Research shows that Iloperidone, a second-generation antipsychotic used to treat schizophrenia, appears to be safe and effective in the treatment of bipolar mania.
The results of a randomized, double-blind, placebo-controlled phase 3 study indicate that patients with bipolar mania who received Iloperidone showed a significantly greater change from baseline to 4 weeks on the Young Mania Rating Scale (YMRS) compared to placebo, with improvement observed as early as 14 days after 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 symptoms of bipolar mania in adults and may be a useful treatment option for people with bipolar disorder,“ wrote lead researcher Rosarelis Torres, PhD, of Vanda Pharmaceuticals Inc., and colleagues.
The study was published online in the Journal of Clinical Psychiatry on January 15th.
Iloperidone was first approved by the US Food and Drug Administration for the treatment of schizophrenia in 2009.
The current study included 414 participants (average age 43; 56% male) at 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 one-day baseline assessment period and a 28-day treatment phase.
The primary efficacy endpoint was the change from baseline to week 4 on the YMRS (compared to placebo), while secondary efficacy endpoints included changes from baseline on the Clinical Global Impressions-Severity and Clinical Global Impression of Change (CGI-S and CGI-C) scales, respectively.
Compared to placebo, Iloperidone was associated with a significant improvement in manic symptoms at week 4, with an average 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 persisted through days 21 and 28.
Post-hoc analyses found no difference in efficacy even when patients who received benzodiazepines were excluded, regardless of whether psychotic features were present at study initiation.
Favorable Akathisia Profile
In terms of safety, 68% of patients in the Iloperidone group experienced at least one adverse event, compared to 49% of patients in the placebo group.
Patient discontinuation rates from the study were higher in the treatment group compared to the placebo group (32.9% vs. 27.1%), and more patients in the Iloperidone group experienced treatment-emergent adverse events (TEAEs) leading to discontinuation of study medication (8.7% vs. 5.3%). However, no patients in either group experienced TEAEs leading to death, and no discontinuation-related TEAEs occurred in more than two patients in either group.
The most common adverse events (AEs) were tachycardia (18%), dizziness (11%), dry mouth (9%), elevated alanine aminotransferase (7%), nasal congestion (6%), weight gain (6%), and somnolence (5%).
Five serious adverse events were reported in four participants in the treatment group and one in the placebo group, with two deemed to be related to study medication. These included sedation and spontaneous penile erection.
While the changes in clinical laboratory parameters did not differ significantly between the groups, QT-interval changes occurred in three Iloperidone patients after randomization. Incidence of orthostatic hypotension was also higher with Iloperidone compared to placebo.
„Although second-generation antipsychotics are significantly better than early antipsychotics, they can still cause significant negative motor side effects,“ wrote the authors. „However, Iloperidone’s akathisia profile is favorable among all second-generation antipsychotics.“
Researchers noted that antipsychotic-induced akathisia was more commonly reported in patients with bipolar disorder than in patients with schizophrenia treated with the same medications.
A limitation of the study is that long-term effectiveness in preventing 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 in New York City, said the results suggest that Iloperidone may be „modestly efficacious“ in patients with bipolar mania or mixed episodes.
„It is helpful to have new treatment options, especially for patients who have difficulties tolerating other agents,“ said Price, who was not involved in the study.
Also commenting on the research for Medscape Medical News, Roger S. McIntyre, MD, Professor of Psychiatry and Pharmacology at the University of Toronto, emphasized the „interesting antipsychotic pharmacodynamics“ of Iloperidone and highlighted the drug’s high binding affinity for serotonin 5HT2A and dopamine D2 and D3 receptors, as well as noradrenergic α1 receptors.
The drug’s profile „suggests benefit in manic symptoms and agitation, potentially with a lower propensity for EPS, which is particularly important in higher-risk individuals, such as those with bipolar disorder,“ said McIntyre.
McIntyre, who was not involved in the study, added that due to its tolerability profile, Iloperidone could potentially be a second-line therapy, pending replication of the study results.
„If alternatives with similar efficacy, lack of titration (or simple titration), minimal to no weight gain, minimal orthostatic hypotension, and no potential concerns about QT are being considered, those alternatives would need to be prioritized in first-line considerations, assuming the study results were replicated,“ he said.
This study was funded by Vanda Pharmaceuticals, Inc. Author disclosures are listed in the original paper. McIntyre has received research grants from CIHR/GACD/National Natural Science Foundation of China and the Milken Institute, as well as speaker/consultation fees from various pharmaceutical companies. McIntyre is also CEO of Braxia Scientific Corp. Price has received fees from several pharmaceutical companies.
Batya Swift Yasgur, MA, LSW, contributed to the writing of this article.