Risperidone and Desipramine in Alcohol Use and Schizophrenia

Alcohol use disorder is at least three times more common in schizophrenia than in the general population, and worsens the course of schizophrenia. Typical antipsychotic agents are of limited value in controlling alcohol use in these "dual diagnosis" patients. Data from our group and others suggest that the atypical antipsychotic drug clozapine limits alcohol and cannabis use in "dual diagnosis" patients with schizophrenia much more effectively than other antipsychotics that have been assessed, however, the side effects produced by clozapine severely limit its use.

The investigators have hypothesized that clozapine will lessen alcohol/substance use in such dual diagnosis patients in part because of its mechanism of action that includes release of dopamine (DA) in the prefrontal cortex which will help to normalize dysfunctional brain reward circuits that may underlie the co- occurring alcohol/substance use in patients with schizophrenia. Our data suggest that the effect of clozapine can be duplicated in rodents when medications with clozapine-like activity (DA D2 antagonism, potent norepinephrine (NE) α2 receptor antagonism and NE reuptake inhibition) are combined together. The investigators have demonstrated that RISP (a medication that is both a DA D2 receptor antagonist, and a potent NE α2 receptor antagonist), in combination with the specific NE reuptake inhibitor desipramine, significantly decreases alcohol consumption in alcohol drinking rodents.

This translational study is a pilot "proof of concept" 14-week double-blind investigation of participants who have co-occurring diagnoses of schizophrenia and an alcohol use disorder. Patients not treated with risperidone (or a risperidone-like agent, including risperidone long-acting, paliperidone and paliperidone palmitate) at the time of consent will be switched to oral risperidone in the first two weeks of the study. At Week 3, all participants will begin treatment with risperidone risperidone plus desipramine and followed for 12 weeks. The primary outcome measure will be days of drinking (per week), as well as days of heavy drinking (per week). The investigators anticipate that data from this study will support a larger trial of risperidone + desipramine in patients with schizophrenia and an alcohol use disorder.

Inclusion criteria

• Meets the diagnostic criteria of schizophrenia or schizoaffective disorder
• Meets the diagnostic criteria for a current alcohol use disorder (abuse or dependence)
• Recent alcohol use as documented on the Timeline Followback
• Receives outpatient treatment with oral antipsychotic medication (including risperidone.
• Is willing to switch to risperidone treatment at the beginning of the study.

Exclusion criteria

• Other substance use disorder other than alcohol, caffeine and nicotine, and cannabis abuse, as defined by DSM-IV criteria.
• Receives current treatment with Clozapine
• Continues to use alcohol despite current adequate treatment with medication to decrease alcohol use(e.g. naltrexone, acamprosate, disulfiram or topiramate)
• Is determined to be a "slow metabolizer" of CYP2D6
• Is currently pregnant, trying to become pregnant, or nursing