Bipolar disorder is a mental disorder characterised by periods of mania and depression. The current bipolar disorder treatment landscape includes a high number of established products that can effectively manage acute manic symptoms and reduce the frequency of relapses. The clinical unmet need most consistently highlighted by key opinion leaders (KOLs) interviewed by GlobalData, however, is the scarcity of treatment options available for bipolar depression. This unmet need is further compounded by the fact that symptomatic patients predominantly experience episodes of depression compared with episodes of mania.

There are currently no antidepressant monotherapies approved for the treatment of bipolar depression. In fact, their use is a point of debate among psychiatrists, as they are believed to precipitate mania, may increase the frequency of mood cycling, and show mixed evidence of efficacy. Because of this, when they are used, antidepressants are prescribed off-label, typically in combination with an antimanic agent. In general, their long-term use is avoided, particularly in bipolar I patients. The only products approved for the treatment of depressive episodes associated with bipolar disorder in the US are atypical antipsychotic agents, namely Latuda (lurasidone), Seroquel/Seroquel XR (quetiapine/quetiapine ER), Vraylar (cariprazine) and Symbyax (fluoxetine + olanzapine).

In addition to this, the long-term use of these products for relapse prophylaxis is typically limited by their association with notable adverse events (AEs), such as akathisia, extrapyramidal symptoms and weight gain. Patients who experience frequent depressive relapses are commonly prescribed generic lamotrigine for long-term maintenance treatment. KOLs have indicated, however, that this drug is weak in terms of its efficacy and is therefore rarely suitable as a monotherapy. Despite this, polypharmacy increases the pill burden for patients and can increase the risk of experiencing treatment-related AEs and reduce compliance.

In the late-stage pipeline for bipolar disorder, three products are being developed for bipolar depression and thus have the potential to fulfil this unmet need. These are Intra-Cellular Therapies’ Caplyta (lumateperone), Sunovion Pharmaceuticals’ SEP-4199 (amisulpride), and Celon Pharma’s Falkieri (esketamine hydrochloride). In addition, NRX Pharmaceutical’s Cyclurad (cycloserine + lurasidone) is currently in development for the treatment of acute suicidal ideation and behaviour associated with bipolar depression. If approved, Cyclurad would become the first marketed product for this indication.

Of these four pipeline agents, Caplyta appears to be the most promising, as it demonstrated efficacy in both bipolar I and bipolar II disorder patients in Phase III clinical trials (NCT03249376 and NCT02600507). It is currently in pre-registration in the US and GlobalData expects it to launch in the first quarter of next year. Thus far, however, Calypta has only been evaluated as a therapy for use during acute depressive episodes, so its potential to fulfil the need for therapies that prevent these episodes remains unknown. Both SEP-4199 and Falkieri have yet to demonstrate their efficacy in Phase III trials. As such, more data is required to fully evaluate their potential to address this unmet need. Based on Phase IIb clinical trial durations, however, it is likely that these products will be developed for acute episodes of depression prior to any evaluation of their potential as maintenance therapies.

There is a need for new therapeutic agents that demonstrate clear efficacy in the treatment and long-term prevention of acute depressive episodes in both bipolar I and II disorder patients without the risk of precipitating mania or affecting mood-cycling rates, and with superior side effect profiles compared to the currently marketed treatment options. Products that meet this need can expect to generate significant uptake in the bipolar market, with the potential to be positioned early in the treatment algorithm despite the availability of generic products. Overall, while the unmet need for acute episodes of depression is likely to be met through the bipolar disorder pipeline, the unmet need for maintenance therapies that can prevent depressive episodes will remain.