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Is iloperidone safe and efficacious in patients with bipolar disorder? Or, put another way, can we expect the same benefit and side-effect profile? For example, a lower risk of extrapyramidal side effects—as in patients with schizophrenia—for which it has an FDA indication?
Hi! Paul Zarkowski here with the Psychopharmacology Institute.
Luckily, the manufacturer of iloperidone funded a phase 3 randomized, double-blind, placebo-controlled study in adults with bipolar mania to answer this question. Subjects were enrolled at 27 sites in the United States, Bulgaria, and Poland between April 2021 and September 2022. Inclusion criteria were a rating in the Young Mania Rating Scale greater than 19 and at least 1 prior manic episode. Subjects were excluded if they met criteria for rapid cycling or if any other DSM-5 diagnosis besides bipolar disorder became the primary focus of clinical attention in the past 6 months. Subjects with dependence on substances in the previous 6 months were also excluded. Although these exclusions removed possible confounds, they also yield a study population that is different from the population I see at my community mental health center, in which many, if not most, patients with bipolar disorder have comorbid conditions. Another exclusion was for subjects with poor response to at least 2 trials of antipsychotic medication in the past 2 years. This seems reasonable from a clinical standpoint, in which we would likely avoid a class of medication with a previous poor response. However, excluding patients with a poor response to antipsychotic medication biases the sample toward response to antipsychotic medication.
Of the 566 subjects that were screened, 417 were randomized, and 414 subjects received at least 1 dose of active medication or placebo; 208 received placebo, and 206 received iloperidone up to 24 mg/day given twice daily. This study implemented a modified intent-to-treat methodology, including subjects that received at least 1 dose of either iloperidone or placebo and received at least 1 post-baseline efficacy assessment. The authors found a statistically significant difference in Young Mania Rating Scale after 2 weeks and at the endpoint of 4 weeks, with a decline of 14 for iloperidone and 10 for placebo. They saw the most robust improvement in elevated mood and speech, with a less robust response in the appearance and thought content items.
The most frequently observed adverse event with iloperidone was tachycardia at 17.5% compared with 5.3% on placebo. The following most frequent adverse effect was dizziness, consistent with alpha-1 blockade and decreased orthostatic response. The authors suggest that this alpha-1 antagonism is also responsible for low rates of akathisia and extrapyramidal symptoms (EPS) in iloperidone. Although 4.4% of those on iloperidone reported akathisia compared with none on placebo, the authors note that there was no statistically significant difference in proportions of patients with worsening from baseline in the Barnes Akathisia Rating Scale. Mild treatment-emergent EPS was reported in 2 subjects receiving iloperidone and none receiving placebo. However, the authors add that there was no significant change from the baseline in the Simpson-Angus Scale or the Abnormal Involuntary Movement Scale. Subjects receiving iloperidone gained 4.6 kg over the month compared with 1.63 kg on placebo. For those of us who think in terms of pounds, that is 10 pounds of weight gain in a month for subjects treated with iloperidone. Also, 7.3% of subjects on iloperidone had a mild-to- moderate increase in alanine aminotransferase vs 0.5% on placebo. Finally, the mean corrected QT interval increased 8.3 ms in subjects taking iloperidone and decreased 1 ms for those in the placebo arm.
As expected, iloperidone speeds the resolution of manic symptoms. The incremental improvement in manic symptoms needs to be balanced against the side-effect profile—in this case, significant weight gain but with a favorable improvement in risk of akathisia and EPS. These factors should be included in the risk–benefit equation, which varies for each patient.
Abstract
Efficacy and Safety of Iloperidone in Bipolar Mania: A Double-Blind, Placebo-Controlled Study
Rosarelis Torres, Emily L Czeisler, Sean R Chadwick, Stephen M Stahl, Sandra P Smieszek, Changfu Xiao, Christos M Polymeropoulos, Gunther Birznieks, Mihael H Polymeropoulos
Objective: To determine if iloperidone, a second-generation antipsychotic, reduces symptoms of bipolar mania.
Methods: This phase 3, randomized, double-blind, placebo-controlled study was conducted in adults with bipolar mania at 27 US and international sites between April 2021 and September 2022. Participants were randomized 1:1 to iloperidone (up to 24 mg/d given twice daily) or placebo for 4 weeks. The primary efficacy endpoint was change from baseline to week 4 in Young Mania Rating Scale (YMRS) total score versus placebo. Secondary efficacy endpoints included change from baseline in the Clinical Global Impressions-Severity and Clinical Global Impression of Change scales.
Results: Altogether, 414 participants were randomized and administered at least 1 dose of study medication (iloperidone, n = 206; placebo, n = 208). Overall, 139 (67.1%) iloperidone patients and 153 (72.9%) placebo patients completed the study. Iloperidone demonstrated significant improvement versus placebo at week 4 for the primary and secondary endpoints. Differences in the least-squares mean (95% CI; P value) of change from baseline for YMRS total scores were -4.0 (-5.70 to -2.25; adjusted P = .000008). The most encountered adverse events with iloperidone were tachycardia, dizziness, dry mouth, alanine aminotransferase increased, nasal congestion, increased weight, and somnolence. The incidence of akathisia and extrapyramidal symptom-related treatment-emergent adverse events was low.
Conclusions: Iloperidone is effective in treating patients with bipolar mania. The tolerability and safety profile of iloperidone in bipolar mania is consistent with previous clinical studies of patients with schizophrenia, and no new safety concerns were identified.
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Reference
Torres, R., Czeisler, E. L., Chadwick, S. R., Stahl, S. M., Smieszek, S. P., Xiao, C., Polymeropoulos, C. M., Birznieks, G., & Polymeropoulos, M. H. (2024).
Efficacy and safety of iloperidone in bipolar mania
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The Journal of Clinical Psychiatry, 85
(1).
