# Risperidone

Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder, as well as aggressive and self-injurious behaviors associated with autism spectrum disorder. It is taken either by mouth or by injection (i.e., subcutaneous or intramuscular). The injectable versions are long-acting and last for 2–4 weeks.
Common side effects include weight gain, drowsiness, fatigue, insomnia, dry mouth, constipation, elevated prolactin levels, and restlessness. Serious side effects may include the potentially permanent movement disorder tardive dyskinesia, as well as neuroleptic malignant syndrome, an increased risk of suicide, and high blood sugar levels. In older people with psychosis as a result of dementia, it may increase the risk of death. It is unknown if it is safe for use in pregnancy. Its mechanism of action is not entirely clear, but is believed to be related to its action as a dopamine and serotonin antagonist.
Study of risperidone began in the late 1980s and it was approved for sale in the United States in 1993. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication. In 2022, it was the 183rd most commonly prescribed medication in the United States, with more than 2 million prescriptions.

## Medical uses

Risperidone is mainly used for the treatment of schizophrenia, bipolar disorder, and irritability associated with autism.

### Schizophrenia

Risperidone is effective in treating psychogenic polydipsia and the acute exacerbations of schizophrenia.
Studies evaluating the utility of risperidone by mouth for maintenance therapy have reached varying conclusions. A 2012 systematic review concluded that evidence is strong that risperidone is more effective than all first-generation antipsychotics other than haloperidol, but that evidence directly supporting its superiority to placebo is equivocal. A 2011 review concluded that risperidone is more effective in relapse prevention than other first- and second-generation antipsychotics with the exception of olanzapine and clozapine. A 2016 Cochrane review suggests that risperidone reduces the overall symptoms of schizophrenia, but firm conclusions are difficult to make due to very low-quality evidence. Data and information are scarce, poorly reported, and probably biased in favour of risperidone, with about half of the included trials developed by drug companies. The article raises concerns regarding the serious side effects of risperidone, such as parkinsonism. A 2011 Cochrane review compared risperidone with other atypical antipsychotics such as olanzapine for schizophrenia:
Summary :
Risperidone seems to produce somewhat more extrapyramidal side effects and clearly more prolactin increase than other atypical antipsychotics. It may also differ from other compounds in the occurrence of other adverse effects such as weight gain, metabolic problems, cardiac effects, sedation, and seizures. Nevertheless, the large proportion of participants leaving studies early and incomplete reporting of outcomes makes drawing firm conclusions difficult. :
| Outcome | Findings in words | Findings in numbers | Quality of evidence |
| Global state ||||
| No clinically significant response | Risperidone is not clearly different when compared to olanzapine. Data supporting this finding are based on moderate-quality evidence. | RR 1.06 (0.99 to 1.13) | Moderate |
| Leaving the study early due to any reason | Risperidone probably slightly increases the chance of leaving the study early, when compared with olanzapine. Data are based on moderate-quality evidence. | RR 1.14 (1.07 to 1.21) | Moderate |
| Service outcome ||||
| Number of patients rehospitalized Follow-up: up to 12 weeks | No clear difference is seen between risperidone and olanzapine for the outcome of how much hospital/community care is used. These findings are based on data of low quality. | RR 1.35 (0.41 to 4.40) | Low |
| Mental state ||||
| Average Positive and Negative Syndrome Scale (PANSS) score (high = poor) Follow-up: up to 12 weeks | On average, people receiving risperidone scored slightly higher (worse) than people treated with olanzapine but there was no clear difference between the groups. The meaning of this in day-to-day care is unclear. This finding is based on data of low quality. | MD 0.97 higher (1.1 lower to 3.05 higher) | Low |
| Adverse effects ||||
| At least one adverse effect | There was no clear difference between risperidone and olanzapine for this very general adverse effect outcome. These findings are based on data of low quality. | RR 0.96 (0.88 to 1.03) | Low |
| Quality of life ||||
| Average QLS scale score (high = poor) Follow-up: over 26 weeks | On average, people receiving risperidone scored higher than people treated with olanzapine. There was no clear difference between the groups. The meaning of this in day-to-day care is unclear. This finding is based on data of moderate quality. | MD 0.97 higher (1.1 lower to 3.05 higher) | Moderate |
Long-acting injectable formulations of antipsychotic drugs provide improved compliance with therapy and reduce relapse rates relative to oral formulations. The efficacy of risperidone long-acting injection appears to be similar to that of long-acting injectable forms of first-generation antipsychotics.

### Bipolar disorder

Second-generation antipsychotics, including risperidone, are effective in the treatment of manic symptoms in acute manic or mixed exacerbations of bipolar disorder. In children and adolescents, risperidone may be more effective than lithium or valproate, but has more metabolic side effects. As maintenance therapy, long-acting injectable risperidone is effective for the prevention of manic episodes but not depressive episodes. The long-acting injectable form of risperidone may be advantageous over long-acting first-generation antipsychotics, as it is better tolerated (fewer extrapyramidal effects) and because long acting injectable formulations of first-generation antipsychotics may increase the risk of depression.

### Autism

Compared to placebo, risperidone treatment reduces certain problematic behaviors in autistic children, including aggression toward others, self-injury, challenging behavior, and rapid mood changes. The evidence for its efficacy appears to be greater than that for alternative pharmacological treatments. Weight gain is an important adverse effect. Some authors recommend limiting the use of risperidone and aripiprazole to those with the most challenging behavioral disturbances to minimize the risk of drug-induced adverse effects. Evidence for the efficacy of risperidone in autistic adolescents and young adults is less persuasive.

### Dementia

While antipsychotic medications such as risperidone have a slight benefit in people with dementia, they have been linked to a higher incidence of death and stroke. Because of this increased risk of death, treatment of dementia-related psychosis with risperidone is not FDA-approved and carries a black box warning. However, many other jurisdictions regularly use it to control severe aggression and psychosis in those with dementia when other non-pharmacological interventions have failed and their pharmaceutical regulators have approved its use in this population.

### Other uses

Risperidone has demonstrated clinical benefit as an augmentation agent in the management of (unipolar) non-psychotic treatment-resistant depression alongside antidepressant treatment. Atypical antipsychotics, such as risperidone, are among the most common augments for antidepressant therapy. Such usage occurs off-label in most jurisdictions and the risk of adverse effects (e.g., weight gain, movement disorders) must be carefully weighed against the clinical benefit.
Risperidone has shown promise in treating therapy-resistant obsessive–compulsive disorder, when serotonin reuptake inhibitors alone are not sufficient.
Risperidone has proven to be effective in treatment of aggression associated with attention deficit hyperactivity disorder (ADHD), or with another mental condition.
Risperidone has not demonstrated a benefit in the treatment of eating disorders or personality disorders, except for limited evidence in schizotypal personality disorder.

### Available forms

Available forms of risperidone include tablet, orally dissolving tablet, oral solution, and powder and solvent for injection.

## Adverse effects

Common side effects include movement problems, sleepiness, dizziness, trouble seeing, constipation, and increased weight. About 9 to 20% of people gained more than 7% of the baseline weight depending on the dose. Serious side effects may include the potentially permanent movement disorder tardive dyskinesia, as well as neuroleptic malignant syndrome, an increased risk of suicide, and high blood sugar levels. In older people with psychosis as a result of dementia, it may increase the risk of death.
While atypical antipsychotics appear to have a lower rate of movement problems as compared to typical antipsychotics, risperidone has a high risk of movement problems among the atypicals. Atypical antipsychotics, however, are associated with a greater amount of weight gain and other metabolic side effects.

### Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.

### Dementia

Older people with dementia-related psychosis are at a higher risk of death.

## Interactions

* Carbamazepine and other enzyme inducers may reduce plasma levels of risperidone. If a person is taking both carbamazepine and risperidone, the dose of risperidone will likely need to be increased. The new dose should not be more than twice the patient's original dose.
* CYP2D6 inhibitors, such as SSRI medications, may increase plasma levels of risperidone and those medications.
* Since risperidone can cause hypotension, its use should be monitored closely when a patient is also taking antihypertensive medicines to avoid severe low blood pressure.
* Risperidone and its metabolite paliperidone are reduced in efficacy by P-glycoprotein inducers such as St John's wort.
* Risperidone has been found to dose-dependently block the effects of serotonergic psychedelics like psilocybin and lysergic acid diethylamide (LSD).

## Pharmacology
### Pharmacodynamics

Risperidone :
| Site | K$_i$ (nM) | |
| 5-HT$_{1A}$ | 423 | Antagonist |
| 5-HT$_{1B}$ | 14.9 | Antagonist |
| 5-HT$_{1D}$ | 84.6 | Antagonist |
| 5-HT$_{2A}$ | 0.17 | Inverse agonist |
| 5-HT$_{2B}$ | 29–61.9 | Inverse agonist |
| 5-HT$_{2C}$ | 12.0 | Inverse agonist |
| 5-HT$_{5A}$ | 206 | Antagonist |
| 5-HT$_6$ | 2060 | Antagonist |
| 5-HT$_7$ | 6.60 | Irreversible antagonist |
| α$_{1A}$ | 5.0 | Antagonist |
| α$_{1B}$ | 9.0 | Antagonist |
| α$_{2A}$ | 16.5 | Antagonist |
| α$_{2B}$ | 108 | Antagonist |
| α$_{2C}$ | 1.30 | Antagonist |
| D$_1$ | 244 | Antagonist |
| D$_2$ | 3.57 | Antagonist |
| D$_{2S}$ | 4.73 | Antagonist |
| D$_{2L}$ | 4.16 | Inverse agonist |
| D$_3$ | 3.6 | Inverse agonist |
| D$_4$ | 4.66 | Antagonist |
| D$_5$ | 290 | Antagonist |
| H$_1$ | 20.1 | Inverse agonist |
| H$_2$ | 120 | Inverse agonist |
| mAChTooltip Muscarinic acetylcholine receptor | 10000+ | Negligible |
Risperidone has been classified as a "qualitatively atypical" antipsychotic agent with a relatively low incidence of extrapyramidal side effects (when given at low doses) that has more pronounced serotonin antagonism than dopamine antagonism. Risperidone contains the functional groups of benzisoxazole and piperidine as part of its molecular structure. Although not a butyrophenone, it was developed with the structures of benperidol and ketanserin as a basis. It has actions at several 5-HT (serotonin) receptor subtypes. These are 5-HT$_{2C}$, linked to weight gain, and 5-HT$_{2A}$, linked to its antipsychotic action and relief of some of the extrapyramidal side effects experienced with typical antipsychotics.
It has been found that D-amino acid oxidase, the enzyme that catalyses the breakdown of D-amino acids (e.g. D-alanine and D-serine — the neurotransmitters) is inhibited by risperidone.
Risperidone acts on the following receptors:
Dopamine receptors: This drug is an antagonist of the D$_1$ (D$_1$, and D$_5$) as well as the D$_2$ (D$_2$, D$_3$ and D$_4$) family receptors, with 70-fold selectivity for the D$_2$ family. It has "tight binding" properties, which means it has a long half-life. Like other antipsychotics, risperidone blocks the mesolimbic pathway, the prefrontal cortex limbic pathway, and the tuberoinfundibular pathway in the central nervous system. Risperidone may induce extrapyramidal side effects, akathisia and tremors, which is associated with diminished dopaminergic activity in the striatum. It can also cause sexual side effects, galactorrhoea, infertility, gynecomastia, and, with chronic use, reduced bone mineral density leading to breaks, all of which are associated with increased prolactin secretion.
Alpha α$_1$ adrenergic receptors: This action accounts for the orthostatic hypotensive effects and perhaps some of the sedating effects of risperidone.
Alpha α$_2$ adrenergic receptors: Risperidone's action at these receptors may cause greater positive, negative, affective, and cognitive symptom control.
Histamine H$_1$ receptors: effects on these receptors account for its sedation and reduction in vigilance. This may also lead to drowsiness and weight gain.
Voltage-gated sodium channels: Because it accumulates in synaptic vesicles, Risperidone inhibits voltage-gated sodium channels at clinically used concentrations.

### Pharmacokinetics

Risperidone undergoes hepatic metabolism and renal excretion. Lower doses are recommended for patients with severe liver and kidney disease. The active metabolite of risperidone, paliperidone, is also used as an antipsychotic.
vte Pharmacokinetics of long-acting injectable antipsychotics :
| Medication | Brand name | Class | Vehicle | Dosage | T$_{max}$ | t$_{1/2}$ single | t$_{1/2}$ multiple | logP$^c$ |
| Aripiprazole lauroxil | Aristada | Atypical | Water$^a$ | 441–1064 mg/4–8 weeks | 24–35 days | ? | 54–57 days | 7.9–10.0 |
| Aripiprazole monohydrate | Abilify Maintena | Atypical | Water$^a$ | 300–400 mg/4 weeks | 7 days | ? | 30–47 days | 4.9–5.2 |
| Bromperidol decanoate | Impromen Decanoas | Typical | Sesame oil | 40–300 mg/4 weeks | 3–9 days | ? | 21–25 days | 7.9 |
| Clopentixol decanoate | Sordinol Depot | Typical | Viscoleo$^b$ | 50–600 mg/1–4 weeks | 4–7 days | ? | 19 days | 9.0 |
| Flupentixol decanoate | Depixol | Typical | Viscoleo$^b$ | 10–200 mg/2–4 weeks | 4–10 days | 8 days | 17 days | 7.2–9.2 |
| Fluphenazine decanoate | Prolixin Decanoate | Typical | Sesame oil | 12.5–100 mg/2–5 weeks | 1–2 days | 1–10 days | 14–100 days | 7.2–9.0 |
| Fluphenazine enanthate | Prolixin Enanthate | Typical | Sesame oil | 12.5–100 mg/1–4 weeks | 2–3 days | 4 days | ? | 6.4–7.4 |
| Fluspirilene | Imap, Redeptin | Typical | Water$^a$ | 2–12 mg/1 week | 1–8 days | 7 days | ? | 5.2–5.8 |
| Haloperidol decanoate | Haldol Decanoate | Typical | Sesame oil | 20–400 mg/2–4 weeks | 3–9 days | 18–21 days | 18–21 days | 7.2–7.9 |
| Olanzapine pamoate | Zyprexa Relprevv | Atypical | Water$^a$ | 150–405 mg/2–4 weeks | 7 days | ? | 30 days | – |
| Oxyprothepin decanoate | Meclopin | Typical | ? | ? | ? | ? | ? | 8.5–8.7 |
| Paliperidone palmitate | Invega Sustenna | Atypical | Water$^a$ | 39–819 mg/4–12 weeks | 13–33 days | 25–139 days | ? | 8.1–10.1 |
| Perphenazine decanoate | Trilafon Dekanoat | Typical | Sesame oil | 50–200 mg/2–4 weeks | ? | ? | 27 days | 8.9 |
| Perphenazine enanthate | Trilafon Enanthate | Typical | Sesame oil | 25–200 mg/2 weeks | 2–3 days | ? | 4–7 days | 6.4–7.2 |
| Pipotiazine palmitate | Piportil Longum | Typical | Viscoleo$^b$ | 25–400 mg/4 weeks | 9–10 days | ? | 14–21 days | 8.5–11.6 |
| Pipotiazine undecylenate | Piportil Medium | Typical | Sesame oil | 100–200 mg/2 weeks | ? | ? | ? | 8.4 |
| Risperidone | Risperdal Consta | Atypical | Microspheres | 12.5–75 mg/2 weeks | 21 days | ? | 3–6 days | – |
| Zuclopentixol acetate | Clopixol Acuphase | Typical | Viscoleo$^b$ | 50–200 mg/1–3 days | 1–2 days | 1–2 days | 1–2 days | 4.7–4.9 |
| Zuclopentixol decanoate | Clopixol Depot | Typical | Viscoleo$^b$ | 50–800 mg/2–4 weeks | 4–9 days | ? | 11–21 days | 7.5–9.0 |
| Note: All by intramuscular injection. Footnotes: $^a$ = Microcrystalline or nanocrystalline aqueous suspension. $^b$ = Low-viscosity vegetable oil (specifically fractionated coconut oil with medium-chain triglycerides). $^c$ = Predicted, from PubChem and DrugBank. Sources: Main: See template. ||||||||||

## Society and culture
### Legal status

Risperidone was approved by the United States Food and Drug Administration (FDA) in 1993 for the treatment of schizophrenia. In 2003, the FDA approved risperidone for the short-term treatment of the mixed and manic states associated with bipolar disorder. In 2006, the FDA approved risperidone for the treatment of irritability in autistic children and adolescents. The FDA's decision was based in part on a study of autistic people with severe and enduring problems of violent meltdowns, aggression, and self-injury; risperidone is not recommended for autistic people with mild aggression and explosive behavior without an enduring pattern. On 22 August 2007, risperidone was approved as the only drug agent available for the treatment of schizophrenia in youths, ages 13–17; it was also approved that same day for the treatment of bipolar disorder in youths, ages 10–17, joining lithium.
On 16 December 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) formally recommended market authorization for Okedi, a long-acting depot injection of risperidone. Okedi was approved for the treatment of schizophrenia in adults for whom the tolerability and effectiveness of risperidone had already been established using an oral formulation. Long-acting depot injectable risperidone was approved for medical use in the European Union in February 2022.

### Lawsuits

In April 2012, Johnson & Johnson (J&J) and its subsidiary Janssen Pharmaceuticals Inc. were fined $1.2 billion for downplaying multiple risks associated with risperidone. The verdict was later reversed by the Arkansas state supreme court.
In August 2012, J&J agreed to pay $181 million to 36 US states to settle claims that it had promoted risperidone and paliperidone for off-label uses including for dementia, anger management, and anxiety.
In November 2013, J&J was fined $2.2 billion for illegally marketing risperidone for use in people with dementia and paying kickbacks to prescribing physicians and nursing home pharmacies.
In 2015, Steven Brill wrote an investigative journalism piece about J&J in The Huffington Post focused on J&J's marketing of risperidone.
J&J has faced numerous civil lawsuits on behalf of children who were prescribed risperidone who grew breasts (a condition called gynecomastia); as of July 2016 there were about 1,500 cases in Pennsylvania state court in Philadelphia, and there had been a February 2015 verdict against J&J with $2.5 million awarded to a man from Alabama, a $1.75 million verdict against J&J that November, and in 2016 a $70 million verdict against J&J. In October 2019, a jury ordered J&J to pay $8 billion in punitive damages to a Pennsylvania man who had grown breasts during adolescence. This verdict amount chosen by the jury was reduced more than 1,000-fold by a judge in January 2020, with the new punitive damages being $6.8 million. A legal scholar commented that punitive damages which exceed the compensatory damages by a factor of 10 or more in cases of this type are usually found to be legally invalid.

### Brand names

Janssen's patent on risperidone expired in December 2003, opening the market for cheaper generic versions from other companies, and Janssen's exclusive marketing rights expired in June 2004 (the result of a pediatric extension). It is available under many brand names worldwide.
Risperidone is available as a tablet, an oral solution, and an ampule, which is a depot injection.
Brand names include Risperdal, Risperdal Consta, Risperdal M-Tab, Risperdal Quicklets, Risperlet, Okedi, and Perseris.