NEW YORK (Reuters Health) - Opioid modulation with the combination of buprenorphine and samidorphan (ALKS 5461) improves symptoms in patients whose depression has not responded adequately to antidepressant treatment, researchers report.
"If the findings are confirmed in phase 3 studies, ALKS 5461 could be used as an augmenting agent in patients not responding to standard antidepressant therapies as an alternative to the atypical antipsychotic agents currently approved for the treatment of this population," Dr. Maurizio Fava, from Massachusetts General Hospital and Harvard Medical School, Boston, told Reuters Health by email.
Buprenorphine is a mu- and kappa-opioid partial agonist, and samidorphan blocks the mu agonist effects of buprenorphine associated with its abuse and addictive potential. A growing body of evidence implicates dysregulation of the endogenous mu- and kappa-opioid system in mood disorders.
Dr. Fava and colleagues at 31 sites in the U.S. used a sequential parallel comparison design to investigate the efficacy of buprenorphine/samidorphan (2 mg/2 mg or 8 mg/8 mg) in 142 patients with major depression inadequately responsive to antidepressant therapy.
At the end of four weeks of treatment, patients in the ALKS 5461 2 mg/2 mg group showed significantly greater improvements in Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), and Clinical Global Impression severity scores, compared with patients in the placebo group. The ALKS 5461 8 mg/8 mg group showed smaller, nonsignificant improvements.
"The overall effect sizes for the 2/2 dosage were 0.50 for HAM-D and 0.54 for MADRS," the researchers noted. "The result compares favorably with results from a meta-analysis of 14 studies with atypical antipsychotics as adjunctive therapy for major depression, with reported effect sizes of 0.35 to 0.48 for individual drugs."
Treatment response rates according to HAM-D and MADRS (at least 50% reduction in scores) were highest with ALKS 5461 2 mg/2 mg treatment group, according to the February 12 onlinereport in the American Journal of Psychiatry.
Two patients (1.6%) in the placebo group and 17 patients (19.3%) in the ALKS 5461 groups discontinued because of treatment-emergent adverse events, but there was no evidence of opioid withdrawal in any patient.
"When depressed patients do not respond to standard monoamine-based therapies for depression, consider the use of an augmenting agent that modulates other systems, such as the opioid one," Dr. Fava concluded.
Dr. Jeffrey F. Scherrer, from Saint Louis University School of Medicine, St. Louis, Missouri, recently examined the association between opioid use and increased depression rates. He told Reuters Health by email, "Our analysis of opioid use and depression did not include buprenorphine among the opioid exposure variable. Therefore, it is difficult to extrapolate our results to a trial of buprenorphine/samidorphan and major depression."
"As the authors noted, the clinical trial was of short duration and the risks of depression that we have observed appears to be greatest among those patients remaining on opioids for more than 90 days," he explained. "Additional work is currently being done to determine if some opioid medications have a greater depressogenic effect than others, which further limits direct comparison of our findings to the current study."
"I will say that it is unlikely for oxycodone, codeine, and hydrocodone (which together account for more than 90% of prescribed opioids) would help depressed patients and be more likely to worsen their depression with chronic treatment," Dr. Scherrer concluded.
Alkermes sponsored the trial, employed seven coauthors, and had various relationships with the other four coauthors.