Risperidone and Desipramine in Alcohol Use and Schizophrenia

Phase 2

Completed

• Conditions: Schizophrenia; Alcoholism; Dual Diagnosis
• Interventions: Drug: Risperidone + Desipramine

• Registration Number: NCT01411085
• Lead Sponsor: Dartmouth-Hitchcock Medical Center

Brief Summary

Note: In June 2013, the study design was changed from a randomized controlled study of risperidone + despiramine vs. risperidone vs. placebo to an open label pre-post study of risperidone (or risperidone-like drug) + desipramine. The aims of the study were revised to read:

1. To determine whether participants treated with risperidone in combination with desiprmaine have less alcohol use (fewer drinking days; fewer heavy drinking days) during the final 8 weeks on these medications as compared to pre-baseline. The primary hypothesis is that compared to pre-baseline, participants will demonstrate fewer days of drinking (per week), as well as fewer days of heavy drinking (per week) in the final eight weeks they are taking risperidone and desipramine, as recorded on the Timeline Follow-Back assessment

2. To explore changes in symptoms (of schizophrenia and of depression) in the final eight weeks of treatment with risperidone + desipramine compared to the period before baseline

3. To assess the side effect burden associated with the combination of these two medications in participants.

The original aims of the study were:

The purpose of this study is to determine whether participants who are treated with risperidone in combination with desipramine have less alcohol use (fewer drinking days; fewer heavy drinking days) than do participants who are treated with RISP with placebo. The primary hypothesis is that compared to treatment with risperidone, participants randomized to a combination of risperidone plus desipramine will have fewer days of drinking, as well as fewer days of heavy drinking. The study will also compare the effects of risperidone as compared to risperidone plus desipramine on participants' symptoms and side effects.

Detailed Description

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.

Study Timeline

• Study First Submitted: 2011-06-16
• Study First Submitted QC: 2011-08-04
• Study First Posted: 2011-08-08
• Study Start: 2011-12
• Primary Completion: 2014-08
• Study Completion: 2014-09
• Results First Submitted: 2017-02-22
• Status Verified: 2018-03
• Results First Submitted QC: 2018-03-21
• Last Update Submitted: 2018-03-21
• Results First Posted: 2018-03-23
• Last Update Posted: 2018-03-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 12

Inclusion Criteria

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

Exclusion Criteria

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Risperidone + Desipramine	Risperidone + Desipramine	All participants will be treated with risperidone (or a risperidone-like agent including: risperidone long-acting, paliperdione, and paliperidone palmitate) at the time treatment with desipramine is initiated. The target dose of oral risperidone is 4mg though variations are allowed. The target dose of desipramine is 100mg.

Primary Outcome Measures

Name	Time	Method
Timeline Followback Assessing Number of Drinks Per Week	Weekly for 14 weeks, using data from last 8 weeks	Alcohol/other substance use (including tobacco) will be assessed primarily by weekly self-report using the Timeline Followback (TLFB) method enhanced by procedures to strengthen the reliability and validity of this measure. It involves asking participants to retrospectively estimate their alcohol and other substance use.

Trial Locations

Locations (4)

University of Massachusetts Medical School; 🇺🇸 Worcester, Massachusetts, United States

University of South Carolina School of Medicine; 🇺🇸 Columbia, South Carolina, United States

Dartmouth Medical School; 🇺🇸 Lebanon, New Hampshire, United States

Michigan State University / Cherry Street Health Services; 🇺🇸 Grand Rapids, Michigan, United States