depression sign
Mental & Emotional Health

Combo Drug May Help Relieve Treatment-Resistant Depression

A clinical trial of an experimental drug for treatment-resistant major depression finds that modulation of the endogenous (inner) opioid system may improve the effectiveness of drugs that target the action of serotonin and related monoamine neurotransmitters. In their paper published online in February 2016 in the American Journal of Psychiatry, a multi-institutional research team reports that adding treatment with ALKS-5461, a medication that combines two drugs with complementary effects on different opioid receptors, to serotonin-targeting antidepressant therapy produced significant symptom improvement in patients with persistent depression. ALKS-5461 is being developed by Alkermes, Inc., which sponsored the trial.

A release from Massachusetts General Hospital quotes Maurizio Fava, MD, executive director of the Clinical Trials Network & Institute in the MGH Department of Psychiatry and lead author of the study, as saying, “We know that more than half of patients with major depression won’t respond to the first antidepressant they try, and almost 40 percent will continue to have symptoms even after switching to or adding different drugs. 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.”

Opioid drugs produce their effects by binding to receptors in the endogenous opioid system, which the body uses to suppress pain and to reward biologically beneficial activities. Two prominent opioid receptors are the mu and kappa receptors, which have overlapping but somewhat different effects. ALKS-5461 is a combination of buprenorphine, which suppresses kappa receptor activity and weakly activates mu receptors, and samidorphan, which blocks mu receptor activity. While buprenorphine is FDA-approved to help treat opioid addiction by easing withdrawal symptoms, samidorphan is an experimental drug being developed by Alkermes for several potential uses. The combination of the two drugs is an effort to balance the opioid system activity while avoiding adverse effects, including the potential for abuse.

The current study, a phase 2 clinical trial, enrolled 142 patients with treatment-resistant depression at 31 sites in the U.S. Since depression treatment trials are likely to have a large placebo response, this study used a design developed in 2003 by Fava and David Schoenfeld, PhD, an MGH biostatician, to reduce the impact of the placebo effect. Using this sequential parallel comparison design (SPCD), the trial was conducted in two stages. In stage 1, 98 participants were randomized to receive placebo doses while 43 participants received ALKS-5461 in daily dosages containing either 2 mg or 8 mg of each of the two drugs.