Iloperidone, a second-generation antipsychotic used to treat schizophrenia, appears to be safe and effective in the treatment of bipolar mania, new research suggested.
Results of the phase 3 randomized double-blind placebo-controlled trial show patients with bipolar mania who received iloperidone had significantly greater change from baseline to 4 weeks on the Young Mania Rating Scale (YMRS) compared with placebo, an improvement detected as early as 14 days from the initial dose.
The incidence of akathisia and extrapyramidal symptoms (EPS) was low in the treatment group, and the medication was well-tolerated.
“This study provides evidence that iloperidone improves the symptoms of bipolar mania in adults and can be a useful treatment option for people with bipolar disorder,” the investigators, led by Rosarelis Torres, PhD, of Vanda Pharmaceuticals Inc., and colleagues wrote.
The study was published online on January 15 in the Journal of Clinical Psychiatry.
Early Improvement
Iloperidone was first approved by the US Food and Drug Administration in 2009 for treatment of schizophrenia.
The current study included 414 participants (mean age, 43 years; 56% male) across 17 US and international sites. Patients with psychotic features received a fixed daily dose of 24 mg of iloperidone (n = 206) or placebo (n = 208).
Participants completed a screening period of up to 7 days before randomization, followed by a 1-day baseline evaluation period and a 28-day treatment phase.
The primary efficacy endpoint was change from baseline to week 4 on the YMRS (vs placebo), while secondary efficacy endpoints included change from baseline on the Clinical Global Impressions-Severity and Clinical Global Impression of Change scales (CGI-S and CGI-C, respectively).
Compared with placebo, iloperidone was associated with significant improvement of mania symptoms at week 4, with a mean reduction on the YMRS scale of −4.0 (P = .000008), and significant decreases on the CGI-S (mean, −0.4; P = .0005) and CGI-C scales (mean, −0.5; P = .0002).
Statistically significant differences between iloperidone and placebo were observed as early as day 14 and continued through days 21 and 28.
Post hoc analyses found no difference in efficacy even when patients who had received benzodiazepines were excluded, regardless of the presence or absence of psychotic features at baseline.
Favorable Akathisia Profile
As for safety, 68% of patients in the iloperidone group experienced at least one adverse event, compared with 49% of patients in the placebo group.
Patients in the treatment group had a higher rate of withdrawal from the study than those in the placebo group (32.9% vs 27.1%), and more patients in the iloperidone group experienced treatment-emergent adverse events (TEAEs) leading to study drug discontinuation (8.7% vs 5.3%). However, no TEAEs associated with discontinuation occurred in more than two patients in either group, and none of the participants experienced any AE leading to death.
The most common adverse events (AEs) were tachycardia (18%), dizziness (11%), dry mouth (9%), increased alanine aminotransferase (7%), nasal congestion (6%), weight gain (6%), and somnolence (5%).
Five serious AEs were reported in four participants in the treatment group and one in the placebo group. Two were identified as related to the study medication. These included sedation and spontaneous penile erection.
Changes from baseline in clinical laboratory parameters were not largely different between the groups, but there were post-randomization changes in QT interval in three iloperidone patients. The incidence of orthostatic response was also higher for iloperidone vs placebo.
Although “much improved compared to early antipsychotics, SGAs can still cause considerable adverse motor side effects,” the authors wrote. “However, among all SGAs, iloperidone’s akathisia profile is favorable.”
Antipsychotic-induced akathisia has been reported more frequently in patients with bipolar disorder than in those with schizophrenia treated with the same medication, investigators noted.
One study limitation is the fact that long-term efficacy in the prevention of manic or depressive episodes was not assessed.
Potential Second-Line Treatment
Commenting on the study for Medscape Medical News, Richard Louis Price, MD, assistant professor of psychiatry, at Weill Cornell Medical College, New York City, said the findings suggest iloperidone may be “modestly effective” for patients with bipolar 1 mania or mixed episodes.
“It’s helpful to have new treatment options, especially for patients who have difficulty tolerating other agents,” said Price, who was not involved with the study.
Also commenting on the research for Medscape Medical News, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, Toronto, Ontario, Canada, noted iloperidone’s “interesting antipsychotic pharmacodynamic,” highlighting the drug’s high-binding affinity for serotonin 5HT2A and dopamine D2 and D3 receptors, as well as the noradrenergic α1 receptors.
The drug’s profile “suggests benefit in manic features and agitation, perhaps with a lower propensity to EPS, which is especially important in persons at higher risk, like persons living with bipolar disorder,” McIntyre said.
McIntyre, who was not involved with the study, added iloperidone could be a second-line therapy because of its tolerability profile, provided the study results can be replicated.
“When considering alternatives with similar efficacy, absence of titration (or simple titration) minimal to no weight gain, no orthostatic hypotension, and no potential concerns with QT, those alternatives would have to be considered first-line, assuming that the study results are replicated,” he said.
This study was funded by Vanda Pharmaceuticals, Inc. The authors’ disclosures are listed in the original paper. McIntyre had received research grant support from CIHR/GACD/National Natural Science Foundation of China and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine Biosciences, Sunovion, Bausch Health, Axsome Therapeutics, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular Therapies Inc., NewBridge Pharmaceuticals, Viatris, Abbvie, and Atai Life Sciences. McIntyre is the CEO of Braxia Scientific Corp. Price had received honoraria from AbbVie, Alkermes, Allergan, Intra-Cellular Therapies Inc., Janssen, Jazz, Lundbeck, Neuronetics, Otsuka, and Supernus.
Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, NJ. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).