The prevalence of substance use disorders in patients with schizophrenia is greater than the rate observed in the general population,1 with a dramatic increase since the 1970s.2
Several theories exist to explain the high rate of comorbidity. The "self-medication" hypothesis3 suggests that persons may abuse substances to treat underlying psychotic symptoms or adverse effects of medications commonly used to treat schizophrenia.4,5 Other hypotheses include the increased availability of substances of abuse, genetic predisposition, and kindling. The findings of a recent laboratory study suggest that persons with schizophrenia may experience enhanced euphoria from alcohol consumption compared with healthy controls.6
No matter what the cause, comorbid substance use disorders among patients with schizophrenia are associated with a number of clinical challenges, including an increased rate of medication noncompliance, more frequent and longer hospitalizations, a higher rate of use of crisis-oriented services, and consequently, a higher cost of care.7 Social problems associated with substance abuse in patients with schizophrenia
include legal entanglement, housing instability, unemployment, and poor money management.8
Because of the serious consequences associated with substance abuse in this population, the development of effective treatments is of utmost clinical importance. Patients with psychotic disorders may be more reluctant to participate in traditional substance abuse treatment programs and self-help groups (such as Alcoholics Anonymous), where most members do not have comorbid psychotic disorders.9 In addition, the cognitive symptoms that are associated with schizophrenia may undermine a patient's motivation and his or her ability to learn new coping strategies in psychosocial treatments. Although specialized psychosocial treatments that focus on behavioral interventions for substance abuse in patients with schizophrenia show promise,10 they require an intensive intervention by highly trained staff.
In contrast, pharmacologic treatments are generally familiar to dually diagnosed patients and require less learning than psychosocial treatments, and the dosing schedule can be readily integrated into the patient's current treatment regimen.
Pharmacologic interventions that have been evaluated (eg, the medications used to treat alcohol dependence, including disulfiram and naltrexone) seem to have clinical use in this population.11 However, these results were from small pilot studies; studies of patients with alcohol dependence and schizophrenia are under way.12,13 In short, effective pharmacotherapies to treat substance abuse in patients with schizophrenia would likely have a widespread positive clinical impact in the treatment of these disorders.
Results of the use of atypical antipsychotics in the treatment of substance use disorders in comorbid populations are promising. The first line of treatment for persons with schizophrenia
is usually an antipsychotic medication. Atypical antipsychotics (including clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and aripiprazole), which have demonstrated efficacy in the treatment of schizophrenia, are referred to as "atypical" because they were originally thought to have fewer extrapyramidal adverse effects than conventional antipsychotic medications.14
It has been hypothesized that if these newer medications are superior in their effects on psychotic symptoms or have fewer adverse effects, they may concomitantly reduce comorbid substance use disorders. Another hypothesis suggests that because atypicals have a different pharmacologic profile from conventional antipsychotics and because they target receptors that may play a direct role in the etiology of substance abuse and dependence,4,5 they may be especially effective in treating substance use disorders as well as psychosis.
1. 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.
2. Westermeyer J. Comorbid schizophrenia and substance abuse: a review of epidemiology and course. Am J Addict. 2006;15:345-355.
3. Khantzian EJ. The self-medication hypothesis of addictive disorders: focus on heroin and cocaine dependence. Am J Psychiatry. 1985;142:1259-1264.
4. Krystal JH, D'Souza DC, Madonick S, Petrakis IL. Toward a rational pharmacotherapy of comorbid substance abuse in schizophrenic patients. Schizophr Res. 1999;35 (suppl):S35-S49.
5. Wilkins JN. Pharmacotherapy of schizophrenia patients with comorbid substance abuse. Schizophr Bull. 1997;23:215-228.
6. D'Souza DC, Gil RB, Madonick S, et al. Enhanced sensitivity to the euphoric effects of alcohol in schizophrenia. Neuropsychopharmacology. 2006;31:2767-2775.
7. Gerding LB, Labbate LA, Measom MO, et al. Alcohol dependence and hospitalization in schizophrenia. Schizophr Res. 1999;38:71-75.
8. Dixon L. Dual diagnosis of substance abuse in schizophrenia: prevalence and impact on outcomes. Schizophr Res. 1999;35(suppl):S93-S100.
9. Hoffman PL. Glutamate receptors in alcohol withdrawal-induced neurotoxicity. Metab Brain Dis. 1995; 10:73-79.
10. Bellack AS, Bennett ME, Gearon JS, et al. A randomized clinical trial of a new behavioral treatment for drug abuse in people with severe and persistent mental illness. Arch Gen Psychiatry. 2006;63:426-432.
11. Petrakis IL, O'Malley S, Rounsaville B, et al. Naltrexone augmentation of neuroleptic treatment in alcohol abusing patients with schizophrenia. Psychopharmacology (Berl). 2004;172:291-297.
12. Batki SL, Dimmock JA, Leontieva L, et al. Recruitment and characteristics of alcohol dependent patients with schizophrenia. Alcohol Clin Exp Res. 2005;29(suppl):78A.
13. Batki S, Dimmock J, Cornell M, et al. Directly observed naltrexone treatment of alcohol dependence in schizophrenia: Preliminary analysis. Alcohol Clin Exp Res. 2002;26:83A.
14. Markowitz JS, Brown CS, Moore TR. Atypical antipsychotics. Part I: pharmacology, pharmacokinetics, and efficacy. Ann Pharmacother. 1999;33:73-85.
15. Kosten TA, Nestler EJ. Clozapine attenuates cocaine conditioned place preference. Life Sci. 1994;55:
16. Broderick PA, Hope O, Okonji C, et al. Clozapine and cocaine effects on dopamine and serotonin release in nucleus accumbens during psychostimulant behavior and withdrawal. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:157-171.
17. Yovell Y, Opler LA. Clozapine reverses cocaine craving in a treatment-resistant mentally ill chemical abuser: a case report and a hypothesis. J Nerv Ment Dis. 1994;182:591-592.
18. Marcus P, Snyder R. Reduction of comorbid substance abuse with clozapine. Am J Psychiatry. 1995;
19. Albanese MJ, Khantzian EJ, Murphy SL, Green AI.
Decreased substance use in chronically psychotic patients treated with clozapine. Am J Psychiatry. 1994;151:
20. Volavka J. The effects of clozapine on aggression and substance abuse in schizophrenic patients. J Clin Psychiatry. 1999;60(suppl 12):43-46.
21. George TP, Sernyak MJ, Ziedonis DM, Woods SW. Effects of clozapine on smoking in chronic schizophrenic outpatients. J Clin Psychiatry. 1995;56:344-346.
22. Zimmet SV, Strous RD, Burgess ES, et al. Effects of clozapine on substance use in patients with schizophrenia and schizoaffective disorder: a retrospective survey. J Clin Psychopharmacol. 2000;20:94-98.
23. Green AI, Burgess ES, Dawson R, et al. Alcohol and cannabis use in schizophrenia: effects of clozapine vs risperidone. Schizophr Res. 2003;60:81-85.
24. Drake RE, Xie H, McHugo GJ, Green AI. The effects
of clozapine on alcohol and drug use disorders among patients with schizophrenia. Schizophr Bull. 2000;26:
25. Brunette MF, Drake RE, Xie H, et al. Clozapine use and relapses of substance use disorder among patients with co-occurring schizophrenia and substance use disorders. Schizophr Bull. 2006;32:637-643.
26. Howell LL, Wilcox KM, Lindsey KP, Kimmel HL. Olanzapine-induced suppression of cocaine self-administration in rhesus monkeys. Neuropsychopharmacology. 2006;31:585-593.
27. Mechanic JA, Maynard BT, Holloway FA. Treatment with the atypical antipsychotic, olanzapine, prevents the expression of amphetamine-induced place conditioning in the rat. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:43-54.
28. Hutchison KE, Rutter MC, Niaura R, et al. Olanzapine attenuates cue-elicited craving for tobacco. Psychopharmacology. 2004;175:407-413.
29. Kampman KM, Pettinati H, Lynch KG, et al. A pilot
trial of olanzapine for the treatment of cocaine dependence. Drug Alcohol Depend. 2003;70:265-273.
30. Tsuang J, Marder SR, Han A, Hsieh W. Olanzapine treatment for patients with schizophrenia and cocaine abuse. J Clin Psychiatry. 2002;63:1180-1181.
31. Longo LP. Olanzapine for cocaine craving and re-lapse prevention in 2 patients. J Clin Psychiatry. 2002;63:
32. Littrell KH, Petty RG, Hilligoss NM, et al. Olanzapine treatment for patients with schizophrenia and substance abuse. J Subst Abuse Treat. 2001;21:217-221.
33. Noordsy DL, Green AI. Pharmacotherapy for schizophrenia and co-occurring substance use disorders. Curr Psychiatry Rep. 2003;5:340-346.
34. Smelson DA, Ziedonis D, Williams J, et al. The efficacy of olanzapine for decreasing cue-elicited craving in individuals with schizophrenia and cocaine dependence: a preliminary report. J Clin Psychopharmacol. 2006;26: 9-12.
35. Smelson DA, Losonczy MF, Davis CW, et al. Risperidone decreases craving and relapses in individuals with schizophrenia and cocaine dependence. Can J Psychiatry. 2002;47:671-675.
36. Rubio G, Martinez I, Ponce G, et al. Long-acting injectable risperidone compared with zuclopenthixol in the treatment of schizophrenia with substance abuse comorbidity. Can J Psychiatry. 2006;51:531-539.
37. Green AI, Salomon MS, Brenner MJ, Rawlins K. Treatment of schizophrenia and comorbid substance use
disorder. Curr Drug Targets CNS Neurol Disord. 2002;1:
38. Weisman RL. Quetiapine in the successful treatment of schizophrenia with comorbid alcohol and drug dependence: a case report. Int J Psychiatry Med. 2003;33:
39. Potvin S, Stip E, Lipp O, et al. Quetiapine in patients with comorbid schizophrenia-spectrum and substance use disorders: an open-label trial. Curr Med Res Opin. 2006;22:1277-1285.
40. Brown ES, Nejtek VA, Perantie DC, Bobadilla L. Quetiapine in bipolar disorder and cocaine dependence. Bipolar Disord. 2002;4:406-411.
41. Beresford TP, Clapp L, Martin B, et al. Aripiprazole in schizophrenia with cocaine dependence: a pilot study.
J Clin Psychopharmacol. 2005;25:363-366.
42. Scheller-Gilkey G, Woolwine BJ, Cooper I, et al. Relationship of clinical symptoms and substance use in schizophrenia patients on conventional versus atypical antipsychotics. Am J Drug Alcohol Abuse. 2003;29:
43. Petrakis IL, Leslie D, Finney JW, Rosenheck R. Atypical antipsychotic medication and substance use-related outcomes in treatment of schizophrenia. Am J Addict. 2006;15:44-49.
44. Green AI. Treatment of schizophrenia and comorbid substance abuse: pharmacologic approaches. J Clin Psychiatry. 2006;67(suppl 7):31-35.
45. Lieberman JA, Stroup TS, McEvoy JS, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209-1223.