ALKS 3831 not superior to olanzapine alone for delaying schizophrenia, alcohol use disorder symptom exacerbation

A combination of olanzapine and samidorphan was not superior to olanzapine alone in the time to first event of exacerbation of disease symptoms in patients with schizophrenia and alcohol use disorder, according to results of a phase 2, randomized clinical trial published in Journal of Clinical Psychiatry.

However, the treatment, ALKS 3831 (Alkermes), was well-tolerated among this patient population.

“Few studies have evaluated whether pharmacologic interventions can address alcohol misuse and associated symptom exacerbations in patients with schizophrenia and comorbid [alcohol use disorder],” Mary F. Brunette, MD, associate professor of psychiatry at Dartmouth Medical School and medical director of the Bureau of Behavioral Health within the New Hampshire Department of Health and Human Services, and colleagues wrote. “[Although] no randomized controlled trial has reported reductions in alcohol use with antipsychotic treatment, some evidence supports better substance use disorder outcomes with clozapine over usual treatment and long-acting injectable risperidone over daily oral risperidone in this difficult-to-treat population; however, no treatment is yet approved by the [FDA] for this indication.”

Studies have shown olanzapine to be one of the most efficacious first-line antipsychotics for schizophrenia, but patients with comorbid disorders have been excluded from trials, and no prospective, controlled trials have evaluated the impact of olanzapine among patients with schizophrenia and comorbid alcohol use disorder.

Brunette and colleagues conducted a phase 2, double-blind study of ALKS 3831, which combines olanzapine with the opioid receptor antagonist samidorphan, among adults with schizophrenia and alcohol use disorder who experienced 10 or more drinking days and 2 or more heavy drinking days in the previous month, as well as disease symptom exacerbation in the previous 6 months. They assigned diagnoses of schizophrenia and alcohol use disorder using DSM-IV-TR and DSM-5 criteria, respectively. Following a 6-week lead-in period, the researchers randomly assigned 234 eligible patients 1:1 to ALKS 3831 or olanzapine alone for 36 weeks to 60 weeks of treatment. They used the log rank test to compare treatments according to the primary outcome of time to the first event of exacerbation of disease symptoms, and a Cox proportional hazards model to estimate hazard ratio. They assessed safety based on adverse events and laboratory measures.

Results showed no significant difference between groups in the time to first event of exacerbation of disease symptoms (HR =0.91; 95% CI, 0.53-1.56). Patients who received ALKS 3831 had numerically lower rates in six of eight criteria to evaluate time to the first event of exacerbation of disease symptoms compared with olanzapine alone. During the double-blind treatment period, change from baseline in percentage of heavy-drinking days was similar among patients treated with ALKS 3831 and those treated with olanzapine alone. ALKS 3831 had a safety profile similar to olanzapine and was generally well-tolerated.

“This study is of particular relevance as few clinical trials have been completed in patients with schizophrenia and comorbid [alcohol use disorder], and this trial demonstrates the feasibility of recruiting and conducting long-term evaluation of this difficult-to-treat patient population,” the researchers wrote. “Further research is needed to identify effective treatments for this group of patients who have been underrepresented in clinical research to date.” – by Joe Gramigna

Disclosures: Brunette reports research support from Alkermes. Please see the study for all other authors’ relevant financial disclosures.