Risperidone

證據等級: L5

預測適應症: 6 個

Risperidone: From Schizophrenia/Bipolar Disorder to Major Affective Disorder

One-Sentence Summary

Risperidone is a well-established atypical antipsychotic (serotonin-dopamine antagonist) originally used for schizophrenia and bipolar mania. The TxGNN model predicts it may also be effective for Major Affective Disorder — covering bipolar maintenance and augmentation therapy for treatment-resistant depression — with 35+ clinical trials and 20 publications currently supporting this direction, including multiple completed Phase 3 RCTs.

Note: TxGNN also flagged five other candidate indications for this drug (see "Other Predicted Indications" below). Three of them are ultra-rare genetic syndromes with no plausible mechanistic link and no supporting trials or literature — these are most likely knowledge-graph noise rather than real signals. This report focuses on the one candidate with substantive clinical evidence.

Quick Overview

Item	Content
Original Indication	Schizophrenia / Bipolar Mania (well-established use, referenced within trial records; formal local regulatory text not available)
Predicted New Indication	Major Affective Disorder (bipolar disorder & treatment-resistant depression)
TxGNN Prediction Score	99.11%
Evidence Level	L1
Norway Market Status	✗ Not Marketed
Number of Authorizations	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Detailed mechanism of action data is not available in the source records for this drug. Based on known information, risperidone is a second-generation ("atypical") antipsychotic acting as a serotonin-dopamine antagonist (D2 and 5-HT2A receptor antagonism). Its efficacy in schizophrenia and bipolar mania is well established — this is explicitly referenced in trial NCT00277654, which notes risperidone "is currently approved by the United States Food and Drug Administration (FDA) for the treatment of schizophrenia and bipolar mania."

Major affective disorder (bipolar disorder and major depressive disorder) shares overlapping neurobiology with the psychotic and manic states risperidone already treats — dysregulated dopaminergic and serotonergic signaling in cortico-limbic circuits. This mechanistic overlap explains why risperidone has long been used clinically as an adjunct: as monotherapy for bipolar maintenance (preventing manic/depressive relapse) and as an SSRI-augmentation strategy in treatment-resistant depression (TRD), consistent with the broader class effect seen with other second-generation antipsychotics (aripiprazole, quetiapine, olanzapine) approved for MDD augmentation.

The volume and quality of supporting evidence — including large randomized, placebo-controlled Phase 3 trials in both bipolar maintenance (n=585) and TRD augmentation (n=630, n=258) — indicate this is not a speculative model artifact but a reflection of an already-recognized, clinically practiced use pattern.

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	Efficacy, safety and long-term maintenance of risperidone augmentation of SSRI monotherapy in unipolar treatment-resistant depression
NCT00391222	Phase 3	Completed	585	Risperidone long-acting injectable (LAI) monotherapy vs. placebo for prevention of mood episodes in Bipolar I disorder
NCT00057681	Phase 3	Completed	379	TEAM study: lithium vs. valproate vs. risperidone for early-onset mania in children/adolescents with bipolar disorder
NCT00277654	Phase 3	Completed	111	Randomized, double-blind, placebo-controlled risperidone monotherapy in bipolar disorder with comorbid anxiety
NCT00167479	Phase 4	Completed	60	Risperidone monotherapy for bipolar disorder with moderate-to-severe anxiety; efficacy, tolerability and safety
NCT00203723	Phase 4	Terminated	45	Combined ECT + risperidone vs. ECT alone for treatment-resistant depression
NCT00176202	Phase 3	Completed	65	Risperidone vs. divalproex sodium in pediatric bipolar disorder, with MRI-based circuitry assessment
NCT00221403	Phase 3	Completed	46	Placebo-controlled trial of valproate and risperidone in young children (ages 3-7) with bipolar disorder
NCT01282632	Phase 1/2	Completed	42	Pilot trial: risperidone vs. olanzapine as add-on to failed SSRI therapy in treatment-resistant depression

Literature Evidence

PMID	Year	Type	Journal	Key Findings
17975181	2007	RCT	Annals of Internal Medicine	Randomized trial of risperidone augmentation for treatment-refractory major depressive disorder
34986373	2022	Systematic Review + NMA	J Affective Disorders	Network meta-analysis comparing augmentation agents (including risperidone) for treatment-resistant depression
35861202	2023	Systematic Review + Meta-analysis	J Psychopharmacology	Augmentation/combination treatments for early-stage treatment-resistant depression
24919175	2014	Meta-analysis	Braz J Med Biol Res	Efficacy/tolerability of atypical antipsychotic augmentation (17 trials, 3807 patients) of antidepressants in MDD
23554581	2013	Meta-analysis	PLoS Medicine	Risk-benefit profile of adjunctive atypical antipsychotics for depression
35510505	2023	Systematic Review + Meta-analysis	Psychological Medicine	Efficacy and safety/tolerability of antipsychotics (mono- and adjunctive) in adult MDD
21154393	2010	Cochrane Review	Cochrane Database Syst Rev	Second-generation antipsychotics added to antidepressants for MDD and dysthymia
25295435	2014	Nationwide Population-Based Study	J Clinical Psychiatry	Real-world effectiveness of SGA (including risperidone) augmentation for MDD
21189367	2011	Review	Annals of Pharmacotherapy	Efficacy and safety of risperidone augmentation in major depressive disorder
20486830	2010	Review	Expert Opin Pharmacotherapy	Risperidone LAI as monotherapy and adjunctive therapy for maintenance treatment of bipolar I disorder

Other Predicted Indications (Lower Priority / Screened Out)

The Evidence Pack also flagged five additional candidates. These are summarized for transparency but are not recommended for further action at this time:

Rank	Disease	TxGNN Score	Evidence Level	Recommendation	Comment
1	Gaze palsy, familial horizontal, with progressive scoliosis	99.76%	L5	Hold	ROBO3-related skeletal/neurological disorder; no plausible mechanistic link to D2/5-HT2A antagonism. Likely graph noise.
2	Asperger syndrome, susceptibility to	99.74%	L5	Hold	Risperidone is used off-label for irritability in autism spectrum disorder, but this entry is a "susceptibility" label, not a treatable clinical diagnosis, and has zero supporting trials/literature.
3	Amelocerebrohypohidrotic syndrome	99.69%	L5	Hold	Ultra-rare genetic syndrome (enamel/CNS/sweat gland). No known pathophysiological connection. Likely graph noise.
4	Phelan-McDermid syndrome	99.59%	L4	Research Question	SHANK3-related neurodevelopmental disorder with comorbid ASD/bipolar features; risperidone is used clinically for comorbid behavioral/mood symptoms, but evidence is limited to case reports and a preclinical zebrafish model.
5	Trichotillomania	99.51%	L3	Research Question	Multiple case reports/series (1997–2025) support risperidone as an SSRI-augmentation strategy for treatment-resistant hair-pulling disorder, but no RCTs exist.

Safety Considerations

Please refer to the package insert for safety information. No structured warnings, contraindications, or drug-interaction data were available in this Evidence Pack (flagged as a Blocking data gap — see Conclusion below).

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: Major affective disorder is supported by an unusually strong evidence base for a TxGNN-predicted indication — multiple completed Phase 3 RCTs in both bipolar maintenance and treatment-resistant depression augmentation, corroborated by systematic reviews, network meta-analyses, and a Cochrane review. This reflects an already-recognized clinical use pattern rather than a novel, unvalidated hypothesis. However, this drug is not currently marketed in this jurisdiction, and critical safety documentation is missing, so proceeding requires explicit guardrails rather than an unconditional go.

To proceed, the following is needed:

TFDA/local package insert warnings and contraindications (currently a Blocking data gap — required before any safety screening can begin)
Confirmed mechanism of action documentation from DrugBank (currently a High-severity data gap)
A defined local regulatory pathway, since the drug currently has zero authorizations and "Not Marketed" status
Safety monitoring plan addressing known antipsychotic-class risks (metabolic syndrome, extrapyramidal symptoms, prolactin elevation) given the drug's established but currently undocumented safety profile
Further prospective/controlled evidence for the lower-tier candidates (trichotillomania, Phelan-McDermid syndrome) before considering escalation beyond "Research Question" status
Disclaimer

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