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Opioid modulation may improve treatment-resistant depression

A combination of buprenorphine and samidorphan as adjunctive treatment demonstrated significant antidepressant effects among adults with major depression and inadequate response to one or two courses of antidepressant treatment.

“We know that more than half of patients with major depression won't respond to the first antidepressant they try, and almost 40% will continue to have symptoms even after switching to or adding different drugs” Maurizio Fava, MD, of the Clinical Trials Network and Institute, Massachusetts General Hospital, Boston, said in a press release. “Opioids have actually been used for centuries to treat mood disorders, and while opioid drugs must be used cautiously because of their potential for abuse, studies have shown that levels of the endogenous opioids released by the central nervous system may be reduced in important brain areas of patients with major depression.”

To assess whether opioid modulation achieved through administration of ALKS 5461 — a combination of a μ- and κ-opioid partial agonist, buprenorphine, and a μ-opioid antagonist, samidorphan — would exhibit antidepressant effects among patients with major depression, researchers conducted a multicenter, randomized, double blind, placebo-controlled, two-stage sequential parallel comparison design study. Adults with major depression with inadequate response to one or two courses of antidepressant treatment were randomly assigned to receive adjunctive treatment with 2 mg of buprenorphine and 2 mg of samidorphan; 8 mg of buprenorphine and 8 mg of samidorphan; or placebo. Change in Hamilton Depression Rating Scale (HAM-D), Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impressions severity scale (CGI-S) scores from baseline to the end of 4 weeks of treatment determined antidepressant effect.

Participants in the 2/2 dosage group exhibited significantly greater improvements, with placebo-adjusted least-squares mean differences on HAM-D (–2.8; 95% CI, –5.1 to –0.6; P = .014), MADRS (–4.9; 95% CI, –8.2 to –1.6; P = .004) and CGI-S (–0.5; 95% CI, –0.9 to –0.1; P = .012), compared with placebo.

Participants in the 8/8 dosage group also exhibited improvements but they did not reach statistical significance.

The buprenorphine/samidorphan combinations were well-tolerated and there was no evidence of opioid withdrawal on treatment discontinuation, according to researchers.

“The robust treatment effect seen in this clinical study suggests that many patients with depression may have a dysregulation of the endogenous opioid system, which may be why they do not respond to monoamine-based antidepressants that target the serotonin system,” Fava said in the release. “For the substantial percentage of patients who do not respond to monoamine based medications, this combination may represent an important new approach to the treatment of depression.” – by Amanda Oldt

Disclosure: Fava reports several relevant financial disclosures. Please see the full study for a complete list of all researchers’ relevant financial disclosures.