Risperidone

證據等級: L5

預測適應症: 6 個

The Evidence Pack is rank-ordered by TxGNN score, but rank 1 (gaze palsy) has L5 evidence / Hold status while rank 6 (major affective disorder) has L1 evidence / Proceed with Guardrails — the highest actionable signal. The report focuses on the most clinically meaningful prediction per the spirit of the format.

Risperidone: From Schizophrenia to Major Affective Disorder

One-Sentence Summary

Risperidone is a second-generation atypical antipsychotic established in the treatment of schizophrenia and acute bipolar mania. The TxGNN model — evaluated across 6 predicted indications in this multi-indication pack — identifies Major Affective Disorder (encompassing major depressive disorder and bipolar spectrum conditions) as the highest-evidence repurposing target, supported by 37 clinical trials and 20 publications, including 5 systematic reviews and meta-analyses.

Quick Overview

Item	Content
Original Indication	Schizophrenia / Bipolar Mania (established drug profile; no Italy authorizations on record)
Predicted New Indication	Major Affective Disorder
TxGNN Prediction Score	99.11%
Evidence Level	L1
Italy Market Status	✗ Not marketed
Number of Authorizations	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Formal mechanism-of-action data from DrugBank was not captured in this evidence pack. However, Risperidone's pharmacology is extensively characterised in the published literature: it acts as a combined D2 dopamine receptor and 5-HT2A serotonin receptor antagonist. D2 blockade provides antimanic and antipsychotic effects by dampening excess dopaminergic tone, while 5-HT2A antagonism disinhibits prefrontal serotonin transmission — a pathway directly linked to antidepressant augmentation. This dual receptor profile maps precisely onto the neurobiological substrate of major affective disorder.

Major affective disorder is pathophysiologically characterised by dysregulation of both dopaminergic and serotonergic circuits. Bipolar mania involves dopaminergic hyperactivity amenable to D2 antagonism, while treatment-resistant depression (TRD) often reflects insufficient serotonergic signalling that benefits from 5-HT2A-mediated disinhibition when Risperidone is added to an antidepressant. This mechanistic duality makes Risperidone uniquely positioned across the affective spectrum, as confirmed by the breadth of Phase 3 RCT evidence in this pack.

One important regulatory caveat must be flagged: Risperidone already holds FDA approval for acute bipolar mania and ASD-related irritability. The original_indications: [] field in this evidence pack almost certainly reflects a data extraction gap rather than the absence of prior approvals. The TxGNN prediction therefore likely represents a mix of existing indication confirmation (bipolar mania) and genuine repurposing (TRD augmentation) — the boundary must be clarified with AIFA before this is classified as a novel repurposing application.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT00391222	Phase 3	Completed	585	Double-blind, placebo- and active-controlled RCT of Risperidone LAI monotherapy vs placebo (+ olanzapine comparator) for prevention of mood episode recurrence in Bipolar I disorder; largest and highest-powered trial in this dataset
NCT00057681	Phase 3	Completed	379	TEAM Study — head-to-head comparison of lithium, valproate, and risperidone in children/adolescents with early-onset mania; landmark paediatric Phase 3 RCT
NCT00095134	Phase 3	Completed	630	Adjunctive risperidone vs placebo in MDD patients with sub-optimal antidepressant response; among the largest Phase 3 augmentation RCTs for treatment-resistant MDD
NCT00044681	Phase 3	Completed	258	Risperidone augmentation of SSRI monotherapy in TRD — includes long-term maintenance phase comparing risperidone vs placebo add-on to demonstrate durability of response
NCT00277654	Phase 3	Completed	111	Risperidone monotherapy vs placebo in ambulatory bipolar disorder with comorbid panic or generalised anxiety disorder; double-blind RCT evaluating single-agent efficacy
NCT00176202	Phase 3	Completed	65	Risperidone vs divalproex sodium in paediatric bipolar disorder with neuroimaging circuit assessment; tests equivalence hypothesis in children
NCT00174577	Phase 3	Unknown	84	Risperidone augmentation in patients who failed or only partially responded to an adequate antidepressant trial; evaluates safety and efficacy in the partial-responder population
NCT00167479	Phase 4	Completed	60	Risperidone monotherapy in ambulatory bipolar disorder with moderately severe anxiety; double-blind, placebo-controlled real-world efficacy data
NCT00203723	Phase 4	Terminated	45	ECT combined with risperidone vs ECT alone for treatment-resistant depression; early termination limits conclusions, but provides preliminary MDD-specific augmentation signal
NCT01282632	Phase 1/2	Completed	42	Double-blind pilot comparing risperidone vs olanzapine as add-on to a failed SSRI in TRD; first direct head-to-head comparison of atypical antipsychotics in treatment-resistant depression

Literature Evidence

PMID	Year	Type	Journal	Key Findings
34986373	2022	Systematic Review & Network Meta-analysis	J Affect Disorders	Compared efficacy and discontinuation rates across augmentation agents for adult TRD using network meta-analysis; risperidone included as an active comparator
35861202	2023	Systematic Review & Meta-analysis	J Psychopharmacology	Evaluated adjunctive and combination treatments for early-stage TRD; SGAs including risperidone assessed for response and remission benefit over antidepressant monotherapy
34238049	2021	Systematic Review & Meta-analysis	J Psychopharmacology	Compared antidepressants + SGAs vs esketamine vs lithium for MDD treatment; provides head-to-head tolerability and efficacy context for risperidone augmentation
35510505	2023	Systematic Review & Meta-analysis	Psychological Medicine	Comprehensive meta-analysis of antipsychotics as both monotherapy and adjunctive therapy in MDD; risperidone efficacy and tolerability data pooled across multiple RCTs
21154393	2010	Systematic Review	Cochrane Database Syst Rev	Cochrane review of second-generation antipsychotics for MDD and dysthymia; foundational evidence synthesis showing risperidone as an effective antidepressant-augmenting agent
17975181	2007	RCT	Ann Intern Med	Randomised trial of risperidone augmentation for treatment-refractory MDD published in Annals of Internal Medicine; demonstrated significant response benefit vs placebo add-on
25295435	2014	Population-based Study	J Clin Psychiatry	Nationwide population-based study evaluating real-world effectiveness of aripiprazole, olanzapine, quetiapine, and risperidone augmentation for MDD using national health insurance data
21189367	2011	Clinical Review	Ann Pharmacother	Reviewed efficacy and safety of risperidone augmentation in MDD patients failing antidepressant monotherapy; synthesises trial-level evidence to support clinical practice guidance
33460070	2020	Clinical Practice Review	Acta Psychiatr Scand	Evidence-based treatment algorithms for bipolar mania; reviews risperidone positioning alongside mood stabilisers with clinical management recommendations
20486830	2010	Clinical Review	Expert Opin Pharmacother	Risperidone LAI as monotherapy and adjunctive therapy in Bipolar I maintenance; addresses long-term prophylaxis and treatment nonadherence with injectable formulation

Italy Market Information

Risperidone currently has no registered authorizations on record in Italy (AIFA). No product names, dosage forms, or approved indications were returned in this evidence pack.

⚠️ This result is anomalous. Risperidone is a widely-used antipsychotic with regulatory approvals across the US, EU, Japan, and most major markets. A zero-authorization result almost certainly reflects a data extraction limitation rather than actual absence from the Italian market. Direct verification via the AIFA online registry (farmaci.agenziafarmaco.gov.it) is mandatory before drawing any regulatory conclusions.

Safety Considerations

Please refer to the package insert for safety information.

The drug interaction (DDI) database returned no results, and Italy-specific package insert warnings were not captured in this evidence pack. Based on Risperidone's established pharmacological profile, the following areas should be proactively addressed in any clinical protocol:

Metabolic monitoring: weight, fasting glucose, HbA1c, lipid panel (metabolic syndrome risk with long-term use)

Neurological monitoring: extrapyramidal symptoms (EPS), tardive dyskinesia (AIMS scale), akathisia

Cardiovascular: QTc prolongation baseline ECG and follow-up

Endocrine: hyperprolactinaemia (especially in women of reproductive age)

Formal safety data retrieval from the EMA SmPC or AIFA-approved package insert is required before any clinical application proceeds.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: Multiple completed Phase 3 RCTs — including a 585-patient double-blind Bipolar I maintenance trial (NCT00391222), the TEAM Study in paediatric mania (NCT00057681, N=379), and a 630-patient TRD augmentation trial (NCT00095134) — combined with five systematic reviews/meta-analyses, constitute L1-grade evidence. Risperidone's D2/5-HT2A dual mechanism is directly aligned with the dopaminergic and serotonergic pathophysiology of major affective disorder, and the evidence base is sufficient to support moving to a formal feasibility and regulatory review stage.

To proceed, the following is needed:

Regulatory boundary clarification: Confirm whether "Major Affective Disorder" partially overlaps with Risperidone's existing approved indications (bipolar mania, schizophrenia). Resolve the original_indications: [] data gap before classifying this as a true repurposing vs. an indication-extension application — this distinction has significant regulatory and commercial implications
Italy AIFA market status verification: The 0-authorization finding must be confirmed directly via the AIFA registry; existing EU approvals (EMA) may already cover the target indication
Safety data retrieval: Obtain the EMA SmPC or AIFA-registered package insert to populate formal warnings, contraindications, and DDI profiles
Indication subgroup stratification: The evidence quality differs by affective subtype — design separate analysis pathways for (a) Bipolar I maintenance, (b) MDD adjunctive/augmentation, and (c) TRD; do not pool these as a single development track
Monitoring protocol definition: Establish baseline and follow-up monitoring schedule for metabolic parameters, EPS/tardive dyskinesia, QTc, and prolactin before any investigator-initiated trial submission
Secondary indication triage: This multi-indication pack also flags Trichotillomania (L3, 10 publications, Research Question) and Phelan-McDermid syndrome (L4, preclinical zebrafish data + case reports) as candidates for future exploratory research after the major affective disorder track is resolved
Disclaimer

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