and sudden-death.  The oldest story about that is the interaction between digitalis and quinidine. We used to give digitalis and quinidine to the patients with the worst cardiac conditions. They would die, which is what was expected, and we did not realize that there was a drug-drug interaction that was promoting the death. Therefore, before we ever enthrone something as a standard of care, we have to look at the evidence and the relevant safety data.

 

Q: What do you recommend for insomnia in depressed elderly patients?

 

 

Dr. Alexopoulos: The expert consensus guideline recommends sleep hygiene first, followed by trazodone. They did not recommend benzodiazepines or hypnotic medications. We sometimes use small doses (5 mg) of zolpidem in those who do not respond to trazodone.

 

Q: What is your first choice for agitated depressed elderly patients? Are small doses of antipsychotics acceptable?

 

 

Dr. Alexopoulos: Our practice at Cornell is not to use antipsychotic medicines in nonpsychotic depression unless it is absolutely necessary. However, there is emerging evidence that there may be a role for antipsychotic medications in geriatric depression. A study was recently conducted in patients who had failed to respond to at least two antidepressants as well as a citalopram trial. These patients achieved good response with risperidone 0.5–1.5 mg/day.

 

Q: It has been demonstrated that medical rehabilitation helps depressed as well as nondepressed hip fracture patients. Does this generalize to other illnesses?

 

 

Dr. Lenze: The study I conducted was in hip fracture patients, but I don’t see any reason why it would not generalize to other disabling medical events. If the disability from the medical illness calls for medical rehabilitation, the treating physician should advocate for their depressed and cognitively impaired patient. Several studies have shown that when someone goes to rehabilitation and recovers function, their depression gets better. This is not at all surprising considering that disability is one of the major risk factors for depression in the elderly.

 

Q: Is there a role for cholinesterase inhibitors in the treatment of late-life depression given the high rate of conversion to Alzheimer’s or cognitive deterioration?

 

 

Dr. Alexopoulos: The theory has been that Alzheimer’s disease begins many years before it becomes clinically evident. Depression is a prodrome of dementia. Therefore, it makes eminent sense to use whatever we have to prevent the development of dementia in high-risk patients such as the depressed patients. I do not believe that there is sufficient evidence to tell us whether we should use cholinesterase inhibitors or not, but in a patient with cognitive impairment, late-onset depression, executive dysfunction, and serious depression, I would be more inclined to consider a cognitive enhancer.

 

Dr. Lenze: There is a large-scale study being done in late-life depression, looking at whether donepezil added to antidepressant monotherapy in remitted depressed patients will delay or prevent cognitive decline. Those findings will be available in about 4 years.

 

Q: Are sympathetic stimulants, such as bupropion and venlafaxine, likely to cause similar side effects as anticholinergic medications?

 

 

Dr. Roose: With anticholinergic drugs, there is particular concern about cognitive side effects and the data has shown that increased anticholinergic load is associated with decreased performance on certain neuropsychological evaluation tests. In terms of the cardiovascular risk, anticholinergic load decreases the already reduced parasympathetic tone that occurs as a result of age or depressive illness. Reduction of parasympathetic tone increases vulnerability to arrhythmia. Sympathetic drugs such as the stimulants and other drugs that may stimulate noradrenergic activity, may increase sympathetic tone, increase QT variability, and increase arrhythmic potential.


 

 
 

Funding for this symposium monograph supplement has been provided through an unrestricted educational grant by Forest Pharmaceuticals, Inc. Sponsorship of this supplement does not imply the sponsor’s agreement with the views expressed herein. Although every effort has been made to ensure that the information is presented accurately in this publication, the ultimate responsibility rests with the prescribing physician. Neither the publisher, the sponsor, nor the participants can be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation.

 

Copyright ©2005 MBL Communications, Inc. 333 Hudson Street, 7th floor, New York, NY 10013. Printed in the USA.

All rights reserved, including the right of reproduction, in whole or in part, in any form.

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Funding for this supplement has been provided by Forest Pharmaceuticals, Inc.

 

Dr. Schatzberg is Kenneth T. Norris, Jr. Professor and Chairman of psychiatry and behavioral science at Stanford University School of Medicine in California.

Disclosures: Dr. Schatzberg is a consultant to Abbott, Bristol-Myers Squibb, Corcept, Eli Lilly, Forest, Merck, NeuroPharmaBoost, Roche, Synosis, and Wyeth; is in receipt of intellectual property royalties from Corcept and Pathways Diagnostics; and holds equity or options in BrainCells, Corcept, Forest, Merck, Neurocrine, Pfizer, and Somaxon.

Acknowledgments: Dr. Schatzberg wishes to thank Eileen McGee, Marsha Kellar, and Hudson Medical Communications for their editorial assistance with this manuscript.


 

Dr. Weiss is professor of psychiatry at Harvard Medical School in Boston, and clinical director of the Alcohol and Drug Abuse Treatment Program at McLean Hospital in Belmont, both in Massachusetts.

Disclosure: Dr. Weiss is a consultant to Novartis and receives research support from Eli Lilly and Forest. He has received grants from the National Institute on Drug Abuse.

Acknowledgments: Dr. Weiss wishes to thank Joyce Waskelo and Hudson Medical Communications for their editorial assistance with this manuscript.


 

Dr. Brady is professor of psychiatry in the Department of Psychiatry and Behavioral Sciences and associate dean for Clinical Research at the Medical University of South Carolina in Charleston.

Disclosures: Dr. Brady is a consultant to Abbott, Eli Lilly, Embera NeuroTherapeutics, Forest, GlaxoSmithKline, Marinus, Novartis, Ovation, Pfizer, and Wyeth; is on the speaker’s bureaus of Abbott, Eli Lilly, Forest, GlaxoSmithKline, and Pfizer; and has received research support from Abbott, Forest, GlaxoSmithKline, Titan, and Wyeth.

Acknowledgments: Dr. Brady wishes to acknowledge Marsha Kellar and Hudson Medical Communications for their editorial assistance with this manuscript.


 

Dr. Culpepper is professor of family medicine and chairman at the Boston University School of Medicine in Massachusetts.

Disclosures: Dr. Culpepper is a consultant to AstraZeneca, Eli Lilly, Forest, Neurocrine, Pfizer, and Wyeth; and is on the speaker’s bureaus of Forest, Pfizer, and Wyeth.

Acknowledgments: Dr. Culpepper wishes to thank Marsha Kellar and Hudson Medical Communications for their editorial assistance with this manuscript.


 

Abstract

Substance abuse and mental disorders commonly occur together and place an incalculable burden on individuals, families, and society at large. Left untreated, co-occurring psychiatric and substance use disorders may result in troubled and unproductive lives, as this comorbidity is associated with underachievement or failure at work and school, poor health, problems fulfilling family responsibilities, abuse, violence, and legal difficulties. Co-occurring disorders frequently have a complex and bidirectional relationship and may require longitudinal, repeated assessments to establish correct diagnosis. A number of reliable instruments have been developed to improve screening and assessment in both primary care and mental health settings, but controversy persists regarding the best approach to treatment. A fundamental issue, for example, is whether to treat a mood or an anxiety disorder in the presence of ongoing alcohol or drug abuse. Although recent recommendations suggest that concurrent substance abuse should not impede treatment of psychiatric symptoms, more evidence is required to facilitate decision making during acute treatment. Further, relapse and recurrence are common among individuals with co-occurring disorders, and the issue of long-term treatment typically needs to be addressed. Optimal patient management requires a collaborative effort by mental health care professionals, addiction specialists, and primary care physicians. Therefore, it is important that physicians who care for this patient population weigh the most recent evidence on effective and integrated treatment of individuals with co-occurring mood, anxiety, and alcohol use disorders.

 

 

 

Introduction

By Alan F. Schatzberg, MD

 

It has been said that “co-occurring mental and substance use disorders represent a public health crisis.”1 Although this statement might seem hyperbolic, historic as well as recent epidemiologic surveys consistently support it.2-5 Mood, anxiety, and substance use disorders (SUDs) are each highly prevalent, and the co-occurrence of mood and anxiety disorders with SUDs is the rule rather than the exception.1

The National Comorbidity Survey Replication study found a 12-month prevalence of 18.1% for any anxiety disorder (3.1% for generalized anxiety disorder), 9.5% for mood disorders (6.7% for major depressive disorder and 2.6% for bipolar disorders), and 3.8% for SUDs (3.1% for alcohol abuse and 1.3% for alcohol dependence).4  Meanwhile, the National Epidemiologic Survey on Alcohol and Related Conditions found a positive and significant association between most SUDs and independent mood and anxiety disorders (P<.05).5 During a 12-month period, 19.7% of respondents with SUD had at least one independent mood disorder, and 17.7% had at least one independent anxiety disorder. Conversely, among respondents with either a mood disorder or an anxiety disorder occurring during a 12-month period, at least one SUD was found among 20% and 15% of the respondents, respectively. Among individuals with bipolar disorders, the 12-month rate for any alcohol use disorder was even higher, at ~24% for both mania and hypomania; conversely, among all respondents with any drug use disorder, the rate of mania was 10% and the rate of hypomania was 4.3%.

The bidirectional, reciprocal relationship between mood and anxiety disorders and SUDs represents a challenge to the healthcare system, and one that has not been fully met. While it is increasingly recognized that these disorders require integrated treatment, such programs are not widespread. Thus, the onus to provide comprehensive management for patients with dual disorders falls to individual practitioners. Understandably, many are reluctant to take on this responsibility, given the daunting hurdles involved, including the paucity of clinical trial data and evidence-based guidelines to help navigate unfamiliar waters.

This supplement is designed to help physicians overcome these obstacles. Readers will benefit from the discussion by Roger D. Weiss, MD, on the importance of early diagnosis, as well as his pragmatic approach to the screening and diagnosis of these disorders. Kathleen T. Brady, MD, PhD, focuses on general treatment considerations that guide the management of these patients and also provides practical guidelines in the selection of the most appropriate pharmacotherapy. Alan F. Schatzberg, MD, addresses issues regarding the risk of recurrence and effective long-term management. Finally, Larry Culpepper, MD, MPH, discusses the formidable challenges faced by primary care physicians in the diagnosis and management of patients with co-occurring depression/anxiety disorders and SUDs.

It should be noted that patients with bipolar disorders are particularly at risk of developing SUD. However, for the purpose of this supplement, our discussion will focus primarily on diagnosing and treating patients with co-occurring depression/anxiety disorders and alcohol dependence.

All of the articles in this supplement are based on a roundtable discussion by the authors—all recognized leaders in the field of co-occurring psychiatric disorders and SUDs. It is hoped that this publication will provide physicians with the insight, information, and tools they need to be more confident in addressing the special healthcare needs of these patients.

 

References

1.   O’Brien CP, Charney DS, Lewis L, et al. Priority actions to improve the care of persons with co-occurring substance abuse and other mental disorders: a call to action. Biol Psychiatry. 2004:56:703-713.
2.    Kessler RC, Nelson CB, McGonagle KA, Edlund MJ, Frank RG, Leaf PJ. The epidemiology of co-occurring addictive and mental disorders: implications for prevention and service utilization. Am J Orthopsychiatry. 1996;66:17-31.
3.    Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) study. JAMA. 1990;264:2511-2518.
4.    Kessler RC, Chiu WT, Demler O, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:617-627.
5.    Grant BF, Stinson FS, Dawson DA, et al. Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry. 2004;61:807-816.

 

Identifying and Diagnosing Co-occurring Disorders

By Roger D. Weiss, MD

 

Prevalence of Co-Occurring Disorders

Epidemiologic studies have shown a significantly greater likelihood of substance misuse in persons with psychiatric disorders.1 One of the largest studies showed that 60.7% of people with bipolar I disorder had a lifetime diagnosis of a substance use disorder (SUD).2 Moreover, 32% of individuals with any mood disorder, including depression, were found to suffer from substance abuse or dependence. In general population surveys, it has been found that the presence of a mood disorder at least doubles the odds of having SUD.3

Why should clinicians be interested in these comorbidities? A key reason is that patients with co-occurring disorders tend to have poorer prognoses and worse overall outcomes than those with either disorder alone. Primary negative outcomes include increased suicidal behavior, increased likelihood of homelessness, more hospitalizations, and poor medication adherence.

Losses that occur in the course of life—death of a loved one, job loss, reduced physical function—tend to be more devastating in people with SUDs than in those with depressive disorders and are more likely to result in suicide. One study found that 50% of alcoholics, as opposed to 20% of patients with depression, had a close personal loss within 1 year of suicide, and approximately one third had a loss within 6 weeks.4 Therefore, a high level of vigilance is warranted when individuals with co-occurring depression and substance abuse suffer a major loss.

Another study showed that patients with co-occurring major depressive disorder (MDD) and alcohol dependence were significantly more likely to have suicidal ideation and suicidal behavior than those with either disorder alone.5 The patients with co-occurring disorders were also found to be more impulsive. Impulsivity, coupled with the use of a disinhibiting agent, further increases the likelihood of suicidal behavior.

 

Dually Diagnosed Patients: A Heterogeneous Population

It is important to recognize the heterogeneity and multidimensionality of patients who have the dual diagnoses of MDD and alcohol dependence. Some areas of heterogeneity include6: severity of SUD (in a long-term study of alcoholism, it was suggested that persons at the mild-to-moderate end of the spectrum were more likely to continue drinking7); stage in the course of illness (first treatment recovery, recent relapse); presence and severity of coexisting medical or psychiatric illness; degree of insight into—and explanation for—the nature of his or her problem; motivation for treatment and stage of readiness for change; and sociodemographic variables (age, gender, marital status, employment status, and ethnicity).

Both mood disorders and SUDs should also be viewed as multidimensional, as a host of problems frequently occur in patients with either disorder or their combination. Some individuals have relatively few problems, and others have multiple difficulties. The Addiction Severity Index (ASI) is a frequently used assessment tool that captures the complexity of SUDs.8 The ASI examines the severity of alcohol use, drug use, employment or legal problems, medical problems, family and social problems, and psychiatric problems. Severity ratings are based on the patient’s history of problems, present condition, and subjective assessment of treatment needs in one or more areas. The ASI can be helpful in conducting a comprehensive interview, treatment planning, and follow-up.

 

The Diagnostic Process

Accurate diagnosis and successful treatment of SUDs and co-occurring psychiatric disorders rely on a careful, comprehensive assessment (Slide 1).9 During an initial assessment, it can be difficult to distinguish between psychiatric symptoms resulting from substance use and those occurring due to an independent psychiatric disorder. Anxiety, depression, mania, and psychosis are all commonly induced by various substances and can be observed with chronic use as well as during specific substance-induced states, including intoxication and withdrawal.9

 

 

However, the following factors increase the probability that the psychiatric disorder is independent and not the result of substance abuse9: a clear history of psychiatric symptoms that preceded onset of SUD; symptoms that remain evident during extended substance-free periods; symptoms that are not typically observed in conjunction with using a particular substance; and having at least one first-degree relative with a documented history of a similar disorder.

 

Timeline Approach to Evaluation

Evaluation of psychiatric symptoms in persons with SUDs can be enhanced with repeated, longitudinal assessments. One of the most effective techniques is to develop a timeline for the co-occurring disorders, relating one to the other. This approach can help determine the chronology of symptom development, the presence or absence of symptoms during extended substance-free periods, and the impact of each disorder on the presentation, clinical course, and outcome of the other.

It is helpful to first establish the chronology of substance use and any associated problems, as well as periods of stable abstinence—especially those lasting at least 3 months, which are most likely to reveal independent psychiatric symptoms.10 Then the patient’s psychiatric symptoms and signs can be reviewed across his or her lifespan. The patient’s recollection can be improved by framing the interview around important landmarks in time, and any available collateral information. This helps to accurately reconstruct the chronology of the patient’s disorders and also helps the patient to recognize any relationships between substance use and mood disorders.

In patients with co-occurring substance abuse and mood disorder, the diagnostic process does not take the traditional path of assessment, diagnosis, and treatment. It begins by identifying current problems and instituting appropriate initial treatment interventions (eg, detoxification) even when the relationship between the two disorders is not yet clear. Whether psychiatric symptoms are the result of a mood disorder or substance abuse might not be determined until stable abstinence is achieved, unless the symptoms are of sufficient intensity or duration that they are unlikely to have been caused by the specific substances used by the patient. On the modified assessment path, reassessment can help lead to a clear diagnosis (Slide 2).11

 

 

Clinical Screening Tools

“At-risk drinking” has been defined as consuming more than seven drinks per week or three drinks per occasion for women, and more than 14 drinks per week or four drinks per occasion for men.12 However, the threshold for at-risk alcohol consumption may be lower for patients who have mood and anxiety disorders.13

Several screening instruments have been shown to be highly accurate in identifying people who have an alcohol problem and are brief and easy to use.14 These include the CAGE questionnaire and the Alcohol Use Disorders Identification Test (AUDIT) (Slide 3).

 

 

The CAGE is a four-question screening instrument used primarily in clinical settings to identify people who have ever been alcohol dependent.15 It asks: Have you ever felt you should Cut down on your drinking? Have people Annoyed you by criticizing your drinking? Have you ever felt bad or Guilty about your drinking? Have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover (ie, an Eye-opener)? Because of its simplicity, the CAGE can be self-administered. A positive response to two or more of the four questions suggests a need for further assessment. The AUDIT is a 10-question screening instrument developed to identify hazardous and harmful alcohol consumption in primary care settings.16 Simple enough to be completed by the patient, the resulting score helps to differentiate between risky and harmful drinking patterns.

Some laboratory tests may help to provide objective evidence of problem drinking.17 Certain blood tests can detect biochemical changes associated with excessive drinking and provide biologic markers that suggest the presence of an alcohol use disorder. These markers include: elevated γ-glutamyl transferase levels after 4–8 weeks of chronic drinking of four or more drinks/day; elevated carbohydrate-deficient transferrin levels after 1–2 weeks of excessive alcohol consumption; and increased mean corpuscular volume (an index of red blood cell size) after 4–8 weeks of excessive alcohol intake.

The tests are generally less sensitive and specific than questionnaires but are valuable for corroborating the results of interviews. Moreover, abnormalities in these tests can raise a clinician’s suspicion that the patient’s self-report does not reflect their true level of drinking. The accuracy of these biological markers is affected by several factors, including nonalcoholic liver damage, use of medications and drugs, and metabolic disorders.17

Screening for psychiatric disorders in persons with SUDs has not been well explored and may be especially challenging because of symptom overlap.1 The Patient Health Questionnaire (PHQ) is a self-administered instrument that has been tested extensively in primary care settings.18 The PHQ depression scale (PHQ-9) consists of the nine criteria on which the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of depressive disorders is based and offers a briefer version of the three-page PHQ questionnaire to screen for depression (Slide 4).19

 

 

Conclusion

A careful and accurate assessment can provide the necessary information for intervention and treatment planning. It can also engage the patient and provide motivation to begin the process of change. Using the timeline approach, clinicians can often arrive at a working diagnosis that helps predict the most likely course of the co-occurring disorders and begin to develop a treatment plan.10 It is important to continue with the process of assessment and re-assessment, monitor the patient’s course, and, if necessary, revise the diagnosis.

 

References

1.   Brady KT, Verduin ML. Pharmacotherapy of comorbid mood, anxiety, and substance use disorders. Subst Use Misuse. 2005;40(13-14):2021-2041.
2.   Regier DA, Farmer ME, Rae DS. Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) study. JAMA. 1990;264(19):2511-2518.
3.   Nunes E, Rubin E, Carpenter K, Hasin D. Mood disorders and substance use. In: Textbook of Mood Disorders. Washington, DC: American Psychiatric Publishing; 2005:653-671.
4.   Murphy GE, Armstrong JW Jr, Hermele SL, Fischer JR, Clendenin WW. Suicide and alcoholism. Interpersonal loss confirmed as a predictor. Arch Gen Psychiatry. 1979;36(1):65-69.
5.   Cornelius JR, Salloum IM, Mezzich J, et al. Disproportionate suicidality in patients with comorbid major depression and alcoholism. Am J Psychiatry. 1995;152(3):358-364.
6.   Greenfield SF, Hennessy G. Assessment of the patient. In: Galanter M, Kleber HD, eds. Textbook of Substance Abuse Treatment, 3rd ed. Washington, DC: American Psychiatric Publishing; 2004:101-119.
7.   Vaillant GE. The Natural History of Alcoholism. Cambridge, Mass: Harvard University Press; 1983.
8.   McLellan AT, Luborsky L, Woody GE, O’Brien CP. An improved diagnostic evaluation instrument for substance abuse patients: the Addiction Severity Index. J Ment Nerv Dis. 1980;168:26-33.
9.   American Psychiatric Association. Practice Guideline for the Treatment of Patients with Substance Use Disorders. 2nd ed. New York, NY: American Psychiatric Association; 2006.
10. Shivani R, Goldsmith J, Anthenelli RM. Alcoholism and psychiatric disorders: diagnostic challenges. Alcohol Res Health. 2002;26:90-98.
11. Hendrickson EL, Schmal MS, Ekleberry SC. Assessment. In: Treating Co-Occurring Disorders. A Handbook for Mental Health and Substance Abuse Professionals. Binghamton, NY: Haworth Press; 2004:77-95.
12. Saitz R. Clinical practice: unhealthy alcohol use. N Engl J Med. 2005;352(6):596-607.
13. Brady KT, Tolliver BK, Verduin ML. Alcohol use and anxiety: diagnostic and management issues. Am J Psychiatry. 2007;164(2):217-221.
14. Cherpitel CJ. Brief screening instruments for alcoholism. Alcohol Health Res World. 1997;21(4):348-351.
15. Mayfield D, McLeod G, Hall P. The CAGE questionnaire: validation of a new alcoholism screening instrument. Am J Psychiatry. 1974;131(10):1121-1123.
16. Babor TF, Higgins-Biddle JC, Saunders JB, Montero MG. The Alcohol Disorders Identification Test: Guidelines for Use in Primary Care, 2nd Edition. Washington, DC: World Health Organization. 2001.
17. National Institute on Alcohol Abuse and Alcoholism. Alcohol Alert, No. 56. Bethesda, MD: National Institute on Alcohol Abuse and Alcoholism; 2002.
18. Spitzer RL, Kroenke K, Williams JB, et al. Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study: primary care evaluation of mental disorders: patient health questionnaire. JAMA. 1999;282(18):1737-1744.
19. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9):606-613.

 

Evidence-Based Pharmacotherapy for Mood and Anxiety Disorders with Concurrent Alcoholism

By Kathleen T. Brady, MD, PhD

 

Introduction

Co-occurring psychiatric and alcohol use disorders can have devastating personal and societal effects, yet little evidence exists to guide clinical treatment. In the face of scant data, individual practitioners must rely instead on professional experience and those limited practice guidelines that currently exist. The American Psychiatric Association (APA) advises that failure to treat a concurrent psychiatric disorder reduces the likelihood that the treatment for a substance use disorder (SUD) will be effective.1 Indeed, the effects of nontreatment were demonstrated in a prospective study assessing alcohol-dependent patients for 1 year following hospitalization for alcohol dependence,2 in which untreated depression was directly associated with a shorter time to first drink. The results also showed that among those patients with depression (Slide 1),2 taking antidepressants at the time of discharge increased the likelihood of an individual remaining abstinent during the follow-up period.

 

 

 

Recommendations for Pharmacotherapy

Alcohol-dependent patients commonly present with symptoms of depression or anxiety, which may be a part of acute intoxication or substance withdrawal and therefore may remit with time. The APA suggests allowing at least 3 weeks of monitored abstinence to permit identification of transient, alcohol-induced, and other substance-induced symptoms before making a decision to use pharmacologic treatment.1 Certain circumstances, however, might warrant earlier treatment, such as the presence of severe affective or anxiety symptoms that worsen rather than improve over the initial period of abstinence; a history of affective or anxiety disorders unrelated to periods of alcohol use; and/or a strong family history of mood or anxiety disorders. In cases of severe mental illness, abstinence is perhaps seen more realistically as a goal of treatment rather than as a prerequisite.3

When selecting and using pharmacotherapy for co-occurring alcohol dependence and psychiatric disorders, clinicians should consider the following1: unwanted synergy between prescribed medications and abused substance (eg, benzodiazepines and alcohol); drug-drug interactions affecting the efficacy of psychiatric treatment; nonadherence due to intoxication and withdrawal states; drug-seeking behavior; intentional or unintentional overdose; and the abuse potential of medications. Benzodiazepines are commonly prescribed to manage alcohol withdrawal, but their use beyond the withdrawal period should be restricted in patients with co-occurring disorders due to a high potential for abuse.1,3 The use of benzodiazepines should be limited to acute episodes targeting specific symptoms, and patients should be closely monitored while taking them. To encourage medication adherence and prevent possible overdose, physicians are advised to dispense drugs in limited amounts, restrict the number of refills, and use random blood or urine toxicology screening to determine the use of both prescribed and nonprescribed drugs.1

 

Treatment of Mood Disorders

Data from controlled trials that inform pharmacologic treatment of co-occurring mood disorders and SUDs have been relatively scarce.4 A recent meta-analysis,5 however, evaluated 14 randomized, placebo-controlled, double-blind trials of tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and other classes of antidepressants in the treatment of patients with a unipolar depressive disorder and concurrent alcohol or other drug dependence (N=848). Results were variable, yet overall, the trials showed a modest beneficial effect of antidepressants on depressive symptoms. As shown in Slide 2,6-19 the significant heterogeneity in effect across studies was strongly linked to placebo response; such a high placebo response (>25%) in several trials was thought to reflect inclusion of individuals with transient, substance-induced depression. Pooled effect size of the medication treatment on depression was 0.38 (95% CI=.18-.58), representing an effect in the small-to-medium range. Importantly, there was no direct impact of antidepressant treatment on alcohol consumption, but in those studies in which the medication had a positive effect on the treatment of depression, a significant reduction in alcohol use also occurred.

 

 

 
Investigations of pharmacologic treatments for alcohol- or other substance-dependent individuals with bipolar affective disease have also been limited. A recent double-blind, placebo-controlled trial, which examined actively drinking bipolar patients treated with valproate plus treatment as usual (lithium and psychosocial intervention) versus placebo plus treatment as usual found lower levels of alcohol consumption in the valproate-treated group.20 No differences occurred in terms of mood outcome, but those individuals receiving valproate demonstrated a trend to remit from mania earlier.

 

Treatment of Anxiety Disorders

Nearly all of the anxiety disorders co-occur more commonly with alcohol dependence than would be expected by chance alone, yet few controlled trials have investigated treatment for these indications. In the following section, existing evidence is reviewed by disorder. In the face of limited data, the best course may be to treat with agents known to be effective for the specific anxiety disorder while being mindful of contraindications to the use of these agents in individuals with alcohol dependence.

 

Generalized Anxiety Disorder

Multiple agents, including SSRIs, TCAs, venlafaxine, and anticonvulsants, have demonstrated benefits in reducing the symptoms of generalized anxiety disorder (GAD) in individuals without SUDs. While benzodiazepines are effective in treating GAD, their use in patients with SUDs is controversial. Several older studies have evaluated buspirone, a partial serotonin agonist nonbenzodiazepine anxiolytic, for the treatment of GAD with concurrent alcohol dependence, with mixed results regarding alcohol intake.21 Future studies of SSRIs—which have demonstrated efficacy in GAD in individuals without alcohol dependence—could be informative.

 

Social Phobia

Irreversible monoamine oxidase inhibitors (MAOIs), reversible MAOIs, SSRIs, and benzodiazepines all have documented efficacy in the treatment of social anxiety disorder.22 One small, placebo-controlled trial of patients with social anxiety disorder and alcohol dependence found that the SSRI paroxetine improved alcohol outcomes and decreased symptoms of social anxiety.23 A larger controlled trial demonstrated that the anticonvulsant gabapentin was efficacious in treating uncomplicated social anxiety disorder in alcoholics.24

 

Posttraumatic Stress Disorder

Posttraumatic stress disorder (PTSD) is one of the most common anxiety disorders in individuals with alcohol use problems. A number of placebo-controlled trials involving relatively large numbers of patients have demonstrated that SSRIs—specifically sertraline, fluoxetine, and paroxetine—are effective in the treatment of PTSD.25-27 A more recent, placebo-controlled trial investigated the use of sertraline in the treatment of PTSD with co-occurring alcohol dependence.28 Both patient cohorts demonstrated a significant decrease in alcohol use, but cluster analysis revealed robust effects in a subgroup of individuals with early trauma, leading investigators to conclude that certain subtypes of alcoholics might respond differently to SSRI treatment.

 

Using Medication to Treat Alcohol Dependence

The APA supports the use of pharmacotherapy to treat alcohol dependence in individuals with concurrent psychiatric disorders based on evidence in populations without psychiatric comorbidity.1 The United States Food and Drug Administration has approved several “anti-alcoholism” treatments, including disulfiram, naltrexone, and acamprosate.29 Earlier trials exploring the use of disulfiram and naltrexone in patients with co-occurring disorders demonstrated that these agents can be effective in treating alcoholism without worsening psychiatric symptoms.30-33 A recent, open-label trial found that in subjects with co-occurring bipolar disorder and alcohol dependence, the combination of valproate and naltrexone versus valproate alone led to better outcomes with regard to alcohol use (0% versus 75% relapse rate, respectively) and to improvement in manic and depressive symptoms.34 The largest controlled trial to date evaluating anti-alcoholism agents in patients with psychiatric comorbidity assessed the efficacy and safety of disulfiram and naltrexone in 254 alcoholics with an Axis I psychiatric disorder.35 Baseline diagnoses included 70% with major depression, 42% with PTSD, and 19% with bipolar disorder. Patients were randomized to one of four groups taking naltrexone or disulfiram alone, placebo alone, or naltrexone or disulfiram combined. Groups receiving either active medication had longer periods of abstinence and less craving; however, combined treatment showed no advantage.

 

Selecting Pharmacotherapeutic Agents

Practice guidelines recommend the use of newer antidepressants, such as SSRIs, to treat depressive and/or anxiety disorders in patients with alcohol dependence (Slide 3).1,3 For the treatment of depression, SSRIs are preferred over TCAs and MAOIs due to fewer adverse effects and a lower risk of morbidity and mortality in overdose situations. For the treatment of anxiety disorders, SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), or buspirone are recommended. The SSRIs escitalopram, fluoxetine, paroxetine, and sertraline, as well as the SNRIs duloxetine and venlafaxine, are indicated for both major depression and specific anxiety disorders, such as GAD, panic disorder, PTSD, social phobia, and obsessive-compulsive disorder.29 Each of these agents, however, is indicated for one or more particular anxiety disorder(s), and clinicians are advised to consult relevant prescribing information when selecting treatment.

 

 

 

Conclusion

Progress has been made in the recognition and treatment of co-occurring psychiatric disorders and alcohol dependence, but much work remains to be done in the area of treatment.4 Relatively few studies have evaluated the use of pharmacotherapeutic agents that specifically target alcohol use disorders concurrent with psychiatric illness. Studies that have been conducted indicate that similar agents work for depressive and anxiety disorders with or without the presence of alcohol dependence. Treatment considerations for individuals with alcohol dependence and concurrent mood and/or anxiety disorders should include safety, toxicity, and abuse liability. Considering the insufficiency of existing evidence, additional controlled trials are clearly needed to help clinicians guide their patients with co-occurring disorders toward sustained remission and recovery.

 

References

1.  American Psychiatric Association. Practice Guideline for the Treatment of Patients with Substance Use Disorders. 2nd Edition. New York, NY: American Psychiatric Association; 2006.
2.  Greenfield SF, Weiss RD, Muenz LR, et al. The effect of depression on return to drinking. Arch Gen Psychiatry. 1998;55(3):259-265.
3.  Substance Abuse and Mental Health Services Administration, United States Department of Health and Human Services. Treatment Improvement Protocols (TIP) 9: Assessment and treatment of patients with coexisting mental illness and alcohol and other drug abuse. Rockville, MD; 2002.
4.  O’Brien CP, Charney DS, Lewis L, et al. Priority actions to improve the care of persons with co-occurring substance abuse and other mental disorders: a call to action. Biol Psychiatry. 2004;56(10):703-713.
5.  Nunes EV, Levin FR. Treatment of depression in patients with alcohol or other drug dependence: a meta-analysis. JAMA. 2004;291(15):1887-1896.
6.  Altamura AC, Mauri MC, Girardi T, Panetta B. Alcoholism and depression: a placebo controlled study with viloxazine. Int J Clin Pharmacol Res. 1990;10(5):293-298.
7.  Roy A. Placebo-controlled study of sertraline in depressed recently abstinent alcoholics. Biol Psychiatry. 1998;44(7):633-637.
8.   Mason BJ, Kocsis JH, Ritvo EC, Cutler RB. A double-blind, placebo-controlled trial of desipramine for primary alcohol dependence stratified on the presence or absence of major depression. JAMA. 1996;275(10):761-767.
9.    Nunes EV, Quitkin FM, Donovan SJ, et al. Imipramine treatment of opiate-dependent patients with depressive disorders. A placebo-controlled trial. Arch Gen Psychiatry. 1998;55(2):153-160.
10.    Nunes EV, McGrath PJ, Quitkin FM, et al. Imipramine treatment of cocaine abuse: possible boundaries of efficacy. Drug Alcohol Depend. 1995;39(3):185-195.
11.    Cornelius JR, Salloum IM, Ehler JG, et al. Fluoxetine in depressed alcoholics. A double-blind, placebo-controlled trial. Arch Gen Psychiatry. 1997;54(8):700-705.
12.    McGrath PJ, Nunes EV, Stewart JW, et al. Imipramine treatment of alcoholics with primary depression: A placebo-controlled clinical trial. Arch Gen Psychiatry. 1996;53(3):232-240.
13.    Roy-Byrne PP, Pages KP, Russo JE, et al. Nefazodone treatment of major depression in alcohol-dependent patients: a double-blind, placebo-controlled trial. J Clin Psychopharmacol. 2000;20(2):129-136.
14.    Moak DH, Anton RF, Latham PK, Voronin KE, Waid RL, Durazo-Arvizu R. Sertraline and cognitive behavioral therapy for depressed alcoholics: results of a placebo-controlled trial. J Clin Psychopharmacol. 2003;23(6):553-562.
15.    Carpenter KM, Brooks AC, Vosburg SK, Nunes EV. The effect of sertraline and environmental context on treating depression and illicit substance use among methadone maintained opiate dependent patients: a controlled clinical trial. Drug Alcohol Depend. 2004;74(2):123-134.
16.    Schmitz JM, Averill P, Stotts AL, Moeller FG, Rhoades HM, Grabowski J. Fluoxetine treatment of cocaine-dependent patients with major depressive disorder. Drug Alcohol Depend. 2001;63(3):207-214.
17.    Kleber HD, Weissman MM, Rounsaville BJ, Wilber CH, Prusoff BA, Riordan CE. Imipramine as treatment for depression in addicts. Arch Gen Psychiatry. 1983;40(6):649-653.
18.    Petrakis I, Carroll KM, Nich C, Gordon L, Kosten T, Rounsaville B. Fluoxetine treatment of depressive disorders in methadone-maintained opiate addicts. Drug Alcohol Depend. 1998;50(3):221-226.
19.    Pettinati HM, Volpicelli JR, Luck G, Kranzler HR, Rukstalis MR, Cnaan A. Double-blind clinical trial of sertraline treatment for alcohol dependence. J Clin Psychopharmacol. 2001;21(2):143-153.
20.    Salloum IM, Cornelius JR, Daley DC, Kirisci L, Himmelhoch JM, Thase ME. Efficacy of valproate maintenance in patients with bipolar disorder and alcoholism: a double-blind placebo-controlled study. Arch Gen Psychiatry. 2005;62(1):37-45.
21.    Goldstein BI, Diamantouros A, Schaffer A, Naranjo CA. Pharmacotherapy of alcoholism in patients with co-morbid psychiatric disorders. Drugs. 2006:66(9):1229-1237.
22.    Lydiard RB, Brawman-Mintzer O, Ballenger JC. Recent developments in the psychopharmacoloy of anxiety disorders. J Consult Clin Psychol. 1996;64(4):660-668.
23.    Randall CL, Johnson MR, Thevos AK, et al. Paroxetine for social anxiety and alcohol use in dual-diagnosed patients. Depress Anxiety. 2001;14(4):255-262.
24.    Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacol.1999;19(4):341-348.
25.    Brady K, Pearlstein T, Asnis GM, et al. Efficacy and safety of sertraline treatment of posttraumatic stress disorder: a randomized controlled trial. JAMA. 2000;283(14):1837-1844.
26.    Marshall RD, Beebe KL, Oldham M, Zaninelli R. Efficacy and safety of paroxetine treatment for chronic PTSD: a fixed-dose, placebo-controlled study. Am J Psychiatry. 2001;158(12):1982-1988.
27.    Davidson JR, Rothbaum BO, van der Kolk BA, Sikes CR, Farfel GM. Multicenter, double-blind comparison of sertraline and placebo in the treatment of posttraumatic stress disorder. Arch Gen Psychiatry. 2001;58(5):485-492.
28.    Brady KT, Sonne S, Anton RF, Randall CL, Back SE, Simpson K. Sertraline in the treatment of co-occurring alcohol dependence and posttraumatic stress disorder. Alcohol Clin Exp Res. 2005;29(3):395-401.
29.    Physicians Desk Reference 2006: Guide to Drug Interactions, Side Effects, and Indications.  60th ed. Montvale, NJ: Thomson PDR; 2006:1175-3419.
30.    Brown ES, Beard L, Dobbs L, Rush AJ. Naltrexone in patients with bipolar disorder and alcohol dependence. Depress Anxiety. 2006;23(8):492-495.
31.    Larson EW, Olincy A, Rummans TA, Morse RM. Disulfiram treatment of patients with both alcohol dependence and other psychiatric disorders: a review. Alcohol Clin Exp Res. 1992;16(1):125-130.
32.    Kofoed L, Kania J, Walsh T, Atkinson RM. Outpatient treatment of patients with substance abuse and coexisting psychiatric disorders. Am J Psychiatry. 1986;143(7):867-872.
33.    Sernyak MJ, Glazer WM, Heninger GR, et al. Naltrexone augmentation of neuroleptics in schizophrenia. J Clin Psychopharmacol. 1998;18(3):248-251.
34.    Salloum IM, Cornelius, JR, Chakravorthy S. Utility of combined naltrexone valproate treatment in bipolar alcoholics: a randomized, open-label, pilot study. In: Diamond I, ed. Abstracts of Papers, 26th Annual Scientific Meeting of the Research Society on Alcoholism, Ft. Lauderdale, FL, June 21-25, 2003. Baltimore, MD: Lippincott, Williams & Wilkins; 2003:843, 146A.
35.    Petrakis IL, Poling J, Levinson C, et al. Naltrexone and disulfiram in patients with alcohol dependence and comorbid post-traumatic stress disorder. Biol Psychiatry. 2006;60(7):777-783.

 

Achieving Remission and Favorable Outcomes in Patients with Depression/Anxiety and Substance Use Disorders

By Alan F. Schatzberg, MD

 

Introduction

Given the frequency with which patients with substance use disorders (SUDs) and those with psychiatric disorders, such as major depressive disorder (MDD) and generalized anxiety disorder (GAD), suffer relapses and recurrences, the issue of long-term treatment for SUDs warrants special attention.1-3 Faced with recommending long-term treatment, the clinician must discern the primacy of disorder, which may have been only obliquely addressed at the time of the patient’s presentation and then solved by concurrent treatment. Establishing primacy relies on determining whether the psychiatric symptoms were induced by SUD or the psychiatric disorder emerged first and substance use was a means of coping with it. A third possibility exists—that the two disorders developed independently of each other, albeit becoming intermingled over time and serving to exacerbate each other. Clues to the temporal relationship of the disorders can be deduced from a meticulous history obtained from multiple sources, the effects that acute treatment has had on either condition, and the patient’s willingness to remain abstinent from the addictive substance.4 Hasin and colleagues5 demonstrated the importance that a history of depression has on long-term remission and relapse outcomes in substance dependence (Slide 1).

 

That depression leads to poorer long-term outcomes in patients with SUDs may be due, in part, to the impaired psychosocial function associated with depression, and the effect that patient impairment may have on the ability to engage in activities supporting remission and avoiding relapse.5 Similarly, the presence of GAD with co-occurring SUDs also affects outcomes, with worse 1-year treatment outcomes reported in patients with dual diagnosis than when GAD is absent.6 When both GAD and depression are present in patients with SUDs, the outcomes are even poorer. This was demonstrated in a study of 326 patients presenting for addiction treatment, in which abstinence at 6 months was achieved by 73% of patients with co-occurring depression, but by only 40% of patients with both depression and anxiety.7

 

Acute Treatment Versus Continuum of Management

Many SUDs are chronic,1 as is GAD,2 and depression is a recurring disorder for at least 60% of patients. Therefore, patients with these disorders may require a continuum of ongoing management, with treatment modalities, intensity of treatment, and monitoring varying by individual needs and over time.

The continuum of treatment begins with the acute phase (6–12 weeks), a stage marked by initiation of treatment and achievement of remission. The subsequent continuation phase (4–9 months) and maintenance phase (≥1 year) are characterized by a continuing of the initial medication at the dosage that helped induce remission and, when the patient’s condition and mode of treatment warrant it, a reduction in the frequency of clinician monitoring. The decision to continue with maintenance treatment in depression is based on factors that include the likelihood of recurrence (Slide 2),8,9 the severity of depressive episodes, any treatment side effects experienced by the patient, and patient preference.

 

In a manner similar to the treatment of patients with depression, patients with GAD who have responded to acute treatment with antidepressants or with buspirone therapy should remain on the medication for 6 to 12 months as a means of preventing relapse/recurrence.10 Clinical monitoring can be stepped down from intervals of every 2 to 4 weeks at initiation of therapy to every 3 to 4 months during maintenance therapy.

 

Long-Term Outcomes in Depression and Generalized Anxiety Disorder

The agent(s) that induced remission in patients with MDD or GAD should be used during the continuation and maintenance phases of treatment. Virtually all of the selective serotonin reuptake inhibitors (SSRIs)—citalopram, escitalopram, fluoxetine, paroxetine, and sertraline—as well as venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI), have demonstrated efficacy in maintaining remission of MDD.11 As noted elsewhere,12 the SSRIs escitalopram and paroxetine and the SNRIs duloxetine and venlafaxine are approved for the treatment of GAD. Slide 3 lists long-term studies of three of these agents; no long-term studies are yet available for duloxetine.13-17

 

 

  

Long-Term Management of Substance Use Disorders with Co-occurring Depression or Generalized Anxiety Disorder

Patients with SUDs have a lifelong vulnerability to relapse.1 Risk of relapse is higher in the first 12 months after remission, but many patients experience several cycles of relapse and remission during the first several years of treatment before concluding that “controlled” use of their favored substance(s) is not possible. Treatment recommendations for patients with SUDs issued by the American Psychiatric Association favor a combination of psychosocial interventions (eg, cognitive-behavioral therapy, motivational enhancement therapy, interpersonal therapy, and 12-step programs) to address issues such as motivation, coping skills, dysfunctional thoughts, or social relationships, and pharmacotherapy to address the physiologic responses to substance use. Disulfiram, naltrexone, and acamprosate may be helpful for patients with alcohol dependence; bupropion may be beneficial for individuals with nicotine dependence; and according to recent studies, disulfiram may be useful in the treatment of cocaine dependence.1,18

 

Long-Term Studies in the Pharmacologic Management of Alcohol Dependence

Concerned with the toxicity and contraindications associated with alcohol-sensitizing drugs (eg, disulfiram), researchers began in the 1980s to explore the possibility that SSRIs might be a better alternative in the treatment of alcohol use disorders.19 Yet 20 years of clinical studies have yielded decidedly mixed results, and a 2006 randomized, placebo-controlled multicenter study designed specifically to address the methodological shortcomings of previous studies found that treatment with the SSRI sertraline did not produce significantly better results than those seen in placebo-treated patients.20 It appears, then, that alcohol dependence in patients with co-occurring depression requires specific, targeted treatment. 

Alcohol-sensitizing drugs remain a therapeutic option. A 9-year, prospective, open-treatment study by Krampe and colleagues21 that evaluated drinking outcomes and use of alcohol deterrents (eg, disulfiram) among 180 patients found that long-term outpatient treatment resulted in a  >50% abstinence rate. Recently, the nine-cell, 16-week Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence study found that alcoholics treated with naltrexone 100 mg/day, acamprosate 3 g/day, combined behavioral intervention (CBI), or both, had substantial reductions in drinking.22 The combination of naltrexone and CBI was associated with significantly more days of abstinence (P=.009), and naltrexone was significantly more effective than placebo in delaying the first day of heavy drinking (P=.02). While there was no statistically significant difference in efficacy between acamprosate and placebo in this study, many other controlled studies23-35 have demonstrated that agent’s efficacy.

 

Preventing Recurrence and Relapse

Because patients with SUDs are subject to relapse and are inconsistent in reporting these incidents, testing of breath, blood, saliva, and urine is helpful in the early detection of relapse.1 Long-term abstinence is more likely to occur in patients with less premorbid psychopathology than in those who are able to develop new relationships, and in those who participate in self-help groups.

 

Conclusion

Patients with co-occurring SUDs and MDD and/or GAD require a continuum of long-term care as a means of avoiding relapse and recurrence. Long-term treatment is associated with better outcomes, but the type of treatments used, their intensity, and the frequency of patient monitoring must be tailored to the individual patient’s needs. The strength of the physician-patient alliance can go far in helping patients achieve remission, avoid relapse, and regain psychosocial functioning.

 

References

1.   American Psychiatric Association. Practice Guideline for the Treatment of Patients with Substance Use Disorders. 2nd ed. New York, NY: American Psychiatric Association; 2006.
2.     Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text revision. Washington, DC: American Psychiatric Association; 2004:372-474.
3.     Yonkers KA, Warshaw MG, Massion AO, Keller MB. Phenomenology and course of generalised anxiety disorder. Br J Psychiatry. 1996;168(3):308-313.
4.     Lehman AF, Myers CP, Corty E. Assessment and classification of patients with psychiatric and substance abuse syndromes. Psychiatr Serv. 2000;51(9):1119-1125.
5.     Hasin D, Liu X, Nunes E, McCloud S, Samet S, Endicott J. Effects of major depression on remission and relapse of substance dependence. Arch Gen Psychiatry. 2002;59(4):375-380.
6.     Compton WM 3rd, Cottler LB, Jacobs JL, Ben-Abdallah A, Spitznagel EL. The role of psychiatric disorders in predicting drug dependence treatment outcomes. Am J Psychiatry. 2003;160(5):890-895.
7.     Charney DA, Palacios-Boix J, Negrete JC, Dobkin PL, Gill KJ. Association between concurrent depression and anxiety and six-month outcome of addiction treatment. Psychiatr Serv. 2005;56(8):927-933.
8.     Practice guideline for the treatment of patients with major depressive disorder (revision). American Psychiatric Association. Am J Psychiatry. 2000;157(4 Suppl):1-45.
9.     Kessler RC, Berglund P, Demler O, et al. National Comorbidity Survey Replication. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289(23):3095-3105.
10.     Fricchione G. Generalized anxiety disorder. N Engl J Med. 2004;351(7):675-682.
11.     Physicians Desk Reference 2006: Guide to Drug Interactions, Side Effects, and Indications.  60th ed. Montvale, NJ: Thomson PDR; 2006:1177-3418.
12.     Brady KT. Evidence-Based Pharmacotherapy for Mood and Anxiety Disorders with Concurrent Alcoholism. CNS Spectr. 2008;13:4(Suppl 6):7-9.
13.     Davidson JR, Bose A, Wang Q. Safety and efficacy of escitalopram in the long-term treatment of generalized anxiety disorder. J Clin Psychiatry. 2005;66(11):1441-1446.
14.     Allgulander C, Huusom AK, Florea I. Prevention of relapse in generalized anxiety disorder by escitalopram treatment. Int J Neuropsychopharmacol. 2006;9(5):495-505.
15.     Stocchi F, Nordera G, Jokinen RH, et al. Efficacy and tolerability of paroxetine for the long-term treatment of generalized anxiety disorder. J Clin Psychiatry. 2003;64(3):250-258.
16.     Bielski RJ, Bose A, Chang CC. A double-blind comparison of escitalopram and paroxetine in the long-term treatment of generalized anxiety disorder. Ann Clin Psychiatry. 2005;17(2):65-69.
17. Montgomery SA, Sheehan DV, Meoni P, Haudiquet V, Hackett D. Characterization of the longitudinal course of improvement in generalized anxiety disorder during long-term treatment with venlafaxine XR. J Psychiatr Res. 2002;36(4):209-217.
18.     Suh JJ, Pettinati HM, Kampman KM, O’Brien CP. The status of disulfiram: a half of a century later. J Clin Psychopharmacol. 2006;26(3):290-302.
19.     Naranjo CA, Sellers EM. Serotonin uptake inhibitors attenuate ethanol intake in problem drinkers. Recent Dev Alcohol. 1989:7:255-266.
20.     Kranzler HR, Mueller T, Cornelius J, et al. Sertraline treatment of co-occurring alcohol dependence and major depression. J Clin Psychopharmacol. 2006;26(1):13-20.
21.     Krampe H, Stawicki S, Wagner T, et al. Follow-up of 180 alcoholic patients for up to 7 years after outpatient treatment: impact of alcohol deterrents on outcome. Alcohol Clin Exp Res. 2006:30(1):86-95.
22. Anton RF, O’Malley SS, Ciraulo DA, et al. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006;295(17):2003-2017.
23.     Pelc I, Le Bon O, Verbanck P, Lehert PH, Opsomer L. Calcium acetyl homotaurinate for maintaining abstinence in weaned alcoholic patients: A placebo-controlled double-blind multicentre study. In: Naranjo C, Sellers E, ed. Novel Pharmacological Interventions for Alcoholism. New York, NY: Springer-Verlag; 1992:348-352.
24.     Ladewig D, Knecht T, Leher P, Fendl A. Acamprosate–a stabilizing factor in long-term withdrawal of alcoholic patients (in German). Ther Umsch. 1993;50(3):182-188.
25.     Geerlings PJ, Ansoms C, van den Brink W. Acamprosate and prevention of relapse in alcoholics. Eur Addict Res. 1997;3:129-137.
26.     Poldrugo F. Acamprosate treatment in a long-term community-based alcohol rehabilitation programme. Addiction. 1997;92(11):1537-1546.
27.     Chick J, Howlett H, Morgan MY, Ritson B. United Kingdom Multicentre Acamprosate Study (UKMAS): a 6-month prospective study of acamprosate versus placebo in preventing relapse after withdrawal from alcohol. Alcohol Alcohol. 2000;35(2):176-187.
28.     Tempesta E, Janiri L, Bignamini A, Chabac S, Potgieter A. Acamprosate and relapse prevention in the treatment of alcohol dependence: a placebo-controlled study. Alcohol Alcohol. 2000;35(2):202-209.
29.     Gual A, Lehert P. Acamprosate during and after acute alcohol withdrawal: a double-blind placebo-controlled study in Spain. Alcohol Alcohol. 2001;36(5):413-418.
30.     Mason BJ, Goodman AM, Chabac S, Lehert P. Effect of oral acamprosate on abstinence in patients with alcohol dependence in a double-blind, placebo-controlled trial: the role of patient motivation. J Psychiatr Res. 2006;40(5):383-393.
31.     Barrias JA, Chabac S, Ferreira L, Fonte A, Potgieter AS, Teixeira de Sousa E. Acamprosate: multicenter Portuguese efficacy and tolerance evaluation study. Psiquiatr. Clín. 1997;18:149-160.
32.     Paille FM, Guelfi JD, Perkins AC, Royer RJ, Steru L, Parot P. Double-blind randomized multicentre trial of acamprosate in maintaining abstinence from alcohol. Alcohol Alcohol. 1995;30(2):239-247.
33.     Sass H, Soyka M, Mann K, Zieglgänsberger W. Relapse prevention by acamprosate. Results from a placebo-controlled study on alcohol dependence. Arch Gen Psychiatry. 1996;53(8):673-680.
34.     Whitworth AB, Fischer F, Lesch OM, et al. Comparison of acamprosate and placebo in long-term treatment of alcohol dependence. Lancet. 1996;347(9013):1438-1442.
35.     Besson J, Aeby F, Kasas A, Lehert P, Potgieter A. Combined efficacy of acamprosate and disulfiram in the treatment of alcoholism: a controlled study. Alcohol Clin Exp Res. 1998;22(3):573-579. 

 

Primary Care Management of Patients with Co-occurring Disorders

By Larry Culpepper, MD, MPH

 

Introduction

Primary care physicians (PCPs) often provide the first line of care for the vast number of United States adults—~30% at any given time—with either a psychiatric or a substance use disorder, or both.1 The widespread prevalence of this comorbidity bears reiterating: During the same 12-month period, 20% of national survey respondents with a substance use disorder (SUD) had at least one mood disorder, and 17% had at least one anxiety disorder.2 Conversely, at least one SUD was found among 20% of respondents with a mood disorder and 15% of those with an anxiety disorder. However, because PCPs are often not aware of or alerted to these problems, it would seem advisable that patients presenting with either a psychiatric or an alcohol use disorder should be evaluated for both conditions.3 Establishing the presence of co-occurring disorders may be difficult, but it is necessary for appropriate and realistic treatment planning.

 

Starting the Diagnostic Process

Given the high rates of co-occurrence of mood, anxiety, and alcohol use disorders, PCPs may want to identify patients likely to have comorbid mood and alcohol use disorders by screening all new patients, as well as those with associated medical conditions or other risk factors, somatic presentations, and high healthcare utilization.

A thorough evaluation can determine whether psychiatric symptoms are caused by a medical illness, medications, or SUD.3 For example, certain medical conditions, including stroke, parkinsonism, HIV infection, endocrinopathies (eg, diabetes), cardiac disease, chronic renal failure, and chronic pain syndromes, are strongly associated with major depression. In addition, chronic conditions that do not respond to treatment, such as depression, diabetes, chronic pain, heart disease, gastrointestinal disorders, and hypertension, may indicate underlying alcohol abuse or dependence.4

Risk factors that are helpful in identifying and monitoring those patients who may be at risk for alcohol misuse and/or psychiatric illness include: personal or family history of mental illness and/or substance abuse; recent loss (eg, death of a loved one, divorce); domestic abuse/violence; multiple somatic symptoms not attributable to specific medical conditions; fatigue; sleep disturbance; weight gain or loss; irritable bowel syndrome; flattened affect; complaints of stress or mood disturbance; work or relationship dysfunction; changes in interpersonal relationships; and decreased adherence to treatment recommendations and self care.5

Valuable information can be gained by contacting a spouse, family member, or friend who can elaborate on past and current symptoms and supply a family history of addictions and mental illness. To facilitate history taking, focused questions can help establish the chronology of symptom development and clarify the effects of each disorder on the clinical course of the other (Slide 1).6

 

 

Screening for Alcoholism

The US Preventive Services Task Force (USPSTF) recommends routine screening of all patients for alcohol abuse or dependence,7 and a single question about heavy drinking can start the diagnostic process: For men, “How many times in the past year have you had five or more drinks in a day?” For women, “How many times in the past year have you had four or more drinks in a day?”4 In this screen, a standard drink is equivalent to 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of 80-proof spirits. A response of 1 or more heavy drinking days during the past year constitutes a positive screen and can be followed by a written self-report instrument, such as the CAGE screen for alcohol-related problems8 or the CAGE-AID (CAGE-Adapted to Include Drugs) for both alcohol and drug misuse.9,10 Once a potential problem has been identified, further clinical assessment is needed to determine the pattern of drinking (ie, number of drinking days per week and drinks per day) and to confirm alcohol dependence.4 Screening tools and related materials are available at the National Institute on Alcohol Abuse and Alcoholism Web site.11

 

Screening for Depression and/or Anxiety

Depression and anxiety are highly comorbid, and experts advise that a screening for one should always be accompanied by an assessment for the other.12 In the primary care setting, a two-step screening tool can be time-efficient and productive. The USPSTF found that asking two questions is just as effective as using longer instruments for the initial recognition of depression (Slide 2).13 If the response to either of these questions is “yes,” a more thorough screen, such as the Patient Health Questionnaire-9,8 can be administered to gather additional information and facilitate a diagnosis.

 

 

 
A similar approach could be used to identify an anxiety disorder. Evidence has demonstrated that the first two items of the Generalized Anxiety Disorder-7 (GAD-7) scale constitute an effective screen for several anxiety disorders (Slide 2).12 Responses of “more than half the time/days,” or “nearly every day” to both questions can be followed by administration of the full GAD-7.14 The GAD-7 reliably identifies anxiety disorders other than GAD, including panic disorder, posttraumatic stress disorder, and social anxiety disorder, all of which have a documented association with alcohol use disorders. A clinical interview of patients with a positive screen (score ≥8) can subsequently verify the diagnosis of an anxiety disorder as well as other psychiatric comorbidities.

 

 

Initial Interventions

In primary care, effective physician interventions for alcoholism include a brief initial counseling session, feedback, advice, and goal setting.7 The process of physician assessment and brief intervention for alcoholism has been summarized as the “5 A’s” approach: First, Assess alcohol consumption. Second, Advise patients to reduce consumption to moderate levels. Third, Agree on individual goals to reduce alcohol intake or achieve abstinence (abstinence is the safest goal for dependence4). Fourth, Assist patients in acquiring the motivations, self-help skills, or supports needed for behavior change. Fifth, Arrange follow-up support and repeated counseling.

The patient’s acceptance of an alcohol use problem and willingness to engage in treatment substantially affect clinical outcomes.3 Evidence shows that brief interventions, especially motivational interviewing (MI), have been effective in reducing alcohol use in patients with co-occurring mental illness.15

MI can help patients resolve ambivalence about current or potential problems and assess their readiness to change.16 This counseling technique shifts the physician away from an authoritarian stance toward a more empathetic and collaborative approach that seeks to elicit the patient’s viewpoint about using substances and reasons for quitting. Indeed, MI may improve adherence with treatment recommendations not only for alcoholism but also for depression and anxiety disorders.

 

Issues Surrounding Treatment

The treatment of co-occurring disorders should strive to achieve both abstinence and psychiatric stabilization.17 A practical approach might be to encourage abstinence while offering psychosocial strategies (eg, referral to a support program or self-help group) and/or pharmacotherapy to help initiate abstinence. Several Food and Drug Administration-approved medications are available to help alcohol-dependent patients,18 and the American Psychiatric Association advocates the use of these agents in individuals with a concurrent psychiatric disorder.19

Although several weeks of abstinence are recommended to differentiate alcohol-induced symptoms from psychiatric symptoms, many outpatients will be unable to achieve this. In these cases, a tentative diagnosis of depression or anxiety can be made after 1 week of abstinence, based on changes in the patient’s psychiatric status, including severity and number of symptoms.3

As a rule, antidepressant treatment of a depressive or an anxiety disorder should not be delayed beyond a reasonable period, even if abstinence is not achieved, due to the unfavorable impact of comorbidity on prognosis.20 A history of depression or an anxiety disorder prior to the development of alcoholism is also supportive of early initiation of such treatment.

Furthermore, simultaneous treatment of co-occurring disorders may encourage adherence as patients gain relief from depressive or anxiety symptoms and alcohol cravings. When initiating pharmacotherapy, clinicians must be mindful of potential drug-drug interactions with any medications that are being taken concomitantly for medical comorbidities.

Medication adherence is especially daunting for dually diagnosed patients. Individuals in recovery frequently have complex and conflicting feelings about taking prescribed drugs and may consider the use of medication as a sign of failure or weakness.21 While remaining sensitive to the implications of pill-taking for these individuals, physicians might improve adherence by framing medication use as a tool to help patients achieve the goals they desire.

 

Importance of Psychosocial Support

In general, pharmacotherapy alone cannot adequately address all the treatment requirements of patients with co-occurring disorders. Because of a continuing need to manage recurring symptoms, patients often benefit from participation in a long-term community support network, such as Alcoholics Anonymous or a specialized 12-step groups for people with dual disorders.22 In these “Double Trouble” meetings, medication adherence is considered part of “working the program.”

For those individuals who desire and can afford psychotherapy, cognitive-behavioral therapy (CBT) has demonstrated effectiveness in treating depression, anxiety, and alcoholism separately and could be integrated successfully for alcohol-dependent patients with anxiety or depression.23 CBT seeks to modify negative or self-defeating thoughts or behaviors and is focused on achieving change in both.

 

Continuity and Integration

The role of the PCP is changing, from focusing on the medical consequences of alcoholism and addiction to a more active involvement in assessment, treatment, and referral to appropriate services.22 Organizations such as the American Society of Addiction Medicine and the American Academy of Psychiatrists on Alcohol and Addiction can provide physicians and other healthcare providers with information and education about the biopsychosocial nature of addiction and treatment. 

A national movement is afoot to integrate services for patients with co-occurring disorders.24 The separate mental health, substance use treatment, and primary care systems in the US have delivered fragmented and often inadequate care. As a result, many state mental health systems have implemented integrated dual diagnosis services, wherein teams of clinicians, typically working in one setting, provide coordinated mental health and substance use interventions, and in some, linkage to primary care services.

In practice, however, many patients continue to participate in treatment at different sites or require varying treatment services during different phases of treatment. In the long term, the PCP may be the health professional best positioned to detect the reemergence of psychiatric symptoms and to help these individuals maintain sobriety.

 

References

1.  Kessler RC, Demler O, Frank RG, et al. Prevalence and treatment of mental disorders, 1990 to 2003. N Engl J Med. 2005;352(24):2515-2523.
2.    Grant BF, Stinson FS, Dawson DA, et al. Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry. 2004;61(8):807-816.
3.    Ziedonis D, Brady K. Dual diagnosis in primary care: detecting and treating both the addiction and the mental illness. Med Clin N Amer. 1997;81(4):1017-1036.
4.    National Institute on Alcohol Abuse and Alcoholism. Helping Patients Who Drink Too Much: A Clinician’s Guide. Updated 2005 ed. Washington, DC: National Institutes of Health; 2007. Publication No. 07-3769.
5.    Institute for Clinical Systems Improvement. Health Care Guideline: Major depression in adults in primary care. 10th ed. Bloomington, MN: Institute for Clinical Systems Improvement; 2007.
6.    Kranzler HR, Rosenthal RN. Dual diagnosis: alcoholism and co-morbid psychiatric disorders. Am J Addictions. 2003;12(Suppl 1):26-40.
7.    US Preventive Services Task Force. Screening and behavioral counseling interventions in primary care to reduce alcohol misuse: recommendation statement. Ann Intern Med. 2004;140:554-556.
8.    Weiss RD. Identifying and diagnosing co-occurring disorders. CNS Spectr.
 2008;13:4(Suppl 6):4-6.
9.    Brown RL, Rounds LA. Conjoint screening questionnaires for alcohol and other drug abuse: criterion validity in a primary care practice. Wis Med J. 1995;94(3):135-140.
10.     CAGEAID. www.cadt.org/audit/cageaid.html. Accessed December 2007.
11.     National Institute on Alcohol Abuse and Alcoholism. www.niaaa.nih.gov/publications. Accessed December 2007.
12.     Kroenke K, Spitzer RL, Williams JB, Monahan PO, Löwe B. Anxiety disorders in primary care: prevalence, impairment, comorbidity, and detection. Ann Intern Med. 2007;146(5):317-325.
13.     US Preventive Services Task Force. Screening for depression: recommendations and rationale. Ann Intern Med. 2002;136(10):760-764.
14.     Spitzer RL, Kroenke K, Williams JB, Löwe B. A brief measure for assessing generalized anxiety disorder—The GAD-7. Arch Intern Med. 2006;166(10):1092-1097.
15.     Hulse GK, Tait RJ. Six-month outcomes associated with a brief alcohol intervention for adult in-patients with psychiatric disorders. Drug Alcohol Rev. 2002;21(2):105-112.
16.     Miller WR, Rollnick S. Motivational Interviewing: Preparing People to Change Addictive Behavior. New York, NY: The Guilford Press; 1991.
17.     Hendrickson EL, Schmal MS, Ekleberry SC. Treating Co-Occurring Disorders: A Handbook for Mental Health and Substance Abuse Professionals. Binghamton, NY: Haworth Press; 2004:97-105.
18.     Brady KT. Evidence-based pharmacotherapy for mood and anxiety disorders with concurrent alcoholism. CNS Spectr. 2008;13:4(Suppl 6):7-9.
19.     American Psychiatric Association. Practice Guideline for the Treatment of Patients with Substance Use Disorders. 2nd ed. New York, NY: American Psychiatric Association; 2006.
20.     Nunes E, Rubin E, Carpenter K, Hasin D. Mood disorders and substance use. In: Stein DJ, Kupfer DJ, Schatzberg AF, ed. The American Psychiatric Publishing Textbook of Mood Disorders. Washington, DC: American Psychiatric Publishing; 2005:653-671.
21.     Brady KT, Verduin ML. Pharmacotherapy of comorbid mood, anxiety, and substance use disorders. Subst Use Misuse. 2005;40(13-13):2021-2041.
22.     Substance Abuse and Mental Health Services Administration, United States Department of Health and Human Services. Treatment Improvement Protocols (TIP) 9: Assessment and Treatment of Patients with Coexisting Mental Illness and Alcohol and Other Drug Abuse. Rockville, MD; 2002.
23.     Petrakis IL, Gonzalez G, Rosenheck R, Krystal JH. Comorbidity of alcoholism and psychiatric disorders: an overview. Bethesda, Md: National Institute on Alcohol Abuse and Alcoholism; 2002.
24.     Drake RE, Essock SM, Shaner A, et al. Implementing dual diagnosis services for clients with severe mental illness. Psychiatr Serv. 2001;52(4):469-476.

 

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This supplement is supported by Pamlab LLC.

Dr. Cummings is director of the Mary S. Easton Center of Alzheimer’s Disease Research in the Departments of Neurology and Psychiatry and Behavioral Sciences, David Geffen School of Medicine, at the University of California, Los Angeles.

Disclosure: Dr. Cummings has provided consultation to Abbott, Acadia, Accera, ADAMAS, Astellas, Avanir, Bristol-Myers Squibb, CoMentis, Eisai, Elan, Eli Lilly, EnVivo, Forest, GlaxoSmithKline, Janssen, Lundbeck, Medivation, Merck, Merz, Myriad, Neuren, Neurokos, Novartis, Noven, Orion, Pfizer, Prana, reMYND, Schering Plough, Signum Bioscience, Sonexa, Takeda, Toyama, and Wyeth; has been a speaker/lecturer on behalf of Eisai, Forest, Janssen, Novartis, Pfizer, Lundbeck, Merz; owns stock in ADAMAS, Neurokos, Prana, and Sonexa; owns the copyright of the Neuropsychiatric Inventory; and has provided expert witness/legal consultation regarding olanzapine and ropinirole.

Acknowledgment: Dr. Cummings is supported by the Sidell-Kagan Foundation and the Jim Easton gift.


 

Abstract

Alzheimer’s disease (AD) and dementia have enormous financial and social impacts on society. It is predicted that almost 36 million people will have dementia in 2010, a figure which is anticipated to double every 20 years as the world population ages.  Prevention of AD or slowing of the progression of AD would provide significant benefits. There are multiple ways in which vitamin B12, vitamin B6, folate, and homocysteine (Hcy) play a role in the pathogenesis of AD. Vitamin B12, vitamin B6, and folate deficiencies are associated with various cognitive disorders, including dementia. Neuroinflammatory oxidative stress occurs early in AD pathology. Total blood Hcy levels are utilized as a marker to assist in diagnosing such deficiencies. Hcy contributes to pathological cascades involving amyloid plaques and neurofibrillary tangles (NFTs). This review provides a thorough description of several factors involved in the development of the pathological changes associated with AD, such as neuroinflammatory oxidative stress and methylation, apoptosis, NFTs, amyloid plaques, and cerebrospinal fluid biomarkers. The review also considers the rationale for a combined B-vitamin and antioxidant supplement (Cerefolin NAC) in treating and slowing AD-related cognitive decline.


In this Expert Review Supplement, Andrew McCaddon, MD, and Peter R. Hudson, PhD provide a comprehensive review of factors involved in AD pathology as well as evidence supporting the use of a combined B-vitamin and antioxidant supplement (Cerefolin NAC) for AD-related cognitive decline. A commentary on this article is provided by leading AD expert Jeffrey L. Cummings, MD.

 

Drs. McCaddon and Hudson provide a thorough review of the multiple ways in which vitamin B12, vitamin B6, folate, and homocysteine (Hcy) are implicated in the pathogenesis of Alzheimer’s disease (AD). They noted that Hcy is more often elevated in AD and in mild cognitive impairment (MCI) than in cognitively healthy elderly; phosphatases needed to limit tau hyperphosphorylation and neurofibrillary tangle formation require methylation and are dependent on folate and methylation status; cerebrospinal fluid (CSF) tau levels correlated with markers of methylation status; reduced folate and B12 levels lead to increase b-secretase and pesenilin 1 (PS1) actions leading to greater amyloid-b production in in vitro models; elevated Hcy levels in rats are associated with increased PS1 activity and spatial memory deficits that are reversed following treatment with B12 and folate; raised Hcy levels in vitro increase amyloid-b protein neurotoxicity; methylation impacts transmitters and transmitter function relevant to AD; in cultured neurons, Hcy induces injury in DNA and stimulates cell death pathways. B12 deficiency leads to accumulation of methyl malonic acid, which inhibits mitochondrial function and may compromise energy generation and impair maintenance of synaptic plasticity. Methylation abnormalities result in excessive generation of reactive oxygen species that contribute importantly to cell injury. Biomarkers of oxidative injury, such as isoprostanes, are elevated in AD and suggest excess oxidation. Thus, there are multiple pathways through which deficient methylation may contribute to AD. In some cases, the observations are derived from models with B12 or folate deficiency and some in vitro observations have not been tested in in vivo models. There are no biomarkers specific to some of the pathways implicated and the magnitude of the impact of the deficiency or its treatment has not been established for all the relationships. Two open-label experiments in early- and late-stage AD patients have suggested benefit.

Epidemiologic data support a role for Hcy elevation as a contributing factor to AD. Based on data from the Framingham study,1 persons with elevated Hcy were at increased risk for developing AD; plasma levels >14 mmol/liter nearly doubled the risk of AD. In a consecutive series of 126 patients with AD, the patients were shown to have reduced CSF levels of L-methylfolate compared to healthy elderly controls.2 

Double-blind, placebo-controlled trials support a role for folate supplementation in older persons with elevated levels of serum Hcy. Durga and colleagues3 assigned 818 elderly individuals to 800 mcg of folic acid or placebo and treated them for 3 years. Subjects had 13–26 mmol/liter of Hcy at baseline. Those receiving folate supplementation performed better on tests of memory and sensory motor speed at the end of the trial. Patients had normal cognition at baseline. Aisen and colleagues4 performed a randomized trial of folic acid 5 mg/day, vitamin B12 1 mg/day, vitamin B6 25 mg/day in patients with mild-to-moderate AD. Hcy levels declined significantly; there was no corresponding cognitive, functional, global, or behavioral benefit.  Prespecified analyses of those with baseline Hcy levels in the highest quartile also showed no clinical benefit. The study shows that AD patients with normal levels are not improved by vitamin supplementation at these doses when used for 18 months and measured with standard clinical trial outcomes. Definitive conclusions about the utility of treatment of pathologically elevated Hcy levels awaits further study.

Cerefolin NAC, the compound described by Drs. McCaddon and Hudson, is available in the United States by prescription as a medical food. Medical foods are not supplements (which are taken by normal individuals, do not address a specific metabolic abnormality, and do not require a prescription) and they are not drugs (shown in rigorous double-blind, placebo-controlled trials to significantly improve a disease state).   Medical foods address a specific metabolic condition associated with a disease state. Cerefolin NAC reduces hyerhomocysteinemia that has been associated with memory impairment, AD, and cerebrovascular disease. The package insert for Cerefolin NAC describes the intended treatment population as individuals under a physician’s treatment for early memory loss with particular emphasis for those individuals diagnosed with or at risk for neurovascular oxidative stress and/or hyperhomocysteinemia, mild-to-moderate cognitive impairment with or without vitamin B12 deficiency, vascular dementia, or AD. Available data do not address all these conditions. The available data support use in older persons with elevated Hcy; studies in other populations are warranted. Cerefolin NAC is safe, with no important adverse events having been identified. 

Cerefolin NAC is currently being studied in a double-blind, placebo-controlled trial to determine its effect on cognition and other biomarkers for patients with early memory loss. This study is being conducted at Rush University in Chicago and the results for the first phase (6-month data) are due in early 2010. The patients will continue in the study for 18 months.

Clinicians must base treatment recommendations on the available pathophysiological and epidemiologic studies until more definitive clinical trial data are available. 

 

References

1. Seshadri S, Beiser A, Selhub J, et al.  Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. New Engl J Med. 2002;346:476-483.
2. Serot JM, Christmann D, Dubost T, Bene MC, Faure GC. CSF-folate levels are decreased in late-onset AD patients. J Neural Transm. 2001;108:93-99.
3. Durga J, von Boxtel MPJ, Schouten EG, et al.  Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomized double-blind, controlled trial. Lancet. 2007;369:208-216.
4. Aisen PS, Schneider LS, Diaz-Arrastia R, et al.  High-dose vitamin B supplementation and cognitive decline in Alzheimer’s disease. JAMA. 2008;300:1774-1783.
 

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Question & Answer Forum

The following question-and-answer session was prepared from a discussion with Roger S. McIntyre, MD, FRCPC, moderated by Diane M. Sloan, PharmD, of Advogent.

Acknowledgments: The authors acknowledge Dennis Stancavish, MA, and Jennifer Hutcheson, BA, of Advogent, for assistance in the preparation of this manuscript.

This question-and-answer session was supported by Wyeth Research, Collegeville, Pennsylvania.

 

Discussant: Roger S. McIntyre, MD, FRCPC

Dr. McIntyre is associate professor of psychiatry and pharmacology at the University of Toronto, and head of the Mood Disorders Psychopharmacology Unit at the University Health Network in Toronto, Canada.

Disclosures: Dr. McIntyre is on the advisory boards of AstraZeneca, Biovail, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Ortho, Lundbeck, Organon, Pfizer, Schering-Plough, Shire, Solvay, and Wyeth; is on the speaker’s bureaus of AstraZeneca, Biovail, Eli Lilly, Janssen-Ortho, Lundbeck, and Wyeth; receives grant/research support from Eli Lilly, Janssen-Ortho, the National Alliance for Research on Schizophrenia and Depression, Shire, and the Stanley Medical Research Institute; and receives honoraria from AstraZeneca, Bristol-Myers Squibb, Solvay, and Wyeth.

 

Abstract

When treating chronic diseases, physicians have long recognized the importance of focusing on the restoration of functioning, in conjunction with alleviating the overt signs and symptoms of such disorders. Until recently, practitioners who treat patients with major depressive disorder (MDD) have typically not prioritized the measurement of functional outcomes, despite the wealth of empirical data quantifying the workplace and interpersonal disability that is associated with MDD. Emerging evidence suggests that the emotional and physical symptoms of MDD as well as the cognitive deficits associated with the disorder are major contributing factors to the psychosocial dysfunction and workforce maladjustment seen in affected patients. Validated measurement devices that assess disability and monitor improvement across the spectrum of functional domains related to MDD may help improve outcomes in patients with the disorder. The use of a scale that measures work, social, and familial disability, such as the Sheehan Disability Scale, in conjunction with a symptom measurement scale, is recommended to quantify the level of impairment and to measure treatment effects in patients with MDD.

 

What level of disability has been shown to be associated with major depressive disorder (MDD)?

Several community-based epidemiological studies have documented that the majority of patients who screen positive for MDD experience significant disability in workforce and overall psychosocial functioning.1-5 According to the National Comorbidity Survey-Replication, patients with MDD experienced ~30 days/year when they were unable to perform their expected work and/or social roles.6

Several international studies have also reported on the extent of disability in the workforce and the direct and indirect costs associated with MDD.7,8 When functional outcomes include measures of disability beyond work—such as being able to participate meaningfully in life, days spent with family, or, conversely, days spent in bed—MDD is as impairing if not more impairing than other chronic medical disorders, such as hypertension,9 diabetes,9,10 and cardiovascular disease.9

Should physicians be cognizant of any particular symptoms of MDD that are associated with functional impairment?

During the last decade, the field has learned from several population-based and clinical studies that there is an inverse and parallel relationship between the severity of MDD symptoms and the level of functioning among patients with MDD (Figure). As the severity of MDD symptoms increases, the less likely it is that the patient will be functioning optimally.6 Attempts to elucidate specific symptoms that are associated with impaired functioning have underscored the persistent neurocognitive impairment associated with MDD. Commonly encountered neurocognitive deficits are disturbances in attention, memory, concentration, executive function, and information processing speed.11-13 Although the effect size of the neurocognitive deficits in patients with schizophrenia and bipolar disorder are greater than MDD, symptomatic (and asymptomatic) patients with MDD frequently exhibit clinically meaningful deficits in neurocognitive functioning. It is hypothesized that the deficits that are encountered in patients with MDD relate to the neurodegenerative changes associated with MDD.14 Moreover, neurocognitive function may be secondarily affected by classic symptoms of MDD, such as loss of energy, motivation, interest, and vitality.

 

 
Another important factor that may mediate the psychosocial, physical, and neurocognitive dysfunction in patients with MDD is the presence of medical comorbidities. Patients with MDD are differentially affected by several “stress-sensitive” medical disorders, such as cardiovascular disease,15 arthritis,16 obesity,17 diabetes,9 multiple sclerosis,18 and metabolic bone disease.19 Increasingly, MDD is conceptualized as an independent risk factor for incident medical illness, which suggests a neurobiological overlap between MDD and some commonly occurring somatic comorbidities.20,21 Medical comorbidities in MDD are associated with increased medical service utilization and overall health care cost.9,22-24 The presence of comorbid general medical disorders in patients with MDD may also exert an additive effect on overall functional decline and a deteriorating effect on quality of life.25 Taken together, the hazard posed by ubiquitous medical comorbidities in patients with MDD supports the recommendations for systematic screening, prevention, detection, and management of comorbid somatic health issues in patients with MDD.

Are data available that examine the ways in which impairment is seen across the different domains of functioning?

MDD is an “equal opportunity disabler” and as such it is rare to encounter abject impairment in one area and meaningful functionality in other areas. Nevertheless, anecdotally physicians do encounter some situations in which a person is certainly more impaired in one area than another. For example, someone who has a cognitively demanding job such as a banker, an accountant, or a school teacher, may be more likely to be affected by MDD in the workforce. 

In my experience, the effect of MDD on a patient’s functioning is heterogeneous. Nevertheless, many patients who are suffering from MDD are severely impaired in the workforce because clinicians are increasingly finding patients with cognitively demanding jobs being referred for assessment and treatment. Although they are experiencing difficulties from an interpersonal perspective, the impairment may not be as severe as in the workplace. Speculatively, this may be due in part to the protective and supportive mechanisms that are provided by the patient’s interpersonal relationships.

As a clinician, I have frequently encountered the bidirectional relationship between MDD and psychosocial functioning. For example, although it seems axiomatic that MDD adversely affects functional outcomes, suboptimal functioning can also portend nonrecovery in MDD.26,27 In everyday clinical practice, mental health professionals occasionally encounter clinical scenarios where a patient has achieved symptomatic remission, but continues to be highly distressed by the fact that they have been unable to recover functionally.

How does the psychosocial disability associated with MDD manifest in a patient’s life?

The psychosocial dysfunction observed in patients with MDD is often apparent in their interpersonal lives and is typically expressed as an increasing distance and disengagement in interpersonal, social, and familial activity. However, it is not uncommon for deficits in psychosocial functioning to impair workforce performance as well.
What impact does MDD have on a patient’s psychosocial functioning at work?

The mechanisms wherein MDD affects the ability to work relates to patient factors as well as interpersonal factors arising from the individual’s social/occupational network. Clinicians know that MDD diminishes functioning, job performance, and the ability to perform commensurate with their aptitude, which may affect the opportunity for job advancement and security. In the workforce, presenteeism is more often a consequence of MDD than is absenteeism.28

MDD also has a virulent effect on the social network within the workforce. Most individuals with MDD work in an environment that includes other coworkers who together create a complicated group dynamic. For example, if an individual is suffering from MDD in an office setting, it often implies that issues of stigma and alienation are introduced. The reactions of other group members toward a patient with MDD may be negative and unsupportive. For example, coworkers may have concerns about work-sharing when a coworker with MDD is unable to fulfill his or her responsibilities. This makes it very difficult for patients in the workplace who have MDD to manage both the burden of their own illness and also reactions from their coworkers, supervisors, direct reports, etc. Available evidence indicates that the probability of returning to the workforce and assuming the previously held, premorbid position diminishes significantly, especially if they are unable to return to work for protracted periods of time (ie, ≥6 months).29-31

Fortunately, many companies have become aware that mood disorders (and psychiatric disorders more broadly) are a significant burden on their employees and overall company performance. As a result, there has been interest by many companies in designing and executing a variety of education-based programs that generally focus on risk factor detection, primary prevention screening, and evidence-based interventions.

How does MDD specifically impact a patient’s personal life?

There has been a tacit assumption in psychiatry that the absence of psychopathology (ie, remission of MDD symptoms) equates to the existence of health. Unfortunately, many patients with MDD, despite the objective verification of MDD symptom abatement, are left with persistent deficits in functioning and detriments in quality of life.

Recently, several objective scales have been developed in an attempt to objectively measure the “happiness” that is often eroded, if not fully abrogated, by MDD. This domain is a relatively new construct dealing with self-regard, self-esteem, and quality of life.

When patients seek treatment or enter the physician’s office presenting with MDD symptoms, do they generally volunteer information regarding disability?

Although I have observed that patients spontaneously mention psychosocial and work-related dysfunction, it still requires careful probing to explore the quality and the quantity of the impairment on the part of the clinician. For example, patients with MDD are not frequently asked “What is your job? Describe the expectations that your employer has for you. What deliverables are expected from you, and how has your performance aligned with these expectations?” The relative lack of attention to workforce aspects of patients’ lives is in part related to medical education and curricula that does not focus on this aspect of assessing and managing MDD.

Until recently, the effect of MDD on the workforce has been underemphasized by patients, families, and practitioners. More recently, however, mental health care providers are beginning to collaborate with various private sector professionals, such as vocational rehabilitation counselors, as part of a chronic disease management approach to treating MDD. The intensified interest in the effect of MDD on the workforce is in part due to destigmatization campaigns, greater public awareness, and the acceptance of the impact that MDD has on employees.

Do clinicians routinely inquire about the disability associated with MDD at the time of diagnosis?

My impression is that clinicians do routinely inquire about disability, but what is missing is a sharpening of focus. In other words, there should be a much more measurement-based approach to quantifying patient functioning. Assessing functional outcomes enables practitioners and patients to more precisely estimate the severity of their functional difficulties. It also refines the measuring of subdomains of functioning (eg, workforce) that require greater attention, providing a more careful evaluation of treatment effectiveness. Moreover, measurement-based care provides a language for communicating with patients, families, employers, and other key stakeholders.

How can clinicians monitor functional impairment across its various domains over the course of treatment?

It is extremely important when clinicians diagnose MDD that they incorporate an evidence-based, algorithmic sequence of pharmacotherapy and psychosocial treatment, but they should also evaluate and measure outcomes with appropriate metrics that have been validated to assess the severity of MDD and the degree of functional impairment. At the Mood Disorder Psychopharmacology Unit at the University Health Network in Toronto, patients with MDD are routinely evaluated with a symptom measurement tool. The tools include the 9-item Patient Health Questionnaire (PHQ-9),32 which is easy to use and serves not only as a symptom measurement device that can establish and compare the efficacy of antidepressant interventions, but also as an MDD screening tool. Other scales include the shortened, 7-item version of the 17-item Hamilton Rating Scale for Depression (HAM-D7)33 and the Inventory for Depressive Symptoms or the Quick Inventory for Depressive Symptoms (QIDS).34,35 The patient’s functional performance was also measured using the Sheehan Disability Scale (SDS).36 The SDS is also easy to use and evaluates patients on three areas of functioning: work, social, and family. These three domains give a clear picture of how the patient is performing prior to treatment, and the scores can be combined to provide an overall level of global functioning. At each visit, clinicans evaluate a patient’s symptoms with a brief MDD rating scale and contemporaneously assess their functioning with the SDS.

Historically, physicians and other health care providers who treat patients with MDD have utilized the Global Assessment of Functioning (GAF), which is a continuous scale that comprises Axis 5 in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision.37 The GAF provides a global estimate of general functioning. However, for a more refined evaluation particularly across the multiple spheres of functioning, a measurement-based device, such as the SDS, offers an opportunity for more specific evaluation.

What additional tools may be useful to assist with measuring or tracking disability in clinical practice?

There are several other tools that have been used in clinical practice for evaluating disability in patients with MDD. Examples include, but are not limited to, the GAF and the 5-item World Health Organization Well-Being Index.38 In addition, there are several work performance tools that have been employed primarily in research settings as well as other scales that are an admixture of functional outcome and quality-of-life measures. The 36-item Short-Form Health Survey39 and the Quality of Life Enjoyment and Satisfaction Questionnaire40 are examples of such tools. Many quality-of-life scales are broad-based and are not specific to psychiatry.

In routine clinical practice, it is preferred to use one of the MDD metrics mentioned previously, such as the PHQ-9, HAM-D7, or the QIDS in conjunction with the SDS. Results from the Sequenced Treatment Alternatives to Relieve Depression study41 and other empirical studies,42 have documented that measurement-based care improves symptomatic and functional outcomes in patients with MDD. Notwithstanding the availability of multiple scales, each with their own merits and limitations, the guiding principle should be the use of a measurement-based approach to treating the symptoms and functional impairment associated with MDD.

What should the goal of treatment be with regard to the restoration of functioning or reduction of functional impairment associated with MDD?

During the past decade, the therapeutic objectives of managing patients with MDD have been refined. The overarching aim in managing a patient with MDD should be a restoration of functioning. Toward that aim, a full and sustained symptomatic remission will increase the probability that a restoration of premorbid functioning will occur. 

There are clinical scenarios (eg, chronicity or a recalcitrance of MDD symptoms) where an affected patient has received multiple antidepressants and adequate psychosocial or novel interventions yet remains symptomatic. The goals of treatment for such patients may have to shift toward improving quality of life and living with a chronic illness. Fortunately, most patients with MDD can expect some degree of responsivity to disparate treatment modalities.

Notwithstanding the availability of many United States Food and Drug Administration-approved conventional antidepressants, efficacious manual-based psychotherapies as well as novel neuromodulatory approaches, most patients with MDD in primary care continue to receive guideline-discordant care. Several lines of evidence indicate that the use of decision support (eg, MDD treatment guidelines) as part of a multidimensional chronic disease management model can significantly improve outcomes in patients with MDD.41,42

References
 

1. Berndt ER, Finkelstein SN, Greenberg PE, et al. Workplace performance effects from chronic depression and its treatment. J Health Econ. 1998;17(5):511-535.
2. Judd LL, Akiskal HS, Zeller PJ, et al. Psychosocial disability during the long-term course of unipolar major depressive disorder. Arch Gen Psychiatry. 2000;57(4):375-380.
3. Kessler RC, Akiskal HS, Ames M, et al. Prevalence and effects of mood disorders on work performance in a nationally representative sample of U.S. workers. Am J Psychiatry. 2006;163(9):1561-1568.
4. Spitzer RL, Kroenke K, Linzer M, et al. Health-related quality of life in primary care patients with mental disorders. Results from the PRIME-MD 1000 Study. JAMA. 1995;274(19):1511-1517.
5. Wells KB, Stewart A, Hays RD, et al. The functioning and well-being of depressed patients. Results from the Medical Outcomes Study. JAMA. 1989;262(7):914-919.
6. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289(23):3095-3105.
7. Saarijärvi S, Salminen JK, Toikka T, Raitasalo R. Health-related quality of life among patients with major depression. Nord J Psychiatry. 2002;56(4):261-264.
8. Sobocki P, Jönsson B, Angst J, Rehnberg C. Cost of depression in Europe. J Ment Health Policy Econ. 2006;9(2):87-98.
9. Druss BG, Rosenheck RA, Sledge WH. Health and disability costs of depressive illness in a major U.S. corporation. Am J Psychiatry. 2000;157(8):1274-1278.
10. Egede LE. Diabetes, major depression, and functional disability among U.S. adults. Diabetes Care. 2004;27(2):421-428.
11. Holmes AJ, Pizzagalli DA. Spatiotemporal dynamics of error processing dysfunctions in major depressive disorder. Arch Gen Psychiatry. 2008;65(2):179-188.
12. Mondal S, Sharma VK, Das S, Goswami U, Gandhi A. Neuro-cognitive functions in patients of major depression. Indian J Physiol Pharmacol. 2007;51(1):69-75.
13. Wang PS, Beck AL, Berglund P, et al. Effects of major depression on moment-in-time work performance. Am J Psychiatry. 2004;161(10):1885-1891.
14. Smith DJ, Muir WJ, Blackwood DH. Neurocognitive impairment in euthymic young adults with bipolar spectrum disorder and recurrent major depressive disorder. Bipolar Disord. 2006;8(1):40-46.
15. Penninx BW, Beekman AT, Honig A, et al. Depression and cardiac mortality: results from a community-based longitudinal study. Arch Gen Psychiatry. 2001;58(3):221-227.
16. Kessler RC, Ormel J, Demler O, Stang PE. Comorbid mental disorders account for the role impairment of commonly occurring chronic physical disorders: results from the National Comorbidity Survey. J Occup Environ Med. 2003;45(12):1257-1266.
17. de Wit LM, van Straten A, van Herten M, Penninx BW, Cuijpers P. Depression and body mass index, a u-shaped association. BMC Public Health. 2009;9:14.
18. Janssens AC, van Doorn PA, de Boer JB, et al. Anxiety and depression influence the relation between disability status and quality of life in multiple sclerosis. Mult Scler. 2003;9(4):397-403.
19. Williams LJ, Pasco JA, Jacka FN, Henry MJ, Dodd S, Berk M. Depression and bone metabolism. A review. Psychother Psychosom. 2009;78(1):16-25.
20. Barefoot JC, Helms MJ, Mark DB, et al. Depression and long-term mortality risk in patients with coronary artery disease. Am J Cardiol. 1996;78(6):613-617.
21. Kaufmann MW, Fitzgibbons JP, Sussman EJ, et al. Relation between myocardial infarction, depression, hostility, and death. Am Heart J. 1999;138(3 pt. 1):549-554.
22. Beekman AT, Penninx BW, Deeg DJ, de Beurs E, Geerling SW, van Tilburg W. The impact of depression on the well-being, disability and use of services in older adults: a longitudinal perspective. Acta Psychiatr Scand. 2002;105(1):20-27.
23. Carta MG, Hardoy MC, Kovess V, Dell’Osso L, Carpiniello B. Could health care costs for depression be decreased if the disorder were correctly diagnosed and treated? Soc Psychiatry Psychiatr Epidemiol. 2003;38(9):490-492.
24. McIntyre RS, Konarski JZ, Soczynska JK, et al. Medical comorbidity in bipolar disorder: implications for functional outcomes and health service utilization. Psychiatr Serv. 2006;57(8):1140-1144.
25. Baune BT, Adrian I, Jacobi F. Medical disorders affect health outcome and general functioning depending on comorbid major depression in the general population. J Psychosom Res. 2007;62(2):109-118.
26. Solomon DA, Leon AC, Coryell W, et al. Predicting recovery from episodes of major depression. J Affect Disord. 2008;107(1-3):285-291.
27. Sotsky SM, Glass DR, Shea MT, et al. Patient predictors of response to psychotherapy and pharmacotherapy: findings in the NIMH Treatment of Depression Collaborative Research Program. Am J Psychiatry. 1991;148(8):997-1008.
28. Stewart WF, Ricci JA, Chee E, Hahn SR, Morganstein D. Cost of lost productive work time among US workers with depression. JAMA. 2003;289(23):3135-3144.
29. Kessler RC, Barber C, Birnbaum HG, et al. Depression in the workplace: effects on short-term disability. Health Aff (Millwood). 1999;18(5):163-71.
30. Lerner D, Adler DA, Chang H, et al. The clinical and occupational correlates of work productivity loss among employed patients with depression. J Occup Environ Med. 2004;46(6 suppl):S46-S55.
31. McIntyre RS, Wilkins K, Gilmour H, et al. The effect of bipolar I disorder and major depressive disorder on workforce function. Chronic Dis Can. 2008;28(3):84-91.
32. Spitzer RL, Kroenke K, Williams JB. Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. Primary Care Evaluation of Mental Disorders. Patient Health Questionnaire. JAMA. 1999;282(18):1737-1744.
33. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56-62.
34. Rush AJ, Trivedi MH, Ibrahim HM, et al. The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol Psychiatry. 2003;54(5):573-583.
35. Trivedi MH, Rush AJ, Ibrahim HM, et al. The Inventory of Depressive Symptomatology, Clinician Rating (IDS-C) and Self-Report (IDS-SR), and the Quick Inventory of Depressive Symptomatology, Clinician Rating (QIDS-C) and Self-Report (QIDS-SR) in public sector patients with mood disorders: a psychometric evaluation. Psychol Med. 2004;34(1):73-82.
36. Sheehan DV. Sheehan Disability Scale. In: Rush AJ, Pincus HA, First MB, et al, eds. Handbook of Psychiatric Measures. 1st ed. Washington, DC: American Psychiatric Association; 2000:113-115.
37. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
38. World Health Organization. Wellbeing measures in primary health care/the depcare project. Copenhagen, Denmark: WHO Regional Office for Europe; 1998.
39. van der Heijden PG, van Buuren S, Fekkes M, Radder J, Verrips E. Unidimensionality and reliability under Mokken scaling of the Dutch language version of the SF-36. Qual Life Res. 2003;12(2):189-198.
40. Endicott J, Nee J, Harrison W, Blumenthal R. Quality of Life Enjoyment and Satisfaction Questionnaire: a new measure. Psychopharmacol Bull. 1993;29(2):321-326.
41. Trivedi MH, Rush AJ, Wisniewski SR, et al, and the STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163(1):28-40.
42. Trivedi MH, Rush AJ, Crismon ML, et al. Clinical results for patients with major depressive disorder in the Texas Medication Algorithm Project. Arch Gen Psychiatry. 2004;61(7):669-680.

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This supplement is supported by Pamlab LLC.

 

Question-and-Answer Session

Q: Studies are showing that treatment initiated when pre-dementia or early memory loss is recognized leads to a better prognosis than waiting to initiate treatment once Alzheimer’s disease (AD) or dementia is established. What options do clinicians have to address early memory loss?

 

Drs. McCaddon and Hudson: Clinical options for early memory loss comprise three broad categories: treating vascular risk factors, providing neuroprotection, and promoting neuronal reserves.1 Vascular risk factors include hypertension, hypercholesterolemia, diabetes, smoking, and hyperhomocysteinemia, all of which should be actively screened for and addressed in all patients presenting with cognitive impairment. Neuroprotection includes ensuring adequate B12 and folate status, use of antioxidants, and addressing neuroinflammation. There is also evidence that neuronal reserves can be developed by encouraging cognitive, physical, and social activity.1
 

Q: Are there symptoms or markers that can be used to diagnose pre-dementia or early memory loss?

 

Drs. McCaddon and Hudson: There is a pathway of cognitive impairment where benign aging develops into mild cognitive impairment (MCI) and eventually AD. Early recognition of this trajectory is vital if the process is to be slowed or halted. Mitrushina and colleagues2 reviewed neuropsychological tests used for the assessment of MCI and AD.2 Many of these are time-consuming to perform and impractical in the busy physician’s office. In addition, fatigue and sensory loss may impair the ability of the very elderly to complete these tests.3 Milne and colleagues4 reviewed shorter tests more suitable for use by the primary care physician, such as The General Practitioner Assessment of Cognition, the Memory Impairment Screen, and the Mini-Cognitive Assessment Instrument, and there is good agreement between these and the Mini-Mental State Examination.

Despite the wide variety of cognitive function tests available to the physician, anatomical and metabolic changes in the brain, demonstrated by magnetic resonance imaging and positron emission tomography, already occur >2 more years before a diagnosis of MCI can be made.5,6  Biomarkers in cerebrospinal fluid, such as tau protein and amyloid-b, are promising candidates as early markers but await long-term studies of their potential clinical utility.7 In summary, there are several techniques available to the physician for the detection of symptomatic MCI or AD. The detection of pre-clinical disease remains a challenge, but is a focus of much current research.
 

Q: What is your goal when treating patients with pre-dementia or early memory loss?

 

Drs. McCaddon and Hudson: The main goal is to delay or possibly even halt cognitive decline. Anything that might delay or prevent the onset of overt dementia would be beneficial from both an individual and epidemiological viewpoint. Remarkably, it is estimated that dementia prevalence would be halved if risk reduction strategies delayed the onset of dementia by only 5 years.8
 

Q: How important is safety and tolerability in a therapy used to address early memory loss?

 

Drs. McCaddon and Hudson: Safety and tolerability are extremely important in all patients, perhaps more so in those presenting with early memory loss. Cerefolin NAC is well tolerated and not associated with any significant drug interactions. It is also easy and convenient to use, being a single dose caplet with no necessary dose adjustment. In addition, in a recent cross-sectional study the relationship between folate and risk of cognitive impairment is reversed in patients with low B12; high folate and low B12 concentrations are associated with an increased  risk of cognitive impairment.9 Although this association requires further investigation, Cerefolin NAC ensures that patients receive an optimal balance of the two vitamins.
 

Q: In your opinion, where does a novel therapy like Cerefolin NAC fit in the options available for memory loss?

 

Drs. McCaddon and Hudson: Cerefolin NAC is a useful option for early memory loss because it offers a synergistic approach to neuroprotection. A recent study confirmed that many patients with dementia have brain changes consistent with both AD and vascular dementia.10 The authors suggested that it may be necessary to develop combination therapies to treat dementia. A similar synergistic approach should perhaps also be considered in patients presenting with early memory loss.

 

Reference List

1.     Purandare N, Ballard C, Burns A. Preventing dementia. Adv PsychTreatment. 2005;11:176-183.
2.     Mitrushina MN, Boone KB, Razani J. Handbook of Normative Data for Neuropsychological Assessment. Oxford University Press Inc; New York, NY; 2005.
3.     Whittle C, Corrada MM, Dick M, et al. Neuropsychological data in nondemented oldest old: the 90+ Study. J Clin Exp Neuropsychol. 2007;29:290-299.
4.     Milne A, Culverwell A, Guss R, Tuppen J, Whelton R. Screening for dementia in primary care: a review of the use, efficacy and quality of measures. Int Psychogeriatr. 2008;20:911-926.
5.     Carlson NE, Moore MM, Dame A, et al. Trajectories of brain loss in aging and the development of cognitive impairment. Neurology. 2008;70:828-833.
6.     de Leon MJ, Mosconi L, Blennow K, et al. Imaging and CSF studies in the preclinical diagnosis of Alzheimer’s disease. Ann N Y Acad Sci. 2007;1097:114-145.
7.     Schmand B, Huizenga HM, van Gool WA. Meta-analysis of CSF and MRI biomarkers for detecting preclinical Alzheimer’s disease. Psychol Med. 2010;40:135-145.
8.     Jorm AF, Korten AE, Henderson AS. The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand. 1987;76:465-479.
9.     Morris MS, Jacques PF, Rosenberg IH, Selhub J. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr. 2007;85:193-200.
10.     Matthews FE, Brayne C, Lowe J, McKeith I, Wharton SB, Ince P. Epidemiological pathology of dementia: attributable-risks at death in the medical research council cognitive function and ageing study. PLoS Med. 2009;6:e1000180.

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This supplement is supported by Pamlab LLC.

Dr. McCaddon is senior honorary research fellow at Cardiff University, Cardiff School of Medicine, in North Wales, United Kingdom. Dr. Hudson is principal biochemist in the Department of Medical Biochemistry, Wrexham Maelor Hospital, in North Wales, United Kingdom.

Disclosures: Drs. McCaddon and Hudson are scientific advisors and shareholders of COBALZ Limited, a private limited company developing novel B-vitamin and antioxidant supplements.  COBALZ has granted certain U.S. rights concerning ‘Cerefolin NAC’ to Pamlab LLC.


 

Abstract

Alzheimer’s disease (AD) and dementia have enormous financial and social impacts on society. It is predicted that almost 36 million people will have dementia in 2010, a figure which is anticipated to double every 20 years as the world population ages.  Prevention of AD or slowing of the progression of AD would provide significant benefits. There are multiple ways in which vitamin B12, vitamin B6, folate, and homocysteine (Hcy) play a role in the pathogenesis of AD. Vitamin B12, vitamin B6, and folate deficiencies are associated with various cognitive disorders, including dementia. Neuroinflammatory oxidative stress occurs early in AD pathology. Total blood Hcy levels are utilized as a marker to assist in diagnosing such deficiencies. Hcy contributes to pathological cascades involving amyloid plaques and neurofibrillary tangles (NFTs). This review provides a thorough description of several factors involved in the development of the pathological changes associated with AD, such as neuroinflammatory oxidative stress and methylation, apoptosis, NFTs, amyloid plaques, and cerebrospinal fluid biomarkers. The review also considers the rationale for a combined B-vitamin and antioxidant supplement (Cerefolin NAC) in treating and slowing AD-related cognitive decline.


In this Expert Review Supplement, Andrew McCaddon, MD, and Peter R. Hudson, PhD provide a comprehensive review of factors involved in AD pathology as well as evidence supporting the use of a combined B-vitamin and antioxidant supplement (Cerefolin NAC) for AD-related cognitive decline. A commentary on this article is provided by leading AD expert Jeffrey L. Cummings, MD.

 

Introduction

Almost 36 million people will have dementia in 2010—an alarming figure set to double every 20 years with the “greying” of the world population.1 Alzheimer’s disease (AD) and dementia have enormous financial and social impacts on society. Prevention or illness delay of even a small percentage of cases would provide significant cost benefits for health-care systems.2 This review considers the rationale for a combined B-vitamin and antioxidant supplement (Cerefolin NAC) in treating and slowing AD-related cognitive decline.

 

B-Vitamins and Dementia

Vitamin B12 and folate deficiencies are associated with various cognitive disorders, including dementia.3 In the 1980s, plasma total homocysteine (tHcy) assays were introduced to assist in diagnosing these deficiencies. Hcy is derived from dietary methionine. Cells re-methylate Hcy to methionine using B12-dependent methionine synthase; 5-methyltetrahydrofolate (5-MTHF) acts as a methyl donor (Figure 1A).  Alternatively, Hcy is converted to cystathionine, and ultimately cysteine, by B6-dependent cystathionine b-synthase. Blood Hcy levels rise in B6, B12, and folate deficiencies.Higher levels are also associated with aging, smoking, male gender, renal impairment, and drugs including methotrexate, metformin, and levodopa.4

 

Using tHcy as a marker, B vitamin deficiencies were found to be highly prevalent in the elderly.5,6 This led to speculation that elevated blood Hcy, hyperhomocysteinemia, might occur commonly in dementias, including AD.7-9 Hyperhomocysteinemia implies impaired methylation reactions (hypomethylation),10 with predictable adverse effects for neurotransmitter synthesis and AD neuropathology. Hcy is also associated with vascular disease,11 itself a risk factor for dementia.12

Evidence for the “homocysteine hypothesis of dementia” came with reports of hyperhomocysteinemia in patients with clinically and pathologically confirmed AD.13,14 Raised blood levels were also observed in mild cognitive impairment (MCI) and vascular dementia.15,16 Although elevated Hcy could be a consequence of, or coincidental with, dementia it is now recognized to be associated with an increased risk for both cognitive decline and incident dementia.17-19

One curious feature of the relationship of Hcy with dementia is the absence of macrocytic anemia.20,21 The relationship is also independent of nutritional status,13,22 suggesting that rather than arising from dietary deficiency or malabsorption, it may reflect effects of oxidative stress on Hcy metabolism.23,24

 

Oxidative Damage,“Neuroinflammation,” and AD

Oxidative damage is a prominent feature of AD.25 Lipid peroxidation and levels of protein and nucleic acid oxidation are significantly increased in vulnerable brain regions.26 Such damage is not confined to AD, but also occurs in patients with amnestic MCI.27

There is also an association between AD and inflammation.28 Epidemiological studies link the use of anti-inflammatory drugs with a reduced risk for AD and expression of inflammatory mediators is increased in postmortem AD brains.29 Such “neuroinflammation” is likely a major driving force in the disease. Rather than being the primary lesion in AD, amyloid plaques and neurofibrillary tangles may be compensatory phenomena, ie, end-stage manifestations of cellular adaptation preceded by elevated markers of oxidative stress.30

 

Oxidative Stress and Methylation

Recycling of Hcy to methionine by methionine synthase (MS) requires vitamin B12 as co-factor and 5-MTHF  as methyl donor (Figure 1A). Methionine adenosyltransferase then converts methionine to S-adenosylmethionine (SAM)—a substrate for multitudinous cellular methylation reactions.

SAM synthesis is impaired by oxidative stress; cob(I)alamin, an intermediate in the MS reaction, is vulnerable to oxidative deactivation to cob(II)alamin.31 Reductive re-methylation of cob(II)alamin requires a methyl group donated by SAM itself. Oxidatively impaired MS activity also depletes folate stores via reduced polyglutamation—an essential prerequisite for cellular folate retention.32

Oxidative stress increases the requirement for, but decreases synthesis of, SAM.23 Naturally, an auto-corrective mechanism exists. Hepatic Hcy is metabolized via the transsulphuration pathway, culminating in synthesis of glutathione—an essential antioxidant for intracellular redox homeostasis.4 Neurones and other central nervous system (CNS) cells do not fully express this pathway, nor does brain tissue possess an alternative pathway for re-methylating Hcy.33 Hence, its capacity to metabolize Hcy is extremely vulnerable to oxidative stress and dependent on an adequate supply of folate and B12.

 

Oxidative Stress and Mitochondrial Dysfunction

Mitochondria are pivotal in cell life and death, producing energy in the form of adenosine triphosphate (ATP) and sequestering calcium, but also generating free radicals and serving as repositories for proteins regulating apoptosis. Perturbations in their function sensitize cells to neurotoxic insults and may initiate cell death.34 Alterations in energy metabolism occur early in AD. Energy consumption is drastically decreased in cortical and hippocampal regions, implying compromised mitochondrial function. This is accompanied by elevated reactive oxygen species (ROS), contributing to increased neuronal loss.35  One potential mechanism is the binding of amyloid-beta (Ab) with mitochondrial membrane proteins involved in adenosine diphosphate (ADP)/ATP transfer.36

Other processes can influence mitochondrial bioenergetics. Succinyl-CoA is an essential component of the mitochondrial citric acid cycle, which generates ATP via the mitochondrial electron-transport chain. One route of synthesis is from a-ketoglutarate via the enzyme complex, b-ketoglutarate dehydrogenase. Oxidative stress can impair this complex, compromising energy metabolism and further enhancing ROS formation in AD and other neurodegenerative diseases.37 

Succinyl-CoA is also synthesised from methylmalonyl-CoA via vitamin B12-dependent methylmalonyl-CoA mutase.38  While inhibition of this enzyme by ROS is still being investigated,39 B12 deficiency causes accumulation of methylmalonic acid (MMA). Evidence from the disorder methylmalonic aciduria suggests that neurodegeneration is associated with inhibition of the respiratory chain and tricarboxylic acid cycle not by MMA alone, but by synergistically acting alternative metabolites, in particular 2-methylcitric acid, malonic acid, and propionyl-CoA.40 Of relevance, a study of healthy elderly individuals showed a high prevalence of metabolically significant vitamin B12 deficiency, with increased MMA being associated with lower cognitive function scores.41

A potentially prudent strategy for maximal protection against these adverse metabolic insults upon mitochondria, and on energy production via the tricarboxylic acid cycle and electron transport chain, is  to optimize both glutathione synthesis and  vitamin B12 status.

 

Relationship Between Hcy, Hypomethylation, and AD Pathology

AD is characterized by intraneuronal neurofibrillary tangles and extracellular amyloid plaques. Hyperhomocysteinemia and hypomethylation influence the development of these lesions.

 

Neurofibrillary Tangle Formation

Neurofibrillary tangles (NFTs) are formed by the microtubule-associated protein tau. Tau is modulated by phosphorylation; the ability of tau to bind to and stabilize microtubules correlates inversely with its phosphorylation.42 Tau is highly phosphorylated in AD and other “tauopathies.” Disordered phosphorylation disrupts the normal co-localization of tau with microtubules, leading to hyperphosphorylation, tau-tau interactions, paired helical filaments, and ultimately aggregation into NFTs.43

Tau phosphorylation is regulated by competing effects of kinases and phosphatases; attention has focused on the kinases GSK3b and CDK5 and the phosphatase PP2A. PP2A actively de-phosphorylates abnormal tau.44

PP2A comprises regulatory and catalytic subunits; methylation of the latter is critical, suggesting that hypomethylation leads to tau hyperphosphorylation (Figure 1C).45 There is a negative correlation between phosphorylated tau and markers of methylation status in cerebrospinal fluid (CSF) of patients with various neurological disorders, including AD.46 Impaired folate and methylation status is closely linked to NFT formation,47,48 but preventable by supplementation in animal models.49,50 Interestingly, a recent study has also shown that GSK3β activity is increased in mice reared on a B-vitamin–deficient diet.51 The authors also confirmed previous reports of decreased substrate specificity for PP2A in folate deficient mice.

Pin1 is another important tau regulatory enzyme. It ensures that phosphorylated-tau is in the correct conformation for de-phosphorylation by PP2A.52 However, Pin1 is downregulated and oxidized in MCI and AD hippocampus, providing further evidence linking oxidative damage and NFT formation.53

 

Amyloid Plaque Formation

Amyloid precursor protein (APP) is cleaved by α­, β­,­ and γ­ secretases (Figure 1B). Normally, APP is cleaved by α­-secretase, releasing an N-­terminal fragment, sAPPα.  sAPPα is neuroprotective, participating in synapse formation and integrity of memory.54,55 Alternative cleavage of APP by β-secretase generates a secreted APP β peptide, sAPPβ. Cleavage by γ­-secretase of the remaining C-­terminal end of APP leads to formation of Aβ peptide, comprising 39­-43 amino acids, depending on the precise cleavage site. Aβ peptides subsequently aggregate into harmful amyloid plaques (AP).56

Similar to tau, Pin1 maintains APP in a configuration that reduces its metabolism by β-secretase, shifting cellular selectivity towards non-amyloidogenic APP processing.57  Thus, oxidative downregulation of Pin1 adversely influences Aβ formation and its subsequent aggregation into AP.52,58

Hypomethylation also contributes to Aβ production. The pathway for APP processing into Aβ involves β­-secretase and γ-­secretase activity. The γ­-secretase complex comprises four individual proteins: presenilin (PS1), nicastrin, APH-1, and PEN-2.59 PS1 is the catalytic subunit, and mutations in its gene are a risk factor for AD.60

The expression of β-secretase and PS1 are downregulated by DNA methylation. In vitro, deficiency of folate and vitamin B12 in cell culture medium reduces SAM levels with a consequent increase in PS1 and β­-secretase levels and increased Aβ production. Adding SAM to deficient medium restores normal gene expression and reduces Aβ levels.61 In vivo, folate deficient mice show increased APP phosphorylation in association with the expected changes in methylation in brain tissue.48 Similarly, hyperhomocysteinemic rats have elevated PS1 and a prominent spatial memory deficit which is reversible by folate and B12 supplementation.62 Elevated Hcy also augments the neurotoxicity of Aβ, at least in vitro, by potentiating oxidative stress.63

 

CSF Biomarkers in AD and MCI

There is evidence for the inter-relationships between Hcy, Aβ, tau, and oxidative stress in CSF. CSF levels of Aβ and tau are associated with progression from MCI to AD.64-67 The association between CSF phospho-tau and Hcy in AD suggests that hypomethylation links hyperhomocysteinemia and neurodegeneration.68,46 Oxidative stress markers, namely lipid peroxidation products (isoprostanes), accompany increases in Aβ, tau, and Hcy. CSF Aβ and isoprostane levels are probably the earliest markers for neuronal damage in AD.69 Brain tissue studies show that other lipid peroxidation products (4-hydroxynonenal and acrolein) are increased in selected regions of patients with MCI, suggesting that lipid peroxidation occurs early in AD pathogenesis.70

 

Neurochemistry

AD is characterized by deficits in the cholinergic neurotransmitter system, although there are also deficiencies in other neurotransmitter systems.71 Glutamate is an excitatory amino acid involved in cortico-cortical association pathways. The N-methyl-d-aspartate (NMDA) receptor is a marker for glutamate activity. NMDA receptors are present in high density in the cortex and hippocampus and play an important role in learning and memory.72 Elevated levels of oxidised Hcy derivatives and limited SAM availability due to vitamin B12 and folate deficiencies might adversely affect both glutamatergic and cholinergic systems.7

 

Glutamatergic

The NMDA receptor complex is a large protein assembly with different binding sites for different ligands, including an NMDA site, a strychnine insensitive glycine-binding site, and a binding site for non-competitive antagonists. Homocysteic acid and homocysteine sulphinic acid are oxidized derivatives of Hcy, and exert toxic effects on NMDA receptors (Figure 1D). These metabolites are 250-fold more efficient in disrupting neuronal networks than Hcy itself, and cause excess calcium influx, free-radical generation, collapse of the mitochondrial membrane potential and, eventually, neuronal death.73,74

 

Cholinergic

Neuronal choline is derived from intrasynaptic choline (via degradation of acetylcholine by acetylcholinesterase), extracellular choline (via a low affinity transport mechanism), and intraneuronal choline (via sequential methylation of membrane phosphatidylethanolamine [PE]).75 Intraneuronal choline will be depleted if SAM availability is limited7 (Figure 1E). Impaired MS activity  also induces the hepatic B12-independent betaine homocysteine methyltransferase pathway, betaine supplying a methyl group instead of methyl-folate.76 Since betaine is derived from choline oxidation, this will reduce extraneuronal choline supplies.7

Impaired PE methylation also influences transmembrane signal transmission. PE largely faces the cytoplasm, whereas phosphatidylcholine faces the extracellular space. The methylating enzymes (PEMT 1 and 2) are also asymmetrically distributed. Phospholipid methylation commences on the cytoplasmic side of the membrane and methylated phospholipids are translocated to the exterior. This increases membrane fluidity, and is coupled to calcium influx and release of intracellular secondary messengers.77

 

PARP Activation, DNA Repair, and Apoptosis

Gene expression is partly attenuated by methylated DNA stretches—CpG islands. Hypomethylation induces gene transcription and DNA strand breakage.78,79 In cultured neurones, Hcy itself induces breakages,80 probably via free-radical induced damage. In vivo, decreased thymidylate synthesis with subsequent uracil misincorporation into DNA probably also contributes.81 Uracil is excised from DNA, generating transient breaks requiring repair. Poly (ADP-ribose) polymerase (PARP) recognizes damaged DNA and prepares it for repair. However, with excessive damage, PARP triggers a cascade of events leading to cell death.82 PARP-controlled cell death is the major pathway for neuronal apoptosis. Hence, hypomethylation is closely linked with neuronal apoptosis (Figure 1F).

 

Cerebral Ischemia, Atrophy, and Blood Brain Barrier Abnormalities

Elevated Hcy is a risk factor for atherothrombotic disease, and folate supplementation is effective in secondary stroke prevention.83 AD commonly co-occurs with stroke, suggesting that hyperhomocysteinaemia and AD might also be partly linked via micro-vascular disease.84 Elevated Hcy is also associated with brain atrophy85,86 and blood-brain barrier (BBB) dysfunction,87 which is reversible by high-dose B-vitamin supplementation.88

 

Method of Action of Cerefolin NAC

Treatments for AD include cholinesterase inhibitors and the NMDA receptor antagonist memantine,89 although these are only indicated for patients with established disease.  Cerefolin NAC provides a unique option in early AD and MCI by addressing inter-related mechanisms associated with oxidative stress and B-vitamin deficiency (Figure 1). Open-label trials adopting a similar synergistic approach show considerable promise in early90 and late-stage AD.91

Unlike other folate supplements which contain synthetic folic acid, Cerefolin NAC contains the naturally occurring 5-MTHF (5.6 mg). This has an important advantage over folic acid. Folic acid can inhibit transport of 5-MTHF across the BBB.92 Hence, an accumulation of unmetabolized folic acid resulting from the use of alternative supplements might actually be detrimental in treating CNS disorders.

Cerefolin NAC also comprises N-acetylcysteine (NAC) (600 mg)—a membrane-permeable cysteine precursor rapidly hydrolyzed intracellularly to cysteine, a precursor of glutathione (GSH). Cysteine availability is the rate-limiting step in GSH synthesis. GSH is a major component of pathways protecting cells from oxidative stress and apoptosis. Other commonly used antioxidants, including vitamin C, vitamin K, and lipoic acid, neutralize free radicals but cannot replenish cysteine required for GSH synthesis.93 NAC itself is also an antioxidant and free-radical scavenger, and can additionally lower Hcy levels by increasing urinary excretion.94 In a double-blind trial of patients with probable AD, NAC improved nearly every outcome measure, although significant differences were obtained only for a subset of cognitive tasks.95

The third component of Cerefolin NAC is methylcobalamin (2 mg)—the co-factor for MS in the conversion of Hcy to methionine. High-dose oral vitamin B12 (1–2 mg/day) is as effective as intramuscular administration.96 GSH is required for  intracellular cobalamin processing.23,97 Hence, Cerefolin NAC might have advantages over other methylcobalamin formulations. Cobalamin itself might also act as a ROS scavenger,98 suppressing apoptosis and preventing cellular damage.99,100

 

Clinical Trials

Although Hcy-reducing clinical trials regarding dementia are disappointing, there are several important caveats.101  Most trials to date are of insufficient size and short duration.2 Also, lowering Hcy addresses only one of several pro-inflammatory mechanisms promoting oxidant stress and neurotoxicity.  Completed trials have only included patients with mildly elevated Hcy levels; the role of Hcy reduction in patients with more robustly elevated levels for both primary prevention and therapeutic treatment of dementia remains unknown.

Nevertheless, a recent expert review concluded that folate, B12, and Hcy levels should be determined in all dementia patients, and abnormal levels should be treated.83  Substitution of these vitamins may also improve cognitive function in the absence of overt deficiency.83 Given the close inter-dependent relationship between Hcy and oxidative stress, it is prudent to simultaneously administer antioxidants such as NAC when correcting such deficiencies. Several case studies, and two open-label studies, confirm the benefits of this synergistic approach.102,103,90,91

 

Summary

Neuroinflammatory oxidative stress occurs early in AD pathology. Elevated blood Hcy is a useful marker for such neuroinflammation. Hcy contributes to pathological cascades involving AP and NFTs. In AD, Hcy should be lowered by B-vitamin supplements and NAC.

 

References

1.   Alzheimer’s Disease International. World Alzheimer Report. 1-96. 21-9-2009. Available at: http://www.alz.co.uk/research/worldreport/. Accessed January 2010.
2.   Smith AD. The worldwide challenge of the dementias: a role for B vitamins and homocysteine? Food Nutr Bull. 2008;29:S143-S172.
3.   Moretti R, Torre P, Antonello RM, Cattaruzza T, Cazzato G, Bava A. Vitamin B12 and folate depletion in cognition: a review. Neurol India. 2004;52:310-318.
4.   Homocysteine in Health and Disease. Carmel R, Jacobsen DW, eds. Cambridge University Press. 2001.
5.   Pennypacker LC, Allen RH, Kelly JP, et al. High prevalence of cobalamin deficiency in elderly outpatients. J Am Geriatr Soc. 1992;40:1197-1204.
6.   Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA. 1993;270:2693-2698.
7.   McCaddon A, Kelly CL. Alzheimer’s disease: a ‘cobalaminergic’ hypothesis. Med Hypotheses  1992;37:161-165.
8.   Regland B, Gottfries CG. Slowed synthesis of DNA and methionine is a pathogenetic mechanism common to dementia in Down’s syndrome, AIDS and Alzheimer’s disease? Med Hypotheses. 1992;38:11-19.
9.   Rosenberg IH, Miller J. Nutritional factors in physical and cognitive functions of elderly people. Am J Clin Nutr. 1992;55:1237s-1243s.
10. Miller AL. The methionine-homocysteine cycle and its effects on cognitive diseases. Altern Med Rev. 2003;8:7-19.
11. Zhou J, Austin RC. Contributions of hyperhomocysteinemia to atherosclerosis: causal relationship and potential mechanisms. Biofactors. 2009;35:120-129.
12. Qiu C, Kivipelto M, von Strauss E. Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention. Dialogues Clin Neurosci. 2009;11:111-128.
13. McCaddon A, Davies G, Hudson P, Tandy S, Cattell H. Total serum homocysteine in senile dementia of Alzheimer type. Int J Geriatr Psychiatry. 1998;13:235-239.
14. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol. 1998;55:1449-1455.
15. Lehmann M, Gottfries CG, Regland B. Identification of cognitive impairment in the elderly: homocysteine is an early marker. Dement Geriatr Cogn Disord. 1999;10:12-20.
16. Malaguarnera M, Ferri R, Bella R, Alagona G, Carnemolla A, Pennisi G. Homocysteine, vitamin B12 and folate in vascular dementia and in Alzheimer disease. Clin Chem Lab Med. 2004;42:1032-1035.
17. McCaddon A, Hudson P, Davies G, Hughes A, Williams JH, Wilkinson C. Homocysteine and cognitive decline in healthy elderly. Dement Geriatr Cogn Disord. 2001;12:309-313.
18. Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med. 2002;346:476-483.
19. Ravaglia G, Forti P, Maioli F, et al. Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr. 2005;82:636-643.
20. Karnaze DS, Carmel R. Low serum cobalamin levels in primary degenerative dementia. Do some patients harbor atypical cobalamin deficiency states? Arch Intern Med. 1987;147:429-431.
21. McCaddon A, Tandy S, Hudson P, et al. Absence of macrocytic anaemia in Alzheimer’s disease. Clin Lab Haematol. 2004;26:259-263.
22. McIlroy SP, Dynan KB, Lawson JT, Patterson CC, Passmore AP. Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland. Stroke. 2002;33:2351-2356.
23. McCaddon A, Regland B, Hudson P, Davies G. Functional vitamin B(12) deficiency and Alzheimer disease. Neurology. 2002;58:1395-1399.
24. Fuchs D, Jaeger M, Widner B, Wirleitner B, Artner-Dworzak E, Leblhuber F. Is hyperhomocysteinemia due to the oxidative depletion of folate rather than to insufficient dietary intake? Clin Chem Lab Med. 2001;39:691-694.
25. Sultana R, Butterfield DA. Role of oxidative stress in the progression of Alzheimer’s disease. J Alzheimers Dis. Epub 2009 Sep 11.
26. Lovell MA, Markesbery WR. Oxidative damage in mild cognitive impairment and early Alzheimer’s disease. J Neurosci Res. 2007;85:3036-3040.
27. Markesbery WR, Kryscio RJ, Lovell MA, Morrow JD. Lipid peroxidation is an early event in the brain in amnestic mild cognitive impairment. Ann Neurol. 2005;58:730-735.
28. McNaull BB, Todd S, McGuinness B, Passmore AP. Inflammation and anti-inflammatory strategies for Alzheimer’s disease – a mini-review. Gerontology. Epub 2009 Sep 10.
29. Wyss-Coray T. Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med. 2006;12:1005-1015.
30. Moreira PI, Zhu X, Liu Q, et al. Compensatory responses induced by oxidative stress in Alzheimer disease. Biol Res. 2006;39:7-13.
31. Banerjee RV, Matthews RG. Cobalamin-dependent methionine synthase. FASEB J. 1990;4:1450-1459.
32. Scott JM, Weir DG. The methyl folate trap. A physiological response in man to prevent methyl group deficiency in kwashiorkor (methionine deficiency) and an explanation for folic-acid induced exacerbation of subacute combined degeneration in pernicious anaemia. Lancet.1981;2:337-340.
33. Molloy A, Weir G. Homocysteine and the nervous system. In: Carmel R, Jacobsen DW, eds. Homocysteine in Health and Disease.Cambridge University Press: Cambridge; 2001:183-197.
34. Onyango IG, Khan SM. Oxidative stress, mitochondrial dysfunction, and stress signaling in Alzheimer’s disease. Curr Alzheimer Res. 2006;3:339-349.
35. Pavlov PF, Petersen CH, Glaser E, Ankarcrona M. Mitochondrial accumulation of APP and Abeta: Significance for Alzheimer disease pathogenesis. J Cell Mol Med. Epub 2009 Sep 1.
36. Singh P, Suman S, Chandna S, Das TK. Possible role of amyloid-beta, adenine nucleotide translocase and cyclophilin-D interaction in mitochondrial dysfunction of Alzheimer’s disease. Bioinformation. 2009;3:440-445.
37. Gibson GE, Starkov A, Blass JP, Ratan RR, Beal MF. Cause and consequence: mitochondrial dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavioral abnormalities in age-associated neurodegenerative diseases. Biochem biophys Acta. 2010;1802:122-134.
38. Green R, Miller JW. Vitamin B12. In: Zempleni J, Rucker RB, eds. Handbook of Vitamins.Taylor and Francis: Boca Raton, Florida; 2007:413-457.
39. Hubbard PA, Padovani D, Labunska T, Mahlstedt SA, Banerjee R, Drennan CL. Crystal structure and mutagenesis of the metallochaperone MeaB: insight into the causes of methylmalonic aciduria. J Biol Chem. 2007;282:31308-31316.
40. Kolker S, Schwab M, Horster F, et al. Methylmalonic acid, a biochemical hallmark of methylmalonic acidurias but no inhibitor of mitochondrial respiratory chain. J Biol Chem. 2003;278:47388-47393.
41. McCracken C, Hudson P, Ellis R, McCaddon A. Methylmalonic acid and cognitive function in the Medical Research Council Cognitive Function and Aging Study. Am J Clin Nutr. 2006;84:1406-1411.
42. Feijoo C, Campbell DG, Jakes R, Goedert M, Cuenda A. Evidence that phosphorylation of the microtubule-associated protein Tau by SAPK4/p38delta at Thr50 promotes microtubule assembly. J Cell Sci. 2005;118:397-408.
43. Stoothoff WH, Johnson GV. Tau phosphorylation: physiological and pathological consequences. Biochim Biophys Acta. 2005;1739:280-297.
44. Wang JZ, Grundke-Iqbal I, Iqbal K. Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci. 2007;25:59-68.
45. Vafai SB, Stock JB. Protein phosphatase 2A methylation: a link between elevated plasma homocysteine and Alzheimer’s Disease. FEBS Lett. 2002;518:1-4.
46. Obeid R, Kasoha M, Knapp JP, et al. Folate and methylation status in relation to phosphorylated tau protein(181P) and {beta}-amyloid(1-42) in cerebrospinal fluid. Clin Chem. 2007;53:1129-1136.
47. Sontag E, Nunbhakdi-Craig V, Sontag JM, et al. Protein phosphatase 2A methyltransferase links homocysteine metabolism with tau and amyloid precursor protein regulation. J Neurosci. 2007;27:2751-2759.
48. Sontag JM, Nunbhakdi-Craig V, Montgomery L, Arning E, Bottiglieri T, Sontag E. Folate deficiency induces in vitro and mouse brain region-specific downregulation of leucine carboxyl methyltransferase-1 and protein phosphatase 2A B(alpha) subunit expression that correlate with enhanced tau phosphorylation. J Neurosci. 2008;28:11477-11487.
49. Zhang CE, Tian Q, Wei W, et al. Homocysteine induces tau phosphorylation by inactivating protein phosphatase 2A in rat hippocampus. Neurobiol Aging. 2008;29:1654-1665.
50. Chan A, Rogers E, Shea TB. Dietary deficiency in folate and vitamin E under conditions of oxidative stress increases phospho-tau Levels: potentiation by ApoE4 and alleviation by s-adenosylmethionine. J Alzheimers Dis. 2009;110:831-836.
51. Nicolia V, Fuso A, Cavallaro RA, Di Luzio A, Scarpa S. B vitamin deficiency promotes tau phosphorylation through regulation of GSK3beta and PP2A. J Alzheimers Dis. Epub 2009 Nov 17.
52. Balastik M, Lim J, Pastorino L, Lu KP. Pin1 in Alzheimer’s disease: multiple substrates, one regulatory mechanism? Biochem Biophys Acta. 2007;1772:422-429.
53. Sultana R, Boyd-Kimball D, Poon HF, et al. Oxidative modification and down-regulation of Pin1 in Alzheimer’s disease hippocampus: a redox proteomics analysis. Neurobiol Aging. 2006;27:918-925.
54. Meziane H, Dodart JC, Mathis C, et al. Memory-enhancing effects of secreted forms of the beta-amyloid precursor protein in normal and amnestic mice. Proc Natl Acad Sci U.S.A. 1998;95:12683-12688.
55. Mattson MP, Cheng B, Culwell AR, Esch FS, Lieberburg I, Rydel RE. Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein. Neuron. 1993;10:243-254.
56. Finder VH, Glockshuber R. Amyloid-beta aggregation. Neurodegener Dis. 2007;4:13-27.
57. Butterfield DA, Poon HF, St Clair D, et al. Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: insights into the development of Alzheimer’s disease. Neurobiol Dis. 2006;22:223-232.
58. Butterfield DA, Abdul HM, Opii W, et al. Pin1 in Alzheimer’s disease. J Neurochem. 2006;98:1697-1706.
59. Chen F, Hasegawa H, Schmitt-Ulms G, et al. TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity. Nature. 2006;440:1208-1212.
60. Willnow TE, Andersen OM. Pin-pointing APP processing. Mol Interv. 2006;6:137-139.
61. Fuso A, Seminara L, Cavallaro RA, D’Anselmi F, Scarpa S. S-adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production. Mol Cell Neurosci. 2005;28:195-204.
62. Zhang CE, Wei W, Liu YH, et al. Hyperhomocysteinemia increases beta-amyloid by enhancing expression of gamma-secretase and phosphorylation of amyloid precursor protein in rat brain. Am J Pathol. 2009;174:1481-1491.
63. Ho PI, Collins SC, Dhitavat S, et al. Homocysteine potentiates beta-amyloid neurotoxicity: role of oxidative stress. J Neurochem. 2001;78:249-253.
64. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol. 2006;5:228-234.
65. Blennow K, Zetterberg H. Cerebrospinal fluid biomarkers for Alzheimer’s disease. J Alzheimers Dis. 2009;18:413-417.
66. Lanari A, Parnetti L. Cerebrospinal fluid biomarkers and prediction of conversion in patients with mild cognitive impairment: 4-year follow-up in a routine clinical setting. ScientificWorldJournal. 2009;9:961-966.
67. Mattsson N, Zetterberg H, Hansson O, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA. 2009;302:385-393.
68. Popp J, Lewczuk P, Linnebank M, et al. Homocysteine metabolism and cerebrospinal fluid markers for Alzheimer’s disease. J Alzheimers Dis. Epub 2009 Aug 3.
69. Glodzik-Sobanska L, Pirraglia E, Brys M, et al. The effects of normal aging and ApoE genotype on the levels of CSF biomarkers for Alzheimer’s disease. Neurobiol Aging. 2009;30:672-681.
70. Williams TI, Lynn BC, Markesbery WR, Lovell MA. Increased levels of 4-hydroxynonenal and acrolein, neurotoxic markers of lipid peroxidation, in the brain in mild cognitive impairment and early Alzheimer’s disease. Neurobiol Aging. 2006;27:1094-1099.
71. Doraiswamy PM. Non-cholinergic strategies for treating and preventing Alzheimer’s disease. CNS Drugs. 2002;16:811-824.
72. Magnusson KR. The aging of the NMDA receptor complex. Front Biosci. 1998;3:e70-e80.
73. Do KQ, Herrling PL, Streit P, Cuenod M. Release of neuroactive substances: homocysteic acid as an endogenous agonist of the NMDA receptor. J Neural Transm. 1988;72:185-190.
74. Lipton SA, Kim WK, Choi YB, et al. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A. 1997;94:5923-5928.
75. Blusztajn JK, Wurtman RJ. Choline and cholinergic neurons. Science. 1983;221:614-620.
76. Chanarin I, Deacon R, Lumb M, Muir M, Perry J. Cobalamin-folate interrelations: a critical review. Blood. 1985;66:479-489.
77. Hirata F, Axelrod J. Phospholipid methylation and biological signal transmission. Science. 1980;209:1082-1090.
78. Pogribny IP, Basnakian AG, Miller BJ, Lopatina NG, Poirier LA, James SJ. Breaks in genomic DNA and within the p53 gene are associated with hypomethylation in livers of folate/methyl-deficient rats. Cancer Res. 1995;55:1894-1901.
79. Fenech M. The role of folic acid and vitamin B12 in genomic stability of human cells. Mutat Res. 2001;475:57-67.
80. Kruman II, Culmsee C, Chan SL, et al. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci. 2000;20:6920-6926.
81. Blount BC, Mack MM, Wehr CM, et al. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci USA. 1997;94:3290-3295.
82. Meli E, Pangallo M, Baronti R, et al. Poly(ADP-ribose) polymerase as a key player in excitotoxicity and post-ischemic brain damage. Toxicol Lett. 2003;139:153-162.
83. Stanger O, Fowler B, Piertzik K, et al. Homocysteine, folate and vitamin B12 in neuropsychiatric diseases: review and treatment recommendations. Expert Rev Neurother. 2009;9:1393-1412.
84. Morris MS. Homocysteine and Alzheimer’s disease. Lancet Neurol. 2003;2:425-428.
85. Sachdev PS. Homocysteine and brain atrophy. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:1152-1161.
86. Den Heijer T, Vermeer SE, Clarke R, et al. Homocysteine and brain atrophy on MRI of non-demented elderly. Brain. 2003;126:170-175.
87. Kamath AF, Chauhan AK, Kisucka J, et al. Elevated levels of homocysteine compromise blood-brain barrier integrity in mice. Blood. 2006;107:591-593.
88. Lehmann M, Regland B, Blennow K, Gottfries CG. Vitamin b(12)-b(6)-folate treatment improves blood-brain barrier function in patients with hyperhomocysteinaemia and mild cognitive impairment. Dement Geriatr Cogn Disord. 2003;16:145-150.
89. Smith DA. Treatment of Alzheimer’s disease in the long-term-care setting. Am J Health Syst Pharm. 2009;66:899-907.
90. Chan A, Paskavitz J, Remington R, Rasmussen S, Shea TB. Efficacy of a vitamin/nutriceutical formulation for early-stage Alzheimer’s disease: a 1-year, open-label pilot study with an 16-month caregiver extension. Am J Alzheimers Dis Other Demen. 2008;23:571-585.
91. Remington R, Chan A, Paskavitz J, Shea TB. Efficacy of a vitamin/nutriceutical formulation for moderate-stage to later-stage Alzheimer’s disease: a placebo-controlled pilot study. Am J Alzheimers Dis Other Demen. 2009;24:27-33.
92. Wollack JB, Makori B, Ahlawat S, et al. Characterization of folate uptake by choroid plexus epithelial cells in a rat primary culture model. J Neurochem. 2008;104:1494-1503.
93. Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA. N-Acetylcysteine-a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol. 2007;7:355-359.
94. Ventura P, Panini R, Abbati G, Marchetti G, Salvioli G. Urinary and plasma homocysteine and cysteine levels during prolonged oral N-acetylcysteine therapy. Pharmacology. 2003;68:105-114.
95. Adair JC, Knoefel JE, Morgan N. Controlled trial of N-acetylcysteine for patients with probable Alzheimer’s disease. Neurology. 2001;57:1515-1517.
96. Butler CC, Vidal-Alaball J, Cannings-John R, et al. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: a systematic review of randomized controlled trials. Fam Pract. 2006;23:279-285.
97. Kim J, Hannibal L, Gherasim C, Jacobsen DW, Banerjee R. A human B12 trafficking protein uses glutathione transferase activity for processing alkylcobalamins. J Biol Chem. 2009;284:33418-33424.
98. Suarez-Moreira E, Yun J, Birch CS, Williams JH, McCaddon A, Brasch NE. Vitamin B(12) and redox homeostasis: cob(II)alamin reacts with superoxide at rates approaching superoxide dismutase (SOD). J Am Chem Soc. 2009;131:15078-15079.
99. Birch CS, Brasch NE, McCaddon A, Williams JH. A novel role for vitamin B(12): Cobalamins are intracellular antioxidants in vitro. Free Radic Biol Med. 2009;47:184-188.
100. Richard E, Jorge-Finnigan A, Garcia-Villoria J, et al. Genetic and cellular studies of oxidative stress in methylmalonic aciduria (MMA) cobalamin deficiency type C (cblC) with homocystinuria (MMACHC). Hum Mutat. 2009;30:1558-1566.
101. Maron BA, Loscalzo J. The treatment of hyperhomocysteinemia. Annu Rev Med. 2009;60:39-54.
102. McCaddon A. Homocysteine and cognitive impairment; a case series in a general practice setting. Nutr J. 2006;5:6.
103. McCaddon A, Davies G. Co-administration of N-acetylcysteine, vitamin B12 and folate in cognitively impaired hyperhomocysteinaemic patients. Int J Geriatr Psychiatry. 2005;20:998-1000.

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Clinical Supplement

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Pediatric ADHD: Clinical Criteria for Diagnosis and Management

Timothy E. Wilens, MD; Floyd R. Sallee, MD, PhD, Dennis J. Rosen, MD James M. Swanson, PhD, James McGough, MD Michael J. Manos, PhD

Moderator: Peter L. Salgo, MD
Section editor: David L. Ginsberg, MD

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 Primary Psychiatry. 2004;11(2):1-10

 

CME accredited monograph of an adapted analysis of a Medical Crossfire© educational initiative

Funding for this supplement has been provided through an unrestricted educational grant by Shire US


Faculty Affiliations and Disclosures

Dr. Wilens is associate professor of psychiatry in the Department of Psychiatry at Massachusetts General Hospital and at Harvard Medical School, both in Boston.

Disclosure: Dr. Wilens is a consultant to, serves on the speakers’ bureaus of, and/or receives grant/research support from Abbott, Celltech, Eli Lilly, GlaxoSmithKline, McNeil, NIDA, NIMH, Novartis, Pfizer, and Shire.

Dr. Rosen is a developmental pediatrician at the Wing Memorial Hospital at the University of Massachusetts Memorial Health Care in Worcester.  
         
Disclosure: Dr. Rosen is a consultant to McNeil and Shire; serves on the speaker’s bureaus of Celltech, Eli Lilly, McNeil, Novartis, and Shire; and receives honorarium/expenses from Celltech, Eli Lilly, McNeil, Novartis, and Shire.

Dr. McGough is associate professor of clinical psychiatry in the Division of Child and Adolescent Psychiatry at the David Geffen School of Medicine, University of California, in Los Angeles.

Disclosure: Dr. McGough is a consultant to Cephalon, Eli Lilly, McNeil, Novartis, and Shire; serves on the speaker’s bureaus of Eli Lilly, McNeil, Novartis, and Shire; and has received grant/research support from Boston Life Sciences, Cephalon, Eli Lilly, Janssen, McNeil, NIMH, Novartis, Pfizer, Shire, and Targacept.

Dr. Sallee is professor of psychiatry and pediatrics and vice chair of the Department of Psychiatry at the University of Cincinnati College of Medicine. He is also director of the Pediatric Pharmacology Research Unit, Division of Child Psychiatry, and Division of Pharmacology Research at Cincinnati Children’s Hospital Medical Center in Ohio.

Disclosure: Dr. Sallee is a consultant to Bristol-Myers Squibb and Otsuka; serves on the speaker’s bureaus of Eli Lilly and Pfizer; and has received grant/research support from Bristol-Myers Squibb, Eli Lilly, Pfizer, and Shire.

Dr. Swanson is director of the Child Development Center and professor of pediatrics and cognitive science at the University of California, Irvine. He is also senior fellow at the Sackler Institute, Weill Medical College of Cornell University, in New York City.

Disclosure: Dr. Swanson has been a consultant to, served on the speaker’s bureaus for, and received grant/research support from Celltech, Cephalon, Eli Lilly, Gliatech, Janssen, McNeil, Novartis, and Shire.
Dr. Manos is director of the ADHD Center for Evaluation and Treatment (ACET) Division of Pediatrics at the Cleveland Clinic Foundation and is also on medical staff at the Children’s Hospital in Cleveland, Ohio.

 

Disclosure: Dr. Manos is a consultant to Shire; serves on the speaker’s bureaus of Eli Lilly, McNeil, and Shire; and has received grant/research support from Noven and Shire.

Focus Points

Review the clinical impact and diagnostic criteria of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents, as well as current diagnostic challenges.

Discuss the comorbid psychiatric conditions often encountered with ADHD and their effect on management.

Describe the role and effectiveness of behavioral interventions in the management of ADHD.

Discuss the role of nonpsychostimulant agents and compare the currently available psychostimulant medications for ADHD.

Abstract

The diagnosis and management of pediatric attention-deficit/hyperactivity disorder (ADHD) are surrounded by puzzling debates and controversies. Although ADHD remains the most commonly diagnosed behavioral disorder in childhood, questions persist in some circles concerning the medical validity of this syndrome. Prevalence estimates of ADHD vary, shaded by methods of ascertainment, diagnostic criteria, informants, and population sample. Symptoms may be developmental in course and change their presentation with age, often presenting diagnostic dilemmas. In addition, psychiatric comorbidities often complicate the clinical picture. Although behavioral approaches are considered an important component of a treatment plan, the effectiveness of specific psychosocial therapies continue to be debated. The role of nonstimulants needs to be further defined, and differing perspectives remain regarding the appropriate selection and use of stimulants, which are considered first-line therapy for ADHD.

 

Timothy E. Wilens, MD

Prevalence and Recognition

According to the Centers for Disease Control and Prevention ~8% of American children have attention-deficit/hyperactivity disorder (ADHD), ~50% of ADHD children remain undiagnosed, and 50% of diagnosed children are untreated.1 Thus, despite claims of overdiagnosis, ADHD remains underdiagnosed. ADHD, which has been dismissed as an “American illness” for many years, is seen in virtually every culture studied. There are extraordinarily strong data to support its occurrence worldwide. Despite the claims of those who say ADHD is simply a manifestation of overzealous physicians or representative of poor parenting, as physicians the onus on us is preventive—to identify the illness early, treat it, and reduce the sequality of the disorder over time.

Several studies of school-age children showed the presence of ADHD symptomatology during the preschool years. In general, one can extend the diagnostic criteria for school-age children to preschoolers. Among those with ADHD, hyperactivity and impulsivity tend to diminish somewhat over time, whereas attention symptoms persist. While there are claims that ADHD diagnoses are not accurate because they are often made by report, psychiatrists have always had confidence in this form of diagnosis. For example, both panic disorder and depression are diagnosed by report. Moreover, parents tend to be good reporters of their child’s psychopathology.

Overlapping symptoms may confuse the differentiation of ADHD from another condition. What is more concerning, however, is the omission of the comorbidity diagnoses. Data show that, in the majority of patients with ADHD, two or three disorders occur simultaneously. Comorbidity has an effect on treatment; for example, certain classes of medicine may result in an exacerbation of mood symptoms in the patient with prominent mood symptoms associated with ADHD. In this case, one would first treat the mood disorder and then focus on treating the ADHD. Reverse comorbidity is very important as well. There are high rates of ADHD among patients who present with a diagnosis of another psychiatric disorder. For example, 20% of adults with depression have ADHD. It is important to clarify what conditions are present initially and then devise a hierarchical treatment rank.  

Pharmacotherapy for ADHD

Nonstimulants

The nonstimulant medications work largely through the catecholaminergic system, including noradrenergic or dopaminergic effects. In 2002 the Food and Drug Administration approved atomoxetine (Strattera), the first nonstimulant for use in ADHD across the life-span. Michelson and colleagues2-4 conducted several studies indicating that atomoxetine was better than placebo in reducing ADHD symptoms and improving social and family functioning. In clinical trials, atomoxetine was not associated with serious adverse events and there were few discontinuations for adverse events.5 Head-to-head studies are ongoing, and atomoxetine may be particularly useful in situations where stimulants may exacerbate symptoms such as comorbid tics, or where there is a significant amount of anxiety or depressive symptomatology. Atomoxetine may also be useful in cases where stimulants fail.

Other nonstimulant medications include tricyclic antidepressants, which have been used since the 1970s, and bupropion. Data show that atypical antipsychotics are not useful for core ADHD symptoms, and subjecting children to this very significant class of agents is typically not necessary for the treatment of this condition. 

Stimulants 

There has been a concern at a preclinical level that stimulants can cause substance abuse. However, children who are not treated for ADHD have twice the risk for substance abuse across the life-span. We conducted a meta-analysis6 of all long-term published studies in which treated and untreated youths with ADHD were followed for substance-use disorders. More than 1,000 children were followed for a mean of 12 years. We found that stimulant use did not increase the risk for substance abuse, rather it reduced the risk for substance abuse by 50%. While stimulant therapy does not immunize against the potential for substance abuse, it may reduce the risk to that of the population without ADHD.

Herbal Remedies

Some parents request that the physician suggest something “natural” for their ADHD child rather than a pharmaceutical agent. However, just because something is natural does not mean it is safe: cyanide, arsenic, and strychnine are all natural compounds. In addition, pharmaceuticals undergo rigorous testing for both efficacy and safety. Naturally occurring compounds often are not tested for safety, are not even tested for true efficacy, and may result in drug interactions that affect the metabolic pathways. Concerned parents should be informed that stimulants and bupropion, medications used for ADHD, have chemical structures similar to the naturally occurring neurotransmitters dopamine and norepinephrine. Moreover, the agents we use to treat ADHD work with the natural machinery of the brain presynaptically, affecting dopamine and norepinephrine and improving the function of affected neurons. They appear to normalize the chemistry to produce an outcome.

It is very important for practitioners to confront this issue with parents and realize that there is a liability when recommending natural treatments. Some herbal agents demonstrate potent inhibition of the P448 system as well as monoaminoxidase inhibition, which we know has widespread application in terms of drug-drug interactions. There may also be absorption problems, chelation problems, and real medical issues.
 

Dennis J. Rosen, MD

Diagnosis and Management

There are many children who should be evaluated for ADHD but are not. Often, parents of these children are not knowledgeable about assessment procedures, do not have an appreciation or understanding of ADHD and its treatment, or are in denial about the presence of the disorder in their children. The rate of diagnosis can be improved through community education initiatives such as educating healthcare providers, teachers, social workers, and mental health professionals. These professionals can then refer appropriate children for an initial diagnostic evaluation with the child’s primary care provider (Slides 1a, 1b).7

Most children display significant core symptoms of inattention and/or impulsivity and hyperactivity. Reports from parents and teachers provided in the form of rating scales available at the American Academy of Pediatrics (AAP) Web site (www.aap.org) form the basis with a complete history and physical exam for evidence-based diagnosis. The recently published ADHD: A Complete and Authoritative Guide8 (including a smaller pamphlet called Understanding ADHD) is now available and includes guidelines for treatment with both behavioral management strategies and medication (Slide 2). Direct contact with teachers can be helpful if possible and direct input from students by interview and rating scale is often helpful.

Ultimately, successful management of ADHD is defined as improvement in core symptoms toward normalization. Keypoints in the guidelines include recognizing ADHD as a chronic condition; collaboration between school personnel, family, and clinician for target outcomes; stimulant medication and/or behavioral therapy; and reassessment evaluating for coexisting conditions in the presence of failure to meet target outcomes on systemic follow-up.

The Role of the Primary Care Physician

Primary care physicians (PCPs) are in the best position to identify ADHD and to develop appropriate tools and strategies for identifying comorbid symptomatology.9 The AAP does not support blood work or x-rays in this regard and neuroimaging and genomic/genetic testing will not be available for many years given limited sensitivity and specificity. Rating scales, interview techniques, and thoroughness of a database from both school and home form the most effective means to clarify diagnosis and monitor treatment effects. Pediatricians’ unique understanding of the family history is critical in defining the possible presence of inherited affective disruptive or comorbid learning disability symptoms.

Alternative Therapy

Stimulant medication and occasionally use of careful nonstimulant medication remain the treatments of choice for ADHD, but many parents remain skeptical and influenced by alternative literature and “natural therapies.” Recent literature10 suggest that parents prefer alternative treatments because they are natural and provide them with “more control over treatment.” Although 54% of parents reported their use, only 11% of the parents shared this information with the child’s physician. Kemper’s11 book The Holistic Pediatrician, and an article by Chan and colleagues12 outline responsible limitations and dangerous side effects of alternative therapies as well as the absence of double-blind, placebo-controlled studies. They also provide specific parent handouts which are available for pediatricians’ use.

Stimulants: Treatment and Adverse Effects

Short, intermediate, and long-acting agents are now available as pumps, patches, and beads, in the smorgasbord of medication treatments with stimulants. A critical developmental question relates to the child’s swallowing capabilities and the number of hours a day treatment is considered. In general, short-acting agents can be abused and have doubled in street value in the last 4 years, particularly in college communities. The safety and efficacy of hard-to-abuse intermediate and long-acting methylphenidate and mixed amphetamine salt products make them highly advantageous, with traditional side effects including insomnia, anorexia, and rebound/mood lability. A careful history and premedication of these potential side effects helps to clarify both the quality and quantity of their presence and establish reasonable treatment alternatives. The most common reason for treatment failure remains poor compliance. Dysphagia or difficulty swallowing without a neurological basis is only occasionally disclosed and is often a manifestation of anxiety and/or posttraumatic symptomatology.

Middle- and high-school students often need control beyond 10–12 hours to address homework concerns post extracurricular activities.13 If behavioral strategies do not work in these situations (though they often allow for a lesser dose of stimulant according to the Multimodal Treatment of Children With ADHD study14) augmentation may be necessary in the afternoon and early evening either with a shorter-acting stimulant, a half dose of a longer acting agent, or a nonstimulant, ie, guanfacine, atomoxetine, or a selective serotonin reuptake inhibitor, depending on which comorbidity is identified.

Multimodal Treatment

Multimodal therapy continues to be the most responsible and thorough approach to treatment both for primary ADHD symptoms and associated side effects, such as insomnia. For more information, the physician is referred to the work of Gardiner and Kemper.15

James McGough, MD

A Biological Condition

Although there is plenty of hard medical evidence that ADHD is a real disease, some say it is a product of modern society or poor parenting. However, medical descriptions of ADHD that date back 140 years have recognized it as a brain-based condition. There was an exception to that in the 1960s where virtually everything was being blamed on poor parenting. We now know that there are genetic contributions to ADHD that are about as strong as genetic contributions to height. In fact, the evidence for a genetic link is much stronger for ADHD than for schizophrenia and many other psychiatric conditions. Many research groups around the world have identified the same genes as risk factors for the disorder.16,17 In addition, we have neuropsychological information that is consistent with pharmacologic response in terms of areas of the brain that are affected. And we have neuroimaging studies that show clear brain differences in both children and adults irrespective of whether the children were medicated or not. The evidence supporting ADHD as a biological condition is probably as strong or stronger than that for any other condition in psychiatry.

The Clinical Diagnosis

ADHD is a clinical diagnosis based on clinical criteria, just as headache is a clinical diagnosis. If properly trained clinicians use the same criteria, they will pick out the same child as having ADHD 90% to 95% of the time. Many parents want to be reassured about the accuracy of a diagnosis through neuroimaging, but although the brain scan formation is fascinating from a research point of view, there is no clinical evidence to support its diagnostic use. In addition, there is no psychological testing for ADHD itself, although there are comorbid conditions of ADHD, eg, a learning disability, that can be ruled out with psychological testing.

Although some claim there are diagnostic differences in gender and ethnicity among children with ADHD, the issue of access to health care cannot be overlooked. Savvy, upper-middle-class parents tend to obtain care for their children. Less-savvy parents with fewer resources often do not know to get care, and this is where disparities show up.

The Art of Medicine

Primary care physicians (PCPs) and pediatricians may not be particularly well versed in the area of psychiatry. However, physicians dealing with ADHD must address comorbidity including learning disabilities, oppositional defiant disorder, conduct disorder, depression, anxiety, and substance abuse and nicotine use in older children. While this is hard to do in a 12-minute consultation, the reality is that ADHD must be dealt with in the HMO (health maintenance organization) situation. In keeping with the art of medicine, PCPs who are savvy and who keep informed become good at this.  

Although 70% of ADHD patients have two or more conditions, there is little research on comorbidity in ADHD. Treatment decisions are therefore largely based on clinical experience. In deciding which condition to treat first, the physician should assess the individual patient and decide where the impairment is. For example, if a person has a severe depression or anxiety, or bipolar disorder, it would be really foolish not to address that first. I would begin with treatment of the comorbid issue that is most life-threatening.

The Stimulant Agents

There is nothing on the market that works better than a stimulant. The development of longer-acting compounds, which are effective for 8–12 hours, provide many advantages. The greatest advantage is the lack of social stigmatization; because long-acting compounds can be administered in the morning, children do not have to suffer the embarrassment of going to the school nurse for their medication during the day. Other advantages include increased compliance and the elimination of controlled substances within the school setting. The downside to the longer-acting compounds is that they may not work long enough for patients in whom the work or school day is longer than 8–12 hours.

In general, my advice to clinicians is to prescribe a 12-hour compound, although there are reasons to scale back to an 8-hour compound in some children. Choosing between two long-acting drugs is a matter of evaluating the individual patient. Methylphenidate (Concerta) is probably a little gentler. Mixed amphetamine salts (Adderall) is stronger, more flexible, and is contained in capsules that can be broken open and sprinkled. However, treatment is individualized and one cannot predict who is going to respond better to which agent.

Alternative Treatment

Successful management of ADHD in children includes a decrease in symptoms or an improvement in the quality of life. However, with the exception of antibiotics for viral colds, most parents do not want their child on medication, so there is a market for “natural” medication. Besides the fact that some of these treatments are dangerous, what is often missed is that having ADHD is dangerous. By not giving a medication that has been well tested and tried, you are increasing the time during which the child grows up having negative developmental experiences and not getting proper treatment. The child thereby becomes subjected more often to peer rejection; school failure; involvement with drugs, sex, and alcohol; and other serious consequences. Thus, failing to give medications that are known to be effective is really detrimental to the children. In fact, several authorities have stated that the evidence supporting the use of approved medicines for ADHD is so strong that a clinician who does not address this issue is probably being negligent.

 

 

Floyd R. Sallee, MD, PhD

Diagnostic Challenges

Many children presenting to the emergency room are victims of accidents both in the home and on the street, and these accidents are often associated with unrecognized ADHD. There are also serious consequences for children who are kicked out of preschool for aggressive behavior without receiving medical follow-up to screen for ADHD.

The ADHD diagnosis is complicated by comorbid conditions. It is more likely than not that an individual with ADHD will also have one or more other disorders. These disorders vary along a continuum as the individual grows older; for example, what may have been an oppositional defiant disorder comorbid with ADHD may develop with advancing age into conduct disorder and/or substance abuse disorder. The most common comorbidities are learning disabilities as well as anxiety and depressive disorders.

ADHD as a comorbid condition can complicate diagnoses of other disorders as well. For example, an adult may present with a diagnosis of major depression and the physician may not appreciate the fact that the patient has ADHD. The depression may not remit or even respond to treatment until the ADHD comorbidity is addressed.

A New Role for Specialty Clinics

The role of some specialty clinics is to help primary care providers (PCPs) with problematic ADHD patients and then return the patients to the primary care practice. The role of clinic is, therefore, not so much to help with diagnosis as to manage the more difficult patients, most of whom have comorbid conditions. The problem is not that pediatricians or PCPs do not recognize comorbidity, but that they need assistance in making broader assessments and providing additional therapies. For example, I run a consultation care clinic in Cincinnati, Ohio, where we have agreed to take all the problematic ADHD patients out of certain pediatric practices, help them with treatment, and then return them to the practice. The idea is to help pediatricians manage more difficult patients, which are usually those with comorbid conditions. While the pediatricians recognized that there was something different about the patient, they could not pinpoint and needed a little bit of extra assistance in making a broader assessment of the patient and figuring out what additional therapies should be used. In treating those patients with comorbid conditions, I would begin treating the impairment first, regardless of diagnosis.

Treatment Management

Behavioral Therapy

Some data, such as that of the Multimodal Treatment of Children with ADHD study (MTA),18 and Pelham and associates,19-21 suggest that clinicians can use fewer medications or less medication if behavioral therapy is included in the management strategy. Clinicians have the ability to reduce total medication and to achieve effectiveness at times when the medication may not be working for a particular patient. However, most of the effective treatments for ADHD elevate catecholamines in the brain. This is not to say that catecholamine disturbance is the reason for ADHD, but all of the effective agents seem to increase both dopamine and noradrenaline in certain brain areas associated with executive functioning and attentional factors.

Stimulants 

There are literally thousands of studies in just the past few years supporting the use of stimulants to mitigate the symptoms of ADHD. These studies are usually double blind and placebo controlled. There are no credible head-to-head comparisons of stimulants. Although studies have firmly established the superiority of stimulants in the treatment of ADHD, most of them are short term, meaning usually no longer than 8–12 weeks in length. Very few are as long as the 18-month MTA study. Thus, while the stimulants are considered the gold standard, there are some deficits in our knowledge of stimulant use, eg, the range of symptoms affected and the long-term outcomes.

The safety factor of stimulants is one point that cannot be argued; there is probably no safer class of medications used in pediatrics than the stimulants. The most common adverse event of stimulants is loss of appetite; there may also be nuisance side effects like headache, mood changes, and change in sleep patterns. Individuals with ADHD often demonstrate poor sleep patterns and poor sleep quality, and it is unknown and highly individualized whether stimulants in certain individuals might improve or worsen the problem.

The Nonstimulant Agents

The nonstimulant agents cannot really be lumped together, because of the variance in efficacy rates among them. For example, clonidine has a response rate of ~40%, meaning that ~40% of patients treated with clonidine will have an improvement in ADHD symptoms, whereas the response rate for a stimulant is ~70%.

 

James M. Swanson, PhD

Diagnostic Challenges

Because ADHD is a disorder identified through subjective criteria, the diagnosis can be difficult, particularly for preschool children. A diagnosis of ADHD requires the manifestation of behavior that is developmentally inappropriate; the range of developmental progress is broader in preschool children than in other age groups as to make appropriateness a difficult determination. Furthermore, in preschool ADHD treatment programs teachers are reluctant to identify children as having psychopathology or deviant behavior, even when the children are very disturbed. Most of the diagnostic information does not come from the physician’s direct observation of the child; rather, it comes from subjective reports of parents and teachers, among whom there is often disagreement.  

Identifying those preschoolers whose symptoms will persist can be problematic. While children who are aggressive at school age probably were aggressive as preschoolers, Campbell and colleagues22-24 showed that preschool children with symptoms and behaviors associated with ADHD often lose them in elementary school. That goes for aggressive behavior, oppositional behavior, and symptoms of ADHD. An ongoing research study, the Preschool ADHD Treatment Study (PATS), is currently evaluating this issue. 

While there are often comorbidities with ADHD, physicians should be aware that symptoms often interpreted as comorbid conditions can actually be consequences of ADHD itself.18 ADHD may present with anxiety symptoms or symptoms of demoralization or depression, for example, and with treatment of ADHD these so-called comorbid conditions that are actually symptoms of ADHD resolve. The Multimodal Treatment of Children with ADHD study found that after 14 months of treatment of ADHD symptoms, the high rates of comorbidity were cut in half.

How the Stimulants Work

The impetus for the development of the first sustained-release preparation of methylphenidate, Concerta, was the discovery that acute tolerance to the use of methylphenidate and amphetamine develops each day. A higher concentration of the drug in the afternoon and the morning is needed to maintain the effect. The once-a-day dosing form of methylphenidate produces a higher level in ascending pattern across the day, maintaining the effect for 10–12 hours. 

Unlike Concerta, which uses an osmotic pump delivery, the next sustained-release methylphenidate, Metadate CD, relies on a coated beaded technology in which 30% of the beads are not coated and thus release the drug immediately; the other 70% are coated with a polymer that, as it is broken down, releases the drug 2 or 3 hours after the pill is swallowed. Ritalin LA also employs a double-beaded system with a 50:50 ratio of uncoated to coated beads.21

A sustained-release amphetamine, Adderall XR, also utilizes a 50:50 double-bead technology.25 However, the half-life of amphetamine is longer than that of methylphenidate; the immediate-release form of the amphetamines in Adderall XR therefore has a longer duration of action than methylphenidate. Adderall has two releases, initially and then 3 or 4 hours after ingestion, with a longer half-life. Whereas Metadate CD and Ritalin LA last ~8 hours, Adderall XR and Concerta last 10–12 hours.

Some clinicians choose a shorter-acting agent despite looking for a longer-acting effect because some parents and practitioners do not want children on medication when they do not need it. However, Adderall XR and Concerta, with 12-hour dosing, are probably the primary agents prescribed now. These drugs are not more effective than giving Ritalin three times a day or Adderall twice a day, but they do remove the stigma associated with taking the pill at school. Compliance is also increased because the patient only needs the medication once a day.

The stimulants are going to be hard to beat because they rapidly act, have a good effect, and are very safe. The long-term follow-up study as part of the MTA research will give firm evidence whether stimulants have an effect on growth over time. In the meantime, based on many small studies that have been done, the American Academy of Pediatrics, the American Academy of Child and Adolescent Psychiatry, and others have come to the conclusion that any adverse effects are temporary.

Behavioral Therapy

The MTA study,18 a 14-month, seven-site intervention trial in 579 children 7–10 years of age, randomized participants to four treatment strategies: medication alone; behavior therapy alone; a combination of medication and treatment; and community care. The goal of the study was to optimize behavioral treatment and compare it against medication. The intensive behavioral treatment program included intensive personal therapy, parent training, teacher consultations, daily behavioral report cards, and an 8-week summer treatment camp. At the end of the trial, children had poorer outcomes with behavioral therapy alone compared with medication alone or combination therapy. Behavioral therapy alone reduced symptoms to levels at which they were no longer defined as symptomatic in 34% of children. Therefore, although behavioral therapy is not as effective as drug therapy, it is certainly necessary to optimize symptom reduction and treatment effectiveness (Slides 3-5).  

Behavioral treatments that are available are not as effective as stimulant therapy. Equal amounts of work on developing both new medications and new behavioral treatments to optimize the management of children with ADHD are necessary.

 

Michael J. Manos, PhD

Diagnostic Differences

There is little mystery regarding the medical evidence for the diagnosis of ADHD. Even from birth, well-documented child temperament characteristics are evident. For example, children show easy, slow-to-warm-up, and difficult temperaments. A clinician who is informed about developmentally appropriate levels of natural, normal behavior can identify deviance at an early age, and it is certainly helpful to do so early to prevent issues such as violence and aggressiveness, for example. Children who show aggressive behavior in preschool are highly likely to show aggressive behavior in adolescence.

While ADHD is identified all over the world, differences in symptoms are evident in cultural expectations of behavior. This is shown in families who are immigrants to the United States. Children who are raised in the US by first-generation parents run into conflicts when behavior conflicts with natal norms and expectations. Research in Hawaii26 found that behaviors that would be considered normal in western culture are defined as deviant in other cultures. Symptomatic characteristics of ADHD are nevertheless evident across cultures.

Regarding differences among children with ADHD, sex is an interesting issue. There is a 3:1 ratio of boys to girls in childhood, but this ratio diminishes as age increases. In adulthood, the ratio of women to men is 1:1 in clinical settings.

Common symptoms of ADHD are generally prevalent across gender and ethnicity. The diagnostic criteria for ADHD are clear and allow consistent identification across cultures. The diagnostic process should include broad-band and narrow-band rating scales as well as a thorough semi-structured interview. In some cases, psychological testing can be helpful to rule out learning disabilities as a cause for inattention. Although some have suggested use of computerized structured interviews to diagnose ADHD (these are often used in research studies such as the Diagnostic Interview for Children), even a structured interview is not enough in and of itself to diagnose.

What is Attention?

Essentially, there are two kinds of attention. One kind is fascination, that is, something a person is intrinsically interested in. Fascination does not require medication or treatment to assist sustained attention. Individuals with ADHD use this kind of attention as well as anyone does. Directed attention, however, is the attention placed on a task that has to be done because it has a significant consequence to it; the task itself, however, is not interesting. A person would not be interested in the task but has to do it, like submitting one’s taxes every year, to avoid a negative result. The action of a stimulant improves directed attention where it is needed. In childhood, the primary problem is using directed attention in school-related tasks. There are many children who do absolutely great—perhaps even better than children without ADHD—when they are in an unstructured situation where there are few demands. However, when you put them in demand situations requiring directed attention, something that assists individuals to meet demand is needed.

Medication Noncompliance

Despite the fact that parents report that their children feel better when they take medication, noncompliance is often a problem. Swanson27 wrote a very interesting article on noncompliance with ADHD medication. He identified that compliance with a medication regimen was probably one of the most undervalued issues in successful management of ADHD. Education, that is, informing both parents and children of the usefulness of treatment, and the availability of long-acting medications make it much easier to treat pharmacologically.

In his review of compliance with stimulant medications in ADHD, Swanson27 noted that rates of noncompliance range from 20% to 65% in published studies. Factors contributing to noncompliance include inadequate supervision, inconvenience of multiple daily doses, the long-term nature of treatment, and reluctance of individuals to take medication due to social pressures or concerns about drug usage. Two approaches are likely to increase compliance with stimulant treatment: effective once-daily formulations and improved treatment information.

Quality of Life

While a primary goal of clinical work is to identify dysfunction and treat it, successful management of ADHD is more than a decrease in symptoms. Improvement in quality of life is important and rarely evaluated in treatment studies. In Bill Pelham’s summer treatment program, children are in a behavioral therapy treatment program for 7–8 weeks, 8:30am to 5:30pm daily. In this program, one participant’s mother commented that it was the first time in her life that she did not have to be startled when the phone rang, fearing a call requiring her to retrieve her misbehaving child. Whether or not behavioral intervention generalizes and makes a long-lasting difference or whether improvement using behavior therapy is better than medication alone is not the issue. The issue is that a parent’s perception of her relationship with her child can significantly improve.

 

Question & Answer Forum

 

Q: Is there any difference in how you treat patients with hyperactivity versus those with inattentive type?

 

Dr. McGough: The medications work equally well for both conditions. There are individual differences amongst all patients and sometimes some may do better on one versus the other, but there is really no way to know ahead of time.

Dr. Rosen: I have a subgroup of preadolescent female patients, who have fairly significant internalizing disorders, frequent developmental problems, and parent-child conflict, in addition to their ADHD inattentive type. They represent almost 20% of my patient population. I sometimes treat them not only with a stimulant but consider alternative treatments that might be nonstimulant in nature. There are also some preliminary studies to suggest that they may be better responders. We do not have enough data yet to be conclusive, but the key in such cases is that the stimulant is the best treatment for their attention-deficit disorder. The question is, diagnostically, is whether we are also dealing with comorbidity that is more subtle and hard to pick up.

Q: How often should a child who is being managed with a stimulant drug be followed?

 

Dr. Rosen: Target outcomes need to be reevaluated on a regular basis. As the child improves, that targeting reassessment can be expanded from every month to every 3 months to every 6 months. My biggest concern in my practice is that many children present having not been evaluated 1 or 2 years. And as they grow and change developmentally they have new dosing needs. They may not need a new dosage necessarily because of their height or weight, but because of new developmental challenges and comorbidities which warrant more regular follow-up. My personal feeling is that twice a year is very appropriate for follow-up of a child on stimulants.

Q: Are there any studies evaluating side effects of long-term use with stimulant and nonstimulant drugs?

 

Dr. McGough: There are studies of several years’ duration that assess safety. I think the safety data are actually very good. We also have 6 million prescriptions being written annually for the past 40 years. And if any major side effects occurred as a result of being on these drugs, epidemiologically that would have surfaced. So we do have studies of several years’ duration and a large epidemiological database showing that these medicines are safe.

Q: In the absence of psychotic symptoms or family history of bipolar disorder, how would you distinguish between bipolar disorder and ADHD?

 

Dr. Wilens: There is one major distinguishing factor, and that is mood. You will see severe mood lability with bipolar disorder. With ADHD, you may have some mild affective dysregulation, but that is all. In terms of the treatment, it is very important to address the bipolar disorder first. Get the mood stable with either a mood-stabilizing agent, such as an anticonvulsant or lithium, or an atypical antipsychotic, and then you can treat the ADHD.

Q: Are children self-aware enough to realize that they are having trouble? And do they report well enough to tell you that they are doing better once they are medicated?

 

Dr. Swanson: There is a difference of opinion on that. It depends on the age of the child. There is some evidence that children do have a hard time telling the difference when they are on medication and off medication. I did an earlier study in which I?asked children to determine whether they were on medication or off medication in a 2-day trial. Typically they could not tell the difference. They were much better on medication, but they were less concerned about their behavior. I am a psychologist, not a physician, so when the physician I work with is interviewing the parents, I?oftentimes talk to the children and ask them what they think about taking medication. The concern I have about embarrassment and stigma comes from asking children such questions. When I ask them if the medication makes them feel bad, they say no. And when I ask if it makes them do better, they say yes. However, when I ask them why they do not want to take the medication, they say it is because they are embarrassed. I think I can get that type of information from interviewing a child directly, doing some observation, and interacting with the child. The symptom reduction, however, you could obtain much more accurately from the parent and the teacher assessment because that is something the child does not always recognize.

Dr. Wilens: You also get a more thorough report of side effects from talking to children. Also, in adolescents, self-report may be more sensitive to medication effect than parental report.  

Q: How do you deal with the problem of children being misdiagnosed?

 

Dr. Rosen: The thoroughness of the assessment process is important. The key to diagnosis is not the physical exam; 80% to 85% of the time it is based on the history. The guidelines are helpful in that they demand, particularly from the American Academy of Pediatrics, that feedback be received from more than one site—not only from parents, but also from other caretakers in the preschool group. I also send the questionnaire to family daycare providers as well as teachers who might not have a bias. Getting feedback from caretakers who are not parents, teachers, and even community members is key. And most important is getting feedback from mental health providers.

Q: Some patients request continuation of ADHD?medications but do not seem to have ADHD. How can you determine whether they are taking a medication as an addiction, or as a habit continued from necessity earlier in life?

 

Dr. Wilens: There is little evidence that these medicines are abused in a stable manner. There are very few methylphenidate addicts whose drug of choice are stimulants, especially the extended-release preparations. Most of the time when people are coming for referral for the diagnosis of ADHD, they have at least some aspect of ADHD?or some type of cognitive impairment that they are indicating is getting better with treatment. But there simply is not a lot of data out there that suggest that a lot of people are becoming addicts on these medications. In fact, a number of studies have been done using this class of agents in cocaine addicts either with or without ADHD. These studies indicate that stimulants do not make the addiction worse. Stimulants do not increase the craving, increase cocaine use, or increase drug-seeking behavior in hard-core addicts who have these conditions. I would not debate that occasional abuse may be occurring once in a while, but I?think in a public health forum it is not a major concern.

Dr. Rosen: Ask the partner of the individual who wants the medication to fill out a Child Behavior Checklist or an Adult Behavioral Checklist form. Or ask the parents to fill them out based on their memory of that individual as a child. It may provide some information about the child’s original biological predisposition.

Q: How would you explain the decreased comorbidity among ADHD children observed in the Multimodal Treatment of Children with ADHD (MTA) study?

 

Dr. Wilens: It may be difficult to translate findings in carefully screened study patients to the realities of unselected clinical patients. In clinical practices, where we treat everyone who walks through the door, we do not see subtle amounts of anxiety, we see robust anxiety. Further evidence for the comorbid nature of ADHD is provided by studies showing that family members have higher-than-expected degrees of the comorbidity in question. Even with depression, for which the argument can be made that it results from ADHD, we can determine through familial risk factors that the depression is really independent of the ADHD. So we have externalizing or converging ways to determine if there is a true comorbid disorder. The identification of comorbidity in ADHD is very significant, because the patient may not achieve a good ADHD outcome if the physician does not address the comorbidity.

Dr. Swanson: The types of children seen in different settings will demonstrate a referral bias. A clinic that has extraordinary expertise in treating bipolar disorder or depression will get more of these cases. A pediatric department will not get as many patients with serious comorbid conditions as will a psychiatry specialty clinic. Therefore each group may have a different best approach to treatment. 

Dr. Wilens: Epidemiological data shows that there is substantial comorbidity among ADHD patients. While some suggest that there is a referral bias, data such as those presented by Busch and colleagues10 show that children who are referred to specialty clinics are very similar in terms of comorbidity to those who are referred to pediatric practices. The difference is that specialists have the ability to make these assessments and thus diagnose them more frequently.

Dr. Swanson: In the MTA study, we had a systematic way of evaluating children. And if you look at the number of children with serious comorbid conditions, the ones that stay and do not remit over time, it is not at the levels generally described in the clinic work done in ones own practice. 

Dr. Wilens: Basing the argument on study data qualifies it. The ratio of patients screened to subjects enrolled in clinical studies, such as the MTA, is ~10:1. One has to be very concerned when generalizing study data to a clinical population. Clinical practitioners, I believe, would say that they are seeing much more depression and other comorbidities than were reported in the MTA trial.

Dr. Rosen: The MTA study found a 50% to 60% improvement when?patients were treated with the right dose of a stimulant, which also improved their comorbidity. However, this high rate may be a reflection of the fact that patients with more serious affective disorders, such as those on antidepressants or antianxiety agents, were not included. In addition, there was a numerically significant improvement with behavioral therapy in children with comorbid oppositional defiant disorder and anxiety disorders not serious enough to be treated with medication.

References

1. Pastor PN, Reuben CA. Attention deficit disorder and learning disability. United States, 1997-98. National Center for Health Statistics. Vital Health Stat. 2002;10:206.

2. Michelson D, Faries D, Wernick J, et al, for the Atomoxetine ADHD Study Group. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study. Pediatrics. 2001;108:E83.

3. Michelson D. Once daily administration of atomoxetine: a new treatment for ADHD. Presented at: 155th Annual Meeting of the American Psychiatric Association; May 18-23, 2002; Philadelphia, Pa.

4. Michelson D, Allen AJ, Busner J, et al. Once-daily atomoxetine treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatry. 2002;11:1896-1901.

5. Wernicke JF, Kratochvil Ch. Safety profile of atomoxetine in the treatment of children and adolescents with ADHD. J Clin Psychiatry. 2002;63(suppl 12):50-55.

6. Wilens TE, Faraone SV, Biederman J, Gunawardene S. Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature. Pediatrics. 2003;5:801-809.

7. Anastopoulous A. Parent Training and ADHD. ADHD?Report. 2000:8:7-14.

8. Reiff M, ed. ADHD: A Complete and Authoritative Guide.American Academy of Pediatrics Publishing; 2003.

9. Busch B, Biederman J, Crawford MH, et al. Adoptive and biological families of children and adolescents with ADHD. J Am Acad Child Adolesc Psychiatry. 2002;9:1103-1111.

10. Chan E, Rapaport K, Kemper K. Complementary and alternative therapies in child attention and hyperactivity problems. J Dev Behav Pediatr. 2003;24:18-36.

11. Kemper KJ. Attention-deficit/hyperactivity disorder. The Holistic Pediatrician. Lippincock, Williams & Wilkins; 1996:233-250.

12. Chan E, Gardiner P, Kemper KJ. At least it’s natural…Herbal and dietary supplements in ADHD. Contemporary Pediatrics. 2000;9:116-130.

13. Connor DF. Preschool attention-deficit/hyperactivity disorder: a review of prevalence, diagnosis, neurobiology, and stimulant treatment. J Dev Behav Pediatr. 2002;23(suppl 1):S1-S9.

14. Pelham B. Implications of the MTA study for behavioral and combined treatments. ADHD Report. 2000;4:9.

15. Gardiner P, Kemper K. Insomnia: herbal and dietary remedies Contemporary Pediatrics. Feb 2002.

16. Smalley SL, Bailey JN, Palmer CG, et al. Evidence that the dopamine D4 receptor is a susceptibility gene in attention-deficit/hyperactivity disorder. Mol Psychiatry. 1998;3:427-430.

17. Faraone SV, Doyle AE, Mick E, et al. Meta-analysis of the association between the 7-repeat allele of the dopamine (D4) receptor gene and attention-deficit/hyperactivity disorder. Am J Psychiatry. 2001;7:1052-1057.

18. The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 1999;56:1073-1086.

19. Pelham WE, Gnagy EM, Swanson JM, et al. Behavioral versus behavioral and pharmacological treatment in ADHD?children attending a summer treatment program. J Abnorm Child Psychol. 2000;6:507-525.

20. Pelham WE, Fabiano GA. Behavior modification. Child Adolesc Psychiatric Clin N Am. 2000;3:671-688.

21. Pelham WE, Wheeler T, Chronic A. Empirically supported psychosocial treatments for ADHD disorder. J Clin Child Psychol. 1998;2:190-205

22. Marakovitz SE, Campbell SB. Inattention, impulsivity, and hyperactivity from preschool to school age: performance of hard-to-manage boys on laboratory measures. J Child Psychol Psychiatry. 1998;6:841-851.

23. Campbell SB, Pierce EW, March CL, et al. Hard-to-manage preschoolers: adjustment at age nine and predictors of continuing symptoms. J Child Psychol Psychiatry. 1990;6:871-889.

24. Campbell SB, Ewing LI. Follow-up of hard-to-manage preschoolers: adjustment at age nine and predictors of continuing symptoms. J Child Psychol Psychiatry. 1990;6:871-889.

25. Spencer T. Pharmacologic treatment of attention-deficit/hyperactivity disorder in children. Medscape. Available at: www.medscape.com/viewprogram/1927. Accessed: February 12, 2003.

26. Mokuau N, ed. Handbook of Social Services for Asian and Pacific Island Americans. Westport, CT: Greenwood Press; 1991.

27. Swanson J. Compliance with stimulants for attention-deficit/hyperactivity disorder: issues and approaches for improvement. CNS Drugs. 2003;2:117-131.

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Clinical Supplement

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Long-Term Issues in the Treatment of Sleep Disorders

Thomas Roth, PhD, Andrew D. Krystal, MD, MS, and Joseph A. Lieberman III, MD, MPH

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 Primary Psychiatry. 2007;14(7 suppl 5):1-16

This clinical supplement is supported by funding from Takeda Pharmaceuticals North America

An expert panel review of clinical challenges in psychiatry

Faculty Affiliations and Disclosures

Dr. Roth is director of the Sleep Disorders and Research Center at Henry Ford Health System in Detroit, and clinical professor of psychiatry at the University of Michigan School of Medicine in Ann Arbor.

Disclosures: Dr. Roth is a consultant to Abbott, Acadia, Acoglix, Actelion, Alchemers, Alza, Ancile, Arena, AstraZeneca, Aventis, Bristol-Myers Squibb, Cephalon, Cypress, Dove, Elan, Eli Lilly, Evotec, Forest, GlaxoSmithKline, Hyperion, Jazz, Johnson and Johnson, King, Lundbeck, McNeil, MediciNova, Merck, Neurim, Neurocrine, Neurogen, Novartis, Orexo, Organon, Orginer, Prestwick, Proctor and Gamble, Pfizer, Purdue, Resteva, Roche, sanofi-aventis, Schering-Plough, Sepracor, Servier, Shire, Somaxon, Syrex, Takeda, TransOral, Vanda, Vivometrics, Wyeth, Yamanouchi, and Xenoport; is on the speaker’s bureaus of sanofi-aventis and Takeda; and receives grant/research support from Aventis, Cephalon, GlaxoSmithKline, Neurocrine, Pfizer, sanofi-aventis, Schering-Plough, Sepracor, Somaxon, Syrex, Takeda, TransOral, Wyeth, and Xenoport.

Dr. Krystal is director of the Sleep Research and Insomnia Program at Duke University School of Medicine in North Carolina.

Disclosures: Dr. Krystal is a consultant to and/or on the advisory boards of Eli Lilly, Evotec, GlaxoSmithKline, Merck, Neurocrine, Neurogen, Novartis, Organon, Pfizer, Respironics, sanofi-aventis, Sepracor, Somaxon, Takeda, and Transoral; and receives research support from Evotec, GlaxoSmithKline, Merck, National Institutes of Health, Neurocrine, Pfizer, Respironics, sanofi-aventis, Sepracor, Somaxon, and Takeda.

Dr. Lieberman is professor of family medicine at Jefferson Medical College, Thomas Jefferson University, in Philadelphia, Pennsylvania, and speaker of the house of the Medical Society of Delaware in Newark, Delaware.

Disclosures: Dr. Lieberman is on the advisory boards of AstraZeneca, Pfizer, sanofi-aventis, and Takeda; and is on the speaker’s bureau of AstraZeneca.

Abstract

Insomnia is a disorder characterized by chronic sleep disturbance associated with daytime disability or distress, such as memory impairment and fatigue, that occurs despite adequate opportunity for sleep. Insomnia may present as difficulty falling/staying asleep or as sleep that is nonrestorative. Studies show a strong correlation between insomnia and impaired quality of life. Pain conditions and depression are commonly associated with insomnia, either as secondary or comorbid conditions. In addition, a greater incidence of anxiety, alcohol and drug dependence, and cardiovascular disease is found in people with insomnia. Data indicate insomnia results from over-engaged arousal systems. Insomnia patients experience increased metabolic rate, body temperature, and heart rate, and elevated levels of norepinephrine and catecholamines. Pharmacologic options for the treatment of insomnia include benzodiazepine hypnotics, a selective melatonin receptor agonist, and sedating antidepressants. However, insomnia may be best treated with cognitive-behavioral therapy and instruction in good sleep hygiene, either alone or in concert with pharmacologic agents. Studies on the effects of insomnia treatment use variable methodologies or do not publish negative results, and there are currently no studies of treatment focusing on morbidity. Further research is necessary to better understand the effects of insomnia therapies on medical and psychiatric disorders.

In this Clinical Information Supplement, Thomas Roth, PhD, describes the nature of insomnia and its pathophysiology. Next, Andrew D. Krystal, MD, MS, reviews morbidities associated with insomnia. Finally, Joseph A. Lieberman III, MD, MPH, provides an overview of therapeutics utilized in patients with insomnia, including behavioral therapies and pharmacologic options.

The Nature of Insomnia

Thomas Roth, PhD

Diagnostic Criteria for Insomnia

Insomnia is increasingly understood to be a disorder. A disorder is a condition  which exhibits morbidity mediated by some kind of pathophysiology. There are a variety of definitions for insomnia. The two most commonly used criteria for insomnia are those of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,1 and the American Academy of Sleep Medicine.2

Insomnia is a symptom-based diagnosis.3 Patients with insomnia experience one or more sleep-related complaints, including difficulty falling asleep, difficulty staying asleep, early-morning awakenings, and sleep that is nonrestorative or not adequately restorative (Slide 1). These sleep-related complaints must be associated with some kind of daytime disability or distress such as fatigue, attention/memory impairment, or sleepiness. Any one of these latter symptoms must be present with the sleep-related complaint, and must occur despite adequate opportunity for sleep. Finally, the sleep difficulty must occur at least three times per week for at least 1 month.

Prevalence of Insomnia

The prevalence rates of insomnia reported in the literature are inconsistent. Perhaps the best synthesis of all of the data comes from the 2005 National Institutes of Health (NIH) State-of-the-Science Consensus Conference on insomnia.4 These data, which are available on the NIH Web site,5 indicate that the prevalence of sleep disturbances  in the United States is ~30% of the population. This number is, of course, volatile. The night after a tornado, for example, a town population may have a sleep disturbance prevalence as high as 70% to 80%. However, the 30% sleep disturbance prevalence does not account for the population suffering from insomnia. When the diagnostic criteria for insomnia—such as difficulty sleeping at night and associated daytime impairment—are applied, the prevalence of insomnia is ~10% of the adult population. Finally, the prevalence of insomnia varies among medical practices in the clinical population. For example, insomnia prevalence in geriatric medicine differs from that in athletic medicine. However, across all medical specialties and all medical clinics, ~50% of patients meet diagnostic criteria for insomnia (Slide 2).

Risk Factors for Insomnia

The disparity between the prevalence in the general population and that in the clinical population may be explained by the risk factors associated with insomnia. Some of the greatest risk factors for insomnia are age and psychiatric disorders (Slide 3).

Women have more insomnia than men, and the reason for that is not well understood. On the other hand, it is very clear that shift work contributes to insomnia by causing changes in circadian rhythm. Familial aggregation is a risk factor, suggesting that there is a genetic basis for this disorder. Age and medical disorders are overlapping risk factors. Age is the greatest risk factor for insomnia; however, the reason elderly people experience increased risk of insomnia is not due to a breakdown of their sleep systems. Rather, the higher prevalence of medical disorders places elderly people at greater risk for insomnia (Slide 4).6

Ninety percent of patients with insomnia have  comorbid conditions (Slide 5). It is important for clinicians to understand that while insomnia interacts with other medical disorders, it is not necessarily caused by them. The majority of patients with medical disorders such as rheumatoid arthritis or neuropathic pain do not have insomnia. The clinical subpopulation that does have insomnia is composed of patients with a predisposition for it.

Comorbid Conditions Associated with Insomnia

Insomnia and comorbid conditions influence each other. Insomnia influences depression, for example, and depression influences insomnia. This interaction between conditions prevails in elderly patients. The more medical conditions they have, the greater the number of precipitants, and the greater their likelihood of developing insomnia. However, the fact that the incidence of insomnia is not 100% among patients who have three or four medical disorders indicates that medical disorders themselves are not responsible for causing insomnia. Rather, they precipitate, coexist with, or interact with insomnia.

Pain conditions are commonly associated with insomnia. It is now known that sleep loss and sleep fragmentation causes pain and increased inflammatory response. In turn, treating insomnia improves pain management. Other medical disorders commonly associated with insomnia include arthritis and other chronic pain syndromes, congestive heart failure, cerebral vascular disease, chronic pulmonary disease, Parkinson’s disease, dementia, gastroesophageal reflux, and renal failure (Slide 6). Virtually every medical disorder can be associated with insomnia because most medical disorders require an arousal response. Patients with a cough must wake up in order to cough. Patients with sleep apnea must wake up to re-enervate the muscles of their airways. To increase swallowing, patients must wake up.

The other major comorbidity, besides the medical conditions associated with dyspnea and pain, is depression. Several studies in the medical literature demonstrate that insomnia increases the risk of depression by a factor of 5. Patients with a history of depression are also at a greater risk of relapse if they have insomnia. As is the case with treating other comorbid conditions, treatment of insomnia diminishes illness severity and improves response to antidepressant treatment. Fava and colleagues7 demonstrated that patients with comorbid insomnia and depression experience a quicker, more effective antidepressant response when treated with a sleep agent and antidepressant combination than when treated with either a sleep agent or antidepressant alone. Clinicians must consider whether chronic treatment of insomnia can prevent the relapse of depression or other like conditions.

Pathophysiology of Hyperarousal

Although 30% of patients with a medical disorder have insomnia, one must consider the fact that 70% do not. This is likely due to the fact that insomnia does not result from sleep disturbance alone. A large amount of data now show that patients with insomnia have increased arousal. Nofzinger and colleagues8 demonstrated increased brain metabolism in the arousal centers in the brain, indicating that insomnia does not result from broken sleep systems but from over-engaged arousal systems (Slide 7).

While most people experience a decline in body temperature at night, this is not as consistently seen among insomniacs. Bonnet and Arand9,10 demonstrated increased metabolic rate in insomnia patients. In addition,  Perlis and colleagues11 showed that these patients experience increased high-frequency electroencephalogram. Lushington and colleagues12 demonstrated that those with insomnia experience an increase in body temperature, and Stepanski and colleagues13 indicated that insomniacs also experience increased heart rate—both at night and during the day. Other studies have found that catecholamines such as norepinephrine, which are markers of hyperarousal, are elevated in patients with insomnia.14

The sleep systems in patients with insomnia are relatively normal, but the individuals are hyperaroused, as reflected in catecholamines, brain metabolism, and body metabolism. Hyperarousal overrides these normal sleep systems and causes insomnia, which then interacts with the comorbid medical and psychiatric disorders.

References

1. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
2. American Academy of Sleep Medicine. Available at: http://www.aasmnet.org. Accessed May 30, 2007.
3. Edinger JD, Bonnet MH, Bootzin RR, et al. Derivation of Research Diagnostic Criteria for Insomnia: Report of an American Academy of Sleep Medicine Workgroup. Sleep. 2004;27:1567-1596.
4. Leshner A. National Institutes of Health State of the Science Conference statement on Manifestations and Management of Chronic Insomnia in Adults, June 13-15, 2005. Sleep. 2005;28:1049-1057.
5. US Department of Health and Human Services: National Institutes of Health. Available at: www.nih.gov. Accessed June 20, 2007.
6. Foley D, Ancoli-Israel S, Britz P, Walsh J. Sleep disturbances and chronic disease in older adults: results of the 2003 National Sleep Foundation Sleep in America Survey. J Psychosom Res. 2004;56(5):497-502.
7. Fava M, McCall WV, Krystal A, et al. Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder. Biol Psychiatry. 2006;59(11):1052-1060.
8. Nofzinger EA, Buysse DJ, Germain A, Price JC, Miewald JM, Kupfer DJ. Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry. 2004;161(11):2126-2128.
9. Bonnet MH, Arand DL. 24-Hour metabolic rate in insomniacs and matched normal sleepers. Sleep. 1995;18(7):581-588.
10. Bonnet MH, Arand DL. Heart rate variability in insomniacs and matched normal sleepers. Psychosom Med. 1998;60(5):610-615.
11. Perlis ML, Smith MT, Andrews PJ, Orff H, Giles DE. Beta/gamma EEG activity in patients with primary and secondary insomnia and good sleeper controls. Sleep. 2001;24:110-117.
12. Lushington K, Dawson D, Lack L. Core body temperature is elevated during constant wakefulness in elderly poor sleepers. Sleep. 2000;23(4):504-510.
13. Stepanski E, Zorick F, Roehrs T, Young D, Roth T. Daytime alertness in patients with chronic insomnia compared with asymptomatic control subjects. Sleep. 1988;11(1):54-60.
14. McClure TK, Drake CL, Roth T, Richardson GS. Sleep and endocrine responses to psychological stress in primary insomnia. Sleep. 2003;26:A311.

The Morbidity of Insomnia

Andrew D. Krystal, MD, MS

Data on the Morbidity of Insomnia

People who experience sleep difficulty often report problems with daily functioning and quality of life. While impairment and decreased quality of life are included among the criteria for the diagnosis of insomnia, the nature and degree of these impairments are difficult to ascertain. One important question is whether insomnia causes alterations in physiology or behavior that might lead to longer-term adverse consequence.

Several epidemiologic studies1-7 have used cross-sectional analysis or longitudinal data to compare people with insomnia to normal sleepers in an effort to determine the specific impairments and alterations in quality of life associated with insomnia. In another type of study, patients with insomnia receive insomnia-specific therapies and are followed to determine how their function and quality of life improve. This type of study has been the most compelling in terms of linking insomnia and morbidities.8,9

Functional Impairment and Quality of Life

Findings from cross-sectional studies show a strong correlation between insomnia and impairment. Compared to normal sleepers, people who meet insomnia criteria have impaired quality of life. They report that they do not feel as well overall, and they do not feel like they are able to function as well. In a study involving 261 insomnia patients and 101 controls, Zammit and colleagues1 employed the 36-item Short Form (SF-36) Health Survey, a well-validated epidemiologic measure of quality of life. The results demonstrated that people with insomnia differ from normal sleepers in their vitality, their emotional role, their health, and their physical role. In all of the different subscales of the survey, quality of life was diminished in the patients with insomnia (Slide 1).

An enlightening study by Katz and McHorney2 compared the SF-36 findings in a group of patients with severe insomnia to those in a group of patients with major depression and a group of patients with congestive heart failure. The striking results indicated that people with insomnia had more impairment in areas of vitality, general health, and physical ability to function than those with congestive heart failure and those with major depression. They had comparable impairments to those with congestive heart failure and major depression in other important subscales, such as emotional role and mental health. Congestive heart failure is a significant medical problem with tremendous consequences for a patient’s quality of life, and major depression is similarly devastating, yet it is becoming evident that insomnia has a comparable, and in some cases greater, impact on people’s lives than those other conditions (Slide 2).

Longitudinal data demonstrate that people with insomnia experience increased absenteeism and decreased productivity in their work roles. They are also more likely to develop psychiatric disorders and medical disorders. A 1997 retrospective analysis by Simon and VonKorff3 compared a database of ~2,000 primary care patients with insomnia to controls. There were significant differences in the groups’ ratings of their social disability, ability to fulfill roles, number of days of limited activity, and number of days spent in bed. The results showed that insomnia was correlated with global impairments in patients’ ability to live their lives (Slide 3). A comparable database analysis of ~800 French employees demonstrated significantly more work absences in people who had insomnia than those with normal sleep function.4 It is not that patients with insomnia simply have more complaints; the disorder prevents them from performing the domestic, work, and recreational activities they normally would.

Insomnia as a Predictor of Psychiatric and Medical Disorders

Several studies have shown that insomnia increases the risk of depression. Breslau and colleagues5 looked at a group of patients who met insomnia criteria at baseline and a group of people without insomnia. Those groups were then assessed 3.5 years later. After that interval, there was a much greater incidence of major depression, anxiety, and alcohol and drug dependence problems in those who had insomnia. The incidence of depression had increased apprxomimately four-fold (Slide 4). While these studies do not prove causality, they show strong association, which is intriguing and worthy of further inquiry.

There are similar longitudinal data related to cardiovascular disorders. In a study by Suka and colleagues,6 4,794 male workers from one company in Japan were diagnosed with insomnia at initial evaluation and followed for 4 years. The incidence of hypertension increased in those who had difficulty initiating sleep or staying asleep compared with those who did not meet have insomnia. There was a ~40% incidence of hypertension in those with sleep problems (initiating or maintaining sleep) versus a 31% incidence in normal sleepers.

Lastly, a Swedish study conducted by Mallon and colleagues7 followed 1,870 people—both those diagnosed with insomnia and abnormal sleepers—for 12 years. In men, the risk of death due to coronary artery disease was increased by a factor of 3. Having an insomnia diagnosis was clearly correlated with this mortality (Slide 5).

Effects of Insomnia Treatment

There are limitations to our knowledge of how treatments for insomnia affect the impairments and risks associated with the disorder.8 Examinations of some measures of daytime function have produced negative findings. As there is a tendency not to publish negative findings, it is not known how often studies fail to find therapeutic effects. Another problem is that studies of daytime function, quality of life, and associated psychiatric and medical conditions have widely variable measures and methodologies. Consolidating these data in a meaningful way is consequently difficult. What is needed is a systematic series of investigations. Finally, there are no studies that have had a primary focus on morbidity; a study of the effects of insomnia therapy on morbidities must examine a group of people who have an identified set of morbidities, and then follow them in a method powered to detect those effects. However, most studies are powered to determine whether therapies include sleep and are not powered to find the effects on non-sleep outcomes.

Nonetheless, there has been a series of placebo-controlled studies with reported findings.8,9 A significant number of studies have reported ratings of insomnia patients’ restedness, alertness, ability to function, overall well-being, and quality of life. In four of these studies, people completed morning self-ratings that indicated their alertness or ability to function had significantly improved after insomnia treatment. Three studies have examined fatigue using the SF-36 or a visual analogue scale. These studies show that reported sleepiness, number of naps, and time spent napping all decreased following treatment, while ability to carry out professional activity increased. While these associations cannot be construed as hard and fast proof, it is notable that the positive findings occurred despite poor or inconsistent methodology (Slide 6). Treatment seems to improve the deficits people with insomnia experience, including those in quality of life, social role, and work performance. Effects of treatment on risks for medical and psychiatric disorders have not yet been sufficiently studied.

References

1. Zammit GK, Weiner J, Damato N, Sillup GP, McMillan CA. Quality of life in people with insomnia. Sleep. 1999;22(Suppl 2):S379-S385.
2. Katz DA, McHorney CA. The relationship between insomnia and health-related quality of life in patients with chronic illness. J Fam Pract. 2002;51(3):229-235.
3. Simon GE, VonKorff M. Prevalence, burden, and treatment of insomnia in primary care. Am J Psychiatry. 1997;154(10):1417-1423.
4. Godet-Cayre V, Pelletier-Fleury N, Le Vaillant M, Dinet J, Massuel MA, Leger D. Insomnia and absenteeism at work. Who pays the cost? Sleep. 2006;29(2):179-184.
5. Breslau N, Roth T, Rosenthal L, Andreski P. Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry. 1996;39(6):411-418.
6. Suka M, Yoshida K, Sugimori H. Persistent insomnia is a predictor of hypertension in Japanese male workers. J Occup Health. 2003;45(6):344-350.
7. Mallon L, Broman JE, Hetta J. Sleep complaints predict coronary artery disease mortality in males: a 12-year follow-up study of a middle-aged Swedish population. J Intern Med. 2002;251(3):207-216.
8. Krystal AD. Treating the health, quality of life, and functional impairments in insomnia. J Clin Sleep Med. 2007;3:63-72.
9. Walsh JK, Krystal AD, Amato DA, et al. Nightly treatment of primary insomnia with eszopiclone for six months: Effect on sleep, quality of life and work limitations. Sleep. 2007. In Press.

Therapeutics for the Treatment of Insomnia

Joseph A. Lieberman III, MD, MPH

National Institutes of Health Consensus Development Program Data

At the National Institutes of Health (NIH) State-of-the-Science Consensus Conference on insomnia, held in June 2005 in Washington, DC, the Federal government addressed insomnia and its associated problems for the first time in >20 years. Two of the major chronic insomnia treatment endorsements came out of that conference: First, cognitive-behavioral therapy (CBT) for insomnia is effective and should be utilized. Second, Food and Drug Administration-approved benzodiazepine receptor agonists are pharmacologically effective.1 Since that time, the FDA has approved ramelteon, a selective MT-1/MT-2 receptor agonist, as an additional hypnotic agent. Although ramelteon works by an altogether different mechanism, it is approved as a hypnotic.

Cognitive-Behavioral Therapy

Cognitive-behavioral therapy (CBT) is an important component to treatment of insomnia. The role of CBT in insomnia is to challenge the dysfunctional beliefs and misconceptions about sleep held by a person with insomnia (Slide 2).2 One of the cornerstones of CBT for insomnia is to stop the patient from focusing too much on the time. More primarily, the goal is to restructure the patient’s thinking about sleep. Although effective, the application of CBT as a wide-spread treatment is hampered by its availability (since specialized training is required) and its lack of consistent coverage by medical insurance carriers. Consequently, in some areas, there is a shortage of cognitive-behavioral therapists and an inability to access them because of insurance policies.

Other forms of behavioral treatment may be administered in the clinician’s office, however. Other CBT techniques that require less training and are thus more easily delivered include relaxation training, in which patients are taught to reduce their physiologic and cognitive arousal at bedtime. In one variation of this technique, patients are taught progressive muscular relaxation, in which they relax the muscles of their body, starting with the feet and working toward the head, until they fall asleep. Other relaxation methods may be commonly available in the community, such as relaxation sessions, transcendental meditation, yoga, and biofeedback. These therapies are available in a variety of settings and in different communities.

Sleep restriction and stimulus control are other behavioral treatments for sleep disorders. Sleep restriction centers on the belief that sleep continuity improves by limiting the time spent in bed. Patients should not lie in bed for 9 hours in hope that they will get 5 hours of sleep. If a patient has not fallen asleep within a period of time, such as half an hour, they should get out of bed and move to another setting or situation—to read a book, drink a glass of warm milk, etc.—until they are tired again. Similarly, stimulus control ensures that patients restrict their psychological associations with the bed to just sleep and sexual activity. The bed should not be used for television watching, dog grooming, stamp collecting, or any other activity executed in hopes of eventually falling asleep. Stimulus control restricts the bed to just those two activities.

Principles of Sleep Hygiene

The principles of sleep hygiene consist of largely common sense practices (Slide 3).3-5 Many patients simply do not fully understand or appreciate the various dimensions of good sleep hygiene. For example, many do not understand the importance of maintaining a regular sleep/wake cycle, in which a person goes to bed at approximately the same time and—perhaps even more importantly—wakes up at the same time, every day, 7 days a week. Patients should not try to catch up on sleep during the weekends, but rather set their own internal clock to consistently go to bed at a certain time and wake up at a certain time. People without insomnia often do not have to worry about maintaining a regular sleep/wake cycle, but for patients with insomnia it is vital to establish a regular sleep rhythm.

Exercise is another valuable part of sleep hygiene. Patients with insomnia should exercise in the morning or, at the very latest, by early afternoon. Because exercise can be stimulating, patients should not attempt to exercise vigorously in the evening in order to tire themselves. This will invigorate and stimulate them, making it more difficult to fall asleep.

Likewise, increasing exposure to bright light during the day and avoiding exposure to it during the night contribute to good sleep hygiene. Even occasional exposure to very bright light may be enough to reset a patient’s circadian clock. Exposure to a 150-watt light bulb during a nighttime lavatory visit can cause difficulty sleeping in very susceptible patients. Patients should replace a bright light with one that that has the least amount of illumination but is compatible with safety. A 4-watt nightlight, for example, might provide light sufficient to prevent injury without interfering with a patient’s ability to go back to sleep. Patients should enhance their sleep environment by reducing ambient noise, keeping the room dark, and having adequate bed covers and sleep surface.

Patients should avoid eating heavy meals or drinking alcohol within 3 hours of bedtime. They should also avoid caffeine and nicotine before going to bed. Caffeine, of course, is ubiquitous in foods and drinks. While most patients realize that coffee and cola drinks contain caffeine, many do not know that tea, many non-cola soft drinks, and chocolate do, as well. Alcohol makes people sleepy, but it has a short half-life, and as it is metabolized the body produces neurotoxins that are irritants to the central nervous system. These irritants act as stimulating agents that can overwhelm the initial sense of sedation alcohol causes. Nicotine is a stimulant as well.

Patients with insomnia should engage in relaxing activities as part of their sleep preparation ritual. They should begin these activities early in the evening so that they are set for sleep at bedtime. A warm bath and socks are just two ways that patients can reduce core body temperature to predispose themselves to sleep.

Pharmacologic Options for Insomnia

Over the years, patients have used a variety of products, alone or in concert with behavioral changes and modifications, to induce sleep (Slide 4). These range from fermented or alcoholic beverages to plant preparations, including a wide variety of herbs.

Laudanum, a combination of opium and alcohol, has been around for over 100 years, and was used extensively during the American Civil War, when it was available at every corner grocery store. This may have produced more drug addicts than any other single period in history. Chloral hydrate has likewise been around for over 100 years.

Barbiturates are more recent advents. Although they are safer than some of the other substances mentioned, they still carry certain hazards and risks. Antihistamines have been—and still are—used for their sedating properties. Antihistamines are commonly found in over-the-counter (OTC) agents. However, caution is indicated in the use of such agents in elderly patients.

Benzodiazepine hypnotics are a more recent invention. These are safer than the aforementioned mentioned products, but they also have drawbacks and side effects. The nonbenzodiazepine hypnotics are agents that act at the benzodiazepine receptor sites but are not benzodiazepines. These, too, can confer some additional safety, and are still more effective than the above agents.  Importantly, these are FDA approved for the treatment of insomnia (Slide 5).

The selective melatonin receptor agonist ramelteon is a recent addition to the sleep-agent armamentarium and is also approved by the FDA for the treatment of insomnia.    

Sedating antidepressants are also widely used as hypnotics (Slide 6). These hold potential benefit for patients experiencing chronic insomnia secondary to depression.6 These agents often share the same antihistaminic action as OTC products.7 Although antidepressants have not been studied as widely as primary hypnotic agents for the treatment of primary insomnia, the hypnotic dose of a sedating antidepressant is typically less than the therapeutic effect for the treatment of depression. As with any medication, there are side effects. Caution is warranted in the elderly, since a limited number of antidepressants can cause postural hypotension8 or have cardiovascular effects.9

 

Pharmacokinetics of Benzodiazepine and Nonbenzodiazepine Hypnotics

In the process of shifting away from chloral hydrates and barbiturates and adopting more efficacious hypnotic products, doctors began prescribing long-acting benzodiazepines like flurazepam and quazepam (Slide 7).10-12 However, these medications have extremely long half-lives, meaning they have a very high risk of producing residual sedation in patients. Even the intermediate-acting agents, such as estazolam and temazepam, have half-lives long enough to cause risk of residual sedation. As a result, insomnia treatment has moved away from these agents.

The benzodiazepine with perhaps the best half-life is triazolam, which has a half-life of 1.5–5.5 hours (Slide 8).10-16 However, because of its poor side-effect profile, triazolam has never been commonly used as a hypnotic.

Many clinicians use other agents from the benzodiapine class of drugs, such as lorazepam, temazepam, and alprazolam, as hypnotics. However, this as an “off label” use of these drugs, and is accompanied by the risks associated with the use of this class of pharmaceuticals.

Conclusion

Currently, the nonbenzodiazepines and ramelteon are the newest pharmacologic treatments for insomnia patients. However, it is strongly recommended that physicians not engage only in pharmacologic treatment. Patients are best treated with the nonpharmacologic behavioral interventions outlined above, such as CBT and relaxation training. Usually, hypnotics should be prescribed only if good sleep hygiene principles and cognitive interventions are not sufficient to allow patients to get a good night’s sleep.

References

1. NIH State-of-the-Science Conference Statement on manifestations and management of chronic insomnia in adults. NIH Consens State Sci Statements. 2005;22(2):1-30.
2. Bootzin RR, Perlis ML. Nonpharmacologic treatments of insomnia. J Clin Psychiatry. 1992;53(suppl):37-41.
3. HLBI Working Group on Insomnia. 1998. NIH Publication 98-4088.
4. Kupfer DJ, Reynolds CF 3rd. Management of insomnia. N Engl J Med. 1997;336(5):341-346.
5. Lippmann S, Mazour I, Shahab H. Insomnia: therapeutic approach. South Med J. 2001;94(9):866-873.
6. National Center on Sleep Disorders Research, National Heart, Lung, and Blood Institute, National Institutes of Health. Insomnia: assessment and management in primary care. Sleep. 1999;22(suppl 2):S402-S408.
7. Mendelson WB, Caruso C. Pharmacology in sleep medicine. In: Poceta JS, Mitler MM, eds. Sleep Disorders: Diagnosis and Treatment. Totowa, NJ: Humana Press; 1998:137-160.
8. Erman MK. Insomnia. In: Poceta JS, Mitler MM, eds. Sleep Disorders: Diagnosis and Treatment. Totowa, NJ: Humana Press; 1998:21-51.
9. Jancin B. Psychotropics modestly raise cardiac arrest risk. Clin Psych News. April, 2000:28.
10. National Institutes of Health Consensus Conference. Drugs and insomnia: the use of medications to promote sleep. JAMA. 1984;251:2410-2414.
11. Physicians’ Desk Reference. 54th ed. Montvale, NJ: Medical Economics Co; 1999.
12. Physicians’ Desk Reference. 45th ed. Montvale, NJ: Medical Economics Co; 1991.
13. Lunesta [package insert]. Marlborough, MA; Sepracor, Inc.; 2005.
14. Ambien CR [package insert]. Bridgewater, NJ; sanofi-aventis; 2007.
15. Rozerem [package insert]. Deerfield, Il; Takeda Pharmaceuticals America; 2006.
16. Sonata [package insert]. Bristol, TN; King Pharmaceuticals; 2002.

Question-and-Answer Session

Q: Is there any way to determine when insomnia is caused by depression, anxiety, or stress?

Dr. Roth: There are data showing that people with insomnia hyperarouse.1 The belief is that people who show increased norepinephrine levels during the day or show increased brain metabolism, are vulnerable to stress. Researchers in our laboratory have tested a behavioral version of this hypothesis. People without any insomnia at all were asked whether they have difficulty sleeping when they experience stress. It turns out that those people who have more disturbed sleep in stressful circumstances, in age- and sex-matched controls, have an ~11-fold increased risk of developing insomnia in the future. We cannot identify those people today, however. I think the more interesting question is how much of that hyperarousal is due to the insomnia, rather than the cause of insomnia. I suspect it is both: hyperarousal causes insomnia and insomnia causes hyperarousal. In addition, physiological hyperarousal—the increased levels of norepinephrine—is only one kind of hyperarousal. There is equally a large body of data indicating that those who suffer from insomnia also experience cognitive hyperarousal, indicating the pathophysiology is not simply biological.

Q: Are there any data in the literature on whether non-antidepressant doses, or “hypnotic doses” of non-sedating antidepressants, have any affect on sleep disorders?

Dr. Lieberman: There have been no solid studies to indicate that primary sleep disorders can be treated by treating depression. My contention has been—and I think will continue to be—that depression and primary insomnia are two separate, distinct conditions, both of which require intervention. Though primary care clinicians may seize upon the potential to use one medication to treat two different problems, the efficacy of using a solitary agent to treat these separate conditions has not been demonstrated. I think both problems must be treated based on their individual symptomatologies, and one cannot be considered secondary to the other, though this was common in the past. Therapies must be tailored to individual patients. Using one agent for both actually results in an incompletely treated patient.

Q: Most clinicians, particularly psychiatrists, are trained to think about insomnia as a symptom of another disorder. Clinicians may look very hard for an underlying psychiatric disorder or for an associated medical problem—even an acute stressor. What percentage of patients with insomnia does not have another identifiable core cause or comorbidity with the insomnia?

Dr. Roth: The most conservative estimate is about 10%, and the most liberal estimate is 25%. A minority of patients have what is euphemistically called “primary insomnia,” or insomnia with no other condition. My guess is that the number is closer to 10% to 15%. However, comorbid insomnia is very different from secondary insomnia, in which a condition or disorder is the primary cause of insomnia. And treating that primary insomnia reverses the insomnia. Most of the insomnia is comorbid with, not secondary to, other conditions. Clinicians may be trained to infer that a patient’s depression causes their insomnia. However, if insomnia is caused by depression, treating depression should, and does, alleviate sleep disruptions. This is not the case if these conditions are comorbid. Dr. Krystal presented data from Breslau and colleagues,2 which shows that in the majority of cases, insomnia precedes the depression. The data show that treating insomnia can actually improve depression. There are also data that would suggest that if you treat depression, then the more refractory symptom is insomnia. Hence, although it is clear that insomnia often is comorbid, this does not preclude the treatment of insomnia as its own distinct condition. I treat both of those conditions when they are present.
 

Q: How should clinicians determine the duration of medication use for patients with insomnia?

Dr. Roth: The National Institutes of Health (NIH) realized that insomnia is not a symptom, but rather a chronic disorder. Ever since the 2005 NIH State-of-the-Science Consensus Conference on insomnia, all drugs approved by the Food and Drug Administration have been indicated for the long-term therapy of insomnia. Equally important, the pharmaceutical companies that are trying to get drugs on the market have to provide chronic data so that those medications can be used in long-term treatment. The decision of the NIH indicates that there is a role for chronic therapy, but for whom and under what circumstances depend very much on the patient, just as in determining treatment for patients with depressive disorders. How long has the patient had insomnia, and have they relapsed? We do not have as much longitudinal data for chronic treatment of insomnia as we do for depressive disorders. These treatment options also depend on their effects on the patient. Chronic therapy has always been an option clinically, but it is now also an option in terms of regulations, both as indicated on medication labels and in terms of clinical guidelines.

Dr. Krystal: When treatment is started, one does not know how long a patient will have insomnia. And after a patient starts pharmacologic treatment, one will not know if the patient still does have insomnia. Because of that ambiguity and the absence of data, I do trial tapers every couple of months. With the agreement of the patient, the agent is tapered to determine if he or she is better off with or without the medication. I find this to be a very practical approach until there are better data on how best to do this.

Dr. Lieberman: I agree. I think there are a couple of things that make this condition distinctive, one of which is that the majority of medications that we can use to treat it are scheduled. There is a natural resistance on the part of physicians to using long-term, scheduled products. However, I think psychiatrists in particular, are used to long-term drug therapy. They know that in cases like patients with recurrent episodes of depression, lifelong pharmacologic therapy is required, so I think they are more easily convinced to use chronic treatments for insomnia. Every patient is different. Some patients respond to a limited course of therapy; after a while the insomnia is ostensibly cured and the therapy can be withdrawn. Others are going to require lifelong therapy. But we can make the analogy to other treatments. For example, we treat diabetes with insulin over the course of a patient’s lifetime. However, some patients who have hypertension are treated temporarily and some require lifelong treatment. We do try to have some withdrawal from some of these medications, in some of these patients, some of the time. But the notion that we need to use some medications chronically, in patients who have severe recurring conditions, is not foreign. This is appropriate so long as we can make the association between that insomnia and some of the other conditions that these clinicians treat.

Q: Approximately 25% of the United States population is involved in shift work. Many of these shift workers have dysfunctional sleeping patterns, such as napping during the daytime and adopting a normal sleep-wake cycle on weekends. What is the impact on the morbidity for these patients, and what can we do for them?

Dr. Roth: A minority of patients with shift work—only 31%—have a sleep disorder, or difficulty sleeping at night and sleepiness in the day. There are two things that are important to understand in any patient. First, if you get them to sleep 8 hours during the day, which is itself an incredible challenge, they still will have difficulty staying awake at work and driving home because they are trying perform these activities in a downside of the circadian rhythm. These shift workers will have worse sleep hygiene, too, because their sleeping environment will be affected by daylight. Several trials have shown that wake-enhancing compounds, such as modafinil, can be helpful for people trying to stay awake during nightshifts. Second, the temptations not to maintain a regular sleep schedule are greater for shift workers, because, for example, they can attend their children’s t-ball games in the middle of the afternoon. More than anything else, people on rotating or night shifts need incredible lessons on sleep environment. Sleep disorder is defined as an inability to sleep despite adequate opportunity. Shift workers must have adequate opportunity, meaning 8 hours in bed in an appropriate environment. If they still cannot sleep—and 20% to 25% cannot—then some of the sleep agents previously discussed may be necessary. The use of light can be helpful in moving their internal clocks, though this may not be the best choice for shift workers with family or social obligations on weekends. Very clearly, use of medications can be helpful, but only after the patient’s opportunity to sleep has been maximized. Finally, it is most important to recognize that guaranteeing 8 hours of sleep will still not guarantee shift workers a safe drive home after a night of work.

Dr. Lieberman: There is a lot of variability from patient to patient. As a general rule of thumb, what we have tried to do in our practice is ensure that the patient understands what good sleep hygiene is. We use the cognitive interventions first, and then we use pharmacotherapeutic agents for awakening or increased alertness, and to help with sleep. But this is only after we have ensured that our patient is pretty well versed in what other things they need to do to help themselves.

Dr. Roth: I think your method is exactly right. One should start out with just cognitive-behavioral therapy, especially the behavioral approaches. However, before one decides that a patient has insomnia, one should make sure that the patient has adequate opportunity to sleep. That means adequate time in bed and an adequate sleep environment.

Dr. Krystal: For some people, you can institute these behavioral changes right away, but their sleep does not improve for several weeks. And there are some people whose anxiety is such that it is difficult to change their behavior. We published data showing that starting a sleep agent with behavioral therapy, with buy-in from the patient, can improve in sleep right away. And as long as there is a plan to taper that medication over the course of three weeks, before the full benefit of behavioral therapy kicks in, you still seem to get full benefit of the behavioral therapy. Some interesting data suggest that if you continue insomnia medication long term, the behavioral therapy benefits do not seem to manifest, perhaps because there is no motivation to change behavior.

Dr. Lieberman: I think you are right on the mark. There are some patients who are so afraid that they are not going to be able to sleep that they keep themselves awake. They lose sleep over the fact that they cannot get to sleep. I think a hypnotic agent, with those folks, may be the first order of business.   

References   

1. Nofzinger EA, Buysse DJ, Germain A, Price JC, Miewald JM, Kupfer DJ. Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry. 2004;161(11):2126-2128.   
2. Breslau N, Roth T, Rosenthal L, Andreski P. Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry. 1996;39(6):411-418.

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Weight Issues in Schizophrenia

Anita H. Clayton, MD

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Primary Psychiatry. 2006;13(3):22-24

 

Dr. Clayton is professor of psychiatric medicine at the University of Virginia in Charlottesville.

 

Disclosure: Dr. Clayton is a consultant to and on the advisory boards of Boehringer-Ingelheim, Eli Lilly, GlaxoSmithKline, Pfizer, Vela, and Wyeth; is on the speaker’s bureaus of and receives honorarium from Eli Lilly, GlaxoSmithKline, Pfizer, and Wyeth; and receives grants and/or research support from Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Neuronetics, Pfizer, and Wyeth.


 

 

Disease-Related Concerns

 

Weight gain in adulthood appears to have significant negative effects on physical health. Among women, weight gain, regardless of baseline weight, is associated with decreased physical function, diminished vitality, and increased body pain.1 In a large naturalistic study,2 nearly 40% of women 45–72 years of age gained >5 lbs in 4 years, with the leanest women who gained >20 lbs having twice the likelihood of developing role limitations due to physical problems. No difference was seen between older and younger women. In addition, adults who gain >10 lbs are at increased risk for medical illnesses and premature death.2 Adults in this group have nearly twice the risk of type II diabetes mellitus and ischemic stroke and 1.25 times the risk of coronary heart disease, compared to adults who lose or maintain a stable weight. Breast cancer risk also appears to be increased with weight gain. Impairments in physical functioning, reduced quality of life, and poor mental health are also associated with weight gain and are an additional burden for patients with schizophrenia.

 

Among individuals with schizophrenia, effects of both the disease and its treatment may contribute to weight gain, metabolic syndrome, and subsequent other impairments and functional limitations. This may be particularly true for women, as women with schizophrenia (from the National Health Interview Survey) had a significantly higher mean body mass index (BMI) than women without schizophrenia (from the National Health and Nutrition Examination Survey III [NHANES III]), 27.36 versus 24.50, respectively (P<.001).3

 

Treatment-Related Issues

 

Very few studies have examined gender differences in weight and metabolic effects in patients with schizophrenia. In addition, separating out the effects of the illness from the effects of the antipsychotic agents has been difficult. It is clear that both men and women with severe and persistent mental illness (Maryland Medicaid recipients with severe and persistent mental illness) had a higher prevalence of obesity than individuals in the general population (NHANES III and Maryland Behavioral Risk Factor Surveillance System), but only men demonstrated a 4-fold greater association between atypical antipsychotics and prevalent obesity.4 However, in a study examining several antipsychotics in patients with schizophrenia, clinically significant weight gain (>7% of baseline body weight) was experienced by 46% of patients receiving olanzapine, 31% of patients receiving risperidone, and 22% of patients receiving haloperidol.5 No subjects treated with quetiapine gained >7% of their baseline body weight. The risk of weight gain was higher in women (odds ratio [OR] 4.4), overweight patients (OR 3.0), and in women receiving risperidone (OR 2.6). Perhaps women with schizophrenia have a greater risk of obesity related to their disease, whereas men may have that risk further increased by treatment with atypical antipsychotics not associated with elevations in prolactin levels.

 

To sort out the effect of disease versus treatment, 15 men and 4 women with drug-naïve, first-episode schizophrenia were evaluated for obesity/fat distribution parameters and 24-hour plasma cortisol levels, and compared to age- and sex-matched controls.6 Patients were treated with olanzapine or risperidone for 6 months, followed by reassessment of the adiposity parameters. At baseline, the patients with schizophrenia had significantly more intra-abdominal fat as measured by computerized tomography and anthropometry, which did not change with treatment. Higher baseline cortisol levels significantly decreased with antipsychotic treatment. No differences were demonstrated between the two antipsychotics. In an open-label study involving the use of olanzapine in six men and three women experiencing their first psychotic episode, a median increase in body weight of 4.7 kg was seen within 12 weeks, a significant increase of >7% from first assessment (within 7 weeks of diagnosis).7 Body fat also increased significantly, primarily as central fat deposits. Fasting insulin, C-peptide, and triglyceride levels significantly increased within 3 months of treatment initiation, but glucose levels did not. Neither did cholesterol or leptin levels. This may suggest insulin resistance, with a decrease in fat oxidation as a secondary or predisposing mechanism for weight gain with antipsychotics, explaining how weight gain and metabolic effects may occur together or independently in patients receiving antipsychotics. Similar outcomes were seen with clozapine in one study (11 women and 8 men),8 with early increases in circulating leptin levels inversely correlated with weight gain over the following 6–8 months (13 men and 9 women) in another trial.9

 

Long-term studies are important, as most patients with schizophrenia require life-long therapy. In one naturalistic 5-year study, patients with schizophrenia were at increased risk of weight gain through month 46 from initiation of clozapine, and of developing diabetes mellitus (36.6%). Weight gain was not a significant risk factor for the onset of diabetes, so these factors appear independent, but co-occurring.10 In addition, calculations reveal that the lives saved from suicide through treatment with clozapine are essentially offset by the additional deaths associated with a 10 kg weight gain.11

 

The Clinical Antipsychotic Trials of Intervention Effectiveness data support these concerns with some of the atypical antipsychotics, as 30% of patients receiving olanzapine gained >7% of their baseline body weight versus 7% to 16% with other antipsychotics.12 Average weight gain with olanzapine was 2 lbs/month. Comparable problems were seen with blood glucose, cholesterol, triglycerides, and hemoglobin A1c. Discontinuation secondary to weight gain and metabolic side effects over the 18 months of the trial was 9% with olanzapine versus 1% to 4% with the other drugs. Other differences among agents included improvement in metabolic effects with ziprasidone and an increase in prolactin levels with risperidone. However, only 25% of the subjects in the trial were women.

 

Women may have a different propensity for weight gain with antipsychotics than men because premenopausal women with schizophrenia require lower medication doses for effective treatment and because women have less of a predisposition for visceral fat storage. However, since 1987, the mean BMI for women with schizophrenia 18–30 years of age has increased dramatically and significantly when compared to women in the general population.13 One factor may be a combination of medications, which can further contribute to weight gain. Women are more likely to have an associated mood disorder requiring additional medication intervention, which may result in subsequent weight gain. However, in an 8-week trial of patients with borderline personality disorder, the combination of fluoxetine with olanzapine was associated with less weight gain than olanzapine alone.14 Women also appear more likely to suffer with hyperprolactinemia secondary to antipsychotics than men, and as a result may experience abnormal menstrual cycles and weight gain. However, iatrogenic weight gain (mean weight increase of 27%) does not explain the emergence of irregular menses (23%) among premenopausal women with psychotic illness taking clozapine.15 Other factors contributing to weight gain may include diet, smoking, exercise, substance use, and hormonal transitions.16

 

Management Options

 

Use of the lowest possible dose of antipsychotic medication may reduce the likelihood of weight gain, as insulin levels have been positively correlated to serum concentration of clozapine.17 Premenopausal women generally require lower doses than men or postmenopausal women. Minimizing additional concomitant medications will also reduce potential weight gain. When other medications are required, utilizing those not associated with weight gain is recommended. Such medications may include lamotrigine, bupropion, and topiramate. Education about interventions such as nutrition, exercise, and living a healthy lifestyle may limit weight gain, as a 6-month study demonstrated a mean weight change in the intervention group of -0.06 lbs versus +9.57 lbs in the standard care group.18 Good general health maintenance may also mitigate against weight gain, so routine monitoring of weight, blood pressure, fasting blood glucose, and lipids is recommended. Once problems with weight gain or metabolic syndrome have been identified, treatment should be instituted immediately, and consideration should be given to change of antipsychotic medication to ziprasidone, quetiapine, and possibly aripiprazole. A long-term view is required, as patients with schizophrenia will require life-long treatment with a goal to maintain general health status. PP

 

References

 

1. Fine JT, Colditz GA, Coakley EH, et al. A prospective study of weight change and health-related quality of life in women. JAMA. 1999;282(22):2136-2142.

 

2. Kawachi I. Physical and psychological consequences of weight gain. J Clin Psychiatry. 1999;60(suppl 21):5-9.

 

3. Allison DB, Fontaine KR, Heo M, et al. The distribution of body mass index among individuals with and without schizophrenia. J Clin Psychiatry. 1999;60(4):215-220.

 

4. Daumit GL, Clark JM, Steinwachs DM, Graham CM, Lehman A, Ford DE. Prevalence and correlates of obesity in a community sample of individuals with severe and persistent mental illness. J Nerv Ment Dis. 2003;191(12):799-805.

 

5. Bobes J, Rejas J, Garcia-Garcia M, et al. Weight gain in patients with schizophrenia treated with risperidone, olanzapine, quetiapine or haloperidol: results of the EIRE study. Schizophr Res. 2003;62(1-2):77-88.

 

6. Ryan MC, Flanagan S, Kinsella U, Keeling F, Thakore JH. The effects of atypical antipsychotics on visceral fat distribution in first episode, drug-naive patients with schizophrenia. Life Sci. 2004;74(16):1999-2008. Erratum in: Life Sci. 2004;75(23):2851.

 

7. Graham KA, Perkins DO, Edwards LJ, Barrier RC Jr, Lieberman JA, Harp JB. Effect of olanzapine on body composition and energy expenditure in adults with first-episode psychosis. Am J Psychiatry. 2005;162(1):118-123.

 

8. Kivircik BB, Alptekin K, Caliskan S, et al. Effect of clozapine on serum leptin, insulin levels, and body weight and composition in patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27(5):795-799.

 

9. Monteleone P, Fabrazzo M, Tortorella A, La Pia S, Maj M. Pronounced early increase in circulating leptin predicts a lower weight gain during clozapine treatment. J Clin Psychopharmacol. 2002;22(4):424-426.

 

10. Henderson DC, Cagliero E, Gray C, et al. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: A five-year naturalistic study. Am J Psychiatry. 2000;157(6):975-981.

 

11. Fontaine KR, Heo M, Harrigan EP, et al. Estimating the consequences of anti-psychotic induced weight gain on health and mortality rate. Psychiatry Res. 2001;101(3):277-288.

 

12. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223.

 

13. Homel P, Casey D, Allison DB. Changes in body mass index for individuals with and without schizophrenia, 1987–1996. Schizophr Res. 2002;55(3):277-284.

 

14. Zanarini MC, Frankenburg FR, Parachini EA. A preliminary, randomized trial of fluoxetine, olanzapine, and the olanzapine-fluoxetine combination in women with borderline personality disorder. J Clin Psychiatry. 2004;65(7):903-907.

 

15. Feldman D, Goldberg JF. A preliminary study of the relationship between clozapine-induced weight gain and menstrual irregularities in schizophrenic, schizoaffective, and bipolar women. Ann Clin Psychiatry. 2002;14(1):17-21.

 

16. Seeman MV. Gender differences in the prescribing of antipsychotic drugs. Am J Psychiatry. 2004;161(8):1324-1333.

 

17. Melkersson KI, Hulting AL. Insulin and leptin levels in patients with schizophrenia or related psychoses—a comparison between different antipsychotic agents. Psychopharmacology (Berl). 2001;154(2):205-212.

 

18. Littrell KH, Hilligoss NM, Kirshner CD, Petty RG, Johnson CG. The effects of an educational intervention on antipsychotic-induced weight gain. J Nurs Scholarsh. 2003;35(3):237-241.

 

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