Schizophrenia and Substance Abuse: Is There a Role for Atypical Antipsychotics?

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.¹⁴It 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.

Clozapine
What is the evidence that the atypical antipsychotics are superior to conventional antipsychotics in treating substance abuse in patients with schizophrenia? The most compelling evidence for the efficacy of the atypicals in treating substance abuse is with clozapine; this includes data from preclinical studies, case reports, retrospective chart reviews evaluating patients in whom treatment was started with clozapine, and uncontrolled comparison studies. Laboratory animal studies suggest that clozapine affects cocaine preference and administration¹⁵ and blocks psychomotor stimulant behavior induced by cocaine.¹⁶ Case reports have suggested that clozapine decreases cocaine craving¹⁷ as well as alcohol and other drug use.^18,19

Retrospective chart reviews in patients have also suggested that patients who are switched to clozapine decrease their substance abuse. One large retrospective report of 331 patients with schizophrenia suggested that clozapine treatment decreased aggression and substance abuse, although measures of actual consumption were not presented.²⁰ A smaller study (N = 18) suggested that clozapine decreases smoking in patients in whom therapy is started with clozapine,²¹ and in a cohort of 58 patients, more than 85% of those who had substance use disorders at baseline decreased their substance use during treatment with clozapine.²²

Several comparison studies also exist. A retrospective comparison of patients treated with clozapine (n = 35) and those treated with risperidone (n = 8) suggested that abstinence rates in a 1-year period were significantly higher in the group treated with clozapine (54% vs 13%),²³ although the sample size was too small to make firm conclusions and the findings need replication in larger studies. In an open-label study (N = 151), significant differences were seen in relapse rates in the 36 patients who were taking clozapine (more than 65%), compared with those taking conventional antipsychotics (34%).²⁴ A recent comparison of patients taking clozapine (n = 25) and those taking other antipsychotic medications (n = 70), all of whom were in remission from substance abuse, suggested that those taking clozapine were much less likely to relapse to substance use than were those taking other medications (8% vs 40%, respectively).²⁵

Olanzapine
After clozapine, olanzapine is the atypical antipsychotic most studied for its effects on patients with substance use disorders (perhaps because its neuropharmacologic profile has been thought to be consistent with a potentially useful medication for stimulant use disorders).²⁶ Laboratory studies have suggested that olanzapine suppresses cocaine self-administration in non-human primates²⁶ and prevents amphetamine place preference (an animal model to test the subjective effects of the drug) in rodents.²⁷ Laboratory evaluation in healthy humans suggested that olanzapine decreases cue-induced craving for tobacco.²⁸ However, in patients without comorbid schizophrenia, results of a placebo-controlled study of olanzapine for cocaine dependence were not encouraging.²⁹

In patients with schizophrenia, case reports have suggested that olanzapine decreases cocaine use.^30,31 However, these findings need confirmation in randomized, double-blind, placebo-controlled studies. In an open-label study, 30 patients taking conventional antipsychotics who abused cocaine and alcohol were treated with olanzapine. Most patients decreased substance use in general; 100% were in remission from cocaine use.³²A study comparing patients who were switched to olanzapine (n = 105) with those who continued to take conventional antipsychotics (n = 49) found that while patients who switched to olanzapine decreased substance abuse from baseline, there were no significant group differences in substance abuse outcomes.³³ In addition, patients randomized to olanzapine (n = 16) had significantly lower measures of cocaine craving than did those randomized to haloperidol (n = 15), but there were no significant differences in urine toxicology screens between groups.³⁴

Other atypicals
A few case reports and pilot studies have been published on the use of risperidone and quetiapine. Open-label risperidone was found to decrease cocaine craving and relapse rates in a small pilot study (N = 18).³⁵ In an open comparison study, those who were randomized to long-acting injectable risperidone (n = 57) had fewer positive urine toxicology screen results than did those who were randomized to depot zuclopenthixol (n = 58).³⁶

As mentioned above, in a comparison with clozapine, patients treated with risperidone had worse substance abuse outcomes.³⁷ Case reports³⁸ and open-label studies have suggested that quetiapine may decrease drug use in patients with schizophrenia³⁹ and bipolar disorder⁴⁰; however, these findings must be replicated in controlled studies. Patients with schizophrenia and co-occurring cocaine dependence and alcohol abuse decreased drug use as well as cravings for drugs and alcohol with open-label aripiprazole.⁴¹

Atypical versus conventional antipsychotics
Two studies comparing the outcomes in patients with substance use disorders taking conventional antipsychotics with those taking atypicals had very different results.^42,43 In one study, patients with schizophrenia who were taking atypical antipsychotics (n = 35) were compared with those taking conventional antipsychotics (n = 35). Patients were interviewed to determine levels of current substance abuse; those who were taking atypicals (including olanzapine, risperidone, clozapine, quetiapine, and ziprasidone) reported lower levels of substance abuse, primarily with alcohol, than did those who were taking conventional antipsychotics.⁴²

Another study used national administrative data from the Department of Veterans Affairs to evaluate changes in substance abuse outcomes in veterans with schizophrenia and comorbid substance abuse and dependence (N = 249) as assessed with the Addiction Severity Index (ASI).⁴³ Outcomes among those who were switched or maintained on an atypical antipsychotic were compared with those who were treated with conventional antipsychotics. For the entire sample and for those taking an atypical agent during the last assessment, there were significant decreases in alcohol and psychological ASI scores.

The initial analysis suggested that patients taking atypicals decreased drug and alcohol use more than patients in the other groups. However, after other factors were included in a multiple regression analysis, there was no greater improvement in alcohol or drug ASI scores in patients who were switched to or maintained on an atypical antipsychotic than in those of patients who were treated with conventional antipsychotic agents.

These data do not support the hypothesis that switching from a conventional to an atypical antipsychotic leads to poorer substance abuse outcomes. It should be noted that no meaningful conclusions were drawn about clozapine from these data because a very small number of patients in the study were taking clozapine (n = 3, or less than 2%).

What conclusions can be drawn about the use of atypical antipsychotics in patients with schizophrenia and comorbid substance use disorders? There is compelling and consistent evidence from a number of different types of studies supporting clozapine's efficacy in decreasing substance abuse in patients with schizophrenia. It has been hypothesized that clozapine, because of its neurochemical profile, can uniquely influence substance abuse because it corrects a reward deficit in patients with schizophrenia via its broad effects on a number of neurotransmitter systems, including the dopaminergic, adrenergic, and noradrenergic.⁴⁴ The data for the other atypicals are much less compelling, in part because of a lack of evidence, but there are a few negative studies in this area as well.

Nevertheless, even the data on clozapine should be interpreted with caution, because the evidence is based on case reports, retrospective chart reviews, and open studies. In addition, nonpharmacologic factors exist that could influence outcome. For example, spontaneous remission from substance abuse in patients with schizophrenia occurs at a fairly high rate.² Furthermore, the close monitoring associated with clozapine treatment may represent an increase in clinical contact for patients previously treated with conventional antipsychotics, and this closer monitoring may account for changes in patterns of substance abuse.

In order to address these issues, definitive randomized controlled clinical trials are still needed to determine the efficacy of atypicals in treating substance use disorders in persons with schizophrenia. While randomized clinical trials are the gold standard in evaluating pharmacotherapies, they are a challenge to conduct in this patient population. Other large, long-term studies, such as the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE),⁴⁵ should also provide important clinical data on the effectiveness of these medications.

Clinical implications
How should these data be translated into clinical practice? Given the high rate of substance use disorders in patients with schizophrenia, accurate detection is the first priority. A comprehensive history, including a detailed history of substance use, is not only important in the initial evaluation but also during treatment, since patients may begin or relapse to substance abuse at any time during treatment.

Clinical guidelines for treatment of patients with schizophrenia suggest that the first-line drug therapy is an atypical antipsychotic other than clozapine. Because these medications may also help with substance abuse, this is likely a good strategy for clinicians who treat patients who have comorbid substance use disorders. A more difficult question might arise as to whether patients should be switched from another antipsychotic to clozapine.

Weighing the risk-benefit ratio in any clinical decision is of utmost importance. The presence of a substance use disorder is only one of many factors to consider; other factors include a patient's history of violence and aggression, his comorbid medical conditions, and patient preference. Clinicians should keep in mind that serious interactions have been described between clozapine and sedatives, as well as with alcohol and cocaine.³³

Nevertheless, substance use disorders and schizophrenia are serious clinical issues and are associated with poor prognosis and health consequences; there are no established treatments for the co-occurrence of these disorders. Clinicians should certainly consider pharmacologic management in this population, but only in the context of a comprehensive treatment plan.

The author wishes to acknowledge the contribution of Diana Limoncelli in preparation of this article.

Dr Petrakis is associate professor of psychiatry at Yale University School of Medicine in New Haven, Conn, and director of the substance abuse treatment program at VA Connecticut Healthcare.

Dr Petrakis reports grant funding from AstraZeneca and Forest Laboratories, and she has been a consultant to Prescott Medical Communications Group.

References:

References1. 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:PL9-PL14.
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;152:959.
19. Albanese MJ, Khantzian EJ, Murphy SL, Green AI. Decreased substance use in chronically psychotic patients treated with clozapine. Am J Psychiatry. 1994;151:780-781.
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;26:441-449.
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;63:595-596.
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;1:129-139.
38. Weisman RL. Quetiapine in the successful treatment of schizophrenia with comorbid alcohol and drug dependence: a case report. Int J Psychiatry Med. 2003;33:85-89.
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;29:553-566.
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.