This article was downloaded by: [University of Liverpool] On: 29 December 2014, At: 08:30 Publisher: Routledge Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Journal of Dual Diagnosis Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/wjdd20
A Randomized Trial of Clozapine Versus Other Antipsychotics for Cannabis Use Disorder in Patients With Schizophrenia a
b
Mary F. Brunette MD , Ree Dawson PhD , Christopher D. O’Keefe c
d
c
MA , Meera Narasimhan MD , Douglas L. Noordsy MD , Joanne e
Wojcik PhD & Alan I. Green MD
c
a
Dartmouth Psychiatric Research Center and Department of Psychiatry , Dartmouth Medical School , Lebanon, New Hampshire, USA b
Frontier Science Research and Technology , Boston, Massachusetts, USA c
Department of Psychiatry , Dartmouth Medical School , Lebanon, New Hampshire, USA d
Department of Psychiatry , University of South Carolina , Columbia, South Carolina, USA e
Department of Psychiatry , Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, Massachusetts, USA Published online: 11 May 2011.
To cite this article: Mary F. Brunette MD , Ree Dawson PhD , Christopher D. O’Keefe MA , Meera Narasimhan MD , Douglas L. Noordsy MD , Joanne Wojcik PhD & Alan I. Green MD (2011) A Randomized Trial of Clozapine Versus Other Antipsychotics for Cannabis Use Disorder in Patients With Schizophrenia, Journal of Dual Diagnosis, 7:1-2, 50-63 To link to this article: http://dx.doi.org/10.1080/15504263.2011.570118
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
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Downloaded by [University of Liverpool] at 08:30 29 December 2014
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JOURNAL OF DUAL DIAGNOSIS, 7(1–2), 50–63, 2011 C Taylor & Francis Group, LLC Copyright ISSN: 1550-4263 print / 1550-4271 online DOI: 10.1080/15504263.2011.570118
Downloaded by [University of Liverpool] at 08:30 29 December 2014
PSYCHOPHARMACOLOGY & NEUROBIOLOGY
A Randomized Trial of Clozapine Versus Other Antipsychotics for Cannabis Use Disorder in Patients With Schizophrenia Mary F. Brunette, MD,1 Ree Dawson, PhD,2 Christopher D. O’Keefe, MA,3 Meera Narasimhan, MD,4 Douglas L. Noordsy, MD,3 Joanne Wojcik, PhD,5 and Alan I. Green, MD3
Objective: Cannabis use disorder is the most common co-occurring drug use disorder in people with schizophrenia and is associated with poor outcomes. The authors launched a randomized controlled trial to assess the impact of clozapine compared with treatment as usual on cannabis use in patients with schizophrenia and co-occurring cannabis use disorder. Methods: Thirty-one patients with schizophrenia and co-occurring cannabis use disorder were randomly assigned to switch to clozapine or to stay on their current antipsychotic and were then followed weekly for 12 weeks. Blinded raters assessed participants weekly with the Timeline Followback for substance use and the expanded Brief Psychiatric Rating Scale for symptoms. Longitudinal random effects models were used to investigate the time-varying differences in cannabis use and other outcomes between the treatment as usual and clozapine groups. Results: The two groups differed in average intensity of cannabis use by approximately 4.5 joints/week, with lesser use in the clozapine group (t = −1.77; df = 28.5; p = .086; effect size ∼ 0.6). Symptoms and functioning were not different between the two groups. Conclusions: Clozapine may reduce cannabis use among patients with schizophrenia and co-occurring cannabis use disorder. Further controlled trials are warranted. (Journal of Dual Diagnosis, 7:50–63, 2011)
Keywords schizophrenia, cannabis, substance use disorder, clozapine, treatment, co-occurring
1Dartmouth
Psychiatric Research Center and Department of Psychiatry, Dartmouth Medical School, Lebanon, New Hampshire, USA 2Frontier Science Research and Technology, Boston, Massachusetts, USA 3Department of Psychiatry, Dartmouth Medical School, Lebanon, New Hampshire, USA 4Department of Psychiatry, University of South Carolina, Columbia, South Carolina, USA 5Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA Address correspondence to Mary F. Brunette, MD, Dartmouth Psychiatric Research Center and Department of Psychiatry, Dartmouth Medical School, 105 Pleasant St., 2nd Floor North, Concord, NH 03301, USA. E-mail: [email protected]
Downloaded by [University of Liverpool] at 08:30 29 December 2014
Clozapine and Cannabis Use in Patients With Schizophrenia
51
Up to 60% of people with schizophrenia have a lifetime co-occurring substance use disorder (Alterman, Erdlen, & Murphy, 1981; Ananth et al., 1989; Freed, 1975; Kessler et al., 2005; Kessler et al., 1994; Mueser et al., 1990). Cannabis use disorder is the most common co-occurring drug use disorder in these individuals (Kessler et al., 2005; Mueser et al., 1990; Regier et al., 1990), with lifetime rates ranging from 13% to 42% (DeQuardo, Carpenter, & Tandon, 1994; Dixon, Haas, Weiden, Sweeney, & Frances, 1991; Hambrecht & Hafner, 1996; Koskinen, Lohonen, Koponen, Isohanni, & Miettunen, 2010; Mueser, Bennett, & Kushner, 1995; Peralta & Cuesta, 1992), a 3to 10-fold increase over the lifetime prevalence of 4% in the general population (Regier et al.). Cannabis use disorder has been associated with clinical exacerbations, noncompliance with treatment, poor global functioning, and increased relapse and rehospitalization rates (DeQuardo et al., 1994; Knudsen & Vilmar, 1984; Linszen, Dingemans, & Lenior, 1994; Negrete, Knapp, Douglas, & Smith, 1986; Peralta & Cuesta, 1992; Treffert, 1978). It adds greatly to the financial costs and emotional toll that schizophrenia places on patients, families, and the mental health system (e.g., Dickey & Azeni, 1996; Kivlahan, Heiman, Wright, Mundt, & Shupe, 1991). Comprehensive psychosocial treatment programs that integrate treatments for schizophrenia and substance (including cannabis) use disorder have been developed and shown to be effective for this population (Drake, Mueser, Brunette, & McHugo, 2004). Nevertheless, even with abstinence, relapse is common (Xie, McHugo, Fox, & Drake, 2005); moreover, almost half of the patients with co-occurring disorders continue to use substances and experience negative consequences after 3 to 12 months of psychosocial treatment. Hence, there continues to be a need for better treatments and for a better understanding of the role of pharmacological treatments of co-occurring cannabis and other substance use disorders in patients with schizophrenia. While typical antipsychotic medications do not appear to limit cannabis or other substance use in patients with schizophrenia (Noordsy, O’Keefe, Mueser, & Xie, 2001), preliminary data suggest that the atypical antipsychotic clozapine may be helpful not only in the treatment of their psychotic symptoms but also in limiting their cannabis and other substance abuse. Case reports, retrospective studies, and a small, open-label, prospective study have reported reduced substance and tobacco use during treatment with clozapine (Albanese, Khantzian, Murphy, & Green, 1994; Buckley, McCarthy, Chapman, Richman, & Yamamoto, 1999; George, Sernyak, Ziedonis, & Woods, 1995; Lee, 1998; Marcus & Snyder, 1995; McEvoy, Freudenreich, Levin, & Rose, 1995; Yovell & Opler, 1994; Zimmet, Strous, Burgess, Kohnstamm, & Green, 2000). A subsequent study by our group provided further evidence of the potential role of clozapine in dual-diagnosis patients. This study, a naturalistic clinical services survey, followed 151 patients with co-occurring psychotic and substance use disorders for 3 years (Drake, Xie, McHugo, & Green, 2000). Patients taking clozapine had higher rates of remission of cannabis abuse (6/9 = 67%) compared to those treated with typical antipsychotics (12/37 = 32%). Similarly, remission of alcohol abuse was higher in patients taking clozapine (15/19 = 79%) compared to those treated with typical antipsychotics (29/86 = 34%). Moreover, in a continuing assessment of those patients whose abuse remitted, only 8% of those treated with clozapine relapsed to abuse in the following 6 months, compared to 40% of those treated with other antipsychotics (Brunette, Drake, Xie, McHugo, & Green, 2006). Given the many side effects of clozapine (which led to restriction of its Food and Drug Administration approval to use for patients with treatment-refractory psychosis), many investigators are currently assessing whether other atypical antipsychotics share with clozapine an ability to limit substance use in patients with schizophrenia. Unfortunately, available data are somewhat
2011, Volume 7, Numbers 1–2
Downloaded by [University of Liverpool] at 08:30 29 December 2014
52
M. F. Brunette et al.
mixed and not overly promising (Green, Noordsy, Brunette, & O’Keefe, 2008) for risperidone (Green, Burgess, Dawson, Zimmet, & Strous, 2003; Smelson et al., 2002; Smelson et al., 2004), olanzapine (Akerele & Levin, 2007; Brunette et al., 2008; Noordsy et al., 2001; Petrakis, Leslie, Finney, & Rosenheck, 2006; Smelson et al., 2006), quetiapine (Brown, Nejtek, Perantie, Rajan Thomas, & Rush, 2003; Brunette, O’Keefe, Dawson, Buckley, & Green, 2009; Potvin et al., 2006), and aripiprazole (Beresford et al., 2005; Brown, Jeffress, Liggin, Garza, & Beard, 2005; Warsi, Sattar, Bhatia, & Petty, 2005). Thus, at present, clozapine remains the only antipsychotic medication for which published research provides consistent evidence of a substantive decrease in cannabis and other substance use. We have presented a neurobiological formulation, based on animal studies, suggesting that clozapine’s unusual clinical effects on substance abuse in patients with schizophrenia may relate to its varied pharmacological actions on dopaminergic and, particularly, noradrenergic systems. Specifically, we have proposed that clozapine’s weak dopamine D2 receptor blockade coupled with its activation of the norepinephrine (NE) system (including its antagonistic effects at the NE α 2 receptor and its ability to release NE) (e.g., Antelman & Caggiula, 1977; Breier et al., 1994; Green et al., 1993; Lieberman et al., 1991; Rice, Smith, Silk, & Rosen, 1984; Sarafoff, Davis, & Ruther, 1979; Svensson et al., 1995; Thierry, Godbout, Mantz, & Glowinski, 1990; Van Kammen et al., 1990) may ameliorate dysfunction in the dopamine-mediated “brain reward system” that may underlie the common use of cannabis and other substances in patients with schizophrenia (Green, Zimmet, Strous, & Schildkraut, 1999). Given the consistent albeit still preliminary data about clozapine’s ability to decrease substance use in patients with schizophrenia, as well as our published rationale of the basis of this effect, our group launched a randomized controlled trial of clozapine (as compared with treatment as usual) of cannabis use in patients with schizophrenia and co-occurring cannabis use disorder. METHODS The study was a 3-month, randomized, open-label investigation (with blinded assessments) of the efficacy and safety of clozapine compared to continued current antipsychotic treatment (i.e., treatment as usual) in outpatients with schizophrenia or schizoaffective disorder and comorbid cannabis use disorder. After researchers established participants’ eligibility at baseline, blinded raters assessed participants weekly for substance use, symptoms, and side effects. Unblinded clinicians prescribed and adjusted study medications weekly for 12 weeks. The institutional review boards at Dartmouth Medical School and at the University of South Carolina approved the study. All procedures were consistent with the Declaration of Helsinki and Good Clinical Practice according to the International Conference on Harmonization guidelines. There was a complete and thorough discussion of the study with potential participants, and all participants gave written informed consent prior to engaging in any study procedures. Study Participants Participants were recruited, primarily through clinician referral, from two urban study sites, one in New Hampshire, affiliated with Dartmouth, and the second in South Carolina, affiliated with the University of South Carolina. Inclusion criteria were as follows: Diagnostic and Statistical
Journal of Dual Diagnosis
Clozapine and Cannabis Use in Patients With Schizophrenia
53
Downloaded by [University of Liverpool] at 08:30 29 December 2014
Manual (DSM-IV) diagnosis of schizophrenia or schizoaffective disorder and current cannabis use disorder; cannabis use on at least 5 days over the 3 weeks prior to screening; age 18 to 65; outpatient status prior to randomization; and current treatment with antipsychotic medication other than clozapine. Patients taking medications with possible effects on alcohol use (e.g., naltrexone, disulfiram, or topiramate) were excluded, as were patients with active, serious medical illness, suicidality, or severe psychiatric instability. Patients for whom clozapine was contraindicated (e.g., white blood cell count
Journal of Dual Diagnosis Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/wjdd20
A Randomized Trial of Clozapine Versus Other Antipsychotics for Cannabis Use Disorder in Patients With Schizophrenia a
b
Mary F. Brunette MD , Ree Dawson PhD , Christopher D. O’Keefe c
d
c
MA , Meera Narasimhan MD , Douglas L. Noordsy MD , Joanne e
Wojcik PhD & Alan I. Green MD
c
a
Dartmouth Psychiatric Research Center and Department of Psychiatry , Dartmouth Medical School , Lebanon, New Hampshire, USA b
Frontier Science Research and Technology , Boston, Massachusetts, USA c
Department of Psychiatry , Dartmouth Medical School , Lebanon, New Hampshire, USA d
Department of Psychiatry , University of South Carolina , Columbia, South Carolina, USA e
Department of Psychiatry , Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, Massachusetts, USA Published online: 11 May 2011.
To cite this article: Mary F. Brunette MD , Ree Dawson PhD , Christopher D. O’Keefe MA , Meera Narasimhan MD , Douglas L. Noordsy MD , Joanne Wojcik PhD & Alan I. Green MD (2011) A Randomized Trial of Clozapine Versus Other Antipsychotics for Cannabis Use Disorder in Patients With Schizophrenia, Journal of Dual Diagnosis, 7:1-2, 50-63 To link to this article: http://dx.doi.org/10.1080/15504263.2011.570118
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content.
Downloaded by [University of Liverpool] at 08:30 29 December 2014
This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/termsand-conditions
JOURNAL OF DUAL DIAGNOSIS, 7(1–2), 50–63, 2011 C Taylor & Francis Group, LLC Copyright ISSN: 1550-4263 print / 1550-4271 online DOI: 10.1080/15504263.2011.570118
Downloaded by [University of Liverpool] at 08:30 29 December 2014
PSYCHOPHARMACOLOGY & NEUROBIOLOGY
A Randomized Trial of Clozapine Versus Other Antipsychotics for Cannabis Use Disorder in Patients With Schizophrenia Mary F. Brunette, MD,1 Ree Dawson, PhD,2 Christopher D. O’Keefe, MA,3 Meera Narasimhan, MD,4 Douglas L. Noordsy, MD,3 Joanne Wojcik, PhD,5 and Alan I. Green, MD3
Objective: Cannabis use disorder is the most common co-occurring drug use disorder in people with schizophrenia and is associated with poor outcomes. The authors launched a randomized controlled trial to assess the impact of clozapine compared with treatment as usual on cannabis use in patients with schizophrenia and co-occurring cannabis use disorder. Methods: Thirty-one patients with schizophrenia and co-occurring cannabis use disorder were randomly assigned to switch to clozapine or to stay on their current antipsychotic and were then followed weekly for 12 weeks. Blinded raters assessed participants weekly with the Timeline Followback for substance use and the expanded Brief Psychiatric Rating Scale for symptoms. Longitudinal random effects models were used to investigate the time-varying differences in cannabis use and other outcomes between the treatment as usual and clozapine groups. Results: The two groups differed in average intensity of cannabis use by approximately 4.5 joints/week, with lesser use in the clozapine group (t = −1.77; df = 28.5; p = .086; effect size ∼ 0.6). Symptoms and functioning were not different between the two groups. Conclusions: Clozapine may reduce cannabis use among patients with schizophrenia and co-occurring cannabis use disorder. Further controlled trials are warranted. (Journal of Dual Diagnosis, 7:50–63, 2011)
Keywords schizophrenia, cannabis, substance use disorder, clozapine, treatment, co-occurring
1Dartmouth
Psychiatric Research Center and Department of Psychiatry, Dartmouth Medical School, Lebanon, New Hampshire, USA 2Frontier Science Research and Technology, Boston, Massachusetts, USA 3Department of Psychiatry, Dartmouth Medical School, Lebanon, New Hampshire, USA 4Department of Psychiatry, University of South Carolina, Columbia, South Carolina, USA 5Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA Address correspondence to Mary F. Brunette, MD, Dartmouth Psychiatric Research Center and Department of Psychiatry, Dartmouth Medical School, 105 Pleasant St., 2nd Floor North, Concord, NH 03301, USA. E-mail: [email protected]
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Clozapine and Cannabis Use in Patients With Schizophrenia
51
Up to 60% of people with schizophrenia have a lifetime co-occurring substance use disorder (Alterman, Erdlen, & Murphy, 1981; Ananth et al., 1989; Freed, 1975; Kessler et al., 2005; Kessler et al., 1994; Mueser et al., 1990). Cannabis use disorder is the most common co-occurring drug use disorder in these individuals (Kessler et al., 2005; Mueser et al., 1990; Regier et al., 1990), with lifetime rates ranging from 13% to 42% (DeQuardo, Carpenter, & Tandon, 1994; Dixon, Haas, Weiden, Sweeney, & Frances, 1991; Hambrecht & Hafner, 1996; Koskinen, Lohonen, Koponen, Isohanni, & Miettunen, 2010; Mueser, Bennett, & Kushner, 1995; Peralta & Cuesta, 1992), a 3to 10-fold increase over the lifetime prevalence of 4% in the general population (Regier et al.). Cannabis use disorder has been associated with clinical exacerbations, noncompliance with treatment, poor global functioning, and increased relapse and rehospitalization rates (DeQuardo et al., 1994; Knudsen & Vilmar, 1984; Linszen, Dingemans, & Lenior, 1994; Negrete, Knapp, Douglas, & Smith, 1986; Peralta & Cuesta, 1992; Treffert, 1978). It adds greatly to the financial costs and emotional toll that schizophrenia places on patients, families, and the mental health system (e.g., Dickey & Azeni, 1996; Kivlahan, Heiman, Wright, Mundt, & Shupe, 1991). Comprehensive psychosocial treatment programs that integrate treatments for schizophrenia and substance (including cannabis) use disorder have been developed and shown to be effective for this population (Drake, Mueser, Brunette, & McHugo, 2004). Nevertheless, even with abstinence, relapse is common (Xie, McHugo, Fox, & Drake, 2005); moreover, almost half of the patients with co-occurring disorders continue to use substances and experience negative consequences after 3 to 12 months of psychosocial treatment. Hence, there continues to be a need for better treatments and for a better understanding of the role of pharmacological treatments of co-occurring cannabis and other substance use disorders in patients with schizophrenia. While typical antipsychotic medications do not appear to limit cannabis or other substance use in patients with schizophrenia (Noordsy, O’Keefe, Mueser, & Xie, 2001), preliminary data suggest that the atypical antipsychotic clozapine may be helpful not only in the treatment of their psychotic symptoms but also in limiting their cannabis and other substance abuse. Case reports, retrospective studies, and a small, open-label, prospective study have reported reduced substance and tobacco use during treatment with clozapine (Albanese, Khantzian, Murphy, & Green, 1994; Buckley, McCarthy, Chapman, Richman, & Yamamoto, 1999; George, Sernyak, Ziedonis, & Woods, 1995; Lee, 1998; Marcus & Snyder, 1995; McEvoy, Freudenreich, Levin, & Rose, 1995; Yovell & Opler, 1994; Zimmet, Strous, Burgess, Kohnstamm, & Green, 2000). A subsequent study by our group provided further evidence of the potential role of clozapine in dual-diagnosis patients. This study, a naturalistic clinical services survey, followed 151 patients with co-occurring psychotic and substance use disorders for 3 years (Drake, Xie, McHugo, & Green, 2000). Patients taking clozapine had higher rates of remission of cannabis abuse (6/9 = 67%) compared to those treated with typical antipsychotics (12/37 = 32%). Similarly, remission of alcohol abuse was higher in patients taking clozapine (15/19 = 79%) compared to those treated with typical antipsychotics (29/86 = 34%). Moreover, in a continuing assessment of those patients whose abuse remitted, only 8% of those treated with clozapine relapsed to abuse in the following 6 months, compared to 40% of those treated with other antipsychotics (Brunette, Drake, Xie, McHugo, & Green, 2006). Given the many side effects of clozapine (which led to restriction of its Food and Drug Administration approval to use for patients with treatment-refractory psychosis), many investigators are currently assessing whether other atypical antipsychotics share with clozapine an ability to limit substance use in patients with schizophrenia. Unfortunately, available data are somewhat
2011, Volume 7, Numbers 1–2
Downloaded by [University of Liverpool] at 08:30 29 December 2014
52
M. F. Brunette et al.
mixed and not overly promising (Green, Noordsy, Brunette, & O’Keefe, 2008) for risperidone (Green, Burgess, Dawson, Zimmet, & Strous, 2003; Smelson et al., 2002; Smelson et al., 2004), olanzapine (Akerele & Levin, 2007; Brunette et al., 2008; Noordsy et al., 2001; Petrakis, Leslie, Finney, & Rosenheck, 2006; Smelson et al., 2006), quetiapine (Brown, Nejtek, Perantie, Rajan Thomas, & Rush, 2003; Brunette, O’Keefe, Dawson, Buckley, & Green, 2009; Potvin et al., 2006), and aripiprazole (Beresford et al., 2005; Brown, Jeffress, Liggin, Garza, & Beard, 2005; Warsi, Sattar, Bhatia, & Petty, 2005). Thus, at present, clozapine remains the only antipsychotic medication for which published research provides consistent evidence of a substantive decrease in cannabis and other substance use. We have presented a neurobiological formulation, based on animal studies, suggesting that clozapine’s unusual clinical effects on substance abuse in patients with schizophrenia may relate to its varied pharmacological actions on dopaminergic and, particularly, noradrenergic systems. Specifically, we have proposed that clozapine’s weak dopamine D2 receptor blockade coupled with its activation of the norepinephrine (NE) system (including its antagonistic effects at the NE α 2 receptor and its ability to release NE) (e.g., Antelman & Caggiula, 1977; Breier et al., 1994; Green et al., 1993; Lieberman et al., 1991; Rice, Smith, Silk, & Rosen, 1984; Sarafoff, Davis, & Ruther, 1979; Svensson et al., 1995; Thierry, Godbout, Mantz, & Glowinski, 1990; Van Kammen et al., 1990) may ameliorate dysfunction in the dopamine-mediated “brain reward system” that may underlie the common use of cannabis and other substances in patients with schizophrenia (Green, Zimmet, Strous, & Schildkraut, 1999). Given the consistent albeit still preliminary data about clozapine’s ability to decrease substance use in patients with schizophrenia, as well as our published rationale of the basis of this effect, our group launched a randomized controlled trial of clozapine (as compared with treatment as usual) of cannabis use in patients with schizophrenia and co-occurring cannabis use disorder. METHODS The study was a 3-month, randomized, open-label investigation (with blinded assessments) of the efficacy and safety of clozapine compared to continued current antipsychotic treatment (i.e., treatment as usual) in outpatients with schizophrenia or schizoaffective disorder and comorbid cannabis use disorder. After researchers established participants’ eligibility at baseline, blinded raters assessed participants weekly for substance use, symptoms, and side effects. Unblinded clinicians prescribed and adjusted study medications weekly for 12 weeks. The institutional review boards at Dartmouth Medical School and at the University of South Carolina approved the study. All procedures were consistent with the Declaration of Helsinki and Good Clinical Practice according to the International Conference on Harmonization guidelines. There was a complete and thorough discussion of the study with potential participants, and all participants gave written informed consent prior to engaging in any study procedures. Study Participants Participants were recruited, primarily through clinician referral, from two urban study sites, one in New Hampshire, affiliated with Dartmouth, and the second in South Carolina, affiliated with the University of South Carolina. Inclusion criteria were as follows: Diagnostic and Statistical
Journal of Dual Diagnosis
Clozapine and Cannabis Use in Patients With Schizophrenia
53
Downloaded by [University of Liverpool] at 08:30 29 December 2014
Manual (DSM-IV) diagnosis of schizophrenia or schizoaffective disorder and current cannabis use disorder; cannabis use on at least 5 days over the 3 weeks prior to screening; age 18 to 65; outpatient status prior to randomization; and current treatment with antipsychotic medication other than clozapine. Patients taking medications with possible effects on alcohol use (e.g., naltrexone, disulfiram, or topiramate) were excluded, as were patients with active, serious medical illness, suicidality, or severe psychiatric instability. Patients for whom clozapine was contraindicated (e.g., white blood cell count
