Nancy A. Melville

April 06, 2015

COLORADO SPRINGS, Colorado — The atypical antipsychotic drug lurasidone (Latuda, Sunovion Pharmaceuticals Inc) may improve depressive symptoms in people with major depressive disorder (MDD) presenting with mixed (subthreshold hypomanic) symptoms, new research suggests.

The results of a randomized, controlled trial presented here at the 15th International Congress on Schizophrenia Research (ICOSR) showed efficacy of the psychotropic agent for patients with unipolar MDD associated with "mixed features," a specifier introduced in the DSM-5 that indicates subthreshold manic or hypomanic features present in MDD, according to lead author Andrei Pikalov, MD, PhD, senior medical director of Sunovion Pharmaceuticals.

"The literature shows 'mixed features' are present in as many as 25% to 40% patients with major depressive disorder," he explained.

"These symptoms can significantly increase risk for suicidal behavior, result in poor antidepressant treatment response, substance abuse, depressive episode recurrence, and manic switch," Dr Pikalov said.

Symptoms can include elevated, expansive mood; inflated self-esteem or grandiosity; being more talkative than usual; having an increase in energy or goal-directed activity; and decreased need for sleep.

As reported by Medscape Medical News, research published last year in the American Journal of Psychiatry showed significant improvement with lurasidone as monotherapy or adjunctive therapy with lithium or valproate over placebo in the treatment of bipolar depression.

To determine the drug's efficacy for the treatment of depressive symptoms, the researchers enrolled 211 patients, aged 18 to 75 years, at 44 sites in the United States and Europe. The patients met criteria for MDD accompanied by two or three of the subthreshold manic symptoms.

First Demonstration of Efficacy

Patients were randomly assigned in the double-blind study to treatment with either lurasidone 20 mg to 60 mg per day (n = 109) or placebo (n = 102) for 6 weeks. Among them, 102 (93.6%) completed the study in the lurasidone group; 87 (85.3%) in the placebo group completed the study.

At baseline, patients in both groups had a relatively high baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score of approximately 33.2.

Following the 6-week treatment, patients in the lurasidone group showed a mean reduction in MADRS score, the study's primary outcome, of 20.5 from baseline, compared with a reduction of 13.0 in the placebo group (P < .001), for an effect size of 0.8.

The mean reduction in Clinical Global Impression–Severity from baseline was 1.83 in the lurasidone group and 1.18 in the placebo group (P < .001; effect size, 0.60).

At 6 weeks, the rate of responders for the lurasidone group was 67.6% vs 33.0% for the placebo group (P < .001; number needed to treat = 3).

The mean change from baseline in the Sheehan Disability Scale total score at 6 weeks among 80 patients in each group was -6.4 in the placebo group and -10.7 in the lurasidone group (P = .001).

Reasons for discontinuation included insufficient clinical response, which occurred at a rate of 1.8% in the lurasidone group and 3.9% in the placebo group.

Adverse events were reported in 2.8% in the lurasidone group and 4.9% in placebo group, with nausea being the only adverse event that occurred, with an incidence of 5% or more with lurasidone compared with placebo (6.4% vs 2.0%).

Patients in the lurasidone group had minimal changes in weight, lipid levels, and measures of glycemic control, as has been shown in previous studies of the drug.

"This study is the first-ever demonstration of efficacy for lurasidone, or any psychotropic agent, associated with mixed features in a placebo-controlled study," Dr Pikalov said. "Lurasidone was generally well tolerated in this study, with a relatively low discontinuation rate compared to placebo."

Peer Pressure

In general, atypical antipsychotic drugs are often of benefit to patients with major depression, said Carol A. Tamminga, MD, professor and chair of the Department of Psychiatry, University of Texas Southwestern School of Medicine, in Dallas.

"Drugs in this class are often used in major depressive disorder with great benefit," she told Medscape Medical News.

"Lurasidone is one with low side effects overall, [and] I believe it can safely be given with antidepressants," she said. "It is the antidepressant which is of more concern in that they have the reputation to move the depression into mania in the major depressive disorder population."

The specific benefits lurasidone may have over other atypical antipsychotics in general remains to be seen, she noted. "There is great pressure for a drug to distinguish itself among its peers," Dr Tamminga said.

"Physicians understand that while this may technically be a distinction, they will want to see if it is clinically distinguishable. What the nature of this distinction is at the bedside is likely unknown."

A Clinical Challenge

Charles Schulz, MD, professor and head of the Department of Psychiatry, at the University of Minnesota, in Minneapolis, and moderator of the session, noted that issues of mania in depression can be particularly challenging.

"We have to advance our care for this [subset] of patients with depression that is not improving well," he told Medscape Medical News.

Other studies ― for instance, with [the atypical antipsychotic] aripiprazole [Abilify, Otsuka Pharmaceutical Co, Ltd] ― suggest that if a patient is not responsive to an antidepressant, that can be added, but depression with ["mixed features"] is a little more difficult to treat, so I thought the findings were of interest."

Dr Pikalov is an employee of Sunovion Pharmaceuticals Inc. Dr Tamminga has been a consultant for Sunovion. Dr Schulz reports no relevant financial relationships.

15th International Congress on Schizophrenia Research (ICOSR). Abstract 2114720. Presented March 31, 2015.

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