Fran Lowry

July 09, 2015

MIAMI — Patients diagnosed with major depressive disorder (MDD) who also exhibit symptoms of hypomania, such as bouts of energy during the day or sleeping fewer hours at night, may benefit from treatment with the atypical antipsychotic drug lurasidone (Latuda, Sunovion Pharmaceuticals Inc).

In a study presented here at the American Society of Clinical Psychopharmacology (ASCP) 2015 Annual Meeting, patients with MDD presenting with mixed (subthreshold hypomanic) features showed significantly greater improvement when treated with lurasidone vs placebo, both on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impression–Severity (CGI-S) scale.

"One of the groundbreaking elements of this study is that it is the first-in-kind prospective, placebo-controlled study looking at this population," Trisha Suppes, MD, PhD, director, Bipolar and Depression Research Program, VA Palo Alto Health Care System, and professor, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford University Medical Center, in California, told Medscape Medical News.

"It's estimated that about 20% to 40% of patients with unipolar depression will have some degree of intrusion of hypomania during a depressive episode. Historically, people have said these folks are bipolar, but that is not what the data actually support. Some will become bipolar over time, but not all," Dr Suppes said.

Dr Trisha Suppes

"DSM-5 introduced a 'with mixed features' specifier for major depressive disorder when subthreshold manic or hypomanic features are present during a depressive episode. I sometimes refer to this as 'energized depression.' Patients are still depressed, but they also may be revved up, very irritable, though this is not one of the DSM-5 symptoms. If patients show a high degree of irritability in a major depressive episode, it's important to look for the possibility of mixed features," she said.

MDD patients with mixed features are a challenge to treat, and to date, there are no established treatments. Standard antidepressants may not be as effective in this population and potentially could worsen the course and outcome of the illness, Dr Suppes said.

In the current study, which was conducted in the United States and Europe, Dr Suppes and her group sought to evaluate the efficacy and safety of lurasidone in this patient population.

Patients were required to meet DSM-IV-TR criteria for MDD, with a MADRS score >26, and to be experiencing two or three DSM-5 diagnostic criteria for manic symptoms with mixed features on most days during at least the 2-week period prior to first screening.

The study excluded patients with any lifetime history of bipolar I manic episodes or any mixed manic episodes.

The patients were randomly assigned to 6 weeks of double-blind treatment with either flexible doses of lurasidone 20 to 60 mg/day or to placebo.

In the 109 patients who received lurasidone, the baseline MADRS score was 33.2; in the 100 patients who received placebo, the baseline MADRS score was 33.3.

Treatment with lurasidone was associated with significantly greater improvement compared with placebo from week 2 through 6 on both the MADRS total score and the CGI-S score.

Table 1. Least Suquare Mean Change on MADRS & CGI-S

Score Lurasidone Placebo P-value Effect Size
MADRS -20.5 -13.0 <0.001 0.80
CGI-S -1.83 1.18 <0.001 0.60


The responder rate at week 6 for patients receiving lurasidone was 67.6%, compared with 33.0% for patients receiving placebo (P < .001; number needed to treat = 3).

The incidence of adverse events resulting in discontinuation was 2.8% in patients receiving lurasidone, and 5.0% in patients receiving placebo.

The only adverse event that occurred with an incidence >5% with lurasidone (and greater than placebo) was nausea, which occurred in 6.4% of lurasidone patients compared with 2.0% of patients receiving placebo.

Minimal changes in weight, lipid levels, and measures of glycemic control were observed.

Table 2. Weight and Other Changes With Lurasidone vs Placebo

Measure Lurasidone Placebo
Mean weight +0.67 kg +0.37 kg
Median total cholesterol level +0.5 mg/dL -1.0 mg/dL
Median triglyceride level -4.0 mg/dL +2.0 mg/dL
Median glucose level -1.0 mg/dL +1.0 mg/dL
Median prolactin level +1.7 ng/mL -0.1 ng/mL


"DSM-5 has added a new subtype for major depression disorder, 'with mixed features,' when subthreshold manic or hypomanic features are present. This subtype may be harder to treat," said Bradley N. Gaynes, MD, MPH, professor of psychiatry, University of North Carolina School of Medicine, in Chapel Hill, wheb asked by Medscape Medical News to comment on this study.

"While it can be common ― reports suggest it's present in 20% to 40% of depressed patients ― we have little clinical trial data addressing what can be effective for this subtype. This trial is one of the first I've seen to try to address this question," Dr Gaynes said.

"The effect sizes reported, 0.8 for the MADRS and 0.6 for the CGI, were impressive and suggest this is a promising potential intervention. It's important to remember that the comparison was to placebo in a pretty severely depressed group and that the study period was only weeks, so we don't know much about maintenance of effect, but it's an important first step and makes me quite interested in seeing more data on this possible treatment for a new MDD subtype," he said.

The study was sponsored by Sunovion Pharmaceuticals. Dr Suppes reports for 2014-2015 financial relationships with the National Institute for Mental Health, Sunovion Pharmaceuticals Inc, Elan Pharma International Limited, VA Cooperative Studies Program, AstraZeneca, Merck, A/S H. Lundbeck, Medscape Education, Global Medical Education, Jones and Bartlett, and UpToDate. Dr Gaynes reports no relevant financial relationships.

American Society of Clinical Psychopharmacology (ASCP) 2015 Annual Meeting. Abstract 3000325. Presented June 23, 2015.


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