Risperidone
| Evidence Level: L1 | Predicted Indications: 10 |
Table of Contents
Using no additional skills — this is a direct content-generation task with a fully specified template; proceeding straight to the report.
Note on indication selection: predicted_indications[0] (rank 1, “gaze palsy, familial horizontal, with progressive scoliosis”) has an L5 evidence level, zero supporting trials/literature, and its own rationale states “no known relationship” to risperidone’s mechanism — it is not reportable. I selected rank 6, “major affective disorder”, which has the highest evidence level (L1) and clearest actionable recommendation in this pack, as the report’s primary candidate.
Risperidone: From Schizophrenia to Major Affective Disorder
One-Sentence Summary
Risperidone is an atypical antipsychotic internationally established for schizophrenia and bipolar mania (5-HT2A/D2 receptor antagonism), though a formal EU authorization record is not present in this dataset. The TxGNN model predicts it may be effective for Major Affective Disorder, including treatment-resistant depression and bipolar disorder, with 34 clinical trials and 20 publications currently associated with this direction, including a completed 630-patient Phase 3 RCT.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not documented in EU authorization data on file (no licenses recorded); internationally established use is schizophrenia and bipolar mania |
| Predicted New Indication | Major Affective Disorder |
| TxGNN Prediction Score | 99.11% |
| Evidence Level | L1 |
| EU Market Status | Not Marketed |
| Number of Authorizations | 0 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Detailed DrugBank mechanism-of-action text is not available in this dataset. Based on known pharmacology, risperidone is an atypical antipsychotic acting via combined dopamine D2 and serotonin 5-HT2A receptor antagonism, a mechanism established for schizophrenia and bipolar mania.
This same receptor profile underlies the drug class effect of “second-generation antipsychotic augmentation” in major depressive disorder — a strategy already used clinically when patients fail first-line antidepressants (SSRIs/SNRIs). Other atypical antipsychotics in this class (aripiprazole, quetiapine) already carry regulatory approval for this exact augmentation use, making risperidone’s extension to major affective disorder mechanistically consistent rather than a novel biological hypothesis.
The evidence base reflects this: a large, completed Phase 3 double-blind RCT (n=630) directly tested risperidone augmentation in antidepressant-refractory MDD, and multiple additional Phase 3/4 RCTs and network meta-analyses support its role in bipolar depression, bipolar mania relapse prevention, and treatment-resistant unipolar depression.
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 response to antidepressant therapy |
| NCT00044681 | Phase 3 | Completed | 258 | Risperidone augmentation of SSRI monotherapy in unipolar treatment-resistant depression, including long-term maintenance effect |
| NCT00391222 | Phase 3 | Completed | 585 | Risperidone long-acting injectable (LAI) monotherapy vs. placebo for prevention of mood episodes in bipolar I disorder |
| NCT00277654 | Phase 3 | Completed | 111 | Risperidone monotherapy vs. placebo in bipolar disorder with comorbid panic/generalized anxiety disorder |
| NCT00667745 | Phase 4 | Completed | 283 | LiTMUS effectiveness trial; lithium-optimized regimens vs. comparators (including risperidone) in bipolar disorder |
| NCT00174577 | Phase 3 | Unknown | 84 | Risperidone augmentation in antidepressant partial/non-responders |
| NCT00203723 | Phase 4 | Terminated | 45 | Combined ECT + risperidone vs. ECT alone for treatment-resistant depression |
| NCT01282632 | Phase 1/2 | Completed | 42 | Pilot RCT: risperidone vs. olanzapine as add-on to SSRIs in treatment-resistant depression |
| NCT00167479 | Phase 4 | Completed | 60 | Risperidone monotherapy in ambulatory bipolar disorder with comorbid anxiety disorder |
| NCT00571688 | Phase 4 | Completed | 50 | Risperidone Consta (LAI) vs. treatment-as-usual for relapse/rehospitalization prevention in bipolar disorder |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 34986373 | 2022 | Systematic review/Network meta-analysis | J Affect Disord | Compared efficacy/discontinuation of augmentation agents (incl. risperidone) in treatment-resistant depression |
| 35861202 | 2023 | Systematic review/Meta-analysis | J Psychopharmacol | Evaluated adjunctive/combination treatments for early-stage treatment-resistant depression |
| 21154393 | 2010 | Cochrane Review | Cochrane Database Syst Rev | Second-generation antipsychotics (incl. risperidone) for MDD and dysthymia |
| 17975181 | 2007 | RCT | Ann Intern Med | Randomized trial of risperidone for treatment-refractory major depressive disorder |
| 20486830 | 2010 | RCT/Open-label extension | Expert Opin Pharmacother | Risperidone LAI as monotherapy and adjunctive therapy in maintenance treatment of bipolar I disorder |
| 23554581 | 2013 | Meta-analysis | PLoS Medicine | Adjunctive atypical antipsychotic treatment for MDD: depression, quality of life, and safety outcomes |
| 24919175 | 2014 | Meta-analysis | Braz J Med Biol Res | Efficacy/tolerability of atypical antipsychotic (incl. risperidone) augmentation of antidepressants, 17 trials, n=3807 |
| 25295435 | 2014 | Nationwide population-based study | J Clin Psychiatry | Effectiveness of SGA augmentation (incl. risperidone) for MDD in a national cohort |
| 15291687 | 2004 | Case series/Cohort | J Clin Psychiatry | Effectiveness of olanzapine, risperidone, quetiapine, ziprasidone as augmentation in treatment-resistant MDD |
| 34238049 | 2021 | Review | J Psychopharmacol | Efficacy/tolerability of combination treatments for MDD: antidepressants + second-generation antipsychotics vs. esketamine vs. lithium |
EU Market Information
No active EU marketing authorization is currently on file for risperidone in this dataset (market_status: Not Marketed, 0 licenses recorded). This may reflect the absence of a centralized EMA procedure rather than true unavailability, since risperidone is a long-genericized molecule typically authorized via national/decentralized procedures across EU member states — this should be verified against national regulatory registries before final decision-making.
Safety Considerations
Please refer to the SmPC for safety information.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Two or more completed Phase 3 RCTs (n=630 and n=258) directly support risperidone augmentation in treatment-resistant/unipolar depression, reinforced by multiple systematic reviews and network meta-analyses and additional Phase 3/4 RCTs in bipolar disorder — meeting the L1 evidence bar. However, the absence of confirmed EU marketing status and safety/label data prevents unconditional “Go.”
To proceed, the following is needed:
- TFDA/EMA-equivalent product label warnings and contraindications (DG001 — currently blocking S1 safety screening)
- Confirmed DrugBank mechanism-of-action documentation (DG002)
- Verification of EU marketing authorization status via national registries (current record shows “Not Marketed”)
- Drug-drug interaction data (current DDI query returned no results)
- Population-specific dosing/monitoring protocol for augmentation use in major affective disorder (e.g., metabolic and prolactin monitoring given antipsychotic class effects)
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.