A randomized trial of clozapine vs. other antipsychotics for cannabis use disorder in patients with schizophrenia.

OBJECTIVE: Cannabis use disorder is the most common co-occurring drug use disorder in people with schizophrenia and is associated with poor outcomes. We 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 Follow-back 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.

Risperidone versus olanzapine among patients with schizophrenia participating in supported employment: Eighteen-month outcomes.

This study compares the efficacy and tolerability of olanzapine versus risperidone among patients with schizophrenia who are established in outpatient psychiatric care and entering supported employment. A multicenter, randomized, double-blind trial was conducted among 107 outpatients with schizophrenia, who were cross-titrated to flexible dose risperidone or olanzapine over 2 weeks. Clinical endpoints included time to hospitalization and persistence on assigned medication. Weight, laboratory tests, psychopathology, neurologic side effects, social adjustment and role functioning were assessed at 3-6 month intervals. Data were analyzed first by randomized treatment, and then reassessed controlling for prior medication treatment. The proportion of patients on assigned medication at 18 months was 30.9% for risperidone and 37.3% for olanzapine. Mean doses were 6.4 ± 3.2 mg daily for risperidone, and 17.0 ± 5.0 mg daily for olanzapine. The groups did not differ significantly in time to medication discontinuation, first hospitalization or first employment. There were few differences in psychopathology, laboratory, or neurological assessments between groups at 18 months. Patients randomized to olanzapine gained modestly more weight. Controlling for pre-randomization medication suggested improvement in some aspects of psychopathology from switching medications; however, switching from olanzapine to risperidone was associated with more hospitalizations. Risperidone and olanzapine have similar efficacy and tolerability in patients with schizophrenia who are participating in supported employment. Randomization to olanzapine was associated with more weight gain, but randomization from olanzapine to risperidone appeared to be associated with a greater likelihood of hospitalization. Careful monitoring of metabolic effects and participation in supported employment may have contributed to minimal weight gain and metabolic effects.

An open-label pilot study of quetiapine plus mirtazapine for heavy drinkers with alcohol use disorder.

Animal research suggests that medications that produce a weak dopamine D2 receptor blockade and potentiate noradrenergic activity may decrease alcohol drinking. In an open-label pilot study of subjects with alcohol dependence, we tested whether the combination of quetiapine, a weak dopamine D2 receptor antagonist, whose primary metabolite, desalkylquetiapine, is a norepinephrine reuptake inhibitor, and mirtazapine, a potent α2 norepinephrine receptor antagonist, would decrease alcohol drinking and craving. Twenty very heavy drinkers with alcohol dependence entered a trial of 8 weeks of treatment with quetiapine followed by 8 weeks of treatment with a combination of quetiapine plus mirtazapine. Alcohol use was assessed weekly with a Timeline Follow-Back interview and craving with the Penn Alcohol Craving Scale. Among the 11 completers, subjects reported improved outcomes in the quetiapine plus mirtazapine period compared to the quetiapine alone period: fewer very heavy drinking days per week (1.3 [SD = 2.4] vs. 2.1 [SD = 2.8]; t = 2.3, df = 10, p = 0.04); fewer total number of drinks per week (39.7 [SD = 61.6] vs. 53.4 [SD = 65.0]; t = 2.8, df = 10, p = 0.02); and lower craving scores (2.5 [SD = 1.4] vs. 3.2 [SD = 1.2]; t = 2.4, df = 10, p = 0.04). All subjects reported at least one adverse event; 72.7% reported somnolence. In this open-label pilot study, treatment with quetiapine plus mirtazapine was associated with a decrease in alcohol drinking and craving. These findings are consistent with our previous work in animal models of alcohol use disorders and suggest that further study of medications or combinations of medications with this pharmacologic profile is warranted.

Reversal of antipsychotic-associated weight gain.

BACKGROUND: Given growing concern about weight gain associated with treatment with antipsychotic agents, we performed a retrospective chart review of patients who reversed weight gain associated with antipsychotic treatment to determine the prevalence of reversal and both the course and methods used. METHOD: Prevalence of weight gain reversal was determined by surveying clinicians. Of 53 patients who gained >/= 20 lb (9 kg) during antipsychotic treatment, an initial sample of 12 patients (23%) who subsequently lost >/= 10 lb (5 kg) was identified. These 12 patients were combined with additional patients, identified by the authors, who met the same criteria for reversal of antipsychotic-associated weight gain to form a total sample of 35 patients. Course and methods of weight loss were determined by reviewing these patients' charts. Information about interventions and both antipsychotic and other medications was collected. RESULTS: At the point of maximum weight gain, the total sample of 35 patients had gained a mean of 29.36 kg (64.73 lb) over a mean of 33 months. At the point of greatest weight loss (56 months), these patients were a mean of 10.86 kg (23.94 lb) over their baseline weight. The most recent weight for patients (63 months) indicated they were 14.81 kg (32.65 lb) over baseline. The most frequent weight loss interventions were regular dietician visits (42.9% [N = 15]), self-directed diet (28.6% [N = 10]), and weight loss as a treatment goal (25.7% [N = 9]). The least frequent interventions were no intervention (5.7% [N = 2]), psychiatrist addressing weight loss (5.7% [N = 2]), and surgery (2.9% [N = 1]). No significant change in medications prescribed was found. CONCLUSION: Some patients who gain weight while taking antipsychotic medications are able to stop gaining and lose weight over time, largely through behavioral interventions. While patients' weight fluctuated, this group sustained a loss of approximately half their initial gain. Dietary interventions appear promising and should be explored further to prevent and reverse weight gain.