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.
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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. Accessed December 2007.
11.     National Institute on Alcohol Abuse and Alcoholism. Accessed December 2007.
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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.
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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.