Efficacy and tolerability of FDA-approved atypical antipsychotics for the treatment of bipolar depression: a systematic review and network meta-analysis.

We employed a Bayesian network meta-analysis for comparison of the efficacy and tolerability of US Food and Drug Administration (FDA)-approved atypical antipsychotics (AAPs) for the treatment of bipolar patients with depressive episodes. Sixteen randomized controlled trials with 7234 patients treated by one of the five AAPs (cariprazine, lumateperone, lurasidone, olanzapine, and quetiapine) were included. For the response rate (defined as an improvement of ≥50% from baseline on the Montgomery-Åsberg Depression Rating Scale [MADRS]), all AAPs were more efficacious than placebo. For the remission rate (defined as the endpoint of MADRS ≤12 or ≤ 10), cariprazine, lurasidone, olanzapine, and quetiapine had higher remission rates than placebo. In terms of tolerability, olanzapine was unexpectedly associated with lower odds of all-cause discontinuation in comparison with placebo, whereas quetiapine was associated with higher odds of discontinuation due to adverse events than placebo. Compared with placebo, lumateperone, olanzapine, and quetiapine showed higher odds of somnolence. Lumateperone had a lower rate of ≥ weight gain of 7% than placebo and other treatments. Olanzapine was associated with a significant increase from baseline in total cholesterol and triglycerides than placebo. These findings inform individualized prescriptions of AAPs for treating bipolar depression in clinical practice.

Effect of Lurasidone on Social Functioning in Schizophrenia: Post Hoc Analysis of the JEWEL Study.

Objective: To evaluate the effects of lurasidone on social functioning in schizophrenia over the course of a 6-week, double-blind, placebo-controlled study and a subsequent 12-week open-label extension study.Methods: A total of 478 patients with schizophrenia (per DSM-IV-TR criteria) randomized to either lurasidone 40 mg/d (n = 245) or placebo (n = 233) in the initial 6-week double-blind study (initiated May 2016, completed November 2018) were included in the analysis. Longer-term changes were examined in a sample of 146 patients who received lurasidone, and 141 who received placebo, during the 6-week study and received flexibly dosed (40-80 mg/d) lurasidone during the 12-week extension phase. The 4-item Positive and Negative Syndrome Scale (PANSS) prosocial subscale was used to examine changes in social functioning.Results: At week 6 of the double-blind phase, lurasidone-treated patients had significantly greater improvement on the PANSS prosocial subscale compared to placebo-treated patients (P < .01, effect size at week 6 = 0.33). Significant differences from placebo were also evident at week 2 (P < .05), week 4 (P < .001), and week 5 (P < .01). Across the 12-week extension phase, patients who received lurasidone during both the 6-week double-blind phase and the 12-week open-label phase continued to show successive decreases in scores on the 4-item PANSS prosocial subscale (score change of -3.0 from double-blind baseline to week 6; mean score change of -4.2 from double-blind baseline to week 12 of the extension phase).Conclusions: In patients with schizophrenia treated with lurasidone, social functioning improved relative to placebo during a 6-week double-blind study and continued to improve over the course of 12 weeks of extension treatment with lurasidone. Effects of lurasidone on social functioning appear to be comparable to what has been reported for other atypical antipsychotics.Trial Registration: EudraCT Numbers: 2016-000060-42 and 2016-000061-23.

Lurasidone for the Treatment of Schizophrenia: Design, Development, and Place in Therapy.

This review aims to provide a comprehensive overview of the current literature on the drug design, development, and therapy of lurasidone for the treatment of schizophrenia. Lurasidone has antagonistic effects on the dopamine D2, 5-hydroxytryptamine (5-HT)2A, and 5-HT7 receptors and a partial agonistic effect on the 5-HT1A receptor with low affinities for muscarinic M1, histamine H1, and a1 adrenergic receptors. The receptor-binding profile of lurasidone is thought to be associated with fewer side effects such as anticholinergic effects, lipid abnormalities, hyperglycemia, and weight gain. Behavioral pharmacological studies have demonstrated that lurasidone exerts anxiolytic and antidepressive effects and improves cognitive function, which are associated with the modulation of 5-HT7 and 5-HT1A receptors. Literature search using PubMed was performed to find published studies of randomized controlled trials and recent meta-analyses regarding efficacy and safety, particularly metabolic side effects of lurasidone in schizophrenia. In short-term studies, the results of randomized placebo-controlled trials and meta-analyses have suggested that lurasidone was superior to placebo in improving total psychopathology, positive symptoms, negative symptoms, and general psychopathology in patients with acute schizophrenia. Regarding safety, lurasidone had minimal metabolic side effects, and was identified as one of the drugs with the most benign profiles for metabolic side effects. Long-term trials revealed that lurasidone had the preventive effects on relapse, with minimal effects on weight gain and other metabolic side effects. Furthermore, lurasidone improves cognitive and functional performance of patients with schizophrenia, especially in long-term treatment. Patients with schizophrenia require long-term treatment with antipsychotics for relapse prevention; thus, minimizing weight gain and other side effects is crucial. Lurasidone is suitable as one of the first-line antipsychotic drugs in the acute phase, and a switching strategy should be considered during the maintenance phase, to balance efficacy and adverse effects and achieve favorable outcomes in the long-term course of schizophrenia.

The Effect of Lurasidone on Anxiety Symptoms in Patients With Bipolar Depression: A Post Hoc Analysis.

Objective: To assess the effects of lurasidone on anxiety symptoms and sleep disruption, and their moderating and mediating roles on treatment response in bipolar depression.Methods: This post hoc analysis included pooled data from 2 previously published 6-week placebo-controlled trials of lurasidone for bipolar I depression conducted between April 2009 and February 2012. Hamilton Anxiety Rating Scale (HAM-A) "psychic anxiety" (items 1-6, 14) and "somatic anxiety" (items 7-13) subscores were calculated. Functional outcome was assessed by the Sheehan Disability Scale.Results: All subjects (n = 824) had at least 1 psychic anxiety and 729 (88.5%) had at least 1 somatic anxiety symptom at baseline. 594 subjects (72.1%) experienced baseline sleep disturbance. Lurasidone, as monotherapy (20-60 mg/d and 80-120 mg/d pooled dose groups vs placebo) and adjunctive therapy (20 to 120 mg/d flexibly dosed vs placebo) with lithium or valproate, significantly reduced HAM-A psychic anxiety (-4.82 vs -2.97, P < .001, monotherapy; -5.56 vs -4.26, P = .009, adjunctive therapy) and somatic anxiety (-1.89 vs -1.37, P = .048, monotherapy; -2.22 vs -1.47, P = .006, adjunctive therapy) subcomponents. Improvement in anxiety symptoms mediated reduction in depressive symptoms and functional impairment. Decrease in sleep at baseline predicted change in anxiety symptoms with lurasidone treatment at week 6.Conclusions: Lurasidone was superior to placebo in reducing psychic and somatic anxiety in the short-term treatment of bipolar depression. Improvement in depressive symptoms and reduction in functional impairment were associated with reduction in anxiety symptoms moderated by baseline sleep disturbance during lurasidone treatment.Trial Registration: ClinicalTrials.gov identifiers: NCT00868699 and NCT00868452.

The efficacy and safety of lurasidone in bipolar I depression with and without rapid cycling: A pooled post-hoc analysis of two randomized, placebo-controlled trials.

BACKGROUND: The efficacy and safety of lurasidone monotherapy in patients with bipolar I depression with or without rapid cycling has not been previously investigated. METHODS: We performed subgroup analysis (rapid cycling/non-rapid cycling) of pooled data from two 6-week, randomized, double-blind, placebo-controlled trials of lurasidone monotherapy (20-60 mg/day or 80-120 mg/day). Analyses included mean change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Safety assessments included the number of treatment-emergent adverse events (TEAEs) and laboratory assessments. RESULTS: Of 1024 patients randomized, 85 were rapid cycling. Mean change in MADRS total score in patients with non-rapid cycling and rapid cycling, respectively, was -14.8 (effect size = 0.47) and - 12.8 (effect size = 0.04) in the lurasidone 20-60 mg/day group, -14.3 (effect size = 0.41) and - 13.0 (effect size = 0.02) in the lurasidone 80-120 mg/day group and -10.6 and -13.3 in the placebo group. The most common TEAE in each subgroup was akathisia in both lurasidone groups. Treatment-emergent mania was reported only in a small number of rapid cycling and non-rapid cycling patients. LIMITATIONS: This was a post-hoc analysis of a short-term study that excluded patients with ≥8 cycles in the past year. CONCLUSIONS: In patients with non-rapid cycling bipolar depression, lurasidone monotherapy significantly improved depressive symptoms relative to placebo at both the 20-60 mg/day and 80-120 mg/day doses. In patients with rapid cycling, both doses of lurasidone displayed depressive symptom score reduction from baseline, but significant improvement was not observed likely due to high levels of improvement on placebo and small sample size.

A Candidate Gliotransmitter, L-ß-Aminoisobutyrate, Contributes to Weight Gain and Metabolic Complication Induced by Atypical Antipsychotics.

Lurasidone and quetiapine are effective atypical mood-stabilizing antipsychotics, but lurasidone and quetiapine are listed as lower-risk and high-risk for weight gain/metabolic complications, respectively. The pathophysiology of the discrepancy of metabolic adverse reactions between these antipsychotics remains to be clarified. The GABA isomer, ß-aminoisobutyric acid (BAIBA) enantiomer, was recently re-discovered as myokine via an AMP-activated protein kinase activator (AMPK) enhancer and inhibitory gliotransmitter. Notably, activation of AMPK in peripheral organs improves, but in the hypothalamus, it aggravates metabolic disturbances. Therefore, we determined effects of chronic administration of lurasidone and quetiapine on intracellular and extracellular levels of the BAIBA enantiomer. L-BAIBA is a major BAIBA enantiomer in the hypothalamus and astrocytes, whereas L-BAIBA only accounted for about 5% of total plasma BAIBA enantiomers. Chronic lurasidone administration did not affect body weight but decreased the L-BAIBA level in hypothalamus and cultured astrocytes, whereas chronic quetiapine administration increased body weight and the L-BAIBA level in hypothalamus and astrocytes. Contrary, neither lurasidone nor quetiapine affected total plasma levels of the BAIBA enantiomer since D-BAIBA levels were not affected by these antipsychotics. These results suggest that activation of intracellular L-BAIBA signaling is, at least partially, involved in the pathophysiology of metabolic adverse reaction of quetiapine. Furthermore, this study also demonstrated that lurasidone and quetiapine suppressed and enhanced astroglial L-BAIBA release induced by ripple-burst stimulation (which physiologically contributes to cognitive memory integration during sleep), respectively. Therefore, L-BAIBA probably contributes to the pathophysiology of not only metabolic adverse reactions, but also a part of clinical action of lurasidone or quetiapine.

Lurasidone and risk of metabolic syndrome: results from short and long-term studies in patients with bipolar depression.

OBJECTIVE: The elevated prevalence of metabolic syndrome (MetS) in patients with depression has been associated with increased mortality. This post hoc analysis assessed the effect of treatment with lurasidone on risk of MetS in patients with bipolar depression. METHODS: Data used in the current analyses consisted of 3 double-blind (DB), placebo-controlled, 6-week studies in adults with bipolar I depression (N = 1192), consisting of 1 monotherapy, and 2 adjunctive trials (lithium or valproate). Also analyzed was a 6-month open-label (OL) extension study (monotherapy, N = 316; adjunctive therapy, N = 497); and a 5-month, OL, stabilization phase followed by randomization to a 28-week DB, placebo-controlled, adjunctive therapy study with lurasidone (N = 490). MetS was defined based on NCEP ATP III criteria (2005 revision). RESULTS: The proportion of patients with new-onset MetS was similar for lurasidone vs placebo in the short-term studies (monotherapy, 13.9% vs 15.3%; adjunctive therapy, 13.6% vs 11.0%); and remained stable during both the 6-month extension phase study (monotherapy, 15.2%; adjunctive therapy, 16.9%), and the 5-month stabilization study (adjunctive therapy, 12.2%). After 28 weeks of DB treatment (following 5-month treatment in the stabilization study), new onset MetS was observed at endpoint (OC) in 26.2% of the lurasidone group, and 30.8% of the placebo group. CONCLUSIONS: This post hoc analysis found that both short and long-term treatment with lurasidone was associated with a relatively low risk for the development of MetS in patients with bipolar I disorder. These findings are consistent with similar analyses in patients with schizophrenia.

Efficacy and safety profiles of mood stabilizers and antipsychotics for bipolar depression: a systematic review.

The whole picture of psychotropics for bipolar depression (BPD) remains unclear. This review compares the differences in efficacy and safety profiles among common psychotropics for BPD. MEDLINE, EMBASE, and PsycINFO were searched for proper studies. The changes in the depressive rating scale, remission/response rates, nervous system adverse events (NSAEs), gastrointestinal adverse events (GIAEs), metabolic parameters, and prolactin were compared between medication and placebo or among medications with the Cohen's d or number needed to treat/harm. The search provided 10 psychotropics for comparison. Atypical antipsychotics (AAPs) were superior to lithium and lamotrigine at alleviating acute depressive symptoms. Lithium was more likely to induce dry mouth and nausea. Cariprazine and aripiprazole seemed to be associated with an increased risk of akathisia and upper GIAEs. Lurasidone was associated with an increased risk of developing akathisia and hyperprolactinemia. Olanzapine, olanzapine-fluoxetine combination (OFC), and quetiapine were associated with an increased risk of NSAEs, metabolic risk, dry mouth, and constipation. Cariprazine, lurasidone, OFC, or quetiapine was optimal monotherapy for BPD. Further studies are needed to assess the efficacy and safety of lamotrigine for treating BPD. Adverse events varied widely across different drug types due to variations in psychopharmacological mechanisms, dosages, titration, and ethnicities.

Antipsychotics and risk of QT prolongation: a pharmacovigilance study.

RATIONALE: While meta-analyses of clinical trials found that lurasidone and partial dopamine agonists (brexpiprazole and aripiprazole) were the antipsychotics less likely to cause QTc prolongation, and sertindole, amisulpride, and ziprasidone were the most frequently associated with this adverse drug reaction; no real-world studies have investigated this risk between the different antipsychotics. OBJECTIVES AND METHODS: Using data recorded from 1967 to 2019 in VigiBase®, the World Health Organization's Global Individual Case Safety Reports database, we performed disproportionality analysis to investigate the risk of reporting QT prolongation between 20 antipsychotics. RESULTS: Sertindole had the highest risk of reporting QT prolongation, followed by ziprasidone and amisulpride. Lurasidone was associated with the lowest risk. First-generation antipsychotics were associated with a greater QT prolongation reporting risk (ROR, 1.21; 95%CI, 1.10-1.33) than second-generation antipsychotics. A positive correlation was found between the risk of reporting QT prolongation and affinity for hERG channel (R2 = 0.14, slope = Pearson coefficient = 0.41, p value = 0.1945). CONCLUSIONS: This large study in a real-world setting suggests that sertindole and ziprasidone were the antipsychotics drugs associated with the highest risk of QT prolongation reporting. Our results suggest that lurasidone is less associated with QT interval prolongation reports. Our study also suggests that antipsychotics with the higher hERG affinity are more associated with to QT prolongations reports.

Systematic literature review and network meta-analysis of lurasidone, brexpiprazole and cariprazine for schizophrenia.

A systematic review was undertaken to identify randomized controlled trials (RCTs) comparing the efficacy and safety of lurasidone, brexpiprazole and cariprazine (selected because of a shared safety profile) with each other or placebo in adult patients with schizophrenia. Key outcomes included: Positive and Negative Syndrome Scales (PANSS), Clinical Global Impression-Severity (CGI-S) scores and cardiovascular and metabolic parameters. A feasibility assessment evaluated the trials' suitability for inclusion in a Bayesian network meta-analysis (NMA). Random effects models were used. In total, 1138 records were identified and 19 RCTs contributed to the NMA. Lurasidone doses of 160 mg performed best in terms of change in PANSS and CGI-S scores at 6 weeks, with stronger evidence when compared with brexpiprazole than cariprazine. The safety outcomes were variable; for all treatments, the 95% credible intervals usually contained 'no difference'. Active treatments were associated with lower odds of discontinuation due to any cause, and higher odds of experiencing any adverse event. Lurasidone was comparable to brexpiprazole and cariprazine for efficacy and safety outcomes assessed at 6 weeks, with the 160 mg dose being superior for the change in PANSS and CGI-S outcomes. The lurasidone results were relatively consistent across doses compared with brexpiprazole and cariprazine.

Lurasidone in adolescents and adults with schizophrenia: from clinical trials to real-world clinical practice.

INTRODUCTION: Lurasidone is an atypical antipsychotic agent approved in the European Union for the treatment of schizophrenia in adults and adolescents (13-17 years). Clinical trials have shown a generally favorable balance between efficacy and tolerability. AREAS COVERED: This paper provides a review and commentary regarding the use of lurasidone in adults and adolescents with schizophrenia. The available information about efficacy, tolerability, dosing, and switching is analyzed, highlighting the strategies that may be most useful in real-world clinical practice. Virtual case studies, designed based on the authors' clinical experience with real-world patients, are provided. EXPERT OPINION: Lurasidone is efficacious in adolescents and adults in a wide range of symptoms of schizophrenia. Choosing the right dose for each patient and combining lurasidone with other medications is key to treatment success. Lurasidone has proven effective both in adolescents and adults in treating the acute phase of schizophrenia and reducing the risk of relapse. It has shown a relatively favorable tolerability profile, with minimal effects on metabolic parameters and prolactin levels.

A Meta-Analysis of Antipsychotic-Induced Hypo- and Hyperprolactinemia in Children and Adolescents.

Objective: Antipsychotic-related prolactin changes may expose children and adolescents to severe adverse reactions (ARs) related to pubertal development and growth. We therefore aimed to assess the effects of antipsychotics on prolactin levels and associated somatic ARs in children and adolescents. Methods: We systematically searched PubMed and CENTRAL for placebo-controlled randomized trials of antipsychotics in children and adolescents aged ≤18 years, reporting prolactin levels and related ARs. We conducted a random-effect meta-analysis and assessed risk of bias version 2 (ROB2). Results: Thirty-two randomized controlled trials with an average trial duration of 6 weeks, covering 4643 participants with an average age of 13 years and a male majority of 65.3%. Risk of bias across domains was low or unclear. The following antipsychotic compounds: aripiprazole (n = 810), asenapine (n = 506), lurasidone (n = 314), olanzapine (n = 179), paliperidone (n = 149), quetiapine (n = 381), risperidone (n = 609), and ziprasidone (n = 16) were compared with placebo (n = 1658). Compared with placebo, statistically significant higher prolactin increase occurred with risperidone (mean difference [MD] = 28.24 ng/mL), paliperidone (20.98 ng/mL), and olanzapine (11.34 ng/mL). Aripiprazole significantly decreased prolactin (MD = -4.91 ng/mL), whereas quetiapine, lurasidone, and asenapine were not associated with significantly different prolactin levels than placebo. Our results on ziprasidone are based on a single study, making it insufficient to draw strong conclusions. On average, 20.8% of patients treated with antipsychotic developed levels of prolactin that were too high (hyperprolactinemia), whereas only 1.03% of patients reported prolactin-related ARs. Data were highly limited for long-term effects. Conclusions: In children and adolescents, risperidone, paliperidone, and olanzapine are associated with significant prolactin increase, whereas aripiprazole is associated with significant decrease. Despite the significant changes in prolactin level, few ARs were reported. Study protocol on PROSPERO: CRD42018116451.

Effectiveness and Tolerability of Lurasidone for Bipolar Types I and II and Other Specified Bipolar Depression: A 12-Week Observational Study.

BACKGROUND: There are few guidelines on the management of depressive episodes in patients with bipolar type II (BDII) and related disorders (other specified bipolar and related disorders [OSBD]). Lurasidone is a potential option for treating depressive episodes in BDII/OSBD. This retrospective chart review study aimed to examine the effectiveness and tolerability of lurasidone for use in patients with bipolar depression. METHODS: We reviewed 66 consecutive outpatients with bipolar depression who were prescribed lurasidone between June 2020 and January 2021 and examined 12-week outcomes. Fourteen patients were diagnosed with BDI, and 52 patients were diagnosed with BDII/OSBD (42 BDII and 10 OSBD). Depressive symptoms were evaluated by the Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR) at baseline and 2, 4, and 12 weeks. Tolerability was assessed throughout the study period by the incidence of adverse events, such as akathisia, nausea, and manic/hypomanic switch, as well as the lurasidone dropout rate due to adverse events. RESULTS: The total QIDS-SR score at 2 ( P < 0.001), 4 ( P < 0.001), and 12 weeks ( P < 0.001) was significantly lower than that measured at baseline. Remission rate during study period was 29.1%. Of the 66 participants, 47 (71.2%) continued taking lurasidone and 27 (40.9%) and 16 (24.2%) reported adverse events and akathisia, respectively. No significant difference in total QIDS-SR score, dropout rate due to adverse events, rate of adverse events, or rate of akathisia was found between the BDII/OSBD and BDI groups. IMPLICATIONS: Lurasidone is tolerated and could be effective for managing depressive episodes in patients with BDII/OSBD and BDI.

Possible Lurasidone-Associated Dose-Dependent QTc Prolongation in First-Episode Psychosis.

This case is one of the earliest to report on lurasidone-related QTc prolongation in a dose-dependent fashion in CAP population at therapeutic doses. Although these reports remain scarce, it behoves prescribers to be vigilant and mindful of these unusual but serious side effects especially in setting of cumulative risks.

Lurasidone-induced hyperosmolar hyperglycemic syndrome: A case report.

INTRODUCTION: Lurasidone has few metabolic adverse effects and is recommended as an alternative when other antipsychotic drugs considerably increase body weight or blood sugar concentrations. CASE PRESENTATION: An 81-year-old man with bipolar disorder developed hyperosmolar hyperglycemic syndrome as a side effect of lurasidone. Routine monitoring of blood glucose concentrations led to the early detection and treatment of this disease, preventing life-threatening complications. DISCUSSION AND CONCLUSION: We describe a rare case of lurasidone-induced hyperosmolar hyperglycemic syndrome. The mortality rate of this syndrome is estimated to be up to 20%. This rate is significantly higher than that of diabetic ketoacidosis (currently <2%). Although lurasidone is considered to have a low risk of raising blood glucose concentrations, symptoms of hyperglycemia must be evaluated and blood glucose concentrations should be monitored regularly.

Efficacy and safety of lurasidone in schizophrenia: pooled analysis of European results from double-blind, placebo-controlled 6-week studies.

The objective of this study is to confirm the efficacy and safety of lurasidone in the acute treatment of schizophrenia in European patients. Data were pooled from three studies of patients randomized to 6 weeks of double-blind, placebo-controlled, fixed-dose (40/80 mg and 120/160 mg) lurasidone. The primary efficacy endpoint was a week 6 change in the Positive and Negative Syndrome Scale (PANSS) total score and secondary endpoints included the Clinical Global Impression, Severity scale (CGI-S). In total 328 safety patients were enrolled; 72.6% were completers. Endpoint change was significantly greater in patients treated with 40-80 mg/d and 120-160 mg/d compared to placebo on the PANSS total score ( P < 0.001) and the CGI-Severity score ( P < 0.001) for all comparisons. For PANSS total scores, endpoint effect sizes for lurasidone 40-80 mg/d and 120-160 mg/d were 0.68 to 0.77, respectively. Adverse events with a frequency ≥5% (and were greater than for combined lurasidone) were insomnia (11.7%), akathisia (11.3%), headache (7.4%), Parkinsonism (6.5%) and nausea (5.7%). Median changes (in mg/dL) at endpoint were minimal for total cholesterol (-8.0); triglycerides (-8.5) and glucose (-2.0) and in mean weight (-0.2 kg). In European patients with schizophrenia, short-term treatment with lurasidone in doses of 40-160 mg/d was generally safe, well-tolerated and effective with minimal effects on weight and metabolic parameters.