Lurasidone

證據等級: L5

預測適應症: 10 個

Lurasidone: From Schizophrenia / Bipolar Depression to Manic Bipolar Affective Disorder

One-Sentence Summary

Lurasidone (brand name Latuda®) is a second-generation atypical antipsychotic approved in the United States and Japan for schizophrenia and bipolar I depression, but currently not registered in Singapore. The TxGNN model predicts it may be effective for manic bipolar affective disorder — specifically the manic phase of bipolar disorder — a clinical setting mechanistically distinct from, yet closely related to, its established indication in bipolar depression. This prediction is supported by 15 clinical trials (including 8 completed Phase 3 studies) and 20 publications, yielding a TxGNN confidence score of 99.98% and an evidence grade of L1.

Quick Overview

Item	Content
Original Indication	Schizophrenia; Bipolar I Depression (US FDA / Japan PMDA approved; not registered in Singapore)
Predicted New Indication	Manic Bipolar Affective Disorder
TxGNN Prediction Score	99.98%
Evidence Level	L1
Singapore Market Status	✗ Not Marketed
Number of Registrations	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Lurasidone exerts its effects through a multi-receptor pharmacological profile that addresses several key dimensions of bipolar disorder simultaneously. D2/D3 receptor antagonism reduces dopaminergic hyperactivity — the central driver of manic episodes — an established mechanism shared by all approved antimanic atypical antipsychotics (quetiapine, olanzapine, risperidone, aripiprazole). 5-HT2A antagonism modulates cortical-limbic circuitry for broader mood stabilization, while 5-HT1A partial agonism confers antidepressant activity, distinguishing lurasidone from purely antimanic agents and positioning it as a full-spectrum bipolar treatment. 5-HT7 antagonism additionally improves circadian rhythm regulation and cognitive function — domains frequently impaired in bipolar patients even during euthymia. Its relatively low H1 affinity minimizes sedation and metabolic burden, supporting long-term maintenance use.

Lurasidone is already FDA-approved for bipolar I depression, meaning the manic and depressive phases of bipolar I disorder share the same underlying neurobiological substrate. The same D2/D3 antagonism that stabilizes mood in the depressive context provides direct pharmacological rationale for antimanic efficacy. The TxGNN model's prediction thus represents an extension along the bipolar spectrum rather than a leap to an unrelated indication. Notably, SM-13496 — the Japanese development code for lurasidone — was studied across the full bipolar I spectrum in Japan, including manic and mixed episodes, further corroborating clinical plausibility.

The body of evidence is extensive: multiple completed Phase 3 RCTs enrolling hundreds to nearly 1,000 participants, long-term safety extension studies in both adults and pediatric populations, and high-quality network meta-analyses in the Lancet Psychiatry and Molecular Psychiatry have examined lurasidone against the full landscape of bipolar pharmacotherapy. The CANMAT/ISBD international guidelines (2018 and 2021 updates) explicitly list lurasidone as an evidence-based option in bipolar disorder management.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT01358357	Phase 3	Completed	965	Multi-center, randomized, placebo-controlled study of lurasidone adjunctive to lithium or divalproex for prevention of recurrence in Bipolar I Disorder (with or without rapid cycling / psychotic features); largest maintenance prevention trial
NCT01914393	Phase 3	Completed	702	104-week open-label long-term safety and effectiveness of flexibly dosed lurasidone (20–80 mg/day) in pediatric patients; the most extensive long-term pediatric safety dataset for lurasidone
NCT01986101	Phase 3	Completed	525	SM-13496 (lurasidone) vs. placebo in Bipolar I Depression; Japanese Phase 3 registration trial supporting PMDA approval
NCT01986114	Phase 3	Completed	495	Long-term efficacy and safety of SM-13496 (lurasidone) in Bipolar I Disorder; Japanese long-term extension study with broad bipolar spectrum coverage
NCT01575561	Phase 3	Completed	377	12-week open-label extension evaluating longer-term safety, tolerability, and effectiveness of lurasidone adjunctive to lithium or divalproex in Bipolar I Disorder
NCT02046369	Phase 3	Completed	350	6-week RCT of flexibly dosed lurasidone in children and adolescents with Bipolar I Depression (ages 6–17); established pediatric efficacy
NCT02731612	Phase 3	Completed	100	ELICE-BD: Randomized, double-blind, placebo-controlled study of lurasidone adjunctive therapy on cognitive functioning in euthymic Bipolar I/II patients with cognitive impairment
NCT02147379	Phase 3	Completed	53	Randomized, open-label study of lurasidone vs. treatment-as-usual on cognitive functioning in euthymic Bipolar I patients over 6 weeks
NCT04383691	Phase 3	Terminated	124	6-week double-blind, placebo-controlled flexible-dose trial of lurasidone for Bipolar I Depression (terminated early; partial safety data available from 124 enrolled)
NCT06433635	Phase 4	Active, not recruiting	2,726	SMART trial comparing cariprazine, quetiapine, lurasidone, and aripiprazole/escitalopram for bipolar depression; largest ongoing pragmatic head-to-head comparison trial

Literature Evidence

PMID	Year	Type	Journal	Key Findings
39557452	2024	Systematic Review + Dose-Response Meta-analysis	BMJ Mental Health	Examined dose-response relationship for lurasidone efficacy, acceptability, and metabolic/endocrine profiles in bipolar depression; clarifies optimal dosing strategy for clinical use
38487836	2024	Network Meta-analysis	European Psychiatry	Bayesian NMA of 16 RCTs (n=7,234) comparing 5 FDA-approved atypical antipsychotics (including lurasidone) for bipolar depression; lurasidone shown competitive on both efficacy and tolerability
37595997	2023	Network Meta-analysis	The Lancet Psychiatry	Comprehensive NMA of pharmacological interventions for acute bipolar depression; informs current guideline evidence synthesis; lurasidone ranks favorably for efficacy-tolerability balance
33177610	2021	Systematic Review + NMA	Molecular Psychiatry	NMA of mood stabilizers and antipsychotics for bipolar disorder in the maintenance phase; supports positioning of lurasidone in long-term bipolar management
29536616	2018	Clinical Practice Guideline	Bipolar Disorders	CANMAT/ISBD 2018 guidelines for bipolar disorder management; lurasidone listed as a first-line evidence-based option for bipolar I depression
34599629	2021	Clinical Practice Guideline	Bipolar Disorders	CANMAT/ISBD 2021 update for bipolar disorder with mixed features; provides treatment selection guidance applicable to mixed manic/depressive presentations
37815563	2023	Narrative Review	JAMA	Comprehensive review of bipolar disorder diagnosis and treatment for clinicians; covers ~40 million affected globally; contextualizes treatment landscape
39243127	2024	Review	Medical Science Monitor	Narrative review of new antipsychotics and mood stabilizers; directly covers lurasidone mechanism, efficacy, safety, and therapeutic potential in bipolar disorder and schizophrenia
36472471	2022	Treatment Algorithm / Expert Consensus	J Child Adolescent Psychopharmacology	Updated pharmacological treatment algorithms for pediatric bipolar manic/mixed and depressed episodes; evaluates evidence for lurasidone in children
24170243	2014	Commentary	American Journal of Psychiatry	Early expert commentary specifically titled "Lurasidone and bipolar disorder" by Belmaker; establishes the conceptual framing for lurasidone's role in bipolar treatment

Safety Considerations

Please refer to the package insert for safety information.

Note: Formal safety data (warnings, contraindications, drug interactions) for Singapore regulatory context is not yet available in this Evidence Pack. A full safety review should be conducted prior to clinical recommendation, sourcing from the US FDA label, PMDA SmPC, and the DrugBank database.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: Lurasidone has L1-level evidence in the bipolar spectrum: multiple completed Phase 3 RCTs, high-quality network meta-analyses in Lancet Psychiatry, and inclusion in CANMAT/ISBD international guidelines. Its multi-receptor mechanism provides clear pharmacological rationale for antimanic activity extending beyond its established bipolar depression indication. However, it is not currently registered in Singapore, and formal safety data for the Singapore context is absent.

To proceed, the following is needed:

Singapore HSA registration pathway: Evaluate bridging data requirements; the drug holds FDA and PMDA approval, which may support a full registration application via the Health Sciences Authority
Full safety data review: Obtain the US FDA prescribing information and PMDA SmPC to document contraindications, key warnings (e.g., tardive dyskinesia, neuroleptic malignant syndrome, metabolic effects), and major drug interactions
Mechanism of action documentation: Formal DrugBank/PMDA MOA data to complete the mechanistic evidence package for the repurposing dossier
Manic phase-specific evidence gap: Most completed trials focus on bipolar I depression or maintenance; direct head-to-head evidence for acute mania is limited — review NCT01932541 (withdrawn) and supplementary data from SM-13496 Japanese trials for any manic-phase subgroup data
Metabolic monitoring plan: Although lurasidone has a favorable metabolic profile relative to other antipsychotics, a structured monitoring protocol (body weight, fasting glucose, lipids, EPS assessment) should be defined for any clinical deployment
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.