Risperidone

What it is

Risperidone is a synthetic benzisoxazole, one of the second-generation or 'atypical' antipsychotics, taken as a tablet, an orally disintegrating tablet, a liquid or a long-acting injection. It blocks dopamine D2 and serotonin 5-HT2 receptors, and also alpha-1 and alpha-2 adrenergic and H1 histamine receptors. Its clinical effect comes from risperidone plus its major active metabolite, 9-hydroxyrisperidone, which is itself marketed as paliperidone.

What the research says

Risperidone reliably reduces the symptoms of acute psychosis and reduces relapse when continued, but Cochrane rated the placebo-controlled evidence for risperidone specifically as very low to low quality, and most of those trials were industry-funded. It also reduces irritability, aggression and self-injury in autistic children. Its harms are substantial and well quantified: movement disorders, sedation, weight gain, and prolactin elevation that is higher than with other antipsychotics. In elderly people with dementia it increases the risk of death, which is the subject of its boxed warning, and it is not approved for that use.

Evidence grade: Well established.

How it works

Drug class: Second-generation (atypical) antipsychotic; dopamine D2 and serotonin 5-HT2 receptor antagonist

Risperidone blocks dopamine D2 receptors and serotonin 5-HT2 receptors in the brain, which is thought to dampen the overactive dopamine signalling associated with psychosis. The label is explicit that the mechanism in schizophrenia is not actually established. It also blocks alpha-1 and alpha-2 adrenergic receptors (which explains the drop in blood pressure on standing) and H1 histamine receptors (which explains the sedation). (Source 1)

Boxed warning

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. RISPERDAL is not approved for the treatment of patients with dementia-related psychosis.

(Source 2)

What it is used for

• A network meta-analysis of 212 trials ranked risperidone fourth of 15 antipsychotics for symptom reduction (standardised mean difference 0.56 against placebo). Cochrane's risperidone-versus-placebo review found benefit for mental state but graded the evidence very low quality and noted that 8 of 15 trials were company-funded. Continuing the drug cuts one-year relapse from 64% to 27%. Evidence: established. (Source 3)
• Two 3-week placebo-controlled trials in adults and one in children and adolescents showed greater reduction in Young Mania Rating Scale scores than placebo. One of the two adjunctive trials was negative, which the label attributes to carbamazepine lowering risperidone levels. Evidence: limited. (Source 4)
• In a 101-child NIH-funded trial the Aberrant Behavior Checklist Irritability score fell 56.9% on risperidone versus 14.1% on placebo, with 69% versus 12% positive responders. The same trial recorded average weight gain of 2.7 kg in eight weeks and the authors warned that it was too short to judge tardive dyskinesia. Evidence: established. (Source 5)
• Not approved for this use and the subject of the boxed warning. A meta-analysis of 15 placebo-controlled trials found death in 3.5% on drug versus 2.3% on placebo. In the 421-patient CATIE-AD trial there was no significant difference from placebo in global improvement at 12 weeks, and more people stopped for intolerability. Evidence: not-supported. (Source 6)

Interactions

• Alcohol and other centrally acting drugs (label): Risperidone's own sedating effect adds to alcohol's, so drowsiness and impairment can be worse than either alone. The label records a caution rather than a measured interaction. (Source 7)
• Carbamazepine (a CYP3A/P-glycoprotein inducer) (pharmacokinetic study): Carbamazepine roughly halves the amount of active risperidone in the blood - the label's Table 18 gives an AUC ratio of 0.51 and a Cmax ratio of 0.55 against reference - which can make risperidone stop working. One of the two adjunctive bipolar trials failed, and the label attributes that to carbamazepine lowering risperidone levels. For the other enzyme inducers often listed alongside it - phenytoin, rifampin, phenobarbital - the label only says a similar effect may be expected; it gives no measured reduction for them. (Source 8)
• Fluoxetine and paroxetine (CYP2D6 inhibitors) (pharmacokinetic study): These antidepressants raise active risperidone exposure by about 30% to 80%, so the label caps the risperidone dose at 8 mg a day when they are combined. (Source 8)
• St John's wort and other herbal enzyme inducers (theoretical): The risperidone label does not name St John's wort. It does state that enzyme inducers cut active risperidone exposure roughly in half and that the dose may need doubling, and names carbamazepine, phenytoin, rifampin and phenobarbital. Any St John's wort effect is inferred from that class behaviour, not measured for risperidone. (Source 9)
• Food (pharmacokinetic study): Food makes no difference to how fast or how much risperidone is absorbed, so it can be taken with or without meals. No specific food interaction is documented. (Source 10)
• Levodopa and dopamine agonists (Parkinson's disease medicines) (label): Risperidone blocks dopamine receptors, so it works against levodopa and dopamine agonists and can worsen Parkinson's symptoms. (Source 7)
• Methylphenidate (case reports): When either dose is changed, the combination may raise the risk of extrapyramidal movement symptoms. (Source 7)
• Blood pressure lowering drugs, including telmisartan and other antihypertensives (label): Risperidone can itself lower blood pressure, especially on standing, and can add to the blood-pressure-lowering effect of other drugs. (Source 7)
• Clozapine (label): Long-term clozapine slows risperidone clearance, so risperidone levels can build up. (Source 7)
• Furosemide in elderly people with dementia (clinical trial): In two of four placebo-controlled dementia trials, deaths were more frequent in people given furosemide plus risperidone than risperidone alone or placebo plus furosemide. No mechanism was identified. (Source 11)

Stopping it

• Stopping an antipsychotic in schizophrenia sharply raises relapse risk: over a year, 64% relapsed on placebo against 27% who stayed on treatment, a number needed to treat of 3. The same meta-analysis found that abrupt versus gradual withdrawal did not significantly change relapse risk. (Source 12)
• About half of people who stop an oral antipsychotic abruptly get withdrawal symptoms, with a number needed to harm of 3 compared with continuing, on five studies and 261 individuals in all. (Source 13)
• In older people with dementia who have been on an antipsychotic for at least three months, Cochrane found low-quality evidence that it can usually be stopped without behaviour getting worse - though people who had clearly responded, or who had severe symptoms to begin with, were more likely to relapse. (Source 14)
• Tardive dyskinesia may partly or fully remit after an antipsychotic is stopped, but it can also first appear after stopping, and continued treatment can mask it. (Source 15)
• The label states that it is unknown how long someone with schizophrenia should stay on risperidone, that responders should generally continue beyond the acute episode, and that if the drug has been off for a while the original titration schedule should be followed again rather than restarting at the old dose. (Source 16)
• The label records that risperidone has not been systematically studied in animals or humans for its potential for abuse. It notes that the clinical trials showed no tendency to drug-seeking behaviour, but says those observations were not systematic and that this limited experience cannot predict how far a CNS-active drug will be misused once marketed. (Source 17)
• The same review's authors say the evidence base for antipsychotic withdrawal is weak, with a lack of randomised trials at low risk of bias. (Source 18)
• The same meta-analysis reports substantial variation between trials, and in a meta-regression the difference between drug and placebo got smaller as trials ran longer, so a one-year relapse figure is likely to overstate the long-term difference. (Source 12)

What goes wrong

In the same autism trial, risperidone caused significantly more weight gain, appetite increase, fatigue, drowsiness, dizziness and drooling than placebo, and the authors said the trial was too short to judge tardive dyskinesia. (Source 5)

• Randomized trial, Moderate certainty.
• Size: 101 children.
• Who: Children 5 to 17 with autistic disorder.
• How long: 8 weeks.
• Result: Average weight gain 2.7 +/- 2.9 kg vs 0.8 +/- 2.2 kg with placebo (P<0.001); increased appetite, fatigue, drowsiness, dizziness and drooling all more common (P<0.05 for each)
• Funding: independent.

Risperidone therapy was associated with an average weight gain of 2.7+/-2.9 kg, as compared with 0.8+/-2.2 kg with placebo (P<0.001). Increased appetite, fatigue, drowsiness, dizziness, and drooling were more common in the risperidone group than in the placebo group (P<0.05 for each comparison)

In adults with schizophrenia, risperidone roughly doubled parkinsonism (14% at 2 to 8 mg a day and 17% above 8 mg against 8% on placebo), roughly tripled akathisia (10% at either dose against 3%), and at 2 to 8 mg a day produced sedation at five times the placebo rate (10% against 2%). (Source 19)

• Official position, Moderate certainty.
• Size: 366 on 2-8 mg/day, 198 on >8-16 mg/day, 225 on placebo.
• Who: Adults with schizophrenia in three 4- to 8-week double-blind placebo-controlled trials.
• How long: 4 to 8 weeks.
• Result: Parkinsonism 14% (2-8 mg) and 17% (>8-16 mg) vs 8% placebo; akathisia 10% and 10% vs 3%; sedation 10% and 5% vs 2%; dizziness 7% and 4% vs 2%; nausea 9% and 4% vs 4%; orthostatic hypotension 2% and 1% vs 0%.
• Funding: not applicable (FDA-approved labelling summarising sponsor trials)

| System/Organ Class Adverse Reaction | 2–8 mg per day (N=366) | >8–16 mg per day (N=198) | Placebo (N=225) | | Cardiac Disorders | | | | | Tachycardia | 1 | 3 | 0 | | Eye Disorders | | | | | Vision blurred | 3 | 1 | 1 | | Gastrointestinal Disorders | | | | | Nausea | 9 | 4 | 4 | | Constipation | 8 | 9 | 6 | | Dyspepsia | 8 | 6 | 5 | | Dry mouth | 4 | 0 | 1 | | Abdominal discomfort | 3 | 1 | 1 | | Salivary hypersecretion | 2 | 1 | <1 | | Diarrhea | 2 | 1 | 1 | | General Disorders | | | | | Fatigue | 3 | 1 | 0 | | Chest pain | 2 | 2 | 1 | | Asthenia | 2 | 1 | <1 | | Infections and Infestations | | | | | Nasopharyngitis | 3 | 4 | 3 | | Upper respiratory tract infection | 2 | 3 | 1 | | Sinusitis | 1 | 2 | 1 | | Urinary tract infection | 1 | 3 | 0 | | Investigations | | | | | Blood creatine phosphokinase increased | 1 | 2 | <1 | | Heart rate increased | <1 | 2 | 0 | | Musculoskeletal and Connective Tissue Disorders | | | | | Back pain | 4 | 1 | 1 | | Arthralgia | 2 | 3 | <1 | | Pain in extremity | 2 | 1 | 1 | | Nervous System Disorders | | | | | Parkinsonism | 14 | 17 | 8 | | Akathisia | 10 | 10 | 3 | | Sedation | 10 | 5 | 2 | | Dizziness | 7 | 4 | 2 | | Dystonia | 3 | 4 | 2 | | Tremor | 2 | 3 | 1 | | Dizziness postural | 2 | 0 | 0 | | Psychiatric Disorders | | | | | Insomnia | 32 | 25 | 27 | | Anxiety | 16 | 11 | 11 | | Respiratory, Thoracic and Mediastinal Disorders | | | | | Nasal congestion | 4 | 6 | 2 | | Dyspnea | 1 | 2 | 0 | | Epistaxis | <1 | 2 | 0 | | Skin and Subcutaneous Tissue Disorders | | | | | Rash | 1 | 4 | 1 | | Dry skin | 1 | 3 | 0 | | Vascular Disorders | | | | | Orthostatic hypotension | 2 | 1 | 0 |

Risperidone is associated with clinically significant weight gain, which the label reports separately for adults and for children and adolescents from two different sets of trials. (Source 20)

• Official position, Moderate certainty.
• Size: Adults: 769 on 1-8 mg/day, 158 on >8-16 mg/day, 597 placebo. Children and adolescents: 448 on risperidone, 375 placebo.
• Who: Adults with schizophrenia or bipolar mania; children and adolescents with schizophrenia, bipolar mania, autistic disorder or other psychiatric disorders.
• How long: 3 to 8 weeks for the pooled trials; open-label extensions to 24 and 48 weeks.
• Result: Adults: weight change -0.3 kg placebo vs +0.7 kg (1-8 mg) vs +2.2 kg (>8-16 mg); 7% or greater gain in 2.9% placebo vs 8.7% vs 20.9%. Children and adolescents: +0.6 kg placebo vs +2.0 kg; 7% or greater gain 6.9% vs 32.6%. Longer term: +4.3 kg at week 24 and +5.3 kg at week 48 in adults; +5.5 kg and +8.0 kg in children.
• Funding: not applicable (FDA-approved labelling)

Limit of this finding: The adult figures and the children's figures come from two different sets of trials - seven adult trials at 1 to 8 and more than 8 to 16 mg a day, and nine paediatric trials at 0.5 to 6 mg a day across four different diagnoses. The label prints the two tables one after the other but never compares them, so the numbers should be read within each group and not as a measure of how much worse the gain is in children.

| | | RISPERDAL | | | Placebo (n=597) | 1–8 mg/day (n=769) | >8–16 mg/day (n=158) | | Weight (kg) | | | | | Change from baseline | -0.3 | 0.7 | 2.2 | | Weight Gain | | | | | ≥7% increase from baseline | 2.9% | 8.7% | 20.9% | In longer-term, controlled and uncontrolled studies, RISPERDAL was associated with a mean change in weight of +4.3 kg at Week 24 (n=395) and +5.3 kg at Week 48 (n=203). Data on mean changes in body weight and the proportion of subjects meeting the criterion of ≥7% gain in body weight from nine placebo-controlled, 3- to 8-week, fixed-dose studies in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), autistic disorder (5–17 years of age), or other psychiatric disorders (5–17 years of age) are presented in Table 7. Table 7. Mean Change in Body Weight (kg) and the Proportion of Subjects With ≥7% Gain in Body Weight From Nine Placebo-Controlled, 3- to 8-Week, Fixed-Dose Studies in Children and Adolescents With Schizophrenia (13–17 Years of Age), Bipolar Mania (10–17 Years of Age), Autistic Disorder (5 to 17 Years of Age) or Other Psychiatric Disorders (5–17 Years of Age) | | Placebo (n=375) | RISPERDAL 0.5–6 mg/day (n=448) | | Weight (kg) | | | | Change from baseline | 0.6 | 2.0 | | Weight Gain | | | | ≥7% increase from baseline | 6.9% | 32.6% |

Risperidone raises prolactin more than other antipsychotics, and the elevation persists with long-term use. (Source 21)

• Official position, Moderate certainty.
• Size: not quantified in this section.
• Who: People taking risperidone long term.
• How long: persists during chronic administration.
• Result: No rate is given. Consequences described are galactorrhoea, amenorrhoea, gynaecomastia and impotence, and reduced bone density where long-standing hyperprolactinaemia is accompanied by hypogonadism.
• Funding: not applicable (FDA-approved labelling)

RISPERDAL elevates prolactin levels and the elevation persists during chronic administration. RISPERDAL is associated with higher levels of prolactin elevation than other antipsychotic agents. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.

Tardive dyskinesia, which can be permanent, becomes more likely the longer risperidone is taken and the higher the cumulative dose, and can also appear after the drug is stopped. (Source 15)

• Official position, Moderate certainty.
• Size: not quantified in the label section.
• Who: People treated with antipsychotic drugs, risk highest in the elderly and especially elderly women.
• How long: risk rises with duration of treatment; can develop after relatively brief treatment.
• Result: No rate is given. The label states the risk and the likelihood of irreversibility both increase with duration of treatment and cumulative dose.
• Funding: not applicable (FDA-approved labelling)

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment.

In elderly people with dementia, atypical antipsychotics including risperidone were associated with a small absolute increase in death over about 10 to 12 weeks. (Source 6)

• Meta-analysis, Moderate certainty.
• Size: 5,110 participants (3,353 randomised to drug, 1,757 to placebo) across 15 trials, 9 of them unpublished; 5 risperidone contrasts.
• Who: Elderly people with Alzheimer's disease or other dementia.
• How long: generally 10 to 12 weeks.
• Result: Death in 118 (3.5%) on drug vs 40 (2.3%) on placebo; odds ratio 1.54, 95% CI 1.06-2.23, P=.02; risk difference 0.01, 95% CI 0.004-0.02, P=.01. Sensitivity analyses showed no evidence of differential risk for individual drugs.
• Funding: not stated.

Death occurred more often among patients randomized to drugs (118 [3.5%] vs 40 [2.3%]. The OR by meta-analysis was 1.54; 95% confidence interval [CI], 1.06-2.23; P = .02; and risk difference was 0.01; 95% CI, 0.004-0.02; P = .01)

Withdrawal symptoms are common after an oral antipsychotic is stopped abruptly, although the evidence base is small and heterogeneous. (Source 13)

• Meta-analysis, Low certainty.
• Size: 261 individuals across five studies.
• Who: People discontinuing an oral antipsychotic, with placebo substitution.
• How long: not stated in the abstract.
• Result: Proportion with withdrawal symptoms 0.53 (95% CI 0.37-0.70; I2 = 82.98%, P < 0.01); odds ratio versus continued treatment 7.97 (95% CI 2.39-26.58; I2 = 82.7%, P = 0.003); number needed to harm 3.
• Funding: not stated.

Limit of this finding: Only five studies and 261 people in all sit behind these figures, and they disagreed with each other a great deal (I-squared of about 83%), so the pooled 53% should be read as a rough signal that withdrawal symptoms are common, not as a reliable rate. The review's authors say plainly that trials at low risk of bias on this question are lacking.

Five studies with a total of 261 individuals were included. The primary outcome, proportion of individuals with withdrawal symptoms after antipsychotic discontinuation, was 0.53 (95% CI, 0.37-0.70; I2 = 82.98%, P < 0.01). An odds ratio of 7.97 (95% CI, 2.39-26.58; I2 = 82.7%, P = 0.003) and NNH of 3 was calculated for the occurrence of withdrawal symptoms after antipsychotic discontinuation.

What the evidence supports

Across 212 randomised trials of 15 antipsychotics, risperidone was significantly more effective than placebo for acute symptoms of schizophrenia, with an effect size near the top of the class but below clozapine. (Source 3)

• Meta-analysis, Moderate certainty.
• Size: 43,049 participants in 212 trials.
• Who: Adults with schizophrenia or related disorders in the acute phase, excluding predominantly negative symptoms, comorbid illness or treatment resistance.
• How long: Acute-phase trials (typically 4 to 12 weeks)
• Result: Standardised mean difference versus placebo for risperidone 0.56, 95% credible interval 0.50-0.63, ranking fourth of 15 behind clozapine 0.88, amisulpride 0.66 and olanzapine 0.59.
• Funding: independent (the paper states funding: None)

All drugs were significantly more effective than placebo. The standardised mean differences with 95% credible intervals were: clozapine 0·88, 0·73-1·03; amisulpride 0·66, 0·53-0·78; olanzapine 0·59, 0·53-0·65; risperidone 0·56, 0·50-0·63; paliperidone 0·50, 0·39-0·60; zotepine 0·49, 0·31-0·66; haloperidol 0·45, 0·39-0·51; quetiapine 0·44, 0·35-0·52; aripiprazole 0·43, 0·34-0·52; sertindole 0·39, 0·26-0·52; ziprasidone 0·39, 0·30-0·49; chlorpromazine 0·38, 0·23-0·54; asenapine 0·38, 0·25-0·51; lurasidone 0·33, 0·21-0·45; and iloperidone 0·33, 0·22-0·43.

In autistic children aged 5 to 17 with severe tantrums, aggression or self-injury, eight weeks of risperidone reduced irritability far more than placebo. (Source 5)

• Randomized trial, Moderate certainty.
• Size: 101 children (49 risperidone, 52 placebo); 82 boys and 19 girls, mean age 8.8 years.
• Who: Children 5 to 17 with autistic disorder accompanied by severe tantrums, aggression or self-injurious behaviour.
• How long: 8 weeks, with 6-month follow-up of responders.
• Result: 56.9% reduction in Irritability score vs 14.1% with placebo (P<0.001); positive response 69% (34 of 49) vs 12% (6 of 52), P<0.001; benefit maintained at six months in 23 of 34 responders. Dose range 0.5 to 3.5 mg per day.
• Funding: independent (NIH Research Units on Pediatric Psychopharmacology network)

Treatment with risperidone for eight weeks (dose range, 0.5 to 3.5 mg per day) resulted in a 56.9 percent reduction in the Irritability score, as compared with a 14.1 percent decrease in the placebo group (P<0.001). The rate of a positive response, defined as at least a 25 percent decrease in the Irritability score and a rating of much improved or very much improved on the CGI-I scale, was 69 percent in the risperidone group (34 of 49 children had a positive response) and 12 percent in the placebo group (6 of 52, P<0.001)

In older people with dementia who have taken an antipsychotic for at least three months, low-quality evidence suggests stopping it may make little or no difference to their behavioural and psychological symptoms. (Source 14)

• Systematic review, Low certainty.
• Size: 632 participants across 10 studies; 575 randomised participants in the nine trials with a success proxy.
• Who: Older people with dementia and neuropsychiatric symptoms in nursing homes or the community, treated with an antipsychotic for at least three months.
• How long: not stated in the abstract.
• Result: Low-quality evidence that discontinuation may make little or no difference to overall neuropsychiatric symptoms (7 trials, 519 participants), adverse events (5 trials, 381 participants), quality of life (2 trials, 119 participants) or cognitive function (5 trials, 365 participants). In the two trials restricted to people who had responded to treatment, stopping carried a higher risk of symptomatic relapse. Evidence on mortality was insufficient.
• Funding: not stated (Cochrane review)

We found low-quality evidence that discontinuation may make little or no difference to overall NPS, measured using various scales (7 trials, 519 participants). There was some evidence from subgroup analyses in two trials that discontinuation may reduce agitation for participants with less severe NPS at baseline, but may be associated with a worsening of NPS in participants with more severe NPS at baseline.

What the evidence does not support

When risperidone was added to clozapine rather than used alone, it produced no detectable benefit over placebo. (Source 22)

• Systematic review, Low certainty.
• Size: 98 to 167 participants across two to three randomised trials.
• Who: People with schizophrenia already taking clozapine.
• How long: not stated in the abstract.
• Result: Clinical response 2 RCTs, N=98, RR 1.15, 95% CI 0.93 to 1.42 (low-quality); attrition 3 RCTs, N=167, RR 1.13, 95% CI 0.53 to 2.42; CGI response 1 RCT, N=68, RR 1.12, 95% CI 0.87 to 1.44.
• Funding: not stated.

When risperidone and placebo were augmented with clozapine, there is no significant differences between groups for clinical response as defined by a less than 20% reduction in PANSS/BPRS scores (2 RCTs, N = 98, RR 1.15, 95% CI 0.93 to 1.42, low-quality evidence) and attrition (leaving the study early for any reason) (3 RCTs, N = 167, RR 1.13, 95% CI 0.53 to 2.42, low quality evidence). One study measured clinically significant responses using the CGI, no effect was evident (1 RCT, N = 68, RR 1.12 95% CI 0.87 to 1.44, low quality evidence)

In a placebo-controlled trial in Alzheimer's disease, risperidone produced no significant improvement in global clinical impression over placebo, and far more people stopped it because they could not tolerate it. (Source 23)

• Randomized trial, Moderate certainty.
• Size: 421 outpatients across 42 sites (risperidone mean dose 1.0 mg per day)
• Who: Outpatients with Alzheimer's disease and psychosis, aggression or agitation.
• How long: Up to 36 weeks; main outcomes at 12 weeks.
• Result: Minimal improvement on the CGIC scale at 12 weeks in 29% on risperidone vs 21% on placebo (P=0.22 across all groups). Median time to discontinuation for any reason 7.4 weeks risperidone vs 8.0 weeks placebo (P=0.52). Discontinuation for intolerability 18% risperidone vs 5% placebo (P=0.009).
• Funding: independent (NIMH-funded CATIE-AD)

No significant differences were noted among the groups with regard to improvement on the CGIC scale. Improvement was observed in 32% of patients assigned to olanzapine, 26% of patients assigned to quetiapine, 29% of patients assigned to risperidone, and 21% of patients assigned to placebo (P=0.22)

One of the two trials of risperidone added to a mood stabiliser was negative. (Source 24)

• Official position, Low certainty.
• Size: 142 inpatients or outpatients.
• Who: Adults with bipolar I disorder and inadequately controlled manic or mixed symptoms on lithium, valproate or carbamazepine.
• How long: 3 weeks.
• Result: Risperidone 1-6 mg/day (mean modal dose 3.7 mg/day) added to lithium, valproate or carbamazepine was not superior to the mood stabiliser alone on Young Mania Rating Scale total score.
• Funding: not applicable (FDA-approved labelling summarising sponsor trials)

was not superior to lithium, valproate, or carbamazepine alone in the reduction of YMRS total score. A possible explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone clearance by carbamazepine, leading to subtherapeutic levels of risperidone and 9-hydroxyrisperidone.

Risperidone has not been systematically studied in animals or humans for tolerance or physical dependence. (Source 25)

• Official position, Low certainty.
• Size: not applicable.
• Who: not applicable.
• How long: not applicable.
• Result: No data: section 9.3 of the label records only the absence of any systematic study of tolerance or physical dependence. The separate statement about abuse potential and drug-seeking behaviour is in section 9.2 and is recorded elsewhere in this write-up.
• Funding: not applicable (FDA-approved labelling)

RISPERDAL has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

Cochrane found too little data to say whether stopping an antipsychotic in dementia changes the risk of dying. (Source 14)

• Systematic review, Very low certainty.
• Size: 10 studies, 632 participants in all.
• Who: Older people with dementia and neuropsychiatric symptoms who had taken an antipsychotic for at least three months.
• How long: not stated in the abstract.
• Result: No pooled estimate: the review reports that there were insufficient data to determine whether discontinuation has any effect on mortality, rated very low-quality evidence.
• Funding: not stated (Cochrane review)

Limit of this finding: Risperidone carries a boxed warning about death in exactly this group, so "insufficient data" is not the same as "no risk": the trials that have been done were too small and too short to measure deaths either way.

There were insufficient data to determine whether discontinuation of antipsychotics has any effect on mortality (very low-quality evidence).

Where the evidence is mixed

Cochrane's dedicated review of risperidone versus placebo found benefit on mental state but graded the evidence very low quality and recorded more extrapyramidal side effects. (Source 26)

• Systematic review, Very low certainty.
• Size: 2,428 participants across 15 studies.
• Who: People with schizophrenia or schizophrenia-like psychoses taking oral risperidone.
• How long: not stated in the abstract.
• Result: Significant clinical improvement in mental state 6 RCTs, N=864, RR 0.64, CI 0.52 to 0.78 (very low-quality evidence); CGI improvement 4 RCTs, N=594, RR 0.69, CI 0.57 to 0.83; leaving early 12 RCTs, N=2261, RR 0.69, 95% CI 0.62 to 0.78 (low-quality); significant extrapyramidal side effect 7 RCTs, N=1511, RR 1.56, 95% CI 1.13 to 2.15.
• Funding: industry-funded trials predominate; the review itself reports that many included trials had industry sponsorship or involvement.

Limit of this finding: The risk ratio of 0.64 is printed in the review beside the words "more likely to achieve a significant clinical improvement", which reads backwards. Cochrane counts the unwanted outcome, so 0.64 means people on risperidone were about a third less likely to end up with NO clinically significant improvement. The direction of benefit is right; the number should not be read as a 36% lower chance of improving. The review rates this evidence very low quality.

Many of the included trials have industry sponsorship of involvement. Nonetheless, generally people in the risperidone group are more likely to achieve a significant clinical improvement in mental state (6 RCTs, N = 864, RR 0.64, CI 0.52 to 0.78, very low-quality evidence). The effect withstood, even when three studies with >50% attrition rate were removed from the analysis (3 RCTs, N = 589, RR 0.77, CI 0.67 to 0.88). Participants receiving placebo were less likely to have a clinically significant improvement on Clinical Global Impression scale (CGI) than those receiving risperidone (4 RCTs, N = 594, RR 0.69, CI 0.57 to 0.83, very low-quality evidence). Overall, the risperidone group was 31% less likely to leave early compared to placebo group (12 RCTs, N = 2261, RR 0.69, 95% CI 0.62 to 0.78, low-quality evidence), but Incidence of significant extrapyramidal side effect was more likely to occur in the risperidone group (7 RCTs, N = 1511, RR 1.56, 95% CI 1.13 to 2.15, very low-quality evidence)

Continuing an antipsychotic rather than switching to placebo more than halved one-year relapse, with a number needed to treat of 3, but at the cost of more weight gain, movement disorders and sedation. (Source 12)

• Meta-analysis, Moderate certainty.
• Size: 6,493 participants from 65 trials (116 reports)
• Who: People with schizophrenia stabilised on an antipsychotic, then continued or withdrawn.
• How long: Primary outcome relapse between 7 and 12 months.
• Result: Relapse 27% on drug vs 64% on placebo, risk ratio 0.40, 95% CI 0.33-0.49, number needed to treat to benefit 3 (95% CI 2-3); readmission 10% vs 26%, RR 0.38, NNTB 5; weight gain 10% vs 6%, movement disorders 16% vs 9% (RR 1.55, 1.25-1.93), sedation 13% vs 9% (1.50, 1.22-1.84)
• Funding: independent (German Ministry of Education and Research)

Limit of this finding: Two cautions, both from the paper itself. The relapse figures come with what the authors call substantial heterogeneity, and in their meta-regression the gap between drug and placebo got smaller the longer a trial ran, so a one-year figure probably overstates the difference over many years. And the weight-gain result is printed in the paper as "RR 2·07, 95% CI 2·31-3·25" - a risk ratio that sits outside its own confidence interval, which is impossible and means one of those three numbers is a typesetting error. The raw percentages beside it, 10% on a drug against 6% on placebo, are the figures to read.

Antipsychotic drugs significantly reduced relapse rates at 1 year (drugs 27%vs placebo 64%; risk ratio [RR] 0·40, 95% CI 0·33-0·49; number needed to treat to benefit [NNTB] 3, 95% CI 2-3)

Where the research disagrees

How good the evidence for risperidone in schizophrenia actually is

• Leucht and colleagues, Lancet 2013 (multiple-treatments meta-analysis), Bayesian network meta-analysis of 212 randomised trials, 43,049 participants, independently funded: All drugs were significantly more effective than placebo. (Source 3)
• Rattehalli and colleagues, Cochrane 2016, Cochrane systematic review of 15 randomised trials, 2,428 participants, with GRADE ratings of very low to low: Based on low quality evidence, risperidone appears to be benefitial in improving mental state compared with placebo, but it also causes more adverse events. (Source 27)

Whether atypical antipsychotics do anything useful for psychosis and agitation in Alzheimer's disease

• Schneider and colleagues, NEJM 2006 (CATIE-AD), 42-site randomised, double-blind, placebo-controlled trial, 421 outpatients, independently funded: Adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer's disease. (Source 28)
• FDA-approved risperidone labelling, regulatory position recorded in the boxed warning (LOINC 34066-1), SPL version 45 effective 28 May 2026: RISPERDAL is not approved for the treatment of patients with dementia-related psychosis. (Source 2)

How much

• Reference intake: Risperidone is a prescription medicine and the dose is set by the prescriber. The FDA label (SPL version 45, effective 28 May 2026) gives a recommended dose range of 2 to 8 mg per day for schizophrenia in adults and 1 to 6 mg per day for bipolar mania, titrated from a lower starting dose, with weight-based dosing in children. (Source 29)
• Upper limit: There is no reference intake or tolerable upper intake level for a prescription drug. The label caps the dose at 8 mg per day when risperidone is combined with fluoxetine or paroxetine, and the adult schizophrenia adverse-event tables cover doses above 8 up to 16 mg per day; the label states no greater benefit was seen at higher doses. (Source 9)
• Studied: The four short-term schizophrenia trials used fixed or titrated doses from 1 mg to 16 mg per day; the most consistently positive responses were at 4 mg and 6 mg per day. (Source 30)
• Studied: The autism trial in 101 children treated them for eight weeks over a dose range of 0.5 to 3.5 mg per day. (Source 5)
• Studied: CATIE-AD used a mean risperidone dose of 1.0 mg per day in outpatients with Alzheimer's disease. (Source 31)
• Studied: The adult bipolar mania trials used 1 to 6 mg per day once daily starting at 3 mg, with mean modal doses of 4.1 mg and 5.6 mg per day. (Source 4)

A common belief, and what the research shows

The belief: Risperidone is a mild, modern antipsychotic that does not cause the movement problems of the older drugs.

What the research shows: Risperidone caused significantly more movement side effects than placebo even in short trials: Cochrane found that "Incidence of significant extrapyramidal side effect was more likely to occur in the risperidone group (7 RCTs, N = 1511, RR 1.56, 95% CI 1.13 to 2.15, very low-quality evidence)." The label's own adult schizophrenia table records parkinsonism at 14% and 17% against 8% on placebo, and the label states that "The risk of developing tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose." The label also says risperidone "is associated with higher levels of prolactin elevation than other antipsychotic agents."

Questions and answers

What is it?

Risperidone is a prescription antipsychotic tablet, liquid or long-acting injection, one of the second-generation or 'atypical' group. It blocks serotonin 5-HT2 and dopamine D2 receptors with high affinity, and also alpha-adrenergic and histamine H1 receptors. Its effect comes from risperidone plus its active metabolite 9-hydroxyrisperidone. (Source 32)

What does it do in the body?

It dampens dopamine and serotonin signalling, which reduces hallucinations, delusions and disorganised thinking, and reduces irritability and aggression in autistic children. The label is candid that nobody knows exactly how it works in schizophrenia. Blocking receptors elsewhere produces the side effects: alpha-adrenergic blockade causes dizziness on standing, histamine blockade causes sedation, and dopamine blockade in the pituitary raises prolactin. (Source 1)

Is it good or bad for you?

Both, and the context decides which. For schizophrenia and for irritability in autistic children the benefit is measurable and worth having. For psychosis or agitation in dementia it is not approved, did not beat placebo on global improvement in the largest independent trial, and raises the risk of death - which is why it carries a boxed warning. Even where it helps, weight gain, movement problems and raised prolactin are common. (Source 2)

How do you get more of it?

Risperidone is not a nutrient and has no food source; it is available only on prescription. The label gives adult schizophrenia dose ranges with titration, weight-based dosing in children, and a lower starting dose in the elderly or in severe kidney or liver impairment. Food does not change absorption, so timing with meals does not alter how much gets in. (Source 29)

If it is harmful, what reduces it?

Stopping risperidone is what reduces it, and what that costs depends on who is taking it. In older people with dementia who had been on an antipsychotic for at least three months, Cochrane found low-quality evidence that stopping may make little or no difference to their behavioural and psychological symptoms, although in the two trials restricted to people who had responded to treatment, stopping carried a higher risk of symptomatic relapse. That review covers older people with dementia only; it did not study stopping risperidone in schizophrenia, which is covered separately in this write-up. (Source 14)

Why might someone be low in it or missing it?

Someone may be on a lower level, or none, for several documented reasons: an enzyme inducer such as carbamazepine roughly halves the active drug in the blood; a lower dose is used in the elderly and in severe kidney or liver impairment; and many people stop because of side effects - nausea, somnolence, sedation, vomiting, dizziness and akathisia were the commonest reasons for discontinuing in trials. (Source 9)

Which whole foods contain it or feed it?

No whole food contains risperidone and no food feeds it. Food has no effect on absorption, so it can be taken with or without meals. The clinically relevant dietary issue is not a food that contains it but alcohol, which adds to its sedating effect. (Source 10)

What happens if you do not have it?

For someone with schizophrenia who has been stabilised, going without an antipsychotic means a much higher chance of relapse: 64% relapsed within a year on placebo against 27% who continued treatment, and readmission was 26% against 10%. For a person who does not have the conditions risperidone treats, not taking it has no consequence - it is not something the body needs. (Source 12)

How can you test for it?

There is no routine blood test that measures risperidone in ordinary care, and the label sets no therapeutic blood level to aim at. What the label asks prescribers to watch is the consequences rather than the drug concentration: in older patients it says to consider monitoring orthostatic vital signs, and that it may be useful to monitor renal function, because risperidone is substantially excreted by the kidneys. So testing in practice means watching blood pressure and kidney function, not measuring a level. (Source 33)

References

1. DailyMed / U.S. National Library of Medicine. RISPERDAL - prescribing information, Section 12.1 Mechanism of Action. 2026. Read the source
2. DailyMed / U.S. National Library of Medicine (labeler: Janssen Pharmaceuticals, Inc.). RISPERDAL (risperidone) tablet, RISPERDAL M-TAB orally disintegrating tablet, RISPERDAL solution - prescribing information, Boxed Warning (LOINC 34066-1), SPL version 45. 2026. Read the source
3. Lancet. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis.. 2013. PMID 23810019, DOI 10.1016/S0140-6736(13)60733-3. Read the source
4. DailyMed / U.S. National Library of Medicine. RISPERDAL - prescribing information, Section 14.2 Bipolar Mania - Monotherapy (Adults). 2026. Read the source
5. New England Journal of Medicine. Risperidone in children with autism and serious behavioral problems.. 2002. PMID 12151468, DOI 10.1056/NEJMoa013171. Read the source
6. JAMA. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials.. 2005. PMID 16234500, DOI 10.1001/jama.294.15.1934. Read the source
7. DailyMed / U.S. National Library of Medicine. RISPERDAL - prescribing information, Section 7.2 Pharmacodynamic-related Interactions. 2026. Read the source
8. DailyMed / U.S. National Library of Medicine. RISPERDAL - prescribing information, Section 7.1 Pharmacokinetic-related Interactions (Table 18). 2026. Read the source
9. DailyMed / U.S. National Library of Medicine. RISPERDAL - prescribing information, Section 2.5 Dose Adjustments for Specific Drug Interactions. 2026. Read the source
10. DailyMed / U.S. National Library of Medicine. RISPERDAL - prescribing information, Section 12.3 Pharmacokinetics - Absorption and Food Effect. 2026. Read the source
11. DailyMed / U.S. National Library of Medicine. RISPERDAL - prescribing information, Section 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis. 2026. Read the source
12. Lancet. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis.. 2012. PMID 22560607, DOI 10.1016/S0140-6736(12)60239-6. Read the source
13. Frontiers in Psychiatry. Antipsychotic Withdrawal Symptoms: A Systematic Review and Meta-Analysis (Results).. 2020. PMID 33132934, DOI 10.3389/fpsyt.2020.569912. Read the source
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15. DailyMed / U.S. National Library of Medicine. RISPERDAL - prescribing information, Section 5.4 Tardive Dyskinesia. 2026. Read the source
16. DailyMed / U.S. National Library of Medicine. RISPERDAL - prescribing information, Section 2.1 Schizophrenia - Maintenance Therapy; Reinitiation of Treatment in Patients Previously Discontinued. 2026. Read the source
17. DailyMed / U.S. National Library of Medicine. RISPERDAL - prescribing information, Section 9.2 Abuse. 2026. Read the source
18. Frontiers in Psychiatry. Antipsychotic Withdrawal Symptoms: A Systematic Review and Meta-Analysis (Conclusion).. 2020. PMID 33132934, DOI 10.3389/fpsyt.2020.569912. Read the source
19. DailyMed / U.S. National Library of Medicine. RISPERDAL - prescribing information, Section 6.1 Clinical Trials Experience - Adult Patients with Schizophrenia (Table 8). 2026. Read the source
20. DailyMed / U.S. National Library of Medicine. RISPERDAL - prescribing information, Section 5.5 Metabolic Changes - Weight Gain. 2026. Read the source
21. DailyMed / U.S. National Library of Medicine. RISPERDAL - prescribing information, Section 5.6 Hyperprolactinemia. 2026. Read the source
22. Cochrane Database of Systematic Reviews. Risperidone versus placebo for schizophrenia (clozapine augmentation comparison).. 2016. PMID 27977041, DOI 10.1002/14651858.CD006918.pub3. Read the source
23. New England Journal of Medicine. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease (Results).. 2006. PMID 17035647, DOI 10.1056/NEJMoa061240. Read the source
24. DailyMed / U.S. National Library of Medicine. RISPERDAL - prescribing information, Section 14.3 Bipolar Mania - Adjunctive Therapy with Lithium or Valproate. 2026. Read the source
25. DailyMed / U.S. National Library of Medicine. RISPERDAL - prescribing information, Section 9.3 Dependence. 2026. Read the source
26. Cochrane Database of Systematic Reviews. Risperidone versus placebo for schizophrenia.. 2016. PMID 27977041, DOI 10.1002/14651858.CD006918.pub3. Read the source
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29. DailyMed / U.S. National Library of Medicine. RISPERDAL - prescribing information, Section 2.1 Schizophrenia - Adults, Usual Initial Dose. 2026. Read the source
30. DailyMed / U.S. National Library of Medicine. RISPERDAL - prescribing information, Section 14.1 Schizophrenia - Short-Term Efficacy. 2026. Read the source
31. New England Journal of Medicine. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease (Methods).. 2006. PMID 17035647, DOI 10.1056/NEJMoa061240. Read the source
32. DailyMed / U.S. National Library of Medicine. RISPERDAL - prescribing information, Section 12.2 Pharmacodynamics. 2026. Read the source
33. DailyMed / U.S. National Library of Medicine. RISPERDAL - prescribing information, Section 8.5 Geriatric Use. 2026. Read the source