Dr. Pavletic is senior staff clinician in the Office of the Clinical Director, Mr. Luckenbaugh is medical statistician in the Mood and Anxiety Program, Dr. Pao is deputy clinical director in the Intramural Research Program, and Dr. Pine is chief of developmental studies in the Mood and Anxiety Program, all at the National Institute of Mental Health in Bethesda, Maryland.

Disclosures: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Disclaimer: The views expressed in this article do not necessarily represent the views of the National Institute of Mental Health, the National Institutes of Health, the United States Department of Health and Human Services, or the United States Government.

Please direct all correspondence to: Adriana J. Pavletic, MD, MS, 10 CRC, Room 6-5340, 10 Center Drive, MSC 1276, Bethesda, MD 20892-1276; Tel: 301-594-7386; Fax: 301-402-2588; E-mail: pavletia@mail.nih.gov.



Focus Points

• Assessments based on research volunteer-provided history are not sufficient in determining eligibility for protocols.
• Physical examination may discover psychiatric and/or medical disorder.
• Toxicology screen is often positive in research volunteers.
• Medical evaluation is equally important in healthy controls and anxiety patients.




Introduction: The importance of psychiatric screening of volunteers participating in research on mental illness is well established. Although psychiatric research frequently relies on subjects presumed to be free of medical conditions that affect nervous system function or safety of participants, little information exists on the value of medical screening in this population. This study describes findings on medical evaluations that potentially impact psychiatric research.
Methods: The authors conducted a retrospective analysis of medical evaluations in 476 consecutively referred healthy controls and 64 anxiety patients to determine the prevalence of conditions that resulted in exclusion from studies. All subjects had history and physical examination by a board-certified family physician and 37% of participants completed laboratory assessment.
Results: One-hundred ten (20%) volunteers were excluded. Exclusion rates were similar for controls and patients. The most common reasons for exclusion were psychiatric conditions (6.3%), positive toxicology screen (5.4%), abnormal liver function tests (4.5%), cardiovascular abnormalities (3.9%), positive viral markers including hepatitis C, hepatitis B, and human immunodeficiency virus (3.5%), anemia (2.5%), neurologic disorders (1.6%), and electrolyte abnormalities (1.0%).
Discussion: Medical screening identifies a relatively high rate of conditions in both healthy controls and anxiety patients that could impact on psychiatric research. A significant proportion of exclusions was found on physical exam, laboratory assessment, and toxicology screen.
Conclusion: These findings demonstrate the complementary nature of medical and psychiatric evaluations and underscore the need to develop further standards in medical screening procedures of volunteers in psychiatric research.



Previous reports demonstrate the importance of psychiatric evaluation1-5 and toxicology screening6-7 in individuals volunteering for mental health research. Research on mental illness typically attempts to recruit volunteers without medical conditions that might affect the functioning of the nervous system or safety of participants. However, in contrast to considerable work on mental health evaluation, few studies consider the value of comprehensive medical evaluation in this population.

Particular debate exists among mental health researchers regarding the need to perform physical exam and laboratory testing in volunteers participating in noninvasive studies such as functional magnetic resonance imaging (fMRI). Consequently, assessment of physical health often relies on a self report of medical history by potential volunteers. However, histories often fail to detect exclusionary conditions in volunteers participating in both psychiatric and medical research, possibly due to financial incentive.6-10 The aim of this article is to describe findings on medical evaluation that resulted in exclusions of volunteers from studies.




Five-hundred forty consecutive research volunteers, between 18–55 years of age (476 healthy controls and 64 anxiety patients) were medically evaluated from May 2003 through April 2005 to determine eligibility for one of nine protocols from four principal investigators. Volunteers were financially compensated for their participation. All protocols were approved by the National Institute of Mental Health (NIMH)-Intramural Research Program (IRP) Institutional Review Board. Two studies involved fMRI, four studies involved fear conditioning with electric nerve stimulation, and three studies involved fear conditioning and/or one-time medication administration.

These subjects were recruited when they contacted the NIMH-IRP. Recruitment methods for NIMH-IRP studies are modeled after those used throughout the various National Institutes of Health (NIH) IRPs, which, in turn, are modeled after those used throughout the medical community. Data on recruitment methods were not collected in this study. All subjects requesting participation were required to undergo an initial phone screen to determine potential eligibility. This initial screen typically led to exclusions among a relatively high proportion of potential subjects. Rates and reasons for these exclusions were not examined since the focus of the current report concerns rates of exclusion among subjects deemed to be eligible based on this initial screen.


Medical and Psychiatric Eligibility Criteria

All protocols required the absence of medical conditions and/or use of psychoactive medications that may affect the functioning of the nervous system or safety of participants. For healthy volunteers, inclusion criterion required the absence of a current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,11 Axis I mental disorder as determined either by the Structured Clinical Interview for DSM-IV Disorders (SCID), Non-Patient Edition,12 in seven studies or history and physical examination (H&P) in two studies. For anxiety disorder patients, inclusion criteria comprised current diagnosis of generalized anxiety disorder, social anxiety disorder, panic disorder, or specific phobia as determined by the SCID, Patient Edition,13 and study psychiatrist (D.S. Pine, MD).


Medical and Psychiatric Screening

Volunteers who passed initial standardized phone screens conducted by college level research assistants for healthy controls and mental health professionals for patients were subsequently evaluated in person. Clinical screening was completed by licensed mental health professionals (psychologists, mental health nurses, social workers) for the SCID and by a board-certified family physician (A.J. Pavletic, MD, MS) for the H&P and laboratory assessment. The order of in-person evaluation was determined by the availability of clinicians. Identification of exclusion criteria on an initial H&P or SCID precluded further evaluation. Thus, for example, volunteers initially receiving the SCID who met exclusion criteria were not medically evaluated and are not included in this report.

For healthy volunteers, screening procedures varied by protocol, including H&P in two studies, H&P and SCID in two studies, and comprehensive evaluations (H&P, laboratory assessment, electrocardiogram, and SCID) in five studies. For anxiety patients, all subjects received the comprehensive evaluation. Laboratory workup included complete blood count with differential, acute care panel (electrolytes, glucose, blood urea nitrogen, creatinine), hepatic panel (alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin), thyroid-stimulating hormone, viral markers (HIV, hepatitis B, hepatitis C), qualitative urine drug screen (amphetamines, benzodiazepines, tetrahydrocannabiol, cocaine, opiates), and urine pregnancy test.


Eligibility Determination

A family physician performed medical clearance of anxiety patients and determined eligibility of healthy controls based on all available information including H&P, SCID, laboratory assessment, and NIH medical record review of subjects who previously participated in NIH studies. The NIH maintains a comprehensive medical record for all potential research participants who have volunteered in any NIH-IRP study. Questionable cases were discussed with principal investigators (experimental psychologists) and study psychiatrist.

All studies used identical criteria to rule out conditions that might influence interpretation of study results. However, relative to noninvasive fMRI studies, medical eligibility criteria were more stringent in provocative fear conditioning studies and studies involving medication exposure, due to safety concerns. For example, liver function test abnormalities present on at least two occasions were exclusionary only in studies with medication exposure, and murmurs and mitral valve prolapse were exclusionary only in provocative studies with electric nerve stimulation. No subjects were excluded based on only one-time abnormal laboratory result, as one-time laboratory abnormality could be transient or caused by a laboratory error.


Data Analysis

Fisher’s Exact test, χ2, chi-square, and t-tests, were used to compare healthy controls and patient volunteers on dichotomous, polychotomous, and continuous measures, respectively. Means and standard deviations are reported. Significance was evaluated at P<.05, two-tailed.



Anxiety patients were older (34±12 years) than healthy controls (27±8 years; P<.0001) and underwent more comprehensive evaluations. Laboratory assessment was completed in 37% of participants, ie, 89% of anxiety patients versus 30% of healthy controls (P<.0001). A SCID was administered in 66% of participants, ie, 97% of patients and 62% of healthy controls (P<.0001).

A total 110 of 540 subjects (20%) were excluded, 102 (19%) for medical or psychiatric reasons. Exclusion rates were similar for healthy controls and anxiety patients (Table).


The most common reasons for exclusion were psychiatric conditions (6.3%), positive toxicology screen (5.4%), abnormal liver function tests (4.5%), cardiovascular abnormalities (3.9%), positive viral markers including hepatitis C, hepatitis B, and HIV (3.5%), anemia (2.5%), neurologic disorders (1.6%), and electrolyte abnormalities (1.0%) (Table). Excluded subjects were older (mean=30.9, SD=10.3) than subjects accepted to protocols (mean=27.3, SD=8) (P<.001). As expected given differences in study criteria, exclusion rates were significantly higher in medication challenge studies (32%) compared to fMRI (18%) and fear conditioning studies (17%; X=13.57, df=2, P=.001).

Proportions of exclusions found during various methods of in-person evaluation are shown in the Figure. Forty-one subjects were excluded by history or history and SCID, while seven subjects were excluded by SCID only (Figure). Significant proportion of exclusions (59/107 or 55%) was detected by physical exam, laboratory testing, and NIH medical record review, ie, screening methods that rely on information beyond volunteer-provided history. Some examples of significant findings on physical exam include scarring from intentional self injury, very low body mass index (BMI) of 14.5, severe hypertension, tachycardia, conjunctivitis, and loud heart murmur probably indicating valvular heart disease.


The importance of laboratory testing for both healthy controls and patients is illustrated in the following examples. A 42 year-old healthy control had unremarkable H&P and SCID, but tested positive for cocaine and hepatitis C. Two anxiety patients tested positive for amphetamines. It is possible that their anxiety disorder was substance induced.

With the exception of one anxiety patient, all volunteers with positive toxicology screen denied any recent illicit drug use during phone screening, SCID, and H&P. For example, one healthy volunteer who had negative SCID had conjunctivitis on exam. He was drinking water from a large container during the interview. His toxicology screen was positive for tetrahydrocannabinol. Volunteers who tested positive for viral markers were significantly older (41±9 years) than those who were negative (21±9; P=.001).

NIH medical record review resulted in exclusion of seven volunteers whose H&P and SCID were unremarkable. For example, a healthy control who denied history of mental illness during the SCID and H&P had participated 1 year earlier in an NIMH treatment study as a patient with recurrent major depressive disorder. Medical record review of a 50-year-old healthy control who denied any medical problems revealed severe anemia with hemoglobin of 6.8 documented 6 months prior to current evaluation; she had applied for fear-conditioning study that did not require laboratory testing. An anxiety patient denied a history of substance abuse, but medical record review revealed a past history of polysubstance dependence. As this was not exclusionary in the study for which he applied, he underwent laboratory testing that later identified hepatitis C infection.

In eight healthy controls that were excluded for psychiatric reasons, the SCID revealed no Axis I diagnosis. However, observations during the H&P in concert with consultation with the study psychiatrist and principal investigators led to exclusion for psychiatric reasons. For example, exclusion followed the observation during physical exam of extensive scarring due to self injury. In another case, history identified attention deficit/hyperactivity disorder that had been previously diagnosed and treated by a psychiatrist outside the NIMH. None of these psychiatric conditions are routinely assessed by the SCID.

Ten subjects had more than one medical exclusion. For example, one healthy control had severe obesity with a BMI of 60, hypertension, and one-sided blindness. Another had history of meningitis with consequent hearing loss, hypothyroidism, and severe migraine headache treated with tryptan.



The current report is the first that specifically addressed findings on medical evaluation in healthy controls and anxiety patients who volunteer in research on mental illness. Although the study population in this cohort was young and relatively healthy, conditions were detected that could have a profound influence on the safety of participants and validity of research results, including severe hypertension, extreme weight disturbances, electrolyte abnormalities, viral infections, and positive toxicology screen. As in previous investigations,1-5 these results confirm that phone screens fail to identify sizable proportion of subjects who are ineligible for research on mental illness. For example, Shtasel and colleagues1 reported 47% of exclusions for medical and psychiatric illness but did not describe medical exclusions. Consistent with previous reports,1-7 the current cohort also displayed relatively high rates of psychiatric disorders and drug use in healthy controls. As the authors of this article did not include subjects who were excluded by the SCID prior to medical evaluation, the prevalence of psychiatric conditions in this cohort was significantly lower than in previous reports. Methods to improve the yield of eligible volunteers and increase the cost-effectiveness of the screening process have been previously reported2 and are not examined in this study.

Exclusion rates were different in various protocols due to differences in eligibility criteria and the extent of evaluation. For example, more stringent eligibility criteria and more extensive evaluation with laboratory assessment explain higher rejection rates in medication challenge studies.

Study results confirm previous observations that histories are often not reliable in assessment of eligibility of research volunteers, possibly due to financial incentive.6-10 Moreover, denial is common in some psychiatric conditions such as substance abuse and eating disorders.

Despite the fact that only 37% of subjects underwent laboratory testing and toxicology screen, 55% of exclusions in this study were found by physical exam, laboratory testing, or medical record review, ie, procedures relying on methods other than volunteer-provided history.

Study procedures in some research protocols required healthy controls to receive less extensive assessments than patients with anxiety disorders, and thus only 30% of healthy controls underwent laboratory assessment and toxicology screen. Gibbons and colleagues14 suggested the importance of screening healthy participants with a level of care equal to that applied to patients as inadequate screening of controls may adversely impact research results.

While healthy controls usually have no complaints, anxiety patients often present with a variety of physical symptoms. For example, dizziness, weakness, and palpitations may indicate anxiety, anemia, cardiac abnormality, substance abuse, or any combination of these conditions. Therefore, medical evaluation is equally important in patients.

Some findings on medical evaluation may represent complications of psychiatric disorders that had been minimized by volunteers during interview. For example, hypertension, tachycardia, abnormal liver function tests, infection with hepatitis B or C, or HIV may be consequences of substance abuse. One of the healthy controls whose blood pressure was 202/87 denied prior history of hypertension but admitted recent cocaine use after further questioning. Other findings in this cohort may represent manifestation of eating disorders, such as hypo-estrogenic amenorrhea, extremely low BMI, and electrolyte abnormalities. In cases where research volunteers may be motivated to conceal their problems, physical exam, laboratory assessment, and medical record review increase the sensitivity of in-person evaluation. However, some potentially serious preexisting medical conditions such as severe hypertension, valvular heart disease, and viral infections may remain unrecognized without a medical evaluation.

There are some limitations in this study inherent to its retrospective design. The variability in exclusion criteria and extent and order of in-person evaluation makes it somewhat difficult to interpret the results.

As some potential medical exclusions were not pre-specified, the research team reached decisions concerning eligibility on a case-by-case basis using all available information including subject’s age, other risk factors, and study procedures and invasiveness. However, it is impossible to pre-specify all potential exclusions. Moreover, there is insufficient knowledge and no consensus regarding many conditions and medications that may impact some forms of psychiatric research. Unlike psychiatric eligibility criteria, medical eligibility criteria and extent of medical evaluation are rarely discussed in psychiatric literature and deserve further study.



Medical screening identified a relatively high rate of conditions in both healthy controls and patients that potentially impacts mental health research. Perhaps most importantly, these findings demonstrate the complementary nature of medical and psychiatric evaluations and underscore the need to develop further standards in medical screening procedures for volunteers in psychiatric research. PP



1.    Shtasel DL, Gur RE, Mozley PD, et al. Volunteers for biomedical research. Recruitment and screening of normal controls. Arch Gen Psychiatry. 1991;48(11):1022-1025.
2.    Schechter D, Lebovitch R. Normal controls are expensive to find: methods to improve cost-effectiveness of the screening evaluation. Psych Res. 2005;136(1):69-78.
3.    Huang DB, Koo H, Dougherty D, Hassan Y. Psychopathology among persons responding to participation as normal controls in behavioral research. Compr Psychiatry. 2003;44(2):83-87.
4.    Halbreich U, Bakhai Y, Bacon KB, et al. The normalcy of self –proclaimed “normal volunteers.” Am J Psychiatry. 1989;146(8):1052-1055.
5.    Bunce SC, Noblett KL, McCloskey MS, Coccaro EF. High prevalence of personality disorders among healthy volunteers for research: implications for control group bias. J Psych Res. 2005;39(4):421-430.
6.    Struve FA, Straumanis JJ, Manno JE, Fitzgerald MJ, Patrick G, Leavitt J. Inadequacies of self-report data for exclusion criteria detection in marihuana research: an empirical case for multi-method direct examination screening. J Addict Dis. 2000;19(3):71-87.
7.    Swerdlow NR, Geyer MA, Perry W, Cadenhead K, Braff DL. Drug screening in “normal” controls. Biol Psychiatry. 1995;38(2):123-124.
8.    Apseloff G, Swayne JK, Gerber N. Medical histories may be unreliable in screening volunteers for clinical trials. Clin Pharmacol Ther. 1996;60(3):353-356.
9.    Watson N, Wyld PJ. The importance of general practitioner information in selection of volunteers for clinical trials. Br J Clin Pharmacol. 1992;33(2):197-119.
10.    Kolata GB. NIH shaken by death of research volunteer. Science. 1980;209(4455):475-476,478-479.
11.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
12.    First MB, Spitzer RL, Gibbon M, Williams JB. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Non-Patient Edition. (SCID-I/NP). New York, NY: Biometrics Research, New York State Psychiatric Institute; 2002.
13.    First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition with Psychotic Screen (SCID-I/P W/PSY SCREEN). New York, NY: Biometrics Research, New York State Psychiatric Institute; 2002.
14.    Gibbons RD, Davis JM, Hedeker DR. A comment on the selection of “healthy controls” for psychiatric experiments. Arch Gen Psychiatry. 1990;47(8):785-786.


Dr. Randall is postdoctoral fellow in the Sleep Disorders and Research Center at the Henry Ford Hospital in Detroit, MI. Dr. Roehrs is director of research at the Sleep Disorders and Research Center at the Henry Ford Hospital and professor of psychiatry in the Department of Psychiatry and Behavioral Neuroscience at Wayne State University School of Medicine in Detroit. Dr. Roth is director of the Sleep Disorders and Research Center at the Henry Ford Hospital and professor of psychiatry in the Department of Psychiatry and Behavioral Neuroscience at Wayne State University School of Medicine.

Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.
Please direct all correspondence to: Surilla Randall, PhD, Henry Ford Hospital Sleep and Research Center, CFP-3, 2799 West Grand Blvd, Detroit, MI 48202; Tel: 313-916-5301: Fax: 313-916-2508; E-mail: srandal1@hfhs.org.




Insomnia is defined as difficulty initiating or maintaining sleep and/or nonrestorative sleep which impairs daytime function. Self treatment with over-the-counter (OTC) sleep aids, herbal and dietary supplements, and/or alcohol is common. Problems associated with insomnia self treatment are ineffectiveness, tolerance, dependency, and potentially harmful side effects. Studies of OTC sleep aids and other non-prescription sleep aids such as antihistamines, valerian, melatonin, and L-tryptophan have inconsistent results and lack objective data on both their efficacy and safety. Lastly, alcohol should never be used as a sleep aid due to its abuse liability.



The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision,1 defines primary insomnia as difficulty initiating or maintaining sleep and/or poor quality (nonrestorative) sleep for at least 1 month, which has some daytime consequences. The duration of insomnia can be transient (days to several weeks) or chronic (≥1 month). Insomnia is associated with impairments in social, occupational, and other areas of functioning. Sleep disturbances can have a significant negative impact on daytime function, evident by mental slowing, reduced concentration, memory lapses, and decreased motivation. Insomnia can be associated with medical conditions, medication use, psychiatric disorders, substance abuse, or other primary sleep disorders (eg, sleep apnea, restless leg syndrome). However, primary insomnia is a disorder independent of these other conditions.

Epidemiologic studies report varying estimates of insomnia prevalence. The estimates are dependent upon whether the data come from patient care settings; female, elderly, or general populations; or the study’s definition of insomnia.2 Taking into consideration the various adult insomniac populations, prevalence estimates range from approximately 10% to 50%. When including only chronic insomnia the prevalence range decreases from 10% to 15%.3-6

Insomnia predisposes one to psychiatric disorders, aggravates medical conditions, decreases the quality of life, and increases the risk of drug and alcohol abuse.7 Greater than 50% of those with depression, psychosomatic disorders, anxiety disorders, neuroses, dementia, and schizophrenia have insomnia complaints.8 In some cases, treating the underlying mental disease may not improve the insomnia.

Self treatment with over-the-counter (OTC) sleep aids, herbal and dietary supplements, and/or alcohol is common among insomniacs. It is thought that the availability of these products, decreased cost compared to prescription sleep aids, and importantly, perceived safety results in the great usage of OTC sleep aids.9-11 A metropolitan Detroit study10 showed that 25.9% of respondents reported using some substance to aid their sleep. Of those who used medications (either prescription, OTC sleep aids, or both) to improve sleep, 57% reported using OTC sleep aids. In a recent study,12 approximately 25% of patients with insomnia used OTC sleep aids, and 5% used these drugs several times a week. A study of insomniac women ≥85 years of age noted that the respondents reported they did not see a physician or nurse practitioner for insomnia until the self treatment (with alcohol, OTC sleep aids, or both) was no longer effective.13 The problems associated with insomnia self treatment are use at higher than recommended doses, tolerance resulting from loss of efficacy, and the development of dependency in at-risk populations. There are even greater concerns with alcohol used as a sleep aid. Ineffective and potentially harmful self treatment is not fully appreciated as a risk of not treating insomnia medically with drugs exhibiting efficacy and safety profiles. This article provides an overview of what is known regarding the efficacy and safety of popular nonprescription products used for insomnia.



Antihistamines consist of a broad class of pharmacologic agents that include the first-generation, central acting histamine (H)1 receptor antagonists. The primary action of this drug class is to block the effects of histamine, which reduces congestion, sneezing, coughing, and allergy symptoms. Centrally, these drugs block histamine receptors, histamine being one of the major alerting central neurotransmitters. Due to the sedative action of antihistamines, they are widely used as non-prescription sleep aids. Evidence appears to suggest that antihistamines may be useful for insomnia for 1–2 nights, but not efficacious in treating chronic insomnia.



In 1982, the Food and Drug Administration authorized the initial marketing of diphenhydramine HCl and diphenhydramine citrate as active ingredients in non-prescription sleep aids. Other general medical uses include relief of allergies, motion sickness, and coughing. Table 1 lists the various OTC products and their doses. For sleep, the available dose range of diphenhydramine is 25–50 mg, with 50 mg being the maximum dose to be taken 30–60 minutes before bed.14,15 While marketed for allergy relief, Benadryl, which contains 12.5 or 25 mg of diphenhydramine depending on the formulation, is commonly used for sleep. Diphenhydramine citrate is often combined with an analgesic; together they are advertised to provide pain relief and induce sleep (Table 1).

Diphenhydramine has a half-life of 5–12 hours and has significant anticholinergic activity. Consequently, its use is associated with next-day mild-to-moderate side effects, namely residual morning sedation, dry mouth, grogginess, and malaise.15,16 Importantly, it has not been determined which aspects of its pharmacologic activity are mediated by H1 receptors and which are mediated by cholinergic receptors. Despite the reported side effects of diphenhydramine, virtually all OTC sleep aids contain diphenhydramine as the active ingredient (Table 1).



The use of diphenhydramine is common, but the number of controlled trials that support its efficacy are limited and many lack objective data. Several studies show evidence of sedative properties. One-week administration of diphenhydramine (50 mg) significantly decreased self-reported sleep latency and improved sleep depth and quality.16 Similar results were reported in psychiatric patients with insomnia following nightly administration of 12.5–50 mg of diphenhydramine for 2 weeks. Sleep quality, duration of sleep, and severity of insomnia symptoms significantly improved as measured by self reports.15 Interestingly, global improvements in sleep were significantly greater in those who had not received previous treatment for insomnia.15 This finding suggests drug tolerance, cross-drug tolerance, or that the efficacy of diphenhydramine is not as robust as other pharmamocologic treatments. Tolerance to the hypnotic effects of diphenhydramine was evident on both objective and subjective measures of sleepiness following 3–4 days of administration.17 Thus, only short-term use is recommended since physical tolerance, can develop.17,18

For several reasons, it is advised that those with chronic medical conditions should not take diphehydramine, and specific precautions should be considered in those with cardiovascular disease, hypertension, or lower respiratory disease. Diphenhydramine produces additive central nervous system effects when taken concomitantly with alcohol, hypnotics, anxiolytics, narcotic analgesics, and neuroleptic drugs. Similarly, significant interactions may occur if the drug is taken concomitantly with anticholinergic agents or tricyclic antidepressants.



In 1978, the FDA approved doxylamine succinate as an active ingredient for OTC sleep aid use. Doxylamine succinate mediates its activity through the H1 receptor. Doxylamine has minimal effects on sleep onset due to its relatively long time to maximum plasma concentration. The time for sleep to be achieved is 45–60 minutes after oral administration. The peak plasma concentration is not reached until 90 minutes after administration. Using patient report outcomes, doxylamine (25 mg) for 1 week significantly decreased sleep latency.19 The authors of this article are unaware of any further published OTC efficacy studies for doxylamine. The elimination half-life is 10.1 hours. Thus, upon waking, plasma levels of doxylamine are present; consequently, residual daytime sedation is a documented side effect. Doxylamine is also potentially dangerous in accidental or intentional overdose. Rhabdomyolysis and secondary acute renal failure are rare but potentially serious complications, making early recognition and treatment essential.20 H1 antihistamines are not recommended for the elderly due to potential adverse effects and drug interactions. Doxylamine shares the same mechanism of action as diphenhydramine and the potential for tolerance to doxylamine’s sedative effects exists.


Supplements and Herbs

In the United States, usage of complementary and alternative medicines showed a secular upward trend from 33.8% to 42.1% for treatment of any health condition between 1990 and 1997. In comparison, treatment for insomnia rose from 20.4% in 1990 to 26.4% in 1997.21 Supplements and herbs are perceived as “natural” and, therefore, a safe alternative to prescription medications and some OTC products. The FDA does not rigorously test or regulate manufacturing of supplements and herbs. Currently, no FDA regulations specific to dietary supplements require a minimum standard for manufacturing of dietary supplements. Thus, the manufacturer is responsible for the strength, purity, composition, and safety of their products. According to FDA regulations, supplement manufacturers are forbidden to market their product as a treatment, prevention, or cure, for any medical disorder, including insomnia.

Supplements and herbs have reported side effects and inconsistent clinical findings, so the risk to benefit is questionable. Care should be used when taking these substances because they still cause physiologic changes in the body and can interact with other medications (Table 2).





Valerian is a flowering plant that includes >200 species. The species Valeriana officinalis is most often used in the treatment of anxiety and insomnia. Valerian preparation methods vary with several different extraction methods used. The aqueous extraction method produces doses range from 270–900 mg and ethanolic valerian extraction doses range from 300–600 mg.22 Other valerian species (V. edulis and V. wallichii) have active ingredients that are minimally present in V. officinalis. The chemical ingredients in valerian products vary depending on the plant species and the extraction method. Valerian roots are prepared as teas and dried plant material and extracts are compounded into capsules or incorporated into tablets. A possible mechanism in which valerian causes sedation is by inhibition of the breakdown of γ-aminobutyric acid (GABA) or GABA-like metabolites.23

The sleep research evaluating the efficacy of valerian as a sleep aid has produced inconsistent results. Variations in study participants, study design, and methodology; valerian preparation; dose; and sleep assessment measures likely account for the mixed results for valerian.

Valerian 400 mg administered on three nonconsecutive nights produced a significant decrease in self-reported sleep latency, which was notable in people >40, men, and those who considered themselves poor or irregular sleepers. Poor or irregular sleepers and those who considered themselves as having long sleep latencies also reported significant improvements in sleep quality.24 Significant decreases in self-reported sleep latencies were also found in healthy subjects without major sleep disturbances following one valerian dose of either 450 or 900 mg. Only the 900 mg dose reduced wake time after sleep onset using self reports. The self ratings of sleep quality were not significantly different among treatments (0, 450, and 900 mg).

In an uncontrolled case study, insomniacs receiving mental health services took valerian for 14 days to supplement their psychotropic regimen. Doses of valerian started at 470 mg (one pill) on nights 1–3 and the insomniacs could increase their dose to a maximum of 1,410 mg (three pills) after week 1. Dose escalation occurred if lower doses proved to be insufficient. After 1 week of treatment, 11 of the 20 participants reported that valerian “moderately” improved their insomnia at the 940 mg dose (two pills). By week 2, all increased their dose to 1,410 mg, nine rated their insomnia “moderately to extremely” improved, and six rated their insomnia “extremely” improved.25 There was no discussion as to what aspect of their sleep disturbances was improved.

Chronic insomniacs were given valarian 450 mg for 1 week and were required to maintain sleep diaries. Valerian was not shown to be appreciably better than placebo adminstration in a series of randomized n-of-1 trials.26 Similarly, valerian (6.4 mg) for 28 days did not relieve insomnia or anxiety to a greater extent than placebo in an Internet-based study. Adverse events occurred with similar frequency between the treatment group and the placebo group except that significantly more reports of diarrhea (18% of 114) occurred in the valerian group compared to those receiving placebo (8%).27

Polysomnography (PSG), the concurrent recording of electroencephalograph (EEG), electromyogram, and electrooculogram, is the standard method of objectively assessing sleep. It is often combined with computer analyses of EEG frequency and power (ie, spectral analyses). PSGs and spectra analyses of sleep EEG showed no significant differences between a 900 mg valerian dose and placebo administration in healthy volunteers. No adverse events or side effects were reported.28 Results of objective assessments of sleep latency have varied. Actigraphy, recording movements of arms or legs, is a less labor-intensive and intrusive method of assessing sleep than PSG. Actigraphs, worn by eight mild insomniacs, showed decreases in sleep latencies following valerian 450 mg for 4 nonconsecutive nights. In contrast, 900 mg did not produce a further improvement in sleep latencies and the higher dose had significantly greater morning sleepiness associated with it.29 In a PSG study, no significant decrease in sleep latency was demonstrated following 8 consecutive days of valerian (405 mg on day 1 and 1,215 mg on days 2–8) in 14 elderly female insomniacs. On other sleep measures, this dosing produced selective effects on non-rapid eye movement (REM) sleep stages. Non-REM is characterized by slower brain activity, divided into sleep stages 1–4, and is not associated with dreaming. Relative to baseline, valerian decreased the percentage of stage 1 sleep on night 1 and further decreased it on night 8. No systematic change occurred in the placebo group. Slow wave sleep (SWS; sum of sleep stages 3 and 4) significantly increased from baseline to night 8. REM sleep (sleep stage characterized by active brain waves and dreams) was unaltered by valerian.30

Sixteen insomniacs given valerian 600 mg for 14 days showed significant decreases in SWS latency in comparison to placebo, and a significant increase in the percentage of SWS compared to baseline as measured by PSG. Other sleep parameters were not significantly altered. Only three independent side effects or adverse effects occurred following valerian administration, which included one episode of gastrointestinal complaints, migraine, and an accident associated with the PSG procedures. Subjective measures of sleep and other sleep parameters were not significantly altered.31 Overall, these double-blind data suggest that although valerian is safe it does not improve the symptoms of disturbed sleep.22 It would be interesting to pursue the question of the increase in slow-wave sleep, its clinical significance, and the degree to which this is mediated by GABA.

Valerian is frequently combined with other herbal extracts such as hops and lemon balm, each purportedly having their own sedative or tranquilizing effects. A valerian preparation (valerian 400 mg, hops 375 mg, and lemon balm 160 mg) was rated better than control following one night of administration. No side effects were reported with this preparation.32 In contrast, for 3 nonconsecutive nights a commercial preparation of valerian 120 mg and hops 60 mg produced no significant change in sleep latency or sleep quality on subjectively rated sleep measures in healthy normal volunteers. This valerian preparation resulted in significantly greater reports of “more sleepy than usual” responses in comparison to the placebo group.33 Similar results were reported in mild insomniacs administered a valerian (374 mg)-hops (83.8 mg) combination for 28 days. This dosing and duration failed to produce a significant effect in sleep parameters using sleep diaries and PSG.


St. John’s Wort

St. John’s wort (hypericum perforatum) is the medicinal herb used for a variety of ailments including depression, anxiety, and fatigue. The active components are thought to be hyperforin and hypericin, although different formulations vary in their level of constituents.34 Most clinical studies focus on the treatment of depression rather than insomnia. No published double-blind placebo controlled studies were found using St. John’s wort to ameliorate primary insomnia.



Kava (or kava kava) comes from the roots of the Polynesian plant Piper methysticum is indigenous to the South Pacific. Supplements containing kava are marketed to alleviate menopausal symptoms, anxiety, and insomnia. Liver damage may be a risk factor associated with kava, and the FDA issued an advisory to consumers of this important potential risk. A meta-analysis of kava in the treatment of anxiety reported adverse events such as stomach complaints, restlessness, tremor, headache and tiredness (Table 2).35

Stress-induced insomnia was ameliorated after 6 weeks of 120 mg of kava and further improved by 6 weeks of valerian (600 mg) as measured by sleep questionnaires. There was a 2-week wash-out period between both treatments and, importantly, sleep during the washout did not differ from baseline. Side effects of kava included, diarrhea, gastric disturbances, and dry mouth.36

A frequent symptom associated with anxiety disorder is sleep disturbances. Kava 300 mg for 28 days did not significantly relieve anxiety or insomnia symptoms using the Insomnia Severity Index and State-Trait Anxiety Inventory, respectively.27 In contrast, significant improvements relative to placebo in sleep quality and the recuperative effects of sleep as well as decreases in anxiety were demonstrated in patients with sleep disturbances associated with anxiety of non-psychotic origin following kava 200 mg (WS®1490) for 4 weeks.37 Sleep questionnaires such as the Hamilton Rating Scale for Anxiety, self-rating scales of well being, and the Clinical Global Impressions scale showed improvements in sleep and anxiety. No drug-related adverse events or changes in clinical or laboratory parameters were noted.

As is the case in many of these products, there are some non-controlled data suggesting efficacy. However, objective and/or other placebo controlled trials that further suggest efficacy for insomnia are limited. Further, the benefit has to balanced against the risk, and the potential of liver toxicity in the case of kava cannot be dismissed.


Neurohormones and Transmitter Precursors


The pineal gland produces the neurohormone melatonin (N-acetyl-5-methoxytryptamine). Synthesis and secretion occurs nocturnally by darkness and is inhibited by environmental light, which suggests that melatonin is involved in modulating circadian rhythm. Melatonin secretion starts at approximately 9:00pm and peaks between 2AM and 4AM.38 Melatonin supplements are commonly used to combat jet lag and sleep disturbances, to protect cells from free-radical damage, and for enhancement of immune function. The mechanism by which melatonin affects sleep, beyond its circadian signaling capability (phase shifting), is unknown, but it likely involves stimulation of melatonin receptors.8

The half-life of melatonin ranges from 0.54–2 hours; with doses ranging from 0.3–5.0 mg, melatonin is less likely to cause residual daytime drowsiness. Side effects reported in the literature included headache, odd taste in mouth, and poor sleep quality (Table 2).39 Melatonin supplements are relatively safe when used short term over days or weeks. However, the safety of melatonin over months has not been studied.

Riemann and colleagues40 showed significant decreases in nighttime melatonin concentrations in insomniacs, and others have shown delays in melatonin secretion. However, several double-blind, placebo-controlled studies have failed to show the effectiveness of supplemental melatonin in treating primary insomnia. Melatonin in doses that range from 0.3–5 mg showed no significant differences over placebo in sleep measures such as sleep efficiency; total sleep time; latency to sleep; number of nocturnal awakenings; average length of the non-REM-REM cycle; percent of stage 1, 2, delta sleep, and REM sleep; total minutes of each sleep stage; and in the latency to REM sleep. The lack of hypnotic activity was evident when measured by self reports or by PSG measures.39-43 MacFarlane and colleagues44 found a significant improvement in subjective assessments of sleep and daytime alertness in insomniacs given a much larger dose, 75 mg, in a single, crossover placebo-controlled study. It is important to recognize that this dose is dramatically higher than the physiologic doses of melatonin (0.5–1 mg) and hence the safety of this dose requires study.

Melatonin appears to ameliorate secondary and age-related insomnia. Increased sleep efficiency was noted in both populations after administration of melatonin.43 Improved sleep efficiency occurred in an elderly population with doses of 0.1–3.0 mg which elevated plasma levels within normal range.45,46 Overall, the present data would suggest that melatonin is not an effective treatment for the management of primary insomnia. However, it has clear phase shifting properties and hence it may have efficacy in elderly insomniacs with decreases in endogenous melatonin and insomnia associated with sleep circadian rhythm disorder.



L-tryptophan is an essential amino acid that comes from food. Once absorbed, it can be converted to serotonin and melatonin. In the brain, serotonin is synthesized from tryptophan, which is the major metabolic route.47 Low levels of serotonin have been reported to be associated with depression, anxiety, and insomnia, and L-tryptophan supplements have been used to treat these disorders despite the absence of convincing data of its benefit.

The tryptophan-depletion model has been used to determine the association between tryptophan and sleep. Tryptophan depletion, following an ingestion of a tryptophan-free amino acid drink, significantly increased stage 1 sleep and decreased stage 2 sleep. However, indices of sleep induction and sleep efficiency were not affected. Indices of REM density (the frequency of eye movements per unit of time during REM sleep) were significantly increased, whereas REM latency remained unaltered.40

L-tryptophan supplements appeared to be effective hypnotic agents in chronic insomniacs with sleep maintenance disturbances that were characterized by 3–6 discrete awakenings during the night. Insomniacs self-reported 100% improvement following 1 g nightly administration for 1 week.48 No consistent significant effects of L-tryptophan on sleep parameters determined by PSG were found in doses <1 g. Significant decreases in sleep latencies were observed following 1–3 g of tryptophan but inconsistent findings were noted on total sleep time, SWS, and REM sleep.49

In a study by Schneider-Helmert and Spinweber,50 chronic insomniacs characterized by both sleep onset and sleep maintenance problems showed therapeutic improvement occurring over time with repeated administration of low doses of L-tryptophan. The hypnotic effects appeared late in the treatment period or, as shown in some studies, even after discontinuation of treatment. L-tryptophan is also effective in reducing sleep onset time on the first night of administration in doses ranging from 1–15 g in young situational insomniacs.50

The treatment of depression with the selective serotonin reuptake inhibitor fluoxetine can exacerbate insomnia. The hypnotic effects of tryptophan in conjunction with an antidepressant were used to potentiate an improvement in insomnia. Tryptophan (2–4 g) and fluoxetine (20 mg) administrated for 8 weeks significantly decreased depression scores and had a SWS protective effect. A significant decrease in SWS was noted in the fluoxetine placebo group but not in the fluoxetine-tryptophan group.51

L-tryptophan administration has not been linked with impairments in visuomotor, cognitive, or memory performance.50 Some side effects of tryptophan can include drowsiness, tiredness/fatigue, nausea, loss of appetite, dizziness, headache, and dry mouth (Table 2).



In 2001, approximately 30% of chronic insomniacs in the general population reported using alcohol to induce sleep and 67% of those reported that alcohol was effective.52 However, in PSG studies insomniacs who used alcohol had significantly impaired measures of sleep continuity and had more severe alcohol dependence and depression.53 Males and those never married or those separated or divorced/widowed are approximately 1.5 times more likely to use alcohol as a sleep aid than females or those who are married.10

Alcohol consumed at bedtime may decrease the time required to fall asleep and increase SWS. Because of alcohol’s sedating effect, many people with insomnia consume alcohol to promote sleep. However, alcohol consumed within an hour of bedtime appears to disrupt the second half of the sleep period.54,55 Alcohol affects the proportions of the various sleep stages with dose-dependent suppression of REM sleep. Higher doses of alcohol increased nocturnal awakenings and/or lighter stages of sleep (stage 1) during the second half of the night. The second-half disruption of sleep continuity is referred to as a “rebound effect,” occurring as alcohol is metabolized or eliminated from the body.54

Overall, the use of alcohol as well as the discontinuation of alcohol is associated with disturbances of sleep. This is most clearly seen in alcoholics who exhibit profoundly disturbed sleep during active drinking and after months of abstinence. Finally, the relation of alcohol consumption to improve sleep to the evolution of chronic alcoholism warrants study.



Much of the data on the efficacy and safety of OTC sleep aids is inconclusive and is associated with problems such as too few participants in the studies, little demographic and diagnostic information regarding study participants, inconsistency in demographic and diagnostic information among studies to allow comparisons, lack of placebo-control groups, subjective reports with a lack of objective data, and short-term treatment with study medication which provides little indication about long-term usage.56

Treatment of insomnia with antihistamine-containing OTC sleep aids may help occasional mild insomnia. Prolonged use of some if not all antihistaminic drugs may result in tolerance and/or dependence and produce daytime sleepiness. The data on other non-prescription sleep aids is too limited or inconsistent in results to consider their use. While alcohol may have initial sedative effects, it is associated with rapid tolerance development and dose escalation (Table 2). PP



1.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
2.    Walsh JK. Clinical and socioecononomic correlates of insomnia. J Clin Psychiatry. 2004;65(suppl 8):13-19.
3.    Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev. 2002;6(2):97-111.
4.     Roth T, Roehrs T. Insomnia: epidemiology, characteristics, and consequences. Clin Cornerstone. 2003;5(3):5-15.
5.    Morin CM, LeBlanc M, Daley M, Gregoire JP, Mérette C. Epidemiology of insomnia: prevalence, self-help treatments, consultations, and determinants of help-seeking behaviors. Sleep Med. 2006;7(2):123-130.
6.     Sproule BA, Busto UE, Buckle C, Herrmann N, Bowles S. The use of non-prescription sleep products in the elderly. Int J Geriatr Psychiatry. 1999;14(10):851-857.
7.     Roehrs, T, Roth, T. Safety of insomnia pharmacotherapy. In: Roth, T, ed. Sleep Medicine Clinics. Philadelphia, PA: W.B. Saunders Company; 2006:399-407.
8.    Roth T. The relationship between psychiatric diseases and insomnia. Int J Clin Pract Suppl. 2001;(116):3-8.
9.     Morin AK, Jarvis CL, Lynch AM. Therapeutic options for sleep-maintenance and sleep-onset insomnia. Pharmacotherapy. 2007;27(1):89-148.
10.     Johnson EO, Roehrs T, Roth, T, Breslau N. Epidemiology of alcohol and medication as aids to sleep in early adulthood. Sleep. 1998:21(2):178-186.
11. Morin CM, LeBlanc M, Daley M, Gregoire JP, Mérette C. Epidemiology of insomnia: prevalence, self-help treatments, consultations, and determinants of help-seeking behaviors. Sleep Med. 2006;7(2):123-130.
12. Ramakrishnan K, Scheid DC. Treatment options for insomnia. Am Fam Physician. 2007;76(4):517-526.
13. Johnson JE. Insomnia, alcohol, and over-the-counter drug use in old-old urban women. J Community Health Nurs. 1997;14(3):181-188.
14.    Bender BG, Berning S, Dudden R, Milgrom H, Tran ZV. Sedation and performance impairment of diphenhydramine and second generation antihistamine: a meta analysis. J Allergy Clin Immunol. 2003;111(4):770-776.
15. Kudo Y, Kurihara M. Clinical evaluation of diphenhydramine hydrochloride for the treatment of insomnia in psychiatric patients: a double blind study. J Clin Pharmacol. 1990;30:1041-1048.
16. Rickels K, Morris RJ, Newman H, Rosenfeld H, Schiller H, Weinstock R. Diphenhydramine in insomniac family practice patients: A double blind study. J Clin Pharmacol. 1983;23(5-6):234-242.
17. Richardson GS, Roehrs TA, Rosenthal L, Koshorek G, Roth T. Tolerance to daytime sedative effects of H1 antihistamines. J Clin Psychopharmacol. 2002;22(5):511-515.
18. Mumford GK, Silverman K, Griffiths RR. Reinforcing, subjective and performance effects of lorazepam and diphenhydramine in humans. Exp Clin Psychopharmacol. 1996;4(4): 421-430.
19. Rickel K, Ginsberg DO, Morris RJ, et al. Doxylamine succinate in insomniac family practice patients: a double-blind study. Curr Ther Res. 1984;35(4):532-540.
20. Leybishkis B, Fasseas P, Ryan KF. Doxylamine overdose as a potential cause of rhabdomyolysis. Am J Med Sci. 2001;322(1):48-49.
21. Bliwise DL, Ansari FP. Insomnia associated with valerian and melatonin usage in the 2002 National Health Interview Survey. Sleep. 2007;30(7):881-884.
22. Taibi DM, Landis CA, Petry H, Vitiello MV. A systematic review of valerian as a sleep aid: safe but not effective. Sleep Med Rev. 2007;11(3):209-230.
23. Ringdahl EN, Pereira SL, Delzell JE. Treatment of primary insomnia. J Am Board Fam Pract. 2004;17(3):212-219.
24.    Leathwood PD, Chauffard F, Heck E, Munoz-Box R. Aqueous extract of valerian root (Valeriana officinalis L.) improves sleep quality in man. Pharmacol Biochem Behav. 1982;17(1):65-71.
25.    Dominguez RA, Bravo-Valverde RL, Kaplowitz BR, Cott JM. Valerian as a hypnotic for Hispanic patients. Cultur Divers Ethnic Minor Psychol. 2000;6(1):84-92.
26.    Coxeter PD, Schluter PJ, Eastwood HL, Nikles CJ, Glasziou PP. Valerian does not appear to reduce symptoms for patients with chronic insomnia in general practice using a series of randomised n-of-1 trials. Complement Ther Med. 2003;11(4):215-222.
27. Jacobs BP, Bent S, Tice JA, Blackwell T, Cummings SR. An internet-based randomized, placebo-controlled trial of kava and valerian for anxiety and insomnia. Medicine (Baltimore). 2005;84(4):197-207.
28.    Balderer G, Borbely AA. Effect of valerian on human sleep. Psychopharmacology (Berl). 1985;87(4):406-409.
29.    Leathwood PD, Chauffard F. Aqueous extract of valerian reduces latency to fall asleep in man. Planta Med. 1985;51(2):144-148.
30.    Schulz H, Stolz C, Muller J. The effects of valerian extract on sleep polygraphy in poor sleepers: a pilot study. Pharmacopsychiatry. 1994;27(4):147-151.
31. Donath F, Quispe S, Diefenbach K, Maurer A, Fietze I, Roots I. Clinical evaluation of the effects of valerian extract on sleep structure and sleep quality. Pharmacopsychiatry. 2000;33(2):47-53.
32.    Lindahl O, Lindwall L. Double blind study of a valerian preparation. Pharmacol Biochem Behav. 1989; 32(4):1065-1066.
33.    Leathwood PD, Chauffard F, Heck E, Munoz-Box R. Aqueous extract of valerian root (Valeriana officinalis L.) improves sleep quality in man. Pharmacol Biochem Behav. 1982;17(1):65-71.
34.    Meoli AL, Rosen C, Kristo D, et al. Oral nonprescription treatment for insomnia: an evaluation of products with limited evidence. J Clin Sleep Med. 2005;1(2):173-187.
35.    Pittler MH, Ernst E. Efficacy of kava extract for treating anxiety: systematic review and meta-analysis. J Clin Psychopharmacol. 2000;20(1):84-89.
36.    Wheatley D. Stress-induced insomnia treated with kava and valerian: singly and in combination. Hum Psychopharmacol. 2001;16(4):353-356.
37. Lehrl S. Clinical efficacy of kava extract WS 1490 in sleep disturbances associated with anxiety disorders. Results of a multicenter, randomized, placebo-controlled, double-blind clinical trial. J Affect Disord. 2004;78(2):101-110.
38. Chung, KF Melatonin use in sleep disorders HK Pract. 1997;19(12):669-672.
39.    Ellis CM, Lemmens G, Parkes JD. Melatonin and insomnia. J Sleep Res. 1996;5(1):61-65.
40. Riemann D, Klein T, Rodenbeck A, et al. Nocturnal cortisol and melatonin secretion in primary insomnia. Psychiatry Res. 2002;113(1-2):17-27.
41.    Almeida Montes LG, Ontiveros Uribe MP, Cortés Sotres J, Heinze Martin G. Treatment of primary insomnia with melatonin: a double-blind, placebo-controlled, crossover study. J Psychiatry Neurosci. 2003;28(3):191-196.
42.    James SP, Mendelson WB, Sack DA, Rosenthal, Wehr TA. The effect of melatonin on normal sleep. Neuropsychopharmacology. 1987;1(1):41-44.
43. Buscemi N, Vandermeer B, Pandya R, et al. Melatonin for treatment of sleep disorders. Agency for Healthcare Research and Quality. Agency for Healthcare Research and Quality. Available at: www.ahrq.gov/clinic/epcsums/melatsum.htm. Accessed March 19, 2008.
44. MacFarlane JG, Cleghorn JM, Brown GM, Streiner DL. The effects of exogenous melatonin on the total sleep time and daytime alertness of chronic insomniacs: a preliminary study. Biol Psychiatry. 1991;30(4):371-376.
45. Garfinkel D, Laudon M, Nof D, Zisapel N. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet. 1995;346(8974):541-544.
46. Zhdanova IV, Wurtman RJ, Regan MM, Taylor JA, Shi JP, Leclair OU. Melatonin treatment for age-related insomnia. J Clin Endocrinol Metab. 2001;86(10):4727-4730.
47. Mendelson WB. Circadian rhythms and sleep. In: Mendelson WB. Human Sleep Research and Clinical Care. Stony Brook, NY: Plenum Medical Book Company; 1987:295-313.
48. Lindsley JG, Hartmann EL, Mitchell W. Selectivity in response to L-tryptophan among insomniac subjects: a preliminary report. Sleep. 1983;6(3):247-256.
49. Hajak G, Rodenbeck A, Ruther, E. Sleep-Inducing effects of l-tryptophan. In: Kochen W, Steinhart H, eds. L-tryptophan Current Prospects in Medicine and Drug Safety. New York, NY: Walter de Gruyter & Company; 1994: 63-83.
50.    Schneider-Helmert D, Spinweber CL. Evaluation of L-tryptophan for treatment of insomnia: a review. Psychopharmacology (Berl). 1986;89(1):1-7.
51. Levitan RD, Shen JH, Jindal R, Driver HS, Kennedy SH, Shapiro CM. Preliminary randomized double-blind placebo-controlled trial of tryptophan combined with fluoxetine to treat major depressive disorder: antidepressant and hypnotic effects. J Psychiatry Neurosci. 2000;25(4):337-346.
52.    Ancoli-Isael, S., Roth, T. Characteristics of insomnia in the United States: results of the 1991 National Sleep Foundation Survey. I. Sleep. 1999;22(suppl 2):347-353.
53. Brower KJ, Aldrich MS, Robinson EA, Zucker RA, Greden JF. Insomnia, self-medication, and relapse to alcoholism. Am J Psychiatry. 2001;158(3):399-404.
54. Roehrs T, Roth T. Sleep, sleepiness, and alcohol use. Alcohol Res Health. 2001;25(2):101-109.
55. Roehrs T, Papineau K, Rosenthal L, Roth T. Ethanol as a hypnotic in insomniacs: self administration and effects on sleep and mood. Neuropsychopharmacology. 1999;20(3):279-286.
56.    American Academy of Sleep Medicine. Clinical Practice Review Committee. Do drugstores have the cure for your insomnia? Taking a closer look at common treatments. Available at: www.sleepeducation.com/Article.aspx?id=2. Accessed March 19, 2008.


FDA Approves Desvenlafaxine Succinate for Treatment of Major Depressive Disorder

The United States Food and Drug Administration approved desvenlafaxine succinate (Pristiq, Wyeth Pharmaceuticals), a serotonin norepinephrine reuptake inhibitor, to treat adult patients with major depressive disorder (MDD). The recommended dosage for an adult with MDD is 50 mg/day. This dosage does not require titration, which allows patients to start immediately at the recommended dosage.

The efficacy of desvenlafaxine was established through four, 8-week randomized, double-blind, placebo-controlled, fixed-dose studies of adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for MDD. Approval was based on several post-marketing commitments, including conducting and submitting data from several studies—a new long-term maintenance relapse-prevention study; a sexual dysfunction study; a lower dosage study; pediatric studies and a non-clinical toxicity study.

The discontinuation rate due to adverse events for desvenlafaxine (4.1%) was similar to the rate for placebo (3.8%). The most common adverse events observed in MDD patients in fixed-dose, short-term studies were nausea, dizziness, insomnia, hyperhidrosis, constipation, somnolence, decreased appetite, anxiety, and specific male sexual function disorders.

For more information, please consult the medication’s full prescribing information (www.pristiq.com). –JC


Symptom Severity of Generalized Social Phobia Not Likely to Determine Success of Cognitive Behavioral Group Therapy

Primary care physicians may hesitate to refer an individual with severe generalized social phobia (GSP) for cognitive-behavioral group therapy (CBGT) because the patient may either not benefit from it or will stop treatment. Approximately 26% of patients who attend CBGT sessions do not complete treatment, and completers do not always show improvement. According to a study by Dave Davies, PhD, of the Royal Ottawa Mental Health Centre in Ontario, Canada, and colleagues, CBGT can benefit patients with GSP, but the severity of symptoms associated with GSP does not necessarily predict patient completion of or response to CBGT.

The 12-week study involved 78 patients between 18 and 61 years of age diagnosed with GSP in accordance with criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–Text Revision and as assessed by the Social Phobia Diagnostic Questionnaire. Patients were randomly divided into groups of five to eight individuals, and each group attended 12 CBGT sessions hosted by two CBT-trained therapists. The program consisted of psycho-education, cognitive restructuring, within-session exposure, in vivo exposure homework, and relapse prevention. Using Social Phobia Inventory (SPIN) scores to determine response to treatment, 30 of the 51 participants who completed therapy (ie, attended ≥7 sessions and completed follow-up surveys) positively responded with a reduction of ≥9 points on the SPIN. Completers demonstrated a substantial decrease in social anxiety, avoidance, and cognitions. Their scores on both the Beck Anxiety Inventory and Beck Depression Inventory-II declined as well. Results suggest that CBGT can reduce social anxiety symptomatology among a majority of individuals with GSP, but they do not necessarily indicate symptom severity as a factor for determining completion of CBGT.

In addition, the researchers unexpectedly found that anxiety and associated avoidance were not the primary reasons for participants’ discontinuation of CBGT.

“[Participants] who completed therapy were not different from their counterparts who discontinued treatment in terms of any anxiety-related variables (eg, symptom severity, avoidance, strength of negative cognitions, and depression) assessed prior to treatment,” Dr. Davies said.

That the research primarily focuses on social anxiety symptomatology before and immediately after group treatment limits the study, as whether or not treatment responses are consistent in the long-term is not assessed. Lack of follow-up with participants who did not complete therapy limits the study as well, leaving the reason for patient discontinuation unknown.

“Ascertaining reasons for discontinuing would be helpful for planning future interventions that would increase retention of participants,” Dr. Davies said. (2008 ADAA, Poster 122). –ML


Increased Prevalence of Anxiety and Internalizing Problems in Children with OCD and Comorbid Depression

In adults, depressive and anxiety disorders often occur as comorbid conditions with obsessive-compulsive disorder (OCD). Studies have shown that approximately 33% of patients with OCD report comorbid depression, which has also been shown to negatively affect overall treatment response. Although researchers have investigated the efficacy of pharmacologic indications for the treatment of OCD and depression in children, few studies examine the prevalence of comorbid depression in children and adolescents with OCD. Research is also lacking in determining possible risk factors for comorbid depression in children and adolescents with OCD.

Kristin E. Canavera, MS, at the Virginia Polytechnic Institute and State University in Blacksburg, and colleagues, evaluated 56 children and adolescents with OCD to determine the prevalence and potential risk factors for comorbid depression. They hypothesized that comorbid depression in patients with OCD may be correlated with the comorbidity of other anxiety disorders, more severe symptomology, and presence of parental depression. They also sought to extend current understanding of comorbid OCD and depression in adults to the child and adolescent population.

Patients were 10–17 years of age (mean age=14.5 years). All participating families received the Anxiety Disorders Interview Schedule, which assessed symptoms of anxiety and depression. Patients were divided into two groups, ie, those who met diagnostic criteria for OCD and did not have comorbid depression (n=28), and those with OCD and a comorbid depressive disorder (n=28). The prevalence, severity, and risk of comorbid depression among patients in the study were measured using the Children’s Depression Inventory, the Penn State Worry Questionnaire for Children (PSWQ-C), and the 39-item Multidimensional Anxiety Scale for Children (MASC). Parental self-reports including the Child Behavior Checklist (CBCL) and the Depression, Anxiety, and Stress Scales were also used to determine depression rates for both children and parents.

Canavera and colleagues found that among children and adolescents with OCD, there were significant differences in symptomology for those with and without comorbid depression. Patients with OCD and comorbid depression showed significantly higher rates of pervasive worry (PSWQ-C score of 38.1 for OCD patients with depression compared to 28.6 for those without depression) and internalizing problems, as measured by the CBCL, than patients without comorbid depression. Anxiety disorders, including social anxiety disorder and generalized anxiety disorder, were commonly associated with presence of OCD with comorbid depression. Although differences in MASC and clinical severity were not significant, differences were present among patients with and without comorbid depression. Contrary to their hypotheses, the authors found that OCD severity was not significantly higher for children and adolescents with comorbid depression, and that mothers’ rates of depression and anxiety were not significantly higher for patients with comorbid depression.

These results show that children and adolescents with OCD and comorbid depression may experience more internalizing problems than those without depression, which may alter the treatment course to include both OCD and depressive symptoms. Although cognitive-behavioral therapy (CBT) has shown to be effective for adults with OCD and depression, the authors suggest that a CBT approach that includes family support may be more effective with children and adolescents. The authors recommend that future research investigate whether comorbid depression is related to specific obsessive or compulsive symptoms of OCD. (2008 ADAA, Poster 72). –CP


PCMAD: A Self-Report Scale for Improved Detection of Mood and Anxiety Disorders

Unrecognized or misdiagnosed mood and anxiety disorders have a taxing effect on the social and economic well being of society. Such strains may be reduced by heightened vigilance and improved detection of mood/anxiety disorders by primary care physicians (PCPs), but all private practices have limited resources, and, certainly, limited time to interact with patients directly.

Monica Vermani, BSc, MA, PsyD, at the START Clinic in Toronto, Canada, and colleagues, assessed the need for and created a self-report measure for diagnosing mood disorders.
“Our goal was to develop a psychometric screening tool that was self report driven and could allow for a primary care practitioner to identify earlier, patients in their clinic, who suffer from an anxiety disorder, major depressive disorder, or bipolar disorder,” Dr. Vermani said.

The Primary Care Mood and Anxiety Diagnoser (PCMAD) was devised to facilitate diagnosis and enhance proper communication of one’s symptoms, with the intention of recognizing psychological causes for physical symptoms patients suffer from. In turn, this would facilitate patients to receive appropriate treatment care and reduce unnecessary physician/lab visits. PCMAD is a 38-item, self-report measure designed as a sensitive assessment tool for the presence of mood and anxiety disorders, with a high positive predictive value to enhance PCPs’ ability to detect features that correlate with the presence of various anxiety and mood disorders. PCMAD was developed from questions in 10 existing psychometric scales, including the Beck Depression Inventory and the Mood Disorder Questionnaire.

To evaluate the clinical accuracy of PCMAD, Vermani and colleagues administered the Mini-International Neuropsychiatric Interview (MINI) to 1,007 recruits in Phase I. From the MINI results, the investigators gauged the presence of generalized anxiety disorder (GAD), panic disorder, social anxiety disorder (SAD), bipolar disorder, and major depressive disorder (MDD). Subjects who demonstrated the presence of a mood and/or anxiety disorder(s) after the MINI were permitted into Phase II, in which the PCMAD was administered. Phase III included a patient’s chart review to determine whether each patient had a record of the mood disorder(s) detected during Phases I and II. Finally, in Phase IV, PCPs were asked to administer a clinical questionnaire pertaining to the specific subject.

When examining the outcome diagnoses after Phase IV, percentages of subjects with a mood/anxiety disorder(s) not detected by PCPs were as follows: 51.1% of patients with MDD, 87.4% with bipolar disorder, 62.2% with GAD, 73.6% with panic disorder, and 97.1% with SAD.

“A variety of factors contribute to the difficulty that physicians had in detecting these illnesses in their patients,” Dr. Vermani said. “Specifically, the constraints included time limited medical appointments, in sufficient resources and poor communication of physical/psychological symptoms and significant life stressors or life altering events by the patient."

According to the authors, PCMAD will promote communication between doctors and patients, leading the way to uncover symptoms that appear to be physical but are sometimes psychologically based, decreasing the occurrence of repeated physician visits and enhancing patients’ quality of life.

“Overall,” Dr. Vermani said, “since majority of the population with mood and anxiety disorders are likely to visit their primary care physician, it is crucial to enhance detection in order to minimize individual, economic, medical and societal costs incurred by such illnesses.”

It is Vermani and colleagues’ hope that the self administered psychometric screener they are developing will allow PCPs to go beyond examining a patient’s physical symptoms and seek for psychological triggers and stressful life events eliciting physical responses.

“This will hopefully allow for earlier detection, mis/overuse of medical services, earlier provision of treatments, and an overall decrease in patient sufferings,” Dr. Vermani said.

Funding for this study was provided by an unrestricted educational grant from Wyeth Canada (Poster presented at the 2008 ADAA). –LS


Increased Cell Phone Use May Heighten Symptoms of Anxiety

Cell phones and other handheld communication devices allow people to contact each other more easily and more often. However, such communication facility may cause people to feel obligated to remain connected and available to others. A study by Lisa Merlo, PhD, and Amanda Stone of the University of Florida in Gainesville, FL, found that individuals with higher levels of trait anxiety likewise have higher levels of cell phone abuse and dependence.

This preliminary investigation involved 183 individuals between 18 and 75 years of age from diverse backgrounds (approximately 76% Caucasian, 10% Asian, 9% Latino, 2% African-American, and 3% “other”). The participants owned a cell phone for an average of 7.2 years and were evaluated using three measures, ie, Cellular Technologies Addiction Scale (CTAS), State-Trait Anxiety Inventory (STAI), and International Personality Item Pool (IPIP-NEO). The CTAS consisted of two subscale questionnaires that gauged cell phone dependence and abuse. The Trait Anxiety subscale of the STAI assessed trait anxiety symptoms, and the Anxiety subscale of the IPIP-NEO measured anxiety. The negative correlation between age and the scores on the CTAS Abuse and Dependency scales suggest that cell phone addiction symptoms are more common in the younger participants regardless of gender. Scores on the STAI-Trait Anxiety scale were highly correlated with scores on the IPIP-NEO Anxiety scale, providing evidence of the association between anxiety symptoms and increased obstructive cell phone use.

The most interesting finding from this study was participant response to the CTAS Dependence subscale item, “I sometimes think that I might be ‘addicted’ to my cell phone.” Approximately 18% (one in five) of individuals admitted that they somewhat or strongly agreed.

“Though cell phone addiction has become a more prominent topic in pop culture, I was surprised that such a large number endorsed feeling this way,” Dr. Merlo said. “It appears that this may be a more prevalent issue than I initially thought.”

Due to the relatively small sample of healthy volunteers, research was unable to assess whether symptoms of cell phone addiction are more common among people with diagnosable anxiety disorder, especially in consideration of race and gender. In addition, whether individuals who manage anxiety disorders well report fewer symptoms of cell phone addiction than individuals who poorly manage anxiety disorders was not addressed.

Despite limitations, the study suggests that excessive cell phone usage may reflect maladaptive attempts at coping, especially among patients with high anxiety.

“Primary care physicians may wish to ask patients about cell phone usage, particularly about ways that cell phone usage may cause distress, impairment, or other negative consequences,” Dr. Merlo said. “Individuals who endorse significant problems would likely benefit from a referral to a mental health professional in order to learn more adaptive coping strategies.” (2008 ADAA, Poster 123). –ML


Environmental Cues and Rituals Often Trigger Hairpulling for Patients with Focused-Type Trichotillomania

Classified as an impulse-control disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, trichotillomania has also been classified as a stress and tension-releasing habit disorder as well as a variant of obsessive-compulsive disorder (OCD), which has led to debate as to the conceptualization of the hairpulling disorder. Research has shown that trichotillomania occurs on a continuum of two types, automatic and focused hairpulling, which each highlight different aspects of the disorder’s varied classifications. While automatic hairpulling occurs when the patient is unaware of the behavior (eg, occurring during other activities, such as reading or watching television), focused hairpulling is caused by intense urges to perform the behavior and satisfaction when the behavior is being performed, which is more representative of the diagnostic criteria for the disorder.

For both forms of trichotillomania, cues associated with the hairpulling are important to identify in order to begin effective treatment and optimize outcomes. Rebecca Nichols at the University of Florida in Gainesville, and colleagues, sought to investigate hairpulling symptoms in a non-clinical population of 527 people to examine the phenomenology of trichotillomania among different populations because such understanding would benefit clinicians in the recognition and treatment of trichotillomania.

Study participants were assessed for presence of trichotillomania using the two-part Florida Hairpulling Scale, which includes the qualitative and quantitative assessment of hairpulling cues and six questions related to the type and severity of hairpulling behavior. Researchers found that among the 527 study participants, between 17–47 years of age, 0.74% engaged in hairpulling behavior with the age of trichotillomania onset being 13.57 years. Among participants with trichotillomania, 80.4% were female and 19.6% were male; 68.7% engaged in automatic hairpulling while 31.3% exhibited focused hairpulling behavior.

Nichols and colleagues compared rituals associated with hairpulling among those who engaged in automatic and focused types of the behavior. They found that participants who were in the focused hairpulling group had a greater frequency of rituals associated with the behavior (56.3% for the focused group, 20% for the automatic group). Rituals included pulling hair from the root, examining the hair root, using certain fingers to pull hair, and dropping hair to the floor.

In addition, those in the focused group reported engaging in hairpulling behavior in more environments than those in the automatic group. Environmental cues included “reading,” “lying in bed,” “looking in the mirror,” “when alone,” and “watching television.” Overall, participants in the focused group reported more rituals and environmental cues triggered hairpulling behavior. The authors concluded that people who engage in focused hairpulling view the activity as a target of their attention, leading to more severe incidence. They added that these results show that there is a difference between focused and automatic hairpulling among those with trichotillomania, and may indicate the differences among current classifications for the disorder with focused hairpulling representing a more severe subtype of the condition. (2008 ADAA, Poster 85). –CP


Biologic Factors May Play a Role in the Development of Eating Disorders in Females

Eating disorders, exhibited mostly in females, are often attributed to environmental factors such as thinness ideals. However, a new study suggests that biologic factors may play a role as well. Kristen Culbert, MA, at Michigan State University in East Lansing, and colleagues, studied the effects of testosterone in twin pairs enrolled at the Michigan State University Twin Registry. The study found that females who were in the womb with a male twin have a lower risk for eating disorders than those with a female twin.

The study consisted of 304 same-sex female twins, 59 opposite-sex female twins, 54 opposite-sex male twins, and 165 same-sex male twins. Levels of disordered eating were measured by the Minnesota Eating Behavior Survey, which measures body dissatisfaction, preoccupation with weight, binge eating, and behaviors to control weight such as purging. As hypothesized, linear trends of disordered eating were found. Same-sex female twins exhibited the highest level of disordered eating, followed by opposite-sex female twins, opposite-sex male twins, and same-sex male twins. This trend was not accounted for by anxiety levels or social factors.

“Given that sociocultural differences, such as pressures for thinness in women, have typically been used to explain sex differences in eating disorder prevalence, findings from this study are most interesting in suggesting a biological explanation,” Culbert said. “Specifically, our findings provide evidence that increased levels of prenatal testosterone exposure may protect against the development of disordered eating attitudes and behaviors.”

The findings also ruled out socialization effects of being reared with a brother. Opposite-sex female twins exhibited lower (ie, more male-like) levels of disordered eating than non-twin females with at least one brother.

As the twins with the most male exposure in the womb were less likely to develop disordered eating, the authors concluded that biologic factors such as masculinization of the central nervous system by prenatal exposure to testosterone may affect the prevalence of disordered eating. Culbert said that in the long term, the identification of neurobiologic processes underlying risk for eating disorders might enhance treatment.

“If prenatal testosterone is protective and acts to organize anatomical and functional brain differences between males and females, then we can begin to identify areas of the brain that might be altered by prenatal testosterone, such as those involved in food intake or satiation,” Culbert said. “This information would be important for understanding how prenatal testosterone confers protection against disordered eating and could ultimately be used to develop new pharmacological treatments that could mimic these protective effects.”

The practical application of this study is that healthcare professionals can help to reduce parental or personal guilt by highlighting that eating disorders are biologically based and that the risk for eating disorders results from socio-cultural and familial factors that act in combination with biologic and genetic vulnerabilities.

The biggest limitation to this study was the inability to directly assess levels of prenatal testosterone exposure. Additional research examining more direct assessments of prenatal testosterone exposure is warranted. However, at present, only prohibitively invasive methods, such as amniocentesis, exist.

“While such methods would be invaluable for directly examining levels of prenatal testosterone exposure, researchers are limited by the lack of access to and difficulties collecting these data,” Culbert said.

Funding for this study was provided by the National Institute of Mental Health. (Arch Gen Psychiatry. 2008;65(3):329-336). –DC


First-Trimester Maternal Stress During Pregnancy Linked to Later-Life Schizophrenia in Offspring

During pregnancy, an elaborate biologic system protects fetuses from the physiologic effects of maternal stress during crucial neurodevelopment—particularly during the first trimester. That system, known as a “fetal-placental barrier,” is hardly impenetrable, however, and a recent study reveals several fetal risk factors associated with antenatal maternal stress. The study weighed the claim that maternal stress during the first trimester of pregnancy was especially associated with the risk of congenital malformations.

Ali S. Khashan, MSc, of the Centre for Women’s Mental Health Research at the University of Manchester, and colleagues, compiled data from several national databases in Denmark. In a cohort of 1.38 million Danish births, born between the years of 1973 and 1995, mothers were considered exposed to stress if ≥1 close relatives died or were diagnosed with cancer, acute myocardial infarction, or stroke syndrome either 6 months before conception or during pregnancy. The offspring were tracked from 10 years of age until their death, migration, or onset of schizophrenia, or until June 2005. Maternal relatives were also tracked for outcomes including death, serious illness, or terminal diagnoses. Of the 1.38 million births included in this investigation, the mothers of 36,193 offspring were exposed to the death, serious illness, or terminal diagnosis of a close relative, of which 21,987 mothers were exposed to the death of a family member. Finally, 14,206 mothers were exposed to a relative with serious illness.

These birth records were compared with psychiatric inpatient and outpatient data in order to assess the relationship between maternal exposure to severe stress and adverse mental health outcomes in their offspring. The most significant finding was that the offspring of mothers who were exposed to the death of a close relative during the first trimester were more likely to develop schizophrenia later in life (adjusted relative risk=1.67 [95% CI]). This increased risk was not associated with maternal stress during the 6 months preceding conception or during other trimesters.

Funding for this study was provided by Tommy’s The Baby Charity and the Stanley Medical Research Institute. (Arch Gen Psychiatry. 2008;65(2):146–152). –LS

Posters were drawn from the 28th Annual Conference of the Anxiety Disorders Association of America (ADAA; March 6–9, Savannah, Georgia). Psychiatric dispatches is written by Dena Croog, Jaime Cunningham, Michelisa Lanche, Carlos Perkins, Jr., and Lonnie Stoltzfoos.


Dr. Erman is clinical professor in the Department of Psychiatry at the University of California, San Diego School of Medicine, a staff scientist for the Scripps Research Institute Department of Neuropharmacology, and chief medical officer of Avastra USA.

Disclosures: Dr. Erman is a consultant to Cephalon, Mallinckrodt, Neurocrine, sanofi-aventis, and Takeda; is on the speaker’s bureaus of Forest, sanofi-aventis, and Takeda; is on the advisory boards of Cephalon, Neurocrine, sanofi-aventis, and Takeda; has received grant/research support from Arena, Cephalon, Eli Lilly, GlaxoSmithKline, Mallinckrodt, Merck, Organon, Pfizer, Pharmacia, ResMed, sanofi-aventis, Schwarz Pharma, and Takeda; and owns stock in Cephalon, Forest, Merck, Neurocrine, Pfizer, sanofi-aventis, and Sepracor.




Complaints of fatigue and sleepiness are common in psychiatric patients. Their expression may reflect core components of various psychiatric disorders, may relate to comorbid conditions which may affect their emotional state, or may occur as a side effect of medications used to treat psychiatric disorders.


Fatigue versus Sleepiness

The first challenge involved in assessment of the complaint “I am tired” is trying to make a distinction between sleepiness or drowsiness and fatigue. Fatigue is usually defined as a feeling of weariness, tiredness, or lack of energy. When such a complaint is raised by patients receiving psychiatric care, specific medical causes (eg, hypothyroidism, anemia) must be ruled out, but the symptom will typically be assessed in the context of the underlying psychiatric complaint being evaluated (eg, depression, anxiety). In such a context, the complaint may be perceived to be understandable or even expected—“fatigue or low energy,” for example, being a core diagnostic component of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,1 criteria for depression. The fatigue complaint may also be presumed to be associated with an accompanying or related condition such as chronic fatigue syndrome or fibromyalgia.

What differentiates complaints of fatigue from those of sleepiness? Patients who are actually “sleepy” (as opposed to “fatigued”) report sleeping an excessive amount, taking involuntary naps, fighting sleepiness while sedentary, or report the capacity to nap voluntarily if given the opportunity. Sleepiness and fatigue may co-exist, but when frank sleepiness is present an effort must be made to identify its cause and to determine what treatment, if any, is appropriate.

Sleepiness complaints may be assessed in various ways. Patients may be asked to rate their sleepiness on a scale of 1–10, or may mark a point on a visual analog scale. Such techniques allow a baseline to be established and provide some basis for assessing responses to interventions. The simple, validated Epworth Sleepiness Scale2 is quite helpful in quantifying the severity of sleepiness complaints. This instrument, developed at the Epworth Hospital in Australia, asks the subject to rate his or herself from 0 (not sleepy) to 3 (very sleepy) in eight situations (eg, sitting quietly in a car, sitting and talking to someone). The maximum score is 24; the minimum is 0. Based on norms established at the time of the original publication, scores of ≥10 are considered to reflect pathologic sleepiness. It may be argued that in “real world” situations scores of <10 may be of clinical concern, especially for individuals in occupations that demand sustained alertness.


Insufficient Sleep

Numerous specific medical conditions have been identified as capable of causing excessive sleepiness. Interestingly, the most common cause of this complaint in modern society is likely to be insufficient sleep, a condition that is identified as a disorder in the formal sleep nosologic schema, The International Classification of Sleep Disorders, Second Edition (ICSD).3 It is estimated by the American Academy of Sleep Medicine that approximately 20% of adult Americans attain little sleep and may suffer consequences as a result.4 This may be on a voluntary basis; the 21st century provides an unending menu of activities that may keep people from their beds and prevent them from getting adequate amounts of sleep. Insufficient sleep may also occur as a consequence of personal or family responsibilities (eg, serving as a caregiver to a sick family member, dealing with the needs of newborn infants or young children) or as a consequence of extended work hours, lengthy commutes, or other job-related issues.

Although the “treatment” for this disorder may arguably be simple—ie, the direction to “get more sleep”—the patient must be willing to give up voluntary, enjoyable activities (eg, late night television, surfing the Internet, Online gaming) or be able to make other changes in their social setting (eg, obtaining help from other family members to help with care provision) that may not be readily accomplished.


Obstructive Sleep Apnea

Another common cause of sleepiness is obstructive sleep apnea (OSA). According to Young and colleagues,5 the lifetime prevalence of OSA in adults has been estimated to be 9% in men and 4% in women. However, this is likely a low estimate since subjects needed a substantial number of apnea events (15/hour) and to complain of excessive sleepiness in order to be defined as positive for this study. The prevalence increases with age, particularly in postmenopausal women. The prevalence in the elderly has been estimated to be 28% in men and 19% in women.6

The major diagnostic criterion for sleep apnea is cessation of breathing lasting at least 10 seconds. Hypopneas (a decrease in respiratory effort of ≤50%) may also produce arousal or hypoxia even when complete apneas do not occur. Most apneic episodes end with transient arousals, leading to light and disrupted sleep. During apneas and hypopneas, the blood-oxygen level often drops precipitously, and cardiac arrhythmias and nocturnal hypertension may occur.

The most common symptoms of OSA include excessive daytime sleepiness and snoring. Daytime sleepiness probably results from sleep fragmentation caused by the frequent nocturnal arousals occurring at the end of the apneas, with possible contribution from hypoxemia. Sleepiness is associated with lethargy, poor concentration, decreased motivation and performance, and inappropriate and inadvertent attacks of sleep.

Loud snoring, another typical complaint, is sometimes noisy enough to be heard throughout or even outside the house. Bed partners describe characteristic loud snoring interrupted by periods of silence, often terminated by snorts or gasps. Snoring results from narrowing of the airway caused by any of a number of factors, including obesity, large tonsils and adenoids, an elongated soft palate, hypothyroidism, or congenital narrowing of the oral pharynx. Because the prevalence of snoring increases with age, especially in women, and because snoring can have serious medical consequences, psychiatrists must give serious attention to complaints of loud snoring.

It has long been established that depression is extremely common in patients with OSA,7 and it is now also clear that effective treatment, typically with continuous nasal positive airway pressure (CPAP), reduces depressive symptomatology.8,9 The goal of OSA treatment is to keep the airway open during sleep so the patient can breathe. Nasal CPAP accomplishes this with the use of mask or interface applied to the face and connected to a small airflow generator, providing positive pressure that functions as a pneumatic splint, preventing airway collapse. When apnea is suspected—on the basis of history of snoring, observed breathing pauses, obesity, hypertension, treatment-resistant depression, and so forth—patients should be referred for sleep studies to determine if OSA is present.


Shift Work

Shift work may also provoke sleepiness complaints. Shift work problems occur when work demands put intrinsic circadian sleep-wake rhythms in conflict with sleep patterns determined by work schedules. Rotating schedules, particularly rapidly shifting schedules, are most problematic because endogenous circadian drives readjust slowly to the imposed sleep-wake cycle. Shift workers demonstrate impaired performance and increased risk of accidents, somatic complaints, and poor morale.10 Hypnotics, stimulants, and alcohol are often used excessively in relationship to unusual or shifting work schedules.

A specific disorder associated with shift work, shift work sleep disorder, has been defined in the ICSD.3 Based on research data showing symptomatic improvements in treated shift workers,10 the United States Food and Drug Administration has approved treatment with modafinil 200 mg 1 hour before the start of shift work for treatment of this disorder.



Narcolepsy, first described by Gelineau in France in the 1870s, is less common than the above-mentioned causes of sleepiness, but is not a rare disease. Its prevalence rate of 0.03% to 0.16% approximates that of multiple sclerosis.

Narcolepsy is associated with a pentad of symptoms. First, it is associated with excessive daytime sleepiness, characterized by irresistible “attacks” of sleep in inappropriate situations such as driving a car, talking to a supervisor, or social events. Second, narcolepsy is associated with cataplexy, a sudden bilateral loss of muscle tone, precipitated by strong emotions such as laughter, anger, or surprise. Third, it is associated with poor or disturbed nocturnal sleep. Fourth, it is associated with hypnagogic hallucinations, which are vivid dreams or dream-like experiences occurring at sleep onset. Last, narcolepsy is associated with sleep paralysis, which is brief paralysis associated with the transitions into, and out of, sleep.
Narcolepsy is associated with significant social and financial impairment for affected individuals and their families. For example, automobile accidents may result from either sleepiness or cataplexy. Most states prohibit narcoleptic patients from driving, at least as long as they are symptomatic.
The first narcolepsy symptom to present is most often excessive sleepiness, typically developing during the late teens or early twenties. The full syndrome including cataplexy and other symptoms usually presents at a later age, typically within several years, but at time presenting in the fifth or sixth decade of life. Once established, narcolepsy symptoms are usually relatively stable, without progressive increases in severity of hypersomnia complaints.

Sleep paralysis and hypnagogic imagery may be seen without cataplexy, and cataplexy may present in isolation without other rapid eye movement (REM)-associated phenomena. Rarely, narcolepsy may present with hallucinations occurring at transitions from wake to sleep that may lead to a diagnosis of psychosis.

Treatment of narcolepsy attempts to improve quality of life, reduce excessive daytime sleepiness, and prevent cataplectic attacks, if present. Wake-promoting medications approved to treat narcolepsy include modafinil, various formulations of amphetamines, and methylphenidate. Modafinil is preferred on grounds of efficacy, safety, availability, and low risk of abuse and diversion. Selective serotonin reuptake inhibitors, such as fluoxetine and citalopram, and tricyclic antidepressants, such as protriptyline and clomipramine, have been used in the past to treat cataplexy, sleep paralysis, and hypnogogic hallucinations, but sodium oxybate, is now approved by the FDA for treatment of cataplexy and symptoms of sleepiness in patients with narcolepsy.11

When narcolepsy is suspected, full sleep studies, including daytime testing of sleep and REM-propensities (multiple sleep latency testing) is typically required to establish the diagnosis. These studies are often needed for a definitive diagnosis to allow access to medications used to treat this disorder, which are expensive and may be tightly controlled due to perceived abuse potential.


Periodic Limb Movements in Sleep and Restless Legs Syndrome

Periodic limb movements in sleep (PLMS) and restless legs syndrome (RLS) are other relatively common disorders associated with complaints of excessive sleepiness. PLMS is a disorder in which repetitive, brief, and stereotyped limb movements occur during sleep, often with a periodicity of approximately 20–40 seconds. RLS is associated with disagreeable sensations in the lower legs, feet, or thighs that occur in a recumbent or resting position and cause an almost irresistible urge to move the legs.12 These disorders are usually associated with transient arousals in sleep, demonstrated by disruptions in the electroencephalograph recording in sleep studies. Both PLMS and RLS usually occur in middle-aged people, but many patients report having had the same sensations as adolescents and even as children. Although these conditions usually present initially with complaints of insomnia, when they become established they may be associated with hypersomnia.

The treatment of choice for both RLS and PLMS are dopamine agonist compounds. To date, only ropinirole and pramipexole have been approved by the FDA for the treatment of RLS. These agents often lead to dramatic relief from symptomatic complaints, including excessive sleepiness, which have plagued RLS and PLMS sufferers for years.



Other conditions may provoke sleepiness complaints but are seen much less frequently. These include idiopathic hypersomnia, also known as primary hypersomnia, and periodic hypersomnias such as Kleine-Levin syndrome, usually seen in male adolescents. The etiology of these disorders is not understood, and symptomatic treatment with alerting or stimulant medications is the usual therapeutic approach.



Psychiatric patients with sleepiness complaints deserve the same careful diagnostic and therapeutic attention as does any other patient. Patients with depression may have hypersomnia complaints distinct from the fatigue associated with their depression, and are likely to have reductions in depressive symptoms when a breathing-related sleep disorder is treated. Shift workers with daytime emotional dysfunction may benefit from treatment with modafinil, with reductions in interpersonal distress as well as improvements in alertness. Recognition of the existence of, and treatment of, long-standing disorders such as narcolepsy and RLS/PLMS may allow patients to be much more active and productive individuals, with associated benefits as well in social and emotional function. The keys to treating sleepiness are attention to the symptomatic complaint of sleepiness, use of appropriate diagnostic procedures to establish that a treatable condition may be present, and provision of appropriate therapy once a diagnosis is established. PP



1.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
2.    Johns MW. Sleepiness in different situations measured by the Epworth sleepiness scale. Sleep. 1994;17(8):703-710.
3.    The International Classification of Sleep Disorders. 2nd ed. Westchester, NY: American Academy of Sleep Medicine; 2005.
4.    Sleep Deprivation. Available at: www.aasmnet.org/Resources/FactSheets/SleepDeprivation.pdf. Accessed April 5, 2008.
5.    Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep disordered breathing among middle-aged adults. N Engl J Med. 1993;328(17):1230-1235.
6.    Ancoli-Israel S, Kripke DF, Klauber MR, Mason WJ, Fell R, Kaplan O. Sleep disordered breathing in community-dwelling elderly. Sleep. 1991;14(6):486-495.
7.    Reynolds CF, 3rd Kupfer DJ, McEachran AB, Taska LS, Sewitch DE, Coble PA. Depressive psychopathology in male sleep apneics. J Clin Psychiatry. 1984;45(7):287-290.
8.    Schwartz DJ, Karatinos G. For individuals with obstructive sleep apnea, institution of CPAP therapy is associated with an amelioration of symptoms of depression which is sustained long term. J Clin Sleep Med. 2007;3(6):631-635.
9.    Suhner AG, Darko DD, Erman MK, Riel KF, Mitler MM. Depressive symptoms in patients with OSA and the impact of nasal CPAP treatment. Sleep. 2003;25:A225.
10.    Czeisler CA, Walsh JK, Roth T, et al. Modafinil for excessive sleepiness associated with shift-work sleep disorder. N Engl J Med. 2005;353(5):476-486. Erratum in: N Engl J Med. 2005;353(10):1078.
11.    Littner M, Johnson SF, McCall WV, et al. Practice parameters for the treatment of narcolepsy: an update for 2000. Sleep. 2001;24(4):451-466.
12.    Walters AS, LeBrocq C, Dhar AK, et al. Validation of the international restless legs syndrome study group rating scale for restless legs syndrome. Sleep Med. 2003;4(2):121-132.


e-mail: ns@mblcommunications.com


In this issue of Primary Psychiatry, an article by Surilla Randall, PhD, and colleagues, provides an overview of what is known regarding the efficacy and safety of popular nonprescription products used for insomnia. Both the prevalence of chronic (estimates can range from approximately 10% to 50%) and self-treatment with over-the-counter (OTC) sleep aids, herbal and dietary supplements, and/or alcohol are very common. The authors report the findings of a survey that showed that 25.9% of respondents reported using some substance to aid their sleep. Of those who used medications (either prescription, OTC drugs, or both) to improve sleep, 57% reported using OTC sleep aids. The authors note that most of the evidence about the efficacy and safety of OTC sleep aids is inconclusive, mainly due to problems with research design and lack of placebo-controlled groups. There is also little data to support long-term usage. As with other sedating agents, prolonged use of antihistaminic drugs may result in tolerance and/or dependence and produce daytime sleepiness. The authors concede that treatment of insomnia with antihistamine-containing OTC sleep aids may help occasional mild insomnia. The data on other non-prescription sleep aids is too limited or inconsistent in results to consider their use. While alcohol may have initial sedative effects, it is associated with rapid tolerance development and dose escalation.

Gary K. Zammit, PhD, focuses on treating sleep disorders in patients with psychiatric disorders. In his article, Dr. Zammit comments about mood disorders and insomnia often being comorbid conditions, and about medications potentially disrupting or enhancing sleep in a variety of different ways. His article examines the evidence supporting the efficacy and safety of mood stabilizers in the treatment of comorbid and primary insomnia. He also points out that insomnia may be a precursor to depression. He notes that in every study completed to date, insomnia was found to be a significant risk factor for the subsequent onset of depression. A greater incidence of affective disorder has been found in people with insomnia. Treatment options to address both depression and insomnia are reviewed.

An article by Adriana J. Pavletic, MD, MS, and colleagues, focuses on the importance of medical screening of volunteers participating in research on mental illness. The authors describe a study of how medical screening identified a relatively high rate of conditions in both healthy controls and patients. This study potentially impacts on mental health research. The authors emphasize the need to develop standards in medical screening procedures for volunteers in psychiatric research.

Circadian disruption is invariably a part of a depressive episode. Numerous studies have shown changes in sleep patterns, daytime alertness, and sleep tendencies in people with depression. Seithikurippu R. Pandi-Perumal, MSc, and colleagues, note that the frequency of circadian dysfunction in affective states supports a major role of the circadian system in the etiology and the treatment of affective disorders. Ironically, many commonly used antidepressants can worsen sleep by producing insomnia, vivid dreams, bruxism, night sweats, and myoclonus. This article discusses melatonin and drugs that act on melatonon receptors. Melatonin influences sleep-promoting and sleep/wake rhythm-regulating actions through the specific activation of receptors, highly concentrated in the suprachiasmatic nuclei of the anterior hypothalamus. Melatonin agonists, such as ramelteon (which is marketed in the United States) and agomelatine (which the European Medicines Agency declined to approve in 2006 because efficacy had not been sufficiently shown) represent possible alternatives for treating sleep disturbances and circadian rhythm sleep disorders associated with mental illness. Agomelatine has shown some anti-anxiety and antidepressant effects in clinical trials. In this article, the authors suggest that combination therapy using an antidepressant plus a melatonergic agent may be an effective strategy for treating sleep disorders in the context of depression. The action of agomelatine is due to its agonist activity on melatonin (MT)1 and MT2 receptors in the suprachiasmatic nucleus. In addition to describing key aspects of brain chemistry involved in insomnia, the authors speculate that disruptions in circadian rhythms are linked to depressive states and that agomelatine’s effectiveness in treating these symptoms may be broader than other antidepressants and, thus, may more effectively address the complexities of depressive illness.

In a response to “Clinical Updates in Sleep Medicine,”1 a critique of trazodone and other non-benzodiazepines analogs for off-label use as soporifics, Michael S. Hanau, MD, FAPA, argues, among other matters, that despite the absence of well-controlled trials, these agents have an extensive history of safe and effective use in clinical practice. He adds that some of the newer agents produce parasomnias, visual hallucinations, and abuse. Milton K. Erman, MD, provides a detailed response to Dr. Hanau’s letter and concludes that, in any event, clinicians should certainly consider issues of risk and benefit before prescribing any medication. PP


1. Erman MK. Is it a sleeping pill? Primary Psychiatry. 2008;15(1)34-36.


This interview took place on February 28, 2008, and was conducted by Norman Sussman, MD.


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

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


Dr. King is president of the American Academy of Family Physicians (AAFP), which respresents 94,000 physicians and medical students nationwide. He is volunteer faculty at the University of Tennessee Center for Health Sciences, Memphis, and medical director of Chester County Healthcare Services in Selmer. In 1997, Dr. King received the Family Physician of the Year Award from the Tennessee Academy of Family Physicians. As member of the board of directors of FamMedPAC, the AAFP’s political action committee, Dr. King advocates the legislative goals of family medicine to members of Congress.


Are there data that show the percentage of patients seen in the primary care setting who have a psychiatric disorder?

Yes. In 2003, reports from the Institute of Medicine showed that approximately 65% to 80% of people with mental illness presented to a primary care physician (PCP) for their first clinical visit.1  Most studies show that approximately 39% to 40% of those patients will continue to be cared for by the family physicians or general internists to whom they intially presented. The physicians may refer as many as 60% of the patients to psychiatrists.1


What is the most common psychiatric disorder seen in primary care?

The most common psychiatric disorder observed is major depressive disorder (MDD). Bipolar and other generalized anxiety disorders are noted, and substance abuse, if it is looked for on a regular basis, can also be seen. Children with attention-deficit/hyperactivity disorder are often cared for as well.


What kind of clinical presentations trigger a referral to a psychiatrist or other mental health clinicians?

A major trigger is when patients do not respond to a medication the way the clinician thinks they should be responding since the start of treatment, particularly in suicidal or homicidal patients. In such cases, the clinician would recommend them for inpatient care under the supervision of a psychiatrist as well. If psychotic symptoms are observed, the patient will be quickly referred to a psychiatrist for help. For example, a patient with bipolar disorder who is manic will be sent to the psychiatrist for a follow-up evaluation.


What kind of barriers do PCPs face when referring patients to psychiatrists?

It is not so much the insurance company barriers, but the main barrier is geographical incovenience and impracticality. For example, I am in Summerton, Tennessee, and the closest psychiatrist is 50 miles away. Having patients be able to visit a psychiatrist and getting them in to see one on a timely basis is difficult. Appointments for some patients run weeks behind. When I try to refer a patient to a psychiatrist at the local mental health center, that psychiatrist comes to Summerton only once a month or once every 2 weeks. Sometimes, it may be 3 months before a patient can see a psychiatrist. As a result, the patient and I have to work with each other for the next 2–3 months until he or she can see the psychiatrist.


What kind of communication between a PCP and psychiatrist would you like to see when they share a patient’s care?

I would like to see a kind of communication very similar to that which physicians have with other subspecialists. Physicians should have a report from the psychiatrist returned to them as quickly as possible that discusses the patient’s condition, treatment plan, and newly administered medications. Because other comorbid problems are possibly being taken care of (eg, diabetes, hypertension, asthma, or arthritis), physicians need that information to make sure the medications do not clash and that everyone is trying to accomplish the same goal. Physicians also need to relay that type of information to the  psychiatrist as soon as possible. Quick, frequent communications between the PCP and the psychiatrist is crucial to ensure that psychiatrists always know that this patient has a family physician and a medical “home.”


Based on your experience, what could psychiatrists do differently or better to improve physicians’ overall treatment of patients?

Psychiatrists and physicians seem to be more concerned with Health Insurance Portability and Accountability Act violations and issues with security and privacy to the point where they have to jump through several hoops to get that information, even though they are both healthcare providers who need to communicate with each other about the patient.

Every person should have a medical home with a PCP. Patients with mental disorders may often need a psychiatrist as part of the team caring for the patient. We need to make sure that we have a two-way communication between healthcare providers so that the many barriers under the name of privacy are removed to provide the best care for the patient. Psychiatrists should make an effort to find out if a patient has a PCP and make sure that physician has needed medical information, such as medicines, diagnosis, and treatment plans as soon as possible.


Where do family doctors get their information about diagnosis and treatment of psychiatric disorders?

There are a few sources from which family doctors get their information, including journals. For example, The American Family Physician, which is the official clinical journal of the American Academy of Family Physicians, usually discusses a psychiatric or mental health condition in each month’s issue. It is one of the favorites of medical students because it gets to the point and helps the physician take care of his or her patient. Family doctors seek other journals as well particularly because there are so many sent to their offices. In addition, physicians are beginning to use electronic health records for information. For example, I have electronic health records in my practice, and the system is frequently updated. If a patient comes in with a particular concern, I can immediately educate myself on that specific problem even while the patient is in the room. Browsing the Internet, attending standard medical meetings, and listening to lectures on a regular basis are other ways through which family doctors get their information.


Do you have a particular area of interest in terms of diagnosing and treating psychiatric disorders?

I usually focus on the patients who have chronic medical conditions such as diabetes, hypertension, heart disease, or cancer complemented by a mental illness. These patients with multiple chronic diseases also very often have mental disorders such as depression and anxiety disorders. It is important to treat the entire patient.


Of the patients who initially present to PCPs with psychiatric symptoms, what percentage are ultimately experiencing the result of a physical disorder or treatment side effect?

I do not have literature that could provide a specific figure, but as an estimate from my practice, approximately 10% to 15%. The most common situation I have encountered is drug treatment side effects. For example, a person could be taking propanolol for his or her blood pressure or another beta blocker, and this medication can lead to depressive symptoms. Even the daily ingestion of chronic pain medications could cause a patient to come across as depressed. In addition, elderly patients who are on medications that lead to mental confusion can cause physicians to question whether the patient has Alzheimer’s disease, depression, or other problems.

When a patient’s lab results do not match his or her symptoms, I usually consider that the patient’s condition could be an impairment based on his or her dependency on a drug or alcohol. I look for those types of things to see which possible condition is coming across.


Are PCPs comfortable with using atypical neuroleptics?

Atypical neuroleptics are very expensive drugs; however, they are fairly safe. They are mostly used by patients with bipolar disorder who are dealing with a manic phase or mood disorder. Atypical neuroleptics may be prescribed to patients who have an extremely agitated type of depression.

As PCPs, we have to make a decision over two issues. We first need to determine whether the patient should be referred to a psychiatrist. Another issue concerns the addition of an atypical neuroleptic to a patient’s treatment. If the patient’s condition is severe, I would refer him or her to a psychiatrist. However, since contacting and meeting with a psychiatrist is difficult to do, I may try the medication and evaluate how it affects the patient.


Has there been a decreased use of antidepressants as a result of all the publicity and the label changes surrounding suicidality?

I have not seen a decrease in the use of  antidepressants. Most family physicians spend more time talking to patients about the suicidal side effects. With my patients, I always inform them of a slight increased risk of suicidal tendencies and let them know that they can contact me if they feel that way. As with any other drugs, PCPs need to make sure that the patient understands and looks for appropriate side effects.


Is there anything else you would like to stress?

It is difficult to tease out the psychiatric perspective from the physical perspective. PCPs do a great job of taking care of mental health issues. However, they need help from psychiatrists regularly as well.

From a personal standpoint, I think that once the insurance industry and patrons of health care realize that mental health is the same thing as diabetes, they will start paying PCPs and psychiatrists equally, regardless of which condition each takes care of. In Tennessee, if a physician gives the insurance company a patient’s mental health diagnosis, the psychiatrist would be paid half of what he or she would have received if a diabetes diagnosis had been turned in. That naturally leads to creative coding. For example, what would be considered a mental health diagnosis might be referred to as a physical diagnosis such as fatigue, tiredess, or insomnia. In order for the data to be accurate, this reality needs to change. PP



1.    American Family Physician. Graham Center One-Pager. Family Physicians Are an Important Source of Mental Health Care. Available at: www.aafp.org/afp/20030401/graham.html. Accessed March 27, 2008.


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.




Psychiatric issues are common in sickle cell disease (SCD)1 but have not received sufficient attention in the clinical or research literature. These issues are further complicated by the social, economic, and healthcare disparities experienced by many African Americans. This column reviews the following psychiatric issues in SCD, with particular focus on recent research: first, depression and anxiety resulting from living with a chronic stigmatizing disease associated with chronic pain, unpredictable painful crises, multiple serious complications, poor health-related quality of life (HRQOL), and high mortality; second, problems of pain management, frequent undertreatment, and potential for substance abuse and addiction; third, coping styles; fourth, alcohol abuse; and last, central nervous system (CNS) injury and resulting cognitive dysfunction from strokes, primarily during childhood.


Overview of Sickle Cell Disease

SCD is an autosomal recessive genetic disorder of hemoglobin (Hb) structure and the most common of the hemoglobinopathies. While it usually results in anemia, the primary symptomatic manifestation of SCD is pain. The most severe form of SCD, homozygous sickle cell anemia (Hb SS), occurs when Hb S is inherited from both parents. In the United States, this happens in approximately one in 375 African-American births. Other genetic variants producing SCD include two forms of sickle cell-beta thalassemia (Sβ° and Sβ+ ) and sickle cell-hemoglobin C (SC). Individuals with sickle cell trait, ie, heterozygotes for Hb S, do not experience any adverse clinical consequences (except under acute hypoxic conditions, eg, exposure to high altitude without time to accommodate) and have had a selective advantage against malaria. Those with the homozygous disease face a chronic disease, with onset in childhood leading to devastating consequences.

SCD occurs primarily in those of African descent, but it also afflicts people of Mediterranean, Middle Eastern, and Asian origins. Approximately one in 300 African-Americans have SCD (>70,000 people) and 8% have sickle cell trait. The consequences of SCD are aggravated by social, economic, and healthcare disparities. African Americans are on average poorer, have more limited access to healthcare services, and die sooner than Caucasians.2 Medical advances, such as prophylactic penicillin for children, have transformed the disease from a pediatric illness with few surviving beyond adolescence into one chronically extending into adulthood. Life expectancy has increased from a mean of 14 years of age in the 1970s to close to 50 years of age at present.3 By the 1980s, the federally funded Cooperative Study of Sickle Cell Disease (CSSCD)4 found median survival was into the fourth decade for homozygous patients. Patients with doubly heterozygous forms of SCD, such as Hb SC, fared even better, and the presence of a higher percentage of persistent fetal hemoglobin (Hb F) was associated with less severe disease and greater longevity.

This improved survival has created the relatively new phenomenon of adults with chronic SCD. Consequently, much less is known about psychosocial factors in adults with SCD than in many other chronic medical disorders, with most studies to date addressing prevalence of depression (see below). The increase in longevity has also resulted in physicians for adults treating pain resulting from a disease for which they have limited training and experience. In one inpatient study, one-third of patients reported inadequate pain relief and nearly 50% reported long delays in being treated for pain.5 The evidence base used to guide treatment for the growing population of adults with SCD has been very limited, with even less data regarding psychosomatic interactions, though both are now an active focus of investigators.

Most familiar to clinicians are the acute painful episodes known as “sickle cell crises,” thought to be due to acute vaso-occlusion by sickled red blood cells. Recurrent crises represent the most common reason patients seek acute medical care. Dehydration, temperature extremes, infection, changes in altitude, stress, and physical exertion may precipitate crises, but most crises occur without an identifiable cause. Vaso-occlusion causes acute pain in the short run and chronic pain and end-organ damage in the long run, potentially affecting all organ systems with particular harm to bones, kidneys, lungs, eyes, and brain. Complications include acute chest syndrome, avascular necrosis, priapism, ischemic leg ulcers, transient ischemic attacks and stroke, osteomyelitis, gallstones and cholecystitis, and renal insufficiency.

Clinicians and investigators have tended to focus on acute crisis pain and to equate crisis with acute healthcare utilization, ie, emergency room visits or hospitalization. However, the recent Pain in Sickle Cell Epidemiology Study (PiSCES)6-13 has demonstrated that pain in adults with SCD is far more prevalent and severe than previous studies have portrayed, and it is mostly managed at home.6 Therefore, it has been vastly underestimated when measured by using only healthcare utilization. In this prospective study, >50% of adults with SCD experienced pain, crises, or healthcare utilization on >50% of the days. Almost 33% experienced pain nearly every day, with the mean intensity in the middle range. In contrast, only approximately 15% rarely experienced pain. Crises and healthcare utilization were far less common than reported pain days; pain days that were not associated with a crisis occurred 10 times more often as pain days associated with healthcare utilization. Thus, contrary to commonly held belief, pain in adults with SCD is the rule rather than the exception. Since SCD adults infrequently utilize health care even in response to severe pain, there is a vast, mostly submerged iceberg of sickle cell pain that is managed outside of medical facilities and not seen by most professionals.

Smaller longitudinal studies measuring daily pain in children have also found that pain was most often managed at home rather than within healthcare facilities.7 How might this be explained? Behavioral theories suggest that many factors, besides pain itself, influence the response to pain.7 Adults with SCD carefully weigh the decision to come to a busy emergency department for treatment of even severe pain, where they may face long waits, stigmatization, and labeling as “drug-seeking.” Some manage their pain at home because of barriers in accessing health care, especially finding clinicians with SCD expertise, competing life priorities (eg, no child care), and lack of transportation. Evidence of each of these may be found in behavioral studies of SCD.7

HRQOL in adults with SCD is significantly worse than national norms.8 Adults with SCD have quality of life (QOL) that is similar to dialysis patients and poorer than adults with cystic fibrosis (except for mental health). Not surpisingly, QOL in adults with SCD significantly decreases as pain levels increase.


Depression and Anxiety

As with most chronic diseases, depression and other psychiatric disorders are common in SCD.13-15 Rates of depression are similar to those found in other serious chronic medical disorders, ranging from 18% to 44%,16-18 and are increased over rates in the general population even when one controls for illness-related physical symptoms.19 In a Nigerian study, subjects with SCD had a prevalence rate of depression greater than those with cancer or malaria (but less than those with HIV/AIDS).20 While studies of depression in children with SCD have shown mixed results, children experience high rates of fatigue and other somatic complaints, impaired self-esteem, feelings of hopelessness in the context of frequent hospitalizations, absences from school, and the inability to experience a normal childhood.1

There are many potential contributing causes to symptoms of depression and anxiety in SCD. These include the chronicity of the illness; unpredictability of crises; chronic pain; overwhelming nature of medical complications, including anemia, fatigue, growth retardation, physical deformities, leg ulcers, renal failure, strokes, and substantially reduced life expectancy; and racial prejudice and stereotyping. SCD may result in social derision, disability, and financial stress21 as well as stigmatization for pseudoaddiction to opioid analgesics.22 One study found that adults with SCD had lower self-esteem than those with HIV/AIDS or cancer.20 Chronically prescribed opioids may contribute a component of substance-induced mood disorder.15

Children with SCD are often underweight, shorter than normal children, and have delayed puberty. With their small stature, adolescents with SCD encounter problems with self esteem, dissatisfaction with body image, and social isolation, with participation in athletics also limited due to fear of initiating a vaso-occlusive crisis.1 School performance suffers when hospitalizations lead to missing multiple school days. Accordingly, adolescents often experience hopelessness and social withdrawal.23

PiSCES found that 27.6% of adults with SCD were depressed and 6.5% had ananxiety disorder.13 Depressed subjects had pain on significantly more days than nondepressed subjects (mean pain days=71.1% versus 49.6%, P<.001). On non-crisis days, depressed subjects had higher mean pain, distress from pain, and interference from pain than those without depression. Both depressed and anxious subjects had poorer functioning on all dimensions of HRQOL, even after controlling for demographics, hemoglobin type, and pain. The anxious subjects had more pain, distress from pain, and interference from pain, both on non-crisis days and on crisis days, and used opioids more often. Anxious patients were also more likely to be emergency room “frequent flyers.”


Chronic and Acute Pain and Opioid Use

As noted above, recurrent painful crises represent the most common reason patients with SCD seek acute medical care. Painful crises most frequently involve the abdomen, chest, back, and extremities. The average adult patient experiences <1 vaso-occlusive crisis per year for which he or she seeks medical care, but a very small fraction (approximately 1%) do so several times per year.24 However, the PiSCES found that most self-defined painful crises do not result in acute healthcare visits.6 Both the unpredictability and the severity of crisis pain contribute to its psychological morbidity and debilitation. It is interesting that higher hematocrit is associated with more pain. Contrary to many studies of acute and chronic pain of other causes, men and women with SCD report generally similar pain experiences, both in terms of acute crisis pain and chronic pain, as well as HRQOL.8,9

Opioid analgesics are the mainstay of therapy for acute pain crises in SCD. Therefore, by adulthood, most patients have had many years of intermittent exposure to opioids. Opioids help control pain, improve functional capacity, and decrease hospitalizations in patients with SCD.25 Chronic opioid use often results in tolerance and physiologic dependence, but much less often abuse and addiction. Opioid abuse and addiction behaviors can be difficult to define when prescribed for chronic pain. While there is little evidence in the medical literature that suggests addiction is frequent in SCD, physicians and other healthcare providers routinely overestimate its risk and prevalence.26 Over 60% of nurses believe addiction is prevalent in SCD,27 and >50% of emergency department physicians and 25% of hematologists thought that >20% of SCD patients are addicted.28 Some of this distorted perception results from failure to distinguish between physiologic tolerance and dependence versus addictive behaviors.22

Because of their fear of causing or exacerbating addiction, physicians may under-treat pain in patients with SCD.29 This may result in pseudoaddiction, where addiction-like behaviors occur as a result of inadequate pain management.30 An example mislabeled as “drug-seeking behavior” occurs when a patient with acute crisis pain asks for a higher dose of opioid than he has been given because the physician has failed to increase normal dosage in recognition of tolerance developed through chronic opioid therapy.22 Opioid abuse and addiction can occur in adults with SCD; some patients may inappropriately use opioids for non-pain symptoms such as insomnia, depression, and anxiety. It should be noted, however, that opioids do not have any specific adverse effects on SCD. In contrast, cocaine is very harmful since in causing small vessel spasm it may precipitate or escalate sickling, and it increases the already elevated risk of stroke and other ischemic events.31 One form of opioid misuse in SCD to be aware of is the barter exchange of prescribed opioids for cocaine. This possibility should always be considered whenever a urine toxicology screen is negative for opioids in a SCD patient who says he has been taking his analgesic as prescribed.


Coping Style

Numerous studies have examined the influence of coping style in SCD, specifically how negative thinking and passive adherence contribute to increases in pain perception, opioid use, and healthcare utilization.11 “Negative thinking” is a cognitive set composed of catastrophizing and self-statements of fear and anger, in which catastrophizing has seemed the most important component in pain research. “Catastrophizing” refers to an exaggerated negative orientation or “mental set” toward pain stimuli and pain experience. Individuals who catastrophize may develop beliefs with a high degree of aversion to pain-eliciting situations, pay more attention to their pain sensations, and consume more opioids.32 Catastrophizing can be understood as a set that includes rumination, magnification, and helplessness to deal with pain. Although it has been identified as an important factor affecting outcomes in several painful conditions, it appears that the role of catastrophizing in other conditions cannot be generalized to SCD. While adults with SCD have higher mean catastrophizing scores than found in studies of other chronic pain conditions that are not lifelong and life-threatening, no differences were found between higher and lower catastrophizers in intensity of pain, distress, interference, opioid use, or healthcare utilization.11


Alcohol Abuse

Alcohol abuse is common in patients with chronic pain and painful medical disorders, but until recently it had not been studied in SCD. In the prospective PiSCES cohort, almost one-third of SCD adults were abusing alcohol.10 There were no significant differences between alcohol abusers and nonabusers on demographics, biologic variables, depression, anxiety, or measures of pain and crisis. Alcohol abusers did not use opioids any more often, but they reported more pain relief from opioids than did nonabusers. Alcohol abusers had fewer unscheduled clinic visits, emergency room visits, hospital days, and any healthcare utilization for SCD; however, this was only statistically significant for emergency room visits. Surprisingly, QOL was similar between both groups, except that alcohol abusers unexpectedly had better overall physical QOL. Alcohol abusers were more likely to report coping by ignoring pain, diverting attention, and using particular self statements.


Psychosocial Interventions

There have only been a few small short-term biobehavioral intervention trials that have attempted to alter pain and healthcare utilization in SCD. A multidimensional, intense intervention to improve pain management of SCD patients through counseling and carefully monitored opioid prescribing reduced emergency department visits and hospital admissions.33

In another trial,34 a pain-coping skills intervention in adults with SCD lowered pain perceptions from a laboratory-induced pain stimulus and significantly increased coping attempts. On pain days when subjects used coping strategies, they had fewer healthcare contacts than on pain days when they did not use coping strategies. Other interventions have met with limited success. A brief training in cognitive coping skills resulted in increased coping attempts, decreased negative thinking, and lower tendency to report pain during laboratory-induced noxious stimulation.35 A family intervention in children met with some success.36 Self hypnosis as an adjunct to traditional treatment improved sleep, reduced pain days, and reduced. the use of pain medications.37 There are no published randomized controlled trials of antidepressants in patients with SCD.


Central Nervous System Injury

Brain disease from SCD complications may begin early in life. Children with SCD may experience a wide variety of neurologic syndromes, including ischemic and hemorrhagic stroke, transient ischemic attacks, “soft neurologic signs,” seizures, headache, coma, visual loss, altered mental status, cognitive difficulties, and covert or “silent” infarction. Approximately 25% to 33% of affected children have CNS consequences of SCD.38 Seizures occur in 12% to 14%.39,40  Once very common in children with SCD, the incidence of stroke has been reduced through chronic transfusion and other interventions.41 Intellectual deficits, including borderline-to-moderate mental retardation and reduced language function, have been reported.42 Not surprisingly, cognitive deficits in children with SCD lead to educational and social problems, and even dementia later in life.43 Acquired neurologic impairments in children with SCD are associated with difficulties in the decoding of emotions of other children and adults.44 A small, nonrandomized study45 suggests that hydroxyurea therapy may improve cognitive functioning in SCD. PP



1. Becker M, Axelrod DJ, Oyesanmi O, Markov DD, Kunkel EJ. Hematologic problems in psychosomatic medicine.Psychiatr Clin North Am. 2007;30(4):739-759.
2. Committee on Understanding and Eliminating Racial and Ethnic Disparities in Health Care. Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care. 1st ed. Washington, DC: National Academies Press; 2002.
3. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994;330(23):1639-1644.
4. Lee A, Thomas P, Cupidore L, Serjeant B, Serjeant G. Improved survival in homozygous sickle cell disease: lessons from a cohort study. BMJ. 1995;311(7020):1600-1602.
5. Gaston MH, Rosse W. The cooperative study of sickle cell disease: review of study design and objectives. Am J Pediatr Hematol Oncol. 1982;4(2):197-200.
6. Smith WR, Penberthy LT, Bovbjerg VE, et al. Daily pain in sickle cell disease. Ann Intern Med. 2008;148(2):94-101.
7. Smith WR, Bovbjerg VE, Penberthy LT, et al. Understanding pain and improving management of sickle cell disease: the PiSCES study. J Natl Med Assoc. 2005;97(2):183-193.
8. McClish DK, Penberthy LT, Bovbjerg VE, et al. Health related quality of life in sickle cell patients: the PiSCES project. Health Qual Life Outcomes. 2005;3:50.
9. McClish DK, Levenson JL, Penberthy LT, et al. Gender differences in pain and health care utilization for adult sickle cell patients: the PiSCES Project. J Womens Health (Larchmt). 2006;15(2):146-154.
10. Levenson JL, McClish DK, Dahman BA, et al. Alcohol abuse in sickle cell disease: the PiSCES project. Am J Addict. 2007;16(5):383-388.
11. Citero VA, Levenson JL, McClish DK, et al. The role of catastrophizing in sickle cell disease–the PiSCES project. Pain. 2007;133(1-3):39-46.
12. Aisiku IP, Penberthy LT, Smith WR, et al. Patient satisfaction in specialized versus nonspecialized adult sickle cell care centers: the PiSCES study. J Natl Med Assoc. 2007;99(8):886-890.
13. Levenson JL, McClish DK, Dahman BA, et al. Depression and anxiety in adults with sickle cell disease: the PiSCES project. Psychosom Med. 2008;70(2):192-196.
14. Alao AO, Cooley E. Depression and sickle cell disease. Harv Rev Psychiatry. 2001;9(4):169-177.
15. Alao AO, Dewan MJ, Jindal S, Effron M. Psychopathology in sickle cell disease. West Afr J Med. 2003;22(4):334-337.
16. Wison Schaeffer JJ, Gil KM, Burchinal M, et al. Depression, disease severity, and sickle cell disease. J Behav Med. 1999;22(2):115-126.
17. Hasan SP, Hashmi S, Alhassen M, Lawson W, Castro O. Depression in sickle cell disease. J Natl Med Assoc. 2003;95(7):533-537.
18. Laurence B, George D, Woods D. Association between elevated depressive symptoms and clinical disease severity in African-American adults with sickle cell disease. J Natl Med Assoc. 2006;98(3):365-369.
19. Molock SD, Belgrave FZ. Depression and anxiety in patients with sickle cell disease: conceptual and methodological considerations. J Health Soc Policy. 1994;5(3-4):39-53.
20. Ehigie BO. Comparative analysis of the psychological consequences of the traumatic experiences of cancer, HIV/AIDS, and sickle cell anemia patients. IFE Psychologia. 2003;11(3):34-54.
21. Scott KD, Scott AA. Cultural therapeutic awareness of sickle cell anemia. J Black Psychol. 1999;25(3):316-335.
22. Elander J, Lusher J, Bevan D, Telfer P, Burton B. Understanding the causes of problematic pain management in sickle cell disease: evidence that pseudoaddiction plays a more important role than genuine analgesic dependence. J Pain Symptom Manage. 2004;27(2):156-169.
23. Hurtig AL, Park KB. Adjustment and coping in adolescents with sickle cell disease. Ann N Y Acad Sci. 1989;565:172-182.
24. Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease. Rates and risk factors. N Engl J Med. 1991;325(1):11-16.
25. Brookoff D, Polomano R. Treating sickle cell pain like cancer pain. Ann Intern Med. 1992;116(5):364-368.
26. Labbe E, Herbert D, Haynes J. Physicians’ attitude and practices in sickle cell disease pain management. J Palliat Care. 2005;21(4):246-251.
27. Pack-Mabien A, Labbe E, Herbert D, Haynes J Jr. Nurses’ attitudes and practices in sickle cell pain management. Appl Nurs Res. 2001;14(4):187-192.
28. Shapiro BS, Benjamin LJ, Payne R, Heidrich G. Sickle cell-related pain: perceptions of medical practitioners. J Pain Symptom Manage. 1997;14(3):168-174.
29. Labbe E, Herbert D, Haynes J. Physicians’ attitude and practices in sickle cell disease pain management. J Palliat Care. 2005;21(4):246-251.
30. Weissman DE, Haddox JD. Opioid pseudoaddiction–an iatrogenic syndrome. Pain. 1989;36(3):363-366.
31. Strauss A, LaCandia S. Sickle cell disease and cocaine abuse–a deadly mixture? South Med J. 1989;82(11):1455-1456.
32. Elander J, Lusher J, Bevan D, Telfer P. Pain management and symptoms of substance dependence among patients with sickle cell disease. Soc Sci Med. 2003;57(9):1683-1696.
33. Grant MM, Gil KM, Floyd MY, Abrams M. Depression and functioning in relation to health care use in sickle cell disease. Ann Behav Med. 2000;22(2):149-157.
34. Gil KM, Carson JW, Porter LS, et al. Daily stress and mood and their association with pain, healthcare use, and school activity in adolescents with sickle cell disease. J Pediatr Psychol. 2003;28(5):363-373.
35. Gil KM, Carson JW, Porter LS, Scipio C, Bediako SM, Orringer E. Daily mood and stress predict pain, health care use and work activity in African-American adults with sickle cell disease. Health Psychol. 2004;23(3):267-274.
36. Vichinsky EP, Johnson R, Lubin BH. Multidisciplinary approach to pain management in sickle cell disease. Am J Pediatr Hematol Oncol. 1982;4(3):328-333.
37. Gil KM, Carson JW, Sedway JA, Porter LS, Schaeffer JJ, Orringer E. Follow-up of coping skills training in adults with sickle cell disease: analysis of daily pain and coping practice diaries. Health Psychol. 2000;19(1):85-90.
38. Schatz J, McClellan CB. Sickle cell disease as a neurodevelopmental disorder. Ment Retard Dev Disabil Res Rev. 2006;12(3):200-207.
39.Prengler M, Pavlakis SG, Boyd S, Connelly A, Calamante F, Chong WK, Saunders D, Cox T, Bynevelt M, Lane R, Laverty A, Kirkham FJ. Sickle cell disease: ischemia and seizures. Ann Neurol. 2005;58(2):290-302.
40. Liu JE, Gzesh DJ, Ballas SK. The spectrum of epilepsy in sickle cell anemia. J Neurol Sci. 1994;123(1-2):6-10.
41. Wang WC. The pathophysiology, prevention, and treatment of stroke in sickle cell disease. Curr Opin Hematol. 2007;14(3):191-197.
42. Hariman LM, Griffith ER, Hurtig AL, Keehn MT. Functional outcomes of children with sickle-cell disease affected by stroke. Arch Phys Med Rehabil. 1991;72(7):498-502.
43. Anie KA. Psychological complications in sickle cell disease. Br J Haematol. 2005;129(6):723-729.
44. Boni LC, Brown RT, Davis PC, Hsu L, Hopkins K. Social information processing and magnetic resonance imaging in children with sickle cell disease. J Pediatr Psychol. 2001;26(5):309-319.
45. Puffer E, Schatz J, Roberts CW. The association of oral hydroxyurea therapy with improved cognitive functioning in sickle cell disease. Child Neuropsychol. 2007;13(2):142-154.

 e-mail: ns@mblcommunications.com


Dr. Sussman is editor of Primary Psychiatry and professor of psychiatry at the New York University School of Medicine in New York City.

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


In this issue, Ahmad Ghanizadeh, MD, and Mohsen Kianpoor, MD, provide a case report on the cessation of risperidone-induced incontinency by valproate in a child with pervasive developmental disorder. They begin by noting that risperidone may be associated with a high rate of urinary incontinency among children with developmental disorders. There are several cases of risperidone-induced incontinency (eg, in autistic children). Some of the studies reported enuresis in cases where patients were taking both risperidone and a selective serotonin reuptake inhibitor. Although there are some explanations for the possible association of risperidone and enuresis, the authors do not have any explanation for this possible effect of valproate on cessation of incontinency.

It is generally agreed that existing pharmacologic agents for psychiatric disorders leave much to be desired both in terms of efficacy and tolerability. The same can be said about the various forms of psychotherapy. Thus, the search for drugs with new mechanisms is ongoing, as are attempts to match existing treatments to symptom subtypes and to apply all types of treatment, both “drug” and “talk,” more effectively. The remaining articles in this issue address this situation.

No area of psychopharmacology research has caught my imagination as much as the studies of the mood effects of ketamine. Ketamine is an anesthetic agent that has also been used recreationally as a so-called “club drug.” Interest in its use as a therapeutic agent in psychiatric disorders has come from observation that some depressed patients given ketamine during surgery experience a dramatic improvement of their mood.

Marije aan het Rot, PhD, and colleagues, report on intravenous ketamine for treatment-resistant major depressive disorder (MDD). The unique aspect of ketamine, apart from its mechanism of action, is that unlike conventional pharmacologic treatments for MDD it does not take several weeks to several months to have a clinically meaningful effect. The authors note that two published studies have provided evidence for rapid and robust antidepressant efficacy of a single intravenous (IV) infusion with a sub-anesthetic dose of ketamine compared with an infusion of saline. Moreover, in >50% of patients who responded, therapeutic benefits were maintained for several days and up to 2 weeks. The authors review the pathophysiologic rationale for ketamine’s antidepressant activity and the clinical evidence for the use of IV ketamine for treatment of MDD, its safety uncertainty to be explored in future studies.

Regarding antidepressant treatment, recent decades have been dominated by selective or dual reuptake inhibitors, which involve serotonin, norepinephrine, or dopamine. In an article about triple reuptake inhibitors, Yanqi Liang, PhD and Elliott Richelson, MD, describe research on possible next-generation antidepressants. They note that preclinical data on these compounds remains limited, but that it is reasonable to speculate that a broad-spectrum antidepressant will produce a more rapid onset and better efficacy than agents that only inhibit the reuptake of serotonin and/or norepinephrine. The triple reuptake agents would also target dopamine. Some triple reuptake inhibitors (serotonin, norepinephrine, and dopamine reuptake inhibitors) are being developed.This article presents preclinical and clinical trials of developing these agents.

One type of depression, psychotic major depression, is both poorly understood and difficult to treat. Treatment is complicated by the presence of delusions, hallucinations, and more severe cognitive symptoms. In their article on psychotic major depression, Charles DeBattista, MD, and Anna Lembke, MD, note that current standard of care for this illness is either combination treatment with an antidepressant plus an antipsychotic, or electroconvulsive therapy (ECT), but that this standard is based on relatively limited data. They review the strength of evidence supporting the use of currently available treatments as well as the risks of treatment. The authors also note how the role of investigational treatments, including glucocorticoid antagonists and transcranial magnetic stimulation, await further investigation.  In the meantime, they suggest that 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.

In addition to having expertise in the selection and use of pharmacologic agents, clinicians need to understand the cultural context of the patient. This is an important and often overlooked dimension of mental illness and its management. Manuel Trujillo, MD, discusses the necessary body of knowledge, skills, and attitudes which can help clinicians bridge the care gaps created by cultural barriers. His article highlights means to overcome these barriers when performing diagnostic interviews, completing mental status examinations, and selecting the most appropriate interventions. He argues that a desired end result of training to treat mental disorders will be an enhanced ability to provide “culturally competent care.” PP


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.



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.





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.



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




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.



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



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.





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.



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



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.



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.



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



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.



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. 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.



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.



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

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.

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.

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.

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 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 (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 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 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 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 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 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 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 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.

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 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.

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.



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.



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



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.