Combination Medication Could Help Relieve Treatment Resistant Depression

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In a clinical trial using an experimental drug for treatment-resistant depression, it was found that modulation of the endogenous opioid system might improve the effectiveness of drugs which target the action of serotonin and related monoamine neurotransmitters.

The Study

A team of medical researchers from Massachusetts General Hospital published the results of their study online in the American Journal of Psychiatry. The team added that treatment with ALKS-5461, a medication that combines two drugs with complementary effects on different opioid receptors, to serotonin-targeting antidepressant therapy produced a significant improvement of symptoms in people with persistent depression.

ALKS-5461 is being manufactured by Alkermes, Inc, which funded the clinical trial.

The Study

Maurizio Fava, MD, executive director of the Clinical Trials Network & Institute in the MGH Department of Psychiatry and lead author of the study said, “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.”

He further states, “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 medication produces its effects through binding to the opiate receptors in the brain, which the body uses to suppress pain and to reward biologically beneficial activities. Two prominent opiate receptors are the mu and kappa receptors, which have overlapping but somewhat different effects on a person. ALKS-5461 is a combination of buprenorphine, which suppresses the activity of kappa receptors and samidorphan, which blocks the activity of mu receptors.

While buprenorphine has been approved by the US Food and Drug Administration to help treat opioid addiction through easing withdrawal symptoms, samidorphan is an experimental drug developed by Alkermes for many possible uses. The combination of these two drugs is an effort to balance out the opioid system activity while avoiding adverse effects, including the probability for abuse.

The current study, a 2-phase clinical trial, enrolled 142 patients with treatment resistant depression at 31 different locations in the United States. Because depression treatment trials are likely to have a large placebo response, this study used a method designed in 2003 by Fava and David Schoenfield. The goal of this treatment protocol is to reduce the impact of the placebo effect.

After the first four week treatment period, the placebo group who didn’t show a response to treatment were randomized either to receive one or two doses of the active drug or to continue on taking the placebo medication. While both dose levels of ALKS-5461 produced a better reduction in depression symptoms than the placebo did, the lower dose of 2 mg of each drug had effects that were stronger and met statistical significance.


Dr. Fava stated, “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. 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.”


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