Asenapine, Iloperidone and Lurasidone

Critical Appraisal of the Most Recently Approved Pharmacotherapies for Schizophrenia in Adults

William V Bobo


Expert Rev Clin Pharmacol. 2013;6(1):61-91. 

In This Article

Safety & Tolerability

Short-term Safety & Tolerability

Iloperidone The short-term safety profile of iloperidone was systematically evaluated in a pooled analysis of three 6-week, randomized studies in patients with schizophrenia.[64] Included in the safety analysis were patients who received at least one dose of study medication (n = 1912 total). The most common treatment-emergent adverse effects for all iloperidone dosage groups (4–8, 10–16 and 20–24 mg/day) were dizziness (10–23%), dry mouth (5–10%), somnolence (5–8%) and dyspepsia (5–8%). The occurrence of dizziness, somnolence and dry mouth was higher for the 20–24 mg dose group than the lower dose groups.[64,202] Iloperidone was not shown to increase the risk of EPS in any of the three dosage groups or to increase prolactin levels in the 4–8-mg and 10–16-mg dosage groups (prolactin levels were not measured in the study that included a 20–24-mg iloperidone dose group) (Table 7).[64] Worsening of akathisia occurred less frequently in the iloperidone groups than with risperidone and was similar to that observed in the placebo group. For prolactin elevation, the pooled results contrast with those of the 4-week pivotal study by Cutler et al, in which elevated prolactin levels were observed in 26% of iloperidone-treated and 12% of placebo-treated patients.[35] Iloperidone was associated with moderate increases in body weight (1.7–2.1 kg) over 6 weeks, similar to that observed with risperidone (1.7 kg). Clinically significant weight gain, defined as an increase in body weight of >7% from baseline, was observed in 12.3% of iloperidone-treated subjects during this time period (Table 7).[64] Mild changes in blood glucose, and only minimal changes in total cholesterol and triglyceride values, were observed in all treatment groups (Table 7); however, increases in glucose values were statistically significant in all three iloperidone dose groups and in the haloperidol group (Table 7).

Rates of orthostatic hypotension were 19.5, 15.3 and 12%, respectively, with iloperidone (all dosage groups combined), haloperidol and risperidone.[64] In most cases, orthostatic hypotension with iloperidone occurred within the first 7 days of treatment and generally did not persist. There were statistically significant increases in the corrected QT (QTc) interval from baseline were significant with all three iloperidone dosage groups and in the haloperidol group (Table 7).[64] No deaths due to fatal arrhythmias occurred in any of the short-term clinical trials.[202]

Asenapine Pooled safety data from three 6-week, fixed-dose trials and one 6-week flexible-dose trial of sublingual asenapine (5–10 mg b.i.d.) for the treatment of adults with schizophrenia (asenapine, n = 572; placebo, n = 378) indicated that the most common adverse effects were insomnia (asenapine [15%]; placebo [13%]), somnolence (asenapine [13%]; placebo [7%]), EPS other than akathisia (asenapine [10%], placebo [7%]) and akathisia (asenapine [6%]; placebo [3%]).[203] Transient oral hypoesthesias that typically resolved within 1 h of study drug administration were reported in 5% of asenapine-treated subjects and 1% of subjects who received placebo.[203] Increases in body weight occurred in 5% of patients randomized to asenapine, and <1% of individuals who received placebo.[203] Of all these effects, only the occurrence of akathisia showed an apparent dose-related increase (asenapine 5 mg b.i.d. [4%] vs asenapine 10 mg b.i.d. [11%]). Minimal change in fasting glucose (asenapine [+3.2 mg/dL]; placebo [−1.6 mg/dL]), total cholesterol (asenapine [+0.4 mg/dL]; placebo [−3.6 mg/dL]), triglyceride (asenapine [+3.8 mg/dL]; placebo [−13.5 mg/dL]) and prolactin (asenapine [−6.5 ng/mL]; placebo [−10.7 ng/mL]) values were observed.[203] Only minimal increases in QTc interval (2–5 ms) occurred with asenapine at doses of 5–20 mg b.i.d., and there were no significant differences in post-baseline QT increases between asenapine (5–10 mg b.i.d.) and placebo.[203]

Lurasidone On the basis of pooled safety data from short-term, placebocontrolled studies of lurasidone (20–160 mg) for treating adults with schizophrenia (lurasidone, n = 1,508; placebo, n = 709), the most common adverse effects were somnolence (lurasidone [17%]; placebo [7%]), akathisia (lurasidone [13%]; placebo [3%]), nausea (lurasidone [10%]; placebo [5%]) and parkinsonism (lurasidone [10%]; placebo [5%]).[204] Minimal changes in body weight were observed among lurasidone-treated subjects (-0.15 to +0.68 kg) and those who received placebo (-0.02 kg). Significant weight gain, defined as a >7% increase in body weight from baseline, was observed in 4.8% of lurasidone-treated and 3.3% of placebo-treated patients. The incidence of adverse events related to EPS (not including akathisia) was 13.5 and 5.8%, respectively, among lurasidone- and placebo-treated patients, while the overall incidence of akathisia with lurasidone and placebo was 12.9 and 3.0%, respectively. The occurrence of akathisia increased with lurasidone in a dose-dependent manner up to 120 mg/day (5.6% at 20 mg; 10.7% at 40 mg; 12.3% at 80 mg; 22.0% at 120 mg). The incidence of akathisia in the 160-mg group was 7.4%.

A recently published systematic review and meta-analysis by De Hert et al. compared the anthropometric and metabolic effects of iloperidone, asenapine, lurasidone and paliperidone in short-term, randomized, placebo-controlled or head-to-head trials of patients with acute schizophrenia or bipolar disorder.[65] Analyzable data from longer-term studies were available only for asenapine and paliperidone. In the short-term studies, the risk of clinically significant weight gain (defined as an increase in body weight of > 7% from baseline) relative to placebo was highest with asenapine (n = 5 trials [1360 randomized subjects]; pooled RR: 4.09 [95% CI: 2.25–7.43]; number needed to harm [NNH]: 17), followed by iloperidone (n = 4 trials [1931 randomized subjects]; pooled RRs 3.13 [95% CI: 2.08–4.70]; NNH: 11) and paliperidone (n = 12 trials [4087 randomized subjects]; pooled RR: 2.17 [95% CI: 1.64–2.86]; NNH: 20). Lurasidone was not associated with a statistically significant change in body weight (n = 6 trials [1793 randomized subjects]; pooled RR: 1.42 [95% CI: 0.87–2.29]). Iloperidone was associated with a statistically significant increase in total-cholesterol (n = 1 trial [300 randomized subjects]; +11.6 mg/dL [95% CI: 5.0–18.2]), HDL-cholesterol (n = 1 trial [300 randomized subjects]; +3.6 mg/dL [95% CI: 1.6–5.6]), and LDL-cholesterol (n = 1 trial [300 randomized subjects]; +10.3 mg/dL [95% CI: 4.9–15.7]), while lurasidone was associated with a statistically significant increase in HDL-cholesterol (n = 5 trials [1004 randomized subjects]; +1.5 mg/dL [95% CI: 0.6–2.4]). As reported by the authors, no other clinically significant short-term changes in glycemic or lipid indices were observed.

Longer-term Safety & Tolerability

Iloperidone Safety data were also included in the previously reviewed pooled analysis of long-term randomized, double-blind iloperidone trials.[55] The safety data set consisted of subjects who achieved a positive treatment response during an initial 6-week phase, received at least one dose of double-blind study medication, and had at least one safety evaluation during the long-term phase (n = 489). Insomnia (18.1%), anxiety (10.8%) and aggravation of schizophrenia symptoms (8.9%) were the most commonly observed adverse effects associated with iloperidone, and occurred at rates similar to those observed with haloperidol. Rates of study drug discontinuation owing to intolerable adverse effects were 4.3 and 8.5%, for iloperidone and haloperidol, respectively.

At the end of the 6-week phase, mean Extrapyramidal Symptoms Rating Scale (ESRS)[66] scores decreased in the iloperidone group (-1.5) and increased in the haloperidol group (+0.3, p < 0.0001). At the end of the long-term treatment phase, 48.2% of patients who received iloperidone and 34.7% of those who received halperidol indicated improvement in overall EPS ratings. A significantly lower proportion of patients who received iloperidone reported worsening of EPS compared with those who receive haloperidol (13.5 vs 36.4%; p < 0.001). Worsening of Barnes Akathisia Scale[67] scores occurred in 9.2% of iloperidone- and 23.7% of haloperidol-treated subjects during the long-term treatment phase (p < 0.001).

Mean baseline to last observation change in body weight and metabolic indices were also assessed.[55] Modest changes in body weight (iloperidone [+ 3.8 kg] vs haloperidol [+2.3 kg]; p = NS), total cholesterol (iloperidone [+ 0.9 kg] vs haloperidol [+7.0 kg]; p = NS), triglycerides (iloperidone [+6.8 kg] vs haloperidol [+12.1 kg]; p = NS) and glucose values (iloperidone [+5.8 kg] vs haloperidol [-0.5 kg]; p = NS) were observed in both treatment groups. Mean weight gain for subjects who completed all 52 weeks of follow up was 4.8 kg in the iloperidone group and 3.0 kg in the haloperidol group.

Both iloperidone and haloperidol were associated with minor changes in the QTcF interval at week 6 (iloperidone [+3.2 ms] vs haloperidol [+4.0 msec]) and at study end point (iloperidone [+10.3 ms] vs haloperidol [+9.4 msec]).[55]

Asenapine In the long-term relapse-prevention study by Kane et al., anxiety (8.2%), weight gain (6.7%) and insomnia (6.2%) were the most frequently reported adverse effects observed in the asenapine group.[56] The incidence of EPS-related adverse events (3.1% vs 4.7%; p = NS) and mean changes in BARS, SIMS and SAS scores were similar in the asenapine and placebo groups. Mean changes in weight during the 26-week double-blind treatment phase was 0.0 ± 3.4 kg with asenapine and −1.2 ± 4.0 kg with placebo, while the proportion of patients who experienced weight increases of >7% from baseline was 3.7% with asenapine and 3.2% with placebo (p = NS). Minimal changes from baseline in fasting glucose (asenapine [+2.09 mg/dL] vs placebo [+ 0.02 mg/dL]), glycosylated hemoglobin (asenapine [+0.05%] vs placebo [−0.06%]), total cholesterol (asenapine [+0.9 mg/dL] vs placebo [−5.6 mg/dL]) and triglyceride values (asenapine [+0.9 mg/dL] vs placebo [−11.2 mg/dL]) were observed during the double-blind phase.

In the 52-week, double-blind comparison of asenapine and olanzapine by Schoemaker et al., the most commonly reported adverse events were weight gain (asenapine [12%] vs olanzapine [29%]), sedation (asenapine [8%] vs olanzapine [10%]), somnolence (asenapine [9%] vs olanzapine [10%]) and gastrointestinal symptoms (asenapine [9%] vs olanzapine [7%]).[57] Mean increases in body weight were greater in the olanzapine group than the asenapine group (+0.9 ± 4.8 kg vs +4.2 ± 7.6 kg) in the last observation carried forward analysis, and in a secondary completer analysis. A significant treatment × time interaction effect favoring asenapine was observed for body weight beginning at week 1 and persisted throughout the remainder of the study (p < 0.0001). The incidence of weight gain >7% above baseline values was higher with olanzapine (57.1%) than with asenapine (22.0%). There were no significant changes from baseline, or between group differences, in total cholesterol or glucose values. However, fasting triglyceride values increased from baseline in the olanzapine group (+30.4 ± 202.6 mg/dL) and decreased in the asenapine group (−9.8 ± 92.2 mg/dL). Predominantly mild EPS-related symptoms were reported among 18% (14% akathisia) of asenapine- and 8% (4% akathisia) of olanzapine-treated patients. Only minimal changes in Abnormal Involuntary Movement Scale, BARS or SAS scores were observed during follow-up in both treatment groups. Prolactin levels decreased from baseline in both groups within the first two weeks of follow-up and remained relatively stable during the remainder of the study. Electrocardiographic abnormalities (asenapine [2.4%], olanzapine [1.3%]) were generally related to QTc prolongation; however, no incident cases of QTc prolongation >500 ms were observed. During the extension phase,[58] there were only minor further changes in body weight, cholesterol or prolactin levels, and incident EPS-related adverse events in both groups.

The previously reviewed meta-analysis by De Hert et al. summarized anthropometric and metabolic safety data from longer-term studies (13 weeks in duration) of asenapine and paliperidone.[65] Compared with placebo, asenapine was associated with a significantly greater increase in body weight (n = 3 trials [568 randomized subjects]; weighted mean difference +1.3 kg [95% CI: 0.6–2.0]) and a higher rate of clinically significant weight gain (n = 3 trials [568 randomized subjects]; pooled RR: 2.05 [95% CI: 1.21–3.46]; NNH: 9). Paliperidone was also associated with significantly greater increases in body weight (n = 6 trials [1174 randomized subjects]; weighted mean difference +0.5 kg [95% CI: 0.2–0.8]) and a higher rate of clinically significant weight gain than placebo (n = 6 trials [1174 randomized subjects]; pooled RR: 1.76 [95% CI: 1.06–2.90]; NNH: 29).

Lurasidone Longer-term safety and tolerability were assessed in the 52-week study by Citrome et al. that compared the clinical effects of lurasidone with risperidone.[63] The most commonly reported adverse effects in both treatment groups were nausea (lurasidone [16.7%] vs risperidone [10.9%]; p < 0.05; NNH: 18; 95% CI: 9–438), insomnia (lurasidone [15.8%] vs risperidone [13.4%]; p = NS), sedation (lurasidone [14.6%] vs risperidone [13.9%]; p = NS), akathisia (lurasidone [14.3%] vs risperidone [7.9%]; p < 0.05; NNH: 16; 95% CI: 9–73), somnolence (lurasidone [13.6%] vs risperidone [17.8%]; p = NS), headache (lurasidone [10.0%] vs risperidone [14.9%]; p = NS) and vomiting (lurasidone [10.0%] vs risperidone [3.5%], p < 0.05; NNH: 16; 95% CI: 10–37). A significantly lower proportion of lurasidone-treated subjects reported treamtent-emergent weight gain (lurasidone [9.3%] vs risperidone [19.8%]; p < 0.05; NNH: −10; 95% CI: -6 to -24). There were statistically significant between-group differences in body weight and BMI (p < 0.001 for each comparison); however, changes from baseline in least-square-mean (standard error) body weight (lurasidone [-0.97 ± 5.06 kg] vs risperidone [+1.47 ± 5.03 kg] and BMI (lurasidone [-0.33 ± 1.71 kg/m2] vs risperidone [+0.53 ± 1.76 kg/m2]) for each respective treatment group were nonsignificant. A higher proportion of patients experienced a >7% increase in body weight from baseline in the risperidone group (14%) than the lurasidone group (7%; NNH: -16; 95% CI: -9 to -104). Baseline to end point changes in total cholesterol (lurasidone [-3.7 ± 29.5 mg/dL] vs risperidone [-4.3 ± 34.0 mg/dL]), triglycerides (lurasidone [-8.4 ± 89.7 mg/dL] vs risperidone [+8.5 ± 97.9 mg/dL]), glucose (lurasidone [+2.4 ± 26.1 mg/dL] vs risperidone [+4.8 ± 20.4 mg/dL], p = 0.005), and glycosylated hemoglobin (lurasidone [+0.04 ± 0.34 %] vs risperidone [+0.07 ± 0.32%]) were minimal or mild in each treatment group. Greater increases in prolactin concentration were observed among risperidone-treated women (lurasidone [+5.16 ± 34.89 ng/mL] vs risperidone [+33.90 ± 53.31 ng/mL], p < 0.001) and men (lurasidone [+2.51 ± 13.46 ng/mL] vs risperidone [+9.45 ± 14.13 ng/mL], p < 0.001). No clinically significant electrocardiographic changes were observed in either treatment group.