Management of Painful Physical Symptoms Associated With Depression and Mood Disorders
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.
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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.
• 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.
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
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
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.
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.
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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.
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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
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.
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.
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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
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.
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.
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.
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
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.
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.
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.
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