An international team of researchers has reported positive results in a phase 3 clinical trial of a drug to treat depressive episodes in patients with bipolar I and bipolar II disorder.

Both bipolar I and bipolar II disorders involve episodes of low mood and elevated mood; individuals with bipolar I experience mania while those with bipolar II experience a less intense form of mania called hypomania. Both forms of the disorder are associated with elevated risk of suicide relative to the rate in the general population.

Antipsychotics are often prescribed in both bipolar I and bipolar II, but carry increased risk to the patient of weight gain, diabetes, cardiovascular, and movement and seizure side effects. Antidepressants are not FDA approved for bipolar disorder but can be prescribed to patients with both forms of bipolar disorder. The use of antidepressants does carry some risk of a patient "switching over" from a depressed mood to a manic one—an undesirable outcome.

In view of these risks, researchers continue to search for medicines that might be effective in reducing the symptoms of depression in the "low mood" phase of bipolar illness while minimizing side-effect risks.

"Bipolar I and bipolar II disorders are serious mental illnesses associated with a wide array of debilitating symptoms," noted a research team in the American Journal of Psychiatry. "Depressive episodes are more prevalent than episodes of mania and hypomania in most patients and are associated with greater disability and decreased quality of life."

Spanning six nations, including the U.S., members of the research team tested an antipsychotic medicine called lumateperone at 54 clinical sites. The double-blinded, randomized trial measured its effectiveness compared with placebo in 376 patients, 188  of whom received 42mg of lumateperone, in capsule form, and 188  of whom received a placebo pill. The treatment was given each evening over a 6-week period. First author on the paper reporting results was Joseph R. Calabrese, M.D., of the Case Western Reserve School of Medicine, 2004 winner of BBRF's Falcone Prize for Outstanding Achievement in Moods Disorders Research.  

Lumateperone is currently FDA-approved for the treatment of schizophrenia in adults and is currently under review by the FDA for the treatment of depressive episodes in bipolar disorder.

All participants in the trial, aged 18 and over, were experiencing a depressive episode of at least moderate severity when the trial began. The typical participant had been diagnosed with bipolar illness at age 33; about 80% had a diagnosis of bipolar I disorder; about half were being treated with antipsychotics, antidepressants and/or mood stabilizers prior to the trial (which were discontinued during the trial). Similar to other clinical trials of this type, individuals with treatment-resistant illness, imminent risk of suicide, rapid cycling of moods, and serious comorbidities were excluded from the trial.

Participants who received lumateperone treatment, with either bipolar I and bipolar II diagnoses, experienced "significant" improvement in their major depression compared with those who received placebo, the team reported. Depression scores were observed to decrease at the first assessment (after 8 days) and continued to improve over the 6-week trial. Improvement was also noted in a secondary assessment criterion, a scale that measures quality of life, including assessments of family and social relationships as well as overall sense of wellbeing, the researchers said.

Importantly, those treated with lumateperone registered improvements in depression symptoms that were similar in magnitude to that seen in patients in prior trials of antipsychotic medicines approved for use in bipolar disorder.  In the lumateperone trial, 51% of participants had a clinical response to the treatment, and 39% had a remission of symptoms by the trial's end.

The potential rationale for prescribing lumateperone rather than quetiapine, the only antipsychotic currently approved by the FDA for use as a monotherapy in bipolar II disorder, concerns side effect risks. "Quetiapine is associated with a high burden of side effects, including extrapyramidal (i.e., movement) symptoms, moderate weight gain, sedation, and risk of metabolic syndrome," the researchers noted.  

Lumateperone was "generally well tolerated," they said, with side effects in the mild-to-moderate range, and consisting of sleepiness and nausea. The incidence of movement disorders was low and similar to placebo. Minimal changes were observed in weight, vital signs, or metabolic or endocrine assessments. Larger trials of lumateperone are still needed, the team said, and might include a wider range of patients and should gauge side effects and safety over the long term.   

The paper's corresponding author, Suresh Durgam, M.D., is the Chief Medical Officer of Intra-Cellular Therapies, Inc., the maker of lumateperone.