Lurasidone Monotherapy in the Treatment of Bipolar I Depression: A Randomized, Double-Blind, Placebo-Controlled Study

This international study enrolled outpatients 18–75 years of age diagnosed with bipolar I disorder who were experiencing a major depressive episode (DSM-IV-TR criteria, ≥4 weeks and <12 months in duration), with or without rapid cycling, without psychotic features, and with a history of at least one lifetime bipolar manic or mixed manic episode. Diagnosis was confirmed by the Mini-International Neuropsychiatric Interview (23) and the Bipolarity Index (24). A Montgomery-Åsberg Depression Rating Scale (MADRS [25]) score ≥20 and a Young Mania Rating Scale (YMRS) score ≤12 were required at both screening and baseline.

Patients were excluded if they demonstrated a decrease of ≥25% in MADRS total score between screening and baseline; scored ≥4 on MADRS item 10 (suicidal thoughts) at screening or baseline; had a history of nonresponse to an adequate (6-week) trial of three or more antidepressants (with or without mood stabilizers) during the current depressive episode, or demonstrated imminent risk of suicide or injury to self, others, or property.

The study was approved by an institutional review board at each investigational site and was conducted in accordance with the International Conference on Harmonisation Good Clinical Practices guidelines and with the ethical principles of the Declaration of Helsinki. All patients who entered the study reviewed and signed an informed consent document explaining study procedures and potential risks before study entry. An independent data and safety monitoring board reviewed and monitored subject data throughout the study.

This randomized, double-blind, placebo-controlled, fixed-flexible dose, parallel-group monotherapy study of lurasidone compared with placebo was conducted between April 2009 and February 2012. A total of 505 patients underwent random assignment at sites in the United States (205 patients from 24 sites), India (76 patients from nine sites), Ukraine (52 patients from five sites), Czech Republic (55 patients from four sites), South Africa (57 patients from four sites), Russia (31 patients from four sites), Romania (16 patients from four sites), and France (13 patients from one site). Following a washout period of at least 3 days, patients were randomly assigned in a 1:1:1 ratio via an interactive voice response system to receive 6 weeks of treatment with lurasidone, at flexible daily doses of either 20–60 mg or 80–120 mg, or 6 weeks of placebo. Study medication was provided in blister packs as either lurasidone 20 mg or 40 mg, or identically matched placebo tablets, and was taken once daily in the evening, with a meal or within 30 minutes after eating.

Patients assigned to receive lurasidone 20–60 mg/day were treated with 20 mg/day for days 1–7. Patients assigned to the lurasidone 80–120 mg/day arm received a fixed titration of lurasidone as follows: 20 mg/day for days 1–2, 40 mg/day for days 3–4, 60 mg/day for days 5–6 and 80 mg/day on day 7. In both treatment arms, lurasidone dosing adjustments within the assigned dosing range were permitted after 7 days to optimize efficacy and tolerability. Lurasidone (or placebo) was taken once daily in the evening, with a meal or within 30 minutes after eating.

Treatment with anticholinergic agents, propranolol, or amantadine, was permitted as needed (but not prophylactically) for movement disorders. Lorazepam, temazepam, or zolpidem (or their equivalent) were permitted during screening and for weeks 1 to 3, as needed for anxiety or insomnia, but not prophylactically, and not within 8 hours of any psychiatric assessment.

Efficacy assessments were obtained at baseline and weekly intervals. The primary efficacy endpoint was the mean change from baseline to week 6 in MADRS total score. At each study visit, a qualified site-based rater conducted the MADRS assessment; a second MADRS assessment was administered and scored by computer as part of a quality control process (Concordant Rater Systems, Boston, MA). The key secondary efficacy endpoint was the mean change from baseline to week 6 in depression severity score on the Clinical Global Impressions scale for use in bipolar illness (CGI-BP [26]).

Additional secondary efficacy assessments included the 16-item Quick Inventory of Depressive Symptomatology (27), the Hamilton Anxiety Rating Scale (HAM-A [28]), the Sheehan Disability Scale (29), and the Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form (30).

Safety and tolerability were assessed by the incidence and severity of adverse events during the study. Movement disorders were assessed by the Simpson-Angus Scale, the Abnormal Involuntary Movement Scale, and the Barnes Akathisia Rating Scale. Additional safety evaluations included vital signs, laboratory tests, 12-lead ECG, and physical examination. Treatment-emergent mania was defined a priori as a Young Mania Rating Scale (YMRS [31]) score ≥16 on any two consecutive visits, or at the final assessment, or an adverse event of mania or hypomania. Suicidal ideation and behavior were assessed using the Columbia Suicide Severity Rating Scale (32).

The intent-to-treat population consisted of randomly assigned subjects who received at least one dose of study medication and had at least one postbaseline efficacy assessment. The primary (MADRS) and key secondary (CGI-BP depression severity) efficacy endpoints were assessed using a mixed model for repeated-measures analysis including treatment, visit, pooled center, baseline score, and a treatment-by-visit interaction term, using an unstructured covariance matrix for within-subject correlation. The Hommel-based tree gatekeeping procedure was applied to control the family-wise type I error rate at 5% by taking into account the primary and key secondary efficacy variables and multiple dose comparisons of lurasidone versus placebo. There was no multiplicity adjustment for the secondary efficacy analyses or safety analyses.

Change from baseline in secondary efficacy measures was evaluated using an analysis of covariance (ANCOVA) model with fixed effects for treatment, pooled center, and baseline score as a covariate. Core depressive symptoms were evaluated using the MADRS-6 subscale (33). The proportions of responders (≥50% reduction from baseline in MADRS total) and remitters (MADRS total ≤12) were compared between the lurasidone and placebo treatment groups using logistic regression. Cohen’s d effect sizes were calculated for the primary outcome as the difference in the change score divided by the pooled standard deviation. The number needed to treat to attain an additional responder was derived for the lurasidone group as follows: number needed to treat=1/(lurasidone response rate−placebo response rate).

The safety population included all subjects who were randomly assigned and received at least one dose of study medication. Descriptive statistics were used for safety variables including adverse events, vital signs, and laboratory results. In addition, a nonparametric rank ANCOVA was used to analyze weight and labaoratory parameters. Change from baseline to last observation carried forward endpoint in the Simpson-Angus Scale, the Abnormal Involuntary Movement Scale, and the Barnes Akathisia Rating Scale scores were analyzed by using an analysis of covariance (ANCOVA) model with fixed effects for treatment, pooled center, and baseline score as a covariate.

Sample size was determined by using an SAS simulation macro (34) and was powered at 82.4% to reject both null hypotheses of no difference in MADRS between placebo and lurasidone dosage groups (3.5-point difference; pooled standard deviation of 9), and was powered at 96% to reject at least one null hypothesis of no difference from placebo for the lurasidone dosage groups. The estimated sample size of N=168 per treatment arm (total N=504) included an additional eight patients (5%) per arm based on expected early attrition (patients randomly assigned but without any postbaseline efficacy measures).

A total of 818 patients were screened, of whom 505 (61.7%) were randomly assigned to 6 weeks of double-blind treatment (Figure 1); 499 received at least one dose of study medication (safety population), and 485 had at least one postbaseline efficacy assessment (intent-to-treat population). Baseline demographic and clinical characteristics were similar for the two treatment groups (Table 1). Study completion rates were similar for the lurasidone 20–60 mg (74%), lurasidone 80–120 mg (73%), and placebo (75%) groups (Figure 1).

The mean daily dose of lurasidone during the study was 31.8 mg in the 20–60 mg group and 82.0 mg in the 80–120 mg group. For the 20–60 mg group (after 20 mg/day for 7 days), 66.7% of patients increased to a dosage of 40 mg/day, and 34.0% increased to a dosage of 60 mg/day at some point during the remaining 5 weeks of study treatment. For the 80–120 mg group (after fixed dose titration from 20 mg/day to 80 mg/day at day 7), 62.0% of patients increased to a dosage of 100 mg/day, and 26.6% increased to a dosage of 120 mg/day at some point during the remaining 5 weeks of study treatment.

As-needed treatment with lorazepam was reported by 12% of patients in the lurasidone 20–60 mg group, 13% of patients in the lurasidone 80–120 mg group, and 19% of patients in the placebo group. As-needed treatment with zolpidem was reported by 13% of patients in the lurasidone 20–60 mg group, 8% of patients in the lurasidone 80–120 mg group, and 8% of patients in the placebo group.

The least squares mean change from baseline to week 6 in MADRS total score (the primary endpoint) was significantly greater than seen with placebo (−10.7) for the lurasidone 20–60 mg group (−15.4; p<0.001 [effect size=0.51]) and the lurasidone 80–120 mg group (−15.4; p<0.001 [effect size=0.51]) (Figure 2A). The least squares mean change from baseline to week 6 in CGI-BP depression severity score (key secondary endpoint) was significantly greater than seen with placebo (−1.1) for the lurasidone 20–60 mg group (−1.8; p<0.001 [effect size=0.61]) and the lurasidone 80–120 mg group (−1.7; p<0.001 [effect size=0.50]) (Figure 2B). For both dosages of lurasidone, superiority compared with placebo on the MADRS was observed starting at week 2 and was maintained at all subsequent study visits. Superiority compared with placebo on the CGI-BP depression severity score was observed starting at week 1 for the lurasidone 80–120 mg group and starting at week 2 for the lurasidone 20–60 mg group and was maintained at all subsequent study visits.

There was a statistically significant reduction from baseline to week 6 in core depressive symptoms (MADRS-6 subscale score) for the lurasidone 20–60 mg group (−10.4; p<0.001) and the lurasidone 80–120 mg group (−10.4; p<0.001) relative to the placebo group (−6.9). Lurasidone was associated with significantly greater improvement than placebo on seven of the 10 MADRS items in both the 20–60 mg and 80–120 mg groups (Figure 2C).

A significantly greater proportion of subjects met a priori response criteria after 6 weeks of treatment with lurasidone 20–60 mg (53%; p<0.001 [number needed to treat=5]) and lurasidone 80–120 mg (51%; p<0.001 [number needed to treat=5]) compared with placebo (30%). Median time to response was shorter in the lurasidone 20–60 mg group (34 days) and the 80–120 mg group (30 days) compared with the placebo group (42 days; log-rank p<0.01 for both comparisons).

The proportion of subjects achieving remission at endpoint was significantly greater in the lurasidone 20–60 mg group (42%; p=0.001 [number needed to treat=6]) and the lurasidone 80–120 mg group (40%; p=0.004 [number needed to treat=7]) compared with the placebo group (25%).

No significant treatment interactions by gender, age, race, or ethnicity were observed for either the MADRS total score or the CGI-BP depression severity score, based on ANCOVA analyses.

Treatment with both dosages of lurasidone was associated with significant improvement compared with placebo in anxiety symptoms, as measured by the clinician-rated Hamilton anxiety scale, the patient-rated Quick Inventory of Depressive Symptomatology, the Quality of Life, Enjoyment, and Satisfaction Questionnaire, and the Sheehan Disability Scale (Figure 3).

Overall, adverse events reported with an incidence ≥5% in at least one of the groups are listed in Table 2. The majority of adverse events were considered mild or moderate, with <10% rated as “severe” in the lurasidone 20–60 mg (9.8%) and 80–120 mg (8.4%) groups or the placebo group (6.0%). The incidence of serious treatment-related adverse events was low and similar in the lurasidone 20–60 mg group (N=2), the 80–120 mg group (N=1), and the placebo group (none). No deaths occurred during the study. The proportion of patients who discontinued due to adverse events was similar in the lurasidone 20–60 mg group (6.6%), the 80–120 mg group (5.9%), and the placebo group (6.5%; Figure 1).

Treatment-emergent mania occurred in 3.7% of patients in the lurasidone 20–60 mg group, 1.9% in the lurasidone 80–120 mg group, and 1.9% in the placebo group. Mean YMRS scores showed a similar endpoint reduction in the lurasidone 20–60 mg group (−1.1), the 80–120 mg group (−0.7), and in the placebo group (−0.9).

The proportion of patients with at least one instance of treatment-emergent suicidal ideation, per the Columbia Suicide Severity Rating Scale, was 13.7% in the lurasidone 20–60 mg group, 14.8% in the lurasidone 80–120 mg group, and 13.6% in the placebo group. There was no occurrence of suicidal behavior or completed suicide during the study.

The incidence of extrapyramidal symptom-related adverse events was less than 10% in both lurasidone groups, with a modest dose-related increase in incidence (Table 2). The proportion of patients who received treatment with anticholinergic medication for acute extrapyramidal symptoms was 3.7% in the lurasidone 20–60 mg group, 4.9% in the lurasidone 80–120 mg group, and 1.9% in the placebo group. Least squares mean changes from baseline to endpoint (lurasidone 20–60 mg and 80–120 mg versus placebo) were small for the Barnes Akathisia Scale (0.0 and 0.2 versus −0.1), and for the Simpson Angus Scale (0.02 and 0.02 versus 0.00). There were no significant changes from baseline to endpoint in the Abnormal Involuntary Movement Scale total score in any treatment group with no statistically significant differences between the lurasidone treatment groups and the placebo group.

There were no notable differences in laboratory measures, vital signs, or ECG assessments between treatment groups. Mean endpoint change in weight was not different for the lurasidone 20–60 mg group (+0.6 kg), the lurasidone 80–120 mg group (0.0 kg), and the placebo group (0.0 kg). The proportion of subjects with ≥7% increase in weight at endpoint was 4.2% in the lurasidone 20–60 mg group, 0.7% in the 80–120 mg group, and 0.7% in the placebo group. Mean change in waist circumference was also similar in the combined lurasidone group compared with the placebo group (0.1 cm versus −0.3 cm).

There were no clinically meaningful differences in the effect of treatment on metabolic parameters between the lurasidone groups and the placebo group (Table 3). Median endpoint change in prolactin for lurasidone 20–60 mg and 80–120 mg, respectively, versus placebo was higher in female than in male subjects. The mean endpoint change in QTcF interval from baseline to endpoint was 0.5 ms in the lurasidone 20–60 mg group, −1.0 ms in the lurasidone 80–120 mg group, and −1.7 ms in the placebo group. No patient in either lurasidone group had a postbaseline change in QTcF>60 ms, and no patient in either lurasidone group had a QTcF>500 ms.