Risperidone
| Evidence Level: L1 | Predicted Indications: 6 |
Table of Contents
Risperidone: From Schizophrenia/Bipolar Mania to Major Affective Disorder
One-Sentence Summary
Risperidone is a second-generation (atypical) antipsychotic originally used to treat schizophrenia and bipolar mania. The TxGNN model predicts it may also be effective for Major Affective Disorder (adjunctive therapy in bipolar disorder and treatment-resistant depression), with 36 clinical trials and 20 publications currently supporting this direction — the strongest-evidenced signal among six candidate indications screened in this evidence pack.
Note: This evidence pack (“TW-DB00734-multi”) contains six TxGNN-predicted indications ranked by raw prediction score. Four of them (gaze palsy with progressive scoliosis, Asperger susceptibility, amelocerebrohypohidrotic syndrome, and — to a lesser extent — Phelan-McDermid syndrome) are rare genetic/neurodevelopmental conditions with little to no supporting clinical evidence (L4–L5, “Hold”). This report focuses on the two candidates with actionable evidence: Major Affective Disorder (L1, primary focus below) and Trichotillomania (L3, secondary — see note in Conclusion).
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Schizophrenia / Bipolar Mania (not recorded in the supplied Taiwan regulatory data — see data gap below) |
| Predicted New Indication | Major Affective Disorder (bipolar disorder / treatment-resistant depression, adjunctive use) |
| TxGNN Prediction Score | 99.11% |
| Evidence Level | L1 |
| Taiwan Market Status | Not marketed (Not Marketed) per available regulatory data |
| Number of Registrations | 0 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Detailed formal mechanism-of-action documentation was not available in this evidence pack (flagged as a High-severity data gap). However, the evidence pack’s own repurposing rationale identifies Risperidone’s established pharmacology: it is a dual dopamine D2 / serotonin 5-HT2A receptor antagonist. This mechanism is the pharmacological basis for its approved use in schizophrenia and bipolar mania.
Major affective disorder — encompassing bipolar disorder and treatment-resistant major depressive disorder (MDD) — shares overlapping neurobiology with psychotic and manic states, particularly dysregulated dopaminergic and serotonergic signaling in mood circuits. D2/5-HT2A antagonism is the established mechanistic basis for second-generation antipsychotics’ role as antidepressant/mood-stabilizer augmentation agents, which is already reflected in clinical guidelines (e.g., FDA-approved SGA augmentation for MDD in other agents of this class).
This mechanistic plausibility is strongly reinforced by direct evidence: multiple completed Phase 3 RCTs test Risperidone specifically as monotherapy or augmentation in bipolar disorder and treatment-resistant depression, and several systematic reviews/meta-analyses (Cochrane, network meta-analyses) confirm efficacy signals for antipsychotic augmentation in this population. This is a mechanistically coherent and evidence-mature repurposing candidate, not merely a graph-similarity artifact.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00095134 | Phase 3 | Completed | 630 | Double-blind adjunctive Risperidone vs. placebo in MDD with sub-optimal antidepressant response |
| NCT00391222 | Phase 3 | Completed | 585 | Risperidone LAI vs. placebo for prevention of mood episodes in bipolar I disorder |
| NCT00044681 | Phase 3 | Completed | 258 | Risperidone augmentation of SSRI monotherapy in unipolar treatment-resistant depression, incl. long-term maintenance effect |
| NCT00107939 | Phase 3 | Completed | 453 | Adjunctive therapy trial in bipolar I mania; atypical antipsychotics incl. Risperidone as background therapy |
| NCT00057681 | Phase 3 | Completed | 379 | TEAM Study — lithium, valproate, and Risperidone compared in pediatric/adolescent bipolar mania |
| NCT00176202 | Phase 3 | Completed | 65 | Risperidone vs. divalproex sodium with MRI assessment of circuitry in pediatric bipolar disorder |
| NCT00277654 | Phase 3 | Completed | 111 | Randomized, double-blind, placebo-controlled Risperidone monotherapy in bipolar disorder with comorbid anxiety |
| NCT00221403 | Phase 3 | Completed | 46 | Placebo-controlled trial of valproate and Risperidone in young children with bipolar disorder |
| NCT00174577 | Phase 3 | Unknown | 84 | Risperidone augmentation in antidepressant partial/non-responders |
| NCT01282632 | Phase 1/2 | Completed | 42 | Pilot comparison of Risperidone vs. olanzapine as antidepressant add-on in treatment-resistant depression |
26 additional trials (mostly schizophrenia-focused, imaging/biomarker studies, or indirect comparator trials) were identified but are less directly relevant; full list available on request.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 17975181 | 2007 | RCT | Annals of Internal Medicine | Randomized trial of Risperidone for treatment-refractory major depressive disorder |
| 21154393 | 2010 | Systematic Review (Cochrane) | Cochrane Database Syst Rev | Second-generation antipsychotics, incl. Risperidone, for MDD and dysthymia |
| 34986373 | 2022 | Systematic Review/Network Meta-analysis | J Affective Disorders | Comparative efficacy/discontinuation of augmentation agents (incl. Risperidone) in treatment-resistant depression |
| 35861202 | 2023 | Systematic Review/Meta-analysis | J Psychopharmacology | Augmentation/combination treatments for early-stage treatment-resistant depression |
| 35510505 | 2023 | Systematic Review/Meta-analysis | Psychological Medicine | Efficacy and tolerability of antipsychotics (monotherapy and adjunctive) in MDD |
| 34238049 | 2021 | Review | J Psychopharmacology | Comparative efficacy/tolerability: antidepressants + second-generation antipsychotics vs. esketamine vs. lithium |
| 24919175 | 2014 | Meta-analysis | Braz J Med Biol Res | Efficacy/tolerability of antidepressant + atypical antipsychotic augmentation (17 trials, n=3807) in MDD |
| 25295435 | 2014 | Nationwide population-based study | J Clinical Psychiatry | Real-world effectiveness of aripiprazole/olanzapine/quetiapine/Risperidone augmentation for MDD |
| 20486830 | 2010 | Review | Expert Opin Pharmacother | Risperidone long-acting injection as monotherapy/adjunct in bipolar I maintenance treatment |
| 7545159 | 1995 | Early clinical study | J Clinical Psychiatry | Early report on Risperidone’s potential in affective illness beyond schizophrenia |
Taiwan Market Information
No active registration records were found in the supplied regulatory dataset (0 licenses, market status “Not marketed”). This should be treated with caution: Risperidone is a globally established, long-marketed antipsychotic, and this “not marketed” status may reflect a data gap in the source registry (see DG001 below) rather than genuine absence from the Taiwan market. This must be verified against the TFDA database directly before finalizing any regulatory conclusion.
Safety Considerations
- Drug Interactions: 362 documented interactions on file. Notable Major-severity interactions include Bupropion and Morphine. Numerous Moderate-severity interactions were identified with antidiabetic agents (Metformin, Alogliptin, Albiglutide, Canagliflozin), anticholinergics (Atropine, Hyoscyamine, Glycopyrronium, Clidinium), H2-blockers (Famotidine), and Epinephrine/Hydrocortisone. A Minor interaction was noted with Ranitidine.
Key warnings, contraindications, and TFDA package-insert data were not available in this evidence pack — please refer to the official package insert for full safety information once located.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Major Affective Disorder is supported by an L1 evidence level — multiple completed Phase 3 RCTs (including large trials with n=630 and n=585) plus several systematic reviews/meta-analyses consistently support Risperidone’s efficacy as an augmentation or mood-stabilizing agent, and the D2/5-HT2A mechanism is well established for this use. However, blocking data gaps in local regulatory/safety documentation prevent an unconditional “Go.”
To proceed, the following is needed:
- TFDA package-insert warnings and contraindications (DG001, Blocking — required before S1 safety review can proceed)
- Formal mechanism-of-action documentation from DrugBank (DG002)
- Verification of actual Taiwan market/registration status, given the discrepancy between “0 registrations” on file and Risperidone’s known global availability
- A monitoring plan addressing the Major-severity interactions (Bupropion, Morphine) and the broader anticholinergic/antidiabetic interaction burden
Secondary research question worth tracking: Trichotillomania (L3, “Research Question”) — supported by ~10 case reports/series over 25+ years showing consistent response signals as SSRI-augmentation therapy, but lacks controlled trial data. Not actionable for guideline-level repurposing yet, but warrants a dedicated small RCT if resources allow.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.