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.

 

 

Dr. Robinson is a consultant with Worldwide Drug Development in Burlington, Vermont.

Disclosure: Dr. Robinson has served as a consultant to Bristol-Myers Squibb, CeNeRx, Epix, Genaissance, Johnson and Johnson, Medicinova, PGxHealth, Pfizer, and Somerset.

 

Patients with schizophrenia suffer mortality rates estimated to be twice that of the general population and have a foreshortened life expectancy.1,2 The excess mortality associated with the diagnosis of schizophrenia is attributable to greater numbers of fatalities due to both natural and unnatural causes of death.3 Increased suicide rates among patients with schizophrenia is well documented, but other causes of excess mortality in this patient population are less clear. Implicated as contributing factors to the high mortality rate are medical illnesses often associated with schizophrenic disorders and, in some instances, possible adverse effects of antipsychotic treatment.

 

Schizophrenia and Risk of Suicide

Nearly one-third of the excess mortality in schizophrenia is attributable to the significantly higher risk of suicide, with an additional 12% due to accidental death. Several large cohort studies clearly document the increased rate of suicide among patients with schizophrenia.3,4 Meta-analyses of studies of long-term outcomes over the course of the disorder estimate the incidence of death by suicide in schizophrenia to be 5% over the patient’s lifetime. Young male patients are particularly liable to commit suicide, especially during the early months following diagnosis of the disorder. 

 

Increased Mortality Due to Natural Causes

Mortality data indicate that patients with schizophrenia also have higher fatality rates due to natural causes of death compared with that of the United States general population.3 Cardiovascular, respiratory, and metabolic disorders are 2–3 times more prevalent in schizophrenia than in the population as a whole and contribute to moderately increased mortality rates from natural causes.5,6 Unhealthy life styles, polypharmacy, and suboptimal health care are all regarded as contributing factors to higher mortality risk. Pleas to implement preventive measures focus on reducing the dramatically increased mortality of schizophrenic patients by more diligent treatment of affective symptoms, improving overall treatment compliance, and greater vigilance in enforcing healthier lifestyles.7,8

 

Antipsychotics and Adverse Cardiac Effects

In addition to sequelae of medical problems associated with schizophrenia, antipsychotics have been implicated as contributing factors. There is some evidence that antipsychotics may cause sudden cardiac death or stroke. A case-controlled survey of medical practices within a network of 150 general practitioners over a 6-year period (1995–2001) found a 3-fold increase in the rate of sudden cardiac deaths associated with antipsychotics in primary care patients.9 The highest rate of sudden cardiac death was in patients receiving treatment with a butyrophenone, a class of antipsychotics known to prolong the QT interval and a particular concern with thioridazine.9 Increased rates of sudden cardiac death as compared with matched controls were apparent even at low doses of antipsychotics. Although in this study a majority of patients were receiving a conventional antipsychotic, adverse cardiac effects associated with atypical antipsychotic use were also noted.10

Atypical antipsychotics are established risk factors for development of diabetes mellitus and the metabolic syndrome. These adverse effects over time indirectly result in cardiovascular sequelae and higher death rates.5 Diabetes and dyslipidemias from extended exposure to atypical antipsychotics, especially clozapine and olanzapine, can lead to atherosclerosis, coronary artery disease, and other vascular lesions.

 

Antipsychotics in Elderly Patients

Increased rates of cerebrovascular events in dementia trials evident in 2001 for risperidone11 and in 2004 for olanzepine12 prompted the decision by the United Kingdom Committee on the Safety of Medicines to warn clinicians about potential risk of stroke with these two agents. In April 2005, the US Food and Drug Administration undertook a meta-analysis of 17 controlled clinical trials conducted for aripiprazole, olanzapine, quetiapine, and risperidone, involving >5,000 patients with dementia-related psychotic symptoms. Nearly all the clinical trials in the FDA analysis exhibited at least a small but significant increase in mortality compared with placebo treatment. This suggested that the finding was a class effect and not due to bias introduced by aberrant data from a few clinical trials.13 The FDA analyses found an approximately 50% higher incidence of stroke with atypical antipsychotics in dementia trials. It led to requiring “black box” warnings in the product labeling for all atypical antipsychotics. The FDA further admonished drug prescribers that atypical antipsychotics had not received approval for a dementia indication. Subsequent to the FDA meta-analysis, similar results were reported by a second group of investigators, which appeared to replicate the findings.13

Questions remain whether these stroke data associated with use of atypical antipsychotics are reliable.14 No mechanism accounting for this largely unexpected finding has been clearly delineated. Proposed theories for apparent increased risk of stroke include increased platelet aggregation due to increased prolactin levels; serotonin blocking effects of atypical antipsychotics; hypotension with small vessel disease; and increased coagulability caused by adverse metabolic effects of these agents on triglycerides, cholesterol, leptin, and glucose.

A cohort analysis of Medicare data of first-time recipients of conventional and atypical antipsychotics (22,000 patients ≥65 years of age) found a 37% higher mortality with conventional versus atypical antipsychotics.15 An unexpected finding of the study was the surprising fact that >25% of Medicare beneficiaries in nursing homes within the state where the survey was conducted received an antipsychotic. However, not all studies of hospitalizations for stroke involving dementia patients have confirmed an association of neurologic sequelae and treatment with conventional or atypical antipsychotics.16

The FDA analysis was confined to elderly patients in clinical trials for dementia and applied only to atypical antipsychotics. Consequently, more definitive data are needed to assess risk-benefit of antipsychotic use in older patients. Presently available information is largely extrapolated from experience with treatment of younger patients or elderly patients with dementia.

 

Mortality Risk of Atypical Antipsychotics in Younger Adults

A recent study examined mortality of patients with schizophrenia during treatment with an atypical antipsychotic in pre-approval clinical trials.17 This review of data derived from FDA summary documents in the public domain permitted assessment of mortality during treatment with several of the newer atypical antipsychotics in clinical trials conducted during the period from 1982–2002. It examined experience in >12,000 patients receiving atypical (investigational) antipsychotics, 2,900 receiving conventional antipsychotics, and 1,200 receiving placebo treatment. Mortality rates based on patient exposure years were 2,055/100,000 for atypical antipsychotics versus 8,081/100,000 for placebo (P<.05). The mortality rate for placebo treatment was significantly higher than that for either atypical or conventional antipsychotic treatment. Suicide was the leading cause of death (28%) during atypical antipsychotic treatment, followed by cardiovascular (18%) and respiratory (17%) disorders. Complete data were unavailable to assess causes of death with the other two treatments. Overall mortality rates for each of three treatment groups, however, exceeded the mortality rate for the general population (850/100,000), an outcome consistent with the finding of higher mortality risk for schizophrenia, as discussed above.

 

Conclusion

Patients with schizophrenia experience higher mortality rates than the general population. The excess mortality is due to both significant suicide risk and a higher likelihood of death from natural causes. Antipsychotics have been impugned as causing increased mortality and strokes in demented elderly patients, which led to the FDA warning included in the current labeling of atypical antipsychotics. No definitive mechanism for the purported adverse events of atypical antipsychotics in elderly dementia patients has been identified. Recent cohort studies suggest there is a similar increased mortality risk with use of conventional antipsychotics in dementia patients. Analyses of pre-approval clinical trial data for the atypical antipsychotics in schizophrenia find a lower mortality risk during treatment with antipsychotics compared with placebo treatment, although all of the groups experienced higher mortality than for the general population. PP

 

References

1.    Amaddeo F, Bisoffi G, Bonizzato P, Micciolo R, Tansella M. Mortality among patients with psychiatric illness. A ten-year case register study in an area with a community-based system of care. Brit J Psychiatry. 1995;166(6):783-788.
2.    Newman SC, Bland RC. Mortality in a cohort of patients with schizophrenia. Can J Psychiatry. 1991;36(4):239-245.
3.    Brown S. Excess mortality of schizophrenia. A meta-analysis. Brit J Psychiatry. 1997;171:502-508.
4.    Palmer BA, Pankratz VS, Bostwick JM. The lifetime risk of suicide in schizophrenia. Arch Gen Psychiatry. 2005;62(3):247-253.
5.    Casey DE. Metabolic issues and cardiovascular disease in patients with psychiatric disorders. Am J Med. 2005;118(suppl 2):12S-22S.
6.    Enger C, Weatherby L, Reynolds RF, Glasser DB, Walker AM. Serious cardiovascular events and mortality among patients with schizophrenia. J Nerv Ment Dis. 2004;192(1):19-27.
7.    Auquier P, Lançon C, Rouillon F, Lader M, Holmes C. Mortality in schizophrenia. Pharmacolepidemiol Drug Saf. 2006;15(12):873-879.
8.    Hawton K, Sutton L, Haw C, Sinclair J, Deeks JJ. Schizophrenia and suicide: systematic review of risk factors. Br J Psychiatry. 2005;187:9-20.
9.    Straus SM, Bleumink GS, Dieleman JP, et al. Antipsychotics and the risk of sudden cardiac death. Arch Int Med. 2004;164(12):1293-1297. Erratum in: Arch Intern Med. 2004;164(17):1839.
10.    Merrill DB, Dec GW, Goff DC. Adverse effects associated with clozapine. J Clin Psychopharmacol. 2005;25(1):32-41.
11.    Wooltorton E. Risperidone (Risperdal): increased rate of cerebrovascular events in dementia trials. CMAJ. 2002;167(11):1269-1270.
12.    Wooltorton E. Olanzapine (Zyprexa): increased incidence of cerebrovascular events in dementia trials. CMAJ. 2004;170(9):1395.
13.    Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of random placebo controlled trials. JAMA. 2005;294(15):1934-1943.
14.    Friedman JH. Atypical antipsychotics in the elderly with Parkinson disease and the “black box” warning. Neurology. 2006;67(4):564-566.
15.    Wang PS, Schneeweiss S, Avorn J, et al. Risk of death in elderly users of conventional versus atypical antipsychotic medications. N Engl J Med. 2005;353(22):2335-2341.
16.    Liperoti R, Gambassi G, Lapane Kl, et al. Cerebovascular events among elderly nursing home patients treated with conventional or atypical antipsychotics. J Clin Psychiatry. 2005;66(9):1090-1096.
17.    Khan A, Schwartz K, Stern C, et al. Mortality risk in patients with schizophrenia participating in premarketing atypical antipsychotic clinical trials. J Clin Psychiatry. 2007;68(12):1828-1833.

 

Dr. Trujillo is professor of psychiatry and director of the Program for Public and Global Psychiatry at New York University School of Medicine in New York City.

Disclosures: Dr. Trujillo reports no affiliation with or financial interest in any organization that may pose a conflict of interest.
Please direct all correspondence to: Manuel Trujillo, MD, Professor of Psychiatry & Vice-Chair, Public & Global Psychiatry, Department of Psychiatry, NYU School of Medicine, 462 First Avenue, Room A648, New York, NY 10016; Tel: 212-263-6220; Fax: 212-263-8097; E-mail: manuel.trujillo@nyumc.org; Website: www.med.nyu.edu/people/M.Trujillo.html.

 


 

Focus Points

• The reduction of health disparities has become a national priority for health and mental health.
• A growing body of knowledge will help clinicians guide the treatment of minorities.
• This body of knowledge encompasses and can serve as a guide to assessment and diagnosis as well as medical, psychiatric, and psychosocial treatments.

 

Abstract

Health disparities, defined as population-specific differences in the prevalence, onset, severity of disease, and differential access to health care, is a rising issue in the mental healthcare debate. The populations most seriously affected by adverse health disparities include protected minorities who often seek and receive care through language and cultural barriers. This article discusses a body of knowledge, skills, and attitudes which can help clinicians bridge the care gaps created by such barriers. The article highlights means to overcome these barriers while performing diagnostic interviews, completing mental status examinations, and selecting and implementing pharmacologic and psychosocial treatments.

 

Introduction

Psychiatrists currently practicing in the United States and in many other countries around the world will undoubtedly have the opportunity to treat many patients belonging to ethnic and cultural groups different than their own. Such is the nature and magnitude of population changes since the end of World War II, which has accelerated through globalization in the last 2 decades. Though such changes will ultimately enrich the practice of psychiatry and its scientific knowledge base, it will, for many transitional years, present significant challenges to the practicing clinician, systems of care and training, and policy makers. Many such patients will have limited command of the English language and will probably hold beliefs about illness and health at some variance from the standard biomedical model that supported the psychiatrist’s training and that has evolved in the US and other Western countries over the last century. Fortunately for the practicing psychiatrist, patients in their care, and healthcare systems that support their work, the growing discipline of cultural psychiatry is developing a substantive and increasingly sophisticated body of knowledge that will enhance the psychiatrist’s capacity to provide quality care across language and cultural barriers. As this knowledge base is mastered, the contemporary psychiatrist will be equipped with the attitudes, basic knowledge, clinical skills, and professional attitude necessary. In confronting the clinical task of providing psychiatric treatment to patients from different cultural groups, psychiatrists have a decisive advantage; namely, their familiarity with Engel’s biopsychosocial model,1 which has long facilitated our understanding of the complex interactions that link our biologic systems to the contents of our minds and to the social environment in which we become unique individuals.

In the context of a well-constructed biopsychosocial formulation, it is relatively easy to understand cultural adscription and identity as a significant specifier of our social context. Enriched with the insights provided by cultural psychiatry, the biopsychosocial model can easily become a biopsycho-sociocultural model. The ultimate end of this process is the construction of a science of the person, culture being a very meaningful frame through which personhood emerges and expresses itself. The end result of acquiring relevant cultural knowledge will be, for the psychiatrist, an enhanced ability to provide culturally competent care, which is an increasingly common requirement of professional societies, regulatory agencies, and licensing and accrediting organizations.

 

Cultural Psychiatry

Before moving on to more clinical grounds, a few basic definitions are in order. Cultural psychiatry is defined as the discipline within psychiatry that studies the numerous interrelationships between culture and psychiatry. As such, it aims to understand variations of the incidence, prevalence, clinical expression, course, and/or outcome of common psychiatric disorders as they appear in different societies and ethnic or cultural groups. The value of such understanding includes the promotion of diagnostic and prognostic accuracy, the development of culturally syntonic interventions, and the achievement of a therapeutic partnership where the patient feels understood and supported. The American Psychiatric Association (APA) has recognized the importance of culture by addressing cultural variations in the text description of most of the major psychiatric disorders listed in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV),2 and by providing guidance to the development of cultural formulations.

A second aim of cultural psychiatry includes the careful description and tracking of patterns of symptoms and behaviors which, first, do not conform to the syndromes described so far in the DSM-IV-TR3 or the International Classification of Diseases, Tenth Edition (ICD-10),4 and second, are closely associated with certain cultural and/or ethnic groups including their belief systems and “idioms of distress.” These syndromes are commonly known as culture-specific or culture-bound syndromes and are recognized and listed in the DSM-IV.

A third aim of cultural psychiatry includes the elucidation and delineation of the pathways that transform culturally derived or mediated stresses into symptoms, syndromes, and adaptive or maladaptive behaviors. This is an area in need of much research if we are to understand basic clinical facts such as the gross variation in incidence and prevalence of major psychiatric disorders observed as a function of a given population ethnic origin, migratory status, and/or acculturation pressures.

 

Culture, Race, and Ethnicity

The diverse origin and confused utilization of these constructs have represented a significant obstacle to progress in the fields of cultural psychiatry and psychology.

Race typically denotes the description of individuals through compelling (but of questionable biologic significance) phenotypic features such as skin color, hair texture, and a few facial features. Some biomedical scientists have argued for the validity of such racial classifications to understand population’s variance in the prevalence of traits such as sickle cell anemia. However, even in such cases, the correlation between trait and race is far from perfect, since sickle cell anemia traits distribute not only among African blacks but also among other Mediterranean and Middle Eastern people. However limited the true biologic value of the construct of race, its social use has had (and unfortunately still has) devastating personal and group consequences through the attitudes and institutions of racism. The construct of ethnicity, a term much preferred by social scientists and anthropologists, may be of more value to psychiatrists since it denotes groups of individuals sharing a sense of common identity, a common ancestry, and shared beliefs and history. Thus, the construct ethnicity, a major contributor to the person’s cultural identity, is an internalized self-definition resulting for the person’s selective incorporation of values, beliefs, foundation myths, and customs from among those available in that person’s human ecology.

Such cultural identity holds great meaning to the person and needs to be ascertained in the clinical interview if the clinician is to develop a sound cultural formulation of their patient’s presenting complaints. Key dimensions of cultural identity include race, gender, language, sexual orientation, ethnic adscription, and religious and spiritual beliefs.

The term “culture” is as key a concept for psychiatry and psychology as it is difficult to define. As defined by the noted British anthropologist Sir Edward Tylor in 1871,5 culture is “the complex whole which includes knowledge, beliefs and morals and other capabilities and habits acquired by man as a member of society.”

For clinical purposes, the definition provided by the National Institute of Mental Health’s Culture and Diagnosis Group may be the most comprehensive and descriptive:

 

Culture refers to meanings, values and behavioral norms that are learned and transmitted in the dominant society and within its social groups. Culture powerfully influences cognition, feelings, and self-concept as well as the diagnostic process and treatment decisions.6

Culture is thus best conceptualized as a totality, composed of a complex system of symbols possessing subjective dimensions represented by values, feelings, and ideals, as well as objective dimensions expressed in the form of beliefs, traditions, and behavioral prescriptions, some of which may be articulated into rituals and codified as laws. This unique capacity of culture to bind the objective world of perceived reality to the subjective world of the personal and intimate lends it its powerful role as expressor, mediator, and moderator of psychological processes and, ultimately, emotional well being or disorder.

 

Through little known mechanisms, culture influences cognitions, feelings, emotional conflicts, self-concept, and the underlying brain functions that control mood and behavior. Culture also represents a normative framework that defines normality and deviance, thus promoting certain behaviors while suppressing others. This process may set the stage for psychological stress and intrapsychic conflict.

It is important to emphasize the great diversity and heterogeneity of each ethnic group. The labels African American, Asian, Hispanic, and Native American, among others, are super-ordinate constructs that hide more than reveal a tremendous diversity of racial features, historic legacies, belief systems, behavioral traits, and the like. As such, clinicians should use these generalized labels as a step in the road to understanding the unique individual that becomes their client. Beyond such provisional labels one must inquire the specific parameters of racial background, native language, religious coordinates, and socioeconomic conditions that define the specific and unique person.

 

Culture and Clinical Psychiatry

The relationship between culture and clinical psychiatry can certainly be studied through three vantage points. First, the presence of health disparities. Second, the clinical encounter across the language and cultural barrier. Last, the presence of culture-bound syndromes.

 

Health Disparities

Health disparities represent a clearly visible effect of cultural and linguistic minority status and are generally defined as population specific differences in domains of health such as incidence of illness, access to care, or outcomes of care.

In the US, health disparities are well documented in minority populations such as African Americans, Asians Americans, Native Americans, and Hispanics. Though much additional research is needed, health disparities can be causally related to barriers to prompt access to care of adequate quality; problems in providing such care across the language, culture, and health beliefs divide; and the compounding health effect of poverty and its attendant adverse environmental conditions.

The most common barriers to care affecting the presence of health disparities include lack of health insurance (or underinsurance), stigma, consumer’s unawareness of the availability or underappreciation of the efficacy of treatment, and health providers’ lack of awareness of the availability of culturally syntonic treatments.

The impact of the linguistic barriers in the clinical encounter needs to be highlighted. In so far as oral communication is the main vehicle for the transmission of mental health information, clinicians need to make significant efforts to compensate for its relative absence when examining and treating monolingual patients (or limited bilinguals) who speak a language different than their own. Language is the key for the patient’s symbolic universe; it determines which words access what emotions and, in bilinguals, which language serves to enhance communication and emotional contact with the therapist and which language can be used as a defense.

When compensating for a linguistic barrier through translation and interpretations, the clinician is best served by some skepticism. A clinician should ask a question several times and from different angles so that the composite picture has additional chances to approximate the clinical reality.

The Surgeon General Culture Race and Ethnicity supplement to the Mental Health Report7 highlights recognized minority health disparities. Tables 1–4 aggregate and summarize minorities’ clinical and health behavior observations for underrepresented groups in the US who experience documented health disparities.

 

 

 

 

 

 

 

Culture and Psychiatric Diagnosis

Cumulative cross-cultural research can help the clinician arrive at a comprehensive diagnosis of patients evaluated across the language and cultural barriers. Such patients could in theory present three different diagnostic pictures. First, the patient may suffer an episode of illness easily clarifiable as a typical DSM-IV-TR syndrome. Alternatively, the patient may present with a syndrome with specific cultural features which warrant special evaluative care. In this regard, the DSM-IV-TR  discusses cultural features for most major diagnoses. Last, the patient meets the description of one (or more) of the culture-bound syndromes reported in the literature, congruent with the patients’ culturally mediated idioms of distress.

 

Cultural Features of Major Psychiatric Diagnosis

Schizophrenia
The diagnosis of schizophrenia depends on the significant presence over a 1-month period of two out of five of the following symptoms: delusions, hallucinations, disorganized speech, disorganized behavior and negative symptoms, and social dysfunction. Social dysfunction is further defined as a significant erosion of work, interpersonal roles or self-care below the level of achievement prior to the onset of illness. All these criteria are subject to attained distortion through the cultural lens. In some cultures (eg, Mediterranean and Hispanic) visual or auditory hallucinations of religious objects, persons, or theme, may be a component of certain religious experiences or may appear as part of other disorders such as dissociative phenomena or psychomotor epilepsy. Some care should be exercised while diagnosing delusional ideas. The boundaries between ideas, overvalued ideas, beliefs, and delusions are also heavily mediated by culture, especially around issues such as demonic possession and paranormal influences (hexing, sorcery, witchcraft) in general.

The criterion “disorganized speech” is extremely difficult to assess in a monolingual patient by a clinician who is unfamiliar with the patient’s language. The articulation of language, sentence structure, and the logical order and focus of speech are also mediated by culture, educational level, and by perceived power differential between speakers.

The evaluation of affect (another key criterion for a schizophrenia diagnosis) is also complex, especially as it pertains to evaluating its congruence with mental content that is produced in a language that the clinician may not understand. Intensity and range of affect are also heavily mediated by culture and by the authority differentials in the therapeutic relationship. Finally, the evaluation of dysfunction has to be adjusted to the norm which constitutes the patient’s adaptive ecology, since “functioning” is heavily shaped by expectations derived from culture and dependent on socioeconomic status.

Depression
In the case of depression, culture can influence the prevalence rates, subjective experience of depression, and preferred channel for the expression of emotions. In some cultures (and socioeconomic conditions) depression may be communicated to the clinician in somatic terms such as fatigue, anergia, headaches, and malaise (“malestar” for some Hispanic populations). Symptoms such as sadness, guilt, and other psychological representations of the depressive experience may not be reported spontaneously during the clinical interview, and its elicitation may need a more active inquiry from the clinician than is the norm when interviewing patients from their own ethnic group.

Anxiety
The experience of anxiety may also be culturally mediated. As in the case of depression, the somatic expression (palpitations, tachycardia, fainting sensations) is emphasized in many cultures over the psychic content. The situational triggers for some episodes of anxiety, including panic, are also often culturally mediated. The fear of being “hexed” or subjected to witchcraft or other forces with malevolent intent may reach to panic proportions.

 

Culture-Bound Syndromes

In evaluating a patient to establish a differential diagnosis for a possible culture-bound syndrome, the clinician should consider the following. First, reflect on the cultural assumptions under which the Western biomedical model of diagnosis and treatment operates. After all, the constructs of illness defined in the DSM-IV-TR and ICD-10 classifications systems represent a uniquely western amalgam of objective knowledge and culturally mediated ideas, as derived from repeated medical observations on patients acculturated to the “Western” medical and social explanatory framework. A dose of cultural humility is the optimum result of such reflection.

Second, as psychiatric disorders, whatever their biologic determinants, usually find expressions through ideas, beliefs, and behavior, all societies have found ways to separate the normal from the abnormal. They all devise rules to attribute causality and motivation to such behaviors. Each culture (and person for that matter) creates an “explanatory framework” for such behaviors which must be teased out during the clinical encounter since it represents a rich lode for therapeutic intervention.

Third, be alert to the presence of symptoms such as unusual forms of anxiety, apathy, and significant withdrawal; sudden outbursts of angry and difficult to explain aggressive behavior; bizarre and unconventional motor behaviors (such as trance-like taking off of clothes, thrashing about, shouting swearing); prominent dissociation; sleep problems with parasomnias; and many others.

Last, ask patients (and their families and other culturally aware informants) about their own and their cultural group’s explanations for those symptoms and behaviors, and assess their “fit” with known culture-bound syndromes.

The APA’s glossary lists3 and describes succinctly some of the best studied culture-bound syndromes and idioms of distress that may be encountered in clinical practice in North America.

Amok
A dissociative episode characterized by a period of brooding followed by an outburst of violent, aggressive, or homicidal behavior directed at people and objects. The episode tends to be precipitated by a perceived slight or insult and seems to be prevalent among men. The episode is often accompanied by persecutory ideas, automatism, amnesia, exhaustion, and return to a premorbid state after the episode. Some instances of amok may occur during a brief psychotic episode or constitute the onset or exacerbation of a chronic psychotic process. Severe bereavement and serious interpersonal results have been noted as precipitants.

Ataque de Nervios
Ataque de nervios is an idiom of distress that is principally reported among Latinos from the Caribbean but recognized among many Latin American and Latin Mediterranean groups. Commonly reported symptoms include uncontrollable shouting, attacks of crying, trembling, heat in the chest rising into the head, and verbal or physical aggression. Dissociative experiences, seizure-like or fainting episodes, and suicidal gestures are prominent in some attacks but absent in others. A general feature of an ataque de nervios is a sense of being out of control. Ataques de nervios frequently occur as a direct result of a stressful event relating to the family (eg, news of the death of a close relative, a separation or divorce from a spouse, conflicts with a spouse or children, witnessing an accident).

Boufée Délirante
Boufée Délirante is a syndrome observed in West Africa and Haiti. This French term refers to a sudden outburst of agitated and aggressive behavior, marked confusion, and psychomotor excitement. It may sometimes be accompanied by visual and auditory hallucinations or paranoid ideation. These episodes may resemble an episode of brief psychotic disorder and need careful differential diagnosis.

Brain Fag
Brain fag is a term initially used in West Africa to refer to a condition experienced by high school or university students in response to the challenges of schooling. Symptoms include difficulties in concentrating, remembering, and thinking. Students often state that their brains are fatigued. Additional somatic symptoms are usually centered around the head and neck and include pain, pressure or tightness, blurring of vision, heat, or burning. Brain tiredness or fatigue from too much thinking is an idiom of distress in many cultures and resulting syndromes can resemble certain anxiety, depression, and somatoform disorders.

Dhat
Dhat is a folk diagnostic term used in India to refer to severe anxiety and hypochrondriacal concerns associated with the discharge of semen, whitish discoloration of the urine, and feelings of weakness and exhaustion. It is similar to jiryan (India), sukra prameha (Sri Lanka) and shen-k’uei (China).

Falling Out or Blacking Out
Episodes of falling out or blacking out occur primarily in the southern US and in Caribbean groups. They are characterized by a sudden collapse, which sometimes occurs without warning but sometimes is preceded by feelings of dizziness. The individual’s eyes are usually open, but the person may claim an inability to see. The person usually hears and understands what is occurring around him or her but feels powerless to move. This may correspond to a diagnosis of conversion disorder or a dissociative disorder.

Ghost Sickness
A preoccupation with death and the deceased (sometimes associated with witchcraft) frequently observed among members of many American Indian tribes. Various symptoms can be attributed to ghost sickness, including bad dreams, weakness, feelings of danger, loss of appetite, fainting, dizziness, fear, anxiety, hallucinations, loss of consciousness, confusion, feelings of futility, and a sense of suffocation.

Hwa-Byung
Hwa-byung (also known as Wool-Hwa-Byung) is a Korean folk syndrome that is literally translated into English as anger syndrome and is attributed to the suppression of anger. The symptoms include insomnia, fatigue, panic, fear of impending death, dysphoric affect, indigestion, anorexia, dyspnea, palpitations, generalized aches and pains, and a feeling of a mass in the epigastrium.

Koro
Koro is a term, probably of Malaysian origin, that refers to an episode of sudden and intense anxiety that the penis (or, in women, the vulva and nipples) will recede into the body and possibly cause death. The syndrome is reported in south and East Asia, where it is known by a variety of local terms such as shook yong and suo yang (Chinese), jinjinia bemar (Assam), or rok-joo (Thailand). It is occasionally found in the West. Koro at times occurs in localized epidemic form in east Asian areas. This diagnosis is included in the Chinese Classification of Mental Disorders, Third Edition (CCMD-3).8 Subjective ideas of genital change may be more common in the general population and among other psychiatric disorders than generally realized.

The fact that genital retraction symptomatology has been reported in association with stimulant abuse (amphetamines) and heroin withdrawal, as well as in the context of epileptic confusional states, cerebral syphilis, brain tumors, and other alterations of brain physiology, should prompt physicians confronted with a complaint of genital retraction to carefully rule out the presence of organic pathology.

Latah
Latah is hypersensitivity to sudden fright, often with echopraxia, echolalia, command obedience, and dissociative or trance-like behavior. The term latah is of Malaysian or Indonesian origin, but the syndrome has been found in many parts of the world. Other terms for this condition are amurakh, irkunii, ikota, olan, myriachit, and menkeiti (Siberian groups); bah tschi, bahtsi, and baah-fi (Thailand); imu (Ainu, Sakhalin, Japan); and mali-mali and silok (Philippines). In Malaysia, it is more frequent in middle-aged women.

Locura
Locura is a term used by Latinos in the US and Latin America to refer to a severe form of chronic psychosis. The condition is attributed to an inherited vulnerability, the effect of multiple life difficulties, or a combination of both factors. Symptoms exhibited by people with locura include incoherence, agitation, auditory and visual hallucinations, inability to follow rules of social interaction, unpredictability, and possible violence.

Mal de Ojo
Mal de ojo is a concept widely found in Mediterranean cultures and elsewhere in the world. Mal de ojo is a Spanish phrase translated into English as evil eye. Children are especially at risk. Symptoms include fitful sleep, crying without apparent cause, diarrhea, vomiting, and fever in a child or infant. Sometimes adults (especially women) have the condition.

Nervios
Nervios if a common idiom of distress among Latinos in the US and Latin America. A number of other ethnic groups have related, although often somewhat distinctive, ideas of nerves (such as nervra among Greeks in North America). Nervios refers to a general state of vulnerability to stressful life experiences and to a syndrome brought on by difficult life circumstances. The term nervios includes a wide range of symptoms of emotional distress, somatic disturbance, and inability to function. Common symptoms include headaches and brain aches, irritability, stomach disturbances, sleep difficulties, nervousness, easy tearfulness, inability to concentrate, trembling, tingling sensations, and mareos (dizziness with occasional vertigo-like exacerbation). Nervios tends to be an ongoing problem, although variable in the degree of disability manifested. Nervios is a broad syndrome that spans the range from cases free of a mental disorder to presentations resembling adjustment, anxiety, depressive, dissociative, somatoform, or psychotic disorders. Differential diagnosis depends on the constellation of symptoms experienced, the kind of social events that are associated with the onset and progress of nervios, and the level of disability experienced.

Pibloktoq
Pibloktoq is an abrupt dissociative episode accompanied by extreme excitement of as long as 30 minutes’ duration and frequently followed by convulsive seizures and coma lasting as long as 12 hours. This is observed primarily in arctic and subarctic Eskimo communities, although regional variations in name exist. The individual may be withdrawn or mildly irritable for a period of hours or days before the attack and typically reports complete amnesia for the attack. During the attack, the individual may tear off his or her clothing, break furniture, shout obscenities, eat feces, flee from protective shelters, or perform other irrational or dangerous acts.

Qi-Gong Psychotic Reaction
Qi-Gong is a term describing an acute, time-limited episode characterized by dissociative, paranoid, or other psychotic or nonpsychotic symptoms that may occur after participation in the Chinese folk health-enhancing practice of qi-gong (meaning exercise of vital energy).

Rootwork
Rootwork is a set of cultural interpretations that ascribe illness to hexing, witchcraft, sorcery, or the evil influence of another person. Symptoms may include generalized anxiety and gastrointestinal complaints (eg, nausea, vomiting, diarrhea), weakness, dizziness, the fear of being poisoned, and, sometimes, the fear of being killed (voodoo death). Roots, spells, or hexes can be put or placed on other people, causing a variety of emotional and psychological problems. The hexed person may even fear death until the root has been taken off (eliminated), usually through the work of a root doctor (a healer in this tradition), who can be called on to bewitch an enemy. Rootwork is found in the southern US among African American and European American populations and in Caribbean societies. It is also known as mal puesto or brujeria in Latino societies.

Sangue Dormido (Sleeping Blood)
Sangue dormido is found among Portuguese Cape Verde Islanders (and immigrants from there to the US) and includes pain, numbness, tremor, paralysis, convulsions, stroke, blindness, heart attack, infection, and miscarriage.

Shenjing Shuairuo (Neurasthenia)
In China, shenjing shuairuo is a condition characterized by physical and mental fatigue, dizziness, headaches, other pains, concentration difficulties, sleep disturbance, and memory loss. Other symptoms include gastrointestinal problems, sexual dysfunction, irritability, excitability, and various signs suggesting disturbance of the autonomic nervous system. In many cases, the symptoms would meet the criteria for a DSM-IV-TR mood or anxiety disorder. This diagnosis is included in the CCMD-3.

Shen-K’uei (Taiwan); Shenkiu (China)
Shen-k’uei or shenkui is a Chinese folk label describing marked anxiety or panic symptoms with accompanying complaints for which no physical cause can be demonstrated. Symptoms include dizziness, backache, fatigability, general weakness, insomnia, frequent dreams, and complaints of sexual dysfunction (such as premature ejaculation and impotence). Symptoms are attributed to excessive, or passing of white, turbid urine believed to contain semen. Excessive semen loss is feared because of the belief that it represents the loss of one’s vital essence and can thereby be life threatening.

Shin-Byung
Shin-byung is a Korean folk label for a syndrome in which initial phrases are characterized by anxiety and somatic complaints (general weakness, dizziness, fear, anorexia, insomnia, and gastrointestinal problems), with subsequent dissociation and possession by ancestral spirits.

Spell
A spell is a trance state in which individuals communicate with deceased relatives or with spirits. At times, this state is associated with brief periods of personality change. This culture-specific syndrome is seen among African Americans and European Americans from the southern US. Spells are considered to be medical events in the folk tradition but may be misconstrued as psychotic episodes in clinical settings.

Susto (Fright or Soul Loss)
Susto is a folk illness prevalent among some Latinos in the US and among people in Mexico, Central America, and South America. Susto is also referred to as espanto, pasmo, tripo ida, perdida del alma, or chibih. Susto is an illness attributed to the experience of a frightening event that causes the soul to leave the body and results in unhappiness and sickness. Individuals with susto also experience significant strains in key social roles. Symptoms may appear any time from days to years after the fright is experienced. It is believed that, in extreme cases, susto may result in death. Typical symptoms include appetite disturbances, inadequate or excessive sleep, troubled sleep or dreams, a feeling of sadness, lack of motivation to do anything, and feelings of low self-worth or dirtiness. Somatic symptoms accompanying susto include muscle aches and pains, headache, stomachache, and diarrhea. Ritual healings are focused on calling the soul back to the body and cleansing the person to restore bodily and spiritual balance. Different experiences of susto may be related to major depressive disorder, posttraumatic stress disorder, and somatoform disorders. Similar etiologic beliefs and symptom configurations are found in many parts of the world.

Taijin Kyofusho
Taijin Kyofusho is a culturally distinctive phobia in Japan, in some ways resembling social phobia in the DSM-IV-TR. This syndrome refers to an individual’s intense fear that his or her body, its parts, or its functions displease, embarrass, or are offensive to other people in appearance, odor, facial expressions, or movements. This syndrome is included in the official Japanese diagnostic system for mental disorders.

Zar
Zar is a general term applied in Ethiopia, Somalia, Egypt, Sudan, Iran, and other North African and Middle Eastern societies to the experience of spirits possessing an individual. People possessed by a spirit may experience dissociative episodes that may include shouting, laughing, hitting the head against a wall, singing, or weeping. Individuals may show apathy and withdrawal, refusing to eat or to carry out daily tasks, or may develop a long-term relationship with the possessing spirit. Such behavior is not considered pathological locally.

 

The Clinical Encounter Across the Language and Cultural Barrier

Key tasks of the psychiatric clinical encounter, such as an accurate diagnostic assessment and the mobilization of rapport along the axis of understanding (for the clinician) and feeling understood (for the patient), may be seriously compromised when the clinical encounter occurs across the language and cultural barriers. The following case vignette illustrates some of these difficulties:

Several years ago I was called to provide a cultural consultation on a patient (Helen) recently admitted to an inner-city inpatient hospital unit with the diagnosis of schizophrenia. The physician in charge of Helen’s care, a non-Hispanic psychiatrist, requested a cultural consultation to facilitate making a decision on a discharge disposition for Helen. He asked me whether this patient should be transferred for long-term care to a state-supported psychiatric hospital, or else discharged to a community based intensive rehabilitation facility. His working diagnosis for Helen was schizophrenia, chronic undifferentiated type, and his prognosis for a socially functional recovery was, at best, guarded.

My first impression as the patient walked into the consultation room supported the physician’s diagnosis. The patient displayed many of the stigmata seen in the later phases of illness in patients suffering from chronic schizophrenia, including a somewhat disheveled appearance, expressionless facial features, a slow somewhat shifting gait, and a relative indifference to her surroundings. As the interview proceeded in perfectly coherent Spanish, the patient gave the following account of her problems. With no prior psychiatric history, she started to develop symptoms shortly after the death of her only son, a 21-year-old substance abuser fatally shot in the aftermath in a narcotic dealer’s power and turf struggle. The patient reacted to her son’s death with intense and prolonged grief which lasted many months. At times, during that grief process, she heard the voice of her son beckoning her to join him in the afterlife. Additionally, having lost her son—her only close bridge to the English-speaking community—Helen became increasingly isolated, prompting the concern of some of her few relatives and friends. One of her nieces finally took Helen to the emergency room for evaluation as she was worried about Helen’s increasing isolation and a potential for suicide should Helen act out her expressed wish to join her son and obtain some “rest.”

Upon arrival to the emergency room, the report of the clinician in charge of her care highlighted in his notes the presence of “auditory hallucinations, possibly delusional, exhibits flat affect.”

Since the patient’s command of English was extremely limited, the physician focused his intake efforts on eliciting the basic set of signs and symptoms which would allow him to establish a working diagnosis and to evaluate clinical risks. While the patient was held in the emergency room, the patient’s increasing desperation was interpreted as “agitation” and the patient received several doses of haloperidol. Upon admission to the ward, the patient—partly in fear of a process that she could not understand, and partly due to the extrapyramidal side effect of the haloperidol—exhibited extremely passive and avoidant behavior, comparable to the stance often seen in cases of severe chronic mental illness.

The case of Helen illuminates some of the difficulties of arriving at an accurate diagnosis when evaluating and treating a patient across the language and cultural barrier. The psychiatric consultant, who first evaluated the patient upon arrival to the emergency room, evidently interpreted her anguished, anxious pacing and rapid “unintelligible” speech in a language which he could not understand, as a sign of psychiatric agitation. The history of “withdrawal” from social interaction supplied by the ambulance attendant was assessed as evidence of schizoid/schizophrenic isolation. The presence of “auditory hallucinations,” the content/type of which could not be fully ascertained because of the clinician’s lack of knowledge of the patient’s Spanish language, added a key step toward a possible diagnosis of schizophrenia.  The patient received several doses of haloperidol a few hours after presenting to the emergency room. In a brief mental status examination shortly afterward, her affect was described as flat, thus locking in the admission diagnosis of schizophrenia. As will be discussed later, the evaluation of key mental health status items, such as affect, thought process, speech, and hallucinations and delusions, are especially sensitive to culture and learning, and thus very vulnerable to distortions when evaluating a patient through the language and cultural barrier.

 

The Diagnostic Assessment Examination

The diagnostic assessment of patients across the language barrier is full of opportunities for misunderstanding, over- and underestimation of psychopathology, and consequent misdiagnosis. Marcos and colleagues9 found that schizophrenic patients of Hispanic origin exhibited higher rates of psychopathology in interviews conducted in English than in interviews held in their native Spanish.

Beyond the language barrier, specific group stressors suffered by certain minority groups may add additional confusion. For example, cross-cultural clinicians working with refugees warn the culturally naïve evaluator not to mislabel as Axis I psychopathology the sometimes vivid and highly emotional narratives of Southeast Asian and other refugees describing having witnessed or suffered terrible atrocities in their countries of origin or in the process of immigration. Fortunately, clinicians practicing today across language and cultural barriers have access to the findings of numerous studies that provide guidance for accurate evaluation and diagnosis and will allow them to correct many distortions and provide culturally syntonic care.10

 

Mental Status Examination

The mental status examination, the key component of a psychiatric diagnostic interview, is subject to many distortions when conducted across a language and cultural barrier. The central process of the mental status examination requires observation and interpretation of the patient’s appearance, behavior, language, and mental activity, both spontaneous and as elicited by the clinician’s questions. In interpreting the patient’s appearance, behavior, language, and thought content, the clinician must guard against what has been called “the category fallacy,” which is the effort to fit all conditions, whatever their cultural context, into the Western diagnostic framework, without regard to validating that diagnostic framework in the local culture. Patient responses to specific mental status items are affected by the patient’s culture of origin, educational level, literacy, language proficiency, and level of acculturation. Investigators consider the following items of the mental status examination to be more sensitive to cross-cultural misinterpretation.

Appearance and Behavior
The mental status sections of psychiatric case reports when describing patient’s appearance and behavior are often replete with such expressions as “normal,” “attractive,” and “appropriate” and other terms subject to significant cultural variation. Appearance and behavior must be carefully evaluated by the clinician, with the patient’s own development and culturally determined normative framework as a referent.

Relationship to the Evaluator
The assessment of a patient’s attitude and relationship to the clinician, who is performing a psychiatric evaluation, is affected by many psychosocial variables, including whether the interview is voluntary and the relative emergency of the clinical situation. Key factors of such as assessment (eg, maintenance or avoidance of eye contact, personal deference, reserve, physical proximity, physical contact) are subject to cultural prescriptions that the clinician should strive to decode.

Motor Behavior
The assessment of motor activity is considered a fundamental part of the mental status assessment. Motor activity while producing speech is an activity which is also culturally mediated. In a prior publication, Marcos and Trujillo11 noted that patients who communicate in a nondominant language may use extra nonverbal activity to facilitate verbalization across the language barrier. This extra activity needs to be carefully evaluated, lest those which are used to facilitate verbalizations be attributed to tension, hyperactivity, or other forms of motor psychopathology.


Speech and Thought

Patients communicating in a language over which they have a poor command often exhibit a high frequency of speech disturbances such as omissions, sentence incompleteness, and long pauses. These must be carefully distinguished from the impact of anxiety, depression, or emotional withdrawal.

Affect
In evaluating the range, responsiveness, and quality of a patient’s affect, clinicians working across the language barrier must recognize that both the spontaneous and the elicited expressions of affect are deeply patterned by cultural norms and expectations. Culturally sanctioned impassiveness should not be misinterpreted as poverty of affect any more than the ebullience often attributed to people of Mediterranean origin should be evaluated as excessively intense affect. Clinicians need to be equally sensitive to the significance of linguistic factors that may cloud the interpretation of affect.

When a mental status evaluation is performed across language and cultural barriers, certain linguistic problems may be misinterpreted as surplus psychopathology, and clinicians should guard against this error by repeating key questions, introducing redundancies to facilitate communication, and identifying paralinguistic cues that may cloud their evaluation of mood and expression. When in doubt they should use trained translators, cultural consultants, or structured, validated interviews as aids in the diagnostic process.

 

Cultural Formulation

The incorporation of cultural content into the DSM-IV represents a major achievement as it may encourage clinical practices that will result in improving the diagnosis and treatment of minority patients. Additionally the clinical cultural knowledge accrued may increase our knowledge of models of psychopathology. Clinicians using the framework proposed in the DSM-IV have three options to improve the diagnostic process when working with patients belonging to a culture different than their own. First, the clinician is invited to consider cultural variations and specifiers as they apply to almost 100 diagnostic categories. Second, the clinician is presented with a guideline to the completion of a cultural formulation which encourages the systematic exploration of the patient’s cultural identity, the perceived causes or explanatory models used by the patient and his or her reference group, and the cultural factors that shape the therapeutic relationship. Third, clinicians are offered a glossary of culture-bound syndromes which may be used to perform a differential diagnosis or to complement, in some cases, the diagnoses made possible by the DSM-IV.

The development of a cultural formulation is probably the jewel in the crown of cultural offerings of the DSM-IV. Just like the psychodynamic formulation is central to the therapeutic process of psychodynamic psychotherapy, the cultural formulation can inform and enrich the clinician’s view of the patient’s problems and guide their treatment.

As described in the DSM-IV-TR, the suggested outline for a cultural formulation contains elements  found in Table 5.

 

 

 

Cultural Identity

The DSM-IV recommends that in assessing an individual’s cultural identity, the clinician should “note the individual’s ethnic or cultural reference group. For immigrants and ethnic minorities, they should assess the degree of involvement with both culture of origin and host culture.”12

To these factors one must add migration history, which is commonly left out of the clinical evaluation of cross-cultural patients. Culturally uninformed clinicians often treat their immigrant patients as if their lives began when they arrived in the US, and their clinical narratives often lack key data from the patients’ preimmigration experience. Careful attention must be paid to the traumas and losses encountered by refugees in their country of origin, often including exposure (as witness or victims) to physical or emotional torture, or both. The process of acculturation is once again key to understanding the psychological distress and psychopathology of immigrants. Rogler13 has identified three major sources of stress in the migration experience. First, insertion into the host society, frequently at lower occupational and social levels. Second, disruption of primary interpersonal networks. Last,  the stress-inducing acculturation process. The clinician can assess the degree of acculturation and the nature of the acculturation process through many indirect means. Age at immigration, number of years in the US, occupational status, language proficiency, and participation in the host culture social networks, give the clinician some idea of the rate and ease of acculturation for a given patient.

Families can also be classified by degree of acculturation. From this perspective immigrant families may be described along a continuum of acculturation as traditional, transitional bicultural, and Americanized. Each of these family structures presents different assets and vulnerabilities in relation to the immigrant experience.

Clinicians need to understand that cultural identity is a very fluid and dynamic construct. Each person develops their own sense of identity by selecting from a rich tapestry of belief systems and behavioral models available in the context of their native and adoptive cultures. As such, any label including Hispanic, African American, and the like, should only support additional lines of inquiry to understand the nuances of the cultural identity of their patients. Beyond these differences, additional refinements and complexities are added as generations of immigrants develop. The loyalties and cultural conflicts of the original immigrant are not the same as those of the first or second generations of their successors.

 

Overall Cultural Assessment

The cultural formulation must be focused on providing a culturally informed explanation for the patient’s actual symptoms and dysfunctions. By thus anchoring the formulation on clinical facts, the clinician ensures its relevance to the patient’s presenting problems and to the process of care. Here, experience will teach the clinician to select succinct and potent explanations while separating what is clinically meaningful from the many interesting but not clinically relevant cultural facts which could easily be collected in any clinical encounter. The place for such synthesis is the last item of the cultural formulation guide, ie, overall cultural diagnosis.

 

Therapies

Much knowledge has accrued about the applications of standard, psychoanalytically based, psychotherapy to populations and ethnic backgrounds other than Caucasians of Western origin. To the repeated observation that ethnic communities are accepted for psychotherapy treatment at lower rates and drop out earlier than their mainstream counterparts, researchers and clinicians have provided a bounty of adaptations ranging from preparations for psychotherapy to substantive framework modifications. The most daring step in this continuum is the development of culture-specific therapies empirically derived from culture-specific behavioral features. Szapocznick and colleagues,14 for example, developed and proposed a model of family therapy for Miami, Florida’s Cuban families guided by empirically derived values prevalent in that population, such as strong familial affliction and preference for hierarchical family structures.

Other therapies such as cognitive and cognitive-behavioral therapies may achieve some modicum of freedom from cultural bias, to the degree that cognitive therapists work with the specific pathogenic beliefs of the patient, whatever the cultural origin of such beliefs. Its application to minority populations suffering from anxiety and depressive disorders may be an area of promising cross-cultural research.

Just like in the practice of psychiatry with any population, the optimum approach to treatment includes the selection of interventions based on evidence. Tables 6 and 715 illustrate how the evidence (still scarce but growing) accumulated regarding the mental health of minorities can be used productively by clinicians, and systems of care, to craft relevant interventions.

 

 

 

All these therapeutic strategies need to be mediated by the ongoing assessment of the patient’s language competence, acculturation status, and voiced personal preference.

 

Ethnic Psychopharmacology

The treatment of psychiatric disorders with psychotropic medications has been one of the great success stories of biomedicine particularly in the second part of the 20th century. However, since most currently used psychotropic agents were developed and tested in Western populations, there is little knowledge of the effects of psychotropics across different ethnic groups to guide clinical practice. Thus, cross-cultural psychopharmacology is a relatively young field. Clinicians prescribing medications to patients belonging to different ethnic groups need to consider the following factors when deciding to prescribe psychotropics to their patients.

First, cultural factors include mediating beliefs and expectations about both the therapeutic and adverse effects of medications. Included here are religious beliefs and taboos that may affect parameters such as the timing of medication intake, acceptability of utilizing certain medications, duration of the episode of treatment, and other factors. In many cultures, the patient’s family may play a role in making medical decisions for the patient and should be involved in psychoeducation efforts.

Second, certain environmental factors that, when maintained over long periods, may lead to adaptations of metabolism and promote a differential response to treatment. Factors such as the use of tobacco, caffeine, preferred foods and food additives, over-the-counter medications, and herbal medicines are ethnically mediated and may affect the effectiveness and safety of psychotropic medications. For example, by promoting the induction of key hepatic enzymes, alcohol may lower the effective level of medications.

Third, biologic factors should be considered. Ethnicity is known to affect the bioavailability and effect of medications through three broad biologic mechanism; namely, pharmacokinetics, pharmacodynamics, and pharmacogenetics.

Potential ethnically mediated cytochrome P450 (CYP) variability should be specially noted. Pharmacokinetics studies the absorption, distribution, metabolism, and excretion of drugs in the human body. CYP plays a key role in the metabolism of psychotropics (and many other endogenous and exogenous chemical compounds) and is subject to genetically mediated variation in activity. Such genetic variation in activity permits the allocation of individuals to any of three groups; these include poor metabolizers, who have reduced (or non-existent) enzyme activity and metabolize certain drugs slowly achieving higher blood levels with equal doses; extensive metabolizers, who have normal amounts and normal enzymatic activity; and intermediate metabolizers, who have intermediate enzymatic activity. The percentages of poor and extensive metabolizers vary in different ethnic populations as reflected in Table 8.16

 

 

 
A fourth category, ultra-rapid metabolizers, have enhanced enzymatic activity and metabolize the drug rapidly, requiring higher dose to sustain therapeutic efficacy. Certain populations (Arabs and Ethiopians) have high prevalence of CYP 2D6 ultra-rapid metabolizers (20% to 30% versus 1% to 5% among Caucasians).

In addition to these activity differences, clinicians need to take into account the fact that many psychotropics act themselves as inhibitors (or inducers) of the isoenzymes. The selective serotonin reuptake inhibitors (SSRIs), for example, inhibit the activity of CYP 2D6 and CYP 2C19, which may affect the therapeutic availability of the SSRI itself and/or co-administered medications. Inducers increase the synthesis of CYP enzymes and reduce the serum level of affected medications. The most common psychotropics which act as inducers are carbamazepine and other anticonvulsants, which increase the synthesis of CYP 3A4 and may reduce the bioavailability of other CYP 3A4 substrates such as benzodiazepines.

The same is true of herbs and dietary products. Chinese herbs such as ginseng and glycyrrhiza promote induction of CYP enzymes. Table 9 summarizes observed clinical effects in the administration of medications that maybe related to differences in CYP enzymatic activity. Table 10 summarizes existing knowledge regarding the effect, in different ethnic populations, of widely used psychotropics.

 

 

As ethnic psychopharmacology continues to make advances in the understanding of pharmacogenetics, pharmacodynamics, and pharmacokinetics, clinicians working with ethnically diverse populations should review the following factors while considering prescribing psychotropics.

Cultural Factors
First, clinicians should review patient (and family) history of use of psychotropic and other medications. Second, one should inquire about expectations of clinical effect and rate of recovery and about tolerance to known side effects. Third, the clinician should assess readiness for maintenance treatment when indicated. Fourth, the clinician should inquire about cultural or religious restrictions or the use of certain medications.

Environmental Factors
Clinicians should review the use of tobacco, alcohol, caffeine, over-the-counter medications, folk herbs, and other remedies.

Biologic Factors
If clinically possible, the clinician should start low and go slow. The clinician should assess family history (if available) of response and side-effects development. In the presence of non-response, psychotropic blood level should be evaluated and other CYP interactions should be considered. The clinician should evaluate for metabolic efficiency status (poor metabolizers, ultra-rapid metabolizers).

 

Cultural Competence

Though there are many definitions of cultural competence, the transformative work of Cross and colleagues17 offered an initial proposal-defining cultural competence as a set of behaviors, attitudes, and policies that come together in a system of care and among their clinicians as well as enable them to work efficiently in cross-cultural situations.

For the Office of Minority Health of the US Department of Health and Human Services, cultural competence involves having the capacity to function effectively as an individual and an organization within the context of the cultural beliefs, behaviors, and needs presented by consumers and their communities.

Cultural competence cannot be thought of as binary present or absent condition. It is best conceptualized as a continuum of beliefs, attitudes, skills and practices that start (at the low point) at a culturally blind position and end (at the high point) in a position that holds the belief that culture makes a difference, cultivates an open attitude to incorporate cultural knowledge, and develops skills in culturally syntonic diagnosis and treatment (Table 11).18

 

 

 

Cultural Consultation

Many approaches have been used to enhance the cultural responsiveness of psychiatric services working with multicultural populations. The scarcity of clinicians and researchers from minority populations limits the development of ethnographic mental health services or clinics in sufficient volume to reach large numbers of minority patients. The services of trained mental health interpreters and translators are very valuable but their engagement in the ongoing process of care is, by necessity, limited. To deal with these limitations Kirmayer and colleagues19 have proposed and evaluated a model of cultural consultation based on the principles and processes utilized in general psychiatry by the sub-specialty of consultation liaison. The cases seen by Kirmayer and colleagues19 broadly demonstrated the impact of cultural misunderstanding in the process of care. Issues such as incomplete assessments, incorrect diagnosis and treatments, and undeveloped treatment alliances were identified and, when possible, corrected by the team carrying through the consultation.

 

Conclusion

As ongoing migrations enhanced by the forces of globalization continues, clinicians practicing psychiatry in most areas of the US and especially in urban centers can expect rising numbers of minority patients seeking their help. Additionally, policy makers and regulators are responding to the Surgeon General’s call to address the health and mental health adverse disparities found among minority populations by developing requirements for the assessment of non-English-speaking patients and standards for cultural competence. On the bright side, much clinical and health services research has accumulated evidence to support the provision of culturally competent mental health services.

Such research has illuminated differences in onset, prevalence, course, and outcome among different ethnic groups, and has alerted clinicians to the presence of systematic diagnostic distortions that may occur when evaluating patients belonging to different ethnicities.

Fortunately, these findings also teach clinicians methods to be alert to, and to compensate for, such possible distortions. Paying special attention to certain elements of the mental status examination can enhance the diagnostic accuracy by correcting potential distortions in evaluating items such as appearance and behavior, speech and language, and affect and mood. Knowledge of the patient’s original ethnic group’s normal “idioms of distress” can also help the clinician to accurately evaluate the patient’s culturally expressed presenting complaint.

When it comes to treatment, an emerging body of knowledge will also help the clinician establish a therapeutic alliance inclusive of the patient’s culturally mediated explanations of their own illness, and will facilitate an accurate assessment of the meaning and severity of symptoms in relation to the patient’s cultural norms. Finally, the clinical evidence accumulated by the discipline of ethnopharmacology can also guide the clinician’s interventions when they decide to provide psychotropics to treat their patient’s disorders. PP

 

References

1.    Engel GL. The clinical application of the bio-psychosocial model. Am J Psych. 1980;137(5):535-544.
2.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.   
3.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
4.    International Statistical Classification of Diseases and Health Related Problems, (The) ICD-10. Second Edition. Geneva, Switzerland: World Health Organization; 2004.
5.    Tylor E. Primitive Culture. London, United Kingdom: Murray Publishers; 1871.
6.    Mezzich JE, Kleinman A, Fabrega H, Parron DL. Introduction. Mezzich JE, Kleinman A, Fabrega H, Parron DL, eds. Culture and Psychiatric Diagnosis: A DSM-IV Perspective. American Psychiatric Press, Inc.  Washington DC, 1996:xvii – xxiii.
7.    Mental Health: Culture Race and Ethnicity: A Supplement to Mental Health: A Report of the Surgeon General. Washington, DC: Substance Abuse and Mental Health Administration; 1999.
8.    Chinese Classification of Mental Disorders. 3rd rev. Beijing, China: Chinese Psychiatric Society; 2001.
9.    Marcos LR, Alpert M, Urcuyo L.  The effect of interview language on the evaluation of psychopathology in Spanish-Americans schizophrenic patients. Am J of Psychiatry. 1973;130(5)549-553.
10.    Trujillo M. Cultural psychiatry. In: Sadock BJ, Sadock VA, eds. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. Vol I, ed. 7. Baltimore, MD: Lippincott Williams & Wilkins; 2000:492-499.
11.    Marcos LR, Trujillo M. The psychiatric examination of Spanish Americans. In: Duran RP, ed. Latino Language and Communicative Behavior. Norwood, NJ: Ablex Publishing; 1981:141-148.
12.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994:843.
13. Rogler LH. The meaning of culturally sensitive research in mental health. Am J Psychiatry. 1989;146(3)296-303.
14.    Szapocznik J, Scopetta MA, King OE. Theory and practice in matching treatments to the special characteristics and problems of Cuban immigrants. J Community Psychol. 1978;6(2):112-122.
15.    Trujillo M. Culture and the organization of psychiatric care. In: Mezzich JE, Fabrega Jr H, eds. The Psychiatric Clinics of North America: Cultural Psychiatry: International Perspectives. Philadelphia, PA: W.B. Saunders Company; 2001:539-552.
16.    Cross T, Bazron B, Dennis K, Isaacs M. Towards a Culturally Competent System of Care. Vol I. Washington DC: Georgetown University Child Development Center, CASSP Technical Assistance Center; 1989.
17.    Trujillo M. Towards a culturally competent system of psychiatric care. Abstract presented at: the 149th Annual Meeting of the American Psychiatric Association; New York, NY; May 4-9, 1996.
18.    Gaw AC. Concise Guide to Cross-Cultural Psychiatry. Washington, DC: American Psychiatric Press; 2001.
19.    Kirmayer JL, Gutder J, Blake C, Jarius E. Cultural consultation: a model of mental health services for multicultural societies. Can J Psychiatry. 2003;48(3):145-153.

 

 

This interview took place on January 17, 2008, and was conducted by Norman Sussman, MD.

 

This interview is also available as an audio PsychCastTM at http://psychcast.mblcommunications.com.

Disclosure: Dr. Diem receives grant support from Eli Lilly, the National Institutes of Health, and Pfizer.

 

Dr. Diem is assistant professor of medicine at the University of Minnesota. She is a general internist, epidemiologist, and clinical trialist of women’s health. In addition, her clinical practice is primarily focused on perimenopausal and postmenopausal women. Dr. Diem is co-investigator on the Study of Osteoporotic Fractures, a prospective cohort study funded by the National Institutes of Health that examines the risk factors for osteoporosis and fractures in postmenopausal women.

 

What did your study on the use of antidepressants and rates of hip bone loss in older women reveal?

Using data collected over a 4.5 year period in the Study of Osteoporotic Fractures,1 we compared the rate of bone loss in older women who use selective serotonin reuptake inhibitors (SSRIs) to the rate of bone loss in older women who do not use SSRIs. We found that the women taking SSRIs had a bone loss rate of approximately 0.8% per year while the women not taking SSRIs had a bone loss rate of approximately 0.5% per year.

There are several differences between women who take SSRIs and women who do not take SSRIs and these differences can influence bone density.

As an observational study, it was important for us to have measures for those differences. The study was adjusted for these potential confounders that influence bone density (ie, differences in physical activity, health conditions, and depression).

 

Are the findings statistically significant?

Of the 2,600 women involved in the study, 198 of them used SSRIs during the 4.5-year period. The difference in the rate of bone loss between the two groups was statistically significant. However, there is some question over whether that difference in the rate of bone loss translates into an increased risk of fracture in the long run.

The companion study2 that looked at men >65 years of age was slightly different. It used cross-sectional analyses to compare the average bone density in men using SSRIs to the average bone density in men not using SSRIs. That study only looked at the average bone density at a particular point in time because follow-up bone density data was not yet available. However, the study found that bone density at the hip and spine in men who used SSRIs was lower than that in men who did not use SSRIs even when factors such as age, physical activity, health status, and smoking status were controlled.

 

What were the major confounders in these studies?

There were several potentially important confounders in these studies. One important issue is that of confounding by indication; SSRIs are typically prescribed for depression, and there is evidence that depression itself may have negative effects on bone.3-5 As a result, it is difficult to verify whether this lower bone density and higher rate of bone loss is due either to the medications or to the underlying condition for which the drugs are being prescribed. In addition, although these studies had measures for comorbid conditions, physical activity, and other confounders, those measures are not perfect. Differences in diet, sunlight exposure, and exercise among people who take SSRIs and people who do not take SSRIs could also be potential explanations for the differences observed in bone loss. Thus, the results of these studies must be considered preliminary.

Are follow-up studies being conducted to verify bone loss as an effect related either to the disorder or to the intake of SSRIs?
There is an interest in trying to replicate these analyses in other groups, especially in younger cohorts. The women in our study were on average 78 years of age, and whether or not the results from that study are generalizable to younger groups is debateable. People are certainly interested in trying to repeat these analyses in other cohorts. However, any observational study is going to be limited by the fact that they are observational and therefore subject to similar issues of confounding. Cohorts that have better measures of depression than we had in our study would be ideal for replicating these analyses.

 

What led you to conduct these studies?

A fair amount of previous work has reported an association between SSRI use and hip fracture. However, the mechanism of that association remains unclear. SSRIs have been associated with an increased risk of falls, and they are likely prescribed to people who are sicker and therefore at risk for fractures because of their other illnesses. However, it has remained unclear whether we have a full understanding of the reasons for the association between SSRI use and fractures.

More recently, serotonin receptors and transporter systems have been described in bone cells, which has raised the possibility that blockade of these transporters could have an effect on bone metabolism. There have been animal data suggesting a possible negative effect of administration of SSRIs on bone, which then prompted us to try to take a look at the data we had in this large cohort study.

 

What findings are there in terms of animal data?

Evidence from animal studies to date has been mixed, with some studies suggesting that blockade of the serotonin transporter may be beneficial to bone and others suggesting a negative effect on bone health. It is unclear what the explanation is for these discrepant results. However, it is clear that more work is needed to try to clarify the effects of inhibition of serotonin transporters on bone. One study6 involved female mice with and without ovaries that underwent fluoxetine treatment. The research reported that the fluoxetine treatment increased volume in the vertebral trabecular bone. However, this beneficial effect of SSRI administration was found only in the female mice with ovaries. The fluoxetine-treated mice that underwent ovariectomy were not protected against bone loss, which suggests some interplay among estrogen, serotonin transport inhibition, and bone. More research is needed to clarify the effects of inhibition of serotonin transporters on bone loss.

 

Should people who take SSRIs use supplementary medications specifically for the prevention of bone loss?

I cannot make blanket recommendations for all patients taking SSRIs because I think the literature is still too preliminary. Recommendations for calcium supplements and for other anti-osteoporosis drugs should be based on current indications. Calcium supplements are a relatively benign intervention, and I generally have a low threshold for suggesting them. For example, most guidelines suggest consideration of calcium supplementation for peri- and postmenopausal women. I think that is a relatively simple thing to do. However, I am not yet convinced that the existing literature about SSRIs justifies having everyone on an SSRI be told they should take calcium supplements.

 

Is additional research being conducted in this field?

Given the widespread use of these medications, there is growing interest in further exploring and better understanding any possible effects of SSRIs on bone health. We are conducting analyses in a younger cohorts of women in a perimenopausal age group. In addition, we are using data from the Study of Osteoporotic Fractures to look at SSRI use and risk of fracture in older women. Other research is exploring the basic science issues in animal models more in depth as well.

 

How will this study affect clinical practice?

In my opinion, the only change the current literature might justify would be related to decisions on screening for low bone density. The current recommendations for ordering a bone mineral density test are based on known risk factors for fracture and osteoporosis, including age, menopausal status, family history, history of previous fracture, and smoking. If a patient has borderline indications for a bone mineral density test, but that patient has depression or is receiving active treatment with an SSRI, then the current literature might suggest that it would be reasonable to obtain the bone density test. I do not think that the current literature should lead to patients and doctors stopping treatment with SSRIs out of concern for bone health because the current literature regarding SSRIs and bone is too preliminary. Depression is a serious illness with significant morbidity and discontinuing a treatment for depression based on our existing understanding of SSRIs and their possible effect on bone would be premature. PP

 

References

1.    Diem SJ, Blackwell TL, Stone KL, et al. Use of antidepressant and rates of hip bone loss in older women: the study of osteoporotic fractures. Arch Intern Med. 2007;167(12):1240-1245.
2.    Haney EM, Chan BK, Diem SJ, et al. Association of low bone mineral density with selective serotonin reuptake iInhibitor use by older men. Arch Intern Med. 2007;167(12):1246-1251.
3.    Diem SJ, Blackwell TL, Stone KL, et al. Depressive symptoms and rates of bone loss at the hip in older women. J Am Geriatr Soc. 2007;55(6):824-831.
4.    Michelson D, Stratakis C, Hill L, et al. Bone mineral density in women with depression. N Engl J Med. 1996;335(16):1176-1181.
5.    Robbins J, Hirsch C, Whitmer R, Cauley J, Harris T. The association of bone mineral density and depression in an older population. J Am Geriatr Soc. 2001;49(6):732-736.
6.    Battaglino R, Vokes M, Schulze-Spate U, et al. Fluoxetine treatment increases trabecular bone formation in mice. J Cell Biochem. 2007;100(6):1387-1394.


Needs Assessment:
When patients present with a major depressive episode, one of the challenges inherent to current pharmacotherapy options is that medications often take several weeks to exert their antidepressant effects. A well-known anesthetic and analgesic medication, ketamine, has shown potential for providing a much more rapid relief of symptoms.

Learning Objectives:
• Summarize the evidence for a role of the glutamate system in major depressive disorder.
• List the most common acute adverse effects of intravenous ketamine infusion.
• Identify the main reasons why the antidepressant efficacy of ketamine is still considered preliminary.

Target Audience: Primary care physicians and psychiatrists.

CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: March 19th, 2008.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by April 1, 2010 to be eligible for credit. Release date: April 1, 2008. Termination date: April 30, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. aan het Rot is postdoctoral fellow in the Department of Psychiatry; Dr. Charney is dean and Anne and Joel Ehrenkranz Professor in the Departments of Psychiatry, Neuroscience, and Pharmacology and Systems Therapeutics; and Dr. Mathew is assistant professor in the Department of Psychiatry, all at the Mount Sinai School of Medicine in New York City.

Disclosure: Dr. aan het Rot reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Drs. Charney and Mathew receive grant support from the General Clinical Research Center, the National Alliance for Research on Schizophrenia and Depression, and the National Institute of Mental Health. Drs. Charney and Mathew have been named as inventors on a use-patent of ketamine for the treatment of depression. If ketamine were shown to be effective in the treatment of depression and received approval from the Food and Drug Administration for this indication, Drs. Charney and Mathew could benefit financially.

Acknowledgments: The authors acknowledge the valuable contributions of David L. Reich, MD, Andrew M. Perez, MD, Richard M. Lewis, MD, James W. Murrough, MD, Katherine A. Collins, MSW, and the New York Mood Disorders Support Group.

Please direct all correspondence to: Sanjay J. Mathew, MD, Mount Sinai School of Medicine, 1468 Madison Ave, Annenberg 21, Room 90, One Gustave L. Levy Place, Box 1217, New York, NY 10029; Tel: 212-241-4480; Fax: 212-241-7973; E-mail: Sanjay.Mathew@MSSM.edu; Website: www.mssm.edu/psychiatry/map.

 


 

 Abstract

Conventional pharmacologic treatments for major depressive disorder (MDD) generally take several weeks to several months to have a clinically meaningful effect. This time lag to response constitutes a major burden for patients and contributes to increased morbidity and mortality. Two published studies in patients with MDD have now provided evidence for rapid and robust antidepressant efficacy of a single intravenous (IV) infusion with a sub-anesthetic dose of ketamine hydrochloride compared with an infusion of saline. In the approximately 60% of patients who responded, ketamine’s acute antidepressant effects were maintained for at least several days and up to 2 weeks. This article reviews the pathophysiologic rationale underlying this approach, the clinical evidence for the use of IV ketamine for treatment of MDD, ketamine’s safety profile, and areas of uncertainty to be explored in future studies.

 

Introduction

The United States National Comorbidity Survey Replication recently estimated the lifetime prevalence of major depressive disorder (MDD) to be approximately 17%.1 The occurrence of a major depressive episode (MDE) is often associated with significant impairment in multiple areas, including functioning in school or at work and interaction with family and friends. This may negatively impact patient outcomes long after the MDE has been resolved and may increase risk of recurrence or relapse.2 The clinical availability of therapeutic interventions with rapid onset of action may help reduce or even prevent the long-term effects of an MDE.

However, most existing pharmacologic treatments for MDD take several weeks to months to achieve their full clinical effects. This constitutes a major burden for patients, contributes to significant morbidity, and increases risk for suicide. The delay in onset of action that is typical of currently available antidepressants may exist because these medications exert their pharmacologic effects on systems upstream from the core pathophysiology of MDD.3 Thus, the interaction of these medications with their corresponding binding molecules (eg, receptors, transporters) activates intracellular signaling cascades that only in turn lead to changes in the expression and sensitivity of downstream neurotransmission molecules that are part of MDD pathophysiology. Most notable in this respect has been the recent accumulation of data indicating that antidepressants impact pathways that regulate cellular plasticity and survival in brain regions involved in mood regulation.4 In keeping with this are studies demonstrating atrophy and cell death in subgroups of patients with MDD.5-7

Plasticity and survival of brain cells involve multiple actions of the excitatory amino acid neurotransmitter glutamate.4 It is not surprising that there is an increasing interest in the use of glutamate system modulators for treatment of MDD.8,9 The potential efficacy of the high-affinity N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, in particular, has received attention both in the scientific community and from the general public.10 This article reviews two published placebo-controlled studies in which ketamine was given intravenously to patients with MDD. A single dose of ketamine (0.5 mg/kg) infused over 40 minutes had robust antidepressant effects that appeared after only a few hours.11,12 In light of these two promising initial reports, ketamine may have potential as a novel antidepressant with rapid onset of action, which is essential for minimizing the long-term effects of an MDE.

 

Depression Pathophysiology and Effect of Treatment

Rational drug development for treatment of MDD should be guided by a solid pathophysiologic model derived from both preclinical data and clinical observations. One such model focuses on the role of stressful experiences on glutamate function.13 The behavioral stress response involves multiple brain systems including not only activation of the hypothalamic-pituitary-adrenocortical axis but also initiation of complex cascades of reactions mediated by several neurotransmitters, including release of the excitatory amino acid neurotransmitter glutamate.14 When a stressor is acute and mild, the stress response helps an organism adapt and cope. However, when the stressor is chronic and severe, and especially when it is considered uncontrollable and inescapable, it may have pathologic consequences, including MDD.15,16 Preclinical studies have found that chronic stress may lead to excessive extrasynaptic accumulation of glutamate.17 In addition, chronic stress induces changes at the level of the glutamatergic NMDA receptor.18 Over time, this persistent hyperactivity of the stress system may contribute to glutamate-mediated excitotoxicity leading ultimately to cell death in brain areas such as the hippocampus.19,20 In addition, accumulating evidence from post-mortem and brain imaging indicates that glutamate metabolism is altered in individuals who are depressed compared to those who are well.21-24

Preclinical data on the involvement of the glutamate system in the mechanism of action of conventional antidepressants go back many years.8 For example, monoaminergic antidepressants have multiple effects on glutamate receptor function.25-27 In addition, there is abundant evidence of the positive effects of glutamatergic drugs in animal models of depression.8 These include antagonists at the NMDA receptor.28-31 Most relevant for this review are animal studies of ketamine, which in glutamatergic pathways works as a high-affinity NMDA antagonist.32 In rats ketamine induces antidepressant-like effects in the forced swimming test and in the learned helplessness model of depression.33-35 These effects may be mediated by regulating the functional interplay between NMDA and non-NMDA ionotropic glutamate receptors, especially α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptors.36

 

Clinical Evidence for Ketamine

Though compelling, it was not the preclinical data that sparked interest in the potential use of ketamine as an antidepressant treatment. Instead, it was an experimental study in patients with MDD that originally aimed to characterize the psychotomimetic effects of a subanesthetic intravenous (IV) dose of ketamine in this population. In 2000, Berman and colleagues11 at Yale University reported on the effects of ketamine 0.5 mg/kg and saline infusions on mood in nine drug-free symptomatic inpatients with recurrent MDD. Mood change following each of the two 40-minute infusions was measured using the 25-item Hamilton Rating Scale for Depression (HAM-D25) and the Beck Depression Inventory, both acutely (40–230 minutes after the start of the infusion) and sub-acutely (1–3 days post-infusion). Treatment order was randomized across patients. The two infusions were separated by ≥1 week. HAM-D25 scores were virtually unchanged in the saline condition. In contrast, a significant ketamine-induced reduction in HAM-D25 scores was first seen after 230 minutes and continued to develop over time. Three days post-ketamine, HAM-D25 scores were reduced by an average of 48%. In four of the eight patients who received ketamine, the HAM-D25 reduction was ≥50% (one patient dropped out after having received saline during the first infusion). Within 1–2 weeks post-ketamine, all patients but one (who started antidepressants after responding to ketamine and never completed the saline condition) had relapsed.

Zarate and colleagues12 replicated this study in a larger sample using an inpatient protocol at the National Institutes of Health which involved administration of IV ketamine (0.5 mg/kg) and IV saline in a randomized order 1 week apart. All 18 patients had a diagnosis of recurrent MDD and a HAM-D21 score ≥18 at baseline. They had responded insufficiently to ≥2 adequate antidepressant trials in their lifetime and were therefore considered to be treatment resistant. Participants were rated 40–230 minutes after the start of the infusion and 1–7 days post-infusion. A significant ketamine-induced reduction in HAM-D21 scores was first seen after 110 minutes. One day post-infusion, HAM-D21 scores were significantly reduced in the ketamine condition (-56%) but not in the saline condition (-10%). At this point, 71% of patients reported ≥50% decreases in HAM-D21 scores following ketamine, versus 0% following saline. After 1 week, these percentages were 34% and 0%, respectively. Notably, whereas 17 patients received the ketamine infusion, only 14 patients received the saline infusion, because four patients who received ketamine first maintained the antidepressant response for >1 week.

These two studies11,12 suggest that IV ketamine can have a robust (large effect size) and rapid (within 2 hours) antidepressant effect in patients with MDD. A recent third study,37 also conducted at Yale University and presented in abstract form at the 2007 Society for Biological Psychiatry Annual Meeting, again replicated the acute response to ketamine in an additional 10 patients (Table 1).11,12,37,38

 

Importantly, although neither study included patients who were actively suicidal, both Berman and colleagues11 and Zarate and colleagues12 observed meaningful reductions in suicidal ideation. Patients who responded acutely subsequently remained well for several days. The authors of this article and several other groups are currently conducting follow-up studies in order to develop adequate continuation treatment, with the goal of sustaining the acute ketamine response for longer time periods. For example, a recent report of two patients with treatment-resistant depression (TRD) who received one or more continuous ketamine infusions of approximately 0.3 mg/kg/h for 5 days found that the patients remained well for >1 year.39 However, another case study in a patient with TRD and comorbid alcohol and benzodiazepine dependence found that the antidepressant effect of a second 0.5 mg/kg ketamine infusion was reduced compared to the first infusion.40 Berman and colleagues11 and Zarate and colleagues12 excluded patients with recent alcohol and drug use disorders. It remains to be seen if including such patients will alter the antidepressant efficacy of IV ketamine in a placebo-controlled study.

 

Clinical Use

While the interest in ketamine as an antidepressant developed fairly recently, its use in anesthesia and sedation in both adults and children goes back many years.41,42 Surgical anesthesia is typically produced by IV doses of approximately 1–3 mg/kg.43,44 The efficacy of ketamine as an analgesic agent is also well documented and may outlast that of anesthesia.41,42 Treatment at sub-anesthetic doses may in fact be sufficient for long-term therapeutic benefit in patients with chronic pain.45,46 Notably, a 2005 study in 40 patients with complex regional pain syndrome (CRPS) who had previously insufficiently responded to conventional treatments found that the effects of 10 open-label ketamine infusions (of up to 20 mg/hour infused over 4-hour periods, or 40–80 mg per infusion) included not only a decrease in subjective pain intensity scores and an increase in mobility, but also a reduced need for antidepressants.47 These benefits lasted for periods lasting from 2 weeks to 15 months.

 

Adverse Effects

Based on an extensive anesthesia literature, ketamine may be considered a very safe drug. Its sympathomimetic effects generally include mild-to-moderate increases in heart rate, blood pressure, and cardiac output.41-43,48 Ketamine produces no or only a mild respiratory depression.41,42 Unless patients present with cardiovascular disease and/or uncontrolled hypertension, acute risks associated with IV ketamine administration are therefore regarded as minimal.48 Other adverse effects may include perceptual disturbances, which usually manifest as floating-in-space sensations and/or out-of-body experiences, but in rare events might also include visual or auditory hallucinations.41 While some patients describe these dissociative experiences as pleasurable, joyful, and fascinating (in 1999 ketamine was placed in Schedule 3 of the Controlled Substance Act), others find them bizarre or frightening.48 The perceptual disturbances are usually mild and do not last long beyond ketamine administration.42 Several studies have addressed the question of prolonged psychological effects of ketamine in the general population, secondary to its anesthetic use, and concluded that ketamine does not place patients at a greater risk than do other anesthetics.49,50 Perceptual disturbances following ketamine may be more common and last longer in individuals with preexisting psychosis.48,49,51 However, an investigation of patients with schizophrenia who received a sub-anesthetic dose of IV ketamine in experimental studies found no evidence of enduring adverse effects and distress at follow-up 8 months later.52

Consistent with ketamine’s acute effects on perception, both Berman and colleagues11 and Zarate and colleagues12 found that, 40–45 minutes after the start of the ketamine infusion, patients reported more positive symptoms on the Brief Psychiatric Rating Scale (BPRS) than at baseline. Ketamine administration was also associated with a significant increase in subjective “high” and in scores on item 1 of the Young Mania Rating Scale (elevated mood).11,12 However, none of these effects were seen beyond 80 minutes. The authors of this article are currently investigating methods to attenuate the acute psychotomimetic and dissociative effects of ketamine. They are also carefully characterizing ketamine’s acute side effect profile in patients with TRD using validated measures for adverse event reporting. A report on data from 295 healthy volunteers who were repeatedly administered ketamine (at the dose found to have antidepressant effects in patients with MDD) revealed no increase in positive symptoms, subjective “high,” and perceptual alterations between the first and subsequent exposures.53

Several experimental studies in healthy volunteers have found acute effects of ketamine on neuropsychological test performance. Ketamine impairs performance on tests of attention (eg, trail making, Stroop color-word test, continuous performance), memory (eg, immediate and delayed, verbal and non-verbal recall) and executive function (eg, word list generation fluency, Wisconsin card sorting).54-57 It has been argued that these acute impairments in cognition may have a long-term impact.10 However, studies investigating cognition in recreational ketamine users are confounded by several factors, including comorbid substance abuse.58 Very few prospective controlled studies have addressed this critical issue, but a recent study in patients with treatment-resistant CRPS found no adverse neuropsychological effects of extended ketamine treatment at relatively high doses of 3–7 mg/(kg*h).59

The absence of enduring adverse effects and behavioral sensitization following administration of a subanesthetic dose of IV ketamine also argues against the idea that its antidepressant effects may be offset by possible glutamate-mediated toxicity and cell death.10 This is corroborated by recent findings from preclinical studies36 of increases in glutamatergic AMPA throughput in response to a subanesthetic dose of IV ketamine. It is likely that any toxicity precipitated by ketamine is dose dependent. Thus, the authors of this article hypothesize that, at the relatively low single dose required to achieve a therapeutic effect on mood, ketamine does not cause the cell death that may result from higher doses and more prolonged courses of treatment. Medications with similar pharmacologic properties, the glutamate receptor modulators riluzole and memantine, have been found to have neuroprotective effects in neurodegenerative disorders (amyotrophic lateral sclerosis and Alzheimer’s disease, respectively).9,60-62

 

Areas of Uncertainty

Despite evidence from two published studies,11,12 ketamine’s effectiveness in relief of MDD symptoms must still be considered a preliminary finding. Drawing conclusions on the effectiveness of ketamine is hindered by the fact that both studies used saline as the placebo control. The acute effects of ketamine and the acute effects (or lack thereof) of saline were likely to be readily distinguishable, which means it was impossible to maintain the integrity of the blind (in both patients and clinicians). The problem is illustrated by the fact that not all study participants received both IV ketamine and IV saline. In the study by Zarate and colleagues,12 crossing participants over from one treatment to another after 1 week was problematic in patients who were administered ketamine on the first infusion day and showed an antidepressant response that lasted longer than 1 week. These patients never received the subsequent saline infusion. A longer inter-treatment interval might be one possible solution for future studies employing a within-group crossover design. Berman and colleagues11 separated the two infusions by up to 2 weeks such that patients who had received ketamine on the first infusion day and showed an antidepressant response had relapsed, except for one patient who initiated continuation treatment following ketamine-induced mood improvement and never completed the saline infusion. A between-groups study may be preferable to ensure that patients complete the placebo condition.

The lack of a placebo control that maintains integrity of the blind in both patients and clinicians during the infusions may also explain why in one of the studies12 the magnitude of psychotomimetic effects during ketamine infusion (ie, increase in BPRS positive symptoms) was correlated with the mood improvement at day 1 (ie, decrease in HAM-D scores). Neither study has reported if the elevated mood reported by patients 40–80 minutes after the start of the ketamine infusion was associated with the observed change in HAM-D scores at later time points.10 Such an association would call into question to what extent ketamine’s antidepressant effects may have been based on patients’ expectations derived from its acute effects. This issue of unmasking participants would remain even if ketamine was compared with saline in a between-groups study. To circumvent this, future studies should therefore consider the use of an active placebo control instead of, or in addition to, saline. The active control should have subjective effects similar to those of ketamine during the infusion but not have any known antidepressant effects after the infusion. A 2002 study63 in medicated depressed patients undergoing surgery has found that those induced with propofol, fentanyl, and ketamine reported improved mood and reduced subjective pain 2–4 days post-surgery, whereas no such changes were seen in patients induced with propofol and fentanyl alone. It is unlikely that patients were unblinded to the different treatments during the procedure, given that post-surgery confusion scores were similar across the two groups. This study provides some evidence that IV ketamine can have an antidepressant effect even when patients are masked to the treatment they are receiving.

The route of drug administration may have influenced the speed of ketamine’s antidepressant response. IV administration bypasses first-pass metabolism and results in higher plasma concentrations than oral administration. Some studies have demonstrated a rapid response to IV administration of conventional antidepressants.64,65 Other studies reported no difference between IV and oral administration in the speed of onset of action of these drugs.66,67 From the point of view of patient convenience, oral administration of antidepressants is usually the preferred route. It remains to be seen if ketamine will have rapid antidepressant properties when administered orally or in other formulations (eg, intramuscularly, intranasally, transdermally). The current data on the efficacy of other glutamate-modulating medications available for oral administration in patients with MDD are mixed. Oral administration of riluzole may improve mood in patients with TRD.68,69 Oral administration of memantine had no significant antidepressant effects in a recent study in patients with MDD.70 However, memantine has significantly lower affinity for the NMDA receptor than ketamine.71

Other areas of uncertainty include the relative effectiveness of the two optical enantiomers, S- and R-ketamine, and the role of neurotransmitters other than glutamate in ketamine’s antidepressant effects. Ketamine is approved by the US Food and Drug Administration only as a racemic mixture of both enantiomers. The more active enantiomer, S-ketamine, has approximately 4–5 times greater affinity for the NMDA receptor than R-ketamine.72 In healthy volunteers, S-ketamine was found to produce emotional disturbances, cognitive impairments, and dissociative experiences, whereas R-ketamine induced a state of relaxation.73 S-ketamine has been approved in some European countries based on evidence that it has more potent anesthetic and analgesic effects such that it can be used in smaller doses and therefore possibly decrease recovery time.74 There is also some indication that the psychotomimetic or unpleasant effects of S-ketamine may be less pronounced than those of the racemic mixture.75 S-ketamine–induced decreases in binding potential of the dopamine-2 receptor antagonist raclopride, measured using positron emission tomography in the striatum and surrounding brain areas, have been shown to correlate with subjective euphoria; this suggests that dopamine may play a role in its acute mood-elevating effects.76 Most experimental studies that administered single subanesthetic IV doses of racemic ketamine to humans have also found that ketamine has effects on dopamine receptors.77-80 These studies have also implicated a role for mu opioid receptors.81 In summary, ketamine has a complex pharmacologic profile, with its actions on the glutamate system and NMDA receptors being only one of multiple pathways that together are responsible for its diverse effects.

Other currently unresolved issues with ketamine include the following. First, the dose used thus far (0.5 mg/kg) may not be the optimal dose for induction and mainte­nance of the mood response. Second, it is unknown which medications are viable continuation treatment options in patients who show an initial favorable response (eg, repeated ketamine administration, use of another glutamatergic drug such as riluzole or memantine, or other more traditional approaches). Third, although there is no current evidence of addiction potential in controlled studies performed to date, the potential of ketamine abuse must continue to be consid­ered. Finally, future studies should more closely measure the acute and longer-term side effects of ketamine at multiple time points following its administration.

 

Comparison with Existing Rapid Antidepressant Treatments

Current treatments for MDD can be divided into “acute” interventions and continuation/maintenance strategies. However, besides ketamine only sleep deprivation produces antidepressant responses within 24 hours (Table 2). Sleep deprivation has a long-known rapid and robust efficacy in approximately 60% of patients with MDD.82 The magnitude of improvement is often equivalent to that observed after 6 weeks of antidepressant treatment. Hence, the acute therapeutic response to sleep deprivation must be mediated by mechanisms different from those mediating the gradual improvement obtained with antidepressants.83 Functional brain imaging studies are highly suggestive of an association between clinical improvement and increased activity in the ventral anterior cingulate cortex.84 Advantages of sleep deprivation include its noninvasive nature and safe use in pregnant and breastfeeding women. However, most patients relapse after one subsequent night of sleep regardless of medication status,82 which may explain why sleep deprivation is rarely administered by clinicians in the US. Nevertheless, sleep deprivation has been successfully used to hasten the onset of action of antidepressants.85 

 

 
Bright light therapy (BLT) can also be administered safely in pregnant and breastfeeding women. Like sleep deprivation, it is non-invasive. However, compliance may be difficult for some, as patients are usually required to self-administer bright light in the early morning.86 BLT reportedly has a response rate of approximately 60%. The effect size may be larger in patients with seasonal affective disorder (SAD) versus non-seasonal MDD.87 Like sleep deprivation, BLT has been successfully used as an adjunct to conventional antidepressant treatment in order to speed up its antidepressant effect.88 While BLT efficacy has mostly been studied over time periods in the range from weeks to months, at least two studies89,90 in patients with SAD are indicative that its onset of action may be faster than that of the commonly prescribed selective serotonin reuptake inhibitor, fluoxetine. Anecdotally, clinically meaningful mood changes have been found to occur even after time periods of 2–3 days.91,92 A 2004 Cochrane review of BLT studies in patients with non-seasonal MDD showed significant benefit in studies of up to a week, but no significant benefit in longer and better-controlled studies.93 However, a 2005 controlled trial reported significant benefit of BLT in approximately 50% of patients with non-seasonal chronic MDD.94

Electroconvulsive therapy (ECT) is usually administered to patients with TRD and generally involves three sessions per week, with most individuals requiring at least 6 treatments to achieve a response. ECT is considered the most effective antidepressant treatment, especially for patients with psychotic, melancholic, or bipolar depression.95 It is considered another rapid antidepressant treatment, although onset of action is rarely achieved during the first treatment session (Table 2). Interestingly, a recent case report in a patient with severe, recurrent MDD showed that intramuscular administration of 100 mg of ketamine in combination with a single session of ECT resulted in marked clinical improvement within 8 hours of treatment which continued at least until the next ECT session 3 days later.96 Disadvantages to ECT include its invasive nature, including the requirement of general anesthesia and the risk of significant retrograde amnesia, which in some patients may be irreversible.97 Without continuation treatment, the majority of patients will relapse within 6 months.98

 

Recommendations

The development of a rapid antidepressant strategy which is effective within 24 hours and can be sustained is an important therapeutic goal in psychiatry. Studies on the antidepressant effects of ketamine are a work in progress. This article has presented the currently available data, with the intention to stimulate future research.

As of yet, there are no established guidelines for ketamine administration in patients with MDD. Berman and colleagues11 and Zarate and colleagues12 have administered ketamine on an inpatient basis. Ongoing studies by the authors of this article and elsewhere also use this approach. Patients are monitored by an anesthesiologist during infusion, are continuously observed by nursing staff, and remain in the inpatient setting for 24 hours post-infusion to ensure safety. Acutely, ketamine’s potential side effects include respiratory or circulatory problems, especially in patients with lung disease and uncontrolled hypertension, respectively. Studies thus far have not encountered these problems; however, patient selection procedures actively excluded patients with known risk factors. At present, the use of ketamine for treatment of TRD in uncontrolled settings is discouraged by the authors of this article.

Nevertheless, in the future ketamine may offer the clinician a potentially efficacious and rapidly acting medication, especially for patients with TRD. As the therapeutic lag time inherent to currently available treatments for MDD is suboptimal, this and similar approaches are worthy of further investigation.

 

Conclusion

Ketamine is a well-known FDA-approved anesthetic and analgesic medication. In at least two placebo-controlled studies in patients with MDD,11,12 one of which included patients with TRD, ketamine has shown additional potential as a rapid and robust antidepressant. There was some evidence of a decrease in suicidality as part of the overall rapid clinical improvement. The acute antidepressant effects of a single ketamine infusion lasted up to 2 weeks. It remains to be seen if ketamine, in combination with existing or future continuation therapies, can be developed as a safe and effective treatment option for patients with an acute MDE. The development of a new pharmacologic intervention with acute and sustained antidepressant effects could have a significant impact on public health. PP

 

References

1.    Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):593-602.
2.    Areán PA, Reynolds CF 3rd. The impact of psychosocial factors on late-life depression. Biol Psychiatry. 2005;58(4):277-282.
3.    Du J, Machado-Vieira R, Maeng S, Martinowich K, Manji HK, Zarate CA Jr. Enhancing AMPA to NMDA throughput as a convergent mechanism for antidepressant action. Drug Discovery Today: Therapeutic Strategies. 2006;3(4):519-526.
4.    Manji HK, Quiroz JA, Sporn J, et al. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol Psychiatry. 2003;53(8):707-742.
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33.    Garcia LS, Comim CM, Valvassori SS, et al. Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(1):140-144.
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46.    Wood PB. A reconsideration of the relevance of systemic low-dose ketamine to the pathophysiology of fibromyalgia. J Pain. 2006;7(9):611-614.
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48.    Green SM, Li J. Ketamine in adults: what emergency physicians need to know about patient selection and emergence reactions. Acad Emerg Med. 2000;7(3):278-281.
49.    Schorn TOF, Whitwam JG. Are there long-term effects of ketamine on the central nervous-system? Br J Anaesth. 1980;52(10):967-968.
50.    Hersack RA. Ketamine’s psychological effects do not contraindicate its use based on a patient’s occupation. Aviat Space Environ Med. 1994;65(11):1041-1046.
51.    Lahti AC, Koffel B, LaPorte D, Tamminga CA. Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology. 1995;13(1):9-19.
52.    Lahti AC, Warfel D, Michaelidis T, Weiler MA, Frey K, Tamminga CA. Long-term outcome of patients who receive ketamine during research. Biol Psychiatry. 2001;49(10):869-875.
53.    Cho HS, D’Souza DC, Gueorguieva R, et al. Absence of behavioral sensitization in healthy human subjects following repeated exposure to ketamine. Psychopharmacology (Berl). 2005;179(1):136-143.
54.    Krystal JH, Karper LP, Seibyl JP, et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994;51(3):199-214.
55.    Harborne GC, Watson FL, Healy DT, Groves L. The effects of sub-anaesthetic doses of ketamine on memory, cognitive performance and subjective experience in healthy volunteers. J Psychopharmacol. 1996;10(2):134-140.
56.    Newcomer JW, Farber NB, Jevtovic-Todorovic V, et al. Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology. 1999;20(2):106-118.
57.    Anand A, Charney DS, Oren DA, et al. Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists. Arch Gen Psychiatry. 2000;57(3):270-276.
58.    Curran HV, Monaghan L. In and out of the K-hole: a comparison of the acute and residual effects of ketamine in frequent and infrequent ketamine users. Addiction. 2001;96(5):749-760.
59.    Koffler SP, Hampstead BM, Irani F, et al. The neurocognitive effects of 5 day anesthetic ketamine for the treatment of refractory complex regional pain syndrome. Arch Clin Neuropsychol. 2007;22(6):719-729.
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62.    Menniti FS, Pagnozzi MJ, Butler P, Chenard BL, Jaw-Tsai SS, Frost White W. CP-101,606, an NR2B subunit selective NMDA receptor antagonist, inhibits NMDA and injury induced c-fos expression and cortical spreading depression in rodents. Neuropharmacology. 2000;39(7):1147-1155.
63.    Kudoh A, Takahira Y, Katagai H, Takazawa T. Small-dose ketamine improves the postoperative state of depressed patients. Anesth Analg. 2002;95(1):114-118.
64.    Malhotra S, Santosh PJ. Loading dose imipramine–new approach to pharmacotherapy of melancholic depression. J Psychiatr Res. 1996;30(1):51-58.
65.    Sallee FR, Vrindavanam NS, Deas-Nesmith D, Carson SW, Sethuraman G. Pulse intravenous clomipramine for depressed adolescents: double-blind, controlled trial. Am J Psychiatry. 1997;154(5):668-673.
66.    Faravelli C, Broadhurst AD, Ambonetti A, et al. Double-blind trial with oral versus intravenous clomipramine in primary depression. Biol Psychiatry. 1983;18(6):695-706.
67.    Guelfi JD, Strub N, Loft H. Efficacy of intravenous citalopram compared with oral citalopram for severe depression. Safety and efficacy data from a double-blind, double-dummy trial. J Affect Disord. 2000;58(3):201-209.
68.    Zarate CA Jr, Payne JL, Quiroz J, et al. An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry. 2004;161(1):171-174.
69.    Sanacora G, Kendell SF, Levin Y, et al. Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry. 2007;61(6):822-825.
70.    Zarate CA Jr, Singh JB, Quiroz JA, et al. A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am J Psychiatry. 2006;163(1):153-155.
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78.    Smith GS, Schloesser R, Brodie JD, et al. Glutamate modulation of dopamine measured in vivo with positron emission tomography (PET) and 11C-raclopride in normal human subjects. Neuropsychopharmacology. 1998;18(1):18-25.
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80.    Aalto S, Hirvonen J, Kajander J, et al. Ketamine does not decrease striatal dopamine D2 receptor binding in man. Psychopharmacology (Berl). 2002;164(4):401-406.
81.    Krystal JH, Madonick S, Perry E, et al. Potentiation of low dose ketamine effects by naltrexone: potential implications for the pharmacotherapy of alcoholism. Neuropsychopharmacology. 2006;31(8):1793-1800.
82.    Wu JC, Bunney WE. The biological basis of an antidepressant response to sleep deprivation and relapse: review and hypothesis. Am J Psychiatry. 1990;147(1):14-21.
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Dr. Luo is associate clinical professor in the Department of Psychiatry and Biobehavioral Sciences at the University of California in Los Angeles; past president of the American Association for Technology in Psychiatry (AATP) in New York City; and Gores Informatics Advocacy chair at the AATP.

Disclosure: Dr. Luo reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

 


 

Today’s patient has likely researched his or her condition on the Internet before even stepping into a doctor’s office for the first time. Some patients have even read articles from scientific journals and have asked physicians about their opinion on that type of treatment option. Although the Internet has made a wealth of information available to patients, there is still a significant amount of conflicting information even in the medical journals, and even more so on the Internet. This column reviews the trends in patient health information access and discusses strategies for physicians on how to navigate and negotiate with patients surfing for information.

 

Background

In the past, patients relied mostly on their physicians to have the expertise to manage the majority of their health issues, and oftentimes did not question the validity of recommendations. The advent of the Internet has ushered in the “information overload” age with health information as one of the most popular destinations. In the 2002 Pew Internet and American Life Project report,1 it was estimated that 52 million American adults, or 55% of those with Internet access, have used the Internet to get health/medical information. This report indicated that patients went online at least once a month to get health information, and that the information they find has a direct effect on decisions regarding healthcare and interactions with doctors. Specifically, 70% of patients indicated that the health information on the Internet influenced their decision about how to treat an illness or condition. Fifty percent of patients said that information on the Internet led them to ask their doctor new questions or seek a second opinion from another doctor, while 48% indicated that Internet-based health information has helped them take care of themselves.

Kaplan and Brennan2 described the beginning trend of consumer health informatics, an area regarding the growth of the organization and delivery of health care and changing roles of patient and provider. At the Spring 2000 Congress of the American Medical Informatics Association, three panels examined the trend of health information, patient participation, shared decision making, and clinician responses in the context of the Internet.2 Several themes emerged, including the change in roles of consumers and providers, support for patient-provider-information technology partnership, virtual structure for health care and health information delivery, and health care as an integrated part of each person’s life. Patients clearly wanted more personalized relationships with their providers as well as interactive tools to help manage their health and diseases.

 

Website Certifications

In the early years of the Internet, it was simple enough for patients and providers alike to determine the potential bias and usefulness of a Website by examining the URL for its domain (either .net, .com, .edu, or .org). It was at that time relatively safe to assume that “.edu” and “.org” were non-profit sites of educational institutions and organizations; therefore. any Website content would not be biased or commercial in nature. Over the years, domain names became a “commodity,” which could demand high prices in the competitive open market. Domain name “squatters” rushed to register the names first or took advantage if registrants who failed to renew their domain in a timely manner. Now, there are numerous additional domain appellations such as “.biz,” “.info,” and even “.md.” To add even more confusion, many Website URLs are actually referrer domain names, which then send the visitor to another site or same site. One example, www.physician.md,3 actually sends visitors to the National Institutes of Health Website, which is normally accessed at www.nih.gov.4 Nowadays, the inherent nature of a Website is no longer predetermined by its domain name. The Mayo Clinic operates three sites, MayoClinic.com5 for health information, MayoClinic.org6 for health services, and Mayo.edu7 for education and research.

One way to help patients determine the relative usefulness and reliability of health information on the Internet is for the site to have accreditation. The Health on the Net (HON) Foundation is a not-for-profit and private Swiss foundation which has been granted non-governmental organization status by the Economic and Social Council of the United Nations.8 It serves to accredit Websites that have fulfilled the eight ethical principles of the HON code of conduct (Table). In addition to accreditation, HON also offers MedHunt, a specialized search engine geared toward the public and designed to find health information on the Internet. HONselect is a meta-search engine that offers medical terms, corresponding pictures, bibliographic references, news, and Websites that adhere to the HON code of conduct.

 

Another accreditation organization is the Utilization Review Accreditation Commission (URAC).9 This organization accredits many types of healthcare organizations. In particular, URAC provides oversight on how an accredited health Website is operated. URAC Health Web Site Accreditation ensures that the site is supervised by clinically trained staff, discloses key information about how the Website operates, and limits how personal health information is used or disclosed to third parties. There are >50 URAC health Website standards, which were developed in conjunction with healthcare providers, consumers, and health Website companies.

 

Online Tools

As indicated in the Pew Internet Report, patients seek information on the Internet because it is convenient and relatively anonymous, especially on sensitive topics, which may include mental health. A previous Tech Advisor10 discussed how Internet-based assessment tools can be used to help patients check for various conditions. Healthplace.com11 has created a collection of links to other Websites that have screening tools for a variety of psychological disorders, encompassing both free and commercial tools. Organizations, such as the Mental Health Association of America, often sponsor free screening tools to encourage patients to discuss matters with their health provider (eg, Depression-Screening.org).12

Today’s patients are quite savvy and are often appropriately concerned about medications and drug-drug interactions. Numerous Websites offer drug information and drug-drug interaction tools, such as DoublecheckMD,13 Drugs.com,14 and Medscape.15 These Websites are fairly easy to use. However, they can create confusion for the patient and some consternation for the practitioner. In a simple check of drug interactions between risperidone and escitalopram, both DoublecheckMD and Drugs.com indicate a potential for central nervous system depression, whereas Medscape indicates that there are no drug interactions at all. Epocrates Online,16 which has been traditionally used by medical professionals but can be used by patients, indicates that the drug-drug interaction can cause potential increased risperidone levels due to inhibition of hepatic metabolism. One advantage for patients using DoublecheckMD is that its explanation of the risks uses less medical jargon. Drugs.com offers a pill identification wizard and will store lists of drugs and interactions once patients register at the Website. Much of the discrepancy of the interaction checks is based on the drug database employed by the Website and its editorial board.

 

Online Forums

Online health information comes from a variety of sources, traditionally from textbooks and journal articles that are edited and distilled but delivered via the interface of the Internet. Patients usually rely on Websites such as WebMD,17 RevolutionHealth,18 and the National Institute of Mental Health19 to find general information on various health conditions. A new trend has been the shift toward online support groups. Patients and family members can log in and read other patients’ experiences with medications and treatment in order to attain a better understanding of symptoms and disease course. DailyStrength.org20 has numerous discussion forums where patients share their thoughts and provide support. Furthermore, it has a specific “advice” column where patients explicitly offer each other advice on how to cope, and “recommendations” where patients recommend books and videos. PatientsLikeMe21 takes the sharing of patient experiences further. Although the Website focuses right now on Parkinson’s disease, multiple sclerosis, HIV/AIDS, and amyotropic lateral sclerosis, patients share their symptoms and treatment, which are tabulated in a running total. Patients track their outcomes, treatment, and symptoms over time, which are nicely plotted in a graphical view. At MedHelp.org,22 patients not only get information and support from one another on forums, but they can also get advice from members and medical professionals who are responsible for answering questions posted on the forum. Yahoo Health23 takes patient sharing a step further by providing inspirational stories from patients as well as video posts from patients. It also offers an amalgam of information including expert opinion from various providers.

 

Health Search Engines

Finding relevant information on the Internet has helped Google24 achieve its marketshare and financial success, but one search engine cannot find everything relevant. Specific health search engines, such as Healia,25 Medstory,26 and Healthline,27 do a better job finding useful information by searching the Internet, ClinicalTrials.gov,28 and Pubmed29 using health-related taxonomies compared to traditional search engines. Healia offers filters such as information based on ethnicity, HON- and URAC-accredited sites, and whether information is easy or harder to read. Medstory also filters information based on keywords identified during the search. For example, upon searching for negative symptoms of schizophrenia, topics such as drugs, procedures, conditions, and personal health can refine the search. A helpful feature is that once the search has been created, an really simple syndication (RSS) feed can be created so any new content can be updated in an RSS reader. Healthline offers information both from its own content as well as the Internet, and the HealthMap creates a flowchart for patients to find new information as well as understand its relevancy.

 

Conclusion

Soon enough, it will be commonplace for every patient coming into the health practitioner’s office to bring information discovered on the Internet. Patients may even begin to “tag” Websites and articles using services such as Digg30 and Del.ici.ous,31 to be shared with their doctor for further discussion. Although it is impossible for all providers to learn in advance what types of information is on the Internet for their patients, they should be prepared to help patients navigate such information because personal relevancy and medical advice is still in the domain of medical practice. PP

 

References

1.    Fox S, Rainie L, Horrigan J, et al. The online health care revolution: how the web helps Americans take better care of themselves. Available at: www.pewinternet.org/PPF/r/26/report_display.asp. Accessed March 1, 2008.
2.    Kaplan B, Brennan PF. Consumer informatics supporting patients as co-producers of quality. J Am Med Inform Assoc. 2001;8(4):309-316.
3.    National Institutes of Health. Available at: www.physician.md. Accessed March 1, 2008.
4.    National Institutes of Health.  Available at: www.nih.gov. Accessed March 12, 2008.
5.    MayoClinic.com. Available at: www.mayoclinic.com. Accessed March 1, 2008.
6.    MayoClinic.org. Available at: www.mayoclinic.org. Accessed March 1, 2008.
7.    Mayo.edu. Available at: www.mayo.edu. Accessed March 1, 2008.
8.    Health on the Net Foundation. Available at: www.hon.ch. Accessed March 3, 2008.
9.    URAC. Available at: www.urac.org. Accessed March 3, 2008.
10.    Luo J. Computerized medicine. Primary Psychiatry. 2006;13(9):20-22.
11.    HealthyPlace.com: Online Psychological Tests. Available at: www.healthyplace.com/site/tests/psychological.asp. Accessed March 12, 2008.
12.    Depression-Screening.org. Available at: http://depression-screening.org. Accessed March 5, 2008.
13.    DoublecheckMD. Available at: www.doublecheckmd.com. Accessed March 5, 2008.
14.    Drugs.com Drug Interaction Checker. Available at: www.drugs.com/drug_interactions.html. Accessed March 5, 2008.
15.    Medscape Drug Interaction Checker. Available at: www.medscape.com/druginfo/druginterchecker. Accessed March 5, 2008.
16.    Epocrates Online. Available at: http://online.epocrates.com. Accessed March 5, 2008.
17.    WebMD. Available at: www.webmd.com. Accessed March 10, 2008.
18.    Revolution Health. Available at: www.revolutionhealth.com. Accessed March 10, 2008.
19.    National Institute of Mental Health. Available at: www.nihm.nih.gov. Accessed March 10, 2008.
20.    DailyStrength.org. Available at: www.dailystrength.org. Accessed March 11, 2008.
21.    PatientsLikeMe. Available at: www.patientslikeme.com. Accessed March 11, 2008.
22.    MedHelp. Available at: www.medhelp.org. Accessed March 11, 2008.
23.    Yahoo Health. Available at: http://health.yahoo.com. Accessed March 11, 2008.
24.    Google. Available at: www.google.com. Accessed March 12, 2008.
25.    Healia. Available at: www.healia.com. Accessed March 11, 2008.
26.    Medstory. Available at: www.medstory.com. Accessed March 11, 2008.
27.    Healthline. Available at: www.healthline.com. Accessed March 11, 2008.
28.    ClinicalTrials.gov. Available at: www.clinicaltrials.gov. Accessed March 11, 2008.
29.    Pubmed. Available at: www.ncbi.nlm.nih.gov/PubMed/. Accessed March 11, 2008.
30.    Digg. Available at: www.digg.com. Accessed March 12, 2008.
31.    Delicious. Available at: http://del.icio.us. Accessed March 12, 2008.

  

 

Needs Assessment: Clinicians need to learn about new psychotherapeutic drugs in late stages of clinical development. This article informs the reader about a new class of antidepressants in development called triple reuptake inhibitors.

Learning Objectives:
• List at least two clinical features of depression thought to be due to deficits in brain dopamine.
• Define what is meant by “triple reuptake inhibitor.”
• Name two triple reuptake inhibitors that have been in Phase II clinical trials.

Target Audience: Primary care physicians and psychiatrists.


CME Accreditation Statement:
This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: March 19th, 2008.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by April 1, 2010 to be eligible for credit. Release date: April 1, 2008. Termination date: April 30, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. Liang is research fellow and Dr. Richelson is principal investigator in the Neuropsychopharmacology Laboratory, Mayo Foundation for Medical Education and Research, and Mayo Clinic in Jacksonville, Florida.

Disclosure: Dr. Liang reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Richelson receives grant support from the National Institutes of Health.

Please direct all correspondence to: Elliott Richelson, MD, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224; Tel: 904-953-2439; Fax: 904-953-7117; E-mail: richel@mayo.edu.

  

 

Abstract

A major advance in the pharmacotherapy of depression was the introduction of the selective serotonin reuptake inhibitors nearly 2 decades ago. These drugs succeed in treating depressed patients with few of the side effects common to tricyclic antidepressants, which they largely replaced. However, there are still unmet clinical needs with respect to efficacy, onset, and side-effect profile. The effects of the antidepressants occur almost immediately; however, a therapeutic lag is required to affect meaningful symptom improvement. Not all patients respond to antidepressants well, with some patients undergoing adverse events such as sexual dysfunction. Novel therapies or targets that may reduce side effects need to be addressed. Dopaminergic circuit dysfunction has been linked to depressive syndrome for many decades, and research on serotonin/norepinephrine-containing circuits has largely overshadowed its role in depression. It has been hypothesized that a broad-spectrum antidepressant will produce a more rapid onset and better efficacy than agents inhibiting the reuptake of serotonin and/or norepinephrine, in part due to the addition of the dopamine component. Triple reuptake inhibitors (serotonin, norepinephrine, and dopamine reuptake inhibitors) are being developed as a new class of antidepressant. This article presents the involvement of the dopaminergic neurotransmission underlying depressive symptoms, as well as preclinical and clinical trials of developing triple reuptake inhibitors.

 

Introduction

Depression is a prevalent, heterogeneous, and recurrent mental disorder with a lifetime prevalence in approximately 16% of American adults and as much as 21% of the world population. According to the World Health Organization, depression is among the leading causes of disability worldwide. Despite the numerous improvements in antidepressants, there continue to be many unmet clinical needs regarding efficacy, onset of action, and side-effect profile. Although novel targets (eg, corticotrophin-releasing factor receptor) are being researched, current pharmacotherapies for depression are based on the decades-old monoamine (serotonin, norepinephrine, and dopamine) deficiency hypothesis underlying the etiology and pathogenesis of the depressive disorder.1

Pharmacotherapy of depression aims to elevate synaptic levels of the three key monoamines. However, the neglected neurotransmitter in this equation is dopamine, because the most widely used antidepressants that block reuptake of biogenic amines do not block dopamine transporters. There is compelling reason to add dopamine to the mix. To achieve reuptake blockade of all three neurotransmitters—serotonin, norepinephrine, and dopamine—triple reuptake inhibitors have been in development for at least the past decade. After a discussion of the importance of dopaminergic neurotransmission in depression, this article discusses some preclinical research and clinical trials of triple reuptake inhibitors in development.

 

Background

The earliest, modern-day antidepressants were monoamine oxidase inhibitors (MAOIs; eg, phenelzine) and tricyclic antidepressants (TCAs; eg, imipramine). These drugs were found to be effective in treating depression, largely by empirical testing, and were subsequently shown to enhance monoamine levels in brain synapses by preventing their metabolism and transport back into the nerve ending (reuptake). Because of various unnecessary receptor blocking effects, these drugs were not always well tolerated. Therefore, “cleaner” drugs were sought and MAOIs and TCAs were largely replaced by selective serotonin reuptake inhibitors (SSRIs; eg, fluoxetine, paroxetine, sertraline) and serotonin norepinephrine reuptake inhibitors (SNRIs; eg, venlafaxine, duloxetine). These are specifically focused on serotonin and/or norepinephrine transporters with desired effects and fewer interactions with certain neurotransmitters and their receptors, effects that limit the use of MAOIs and TCAs.2-4

Despite higher selectivity and better tolerance by patients, the newer-generation antidepressants are not superior to MAOIs and TCAs in clinical response and remission rates. Their pharmacologic effects occur almost immediately; however, a therapeutic lag occurs before meaningful symptom improvement occurs.5,6 Although the reason for this lag is not completely understood, it is thought to reflect the time required for desensitization of the receptors regulating monoamine release (serotonin [5-HT]1A, 5-HT2C, and α2-adrenergic receptors)7-9 and changes in expression of certain genes (brain-derived neurotrophic factor [BDNF]; neuropeptide VGF).10-12

In addition to the fact that not all depressed patients are satisfactorily treated with these new drugs, there are some unwanted adverse events such as sexual dysfunction, which are hypothetically due in part to the failure of SSRIs or SNRIs to induce similar alterations in dopamine signaling while increasing serotonergic or noradrenergic neurotransmission.13 Despite the dysfunction of dopaminergic circuits, which has been linked to depressive syndrome for decades, research on norepinephrine- and serotonin-containing circuits has largely overshadowed research on the role of dopamine in depression. Dopamine is thought to play a critical role in mediating some depressive symptoms such as anhedonia. Research is being reported on the improvement in depressive symptoms in treatment-resistant patients with addition of a dopamine agonist.14,15 Thus, with this information and the clinical success of SSRIs and SNRIs, there is considerable rationale for targeting all three monoamine reuptake sites (transporters) using drugs that are termed triple reuptake inhibitors (serotonin, norepinephrine, and dopamine transport blockers) in the treatment of depression.16,17

 

Dopaminergic Mechanism in Depression

The mesocorticolimbic dopamine system is involved in motivation, psychomotor speed, concentration, the ability to experience pleasure, and neurogenesis.13,18 There is considerable evidence linking mesocorticolimbic dopaminergic pathways with depression, especially with anhedonia and the lack of motivation observed in many depressed patients.19 Apathy and anhedonia together, defined as a loss of interest or pleasure in normally rewarding activities, are cardinal criteria for a diagnosis of depression according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.20 Moreover, hippocampal neurogenesis is implicated in the physiopathology of depression and partially underlies antidepressant therapy.21,22

Multiple sources of evidence support a role for diminished dopaminergic neurotransmission in depression and especially in major depressive disorder (MDD). This may result from either diminished dopamine release from presynaptic neurons or impaired signal transduction, including changes in receptor number or function and altered intracellular signal processing.13 Impairments of the mesolimbic dopamine system, including reduction in dopamine levels,23 decreased dopamine (D)2/D3 receptor binding,24 and supersensitivity of dopamine postsynaptic receptors25 were seen in animal models of depression and were reversed by ongoing antidepressant treatment.19,24,26 Transgenic mice with a disruption of the prostate apoptosis-response-4/D2 receptor interaction exhibit depression-like behaviors.27 Clinical studies also found lower concentrations of dopamine metabolites, primarily homovanillic acid (HVA), in the cerebrospinal fluid of depressed patients compared to that for healthy individuals, particularly in patients with psychomotor retardation. Dopamine turnover correlated inversely with the severity of depression as measured by the Hamilton Rating Scale for Depression (HAM-D).28 Genetically, more than one vulnerable dopaminergic-related gene may significantly increase the likelihood of developing MDD via the D4 receptor, dopamine transporter, catechol-O-methyl transferase, or the dopamine β-hydroxylase gene.29-31

Drugs that are known to decrease or increase dopaminergic neurotransmission can have depression-like or antidepressant-like effects, respectively. Treatment with reserpine, which depletes synaptic stores of dopamine and other monoamines, and neuroleptics, which block dopamine receptors, down-regulate dopaminergic circuits and can produce depression-like symptoms in humans.32 Conversely, psychostimulants, which increase synaptic levels of dopamine by releasing dopamine or blocking its reuptake, induce a hedonic mood by activation of mesolimbic dopamine transmission. Several drugs acting on the dopamine system have been evaluated for their efficacy in MDD, such as MAOIs and dopamine agonists.13 The efficacy of MAOIs in atypical depression and anergic bipolar depression partly depends on their effect on dopamine metabolism.33 Dopamine agonists bromocriptine and pramipexole exert antidepressant efficacy in a randomized placebo-controlled study in patients with MDD.34,35 In addition, it is suggested that dopaminergic neurotransmission may be a final pathway common for many antidepressant treatments.36 Chronic antidepressants potentiate dopamine transmission by causing supersensitivity of postsynaptic D2-like receptors (ie, D2 and D3), and subsensitivity of D1 receptors occurs preferentially in the limbic system.19 These receptor sensitivity changes may contribute to therapeutic effects of antidepressants.37

Additional evidence that associates dopamine neurotransmission with depression is the high incidence of depression among patients diagnosed with Parkinson’s disease, a neurologic disease involving the degeneration mainly of dopamine-synthesizing neurons. The incidence of depression in Parkinson’s disease is in the range 30% to 50% and prevalence in some surveys is >60%.38 Anecdotally, depression in Parkinson’s disease is very difficult to treat. Overlapping symptoms between depression and Parkinson’s disease such as apathy, anhedonia, sleep-wake dysregulation, and lack of energy correlate with the dysfunction of mesocorticolimbic or nigrostriatal dopaminergic, serotonergic, and noradrenergic circuits in Parkinsonian depression.38

Dopaminergic medication can bring about improvement in episodes of severely depressed mood in Parkinson’s disease patients. Adjunct treatment with dopamine agonists, either pergolide or pramipexole, had significant antidepressant effects in Parkinson’s disease patients according to the Zung self-rating scores or HAM-D.39 Pramipexole showed the greater effect with 61% of Parkinsonian depressed patients reaching the “recovered” points in HAM-D, as compared with only 27% of those on sertraline.40 SSRIs, including fluoxetine, sertraline, citalopram, and paroxetine failed to improve Parkinson’s disease depression,41-43 while beneficial effects of paroxetine, nefazodone, fluoxetine, and venlafaxine were observed in Parkinson’s disease-associated depression in other clinical trials.44-48 Although SSRIs are still the most commonly used drugs to treat depression in Parkinson’s disease, there is a high risk of worsening Parkinson’s disease tremor (possibly due to effects of serotonin-mediated inhibition of dopamine release). Given that the dopaminergic system is involved in the pathogenesis of both depression and Parkinson’s disease, it is hypothesized that triple reuptake inhibitors might have improved efficacy in treating Parkinson’s disease depression with less likelihood of aggravating tremors.

Disturbances in reward functioning in MDD further implicate dopamine neurotransmission in depression. The drug-addicted state shares some underlying neurobiologic substrates and common symptoms with depression and there is a high rate of comorbidity of drug addiction with depression.49 Anhedonia, in addition to being a cardinal criterion for the diagnosis of depression, is also a core symptom required for the diagnosis of drug withdrawal, which is thought to involve a reduction in mesolimbic dopamine neurotransmission. Severity of MDD has been found to correlate directly with the magnitude of the reward experience after psychostimulant (d-amphetamine) treatment.50 Specifically, medication-free, severely depressed subjects experienced greater reward than controls after treatment with a psychostimulant, while mildly depressed patients did not differ from controls. Compensatory mechanisms resulting from the reduction of dopamine release in MDD, such as up-regulation of postsynaptic dopamine receptors and decreased dopamine transporter density, may contribute to the greater effect of amphetamine in these patients. Additionally, the hyperactivity of the hypothalamic-pituitary-adrenal axis in MDD may selectively facilitate dopamine transmission, thus supporting the theory that a depressed patient has increased reward processing of psychostimulants.51

 

Broad-Spectrum Antidepressants: Triple Reuptake Inhibitors

Given the critical role of dopamine circuits in mediating some depressive symptoms, a triple reuptake inhibitor—a broad-spectrum drug combining blockade of dopamine, serotonin, and norepinephrine transporters—is an attractive strategy to treat depression. Hypothetically, this type of drug would produce a more rapid onset and better efficacy (higher response and remission rates) than current antidepressants in part due to the addition of the dopamine component.16 In addition, it is possible that some of the sexual dysfunction related to serotonin transport blockade, seen very commonly with SSRIs,52 would be attenuated or even eliminated due to the addition of the dopamine component. In particular, hyperprolactinemia, which causes impotence in males, would be less likely to occur since dopamine opposes serotonin-promoted prolactin release.53 In addition, due to the link to the dysfunction of dopamine neurotransmission, triple reuptake inhibitors may be of benefit in Parkinson’s disease2 and psychostimulant withdrawal with or without depression.49
Enhancements of BDNF gene expression and hippocampal neurogenesis followed by downstream effects are considered to be important mechanisms after chronic antidepressant treatment.54,55 However, neurogenesis more likely relates to their antianxiety rather than their antidepressant effects.56 A triple reuptake inhibitor antidepressant may show a more robust ability to up-regulate BDNF transcripts than SSRIs,57 assumedly via distinct signaling cascades targeting regulatory segments at different exons.58

A concern with drugs that block dopamine transporters is their potential reinforcing effects and abuse liability.59 Thus, triple reuptake inhibitors will likely receive extra scrutiny by regulatory bodies regarding their abuse liability. This will require preclinical (testing for reinforcing effects in animals) as well as clinical testing. However, just because a drug blocks the dopamine transporter does not mean that it will be abused. Using positron emission tomography (PET), Volkow and colleagues59 showed that dopamine transporter-blocking drugs must induce >50% dopamine transporter blockade and the blockade must be timely (within 15 minutes) to produce reinforcing effects. For example, radafaxine, a hydroxy metabolite of bupropion being developed as a new antidepressant, blocks the dopamine and norepinephrine transporters and is not reinforcing in animals, since animals will not self-administer the drug. In PET studies,43 it shows relatively low potency and slow blockade of the dopamine transporter in human brain.59 These animal and human studies suggest that radafaxine is unlikely to have reinforcing effects in humans. For triple reuptake inhibitors, PET studies of dopamine transporter blockade in humans may be an easy way to test for their tendency for abuse.

 

Developing Triple Reuptake Inhibitors

If these hypotheses are proven correct, the therapeutic profile of triple reuptake inhibitors would offer clear advantages over currently available antidepressants. Although the clinical efficacy of such a broad-spectrum antidepressant has not yet been fully demonstrated, several compounds have entered clinical trials, such as DOV 216,303, DOV 21,947, NS-2359, and SEP-225289. Information on the binding profiles of the known triple reuptake inhibitors is limited. Some data for inhibition at human or rat transporters are listed in the Table (Albany Molecular Research Inc. Drug Discovery Symposium, unpublished data, October 2006).60-63

 

 

 

PRC Series

In collaboration with Paul R. Carlier, PhD (Virginia Tech, Blacksburg, VA), the authors of this article have synthesized a series of compounds based on the structure of venlafaxine (Figure).17 Racemic PRC025 {(1S/1R,2S/2R)-1-cyclohexyl-3-(dimethylamino)-2-(naphthalen-2-yl)propan-1-ol} and racemic PRC050 {(1S/1R,2S/2R)-3-(methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol} are both highly potent at human serotonin, norepinephrine, and dopamine transporters and also potently inhibit the reuptake of serotonin, norepinephrine, and dopamine into rat brain synaptosomes.64 Both are active in tests predictive of antidepressant activity in humans including the mouse tail-suspension test and the rat forced swim test.64 PRC200-SS {(1S,2S)-3-(methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol} (Figure), which is the more active enantiomer of PRC050, potently binds to the human serotonin, norepinephrine, dopamine transporters (Table) and potently inhibits serotonin, norepinephrine, and dopamine uptake in cells expressing the corresponding transporter.60 Consistent with these in vitro data, in vivo, PRC200-SS (10 mg/kg, ip) significantly increased the extracellular levels of serotonin and norepinephrine in the medial prefrontal cortex, and of serotonin and dopamine in the core of nucleus accumbens, with reduction of levels of 3,4-dihydroxyphenylacetic acid, HVA, and 5-hydroxyindoleacetic acid compared to levels for saline control (Y Liang, PhD, unpublished data, October 2007). In addition, PRC200-SS dose-dependently decreased immobility in the forced swim test in rats and in the tail-suspension test in mice, with effects comparable to imipramine, but at a much lower dosage.60 The results in these behavioral models do not appear to be from the stimulation of locomotor activity, which would give a false-positive result in these predictive tests of antidepressant activity in humans. Further, PRC200-SS self-administration, which was used as a test of abuse liability, was not observed with rats (Y Liang, PhD, unpublished data, October 2007). To these authors’ knowledge, this is the first study to address the abuse property of a triple reuptake inhibitor. Therefore, it appears that PRC200-SS is a novel triple reuptake inhibitor that possesses antidepressant-like activity. It is expected that PRC200-SS will be in clinical testing in 2009.

 

 

 

DOV Series

DOV Pharmaceutical, Inc. (Somerset, NJ), is developing a DOV series of triple reuptake inhibitors (Table). DOV 216,303 (racemic) is active in the mouse forced swim test, with the reversal of tetrabenazine-induced ptosis and locomotor depression.16 DOV 21,947, as the (+)-enantiomer of DOV 216,303, is effective in the rat forced swim test with an oral minimum effective dose of 5 mg/kg without significant locomotor activity and in the mice tail suspension test in a dose-dependent manner with a minimum effective oral dose of 5 mg/kg.16,61 DOV 102,677 (20 mg/kg, ip) increased extracellular levels of dopamine, serotonin, and norepinephrine in the prefrontal cortex and levels of dopamine and serotonin in the nucleus accumbens, along with reduction of their metabolites in both regions. These results are consistent with the dosage used for antidepressant-like activity in the forced swim test with a minimum effective dose of 20 mg/kg.62 DOV 102,677 was also as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity. Further, DOV 102,677 potently blocked volitional consumption of alcohol and reduced the operant response to alcohol.65 DOV 216,303 has already entered into clinical trials. Dose-escalating, placebo-controlled, double-blind Phase Ia trials show rapid absorption following oral administration. Severe side effects in Phase Ia and Phase Ib trials were limited to diarrhea, vomiting, and nausea. Phase I trials indicated DOV 216,303 to be safe and well tolerated at single doses of up to 100 mg and at multiple doses of up to 100 mg/day for 10 days. Phase II trials showed that DOV 216,303 is as effective as the SSRI citalopram in severely depressed patients based on changes in the HAM-D.66

 

NS-2359 (GSK-372475)

NS-2359 (GSK-372475), which was developed by Neurosearch A/S (Ballerup, Denmark) and subsequently out-licensed to GlaxoSmithKline (GSK; United States and United Kingdom), is another triple reuptake inhibitor entering clinical trials. Phase I trials showed it was well tolerated by patients, with increased attention and improved ability to recall verbal information. It is proposed to be a treatment for attention-deficit/hyperactivity disorder. In 2006, GSK initiated Phase II trials in patients with MDD.66

 

Tesofensine (NS-2330)

Tesofensine (NS-2330) is another triple reuptake inhibitor developed by NeuroSearch. It indirectly stimulates cholinergic action, and is suggested by NeuroSearch to be a potential therapy for Alzheimer’s disease and Parkinson’s disease.67 Tesofensine has a longer half-life (8 days) in humans than most other antidepressants. It shows antidepressant-like properties with respect to enhancement of hippocampal neurogenesis and BDNF messenger ribonucleic acid (mRNA) augmentation. Chronic (14 days) but not sub-chronic (5 days) treatment with tesofensine induced increases in BDNF mRNA in the CA3 region of the hippocampus, cytoskeleton protein mRNA in the CA1 of the hippocampus. There was also an increase in hippocampal markers for cell proliferation as measured by immunoreactivity for Ki-67 (a marker of proliferating cells) and NeuroD (a transcription factor regulating neurogenesis).68 Such results correspond with the profiles of current antidepressants.54 In a small Phase IIa pilot study of Alzheimer’s disease, NS 2330 (10.75 mg and 12.25 mg over 28 days) improved aspects of cognition, including attention and ability to store and retrieve information. However, due to inadequate inhibition of dopamine reuptake, tesofensine failed to provide clinical benefit as monotherapy in early Parkinson’s disease compared to placebo in a proof-of-concept, randomized, and double-blind trial.69

 

Others

Sepracor has developed SEP-225289 for treatment of refractory depression and for generalized anxiety disorder. This compound is undergoing Phase I clinical trials. Albany Molecular Research Institute (AMRI; Albany, New York and elsewhere) has developed AMRI CNS-1 and CNS-2 (Table), which have been licensed by Bristol-Myers Squibb (New York, New York; Albany Molecular Research Inc. Drug Discovery Symposium, unpublished data, October 2006). Acenta Discovery Inc. (Tucson, AZ) has designed and synthesized piperidine-based nocaine/modafinil hybrid ligands displaying an improved potency at all three monoamine transporters and particularly for the dopamine transporter and/or norepinephrine transporter.70

 

Conclusion

Clearly, triple reuptake inhibitors hold great promise for the next generation of antidepressants. In the meantime, the available clinical data are too limited to draw any conclusions. Publicly available preclinical data on these compounds are also limited. Some of the in vitro data, presented in the Table, suggest some pharmacodynamic differences among these compounds. Of the compounds listed, PRC200-SS is the most potent at norepinephrine transporter, and AMRI CNS-1 at the serotonin and dopamine transporters.

The rank-order of potency at the various transporters differs among these compounds as well (Table). For example, PRC200-SS is norepinephrine (N)> serotonin (S)>dopamine (D), while DOV 21,947 is S>D>N (Table). It is reasonable to speculate that triple re-uptake inhibitors will have distinctly different clinical profiles depending on their rank order of potency, as well as on their relative potencies at the three transporters. It is also possible to have a perfectly balanced triple reuptake inhibitor, where the potencies at all three transporters are equal. What are the ideal rank order and the ideal relative potency? It is probably easier to answer the latter question, the answer for which derives from occupancy theory. Simply stated, if a drug has a very large range from its most potent to its least potent effect, it may not be possible clinically to achieve a dosage that blocks all three transporters. Thus, a narrow range (10–30-fold) is better. Additionally, it would probably be better to have serotonin transporter blockade as the weakest of the three, to minimize the adverse effects associated with this blockade (eg, sexual dysfunction). Dopamine transporter blockade as the most potent effect may lead to concerns about the abuse potential of the compound. Therefore, the ideal rank order would probably be N>D>S. This would provide a triple re-uptake inhibitor with some nomifensine-like qualities (Table). PP

 

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29.    Sullivan PF, Neale MC. Kendler KS. Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry. 2000;157(10):1552-1562.
30.    Haeffel GJ, Getchell M, Koposov RA, et al. Association between polymorphisms in the dopamine transporter gene and depression: evidence for a gene-environment interaction in a sample of juvenile detainees. Psychol Sci. 2008;19(1):62-69.
31.    Togsverd M, Werge TM, Tanko LB, et al. Association of a dopamine beta-hydroxylase gene variant with depression in elderly women possibly reflecting noradrenergic dysfunction. J Affect Disord. 2008;106(1-2):169-172.
32.    Jimerson DC. Role of dopamine mechanisms in affective disorder. In: Meltzer HY, ed. Psychopharmacology: The Third Generation of Progress. New York: Raven Rress; 1987:505-511.
33.    Thase ME, Trivedi MH, Rush AJ. MAOIs in the contemporary treatment of depression. Neuropsychopharmacology. 1995;12(3):185-219.
34.    Jouvent R, Abensour P, Bonnet AM, Widlocher D, Agid Y, Lhermitte F. Antiparkinsonian and antidepressant effects of high doses of bromocriptine. An independent comparison. J Affect Disord. 1983;5(2):141-145.
35.    Corrigan MH, Denahan AQ, Wright CE, Ragual RJ, Evans DL. Comparison of pramipexole, fluoxetine, and placebo in patients with major depression. Depress Anxiety. 2000;11(2):58-65.
36.    Dailly E, Chenu F, Renard CE, Bourin M. Dopamine, depression and antidepressants. Fundam Clin Pharmacol. 2004;18(6):601-607.
37.    Serra G, Collu M, D’Aquila PS, Gessa GL. Role of the mesolimbic dopamine system in the mechanism of action of antidepressants. Pharmacol Toxicol. 1992;71(suppl 1):72-85.
38.    Poewe W. Depression in Parkinson’s disease. J Neurol. 2007;254(suppl 5):49-55.
39.    Rektorova I, Rektor I, Bares M, et al. Pramipexole and pergolide in the treatment of depression in Parkinson’s disease: a national multicentre prospective randomized study. Eur J Neurol. 2003;10(4):399-406.
40.    Barone P, Scarzella L, Marconi R, et al. Pramipexole versus sertraline in the treatment of depression in Parkinson’s disease: a national multicenter parallel-group randomized study. J Neurol. 2006;253(5):601-607.
41.    Leentjens AF, Vreeling FW, Luijckx GJ, Verhey FR. SSRIs in the treatment of depression in Parkinson’s disease. Int J Geriatr Psychiatry. 2003;18(6):552-554.
42.    Weintraub D, Morales KH, Moberg PJ, et al. Antidepressant studies in Parkinson’s disease: a review and meta-analysis. Mov Disord. 2005;20(9):1161-1169.
43.    Wermuth L, Sørensen PS, Timm S, et al. Depression in idiopathic Parkinson’s disease treated with citalopram. Nord J Psychiatry. 1998;52:163-169.
44.    Avila A, Cardona X, Martin-Baranera M, et al. Does nefazodone improve both depression and Parkinson disease? A pilot randomized trial. J Clin Psychopharmacol. 2003;23(5):509-513.
45.    Ceravolo R, Nuti A, Piccinni A, et al. Paroxetine in Parkinson’s disease: effects on motor and depressive symptoms. Neurology. 2000;55(8):1216-1218.
46.    Tesei S, Antonini A, Canesi M, Zecchinelli A, Mariani CB, Pezzoli G. Tolerability of paroxetine in Parkinson’s disease: a prospective study. Mov Disord. 2000;15(5):986-989.
47.    Bayulkem K, Torun F. Therapeutic efficiency of venlafaxin in depressive patients with Parkinson’s disease. Mov Disord. 2002;17(suppl 5):204.
48.    Okun MS, Watts RL. Depression associated with Parkinson’s disease: clinical features and treatment. Neurology. 2002;58(4 suppl 1):63-70.
49.    Paterson NE, Markou A. Animal models and treatments for addiction and depression co-morbidity. Neurotox Res. 2007;11(1):1-32.
50.    Tremblay LK, Naranjo CA, Cardenas L, Herrmann N, Busto UE. Probing brain reward system function in major depressive disorder: altered response to dextroamphetamine. Arch Gen Psychiatry. 2002;59(5):409-416.
51.    Marinelli M, Piazza PV. Interaction between glucocorticoid hormones, stress and psychostimulant drugs. Eur J Neurosci. 2002;16(3):387-394.
52.    Rosen RC, Lane RM, Menza M. Effects of SSRIs on sexual function: a critical review. J Clin Psychopharmacol. 1999;19(1):67-85.
53.    Ben-Jonathan N, Hnasko R. Dopamine as a prolactin (PRL) inhibitor. Endocr Rev. 2001;22(6):724-763.
54.    Russo-Neustadt AA, Chen MJ. Brain-derived neurotrophic factor and antidepressant activity. Curr Pharm Des. 2005;11(12):1495-1510.
55.    Castren E. Neurotrophic effects of antidepressant drugs. Curr Opin Pharmacol. 2004;4(1):58-64.
56.    Sapolsky RM. Is impaired neurogenesis relevant to the affective symptoms of depression? Biol Psychiatry. 2004;56(3):137-139.
57.    Russo-Neustadt AA, Alejandre H, Garcia C, Ivy AS, Chen MJ. Hippocampal brain-derived neurotrophic factor expression following treatment with reboxetine, citalopram, and physical exercise. Neuropsychopharmacology. 2004;29(12):2189-2199.
58.    Tardito D, Perez J, Tiraboschi E, Musazzi L, Racagni G, Popoli M. Signaling pathways regulating gene expression, neuroplasticity, and neurotrophic mechanisms in the action of antidepressants: a critical overview. Pharmacol Rev. 2006;58(1):115-134.
59.    Volkow ND, Wang GJ, Fowler JS, et al. The slow and long-lasting blockade of dopamine transporters in human brain induced by the new antidepressant drug radafaxine predict poor reinforcing effects. Biol Psychiatry. 2005;57(6):640-646.
60.    Shaw AM, Boules MM, Williams K, Robinson J, Carlier PR, Richelson E. Antidepressant-like effects of PRC200, a novel norepinephrine, serotonin, and dopamine reuptake inhibitor [abstract]. Biol Psychiatry. 2006;59(8):61S.
61.    Skolnick P, Popik P, Janowsky A, Beer B, Lippa AS. Antidepressant-like actions of DOV 21,947: a “triple” reuptake inhibitor. Eur J Pharmacol. 2003;461(2-3):99-104.
62.    Popik P, Krawczyk M, Golembiowska K, et al. Pharmacological profile of the “triple” monoamine neurotransmitter uptake inhibitor, DOV 102,677. Cell Mol Neurobiol. 2006;26(4-6):857-873.
63.    Tatsumi M, Groshan K, Blakely RD, Richelson E. Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997;340(2-3):249-258.
64.    Shaw AM, Boules M, Zhang Y, et al. Antidepressant-like effects of novel triple reuptake inhibitors, PRC025 and PRC050. Eur J Pharmacol. 2007;555(1):30-36.
65.    McMillen BA, Shank JE, Jordan KB, Williams HL, Basile AS. Effect of DOV 102,677 on the volitional consumption of ethanol by Myers’ high ethanol-preferring rat. Alcohol Clin Exp Res. 2007;31(11):1866-1871.
66.    Chen Z, Skolnick P. Triple uptake inhibitors: therapeutic potential in depression and beyond. Expert Opin Investig Drugs. 2007;16(9):1365-1377.
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68.    Larsen MH, Rosenbrock H, Sams-Dodd F, Mikkelsen JD. Expression of brain derived neurotrophic factor, activity-regulated cytoskeleton protein mRNA, and enhancement of adult hippocampal neurogenesis in rats after sub-chronic and chronic treatment with the triple monoamine re-uptake inhibitor tesofensine. Eur J Pharmacol. 2007;555(2-3):115-121.
69.    Hauser RA, Salin L, Juhel N, Konyago VL. Randomized trial of the triple monoamine reuptake inhibitor NS 2330 (tesofensine) in early Parkinson’s disease. Mov Disord. 2007;22(3):359-365.
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Needs Assessment:
Psychotic depression is a more common illness than previously believed. It differs from other psychotic disorders in the type and manifestation of psychotic symptoms. The purpose of this article is to synthesize the available literature on the phenomenology and treatment of psychotic major depression.


Learning Objectives:

• Understand the unique symptoms of psychotic major depression.
• Learn the limitation of clinical trials in the treatment of psychotic depression.
• Learn about investigational treatments for psychotic depression.

Target Audience: Primary care physicians and psychiatrists.

CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: March 19th, 2008.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by April 1, 2010 to be eligible for credit. Release date: April 1, 2008. Termination date: April 30, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. DeBattista is associate professor of Psychiatry and Behavioral Sciences, director of Depression Research and Psychopharmacology Clinics, and director of Medical Student Education in Psychiatry; and Dr. Lembke is senior research associate and clinical instructor, both at Stanford University School of Medicine in California.

Disclosure: Dr. DeBattista is on the speaker’s bureaus and/or consultant to Bristol-Myers Squibb, Cephalon, Corcept, Cyberonics, Eli Lilly, Forest, Pfizer, and Wyeth; receives grant support from AstraZeneca, Boehringer-Ingelheim, Cephalon, Cyberonics, Eli Lilly, Forest, Neuronetics, Novartis, Pfizer, and Wyeth; and is a stockholder of Corcept Therapeutics (Corcept is the developer of mifepristone for use in psychotic depression). Dr. Lembke receives research support from the National Institutes of Health.

Please direct all correspondence to: Charles DeBattista, MD, Stanford University School of Medicine, 401 Quarry Rd, Stanford, CA 94305; Tel: 650-723-8324; Fax: 650-723-8331; E-mail: debattista@stanford.edu.

 


 

 

Abstract

Psychotic major depression appears to be a unique subtype of depression with its own phenomenology and treatment response. However, the symptom profile of psychotic depression is not well described in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and the psychotic symptom features of psychotic depression may be distinct. While treatments such as electroconvulsive therapy and the combination of antidepressants and antipsychotics appear effective, data that supports the efficacy of these treatments have substantial limitations. The symptoms and treatment of psychotic major depression are critically reviewed in this article.

 

Introduction

Psychotic major depression (PMD) is classified in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV),1 as a severe form of depression characterized by meeting the full criteria for major depressive disorder (MDD) plus the presence of delusions or hallucinations. Growing evidence suggests that PMD is more common than once believed. It is estimated that at least 14% to 20% of depressive episodes have psychotic features.2,3 Psychotic depression may represent a unique subtype of MDD with a distinct phenomenology and treatment response.4 Psychotic features are not necessarily the only symptoms that distinguish PMD from non-psychotic major depression (NPMD) For example, cognitive deficits may also distinguish PMD form NPMD.5 Furthermore, the psychotic features of PMD may not completely parallel the kinds of symptoms seen in other psychotic disorders such schizophrenia. In fact, specialized scales have been proposed for assessing psychosis in PMD.6,7 Given that the symptoms of PMD differ from other types of depression, it is not surprising that PMD may require different treatment than NPMD. However, relative to NPMD, very few trials have ever been completed in the treatment of PMD, and those trials have significant limitations.

 

Phenomenology

The DSM-IV describes the psychotic features of PMD as predominately delusions that are mood congruent, such as delusions of guilt, delusions of poverty, somatic delusions, or nihilistic delusions.1 Furthermore, the DSM-IV suggests that mood incongruent delusions such as persecutory delusions (without a depressive theme) are less common as are hallucinations. When present, hallucinations are described as transient, auditory, and likely to be mood congruent.

The rate of paranoid delusions in PMD samples has varied considerably. Lykourous and colleagues8 found that paranoid delusions were the most common, with nine of eleven patients presenting with delusions of impending disaster, guilt, and somatization. Likewise, a subsequent study by Lykourous and colleagues9 found that all 22 PMD patients had delusions, with ideas of reference and persecution being the most common. Breslau and Meltzer10 found that delusions of reference occurred in 23% of the PMD, 62% of the schizoaffective, and 32% of the bipolar patients. Persecutory delusions occurred in 38% of the PMD, 56% of the schizoaffective, and 53% of the bipolar patients. Other types of depressive delusions occurred in 49% of the PMD, 41% of the schizoaffective, and 51% of the bipolar patients.

The delusions in PMD may be more subtle than those seen in schizophrenia. Many patients with depressive disorders have ruminations that may not quite meet the threshold of delusion. However, these “near delusions” tend to predict poor response to antidepressant monotherapy.11

Hallucinations have been characterized as being less common in PMD than in schizophrenia but may still be quite common. For example, Breslau and Meltzer10 found that visual hallucinations were somewhat more common in psychotically depressed unipolar than bipolar or schizoaffective patients, occurring in 31% of unipolar patients. In contrast, auditory hallucinations were much less common in unipolar psychotic patients (28%) than in schizoaffective (62%) patients. Lykourous and colleagues8 found that 50% of patients with PMD had hallucinations, but that these only occurred in patients who also had delusions and with whom the content of the hallucinations was consistent with those of the delusions. In general, the hallucinations in PMD have been thought to be less severe than those found in schizophrenia.

Thought disorder has historically been most associated with schizophrenia spectrum illnesses. However, disorders of thought may be even more common in mood disorders such as bipolar disorder. The rate of thought disorder in PMD has been considered low. For example, Breslau and Meltzer10 found that only 10% of patients with unipolar depression with psychotic depression had evidence of a thought disorder, versus 40% of bipolar and 50% of schizoaffective patients. Wilcox and colleagues12 found that thought disorders were also predictive of a greater relapse rate over 7 years than other psychotic symptoms in PMD.

While a formal thought disorder may be less common in unipolar patients with psychotic depression, cognitive deficits in general appear quite common. Patients with psychotic depression have more difficulty processing, manipulating, and encoding new information5 than do NMPD patients. Other types of deficits seen in psychotic versus nonpsychotic depressed patients include difficulty with attention, response inhibition, and verbal declarative memory.13 In fact, the cognitive deficits seen in PMD appear to resemble those seen in schizophrenia more than those in patients with non-psychotic depression.14

Treatment

Antidepressant Monotherapy

Given the unique phenomenology of psychotic depression, it is not surprising that the standard treatment for MDD may not be as consistently useful in PMD. For example, monotherapy with antidepressants is thought to be less useful in PMD. Many of the treatment studies of psychotic depression have employed tricylcic antidepressants (TCAs). While TCA monotherapy has been an established treatment for MDD, studies of amitriptyline, imipramine, and other TCAs in the treatment of PMD have shown poor response. For example, Avery and Lubrano15 considered the DeCarolis study, where 437 patients with and without psychotic features were prospectively treated with imipramine. Only 40% of PMD patients responded to imipramine treatment versus 60% of the non-psychotic depressed patients. Similarly, an analysis of 12 studies by Chan and colleagues16 found that only 35% of PMD patients responded to TCAs versus 67% of NPMD patients. In the National Institute of Mental Health Collaborative Program on the Psychobiology of Depression, 32% of patients with psychotic features responded to amytryptyline or imipramine compared with 37% of nonpsychotic severely depressed patients and 67% of patients with moderate nonpsychotic depression.17 However, the differences between PMD and severely depressed NPMD patients was not significant. Other TCA studies also have not necessarily shown a difference between response to TCAs in PMD versus NPMD patients.18

More recent monotherapy studies have reported efficacy with SSRIs in the treatment of PMD. For example, Gatti and colleagues19 reported that 84% of 57 patients treated for 6 weeks with fluvoxamine responded to treatment. In subsequent PMD trials, fluvoxamine was found to be at least as efficacious as venlafaxine in the treatment20 and even more rapidly efficacious in combination with pindolol.21 Long-term treatment with fluvoxamine was also reported to prevent relapse in PMD patients treated for 18 months.22 The pharmacologic profile of fluvoxamine differs from other SSRIs in that it has substantial effects on the Sigma receptor which is also thought to play a role in the pathophysiology of psychosis.23

Other SSRIs have also been proposed to be effective in the monotherapy of PMD. Zanardi and colleagues24 found that sertraline was more effective than paroxetine in the treatment of 46 patients hospitalized with PMD. In contrast, Simpson and colleagues25 found that sertraline was much less effective in PMD patients than NPMD patients treated with up to 200 mg/day. Thus, the utility of sertraline monotherapy in the treatment of PMD is unclear. As with the TCA studies, methodologic problems limit conclusions that can be surmised from the SSRI studies. Among the limitations of the SSRI studies in PMD include the lack of a placebo group, the lack of a comparison with response NPMD patients, and possibly differences in the criteria for defining PMD.

Amoxapine, a tetracyclic antidepressant related to loxapine and rarely used currently, was also reported to be effective as a monotherapy in the treatment of PMD. Anton and Burch26 compared amoxapine to the combination of amitriptyline and perphenazine in the treatment of PMD. After 4 weeks of treatment, >80% of patients in both the combination group and the amoxapine group exhibited a moderate or marked response without significant differences between treatments. However, the combination treatment was more poorly tolerated. While the Anton and Burch26 study was a double-blind randomized study with a placebo wash out, there was no placebo comparison group in the study.

Thus, there is some evidence that monotherapy with amoxapine and perhaps SSRIs may be effective in the treatment of PMD, and that TCA monotherapy has generally not been effective. However, the methodologic problems of the monotherapy trials are many and it is uncertain whether monotherapy is a reasonable treatment or whether combination treatment with an antipsychotic is generally necessary to achieve response.

 

Combination Treatment: Antidepressants and Antipsychotics

Numerous studies that found monotherapy with TCAs ineffective in the treatment of PMD found that the addition of a standard antipsychotic significantly improved efficacy. For example, Minter and Mandel,27 in a retrospective chart review of 54 PMD patients, found patients generally did not respond to monotherapy with a TCA but became responders when an antipsychotic was added. Similarly, Charney and Nelson,28 in a retrospective review of 120 PMD and NPMD patients, found that the PMD patients responded poorly to TCAs but well to the combination of TCAs and typical antipsychotics.

In one of the few prospective randomized trials to compare combination treatment with monotherapy, Spiker and colleagues29 compared the efficacy of amitriptyline alone, perphenazine alone, and the combination of amitriptyline and perphenazine in PMD patients. The response rate to treatment after 35 days was as follows. Amitriptyline alone was 41%, perphenazine alone was 19%, and combination of amitriptyline and perphenazine was 78%. Patients who failed to respond to monotherapy tended to respond when the second agent was added.

The combination of fluoxetine and olanzapine has also been evaluated in larger and more rigorous studies than previous combination trials. Patients who met DSM-IV criteria for PMD were randomized to either the combination of olanzapine and fluoxetine, olanzapine alone, or placebo.30 Two studies (study 1 with 124 patients, study 2 with 125 patients) were conducted in parallel at 27 sites under the same protocol. In study 1, the combination treatment was superior to placebo and olanzapine on the primary outcome, which was defined as change from baseline on the Hamilton Rating Scale for Depression (HAM-D). In addition, the categorical response rate (50% improvement on the HAM-D) was significantly higher in the combination treatment in study 1 (63%) compared to olanzapine alone (35%) or placebo (28%). There were no differences between groups in the second trial on the primary outcome measure, response rates, or remission rates. Furthermore, the pooled data of trials 1 and 2 did not apparently show a benefit of combination treatment over placebo or olanzapine. Both studies had much higher placebo response rates than have been typically reported for PMD. The long hospitalization allowed in the study may have contributed to this high placebo response rate. In addition, the lack of a fluoxetine alone arm also prevented a comparison with antidepressant monotherapy.

 

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) has been reported to be among the most effective treatments for PMD. The American Psychiatric Association Guidelines for the treatment of depression endorse ECT as a first-line treatment only for PMD.31 As with other treatments for PMD, there are few prospective randomized or sham-controlled trials. Retrospective reviews and open trials have generally shown ECT to be highly effective in the treatment of PMD.27,28,32-35 The DeCarolis study, as noted by Avery and Lubrano,15 found that while only 40% of PMD patients responded to TCA monotherapy, 83% of these nonresponders subsequently responded to ECT. While a large prospective trial, the DeCarolis study is an older trial without a control group or clear entry or response criteria.

There are few sham-controlled studies that specifically include PMD patients. In the Northwick Park Electroconvulsive therapy trial, both delusional and nondelusional depressed patients were evaluated.36 Seventy patients who met endogenous depression criteria were randomized to a series of eight ECT treatments or eight sham treatments. While the treating psychiatrists tended to consider the active ECT patients to be better responders than the sham treated patients, the differences between groups were small and there were no differences between groups at 1 and 6 months after treatment. Delusional patients were not separately evaluated in the initial analysis. However, when the results of the Northwick Park ECT trial were combined with results of the subsequent Liecester ECT trial, patients with delusional depression and/or psychomotor retardation appeared to have more benefit than sham-treated patients at 4 weeks.37 Patients without delusions or psychomotor retardation did not show a difference between active ECT treatment and sham treatment. In addition, there were no differences between the active and sham groups at 6 months. The conclusion in both sham-controlled trials was that ECT did not appear effective because there were no sustained benefits. These randomized trials have been criticized as using an ECT stimulus dose that might be considered ineffective currently,38 and as not providing a standardized treatment option after 4 weeks of twice weekly ECT. It has been more recently established that most patients can be expected to relapse within 6 months of successful ECT without effective follow-up treatment.39 Thus, the conclusion that ECT was ineffective because no difference could be observed 6 months after the ECT was discontinued appears invalid in retrospect.

More recent ECT trials comparing response in PMD compared to NPMD patients have suggested that there may be a more favorable response to ECT in PMD patients. Petrides and colleagues40 prospectively compared the efficacy of ECT in 176 patients with NPMD and 77 patients with PMD. Approximately 95% of PMD patients experienced a full remission with acute ECT compared to 83% of patients with NPMD on the HAM-D. Remission also occurred earlier in the PMD patients. Birkenhager and colleagues41 found a 92% response rate (defined as 50% improvement on the HAM-D) in PMD patients compared with only a 55% response rate to ECT in NPMD patients. PMD patients who respond to ECT also may be somewhat less likely to relapse than NPMD patients who respond to ECT. Birkenhager and colleagues42 prospectively followed 29 PMD and 30 NPMD patients who responded to ECT for 1 year. Only 15% of PMD patients relapsed at 12 months compared to 58% of NPMD patients. Since relapse to ECT may be related to factors other than psychosis (eg, number of previous episodes, number of failed previous medication trials),39 it is uncertain in this study whether the PMD and NPMD groups were comparable. Other trials have not found an advantage of ECT treatment in PMD patients compared to NPMD patients, and some trials have suggested a poorer response to ECT in PMD patients.43 Numerous factors might lead to disparate results in the evaluation of ECT for PMD. For example, ECT variables including stimulus dose, lead placement, frequency and number of treatments, and seizure duration tend to differ from trial to trial. In addition, assessment scales and inclusion criteria are also not uniform in ECT studies.

Despite the limitations of the ECT data, there has been a consistent theme in the literature over the past 40 years that suggests that ECT is an effective acute treatment for PMD with reported response and remission rates that are generally higher than those reported in pharmacotherapy trials. However, there are a lack of randomized, head to head comparison trials between ECT and pharmacotherapy in PMD patients, and such trials would be difficult to design and control given the obvious disparities between treatments.

 

Experimental Treatments

Among the treatments under investigation for PMD include the use of the glucocorticoid receptor antagonist mifepristone and transcranial magnetic stimulation (TMS). The glucocortiod/progesterone receptor antagonist mifepristone has been explored in the treatment of PMD with the rationale that some symptoms of PMD may be driven by abnormalities in the hypothalamic-pituitary-adrenal axis.44 Early open and controlled studies by the authors of this article have suggested that there might be benefits of mifepristone in the treatment of the psychotic symptoms of PMD.45,46 However, the most recent controlled studies of mifepristone failed to replicate these findings. Among the methodologic limitations of the mifepristone trials might include the representativeness of the patient sample, the adequacy of the endpoints, the high placebo response rates, and whether the optimal dose and duration of mifepristone treatment was employed. A summary of the mifepristone studies completed to date in the treatment of PMD can be found elsewhere.47 Additional controlled studies of mifepristone in the treatment of PMD are currently underway.

Another experimental treatment that has been examined in PMD is TMS, which uses a focused electromagnetic field to stimulate very specific areas of the cortex.48 Numerous studies have suggested efficacy for TMS, including a recently completed multi-center American trial of TMS in treatment-resistant depression.49 However, TMS, while more benign than ECT, appears to be substantially less effective than the latter.50-52 In addition, psychotic features of depression appear to predict poorer response to TMS.48 Thus, most recent studies of TMS exclude patients with PMD. It is possible, however, that different stimulation parameters might improve the efficacy of TMS of both PMD and NPMD.

 

Conclusion   

PMD remains a relatively poorly understood illness. The unique symptom profile of PMD is consistent with the finding that standard treatments for NPMD are often not as effective in the treatment of PMD. The increased prevalence of delusions, hallucinations, and more severe cognitive symptoms in PMD might require different strategies for effective treatment. The current standard of care for PMD is either combination treatment with an antidepressant plus an antipsychotic, or ECT. However, this standard is based on relatively limited data. While anecdotal experience tends to support the efficacy of combination treatment and ECT in PMD, there is a paucity of randomized controlled data evaluating these strategies. Furthermore, the few randomized controlled trials have not necessarily supported these strategies as the optimal treatments.
Trends in the treatment data suggest that TCAs alone are not effective in the treatment of PMD. It is conceivable that the anti-muscarinic effects of TCAs such as amitriptyline might exacerbate some of the more severe cognitive deficits in PMD.53 As suggested earlier, the unique pharmacology of some SSRIs, such as the effects of fluvoxamine on the sigma receptor, might be of specific benefit in PMD patients.23 The role of investigational treatments including glucocorticoid antagonists and TMS await further investigation. Given the substantial side-effect burden that antipsychotics may produce, further study is needed to evaluate whether combination treatment, especially with newer atypical antipsychotics, is the optimal pharmacotherapy.

Future treatment studies in PMD are hampered by the lack of adequate measures to assess outcome. It is not at all clear that the HAM-D, which has been used in most PMD studies, is the ideal scale for evaluating improvement in PMD patients. The HAM-D does not capture the unique phenomenology of PMD. Likewise, most scales employed to evaluate psychosis in PMD, such as the Brief Psychiatric Rating Scale, were designed to evaluate symptoms in schizophrenia. The psychotic symptoms in PMD do not necessarily parallel those in schizophrenia. Until better measures are developed and randomized comparison trials are completed with newer agents, the optimal treatment for PMD in most patients cannot be established with confidence. In clinical practice, most clinicians appear to be more likely to treat PMD with an antidepressant alone and seem hesitant to add an antipsychotic.54 The available data would at least suggest that patients who do not respond initially to an antidepressant alone should be treated with the combination of an antidepressant and an antipsychotic or ECT. PP

 

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8.    Lykouras E, Christodoulou GN, Malliaras D. Type and content of delusions in unipolar psychotic depression. J Affect Disord. 1985;9(3):249-252.
9.    Lykouras L, Gournellis R, Fortos A, Oulis P, Christodoulou GN. Psychotic (delusional) major depression in the elderly and suicidal behaviour. J Affect Disord. 2002;69(1-3):225-229.
10.    Breslau N, Meltzer HY. Validity of subtyping psychotic depression: examination of phenomenology and demographic characteristics. Am J Psychiatry. 1988;145(1):35-40.
11.    Nelson JC, Mazure CM, Jatlow PI. Characteristics of desipramine-refractory depression. J Clin Psychiatry. 1994;55(1):12-19.
12.    Wilcox JA, Ramirez AL, Baida-Fragoso N. The prognostic value of thought disorder in psychotic depression. Ann Clin Psychiatry. 2000;12(1):1-4.
13.    Schatzberg AF, Posener JA, DeBattista C, Kalehzan BM, Rothschild AJ, Shear PK. Neuropsychological deficits in psychotic versus nonpsychotic major depression and no mental illness. Am J Psychiatry. 2000;157(7):1095-1100.
14.    Hill SK, Keshavan MS, Thase ME, Sweeney JA. Neuropsychological dysfunction in antipsychotic-naive first-episode unipolar psychotic depression. Am J Psychiatry. 2004;161(6):996-1003.
15.    Avery D, Lubrano A. Depression treated with imipramine and ECT: the DeCarolis study reconsidered. Am J Psychiatry. 1979;136(4B):559-562.
16.    Chan CH, Janicak PG, Davis JM, Altman E, Andriukaitis S, Hedeker D. Response of psychotic and nonpsychotic depressed patients to tricyclic antidepressants. J Clin Psychiatry. 1987;48(5):197-200.
17.    Kocsis JH, Croughan JL, Katz MM, et al. Response to treatment with antidepressants of patients with severe or moderate nonpsychotic depression and of patients with psychotic depression. Am J Psychiatry. 1990;147(5):621-624.
18.    Quitkin F, Rifkin A, Klein DF. Imipramine response in deluded depressive patients. Am J Psychiatry. 1978;135(7):806-811.
19.    Gatti F, Bellini L, Gasperini M, Perez J, Zanardi R, Smeraldi E. Fluvoxamine alone in the treatment of delusional depression. Am J Psychiatry. 1996;153(3):414-416.
20.    Zanardi R, Franchini L, Serretti A, Perez J, Smeraldi E. Venlafaxine versus fluvoxamine in the treatment of delusional depression: a pilot double-blind controlled study. J Clin Psychiatry. 2000;61(1):26-29.
21.    Zanardi R, Franchini L, Gasperini M, Lucca A, Smeraldi E, Perez J. Faster onset of action of fluvoxamine in combination with pindolol in the treatment of delusional depression: a controlled study. J Clin Psychopharmacol. 1998;18(6):441-446.
22.    Zanardi R, Franchini L, Gasperini M, Smeraldi E, Perez J. Long-term treatment of psychotic (delusional) depression with fluvoxamine: an open pilot study. Int Clin Psychopharmacol. 1997;12(4):195-197.
23.    Stahl SM. Antidepressant treatment of psychotic major depression: potential role of the sigma receptor. CNS Spectr. 2005;10(4):319-323.
24.    Zanardi R, Franchini L, Gasperini M, Perez J, Smeraldi E. Double-blind controlled trial of sertraline versus paroxetine in the treatment of delusional depression. Am J Psychiatry. 1996;153(12):1631-1633.
25.    Simpson GM, El Sheshai A, Rady A, Kingsbury SJ, Fayek M. Sertraline as monotherapy in the treatment of psychotic and nonpsychotic depression. J Clin Psychiatry. 2003;64(8):959-965.
26.    Anton RF Jr, Burch EA Jr. Amoxapine versus amitriptyline combined with perphenazine in the treatment of psychotic depression. Am J Psychiatry. 1990;147(9):1203-1208.
27.    Minter RE, Mandel MR. The treatment of psychotic major depressive disorder with drugs and electroconvulsive therapy. J Nerv Ment Dis. 1979;167(12):726-733.
28.    Charney DS, Nelson JC. Delusional and nondelusional unipolar depression: further evidence for distinct subtypes. Am J Psychiatry. 1981;138(3):328-333.
29.    Spiker DG, Weiss JC, Dealy RS, et al. The pharmacological treatment of delusional depression. Am J Psychiatry. 1985;142(4):430-436.
30.    Rothschild AJ, Williamson DJ, Tohen MF, et al. A double-blind, randomized study of olanzapine and olanzapine/fluoxetine combination for major depression with psychotic features. J Clin Psychopharmacol. 2004;24(4):365-373.
31.    Practice guideline for the treatment of patients with major depressive disorder (revision). American Psychiatric Association. Am J Psychiatry. 2000;157(4 suppl):1-45.
32.    Minter RE, Mandel MR. A prospective study of the treatment of psychotic depression. Am J Psychiatry. 1979;136(11):1470-1472.
33.    Glassman AH, Kantor SJ, Shostak M. Depression, delusions, and drug response. Am J Psychiatry. 1975;132(7):716-719.
34.    Kantor SJ, Glassman AH. Delusional depressions: natural history and response to treatment. Br J Psychiatry. 1977;131:351-360.
35.    Frances A, Brown RP, Kocsis JH, Mann JJ. Psychotic depression: a separate entity? Am J Psychiatry. 1981;138(6):831-833.
36.    Johnstone EC, Deakin JF, Lawler P, et al. The Northwick Park electroconvulsive therapy trial. Lancet. 1980;2(8208-8209):1317-1320.
37.    Buchan H, Johnstone E, McPherson K, Palmer RL, Crow TJ, Brandon S. Who benefits from electroconvulsive therapy? Combined results of the Leicester and Northwick Park trials. Br J Psychiatry. 1992;160:355-359.
38.    Sackeim HA, Prudic J, Devanand DP, et al. A prospective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities. Arch Gen Psychiatry. 2000;57(5):425-434.
39.    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.
40.    Petrides G, Fink M, Husain MM, et al. ECT remission rates in psychotic versus nonpsychotic depressed patients: a report from CORE. J ECT. 2001;17(4):244-253.
41.    Birkenhäger TK, Pluijms EM, Lucius SA. ECT response in delusional versus non-delusional depressed inpatients. J Affect Disord. 2003;74(2):191-195.
42.    Birkenhäger TK, van den Broek WW, Mulder PG, de Lely A. One-year outcome of psychotic depression after successful electroconvulsive therapy. J ECT. 2005;21(4):221-226.
43.    de Vreede IM, Burger H, van Vliet IM. Prediction of response to ECT with routinely collected data in major depression. J Affect Disord. 2005;86(2-3):323-327.
44.    Schatzberg AF, Rothschild AJ, Langlais PJ, Bird ED, Cole JO. A corticosteroid/dopamine hypothesis for psychotic depression and related states. J Psychiatr Res. 1985;19(1):57-64.
45.    Belanoff JK, Rothschild AJ, Cassidy F, et al. An open label trial of C-1073 (mifepristone) for psychotic major depression. Biol Psychiatry. 2002;52(5):386-392.
46.    DeBattista C, Belanoff J, Glass S, et al. Mifepristone versus placebo in the treatment of psychosis in patients with psychotic major depression. Biol Psychiatry. 2006;60(12):1343-1349.
47.    Nihalani ND, Schwartz TL. Mifepristone, a glucocorticoid antagonist for the potential treatment of psychotic major depression. Curr Opin Investig Drugs. 2007;8(7):563-569.
48.    Mitchell PB, Loo CK. Transcranial magnetic stimulation for depression. Aust N Z J Psychiatry. 2006;40(5):406-413.
49.    O’Reardon JP, Solvason HB, Janicak PG, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. 2007;62(11):1208-1216.
50.    Martin JL, Barbanoj MJ, Schlaepfer TE, et al. Transcranial magnetic stimulation for treating depression. Cochrane Database Syst Rev. 2002;(2):CD003493.
51.    Loo CK, Mitchell PB. A review of the efficacy of transcranial magnetic stimulation (TMS) treatment for depression, and current and future strategies to optimize efficacy. J Affect Disord. 2005;88(3):255-267.
52.    Couturier JL. Efficacy of rapid-rate repetitive transcranial magnetic stimulation in the treatment of depression: a systematic review and meta-analysis. J Psychiatry Neurosci. 2005;30(2):83-90.
53.    Wadsworth EJ, Moss SC, Simpson SA, Smith AP. Psychotropic medication use and accidents, injuries and cognitive failures. Hum Psychopharmacol. 2005;20(6):391-400.
54.    Andreescu C, Mulsant BH, Peasley-Miklus C, Persisting low use of antipsychotics in the treatment of major depressive disorder with psychotic features. J Clin Psychiatry. 2007;68(2):194-200.

 

 

Needs Assessment: Recent research advances have raised the potential for clinical application of biomarkers in psychiatric care. It is important for clinicians to understand not only the benefits that biomarkers may bring to practice, but also the needed scientific hurdles these advances should clear before they can be embraced by the field.


Learning Objectives:

• Describe what biomarkers may be able to contribute to care for mental illnesses.
• Discuss proposed characteristics of a clinically-appropriate biomarker in psychiatry.
• Evaluate the applicability of potential biomarkers to patient care.

Target Audience: Primary care physicians and psychiatrists.


CME Accreditation Statement:
This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.


Credit Designation:
The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.


Faculty Disclosure Policy Statement:
It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: February 20, 2008.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by March 1, 2010 to be eligible for credit. Release date: March 1, 2008. Termination date: March 31, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. Cook is director of the Depression Research Program at the University of California, Los Angeles (UCLA) and associate director of the UCLA Laboratory of Brain, Behavior, and Pharmacology at the Semel Institute for Neuroscience and Human Behavior.

Disclosure: Dr. Cook receives grant support from Aspect Medical Systems, Cyberonics, Eli Lilly, Hi Q Foundation, the National Institutes of Health, Novartis, Pfizer, and Sepracor; and is on the speakers’ bureaus of Bristol-Myers Squibb, the Medical Education Speakers Network, and Wyeth. Dr. Cook is co-inventor of the cordance method, and his patent rights have been assigned to and are owned by the Regents of the University of California.

Acknowledgments: Dr. Cook wishes to acknowledge the mentoring of Dr. Andrew Leuchter; collegial discussions with Dr. Aimee Hunter and technical assistance from Ms. Kelly Nielson in the preparation of this manuscript; and the support of the professional staff at the UCLA Depression Research Program and the UCLA Laboratory of Brain, Behavior, and Pharmacology at the Semel Institute.

Please direct all correspondence to: Ian A. Cook, MD, UCLA Depression Research Program, Semel Institute, 760 Westwood Plaza, Los Angeles, CA 90024-1759; Tel: 310-825-0304; Fax: 310-825-7642; E-mail: icook@ucla.edu; Website: www.DepressionResearch.com.

 


 

Abstract

Advances in fundamental neurobiology, neuroimaging, neurophysiology, behavioral genetics, and other current high-throughput “omics” fields have yielded considerable advances in understanding the machinery of the brain and how it is altered in disorders of the mind. A recurrent theme for several decades of psychiatric research has been an interest in clinical biomarkers, namely, those biologic features that inform diagnosis, prognosis, or response to treatment. Recent research findings have increased the visibility of several promising biomarker approaches; some illustrative examples are drawn from studies of physiologic measures in mood disorders. The potential for biomarkers to advance the care of mental illness is great, but several caveats must be considered in order to avoid pitfalls that prevent adoption by the field. Pragmatic aspects of evaluating biomarker technologies are proposed that may guide useful development and possible adoption of these techniques.

 

Introduction

Biomarkers are commonplace in most branches of medicine: specific biologic features of an individual patient provide critical information about that person’s diagnosis, prognosis, or predicted response to treatment. Examples include tumor markers in oncology,1-4 troponin in cardiology,5-7 a-feto-protein in obstetrics,8 and inflammatory markers and specific serum antibody levels in rheumatology.9 Additionally, the use of biomarkers may be useful in drug discovery and development, by monitoring response to a test exposure of an experimental medication.10 Nonetheless, in the field of psychiatry, the biologic features of a patient’s illness generally continue to be eclipsed by the central role played by clinical signs and symptoms.11

While numerous new research findings suggest that biomarkers may soon be suitable for clinical use in psychiatric disorders, the quest for biomarkers to improve the care of mental illnesses is not new in the 21st century. For several decades, measurements of specific molecules in cerebrospinal fluid (eg, homovanillic acid, 5-hydroxy-indoleacetic acid),12 metabolites of neurotransmitters in urine (eg, 3-methoxy-4-hydroxyphenylglycol),13 and serum markers of neuroendocrine dysregulation (dexamethasone suppression test)14,15 have been complemented by studies of sleep architecture,16,17 eye movement abnormalities,18,19 and electrodermal and other autonomic responses.20 Other recent investigations have used imaging methods to detect the presence and location of abnormal proteins21,22  or abnormal organization of white matter tissue,23 to monitor neurochemistry with spectroscopy,24 or to detect brain metabolic responses to cognitive “stress tests.”25 While these approaches greatly expanded knowledge of the neurobiology of psychiatric disorders by serving as research tools, they have unfortunately found limited application in daily clinical practice or in evidence-based practice guidelines.11,26 As biologic measures (“biomeasures”26) and new techniques are reported and considered for use as clinically-applicable biomarkers, it is important for clinicians to understand how these may or may not be “ready for prime time.”

 

The Potential

Biomarkers have great potential for improving care for psychiatric patients. Three areas in particular can be identified, including enhanced diagnostic accuracy, prognostic information about the natural course of an individual’s illness, and prediction of response to treatment.

As noted above, clinical signs and symptoms are the central basis for establishing psychiatric diagnoses.11 Yet, some symptoms may be present in multiple diagnoses; a reduction in sleep can be a diagnostic element of a depressive episode, a manic episode, or generalized anxiety disorder. Biomarkers have promise for enhancing diagnostic accuracy in this arena. Consider, for example, a patient 20 years of age with a 2-month bout of disabling depression. Is this depression a component of unipolar major depressive disorder (MDD) or does the person really suffer from bipolar disorder but has not yet experienced a floridly manic episode? In an older patient with mild but clear cognitive impairments, are these problems originating from the neurodegenerative changes of Alzheimer’s disease, from ischemic damage in vascular dementia, or from MDD (the “pseudo-dementia” of depression)? In a child, are inattention and disruptive behaviors a part of attention-deficit/hyperactivity disorder, the early onset of bipolar disorder, or simply reflective of coping skills that are overwhelmed by stressful circumstances (eg, parental divorce)? For most patients, clinical information is sufficient to converge on the salient psychiatric diagnosis rapidly, but for some, diagnostic ambiguity may challenge even expert clinicians. The use of biologic markers has potential to assist in this important process, but more work is needed before the field will have useful tools for this application.

Prognostic information is another area where biomarkers could offer valuable insights. In oncology, the elevation of a tumor marker may lead to a workup for a recurrence of disease and initiation of treatment, even before clinical manifestations would have prompted a re-evaluation. In psychiatry, in contrast, an impending full relapse of psychosis in schizophrenia is heralded principally by the return of symptoms. In recurrent depressions, the question can be framed by a patient as “when is a bad day just a ‘bad day,’ and when is it the start of a new episode?” In the care of older adults with depression, some will likely progress from late-life depression to dementia,27 but identification of this subset of patients remains problematic. Lastly, many patients with mood disorders experience recurrent thoughts of death and perceive life as painful and/or meaningless. While this group of patients has an elevated risk for suicidal behaviors, accurately determining which individuals will go on to harm themselves and which will not cannot be forecast reliably on clinical or historical grounds.28 Some preliminary work suggests measures of brain structure and function29 or genotyping30,31 may be developed to refine this process. Rather than believing that research will eventually identify the single, measurable factor that leads to a phenomenon as complex as suicide, it may be more reasonable to anticipate that the greatest utility for this prediction may emerge from a model combining genetic and neurobiologic features with current and past clinical features and familial history, though the relative weightings of these factors remains indeterminate at this time.

Prediction of individual treatment response is viewed by some as a critical area for improvement in psychiatry. While treatments are effective for managing psychiatric illnesses in general, no single treatment works for everyone with a given disorder, and selection of the best treatment for each patient remains a challenge. The general standard of care is to embark upon a course of treatment that is likely to be effective for that disorder, based on evidence from randomized clinical trials and myriad other data (eg, clinical experience, past patient response to treatment); one then monitors for a good outcome and allows for course correction if improvement fails to occur. Both steps fundamentally rely on clinical findings to assess the degree of symptomatic or functional response. Nobel laureate Niels Bohr is often considered to have observed that “prediction is difficult, especially about the future,” and this statement rings true in this aspect of psychiatric care. The failure of depressive symptoms to improve early in treatment is often a harbinger of poor eventual outcome,32 but what is true on a group level does not necessarily provide useful guidance patient by patient, and some patients simply may take longer than others to respond to treatment that will eventually work well for them.33 Measurement-based care,34,35 with its systematic collection of clinical data with rating scales, can improve detection of good or poor response to treatment with greater utility than a clinician’s global impression, but fundamentally these are better observations of what is already occurring, rather than predictions of future outcomes.

Genetic factors have been examined with inconsistent results (eg, as summarized by Rasmussen-Torvik and McAlpine36). In the largest prospective treatment trial dataset examined in MDD, several genes have been linked with response to antidepressants, including serotonin-2A receptor polymorphisms,37 differences in the GRIK4 gene encoding for a glutamate receptor,38 and a chaperone protein that may regulate hypothalamic-pituitary-adrenal axis function (FKBP5 gene).39 While group differences between responders and non-responders can be found, none of these genetic factors have yet shown adequate utility for guiding individual patient treatment decisions. Similarly, the Evaluation of Genomic Applications in Practice and Prevention Working Group was convened by the federal Centers for Disease Control and Prevention to evaluate the evidence for genetic tests and other genomics applications, and their recommendation for depression was that routine genotyping was not yet supported by the evidence.40 In the care of schizophrenia, there is promise that polymorphisms in the genes that relate to drug metabolism may help guide medication dosing,41 but the choice of a specific agent for any given patient cannot yet be guided by biomarkers. In terms of anxiety disorders, it appears that some genes may predispose individuals to develop anxiety disorders under conditions of stress, but predicting individual response to treatment remains elusive.42 Indeed, it may be that consideration of gene-environment interactions becomes essential to take full advantage of genetic information in the care of psychiatric patients.43

Three physiologically based biomarker approaches to predicting outcomes have emerged in recent years in the area of depression with peer-reviewed publication and independent replication of findings, and can serve as useful examples for evaluating a candidate biomarker for clinical use.

The first measure uses changes in resting-state prefrontal brain activity (“quantitative electroencephalography [EEG] cordance”)44 over the course of a test exposure to an antidepressant; that early change is predictive of later treatment outcome with that agent for an individual patient’s care, in studies using either serotonin reuptake inhibitors or dual-reuptake inhibitors. (n=7,45 n=51,46 n=1247).45-49 Cordance is a measure which combines features of absolute and relative EEG power. Because cordance is better correlated with regional cerebral blood flow than other EEG measures,44 findings with this measure can be interpreted within the same conceptual framework as other functional neuroimaging studies. A multi-site replication and extension project (NCT00375843) has recently closed enrollment (200 subjects), and data analysis is now underway. The relationship between early change in cordance and later clinical outcome was independently replicated in an inpatient sample (n=17).50 These findings collectively supported an even larger collaborative, multi-site trial, Biomarkers for Rapid Identification of Treatment Effectiveness in Major Depression (NCT00289523; n=375), using a related EEG measure (the antidepressant treatment response [ATR] index). The ATR can be computed using a simplified electrode array with five electrodes placed over prefrontal and frontal brain regions, instead of approximately 35–40 electrodes placed over all scalp locations for measuring cordance (“full head montage”); thus, this is a technology well suited for use in outpatient physicians’ offices, avoiding the need to send patients to a dedicated EEG facility. After a 1-week test period of escitalopram, subjects were randomized to receive either continued escitalopram treatment, a switch to bupropion, or a combination of the two medications; EEG data were recorded before and after the 1-week test period. In a real-world sample of outpatients with MDD, individuals who received treatment consistent with their biomarker prediction were significantly more likely to experience response and remission than individuals who were randomized to a treatment not predicted to be useful.51-53 Further development and replication projects are underway and must be completed before this paradigm of early physiologic change can be considered for clinical application.

The second approach utilizes an EEG measure which is proposed to reflect central serotonergic activity, the loudness dependent auditory evoked potential (LDAEP),54-56 though some other reports have suggested that the interpretation may be more complex than just central serotonergic activity.57,58 EEG data recorded prior to treatment are interpreted to indicate whether a depressed patient has a low or high level of serotonergic activity, and those with low activity are predicted to have a favorable response to a serotonergic medication (while high activity is linked to better outcomes with a noradrenergic agent). This method has been examined using treatment with serotonergic reuptake inhibitors (n=29,59 n=15,60 n=10061) or a noradrenergic agent (n=14,62 n=2063). The relationship between level of serotonergic activity and predicted treatment response has been observed in all these studies, though data presented in these reports generally does not permit evaluation on an individual case-prediction level. That level of detail in reporting of results would facilitate evaluation of the LDAEP approach for use in guiding clinical decisions. LDAEP values were calculated using dipole source analysis methods and data from full-head EEG electrode arrays.
The third approach links resting-state pretreatment measures of activity in the rostral anterior cingulate cortex (rACC) to outcome with a variety of treatments, including sleep deprivation (n=15,64 n=3665), numerous different medications (n=1866), nortriptyline (n=1867), and paroxetine (n=2768). Across all these studies, higher rACC activity was significantly associated with good treatment response. All utilized positron emission tomography methods to study regional brain metabolism, except one study67 in which an EEG method (low resolution electromagnetic tomography) was used to determine the level of electrical activity at current sources located in the rACC. An inexpensive, non-invasive measure, such as that used by Pizzagalli and colleagues,67 presents an intriguing approach, and independent replication with that methodology would be important for evaluating clinical applicability.

 

Some Pitfalls

There are numerous pitfalls that prior biomarker work has encountered, and researchers and clinicians should learn from past experiences. Perhaps most worrisome is the problem of premature clinical application, both because of the risk for harm to patients (misdirected in treatment decisions) and for the cynicism about biomarkers in general this engenders; still, the need for useful biomarkers is so great that sometimes enthusiasm and optimism may overtake consideration of results from carefully conducted controlled clinical trials. To paraphrase the film Jerry Maguire, “show me the data!” must be the watchword if clinicians are to make prudent choices for their patients. The usual vetting of new biomedical innovations—procedures, techniques, medications, and devices—requires peer review of findings and independent replication. What applicability is there to a biomarker if it has only been shown to work in a single laboratory and other researchers are unable to validate the results? Furthermore, it must be clearly disclosed what patient group was used to develop the biomarker, as this has great relevance to generalizability. In the universe of all patients with any psychiatric disorder, only a minority will have a syndrome that is refractory to multiple treatments; yet, this is just the sort of patient who may seek out expert care in desperation and consequently be enrolled in a biomarker discovery research program. The generalizability of such a biomarker may be quite limited, and without clear disclosure of these details it is difficult to evaluate the quality of a biomarker.

An additional caveat about biomarkers relates to the heterogeneity within a given clinical diagnosis. With current clinically defined diagnostic categories, there is variety both in the patients who seek care and in the individuals enrolled in research projects. A telling example is shown in Table 1, in which two individuals who both meet the diagnostic criteria for MDD have zero symptoms in common. Thus, development of biomarkers also should disclose the nature of the patient population and consider evaluating whether the accuracy and reliability of the measure are improved or degraded in some sub-populations (eg, psychotic depression, depression in bipolar type I versus bipolar type II patients).

 

 

While biomarkers should have a high degree of clinical utility in order to be considered for use, there is also a need for them to be interpretable in the context of the rest of neuroscience. What aspect of a patient’s pathophysiology is being assessed by a test? Is it the form of a reuptake transporter that is associated with greater or lesser efficiency, the level of activity in a particular brain region, or a component of a neuroendocrine feedback loop? Biomarker methods which fail to be comprehensible within or integrated into the extant body of neurobiologic knowledge are unlikely to gain clinical acceptance, even if an empiric trial suggests that they might be useful.

Finally, it is worthwhile to note that statistical significance is not the same thing as clinical significance. Studies may report that a result is significant at the P<.05 level, meaning simply that there is less than one chance in 20 that a finding arose by chance alone. Given a large enough sample, even a clinically-irrelevant difference (eg, a very small improvement on a clinical rating scale) might be reported to occur with an impressive P-value. An important measure for evaluating biomarkers includes the number needed to treat,69 which assesses the number of patients needed to be treated differently (eg, with biomarker guidance, with a new medication) in order to have one additional patient experience the desired, positive outcome. Predictive biomarkers are also often characterized by a series of metrics which can help evaluate the usefulness of a potential biomarker, ie, receiver operating characteristic (ROC) curves and measures such as sensitivity, specificity, and overall predictive accuracy.70-72 Sensitivity is the ratio of “true positive” tests to the number of individuals with the condition. For an outcome predictor, it would be the number of people in a sample who are predicted to respond to a treatment, divided by the total number of people who actually respond. Specificity is the ratio of “true negative” tests to the number of people who do not have a particular condition. In the outcome predictor context, this would be the number of people predicted not to respond divided by the total number of non-responders. Overall predictive accuracy is the proportion of predictions that are correct. ROC curves plot the trade-offs between sensitivity and specificity as different thresholds (cut-points) are used to differentiate between positive and negative tests (eg, between predicting response and non-response to a treatment).

 

Pragmatic Evaluation of Biomarkers for Psychiatric Management

Given the potential for improving care and the pitfalls that may await possible biomarkers, how then can one judge a biomarker for use in psychiatric management? Table 2 summarizes some key, desirable characteristics of psychiatric biomarkers. Many of them follow directly from the pitfalls detailed above, but the last three on the list merit special mention.

First, the information provided by the biomarker must be timely, clinically useful, and cost effective. A test that is able to predict 8-week treatment response at week 5 is much less timely than a prediction made at week 1. A biomarker that identifies an individual with a treatment-refractory illness (a “biomarker of doom”) is less useful than one which points the way to an alterative treatment strategy. It is unlikely that the field would adopt a biomarker which consumes more resources than it saves, either by direct expenses or by wrongly suggesting an alternative treatment.

Second, the technology needed to assess the biomarker must be available and well tolerated by the target patient population. For example, some neuroimaging methods may be well suited to neuroscience research applications, where a small number of subjects can be observed with great detail, but if the scanning technology costs too much to be deployed widely in the community, the method may not come to be translated into practice. Similarly, a procedure that is perceived as painful (eg, lumbar puncture) or challenging (eg, agitated children remaining conscious yet immobile during a scanning procedure) may have low penetration into the clinical arena for reasons of practicality.

Third, methods that can be seamlessly integrated into existing clinical care practice patterns are more likely to be accepted than those that require major shifts in the delivery of care. For example, sending a patient to a different facility for a biomarker procedure and waiting for test results is less desirable than being able to perform a test in one’s office or ward.

 

Conclusion

Biomarkers have great potential for improving the care of patients with psychiatric disorders, much as they have in other medical specialties. Adoption of biomarkers into clinical care, however, requires careful and thorough evaluation, and there is risk to patients if measures are embraced prematurely. A set of proposed criteria can be used in the pragmatic evaluation of candidate biomarkers. PP

 

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12.    Berger PA, Faull KF, Kilkowski J, et al. CSF monoamine metabolites in depression and schizophrenia. Am J Psychiatry. 1980;137(2):174-180.
13.    Garvey M, Hollon SD, DeRubeis RJ, Evans MD, Tuason VB. Does 24-h urinary MHPG predict treatment response to antidepressants? I. A review. J Affect Disord. 1990;20(3):173-179.
14.    Carroll BJ, Cassidy F, Naftolowitz D, et al. Pathophysiology of hypercortisolism in depression. Acta Psychiatr Scand Suppl. 2007;(433):90-103.
15.    Carroll BJ. Dexamethasone suppression test: a review of contemporary confusion. J Clin Psychiatry. 1985;46(2 Pt 2):13-24.
16.    Rush AJ, Weissenburger JE. Melancholic symptom features and DSM-IV. Am J Psychiatry. 1994;151(4):489-498.
17.    Howland RH, Thase ME. Biological studies of dysthymia. Biol Psychiatry. 1991;30(3):283-304.
18.    Lee KH, Williams LM. Eye movement dysfunction as a biological marker of risk for schizophrenia. Aust N Z J Psychiatry. 2000;34(suppl):S91-S100.
19.    Copolov D, Crook J. Biological markers and schizophrenia. Aust N Z J Psychiatry. 2000;34(suppl):S108-S112.
20.    Crowell SE, Beauchaine TP, Gatzke-Kopp L, et al. J. Autonomic correlates of attention-deficit/hyperactivity disorder and oppositional defiant disorder in preschool children. J Abnorm Psychol. 2006;115(1):174-178.
21.    Nichols L, Pike VW, Cai L, Innis RB. Imaging and in vivo quantitation of beta-amyloid: an exemplary biomarker for Alzheimer’s disease? Biol Psychiatry. 2006;59(10):940-947.
22.    Small GW, Bookheimer SY, Thompson PM, et al.  Current and future uses of neuroimaging for cognitively impaired patients. Lancet Neurol. 2008;7(2):161-172.
23.    Kumar A, Ajilore O. Magnetic resonance imaging and late-life depression: potential biomarkers in the  era of personalized medicine. Am J Psychiatry. 2008;165(2):166-168.
24.    Olvera RL, Caetano SC, Fonseca M, et al.  Low levels of N-acetyl aspartate in the left dorsolateral prefrontal cortex of pediatric bipolar patients. J Child Adolesc Psychopharmacol. 2007;17(4):461-473.
25.    Bookheimer SY, Strojwas MH, Cohen MS, et al.  Patterns of brain activation in people at risk for Alzheimer’s disease. N Engl J Med. 2000;343(7):450-456.
26.    Kraemer HC, Schultz SK, Arndt S. Biomarkers in psychiatry: methodological issues. Am J Geriatr Psychiatry. 2002;10(6):653-659.
27.    Smith GS, Gunning-Dixon FM, Lotrich FE, Taylor WD, Evans JD. Translational research in late-life mood disorders: implications for future intervention and prevention research. Neuropsychopharmacology. 2007;32(9):1857-1875.
28.    Baldessarini RJ, Conwell Y, Fawcett JA, et al. Practice Guideline for the Assessment and Treatment of Patients with Suicidal Behaviors. Arlington, VA: American Psychiatric Association; 2003.
29.    Pompili M, Ehrlich S, De Pisa E, et al. White matter hyperintensities and their associations with suicidality in patients with major affective disorders. Eur Arch Psychiatry Clin Neurosci. 2007;257(8):494-499.
30.    Laje G, Paddock S, Manji H, et al. Genetic markers of suicidal ideation emerging during citalopram treatment of major depression. Am J Psychiatry. 2007;164(10):1530-1538.
31.    Perlis RH, Purcell S, Fava M, et al. Association between treatment-emergent suicidal ideation with citalopram and polymorphisms near cyclic adenosine monophosphate response element binding protein in the STAR*D study. Arch Gen Psychiatry. 2007;64(6):689-697.
32.    Nierenberg AA, McLean NE, Alpert JE, Worthington JJ, Rosenbaum JF, Fava M. Early nonresponse to fluoxetine as a predictor of poor 8-week outcome. Am J Psychiatry. 1995;152(10):1500-1503.
33.    Trivedi MH, Rush AJ, Wisniewski SR, et al. 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.
34.    Trivedi MH, Rush AJ, Gaynes BN, et al. Maximizing the adequacy of medication treatment in controlled trials and clinical practice: STAR(*)D measurement-based care. Neuropsychopharmacology. 2007;32(12):2479-2489.
35.    Sussman N. Translating science into service: lessons learned from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Prim Care Companion J Clin Psychiatry. 2007;9(5):331-337.
36.    Rasmussen-Torvik LJ, McAlpine DD. Genetic screening for SSRI drug response among those with major depression: great promise and unseen perils. Depress Anxiety. 2007;24(5):350-357.
37.    McMahon FJ, Buervenich S, Charney D, et al. Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet. 2006;78(5):804-814.
38.    Paddock S, Laje G, Charney D, et al. Association of GRIK4 with outcome of antidepressant treatment in the STAR*D cohort. Am J Psychiatry. 2007;164(8):1181-1188.
39.    Lekman M, Laje G, Charney D, et al. The FKBP5-gene in depression and treatment response-an Association Study in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) cohort. Biol Psychiatry. Jan 10, 2008 [Epub ahead of print].
40.    Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: testing for cytochrome P450 polymorphisms in adults with nonpsychotic depression treated with selective serotonin reuptake inhibitors. Genet Med. 2007;9(12):819-825.
41.    Arranz MJ, de Leon J. Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research. Mol Psychiatry. 2007;12(8):707-747.
42.    Xu K, Ernst M, Goldman D. Imaging genomics applied to anxiety, stress response, and resiliency. Neuroinformatics. 2006;4(1):51-64.
43.    Caspi A, Moffitt TE. Gene-environment interactions in psychiatry: joining forces with neuroscience. Nat Rev Neurosci. 2006;7(7):583-590.
44.    Leuchter AF, Uijtdehaage SH, Cook IA, O’Hara R, Mandelkern M. Relationship between brain electrical activity and cortical perfusion in normal subjects. Psychiatry Res. 1999;90(2):125-140 
45.    Cook IA, Leuchter AF. Prefrontal changes and treatment response prediction in depression. Semin Clin Neuropsychiatry. 2001;6(2):113-120
46.    Cook IA, Leuchter AF, Morgan M, et al. Early changes in prefrontal activity characterize clinical responders to antidepressants. Neuropsychopharmacology. 2002;27(1):120-131.
47.    Cook IA, Leuchter AF, Morgan ML, Stubbeman W, Siegman B, Abrams M. Changes in prefrontal activity characterize clinical response in SSRI nonresponders: a pilot study. J Psychiatr Res. 2005;39(5):461-466.
48.    Leuchter AF, Cook IA, Uijtdehaage SH, et al. Brain structure and function and the outcomes of treatment for depression. J Clin Psychiatry. 1997;58(suppl 16):22-31.
49.    Hunter AM, Cook IA, Leuchter AF. The promise of the quantitative electroencephalogram as a predictor of antidepressant treatment outcomes in major depressive disorder. Psychiatr Clin North Am. 2007;30(1):105-124.
50.    Bareš M, Brunovsky M, Kopecek M, et al. Changes in QEEG prefrontal cordance as a predictor of response to antidepressants in patients with treatment resistant depressive disorder: a pilot study. J Psychiatr Res. 2007;41(3-4):319-325.
51.    Leuchter AF, Cook IA, Marangell LB, et al. Biomarkers for Rapid Identification of Treatment Effectiveness in Major Depression (BRITE-MD): Predictors of Clinical Treatment Response. Poster presented at: the Annual Meeting of the Society of Biological Psychiatry; San Diego, CA; May 17, 2007.
52.    Leuchter AF, Cook IA, Gilmer W, et al. EEG-guided Antidepressant Selection May Improve Response Rates: Insights from the BRITE-MD Trial. Poster presented: the 47th Annual Meeting of the New Clinical Drug Evaluation Unit; Boca Raton, FL; June 11-14, 2007.
53.    Leuchter AF, Cook IA, Marangell LB, et al. Biomarkers for Rapid Identification of Treatment Effectiveness in Major Depression (BRITE-MD): Predictors of clinical response and remission to escitalopram. Poster presented at: the Annual Meeting of the American College of Neuropsychopharmacology; Boca Raton, FL; December 8-12, 2007.
54.    Hegerl U, Juckel G. Identifying psychiatric patients with serotonergic dysfunctions by event-related potentials. World J Biol Psychiatry. 2000;1(2):112-118.
55.    Nathan PJ, Segrave R, Phan KL, O’Neill B, Croft RJ. Direct evidence that acutely enhancing serotonin with the selective serotonin reuptake inhibitor citalopram modulates the loudness dependence of the auditory evoked potential (LDAEP) marker of central serotonin function. Hum Psychopharmacol. 2006;21(1):47-52.
56.    Pogarell O, Juckel G, Norra C, et al. Prediction of clinical response to antidepressants in patients with depression: neurophysiology in clinical practice. Clin EEG Neurosci. 2007;38(2):74-77.
57.    Norra C, Becker S, Bröcheler A, Kawohl W, Kunert HJ, Buchner H. Loudness dependence of evoked dipole source activity during acute serotonin challenge in females. Hum Psychopharmacol. 2008;23(1):31-42.
58.    Guille V, Croft RJ, O’Neill BV, Illic S, Phan KL, Nathan PJ. An examination of acute changes in serotonergic neurotransmission using the loudness dependence measure of auditory cortex evoked activity: effects of citalopram, escitalopram and sertraline. Hum Psychopharmacol. Jan 15, 2008; [Epub ahead of print].
59.    Gallinat J, Bottlender R, Juckel G, et al. The loudness dependency of the auditory evoked N1/P2-component as a predictor of the acute SSRI response in depression. Psychopharmacology (Berl). 2000;148(4):404-411.
60.    Mulert C, Juckel G, Augustin H, Hegerl U. Comparison between the analysis of the loudness dependency of the auditory N1/P2 component with LORETA and dipole source analysis in the prediction of treatment response to the selective serotonin reuptake inhibitor citalopram in major depression. Clin Neurophysiol. 2002;113(10):1566-1572.
61.    Lee TW, Yu YW, Chen TJ, et al. Loudness dependence of the auditory evoked potential and response to antidepressants in Chinese patients with major depression. J Psychiatry Neurosci. 2005;30(3):202-205.
62.    Linka T, Müller BW, Bender S, Sartory G, Gastpar M. The intensity dependence of auditory evoked ERP components predicts responsiveness to reboxetine treatment in major depression. Pharmacopsychiatry. 2005;38(3):139-143.
63.    Mulert C, Juckel G, Brunnmeier M, et al. Prediction of treatment response in major depression: integration of concepts. J Affect Disord. 2007;98(3):215-225.
64.    Wu JC, Gillin JC, Buchsbaum MS, Hershey T, Johnson JC, Bunney WE Jr. Effect of sleep deprivation on brain metabolism of depressed patients. Am J Psychiatry. 1992;149(4):538-543.
65.    Wu J, Buchsbaum MS, Gillin JC, et al. Prediction of antidepressant effects of sleep deprivation by metabolic rates in the ventral anterior cingulate and medial prefrontal cortex. Am J Psychiatry. 1999;156(8):1149-1158. Erratum in: Am J Psychiatry. 1999;156(10):1666.
66.    Mayberg HS, Brannan SK, Mahurin RK, et al. Cingulate function in depression: a potential predictor of treatment response. Neuroreport. 1997;8(4):1057-1061.
67.    Pizzagalli D, Pascual-Marqui RD, Nitschke JB, et al. Anterior cingulate activity as a predictor of degree of treatment response in major depression: evidence from brain electrical tomography analysis. Am J Psychiatry. 2001;158(3):405-415.
68.    Saxena S, Brody AL, Ho ML, et al. Differential brain metabolic predictors of response to paroxetine in obsessive-compulsive disorder versus major depression. Am J Psychiatry. 2003;160(3):522-532.
69.    Laupacis A, Sackett DL, Roberts RS. An assessment of clinically useful measures of the consequences of treatment. N Engl J Med. 1988;318(26):1728-1733.
70.    Zweig MH, Campbell G. Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chemistry. 1993;39(8):561-577.
71.    Altman DG, Bland JM. Diagnostic tests 1: sensitivity and specificity. BMJ. 1994;308(6943):1552.
72.    Altman DG, Bland JM. Diagnostic tests 2: predictive values. BMJ. 1994;309(6947):102.

 

Dr. Levenson is professor in the Departments of Psychiatry, Medicine, and Surgery, chair of the Division of Consultation-Liaison Psychiatry, and vice chair for clinical affairs in the Department of Psychiatry at Virginia Commonwealth University School of Medicine in Richmond.

Disclosure: Dr. Levenson is on the depression advisory board for Eli Lilly.

 


 

Important psychiatric issues affecting diagnosis and management arise in patients with neurologic illness more often than any other area of medicine. These include cognitive impairment either as a primary feature or a secondary complication of a known neurologic disorder, other psychiatric symptoms as a manifestation or complication of neurologic disease, and physical neurologic symptoms that do not correspond to any recognized pattern of neurologic disease (ie, conversion disorder or somatization disorder). In addition, behavioral, cognitive, or emotional symptoms may occur as a complication of drug therapy of neurologic disease. More detailed coverage of these topics can be found elsewhere.1,2 In previous columns, psychiatric issues in stroke, Parkinson’s disease, multiple sclerosis, and epilepsy were reviewed.3-5 In this column, psychiatric issues related to amnestic syndromes and conversion disorder are reviewed.

 

Amnestic Syndromes

Amnestic syndromes are conditions in which memory functions are disproportionately impaired compared to other cognitive functions in an otherwise alert patient. Causes include the Wernicke-Korsakoff syndrome, carbon monoxide poisoning, herpes encephalitis and other central nervous system infections, hypoxic and other acquired brain injuries, stroke, brain tumors, and neurosurgical resections (eg, for intractable epilepsy).1 There are also transient amnestic syndromes, and amnesia can be a manifestation of conversion disorder, posttraumatic stress disorder (PTSD), dissociative disorders, or malingering. Transient as well as persistent amnestic symptoms also occur following electroconvulsive therapy.

 

Wernicke-Korsakoff Syndrome

The Wernicke-Korsakoff syndrome (WKS) is the most common amnestic disorder and is the result of thiamine deficiency of any cause. The great majority of cases in the developed world are caused by chronic alcohol abuse which results in both decreased intake and absorption of thiamine. However, the disorder has also been reported in patients with a wide array of causes of malnutrition, including anorexia nervosa, chronic schizophrenia, post-gastric surgery for obesity, gastrointestional disorders, and hemodialysis. Thiamine deficiency may also result in beriberi, a cardiac and peripheral nervous system disease, and may also result in cerebellar degeneration and peripheral neuropathy. The onset of Wernicke’s encephalopathy is usually acute, manifested by confusion, ataxia, nystagmus, and ophthalmoplegia. The administration of intravenous fluid with glucose to a thiamine-deficient patient is a common iatrogenic precipitant of acute WKS. Emergent administration of parenteral thiamine is indicated to avoid irreversible nervous system damage. Since alcoholics and others with thiamine deficiency are also often deficient in other B vitamins (especially folate, niacin, and vitamin B12), they should receive parenteral multivitamins. In refeeding starving patients of whatever cause, phosphate supplementation is often required.

Chronic thiamine deficiency results in Korsakoff syndrome, with most cases following an earlier acute Wernicke’s encephalopathy. On clinical examination, patients with classic Korsakoff syndrome have severe impairment of memory with both anterograde and retrograde deficits.6 Such patients have particular difficulty encoding new information. While retrieval of recent memories is most impaired, Korsakoff patients also have difficulty retrieving more remote memories. Confabulation (the replacement of a gap in a patient’s memory by a falsification that he or she believes to be true) commonly but not invariably occurs in Korsakoff syndrome.

Other cognitive, behavioral, and emotional changes may accompany the amnesia, such as executive dysfunction, disorientation, apathy, and labile irritability. However, since most cases of Korsakoff syndrome are caused by chronic alcoholism, it is impossible to know which deficts in cerebral function can be attributed to thiamine deficiency and which are due to other causes common in alcoholics, including other B vitamin deficiencies, head trauma, and the toxic effects of alcohol itself.

With vitamin replacement and abstinence from alcohol, the prognosis in Korsakoff syndrome is fair. Twenty five percent of patients will recover, 50% will improve but with some persistent memory impairment, and 25% will show no change.1 Thiamine is inexpensive and harmless. Hence, any patient presenting with an acute amnestic syndrome should probably receive high-dose thiamine, even in the absence of a history of alcoholism or obvious malnutrition (the absence of proof of alcohol abuse is not proof of the absence of alcohol abuse). There are no good data to guide how long thiamine (and other B vitamins) should be given to patients with chronic alcoholism.

 

Transient Amnestic Syndromes

Transient amnesia occurs in a variety of neuropsychiatric disorders and as a normal phenomenon starting in midlife (at a relatively minor but annoying magnitude and frequency). There are some disorders in which dramatic but short-lived amnesia is the sole symptom. The best known, though still poorly understood, is transient global amnesia (TGA). TGA is a benign and temporary disorder affecting middle-aged or elderly individuals who present with the abrupt onset of loss of anterograde memory with the preservation of remote memories and immediate recall. They become amnestic for recent events and unable to lay down new memories for a few hours. They tend to repetitively question their companions. Episodes can be provoked by physical or emotional stress. A recent review7 of 142 cases of TGA found that in women, TGA episodes mainly follow emotional precipitating events, whereas in men they occur more frequently after a physical precipitating event. Most episodes of TGA are single isolated events; however, the recurrence rate is approximately 14% to 18%.8,9 A variety of hypthoses of its pathophysiology have been proposed, but the etiology remains uncertain. Cases of TGA have been reported after a diversity of apparent precipitants such as temporal lobectomy for epilepsy,10 divers breathing hyperoxic mixtures,11 sildenafil,12 sexual intercourse,13 coronary angiography, and aortic dissection. No link has been found with vascular risk factors.7 In addition, there is no increased risk of transient ischemic attack or stroke in patients who have had TGA nor is there any increase in mortality.

Temporal lobe epilepsy occasionally mimics TGA, and this is described in the literature as transient epileptic amnesia (TEA). In contrast to TGA, amnestic episodes caused by epilepsy are frequent and recurrent (median=12 episodes/year), brief (median duration=30–60 minutes), and often occur on waking (approximately 66% of cases). The diagnosis of epilepsy is very often initially missed even by specialists. TEA episodes typically disappear after treatment with anticonvulsants, but many patients continue to complain of persistent memory difficulties despite normal performance on standard memory tests.14

Other common causes of transient amnesia include transient cerebral ischemia (usually accompanied by other neurologic symptoms and signs), migraine, alcohol intoxication (“blackouts”), drugs (eg, benzodiazepines, barbiturates, ketamine15) and head injury. Concussion is often followed by temporary retrograde and anterograde amnesia; the more prolonged the anterograde amnesia, the more severe the injury.
Several psychiatric conditions can also be the cause of amnestic symptoms. Amnesia should not be attributed to a psychogenic cause solely on the basis of an otherwise normal neurologic examination, electroencephalogram (EEG), and imaging studies, since they would be normal in most cases of TGA and many cases of TEA. Psychogenic amnesia is one form of conversion disorder. In patients whose amnesia is due to conversion disorder, memory for their personal life histories is much more severely affected than is their ability to learn and retain new information; that is, they have isolated retrograde amnesia.16 This pattern is the opposite of that seen in TGA. In cases where the diagnostic picture is unclear, neuropsychological testing is very helpful in distinguishing conversion (and other psychogenic memory disturbances) from neurologic amnestic syndromes. Amnesia also occurs frequently in PTSD and dissociative disorders. Psychogenic amnesia serves to block out memory of a traumatic experience with intolerable associated affect, such as terror or shame.17 While controlled trials are lacking, psychotherapy and hypnosis have often been used successfully in treatment of conversion amnesia.

Amnesia is also a common symptom of malingering, especially in forensic contexts. Neuropsychological testing is invaluable in identifying suspected malingering in amnestic patients. The tests are based on the assumption that naive simulators or exaggerators do not know either that amnestic patients can perform some tests normally, or near normally, or that subjects can only fail them by deliberate suppression of the correct response.18

 

Conversion Disorder

Neurologic symptoms in the absence of neurologic disease or grossly disproportionate to disease affect approximately one-third of patients attending neurologic clinics.19 Many such patients have somatoform disorders, one of which is conversion disorder. Pain is the most common symptom in outpatient neurological practice,19 but the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,20 criteria for conversion disorder exclude pain. Patients with conversion disorder are those who develop other (ie, nonpain) neurologic symptoms or deficits that do not conform to known pathophysiology or are grossly disproportionate to it. Almost any neurologic symptom may be produced, such as paralysis, weakness, seizures, anesthesia, aphonia, blindness, amnesia, and stupor. Conversion disorder often coexists with neurologic illness, the most common example being epileptic seizures and “pseudoseizures” in the same patient.

Conversion symptoms can occur at any age but are most likely in adolescence or early adulthood. New onset of unexplained neurologic symptoms in elderly patients without a prior psychiatric history is rarely due to conversion disorder. Some conversion symptoms occur as brief, isolated episodes, but others are chronic and recurrent. Many individuals with chronic conversion symptoms have a history of having been sexually abused in childhood. Conversion symptoms are usually precipitated by an acute stressor or a current emotional conflict. The prevalence of conversion disorder has varied culturally and historically. The major task in differential diagnosis is determining whether the patient has a neurologic disorder, conversion, or both.

Symptoms remit spontaneously in <50% of patients.21 Recent stressful life events, a history of childhood abuse and neglect, personality dysfunction, abnormal illness beliefs, and/or secondary gain (financial or otherwise) are all common in conversion disorder, but their presence does not allow one to infer a diagnosis of conversion disorder.22 The neurologic examination plays a key role in diagnosis. Examples of helpful signs include tunnel vision, collapsing (“giveaway”) weakness, and unusual distribution of sensory loss. Physicians tend to worry excessively about missing “organic” disease and are, therefore, often very conservative in making a diagnosis of conversion disorder, erring in the other direction (ie, ordering too many diagnostic tests and prescribing unneeded treatment for presumptive neurologic disorders). This, in turn, reinforces the patient’s illness beliefs and sick role and risks iatrogenic complications and invalidism. In fact, the evidence suggests that diagnostic accuracy for conversion disorder is high with an error rate in modern studies of <5%.23

Conversion disorders have classically been thought to arise out of unconscious psychological conflicts, needs, or responses to trauma. Sigmund Freud posited that conversion symptoms served to protect the individual from unacceptable feelings or unresolvable conflicts, which keep such feelings out of conscious awareness. This function of conversion symptoms is referred to as “primary gain.” However, this model only fits some patients. Furthermore, while conversion symptoms often have unconscious meaning, this will not usually be apparent in initial encounters. Patients with conversion disorder tend to be very suggestible. Some but not all have a strikingly blasé attitude toward their symptoms (eg, la belle indifferénce), but it is neither sensitive nor specific enough to be useful in the diagnosis of conversion disorder.24

Patients with conversion disorder are usually consciously unaware of the cause of the symptoms, even when the cause might seem obvious to the clinician (eg, onset of paraplegia following rape). Such symptoms often elicit gratifying or protective responses from the environment (eg, sympathy, extra assistance, release from obligations, disability payments), which in turn reinforce the symptom.

The management of conversion symptoms begins with careful assessment; a thorough neurologic and physical examination can often distinguish between conversion disorder and organic neurologic disease without the need for other tests. In some cases, specific studies may be required including imaging, EEG, and electromyogram. It is never helpful to confront the patient in a negative way. Telling the patient “It is all in your head” or “There is nothing wrong with you” angers the patient, reinforces their insistence that the symptoms are “real,” and undermines the doctor-patient relationship. The appropriate approach is to first offer explicit acceptance of the reality of the symptoms and then reassure the patient that serious causes like tumor, stroke, or multiple sclerosis have been ruled out. This is then followed by telling the patient that they have a form of benign neurologic dysfunction that tends to be exacerbated by stress. An analogy to migraine can be helpful, ie, that even though stress aggravates migraine, there is no question that migraine pain and other symptoms are real. Psychotherapy can be very helpful, and the patient is more likely to pursue it if the clinician takes an encouraging and destigmatizing attitude toward the patient’s symptoms. For patients whose conversion disorder is manifested in weakness or paralysis, physical therapy can be very helpful in providing “a graceful way out” of the disabled sick role.25 Physical therapy is essential for patients who have been chronically immobilized by conversion disorder because they develp disuse atrophy. PP

 

References

1.    Carson AJ, Zeman A, Myles L, Sharpe MC. Neurology and neurosurgery. In: Levenson JL, ed. American Psychiatric Publishing Textbook of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2005:701-732.
2.    Carson AJ, Zeman A, Myles L, Sharpe MC. Neurology and neurosurgery. In: Levenson JL, ed. Essentials of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2007:313-342.
3.    Levenson JL. Psychiatric issues in neurology, part 1: stroke. Primary Psychiatry, 2007;14(9):37-40.
4.    Levenson JL. Psychiatric issues in neurology, part 2: parkinson’s disease and multiple sclerosis. Primary Psychiatry. 2007;14(11):35-39.
5.    Levenson JL. Psychiatric issues in neurology, part 3: epilepsy. Primary Psychiatry, 2008;15(1):21-25.
6.    Kopelman MD, Stanhope N, Kingsley D. Retrograde amnesia in patients with diencephalic temporal lobe or frontal lesions. Neuropsychologia. 1999;37(8):939-958.
7.    Quinette P, Guillery-Girard B, Dayan J, et al. What does transient global amnesia really mean? Review of the literature and thorough study of 142 cases. Brain. 2006;129(Pt 7):1640-1658.
8.    Agosti C, Akkawi NM, Borroni B, Padovani A. Recurrency in transient global amnesia: a retrospective study. Eur J Neurol. 2006;13(9):986-989.
9.    Gandolfo C, Caponnetto C, Conti M, Dagnino N, Del Sette M, Primavera A. Prognosis of transient global amnesia: a long-term follow-up study. Eur Neurol. 1992;32(1):52-57.
10.    Dupont S, Samson S, Baulac M. Is anterior temporal lobectomy a precipitating factor for transient global amnesia? J Neurol Neurosurg Psychiatry. 2007 Nov 21 [Epub ahead of print].
11.    Spigno F, De Lucchi M, Migliazzi L, Cocito L. Transient global amnesia after breathing hyperoxic mixtures in otherwise regular dives. Clin Neurol Neurosurg. 2007 Oct 5 [Epub ahead of print].
12.    Shihman B, Auriel E, Bornstien NM. Two cases of transient global amnesia (TGA) following sildenafil use [Hebrew]. Harefuah. 2006;145(9):656-657,703.
13. Bucuk M, Muzur A, Willheim K, Jurjevic A, Tomic Z, Tuskan-Mohar L. Make love to forget: two cases of transient global amnesia triggered by sexual intercourse. Coll Antropol. 2004;28(2):899-905.
14.    Butler CR, Graham KS, Hodges JR, Kapur N, Wardlaw JM, Zeman AZ. The syndrome of transient epileptic amnesia. Ann Neurol. 2007;61(6):587-598.
15.    Morgan CJ, Curran HV. Acute and chronic effects of ketamine upon human memory: a review.Psychopharmacology (Berl). 2006;188(4):408-424.
16.    Brandt J, Van Gorp WG. Functional (“psychogenic”) amnesia. Semin Neurol. 2006;26(3):331-340.
17. Wong CK. Too shameful to remember: a 17-year-old Chinese boy with psychogenic amnesia. Aust N Z J Psychiatry. 1990;24(4):570-574.
18. Leng NR, Parkin AJ. The detection of exaggerated or simulated memory disorder by neuropsychological methods. J Psychosom Res. 1995;39(6):767-776.
19. Carson AJ, Ringbauer B, Stone J, MacKenzie L, Warlow C, Sharpe M. Do medically unexplained symptoms matter? A study of 300 consecutive new referrals to neurology outpatient clinics. J Neurol Neurosurg Psychiatry. 2000;68:207-210.
20.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
21. Carson AJ, Postma K, Stone J, Warlow C. Sharpe M. The outcome of neurology patients with medically unexplained symptoms: a prospective cohort study. J Neurol Neurosurg Psychiatry. 2003;74(7):897-900.
22. Stone J, Zeman A, Sharpe M. Physical signs: functional weakness and sensory disturbance. J Neurol Neurosurg Psychiatry. 2002:73(3):241-245.
23. Stone J, Smyth R, Carson A, Lewis S, Prescott R, Warlow C, Sharpe M. Systematic review of misdiagnosis of conversion symptoms and “hysteria”. BMJ. 2005;331(7523):989.
24. Stone J, Smyth R, Carson A, Warlow C, Sharpe M. La belle indifférence in conversion symptoms and hysteria: systematic review. Br J Psychiatry. 2006;188:204-209.
25. Ness D. Physical therapy management for conversion disorder: case series. J Neurol Phys Ther. 2007;31(1):30-39.

 

Return

 

Dr. Levenson is professor in the Departments of Psychiatry, Medicine, and Surgery, chair of the Division of Consultation-Liaison Psychiatry, and vice chair for clinical affairs in the Department of Psychiatry at Virginia Commonwealth University School of Medicine in Richmond.

Disclosure: Dr. Levenson is on the depression advisory board for Eli Lilly.

 


 

Important psychiatric issues affecting diagnosis and management arise in patients with neurologic illness more often than any other area of medicine. These include cognitive impairment either as a primary feature or a secondary complication of a known neurologic disorder, other psychiatric symptoms as a manifestation or complication of neurologic disease, and physical neurologic symptoms that do not correspond to any recognized pattern of neurologic disease (ie, conversion disorder or somatization disorder). In addition, behavioral, cognitive, or emotional symptoms may occur as a complication of drug therapy of neurologic disease. More detailed coverage of these topics can be found elsewhere.1,2 In previous columns, psychiatric issues in stroke, Parkinson’s disease, multiple sclerosis, and epilepsy were reviewed.3-5 In this column, psychiatric issues related to amnestic syndromes and conversion disorder are reviewed.

 

Amnestic Syndromes

Amnestic syndromes are conditions in which memory functions are disproportionately impaired compared to other cognitive functions in an otherwise alert patient. Causes include the Wernicke-Korsakoff syndrome, carbon monoxide poisoning, herpes encephalitis and other central nervous system infections, hypoxic and other acquired brain injuries, stroke, brain tumors, and neurosurgical resections (eg, for intractable epilepsy).1 There are also transient amnestic syndromes, and amnesia can be a manifestation of conversion disorder, posttraumatic stress disorder (PTSD), dissociative disorders, or malingering. Transient as well as persistent amnestic symptoms also occur following electroconvulsive therapy.

 

Wernicke-Korsakoff Syndrome

The Wernicke-Korsakoff syndrome (WKS) is the most common amnestic disorder and is the result of thiamine deficiency of any cause. The great majority of cases in the developed world are caused by chronic alcohol abuse which results in both decreased intake and absorption of thiamine. However, the disorder has also been reported in patients with a wide array of causes of malnutrition, including anorexia nervosa, chronic schizophrenia, post-gastric surgery for obesity, gastrointestional disorders, and hemodialysis. Thiamine deficiency may also result in beriberi, a cardiac and peripheral nervous system disease, and may also result in cerebellar degeneration and peripheral neuropathy. The onset of Wernicke’s encephalopathy is usually acute, manifested by confusion, ataxia, nystagmus, and ophthalmoplegia. The administration of intravenous fluid with glucose to a thiamine-deficient patient is a common iatrogenic precipitant of acute WKS. Emergent administration of parenteral thiamine is indicated to avoid irreversible nervous system damage. Since alcoholics and others with thiamine deficiency are also often deficient in other B vitamins (especially folate, niacin, and vitamin B12), they should receive parenteral multivitamins. In refeeding starving patients of whatever cause, phosphate supplementation is often required.

Chronic thiamine deficiency results in Korsakoff syndrome, with most cases following an earlier acute Wernicke’s encephalopathy. On clinical examination, patients with classic Korsakoff syndrome have severe impairment of memory with both anterograde and retrograde deficits.6 Such patients have particular difficulty encoding new information. While retrieval of recent memories is most impaired, Korsakoff patients also have difficulty retrieving more remote memories. Confabulation (the replacement of a gap in a patient’s memory by a falsification that he or she believes to be true) commonly but not invariably occurs in Korsakoff syndrome.

Other cognitive, behavioral, and emotional changes may accompany the amnesia, such as executive dysfunction, disorientation, apathy, and labile irritability. However, since most cases of Korsakoff syndrome are caused by chronic alcoholism, it is impossible to know which deficts in cerebral function can be attributed to thiamine deficiency and which are due to other causes common in alcoholics, including other B vitamin deficiencies, head trauma, and the toxic effects of alcohol itself.

With vitamin replacement and abstinence from alcohol, the prognosis in Korsakoff syndrome is fair. Twenty five percent of patients will recover, 50% will improve but with some persistent memory impairment, and 25% will show no change.1 Thiamine is inexpensive and harmless. Hence, any patient presenting with an acute amnestic syndrome should probably receive high-dose thiamine, even in the absence of a history of alcoholism or obvious malnutrition (the absence of proof of alcohol abuse is not proof of the absence of alcohol abuse). There are no good data to guide how long thiamine (and other B vitamins) should be given to patients with chronic alcoholism.

 

Transient Amnestic Syndromes

Transient amnesia occurs in a variety of neuropsychiatric disorders and as a normal phenomenon starting in midlife (at a relatively minor but annoying magnitude and frequency). There are some disorders in which dramatic but short-lived amnesia is the sole symptom. The best known, though still poorly understood, is transient global amnesia (TGA). TGA is a benign and temporary disorder affecting middle-aged or elderly individuals who present with the abrupt onset of loss of anterograde memory with the preservation of remote memories and immediate recall. They become amnestic for recent events and unable to lay down new memories for a few hours. They tend to repetitively question their companions. Episodes can be provoked by physical or emotional stress. A recent review7 of 142 cases of TGA found that in women, TGA episodes mainly follow emotional precipitating events, whereas in men they occur more frequently after a physical precipitating event. Most episodes of TGA are single isolated events; however, the recurrence rate is approximately 14% to 18%.8,9 A variety of hypthoses of its pathophysiology have been proposed, but the etiology remains uncertain. Cases of TGA have been reported after a diversity of apparent precipitants such as temporal lobectomy for epilepsy,10 divers breathing hyperoxic mixtures,11 sildenafil,12 sexual intercourse,13 coronary angiography, and aortic dissection. No link has been found with vascular risk factors.7 In addition, there is no increased risk of transient ischemic attack or stroke in patients who have had TGA nor is there any increase in mortality.

Temporal lobe epilepsy occasionally mimics TGA, and this is described in the literature as transient epileptic amnesia (TEA). In contrast to TGA, amnestic episodes caused by epilepsy are frequent and recurrent (median=12 episodes/year), brief (median duration=30–60 minutes), and often occur on waking (approximately 66% of cases). The diagnosis of epilepsy is very often initially missed even by specialists. TEA episodes typically disappear after treatment with anticonvulsants, but many patients continue to complain of persistent memory difficulties despite normal performance on standard memory tests.14

Other common causes of transient amnesia include transient cerebral ischemia (usually accompanied by other neurologic symptoms and signs), migraine, alcohol intoxication (“blackouts”), drugs (eg, benzodiazepines, barbiturates, ketamine15) and head injury. Concussion is often followed by temporary retrograde and anterograde amnesia; the more prolonged the anterograde amnesia, the more severe the injury.
Several psychiatric conditions can also be the cause of amnestic symptoms. Amnesia should not be attributed to a psychogenic cause solely on the basis of an otherwise normal neurologic examination, electroencephalogram (EEG), and imaging studies, since they would be normal in most cases of TGA and many cases of TEA. Psychogenic amnesia is one form of conversion disorder. In patients whose amnesia is due to conversion disorder, memory for their personal life histories is much more severely affected than is their ability to learn and retain new information; that is, they have isolated retrograde amnesia.16 This pattern is the opposite of that seen in TGA. In cases where the diagnostic picture is unclear, neuropsychological testing is very helpful in distinguishing conversion (and other psychogenic memory disturbances) from neurologic amnestic syndromes. Amnesia also occurs frequently in PTSD and dissociative disorders. Psychogenic amnesia serves to block out memory of a traumatic experience with intolerable associated affect, such as terror or shame.17 While controlled trials are lacking, psychotherapy and hypnosis have often been used successfully in treatment of conversion amnesia.

Amnesia is also a common symptom of malingering, especially in forensic contexts. Neuropsychological testing is invaluable in identifying suspected malingering in amnestic patients. The tests are based on the assumption that naive simulators or exaggerators do not know either that amnestic patients can perform some tests normally, or near normally, or that subjects can only fail them by deliberate suppression of the correct response.18

 

Conversion Disorder

Neurologic symptoms in the absence of neurologic disease or grossly disproportionate to disease affect approximately one-third of patients attending neurologic clinics.19 Many such patients have somatoform disorders, one of which is conversion disorder. Pain is the most common symptom in outpatient neurological practice,19 but the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,20 criteria for conversion disorder exclude pain. Patients with conversion disorder are those who develop other (ie, nonpain) neurologic symptoms or deficits that do not conform to known pathophysiology or are grossly disproportionate to it. Almost any neurologic symptom may be produced, such as paralysis, weakness, seizures, anesthesia, aphonia, blindness, amnesia, and stupor. Conversion disorder often coexists with neurologic illness, the most common example being epileptic seizures and “pseudoseizures” in the same patient.

Conversion symptoms can occur at any age but are most likely in adolescence or early adulthood. New onset of unexplained neurologic symptoms in elderly patients without a prior psychiatric history is rarely due to conversion disorder. Some conversion symptoms occur as brief, isolated episodes, but others are chronic and recurrent. Many individuals with chronic conversion symptoms have a history of having been sexually abused in childhood. Conversion symptoms are usually precipitated by an acute stressor or a current emotional conflict. The prevalence of conversion disorder has varied culturally and historically. The major task in differential diagnosis is determining whether the patient has a neurologic disorder, conversion, or both.

Symptoms remit spontaneously in <50% of patients.21 Recent stressful life events, a history of childhood abuse and neglect, personality dysfunction, abnormal illness beliefs, and/or secondary gain (financial or otherwise) are all common in conversion disorder, but their presence does not allow one to infer a diagnosis of conversion disorder.22 The neurologic examination plays a key role in diagnosis. Examples of helpful signs include tunnel vision, collapsing (“giveaway”) weakness, and unusual distribution of sensory loss. Physicians tend to worry excessively about missing “organic” disease and are, therefore, often very conservative in making a diagnosis of conversion disorder, erring in the other direction (ie, ordering too many diagnostic tests and prescribing unneeded treatment for presumptive neurologic disorders). This, in turn, reinforces the patient’s illness beliefs and sick role and risks iatrogenic complications and invalidism. In fact, the evidence suggests that diagnostic accuracy for conversion disorder is high with an error rate in modern studies of <5%.23

Conversion disorders have classically been thought to arise out of unconscious psychological conflicts, needs, or responses to trauma. Sigmund Freud posited that conversion symptoms served to protect the individual from unacceptable feelings or unresolvable conflicts, which keep such feelings out of conscious awareness. This function of conversion symptoms is referred to as “primary gain.” However, this model only fits some patients. Furthermore, while conversion symptoms often have unconscious meaning, this will not usually be apparent in initial encounters. Patients with conversion disorder tend to be very suggestible. Some but not all have a strikingly blasé attitude toward their symptoms (eg, la belle indifferénce), but it is neither sensitive nor specific enough to be useful in the diagnosis of conversion disorder.24

Patients with conversion disorder are usually consciously unaware of the cause of the symptoms, even when the cause might seem obvious to the clinician (eg, onset of paraplegia following rape). Such symptoms often elicit gratifying or protective responses from the environment (eg, sympathy, extra assistance, release from obligations, disability payments), which in turn reinforce the symptom.

The management of conversion symptoms begins with careful assessment; a thorough neurologic and physical examination can often distinguish between conversion disorder and organic neurologic disease without the need for other tests. In some cases, specific studies may be required including imaging, EEG, and electromyogram. It is never helpful to confront the patient in a negative way. Telling the patient “It is all in your head” or “There is nothing wrong with you” angers the patient, reinforces their insistence that the symptoms are “real,” and undermines the doctor-patient relationship. The appropriate approach is to first offer explicit acceptance of the reality of the symptoms and then reassure the patient that serious causes like tumor, stroke, or multiple sclerosis have been ruled out. This is then followed by telling the patient that they have a form of benign neurologic dysfunction that tends to be exacerbated by stress. An analogy to migraine can be helpful, ie, that even though stress aggravates migraine, there is no question that migraine pain and other symptoms are real. Psychotherapy can be very helpful, and the patient is more likely to pursue it if the clinician takes an encouraging and destigmatizing attitude toward the patient’s symptoms. For patients whose conversion disorder is manifested in weakness or paralysis, physical therapy can be very helpful in providing “a graceful way out” of the disabled sick role.25 Physical therapy is essential for patients who have been chronically immobilized by conversion disorder because they develp disuse atrophy. PP

 

References

1.    Carson AJ, Zeman A, Myles L, Sharpe MC. Neurology and neurosurgery. In: Levenson JL, ed. American Psychiatric Publishing Textbook of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2005:701-732.
2.    Carson AJ, Zeman A, Myles L, Sharpe MC. Neurology and neurosurgery. In: Levenson JL, ed. Essentials of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2007:313-342.
3.    Levenson JL. Psychiatric issues in neurology, part 1: stroke. Primary Psychiatry, 2007;14(9):37-40.
4.    Levenson JL. Psychiatric issues in neurology, part 2: parkinson’s disease and multiple sclerosis. Primary Psychiatry. 2007;14(11):35-39.
5.    Levenson JL. Psychiatric issues in neurology, part 3: epilepsy. Primary Psychiatry, 2008;15(1):21-25.
6.    Kopelman MD, Stanhope N, Kingsley D. Retrograde amnesia in patients with diencephalic temporal lobe or frontal lesions. Neuropsychologia. 1999;37(8):939-958.
7.    Quinette P, Guillery-Girard B, Dayan J, et al. What does transient global amnesia really mean? Review of the literature and thorough study of 142 cases. Brain. 2006;129(Pt 7):1640-1658.
8.    Agosti C, Akkawi NM, Borroni B, Padovani A. Recurrency in transient global amnesia: a retrospective study. Eur J Neurol. 2006;13(9):986-989.
9.    Gandolfo C, Caponnetto C, Conti M, Dagnino N, Del Sette M, Primavera A. Prognosis of transient global amnesia: a long-term follow-up study. Eur Neurol. 1992;32(1):52-57.
10.    Dupont S, Samson S, Baulac M. Is anterior temporal lobectomy a precipitating factor for transient global amnesia? J Neurol Neurosurg Psychiatry. 2007 Nov 21 [Epub ahead of print].
11.    Spigno F, De Lucchi M, Migliazzi L, Cocito L. Transient global amnesia after breathing hyperoxic mixtures in otherwise regular dives. Clin Neurol Neurosurg. 2007 Oct 5 [Epub ahead of print].
12.    Shihman B, Auriel E, Bornstien NM. Two cases of transient global amnesia (TGA) following sildenafil use [Hebrew]. Harefuah. 2006;145(9):656-657,703.
13. Bucuk M, Muzur A, Willheim K, Jurjevic A, Tomic Z, Tuskan-Mohar L. Make love to forget: two cases of transient global amnesia triggered by sexual intercourse. Coll Antropol. 2004;28(2):899-905.
14.    Butler CR, Graham KS, Hodges JR, Kapur N, Wardlaw JM, Zeman AZ. The syndrome of transient epileptic amnesia. Ann Neurol. 2007;61(6):587-598.
15.    Morgan CJ, Curran HV. Acute and chronic effects of ketamine upon human memory: a review.Psychopharmacology (Berl). 2006;188(4):408-424.
16.    Brandt J, Van Gorp WG. Functional (“psychogenic”) amnesia. Semin Neurol. 2006;26(3):331-340.
17. Wong CK. Too shameful to remember: a 17-year-old Chinese boy with psychogenic amnesia. Aust N Z J Psychiatry. 1990;24(4):570-574.
18. Leng NR, Parkin AJ. The detection of exaggerated or simulated memory disorder by neuropsychological methods. J Psychosom Res. 1995;39(6):767-776.
19. Carson AJ, Ringbauer B, Stone J, MacKenzie L, Warlow C, Sharpe M. Do medically unexplained symptoms matter? A study of 300 consecutive new referrals to neurology outpatient clinics. J Neurol Neurosurg Psychiatry. 2000;68:207-210.
20.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
21. Carson AJ, Postma K, Stone J, Warlow C. Sharpe M. The outcome of neurology patients with medically unexplained symptoms: a prospective cohort study. J Neurol Neurosurg Psychiatry. 2003;74(7):897-900.
22. Stone J, Zeman A, Sharpe M. Physical signs: functional weakness and sensory disturbance. J Neurol Neurosurg Psychiatry. 2002:73(3):241-245.
23. Stone J, Smyth R, Carson A, Lewis S, Prescott R, Warlow C, Sharpe M. Systematic review of misdiagnosis of conversion symptoms and “hysteria”. BMJ. 2005;331(7523):989.
24. Stone J, Smyth R, Carson A, Warlow C, Sharpe M. La belle indifférence in conversion symptoms and hysteria: systematic review. Br J Psychiatry. 2006;188:204-209.
25. Ness D. Physical therapy management for conversion disorder: case series. J Neurol Phys Ther. 2007;31(1):30-39.

 

 

Inhibitory Endophenotypes Help Classify Schizophrenia and Bipolar Patients

Clinicians often misdiagnose mania as schizophrenia while schizophrenia is usually mistaken for schizoaffective disorder. According to a study by Laura F. Martin, MD, of the University of Colorado, and colleagues, physiologic inhibitory endophenotypes may be able to differentiate patients with schizophrenia from patients with bipolar disorder.

The study involved 29 patients with schizophrenia, 40 patients with bipolar disorder, and 18 patients with schizoaffective disorder. The study evaluated suppression of the three biologic indicators of sensory response inhibition, ie, P50 auditory evoked response, leading saccades during smooth pursuit eye movements, and inhibition of saccades during antisaccade tasks. Despite group differences in the electrophysiologic tests, there is a large degree of overlap among individuals from the groups. After logistic regression analysis, results found that P50 ratio and frequency of leading saccades distinguished schizophrenia patients from bipolar patients with a sensitivity of 95% and a specificity of 83%. Participants in the schizoaffective group were split with six patients characterized as schizophrenia-like and 12 patients characterized as bipolar-like.

“I was surprised at how well a combination of only three tests correctly identified so many individuals,” Dr. Martin said.

The biggest limitation to this study was the lack of variety within the sample. The results need to be cross-validated among a different sample of individuals. In addition, it would be helpful to complete the same study in an inpatient group as this study was only completed in an outpatient group with clinically stable disease.

“I would have liked to see if the electrophysiology continued to support the clinical nosology,” Dr. Martin said. “With the increasingly complex task of differentiating acute psychotic mania from shizophrenia, would the area under the receiver operating characteristic curve also decrease?”

While identifying endophenotypes may help clinicians understand genetic studies and the neurobiology of these disorders, this study’s results do not have direct clinical applicability. However, this knowledge may help determine how affective features associated with schizophrenia and psychotic features associated with bipolar disorder make them clearly distinguishable disorders.

Funding for this research was provided by the Veterans Affairs Research Service and the National Institute of Mental Health. (Am J Psychiatry. 2007;164(12):1900-1906.) —ML

 

Increased Risk of PTSD Symptoms in Combat-Exposed Military Personnel

Soldiers returning from war have long been reported to exhibit symptoms of posttraumatic stress disorder (PTSD). Historically, the prevalence rate of PTSD in military cohorts seems to have corresponded with the level of “boots on the ground” combat. According to previous reports, for example, as many as 30% of returning United States soldiers who fought in the Vietnam War, and 10% of soldiers in the 1991 Gulf War, exhibited PTSD symptoms.

Past studies of PTSD in this population have been retrospective. However, a recent study by Tyler C. Smith, MS, of the Department of Defense Center for Deployment Health Research at the Naval Health Research Center in San Diego, California, and colleagues, includes pre-deployment baseline data on PTSD symptoms in military personnel along with a comprehensive follow-up analyses.

Baseline data were compiled between July 2001 and June 2003 from a cohort of 70,047 active US military personnel; 50,184 personnel participated in follow up questionnaires administered between June 2004 and February 2006. Using follow up data, the investigators determined the incidence of new-onset PTSD in both deployed and non-deployed military personnel. Outcome measures were based on two levels of data collection, including “sensitive” and “specific” definitions. The “sensitive” definition of PTSD symptoms was based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), criteria alone; the “specific” definition included DSM-IV criteria along with a required sum of 50, on a scale of 17–85, on the PTSD checklist–civilian version, a 17-item self-report PTSD measure.

Exposure to combat was a significant incidental factor in this study. During follow up, one survey asked participants whether they had ever been exposed to or witnessed “a person’s death due to war, disaster, or tragic event,” “instances of physical abuse (torture, beating, rape),” or “maimed soldiers or civilians.”

New instances of self-reported PTSD were found in 7.6% to 8.7% of deployed personnel who reported combat exposure, 1.4% to 2.1% of deployers with no combat exposure, and 2.3% to 3.0% of non-deployed personnel. Overall, these data indicate a threefold increase in new-onset PTSD cases from baseline. Subjects who reported PTSD symptoms at baseline were excluded from these analyses.

By the “sensitive” criteria, new-onset PTSD symptoms were reported in 4.9% of Army personnel (the highest reported percentage) and 1.8% in the Air Force (the lowest reported percentage). Deployed personnel across all military branches were more likely to be male, born between 1970–1979, less educated (high school/equivalent or less), and combat specialists. However, new-onset PTSD symptoms were proportionately higher in those who were younger, female, never married or divorced, enlisted, black non-Hispanics, and less education (high school/equivalent or less). The researchers note, however, that higher-educated, older members of this cohort, such as officers or Marines, were more likely to report persisting symptoms at follow up, suggesting a reason for this group’s lower odds of new-onset PTSD symptoms.

Another significant finding of this study includes the data that were collected on problem drinking and smoking status across all military branches and occupations. Those who reported current smoking and problem drinking at baseline also had an increased risk of new-onset PTSD, although smoking and problem drinking were also tied to persistent PTSD symptoms.
Funding for this research was provided by the Department of Defense. (BMJ. 2008;336:366-371.) —LS

 

Symptom Changes in ADHD Found as Children Grow into Adolescence

Affecting approximately 5% to 10% of children and adolescents worldwide, attention-deficit/hyperactivity disorder (ADHD) is a common, chronic behavioral condition associated with cognitive deficits and diminished academic performance, which is characterized by inattention, impulsivity, and hyperactivity. Although children with ADHD may present more often with symptoms of impulsivity and hyperactivity, adolescents with the disorder may have more cognitive deficits, such as impairments with working memory and inhibition. While ADHD is often studied in children and adolescents separately, there have been few large, longitudinal studies of the prevalence of ADHD in adolescents.

Susan L. Smalley, PhD, of the Semel Institute at the University of California at Los Angeles, and colleagues, evaluated adolescents who participated in the Northern Finland Birth Cohort 1986, which studied 9,432 children from the early fetal period to adolescence (16–18 years of age) for ADHD prevalence. The authors also sought to assess the clinical characteristics of ADHD in the adolescent population as compared to the course of the disorder in childhood.

Among the children studied in the Northern Finland Birth Cohort 1986, 6,622 participants responded to a survey about adolescence and ADHD. Smalley and colleagues identified a subset of 457 adolescents among those who responded; this subset included adolescents who may have ADHD and other psychiatric conditions as well as those who did not have the disorder and could act as controls. The authors used a standard screening survey and diagnostic criteria to identify adolescents with ADHD and comorbid disorders.

Smalley and colleagues found that the estimated prevalence of ADHD among adolescents in the birth cohort was 8.5%. They also found that as children with ADHD age, hyperactivity and impulsivity related to the disorder decrease while inattention increases. Most adolescents with ADHD exhibited the inattentive subtype (64%), while the hyperactive-impulsive (8%) and combined (28%) subtypes were found in fewer adolescents.

The study also found that ADHD in adolescence is significantly associated with increased rates of other psychiatric conditions including depression and anxiety disorders. In addition, conduct disorders, such as vandalism and truancy, oppositional behavior, and posttraumatic stress disorder were elevated in adolescents with ADHD as compared to those without the disorder. A lifetime diagnosis of ADHD had a prevalence of 18.2%, and a lifetime diagnosis was also significantly associated with the presence of anxiety and disruptive behavioral disorders.

The authors concluded that although cognitive deficits are present in adolescents with ADHD, they are often not used as an indicator for the disorder in childhood as children with cognitive deficits typically do not show increased symptoms of hyperactivity or inattention, which are symptoms used to identify the disorder in children. Thus, Smalley and colleagues suggest that researchers examine more closely what environmental conditions lead to impairment in children and adolescents with ADHD. 

Regarding medication use to treat the disorder, the authors conclude that researchers should also examine the efficacy of stimulant use in the United States as medication use in Finland was limited and the presentation of ADHD in adolescence was similar to the presentation of the disorder among patients in the US. Although medications are beneficial in the short term, the authors suggest that further study into the long-term course of ADHD and its overall effects is needed.

Funding for this research was provided by the National Institute of Mental Health, the Juselius Foundation, and the Academy of Finland. (J Am Acad Child Adolesc Psychiatry. 2007;46(12):1575-1583.) —CP

 

Cognitive and Genotypic Predictors of Impulsive Behavior in Alcoholism

The etiology and development of addictive disorders might imply a more serious neurobiologic effect than previously believed, according to a recent study that analyzed the immediate reward bias in the human brain. Using a combination of imaging and genotyping analyses, Charlotte A. Boettiger, PhD, and colleagues at the University of California, San Francisco’s Gallo Clinic and Research Center examined the reaction of several brain regions in recovering, abstinent alcoholics and in subjects with no history of substance abuse.
“Our data suggest possible brain mechanisms for decision-making impairment among alcoholics, which provides an endophenotype and thus an intermediate therapeutic target for testing clinical interventions prior to clinical trials,” Dr. Boettiger said. 

A pronounced bias toward immediate gratification, compared to choosing greater benefits derived over a longer term, is characteristic of people with alcoholism and addictive disorder. Nine recovering, abstinent alcoholics and 10 subjects with no history of substance abuse underwent functional magnetic resonance imaging (fMRI) bold oxygen level-dependent (BOLD) analysis. Subjects were asked to consider hypothetical scenarios in which a lesser award, or a greater, long-term award, was available. fMRI BOLD was conducted during the decision-making process at sites within the posterior parietal cortex, the dorsal prefrontal cortex, and the rostral parahippocampal gyrus regions.

The recovering alcoholic subgroup chose the immediate gratification option three times more often than the control group, and they showed diminished orbital frontal cortex activity—a region of the brain that Dr. Boettiger suggests may be associated with the long-term award. High activity in the dorsal prefrontal cortex and the parietal cortex was associated with a bias toward immediately gratification, which, as Dr. Boettiger explains, “runs counter to the belief that addicts make such choices due to heightened reward sensitivity and suggests that abnormalities in cognitive processing contribute to immediate reward bias.”

This investigation also included a genotyping aspect. Genotype at the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene predicted impulsive behavior and correlated with high activity in the posterior parietal cortex and the dorsal prefrontal cortex. Boettiger and colleagues noted that the data indicate that COMT genotype confers behavioral differences which may be relevant for therapeutic response to specific treatments for substance abuse.

“Behavioral addiction treatment often focuses on learning to think more concretely about the consequences of relapse,” Dr. Boettiger added, “suggesting that stronger mental representations of long-term consequences enables more future-oriented decisions. Our results point to the lateral orbitofrontal cortex as a possible key site for such representations, and support identifying addiction therapies that strengthen orbitofrontal cortex activity during decision making.”

Funding for this research was provided by the Department of Defense and the Wheeler Center for the Neurobiology of Addiction. (J Neurosci. 2007;27(52):14383-14391.) –LS

 

Sleep Medications Often Denied to Insomnia Patients with Anxiety and Depression

Approximately 20% of the United States population has sleep problems, and every one out of 10 patients experiences chronic insomnia. Patients with insomnia usually endure other comorbidities such as depression and anxiety. According to a study by Rajesh Balkrishnan, PhD, of Ohio State University, and colleagues, patients who suffer from both insomnia and mental health disorders are denied sleep medication more often than those without mental health diagnoses.

The study involved a retrospective data analysis of the National Ambulatory Medical Care Survey. It recorded 5,487 physician visits by patients with insomnia between 1995 and 2004, a sample calculated to represent 161.4 million US patients. Approximately 38% of those surveyed were diagnosed with at least one other condition, including anxiety, episodic mood disorders, high blood pressure, depression, and diabetes. Patients with both insomnia and mental health disorders were 36% less likely to receive pharmacotherapy for insomnia while anxiety patients were 45% less likely. These results reveal that patients with these comorbid disorders are the lowest candidates for sleep medication. In addition, the findings suggest that physicians are tentative to prescribe sleep aids due to these patients’ higher risk of dependence and abuse, a groundless assumption that could lead to worsened mental health conditions.

Funding for this research was provided by a grant from sanofi-aventis. (J Med Econ. 2008;11(1):41-56.) –ML

Dispatches is written by Michelisa Lanche, Carlos Perkins, Jr., and Lonnie Stoltzfoos.