Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder

Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder

The purpose of this study is to examine the efficacy of quetiapine (Seroquel) in reducing substance use in persons diagnosed with schizophrenia. The primary hypothesis is that quetiapine treatment will be associated with a decrease in substance use.

Comorbid alcohol/substance use disorder (SUD) in schizophrenia is a major concern, both in view of the high frequency of SUD among patients with schizophrenia and the difficulty in managing such patients. Though antipsychotic medications are effective in reducing symptoms and impairment in persons with schizophrenia, the typical antipsychotic agents are of limited value in controlling alcohol/substance use in these patients. Extrapyramidal, dysphoric side effects of conventional neuroleptics may actually promote the use of substances in an attempt to counteract these effects. Novel antipsychotics have radically altered treatment expectations and outcomes for patients with severe forms of schizophrenia. With the greater availability of novel agents in clinical practice, it has been noted that these benefits have also extended to specific subgroups of patients including patients with comorbid SUD. Several retrospective studies have demonstrated a decrease in comorbid substance use in patients with schizophrenia treated with clozapine. There is little data available, however, on the efficacy of quetiapine in patients with schizophrenia and comorbid SUD. Its receptor profile, including a weak Dopamine2 (D2) receptor blocking ability and substantial effects at noradrenergic receptors, makes it a logical antipsychotic to use in the comorbid population. The study is an open-label investigation of the efficacy of quetiapine in a group of 30 patients with schizophrenia and comorbid substance use disorder. Patients diagnosed with schizophrenia or schizoaffective disorder and a comorbid substance use disorder are switched to quetiapine for 12 weeks. We hypothesize that quetiapine treatment will be associated with a decrease in substance use. Moreover, we further hypothesize that measures of symptoms, cognition and quality of life will also improve over baseline assessments in patients treated with quetiapine. Data suggesting a beneficial effect of quetiapine will have to be confirmed in a prospective double-blind study. This pilot investigation will provide preliminary data and effect sizes that will be used in the design of this subsequent investigation.

After patients provided informed consent and completed baseline measures, quetiapine was initiated in all participants and titrated up to a target dose of 600 mg (in divided daily doses) over two weeks as the previous antipsychotic medication was slowly tapered and discontinued. Participants met with study physicians weekly to assess tolerability and response to the medication. Concomitant medications were held constant. After the initial titration period, quetiapine was dosed in a flexible manner up to 800 mg /day, with dose adjustments based on symptomatic response and side effects.

After patients provided informed consent and completed baseline measures, quetiapine was initiated in all participants and titrated up to a target dose of 600 mg (in divided daily doses) over two weeks as the previous antipsychotic medication was slowly tapered and discontinued. Participants met with study physicians weekly to assess tolerability and response to the medication. Concomitant medications were held constant. After the initial titration period, quetiapine was dosed in a flexible manner up to 800 mg /day, with dose adjustments based on symptomatic response and side effects.

Timeline Follow-back (TLFB) procedure was used at screening and baseline to establish current substance use, and it was also used weekly during the course of the study to assess continued alcohol and other substance use. TLFB cosisted of using a calendar and sasking participants to report alcohol and other drug use since last visit. At the screening visit, the TLFB was done for the four weeks prior to the visit.

The main outcome measure of clinical symptoms was the Positive and Negative Symptoms Scale. This is a 30 item scale for assessing patients diagnosed with schizophrenia. Each item is rated on a 1 (absent) to 7 (extreme) scale. The minimum total score is 30 and the maximum is 210.

Inclusion Criteria: Age 18-65 Schizophrenia or schizoaffective disorder Meets Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID) criteria for a substance use disorder (alcohol use disorder [AUD]; abuse or dependence) Active substance use on at least 8 days during the 4 weeks prior to randomization. Current treatment with antipsychotic medication. Able to provide informed consent, or in the case of patients with legal court appointed guardians willing to give assent, with the consent of the guardian. Not actively suicidal. Exclusion Criteria: Current treatment with, decanoate antipsychotic, clozapine, or doses of quetiapine not approved by the team of investigators. Individuals treated with depot antipsychotic must wait until the end of their injection cycle before starting on study medication. Currently pregnant, planning to become pregnant, or unwilling to use an acceptable form of birth control. Currently residing in a residential program designed to treat substance use disorders. Treatment at baseline with a psychotropic agent proposed to curtail substance use. Patients who, in the opinion of the investigator, are judged unsuitable to participate in the study. Unable to take part in the assessments in a meaningful way Hypersensitivity/intolerance to quetiapine Serious, unstable medical condition Participation in clinical trial of an investigational drug within 30 days of baseline visit, or concurrent participation in a treatment study of a psychosocial intervention

Albanese MJ, Khantzian EJ, Murphy SL, Green AI. Decreased substance use in chronically psychotic patients treated with clozapine. Am J Psychiatry. 1994 May;151(5):780-1. doi: 10.1176/ajp.151.5.780b. No abstract available.

Bartels SJ, Teague GB, Drake RE, Clark RE, Bush PW, Noordsy DL. Substance abuse in schizophrenia: service utilization and costs. J Nerv Ment Dis. 1993 Apr;181(4):227-32. doi: 10.1097/00005053-199304000-00003.

Bowers MB Jr, Mazure CM, Nelson JC, Jatlow PI. Psychotogenic drug use and neuroleptic response. Schizophr Bull. 1990;16(1):81-5. doi: 10.1093/schbul/16.1.81.

Brown ES, Nejtek VA, Perantie DC, Rajan Thomas N, Rush AJ. Cocaine and amphetamine use in patients with psychiatric illness: a randomized trial of typical antipsychotic continuation or discontinuation. J Clin Psychopharmacol. 2003 Aug;23(4):384-8. doi: 10.1097/01.jcp.0000085412.08426.08.

Buckley PF, Naber D: Quetiapine and sertindole: clinical use and experience. In: Schizophrenia and Mood Disorders: The New Drug Therapies in Clinical Practice. Edited by PF Buckley and JL Waddington. Butterworth-Heinemann, 2000.

Buckley P, Thompson PA, Way L, Meltzer HY. Substance abuse and clozapine treatment. J Clin Psychiatry. 1994 Sep;55 Suppl B:114-6.

Buckley PF. Novel antipsychotic medications and the treatment of comorbid substance abuse in schizophrenia. J Subst Abuse Treat. 1998 Mar-Apr;15(2):113-6. doi: 10.1016/s0740-5472(97)00134-7.

Buckley PF, Miller A, Chiles JA, Sajatovic M. Implementing effectiveness research and improving care for schizophrenia in real-world settings. Am J Manag Care. 1999 Jun 25;5 Spec No:SP47-56.

Buckley P, McCarthy M, Chapman P, Richman C, Yamamoto B. Clozapine treatment of comorbid substance abuse in patients with schizophrenia. Schizophr Res 1999; 36: 272.

Carey KB, Cocco KM, Simons JS. Concurrent validity of clinicians' ratings of substance abuse among psychiatric outpatients. Psychiatr Serv. 1996 Aug;47(8):842-7. doi: 10.1176/ps.47.8.842.

Conley RR, Kelly DL, Gale EA. Olanzapine response in treatment-refractory schizophrenic patients with a history of substance abuse. Schizophr Res. 1998 Sep 7;33(1-2):95-101. doi: 10.1016/s0920-9964(98)00062-0.

Drake RE, Osher FC, Noordsy DL, Hurlbut SC, Teague GB, Beaudett MS. Diagnosis of alcohol use disorders in schizophrenia. Schizophr Bull. 1990;16(1):57-67. doi: 10.1093/schbul/16.1.57.

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(2):441-9. doi: 10.1093/oxfordjournals.schbul.a033464.

Green AI, Alam MY, Sobieraj JT, Pappalardo KM, Waternaux C, Salzman C, Schatzberg AF, Schildkraut JJ. Clozapine response and plasma catecholamines and their metabolites. Psychiatry Res. 1993 Feb;46(2):139-49. doi: 10.1016/0165-1781(93)90016-a.

Green AI, Alam MY, Boshes RA, Waternaux C, Pappalardo KM, Fitzgibbon ME, Tsuang MT, Schildkraut JJ. Haloperidol response and plasma catecholamines and their metabolites. Schizophr Res. 1993 Jun;10(1):33-7. doi: 10.1016/0920-9964(93)90074-s.

Green AI, Zimmet SV, Strous RD, Schildkraut JJ. Clozapine for comorbid substance use disorder and schizophrenia: do patients with schizophrenia have a reward-deficiency syndrome that can be ameliorated by clozapine? Harv Rev Psychiatry. 1999 Mar-Apr;6(6):287-96. doi: 10.3109/10673229909017206.

Heinrichs DW, Hanlon TE, Carpenter WT Jr. The Quality of Life Scale: an instrument for rating the schizophrenic deficit syndrome. Schizophr Bull. 1984;10(3):388-98. doi: 10.1093/schbul/10.3.388.

Khantzian EJ. The self-medication hypothesis of addictive disorders: focus on heroin and cocaine dependence. Am J Psychiatry. 1985 Nov;142(11):1259-64. doi: 10.1176/ajp.142.11.1259.

Khantzian EJ. The self-medication hypothesis of substance use disorders: a reconsideration and recent applications. Harv Rev Psychiatry. 1997 Jan-Feb;4(5):231-44. doi: 10.3109/10673229709030550.

Meats P. Quetiapine ('Seroquel'); an effective and well-tolerated atypical antipsychotic. Int J Psychiatry Clin Pract. 1997;1(4):231-9. doi: 10.3109/13651509709024734.

Siris SG. Pharmacological treatment of substance-abusing schizophrenic patients. Schizophr Bull. 1990;16(1):111-22. doi: 10.1093/schbul/16.1.111.

Small JG, Hirsch SR, Arvanitis LA, Miller BG, Link CG. Quetiapine in patients with schizophrenia. A high- and low-dose double-blind comparison with placebo. Seroquel Study Group. Arch Gen Psychiatry. 1997 Jun;54(6):549-57. doi: 10.1001/archpsyc.1997.01830180067009.

Zimmet SV, Strous RD, Burgess ES, Kohnstamm S, Green AI. Effects of clozapine on substance use in patients with schizophrenia and schizoaffective disorder: a retrospective survey. J Clin Psychopharmacol. 2000 Feb;20(1):94-8. doi: 10.1097/00004714-200002000-00016.

Arvanitis LA, Miller BG. Multiple fixed doses of "Seroquel" (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry. 1997 Aug 15;42(4):233-46. doi: 10.1016/s0006-3223(97)00190-x.

Weiden PJ. Quetiapine ('seroquel'): a new 'atypical' antipsychotic. J Prac Psychiatry and Behav Health 1997; 3(6): 368-374.