CONCLUSIONS

This chapter reviewed both the literature and the authors' recent studies bearing on the hypothesis that depression can be treated in patients with substance use disorders and that such treatment will improve the outcome of substance abuse. The literature actually covers a large number of placebo-controlled trials in which various antidepressant medications were tested as treatments in clinical populations with substance use disorders. These include studies of several antidepressants and lithium in alcoholic samples, of antidepressants in samples with cocaine abuse, as well as samples with opiate dependence. As a whole, the literature is inconclusive on the question of whether treatment of depression is effective in such populations. Many of the studies selected depressed patients on the basis of cross-sectional mood scales rather than clinical history and syndromal diagnosis, which may have resulted in samples replete with transient, substanceinduced mood syndromes or adjustment reactions to stress rather than true mood disorders. The result is high placebo response rates and little or no medication effect. Other studies, including those of cocaine abusers, were not designed to treat depression, but to test whether the medication had any direct effect on drug use behavior. The authors and colleagues, seeking to fill the gap in the literature, are conducting a series of studies in substance abusers with depression diagnosed by clinical interview, using criteria designed to select patients with primary or chronic depression. Pilot studies in depressed outpatient alcoholics and in depressed methadone maintenance patients, as well as preliminary analysis of a large trial in methadone patients, suggest that depression can be identified in substance abusers and that it responds robustly to standard antidepressant medication treatment. There is also evidence of a beneficial effect on substance use itself, although this appears to be less robust and further study is needed to determine its true extent. These findings have theoretical implications for the relationship between substance use disorders and depression (see table 1), suggesting that the disorders are at least in part independent. Depression can be identified and treated, and substance use may be reduced, but in most cases it does not vanish as one would predict were a patient taking drugs purely to self-medicate. Instead, depression is probably only one of several factors that contribute to the onset or maintenance of an addiction. It is also possible that mood disorders are responsible for initiation of drug use, but that the drug use itself is so rewarding that it takes on a life of its own. In terms of clinical implications, the conclusion that pure selfmedication is rare does not diminish the importance of identifying and treating depression as part of a comprehensive plan of addiction treatment. Even if depression and addiction are entirely independent disorders, depression carries its own associated morbidity and mortality (Murphy et al. 1992). There is ample evidence that psychopathology is associated with poor prognosis for substance abuse. The effect of ameliorating these symptoms on prognosis of drug abuse requires further study. Future Directions

These findings suggest several future directions for research. There are still relatively few well-designed studies of the treatment of comorbid psychiatric disorders in substance-dependent patients. The older studies, as noted, tended to have methodologic limitations. Recent studies on treatment of depression (Mason and Kocsis 1991; Nunes et al. 1993), as well as a recent series on buspirone in anxious alcoholics (Malcolm et al. 1992; Tollefson et al. 1990; Kranzler et al. 1994), suggest that the strategy of identifying and treating psychiatric comorbidity in substance abusers is worth pursuing. Several replication-extensions of the recent work might be considered with other antidepressant agents, other comorbid mood or anxiety disorders, and other substance use disorders. Several examples follow. • Newer antidepressant agents: Most trials to date have involved tricyclic antidepressants. Trials with newer agents, such as specific serotonin uptake inhibitors, seem worthwhile because these may have fewer side effects and a greater margin for safety, or exert a stronger effect on depression or substance abuse or both. • Depressed cocaine abusers: Given the inconsistent results of desipramine trials in unselected cocaine abusers, a trial of desipramine in selected depressed cocaine abusers would be useful. No such trial has been reported to date. • Psychotherapy of depression: Recently developed shortterm psychotherapy methods, cognitive therapy (Wright 1988; Elkin et al. 1989; Klein and Ross 1993), and interpersonal psychotherapy (Klerman et al. 1984; Elkin et al. 1989; Klein and Ross 1993) have demonstrated some efficacy in the treatment of depression. These warrant testing as alternatives to pharmacotherapy in depressed substance abusers because of concerns about the risks of medication interactions with illicit substances. • Combined pharmacotherapy and psychotherapy: The literature suggests that effective antidepressant medication treatment in depressed substance abusers only partially reduces the drive to use drugs or alcohol. This suggests that antidepressants might best be applied as part of a multifaceted treatment strategy. For example, antidepressants could be studied in combination with promising techniques such as cognitive-behavioral therapy (Woody et al. 1983), relapse prevention (Carroll et al. 1991; Daley and Marlatt 1992; Marlatt and Gordon 1985; McAuliffe and Chi'en 1986; Rawson et al. 1991), cue extinction (Childress et al. 1992), or contingency management (Higgins et al. 1993; Iguchi et al. 1988; Stitzer et al. 1992). A two-way factorial design is possible, crossing two levels of medication (placebo, antidepressant) with two levels of therapy (standard versus enhanced intervention). An elegant example of such a study in cocaine abusers not selected for depression has recently been published (Carroll et al. 1994). A second important line of research would focus on improving methods of identifying "true" depression in substance abusers, including those who may still be actively using. Certainly, the ideal method is to conduct a psychiatric diagnostic interview after at least 2 to 4 weeks of abstinence. However, the ideal is often difficult to achieve. Many patients will have difficulty abstaining as outpatients, and inpatient stays may not be available to uninsured patients, for example, or too short to be useful, even with insurance. In addition, some patients will decline hospitalization for legitimate reasons such as work or family responsibilities. Hypothesizing that features of the clinical history can be used to identify treatable depression, the authors have developed a special version of the Structured Clinical Interview for DSM, the SCIDSubstance Abuse Comorbidity (SCID-SAC) (Nunes et al., in press), which elicits these features. They include whether the depression antedated the onset of substance abuse, whether it persisted during historical periods of abstinence (such as during an episode of successful treatment or a stint in jail), and the extent to which the depression is chronic or longstanding. Rounsaville and colleagues (1991) suggest that depression emerging during a period of stable substance use may be a valid criterion for selecting "true" depression. Hasin and colleagues have developed a highly detailed structured interview, the PRISM (Hasin et al. 1994), which elicits a number of historical features connecting substance use to comorbid mental disorders. Further study of the reliability and predictive validity of such historical features and of instruments such as the SCID-SAC and PRISM are needed. Clearly, better tools for sample selection will improve the power and precision of clinical trials of antidepressant agents in substance abusers. Research should also be considered on biological tests that might aid in diagnosis. Unfortunately, biological tests for depression, such as the dexamethasone suppression test (DST), are still of very limited use, and lack sensitivity and specificity. The extensive literature on the DST in substance abusers (Kroll et al. 1983; Willenbring et al. 1984; Ravi et al. 1984; Khan et al. 1984; Abou-Saleh et al. 1984; Newsom and Murray 1983; Johnson and Perry 1986; Burch et al. 1986; Dackis et al. 1984, 1986; Zern et al. 1986), for example, shows that the DST is influenced by recent substance use, and therefore it is not very useful in distinguishing depression. However, better tests may become available. In addition, a nascent literature suggests that physiologic challenge with sodium lactate infusion (Baron et al. 1990; Cowley et al. 1989; George et al. 1989) may have promise for identifying panic disorder in alcoholics. Finally, a number of research questions exist in the realm of services. If the approach to diagnosing and treating depression and other comorbid mental disorders is applied in drug treatment clinics in the community, what are the risk-benefit and cost-effectiveness ratios? Do the benefits outweigh the risks? How can a diagnostic-therapeutic enhancement be delivered efficiently, at a low enough cost to justify what may be marginal improvements in outcome? For example, having an experienced psychiatric diagnostician interview all patients admitted to a substance use clinic and follow those with suspected comorbidity requires a substantial amount of the time of an expensive staff member. Could regular counselors use screening instruments to do the case finding during their routine contacts with patients? Answering this question calls for a straightforward design comparing the sensitivity and specificity of counselors' screenings, of different screening instruments instead of gold standard psychiatric interview, and the time and cost of the approaches. Designs addressing risk-benefit and cost-effectiveness of treatment interventions are more problematic and require further methodologic development. The crux of the problem is that long-term treatment and followup are needed, but it is ethically difficult to justify randomizing depressed patients, for example, to a placebo control condition for 6 to 12 weeks when acute efficacy studies suggest that the depression would respond to treatment. Quasi-experimental designs, with careful attention to identifying and minimizing potential biases in nonrandomized control conditions, may be needed.

REFERENCES

Abou-Saleh, M.T.; Merry, J.; and Coppen, A. Dexamethasone suppression test in alcoholism. Acta Psychiatry Scand 69:112-116, 1984. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994. Arndt, I.O.; Dorozynsky, L.; Woody, G.E.; McLellan, A.T.; and O'Brien, C.P. Desipramine treatment of cocaine dependence in methadone-maintenance patients. Arch Gen Psychiatry 49:888-893, 1992. Baron, D.H.; Sands, B.F.; Ciraulo, D.A.; and Shader, R.I. The diagnosis and treatment of panic disorder in alcoholics: Three cases. Am J Drug Alcohol Abuse 16(3 & 4):287-295, 1990. Batki, S.; Wheeler, S.; Jones, R.; Sorensen, J.; and Brennan, K. Doxepin treatment of depressed opiate addicts undergoing methadone detoxi-fication. National Institute on Drug Abuse Research Monograph. NIH Pub. No. 61-12192. Washington, DC: Supt. of Docs., U.S. Govt. Print. Off., 1987. pp. 81-292. Batki, S.L. Double-blind fluoxetine treatment for cocaine dependence in MMT. In: Harris, L., ed. Problems of Drug Dependence, 1992. National Institute on Drug Abuse Research Monograph 132. NIH Pub. No. 93-3505. Washington, DC: Supt. of Docs., U.S. Govt. Print. Off., 1993. Batki, S.L.; Manfredi, L.B.; Sorensen, J.L.; Jacob, P.; Dumontet, R.; and Jones, R.T. Fluoxetine for cocaine abuse in methadone patients: Preliminary findings. National Institute on Drug Abuse Research Monograph. Washington, DC: Supt. of Docs., U.S. Govt. Print. Off., 1991. pp. 105, 516-517. Burch, E.A., Jr.; Goldschmidt, T.J.; and Schjwartz, B.D. Drug intake and the dexamethasone suppression test. J Clin Psychiatry 47:144-146, 1986. Carroll, M.E.; Lac, S.T.; Asencio, M.; and Kragh, R. Fluoxetine reduces intravenous cocaine self-administration in rats. Pharmacol Biochem Behav 35:237-244, 1990. Carroll, K.M.; Power, M.E.; Bryant, K.; and Rounsaville, B.J. One-year follow-up status of treatment-seeking cocaine abusers. Psychopathology and dependence severity as predictors of outcome. J Nerv Ment Dis 181:71-79, 1993. Carroll, K.M.; Rounsaville, B.J.; and Gawin, F.H. A comparative trial of psychotherapies for ambulatory cocaine abusers: Relapse prevention and interpersonal psychotherapy. Am J Drug Alcohol Abuse 17:229-247, 1991. Carroll, K.M.; Rounsaville, B.J.; Gordon, L.T.; Nich, C.; Jatlow, P.; Bisighini, R.M.; and Gawin, F.H. Psychotherapy and pharmacotherapy for ambulatory cocaine abusers. Arch Gen Psychiatry 51:177-187, 1994. Childress, A.R.; Ehrman, R.; Robsenow, D.J.; Robin, S.J.; and O'Brien, C.P. Classically conditioned factors in drug dependence. In: Lowinson, J.H.; Millman, R.; and Ruiz, P., eds. Substance Abuse: A Comprehensive Textbook. 2d ed. Baltimore: Williams & Wilkins, 1992. pp. 56-69. Childress, A.R.; Ehrman, R.N.; McLellan, A.T.; MacRae, J.; Natale, M.; and O'Brien, C.P. Can induced moods trigger drug-related responses in opiate patients. J Subst Abuse Treat 11:17-23, 1994. Ciraulo, D.A., and Jaffe, J.H. Tricyclic antidepressants in the treatment of depression associated with alcoholism. J Clin Psychopharmol 1:146-150, 1981. Covi, L. "Fluoxetine Treatment of Cocaine Abuse." Paper presented at the annual meeting of the American Psychiatric Association, 1992. Covi, L.; Hess, J.M.; Kreiter, N.A.; and Haertzen, C.A. Effects of combined fluoxetine and counseling in the outpatient treatment of cocaine abusers. Am J Drug Alcohol Abuse 21:327-344, 1995. Cowley, D.S.; Jensen, C.F.; Johannessen, D.; Parker, L.; Dager, S.R.; and Walker, R.D. Response to sodium lactate infusion in alcoholics with panic attack. Am J Psychiatry 146(11):1479-1483, 1989. Croughan, J.L.; Miller, J.P.; Koepke, J.; and Whitman, B.Y. Depression in narcotic addicts—A prospective study with a five-year follow-up. Compr Psychiatry 22:428-433, 1981. Dackis, C.A.; Pottash, A.L.; Gold, M.S.; and Annitto, W. The dexamethasone suppression test for major depression among opiate addicts. Am J Psychiatry 141:810-811, 1984. Dackis, C.A.; Stuckey, R.F.; Gold, M.S.; and Pottash, A.L. Dexamethasone suppression test testing of depressed alcoholics. Alcoholism (NY) 10:50-59, 1986. Daley, D.C., and Marlatt, G.A. Relapse prevention: Cognitive and behavioral interventions. In: Lowinson, J.H.; Ruiz, P.; Millman, R.B.; and Langrod, G., eds. Substance Abuse: A Comprehensive Textbook. Baltimore: Williams & Wilkins, 1992. pp. 533-542. DeLeon, G.; Skodol, A.; and Rosenthal, M.S. Phoenix House: Changes in psychopathological signs of resident addicts. Arch Gen Psychiatry 28:131-135, 1973. Dorus, W.; Ostrow, D.G.; Anton, R.; Cushman, P.; Collins, J.F.; Schaefer, M.; Charles, H.L.; Desai, P.; Hayashida, M.; Malkermeker, U.; Willenbring, M.; Fiscella, R.; and Sather, M.R. Lithium treatment of depressed and non-depressed alcoholics. JAMA 262:1646-1652, 1989. Elkin, I.; Shea, M.T.; and Watkins, J.T. National Institute of Mental Health treatment of depression collaborative research program: General effectiveness of treatments. Arch Gen Psychiatry 46:971-982, 1989. Fawcett, J.; Clark, D.C.; Aagesen, C.A.; Pisani, V.D.; Tilkin, J.M.; Sellers, D.; McGuire, M.; and Gibbons, R.D. A double-blind, placebo-controlled trial of lithium carbonate therapy for alcoholism. Arch Gen Psychiatry 44:248-258, 1987. Fawcett, J.; Clark, D.C.; and Gibbons, R.D. Evaluation of lithium therapy for alcoholism. J Clin Psychiatry 45:494-499, 1984. Gawin, F.H.; Kleber, H.D.; Byck, R.; Rounsaville, B.J.; Kosten, T.R.; Jatlow, P.I.; and Morgan, C. Desipramine facilitation of initial cocaine abstinence. Arch Gen Psychiatry 46:117-121, 1989. George, D.T.; Nutt, D.J.; Waxman, R.P.; and Linnoila, M. Panic response to lactate administration in alcoholic and nonalcoholic patients with panic disorder. Am J Psychiatry 146:11611165, 1989. Giannini, A.J., and Billett, W. Bromocriptine-desipramine protocol in treatment of cocaine addiction. J Clin Pharmacol 27:549554, 1987. Goldstein, --; McBride, --; and Westy, --. as reported in Woody, G.E. 1982. The use of antidepressants with methadone in depressed maintenance patients. Ann New York Acad Sci, 1992. p. 124. Gorelick, D. Serotonin uptake blockers and the treatment of alcoholism. In: Recent Developments in Alcoholism: Treatment Research. Vol. 7. New York: Plenum Press, 1989. pp. 267-281. Grabowsky, J.; Rhoades, H.; Elk, R.; Schmitz, J.; Davis, C.; Creson, D.; and Kirby, K. Fluoxetine is ineffective for treatment of cocaine dependence or concurrent opiate and cocaine dependence: Two placebo-controlled trials. J Clin Psychopharmacol 15(3):163-174, 1995. Hasin, D.; Dietz-Trautman, K.; Grant, B.; and Endicott, J. PRISM. New York State Psychiatric Interview. New York: New York State Psychiatric Institute, 1994. Higgins, S.T.; Budney, A.J.; Bickel, W.K.; Hughes, J.R.; Foerg, F.; and Badger, G. Achieving cocaine abstinence with a behavioral approach. Am J Psychiatry 150:763-769, 1993. Iguchi, M.Y.; Stitzer, M.L.; Bigelow, G.E.; and Liebson, I.A. Contingency management in methadone maintenance: Effects of reinforcing and aversive consequences on illicit polydrug use. Drug Alcohol Depend 22:1-7, 1988. Johnson, B., and Perry, J.C. The relationship between depression and the dexamethasone suppression test following alcohol withdrawal in a psychiatric population. J Clin Psychopharmacol 6:343-349, 1986. Keeler, M.H.; Taylor, G.I.; and Miller, W.C. Are all recently detoxified alcoholics depressed? Am J Psychiatry 136:586-588, 1979. Khan, A.; Ciraulo, D.A.; Nelson, W.H.; Becker, J.T.; Nies, A.; and Jaffe, J.H. Dexamethasone suppression test in recently detoxified alcoholics: Clinical implications. J Clin Psychopharmacol 4:94-97, 1984. Khantzian, E.J. The self-medication hypothesis of addictive disorders: Focus on heroin and cocaine dependence. Am J Psychiatry 142(11):1259-1264, 1985. Kleber, H.D.; Weissman, M.M.; Rounsaville, B.J.; Wilber, C.H.; Prusoff, B.A.; and Riordan, C.E. Imipramine as treatment for depression in addicts. Arch Gen Psychiatry 40:649-653, 1983. Klein, D.F., and Ross, D.C. Reanalysis of the National Institute of Mental Health treatment of depression collaborative research report: General effectiveness. Neuropsychopharmacology 8:241-252, 1993. Klerman, G.L.; Weissman, M.M.; Rounsaville, B.J.; and Chevron, E.S. Interpersonal Psychotherapy of Depression. New York: Basic Books, 1984. Kleven, M.S., and Woolverton, W.L. Effects of three monoamine uptake inhibitors on behavior maintained by cocaine or food presentation in rhesus monkeys. Drug Alcohol Dependence 31:149-158, 1993. Kline, N.S.; Wren, J.C.; Cooper, T.B.; Varga, E.; and Canal, O. Evaluation of lithium therapy in chronic and periodic alcoholism. Am J Med Sci 268:15-22, 1974. Kosten, T.R.; Gawin, F.H.; Morgan, C.; Nelson, J.C.; and Jatlow, P. Evidence for altered desipramine disposition in methadone-maintained patients treated for cocaine abuse. Am J Drug Alcohol Abuse 16:329-336, 1990. Kosten, T.R.; Morgan, C.M.; Falcione, J.; and Schottenfeld, R.S. Pharmacotherapy for cocaine-abusing methadonemaintained patients using amantadine or desipramine. Arch Gen Psychiatry 49:894-898, 1992. Kosten, T.R.; Rounsaville, B.J.; and Kleber, H.D. A 2.5 year follow-up of depression, life crises, and treatment effects on abstinence among opioid addicts. Arch Gen Psychiatry 43:733-738, 1986. Kranzler, H.R.; Burleson, J.A.; DelBoca, F.K.; Babor, T.F.; Korner, P.; Brown, J.; and Bohn, M.J. Buspirone treatment of anxious alcoholics: A placebo controlled trial. Arch Gen Psychiatry 51:720-731, 1994. Kroll, P.; Palmer, C.; and Greden, J.F. The Dexamethasone Suppression Test in patients with alcoholism. Biol Psychiatry 18:441450, 1983. LaPorte, D.J.; McLellan, A.T.; O'Brien, C.P.; and Marshall, J.R. Treatment response in psychiatrically impaired drug abusers. Compr Psychiatry 22:411-419, 1981. Liskow, B.I., and Goodwin, D.W. Pharmacological treatment of alcohol intoxication, withdrawal and dependence: A critical review. J Stud Alcohol 48:356-370, 1987. Loosen, P.T.; Dew, B.W.; and Prange, A.J. Long-term predictors of outcome in abstinent alcoholic men. Am J Psychiatry 147:1662-1666, 1990. Malcolm, R.; Anton, R.F.; Randall, C.L.; Johnston, A.; Brady, K.; and Thevos, A. A placebo-controlled trial of buspirone in anxious inpatient alcoholics. Alcohol Clin Exp Res 166(6):1007-1013, 1992. Markou, A.; Hauger, R.L.; and Koob, G.F. Desmethylimipramine attenuates cocaine withdrawal in rats. Psychopharmacology 109:305-314, 1992. Marlatt, G.A., and Gordon, J.R. Relapse Prevention: Maintenance Strategies in the Treatment of Addictive Behaviors. New York: Guilford Press, 1985. Mason, B.J., and Kocsis, J.H. Desipramine treatment of alcoholism. Psychopharmacol Bull 27:155-161, 1991. McAuliffe, W.E., and Chi'en, J.M.N. Recovery training and self-help: A relapse-prevention program for treated opiate addicts. J Subst Abuse Treat 3:9-20, 1986. Merry, J.; Reynolds, C.M.; Bailey, J.; and Coppen, A. Prophylactic treatment of alcoholism by lithium carbonate: A controlled study. Lancet September 4, 1976. pp. 481-482. Meyer, R.E. How to understand the relationship between psycho-pathology and addictive disorders: Another example of the chicken and the egg. In: Meyer, R.E., ed. Psychopathology and Addictive Disorders. New York: Guilford Press, 1986. pp. 3-16. Murphy, G.E.; Wetzel, R.D.; Robins, E.; and McEvoy, L. Multiple risk factors predict suicide in alcoholism. Arch Gen Psychiatry 49:459-463, 1992. Nakamura, M.M.; Overall, J.E.; Hollister, L.E.; and Radcliffe, E. Factors affecting outcome of depressive symptoms in alcoholics. Alcoholism (NY) 7:188-193, 1983. Naranjo, C.; Kadlec, K.; Sanhueza, P.; Woodley-Remus, D.; and Sellers, E. Fluoxetine differentially alters alcohol intake and other consummatory behaviors in problem drinkers. Clin Pharmacol Ther 47:490-498, 1990. Newsom, G., and Murray, N. Reversal of the dexamethasone suppression test: Nonsuppression in alcohol abusers. Am J Psychiatry 140:353-354, 1983. Nunes, E.V.; Goehl, L.; Seracini, A.; Deliyannides, D.; Donovan, S.; PostKoenig, T.; Quitkin, F.M.; and Williams, J.B.W. Evaluation of depression and panic disorder in substance abusers using a modification of the structured clinical interview for DSM-III-R: Test-retest reliability. Am J Addict, in press. Nunes, E.V.; McGrath, P.J.; Quitkin, F.M.; Stewart, J.P.; Harrison, W.; Tricamo, E.; and Ocepek-Welikson, K. Imipramine treatment of alcoholism with comorbid depression. Am J Psychiatry 150:963-965, 1993. Nunes, E.V.; McGrath, P.J.; Quitkin, F.M.; Stewart, J.W.; Ocepek-Welikson, K.; Wager, S.; Koenig, T.; and Klein, D.F. Imipramine treatment of cocaine abuse: Possible boundaries of efficacy. Drug Alcohol Depend 39:185-195, 1995. Nunes, E.V.; Quitkin, F.; Brady, R.; and Post-Koenig, T. Antidepressant treatment in methadone maintenance patients. J Addict Dis 13:13-24, 1994. Nunes, E.V.; Quitkin, F.M.; Brady, R.; and Stewart, J.W. Imipramine treatment of methadone maintenance patients with affective disorder and illicit drug use. Am J Psychiatry 148:667-669, 1991. Pond, S.; Becker, C.; Vandervoort, R.; Philipps, N.; Bowler, R.; and Peck, C. An evaluation of the effects of lithium in the treatment of chronic alcoholism: Clinical reports. Alcohol Clin Exp Res 5:247-251, 1981. Pottenger, M.; McKernon, J.; and Patrie, L.E. The frequency and persistence of depressive symptoms in the alcohol abuser. J Nerv Ment Dis 166:562-570, 1978. Quitkin, F.M. The importance of dosage in prescribing antidepressants. Br J Psychiatry 147:593-597, 1985. Quitkin, F.M.; Rabkin, J.G.; Ross, D.; and McGrath, P.J. Duration of antidepressant drug treatment: What is an adequate trial? Arch Gen Psychiatry 41:238-245, 1984. Quitkin, F.M.; Rifkin, A.; Kaplan, J.; and Klein, D.F. Phobic anxiety syndrome complicated by drug dependence and addiction: A treatable form of drug abuse. Arch Gen Psychiatry 27:159-162, 1972. Ravi, S.D.; Dorus, W.; Park, Y.N.; Collins, M.C.; Reid, R.W.; and Borge, G.F. The dexamethasone suppression test and depressive symptoms in early and late withdrawal from alcohol. Am J Psychiatry 141:1445-1448, 1984. Rawson, R.A.; Obert, J.L.; McCann, M.J.; and Ling, W. Psychological approaches for the treatment of cocaine dependence—A neurobehavioral approach. J Addict Dis 11:97-119, 1991. Regier, D.A.; Farmer, M.E.; Rae, D.S.; Locke, B.Z.; Keith, S.J.; Judd, L.L.; and Goodwin, F.K. Comorbidity of mental disorders with alcohol and other drug abuse. JAMA 264:2511-2518, 1990. Rounsaville, B.J.; Anton, S.F.; Carroll, K.; Budde, D.; Prusoff, B.A.; and Gawin, F. Psychiatric diagnoses of treatment seeking cocaine abusers. Arch Gen Psychiatry 48:43-51, 1991. Rounsaville, B.J.; Dolinsky, Z.S.; Babor, T.F.; and Meyer, R.E. Psychopathology as a predictor of treatment outcome in alcoholics. Arch Gen Psychiatry 44:505-513, 1987. Rounsaville, B.J.; Kosten, T.R.; and Kleber, H.D. Long-term changes in current psychiatric diagnoses of treated opiate addicts. Compr Psychiatry 27:480-498, 1986a. Rounsaville, B.J.; Kosten, T.R.; Weissman, M.M.; and Kleber, H.D. Prognostic significance of psychopathology in treated opiate addicts: A 2.5 year follow-up study. Arch Gen Psychiatry 43:739-745, 1986b. Rounsaville, B.J.; Weissman, M.M.; Crits-Christoph, K.; Wilber, C.; and Kleber, H. Diagnosis and symptoms of depression in opiate addicts: Course and relationship to treatment outcome. Arch Gen Psychiatry 39:151-156, 1982b. Satel, S.L.; Kosten, T.R.; Schuckit, M.A.; and Fischman, M.W. Should protracted abstinence from drugs be included in DSM-IV? Am J Psychiatry 150:695-704, 1993. Schuckit, M.A. Genetic and clinical implications of alcoholism and affective disorder. Am J Psychiatry 143:140-147, 1986. Stitzer, M.L.; Iguchi, M.Y.; and Felch, L.J. Contingent take-home incentive: Effects on drug use of methadone maintenance patients. J Consult Clin Psychol 60:927-934, 1992. Titievsky, J.; Seco, G.; Barranco, M.; and Kyle, E.M. Doxepin as adjunctive therapy for depressed methadone maintenance patients: A double-blind study. J Clin Psychiatry 43:454-456, 1982. Tollefson, G.D.; Montague-Clouse, J.; and Lancaster, S.P. Buspirone in comorbid alcohol dependency and generalized anxiety disorders. Drug Ther Suppl 1990. pp. 35-50. Weddington, W.W.; Brown, B.S.; Haertzen, C.A.; Cone, E.J.; Dax, E.M.; Herning, R.I.; and Michaelson, B.S. Changes in mood, craving, and sleep during short-term abstinence reported by male cocaine addicts. Arch Gen Psychiatry 47:861868, 1990. Weddington, W.W.; Brown, B.S.; Haertzen, C.A.; Hess, J.M.; Mahaffey, J.R.; Kolar, A.F.; and Jaffe, J.H. Comparison of amantadine and desipramine combined with psychotherapy for treatment of cocaine dependence. Am J Drug Alcohol Abuse 17:137-152, 1991. Weissman, M.D.; Slobetz, F.; and Prusoff, B. Clinical depression among narcotic addicts maintained on methadone in the community. Am J Psychiatry 133:1434-1438, 1976. Willenbring, M.L.; Morley, J.E.; Niewoehner, C.B.; Heilman, R.O.; Carlson, C.H.; and Shafer, R.B. Adrenocortical hyperactivity in newly admitted alcohholics: Prevalence, course and associated variables. Psychoneuroendocrinology 9:415422, 1984. Willis, J.H., and Osbourne, A.B. What happens to heroin addicts? A followup study. Br J Addict 73:189-198, 1978. Wright, J.H. Cognitive therapy of depression. In: Frances, A.J., and Hales, R.E., eds. Review of Psychiatry, Vol. 7. Washington, DC: American Psychiatric Press, 1988. pp. 554-570. Woody, G.E.; Luborsky, L.; and McLellan, A.T. Psychotherapy for opiate addicts: Does it help? Arch Gen Psychiatry 40:639-645, 1983. Woody, G.E.; O'Brien, C.P.; McLellan, A.T.; Marcovici, M.; and Evans, B.D. The use of antidepressants with methadone in depressed maintenance patients. Ann N Y Acad Sci, 1982. pp. 120-127. Woody, G.E.; O'Brien, B.P.; and Rickels, K. Depression and anxiety in heroin addicts: A placebo controlled study of doxepin in combination with methadone. Am J Psychiatry 132:447450, 1975. Zern, M.A.; Halbreich, U.; Bacon, K.; Galanter, M.; Kang, B.J.; and Gasparini, F. Relationship between serum cortisol, liver function, and depression in detoxified alcoholis. Alcoholism (NY) 10:320-322, 1986. Ziedonis, D.M., and Kosten, T.R. Pharmacotherapy improves treatment outcome in depressed cocaine addicts. J Psychoactive Drugs 23:417-425, 1991.