Is risperidone effective for maintenance of bipolar disorder?

Comment by InpharmD Researcher

The efficacy of risperidone for the maintenance of bipolar disorder has been established in multiple guidelines and systematic reviews. Societal guidelines consistently recommend risperidone, either administered as monotherapy or combination therapy, as an initial agent for the management of manic episodes associated with bipolar disorder. Meta-analyses evaluating the administration of risperidone long-acting injection monotherapy for prevention of mood and manic episodes as maintenance therapy found its use to be associated with significantly lower recurrence episodes and discontinuation rates compared to placebo. However, the efficacy of risperidone for the management of depressive episodes associated with bipolar disorder remains uncertain.

According to the 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) guidelines for management of bipolar disorders, risperidone is recommended for the management of various symptoms related to bipolar disorder. For management of agitation, risperidone as an oral disintegrating tablet is recommended as a second-line treatment option, and risperidone PO is recommended as a third-line treatment option. For manic episodes, risperidone may be considered for first-line monotherapy or combination therapy. Biweekly long-acting risperidone monotherapy has reported efficacy in preventing mood or manic episodes as maintenance therapy but was not effective for preventing depressive episodes. For bipolar II episodes, risperidone is recommended as a third-line treatment, mainly for prevention of hypomania. Risperidone is associated with weight gain and may not be preferred for overweight patients. Cardiovascular and neurological adverse events may also limit use in vulnerable populations. [1]

The International College of Neuro-Psychopharmacology (CINP) guidelines for bipolar disorder in adults recommend risperidone as part of the first step to managing acute mania/hypomania. If risperidone is not initially chosen, it may be added in combination with lithium or valproate. In contrast, risperidone is generally not recommended for acute bipolar depression. During the maintenance phase, risperidone may be considered as initial monotherapy, including the long-acting injectable. [2]

The British Association of Psychopharmacology 2016 guidelines make similar recommendations for risperidone as an effective agent for the acute management of severe manic bipolar episodes along with prevention of new episodes as maintenance treatment. [3]

A 2022 meta-analysis compared different pharmacologic interventions for management of acute bipolar mania in adult patients. Out of a total of 72 included double-blinded randomized controlled trials (RCTs), 7 studies compared risperidone to placebo (N= 676). The risk ratio (RR) of 1.689 (95% confidence interval [CI] 1.411 to 2.021) between risperidone versus placebo was defined by the response to treatment (commonly seen as 50% or greater improvement on the mania rating scale score), suggesting a statistically significant benefit. Only carbamazepine and tamoxifen reported higher RRs. Risperidone was also associated with significantly lower all-cause discontinuation rates compared to placebo (RR 0.428; 95% CI 0.290 to 0.630). Safety measures reported a higher incidence of akathisia, extrapyramidal symptoms, somnolence, nausea, and rate of anticholinergic use. Along with aripiprazole, olanzapine, and quetiapine, risperidone was consistently more effective than placebo based on the findings. [4]

A 2021 network meta-analysis investigated the efficacy, tolerability, and safety of antipsychotics and mood stabilizers for patients with bipolar disorder in the maintenance phase. Two categorical analyses were performed, where the first included monotherapy studies (i.e., risperidone long-acting injection [RISLAI]) and the second included studies of second-generation antipsychotic (SGA) combination therapies with lithium or valproate (LIT/VAL) compared with placebo and LIT/VAL. A total of 41 RCTs and 9,821 patients were included in the analysis (mean study duration 70.5 ± 36.6 weeks, female 54.1%, mean age 40.7 years). In terms of the recurrence/relapse rate of any mood episode, RISLAI outperformed the placebo (risk ratio [RR] 0.637, 95% credible interval [CrI] 0.484 to 0.839). Additionally, for recurrence/relapse rate of manic/hypomanic/mixed episodes, RISLAI outperformed placebo (RR 0.368, 95% CrI 0.268 to 0.507), lamotrigine (RR 0.890, 95% CrI 0.650 to 1.219), lithium (RR 0.540, 95% CrI 0.445 to 0.655), quetiapine (RR 0.555, 95% CrI 0.435 to 0.707), and valproate (RR 0.640, 95% CrI 0.477 to 0.857). The second analysis with the combination of SGA and LIT/VAL therapy did not include risperidone as part of the investigation. The findings of this study emphasized that clinicians and patients should consider the maintenance phase of bipolar disorder when selecting treatment for the acute phase. However, since the range of study durations included was between 17.3 to 171.4 weeks, the long-term safety and efficacy of drugs still need to be verified. [5]

Another 2021 meta-analysis evaluated the available evidence from 22 RCTs (N= 7,773) to consolidate relative efficacy of maintenance pharmacotherapy for bipolar disorder in patients stabilized for 1-12 weeks and followed up for 24-104 weeks. Among included studies, 3 of them reported use of risperidone, with 2 stabilized on long-acting injectable risperidone and 1 on oral risperidone along with lithium or valproate. Significantly lower risk of new bipolar disorder episodes was observed with risperidone long-acting monotherapy (odds ratio [OR] 0.41; 95% CI 0.28 to 0.60; p<0.00001; number-needed-to-treat 4.5). Similar results were reported when analysis included add-on treatment with oral risperidone. Of note, the actual time spent in the “stabilization” phase was not clearly defined and seemed to vary among different patients. Results may be further limited by the small number of risperidone trials included. [6]


[1] Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170. doi:10.1111/bdi.12609
[2] Fountoulakis KN, Grunze H, Vieta E, et al. The International College of Neuro-Psychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), Part 3: The Clinical Guidelines. Int J Neuropsychopharmacol. 2017;20(2):180-195. doi:10.1093/ijnp/pyw109
[3] Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2016;30(6):495-553. doi:10.1177/0269881116636545
[4] Kishi T, Ikuta T, Matsuda Y, et al. Pharmacological treatment for bipolar mania: a systematic review and network meta-analysis of double-blind randomized controlled trials. Mol Psychiatry. 2022;27(2):1136-1144. doi:10.1038/s41380-021-01334-4
[5] Kishi T, Ikuta T, Matsuda Y, et al. Mood stabilizers and/or antipsychotics for bipolar disorder in the maintenance phase: a systematic review and network meta-analysis of randomized controlled trials. Mol Psychiatry. 2021;26(8):4146-4157. doi:10.1038/s41380-020-00946-6
[6] Nestsiarovich A, Gaudiot CES, Baldessarini RJ, Vieta E, Zhu Y, Tohen M. Preventing new episodes of bipolar disorder in adults: Systematic review and meta-analysis of randomized controlled trials. Eur Neuropsychopharmacol. 2022;54:75-89. doi:10.1016/j.euroneuro.2021.08.264

Relevant Prescribing Information

Risperidone tablets are indicated for the treatment of schizophrenia. Efficacy was established in 4 short-term trials in adults, 2 short-term trials in adolescents (ages 13 to 17 years), and one long-term maintenance trial in adults

Bipolar Mania
Risperidone tablets are indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in 2 short-term trials in adults and one short-term trial in children and adolescents (ages 10 to 17 years
Adjunctive Therapy
Risperidone tablets adjunctive therapy with lithium or valproate is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in one short-term trial in adults

Irritability Associated with Autistic Disorder
Risperidone tablets are indicated for the treatment of irritability associated with autistic disorder, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. Efficacy was established in 3 short-term trials in children and adolescents (ages 5 to 17 years). [7]


[7] Risperidone tablet. Prescribing information. Ajanta Pharma Ltd.; 2022

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Is risperidone effective for maintenance of bipolar disorder?

Level of evidence

A - Multiple high-quality studies with consistent results  Read more→

Please see Table 1 for your response.


Risperidone Long-Acting Injectable Monotherapy in the Maintenance Treatment of Bipolar I Disorder


Multicenter, parallel-group, randomized, phase III study

N= 303


To determine the efficacy of risperidone long-acting injectable (LAI) in the maintenance treatment of bipolar I disorder

Study Groups

Risperidone LAI (n= 154)

Placebo (n= 149)

Inclusion Criteria

Aged 18 to 65 years, body mass index ≥17 and ≤33 kg/m2, diagnosis of bipolar I disorder, experienced an acute manic or mixed episode or stable on risperidone (oral or LAI) or on other oral antipsychotics or mood stabilizers but requiring change due to safety or tolerability concerns, experienced ≥ 2 mood episodes (manic, mixed manic, or depressed) during the 2 years preceding enrollment, stable with one episode within 4 months of enrollment

Exclusion Criteria

History of more than four mood episodes per year in the 2 years before screening or met criteria for a depressive episode or antisocial or borderline personality disorder, unstable or serious general medical illnesses, history of substance dependence in the 6 months before screening or chronic stimulant use within 4 weeks before screening, use of depot antipsychotics (except risperidone LAI) within one treatment cycle before screening, and women who were pregnant or nursing 


Following screening, patients who were stable on other antipsychotics or mood stabilizers were titrated off their previous medication and oral risperidone was initiated by day 8. Patients subsequently continued on their screening dose of risperidone LAI (25, 37.5, or 50 mg, except those unable to tolerate 25 mg, who were then started on 12.5 mg). Stabilized patients who maintained their treatment response were randomly assigned to either risperidone LAI at the same dose (12.5, 25, 37.5, or 50 mg), or switched to a placebo injection. Oral risperidone supplementation was allowed during the first 3 weeks after initiating LAI treatment (1–6 mg/day) and for the first 3 weeks (1–2 mg/day) after any increase in LAI dose.


January 2005 to December 2007

Continued risperidone LAI: up to 24 months

Outcome Measures

Change from baseline in Young Mania Rating Scale (YMRS), Montgomery Asberg Depression Rating Scale (MADRS), and Clinical Global Impressions-Severity Scale (GIS-S) Time to recurrence for any mood episode

Baseline Characteristics


Risperidone LAI (n= 154)

placebo (n= 149)


Age, years

39 39  


49% 54%  


80% 80%  

Body mass index, kg/m2

26 26  

Patient Type at Screening


Stable on risperidone (oral or LAI)

Stable on other antipsychotic










Years since diagnosis of bipolar disorder




Prior psychiatric hospitalizations





Change from Baseline in Rating Scale Scores at the End of Double-Blind Treatment Period

Rating Scale Scores

Risperidone Long-Acting Injectable

(n= 135)


(n= 133)

Difference of Least Square Means, 95% Confidence Interval, p-values



Change from baseline


2.3 ± 2.58

2.9 ± 7.34


2.5 ± 2.49

9.1 ± 10.78

-5.9 ± 1.09 (-8.08 to -3.79), p< 0.001



Change from baseline


1.9 ± 2.73

2.8 ± 6.66


2.0 ± 2.78

4.9 ± 8.09

-2.0 ± 0.87 (-3.75 to -0.32), p= 0.02



Change from baseline


1.6 ± 0.63

0.6 ± 1.18


1.7 ± 0.68

1.4 ± 1.54

-0.7 ± 0.15 (-1.05 to -0.45), p< 0.001

Proportion of patients experienced recurrence*

30% (42/140) 

56% (76/135)


Reason for recurrence

Elevated mood



22 (16%)

20 (14%)


62 (46%)

14 (10%

*Time to recurrence was significantly longer in the risperidone LAI group than in the placebo group (p<0.001). Patients in the risperidone LAI group were less than half as likely to experience a recurrence than patients in the placebo group (estimated hazard ratio 0.4, 95% CI 0.27 to 0.59). 

Risperidone LAI treatment significantly prolonged the time to discontinuation for any reason compared with placebo (p< 0.001; hazard ratio 0.49, 95% CI 0.36 to 0.67). 

Adverse Events

Common Adverse Events (risperidone LAI vs. placebo): weight increase (5% vs. 1%), depression (6% vs. 2%)

Serious Adverse Events (risperidone LAI vs. placebo): diabetes mellitus (1% in LAI vs. 0)

Percentage that Discontinued due to Adverse Events (risperidone LAI vs. placebo): 11% vs. 25%

Study Author Conclusions

Risperidone LAI monotherapy delayed the time to recurrence of mood episodes, versus placebo. Risperidone LAI was tolerable and no new safety concerns emerged compared with previous studies of risperidone LAI.

InpharmD Researcher Critique

While the stabilization period was deemed to be necessary in this study in order to demonstrate the prevention of episodes of true recurrence, the associated attrition rates might limit the generalizability of the results. The findings of this study are further limited by its treatment withdrawal design which may have deleterious effects since patients who are stabilized on an efficacious medication are randomly assigned to a placebo. Due to the exclusion of patients with rapid cycling, depression index episodes, and body mass index <17 and >33 kg/m2 the applicability of results may not be extended to this patient population. 


Quiroz JA, Yatham LN, Palumbo JM, Karcher K, Kushner S, Kusumakar V. Risperidone long-acting injectable monotherapy in the maintenance treatment of bipolar I disorder. Biol Psychiatry. 2010;68(2):156-162. doi:10.1016/j.biopsych.2010.01.015