Caplyta Now Approved for Bipolar Depression

Last December, the U.S. Food and Drug Administration (FDA) approved an expanded indication for the antipsychotic Caplyta (lumateperone) for the treatment of bipolar I and II depression in adults. Caplyta, marketed by Intra-Cellular Therapies Inc., was already approved for the treatment of schizophrenia in adults.

People with bipolar I disorder cycle between episodes of mania and depression, whereas those with bipolar II experience hypomania between more severe and longer-lasting depressive episodes.

“Bipolar disorder is a complex illness that has few treatment options for the depressive side of the cycle,” Suresh Durgam, M.D., chief medical officer of Intra-Cellular Therapies, told Psychiatric News. “Caplyta will be an important addition to therapy given the broad label of the new indication.” Caplyta was approved both as a monotherapy and as adjunct therapy with the mood stabilizers lithium or valproate for patients with bipolar I and bipolar II depression.

Chris Aiken, M.D., director of the Mood Treatment Center in Winston-Salem and an adjunct professor of psychiatry at Wake Forest University in North Carolina, noted that people with bipolar II might particularly benefit from the medication’s approval. Aiken has no financial ties to Intra-Cellular Therapies.

Prior to Caplyta, the only authorized medication shown to be effective for bipolar II depression was the antipsychotic quetiapine, which is only approved as a monotherapy and has some adverse side effects including weight gain and abnormal heart rhythms. Vraylar (cariprazine), which was approved for bipolar I depression in 2019, failed to show any clinical effect in patients with bipolar II.

The approval of Caplyta may help to raise awareness about bipolar II, which is still frequently misdiagnosed as either bipolar I disorder or unipolar depression, Aiken said.

The FDA approval of Caplyta was based on positive findings from two six-week, phase 3 trials. The first trial evaluated the effects of 42 mg/day lumateperone monotherapy versus placebo in 381 adults aged 18 to 75 with bipolar I or II depression. The second trial evaluated 28 mg/day or 42/mg day lumateperone versus placebo in 529 adults with bipolar I or II depression who were also taking lithium or valproate.

In both studies, participants taking 42 mg/day lumateperone showed statistically stronger improvements in their depression symptoms after six weeks compared with those taking placebo. In the monotherapy study, which was published in the American Journal of Psychiatry, Montgomery-Åsberg Depression Rating Scale (MADRS) scores dropped by an average of 16.7 points after six weeks in the lumateperone group compared with 12.1 points in the placebo group. In the adjunct therapy study, MADRS scores dropped by an average of 16.9 points after six weeks in the lumateperone group compared with 14.5 points in the placebo group.

The drug was also superior to placebo in the secondary outcome—change in the Clinical Global Impressions scale, which assesses the overall severity of patients’ illness.

These improvements align with what has been found for other antipsychotics approved for bipolar depression, but where Caplyta shined was in its tolerability profile, Durgam noted. “The rates of weight gain or EPS [extrapyramidal symptoms] for Caplyta were almost at placebo levels, which is very favorable,” he said. Durgam added that a six-month, open-label safety study did not reveal additional health risks.

In an editorial that accompanied the AJP monotherapy study, Michael Ostacher, M.D., M.P.H., a professor of psychiatry at Stanford Medical School, noted some concerns about the findings. For one, only 20% of the participants were categorized as having bipolar II disorder and in many cases were categorized retrospectively. “Even as bipolar I disorder is difficult to diagnose retrospectively without the presence of a clear index manic episode (requiring hospitalization, for example, or present with psychotic symptoms), it is even more difficult to accurately diagnose the hypomanic episodes required for the diagnosis of bipolar II disorder,” he wrote. As such, the true efficacy of this medication for patients with bipolar II data is quite uncertain, he said.

Aiken cautioned that Caplyta—as with other antipsychotics—should be seen as a short-term solution for bipolar disorder. “All the antipsychotics approved over the last decade look great when it comes to managing depressive symptoms over a few weeks,” he told Psychiatric News. “As a field, though, we need to focus not just on acute symptoms, but also on treatments that improve long-term functioning in patients.” When considering longer-term outcomes such as relapse rates, mood stabilizers like lithium still have the most robust efficacy data, Aiken noted.

Durgam is hopeful that this recent approval will be just the first in a long series for Caplyta. Intra-Cellular Therapies is currently conducting phase 3 studies testing Caplyta for both major depression and depression with mixed features (in which patients exhibit features of both depression and mania) in adults. The company has also begun preliminary studies evaluating Caplyta for the treatment of schizophrenia and bipolar disorder in youth. ■