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Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic<ref name=AHFS2015>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> used to treat schizophrenia and bipolar disorder,<ref name="AHFS2015" /> as well as aggressive and self-injurious behaviors associated with autism spectrum disorder.<ref name=":0" /> It is taken either by mouth or by injection (i.e., subcutaneous or intramuscular).<ref name=AHFS2015/> The injectable versions are long-acting and last for 2–4 weeks.<ref name=Ric2015>Template:Cite book</ref>
Common side effects include weight gain, drowsiness, fatigue, insomnia, dry mouth, constipation, elevated prolactin levels, and restlessness.<ref name=AHFS2015/><ref name=Has2012>Template:Cite journal</ref> 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.<ref name=AHFS2015/><ref name=Ric2015/> In older people with psychosis as a result of dementia, it may increase the risk of death.<ref name=AHFS2015/> It is unknown if it is safe for use in pregnancy.<ref name=AHFS2015/> Its mechanism of action is not entirely clear, but is believed to be related to its action as a dopamine and serotonin antagonist.<ref name=AHFS2015/>
Study of risperidone began in the late 1980s and it was approved for sale in the United States in 1993.<ref name=AHFS2015/><ref name=":0">Template:Cite book</ref><ref name="Risperdal FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">Template:Cite book</ref> It is available as a generic medication.<ref name=Ric2015/> In 2022, it was the 183rd most commonly prescribed medication in the United States, with more than 2Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Medical usesEdit
Risperidone is mainly used for the treatment of schizophrenia, bipolar disorder, and irritability associated with autism.<ref name=AHFS>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
SchizophreniaEdit
Risperidone is effective in treating psychogenic polydipsia and the acute exacerbations of schizophrenia.<ref name="auto1">Template:Cite journal</ref><ref>Template:Cite journal</ref>
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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> 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.<ref name=Cochrane2016>Template:Cite journal</ref> A 2011 Cochrane review compared risperidone with other atypical antipsychotics such as olanzapine for schizophrenia:<ref name=Kom2011>Template:Cite journal</ref>
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| 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.<ref name=Kom2011/> | ||||||||||||||||||||||||||||||||||||||||||||||||
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Long-acting injectable formulations of antipsychotic drugs provide improved compliance with therapy and reduce relapse rates relative to oral formulations.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> The efficacy of risperidone long-acting injection appears to be similar to that of long-acting injectable forms of first-generation antipsychotics.<ref>Template:Cite journal</ref>
Bipolar disorderEdit
Second-generation antipsychotics, including risperidone, are effective in the treatment of manic symptoms in acute manic or mixed exacerbations of bipolar disorder.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> In children and adolescents, risperidone may be more effective than lithium or valproate, but has more metabolic side effects.<ref>Template:Cite journal</ref> As maintenance therapy, long-acting injectable risperidone is effective for the prevention of manic episodes but not depressive episodes.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>
AutismEdit
Compared to placebo, risperidone treatment reduces certain problematic behaviors in autistic children, including aggression toward others, self-injury, challenging behavior, and rapid mood changes.<ref>Template:Cite journal</ref> The evidence for its efficacy appears to be greater than that for alternative pharmacological treatments.<ref>Template:Cite journal</ref> Weight gain is an important adverse effect.<ref name="Risperdal FDA label" /><ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> Evidence for the efficacy of risperidone in autistic adolescents and young adults is less persuasive.<ref>Template:Cite journal</ref>
DementiaEdit
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.<ref name="pmid22784311" /> Because of this increased risk of death, treatment of dementia-related psychosis with risperidone is not FDA-approved and carries a black box warning.<ref name="Risperdal FDA label" /> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Other usesEdit
Risperidone has demonstrated clinical benefit as an augmentation agent in the management of (unipolar) non-psychotic treatment-resistant depression alongside antidepressant treatment.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>
Risperidone has shown promise in treating therapy-resistant obsessive–compulsive disorder, when serotonin reuptake inhibitors alone are not sufficient.<ref name="pmid22932229">Template:Cite journal</ref>
Risperidone has proven to be effective in treatment of aggression associated with attention deficit hyperactivity disorder (ADHD), <ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> or with another mental condition.<ref>Template:Cite journal</ref>
Risperidone has not demonstrated a benefit in the treatment of eating disorders or personality disorders, except for limited evidence in schizotypal personality disorder.<ref name="pmid22784311">Template:Cite journal</ref>
Available formsEdit
Available forms of risperidone include tablet, orally dissolving tablet, oral solution, and powder and solvent for injection.<ref>Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press http://www.medicinescomplete.com Template:Webarchive [Accessed on 2 February 2020]</ref>
Adverse effectsEdit
Common side effects include movement problems, sleepiness, dizziness, trouble seeing, constipation, and increased weight.<ref name=AHFS2015/><ref name=Has2012/> About 9 to 20% of people gained more than 7% of the baseline weight depending on the dose.<ref name=AHFS2015/> 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.<ref name=AHFS2015/><ref name=Ric2015/> In older people with psychosis as a result of dementia, it may increase the risk of death.<ref name=AHFS2015/>
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.<ref name=Div2014>Template:Cite journal</ref><ref name=Pil2017>Template:Cite journal</ref> Atypical antipsychotics, however, are associated with a greater amount of weight gain and other metabolic side effects.<ref>Template:Cite journal</ref><ref name=Pil2017/>
DiscontinuationEdit
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.<ref>Template:Cite book</ref>
DementiaEdit
Older people with dementia-related psychosis are at a higher risk of death.<ref name="Risperdal FDA label" />
InteractionsEdit
- Carbamazepine and other enzyme inducers may reduce plasma levels of risperidone.<ref name="Risperdal FDA label" /> 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.<ref name="Risperdal FDA label" />
- CYP2D6 inhibitors, such as the SSRI medications fluoxetine and paroxetine, may increase plasma levels of risperidone. <ref name="Risperdal FDA label" />
- 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.<ref name="Risperdal FDA label" />
- Risperidone and its metabolite paliperidone are reduced in efficacy by P-glycoprotein inducers such as St John's wort.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
- Risperidone has been found to dose-dependently block the effects of serotonergic psychedelics like psilocybin and lysergic acid diethylamide (LSD).<ref name="HalmanKongSarris2024">Template:Cite journal</ref><ref name="VollenweiderVollenweider-ScherpenhuyzenBäbler1998">Template:Cite journal</ref>
PharmacologyEdit
PharmacodynamicsEdit
| CitationClass=web
}}</ref><ref name="BenderParrLivingston2023">Template:Cite journal</ref> | ||
| Site | Ki (nM) | |
|---|---|---|
| 5-HT1A | 423 | Antagonist |
| 5-HT1B | 14.9 | Antagonist |
| 5-HT1D | 84.6 | Antagonist |
| 5-HT2A | 0.17 | Inverse agonist |
| 5-HT2B | 29–61.9 | Inverse agonist |
| 5-HT2C | 12.0 | Inverse agonist |
| 5-HT5A | 206 | Antagonist |
| 5-HT6 | 2060 | Antagonist |
| 5-HT7 | 6.60 | Irreversible antagonist<ref name="SmithRahman2006">Template:Cite journal</ref> |
| α1A | 5.0 | Antagonist |
| α1B | 9.0 | Antagonist |
| α2A | 16.5 | Antagonist |
| α2B | 108 | Antagonist |
| α2C | 1.30 | Antagonist |
| D1 | 244 | Antagonist |
| D2 | 3.57 | Antagonist |
| D2S | 4.73 | Antagonist |
| D2L | 4.16 | Inverse agonist |
| D3 | 3.6 | Inverse agonist |
| D4 | 4.66 | Antagonist |
| D5 | 290 | Antagonist |
| H1 | 20.1 | Inverse agonist |
| H2 | 120 | Inverse agonist |
| Template:Abbrlink | 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-HT2C, linked to weight gain, and 5-HT2A, linked to its antipsychotic action and relief of some of the extrapyramidal side effects experienced with typical antipsychotics.<ref name="GG">Brunton L, Chabner B, Knollman B. Goodman and Gilman's The Pharmacological Basis of Therapeutics, Twelfth Edition. McGraw Hill Professional; 2010.</ref>
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.<ref>Template:Cite journal</ref>
Risperidone acts on the following receptors:
Dopamine receptors: This drug is an antagonist of the D1 (D1, and D5) as well as the D2 (D2, D3 and D4) family receptors, with 70-fold selectivity for the D2 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.<ref name = "GG" />
Alpha α1 adrenergic receptors: This action accounts for the orthostatic hypotensive effects and perhaps some of the sedating effects of risperidone.<ref name = "GG" />
Alpha α2 adrenergic receptors: Risperidone's action at these receptors may cause greater positive, negative, affective, and cognitive symptom control.<ref>Template:Cite journal</ref>
Histamine H1 receptors: effects on these receptors account for its sedation and reduction in vigilance. This may also lead to drowsiness and weight gain.<ref name = "GG" />
Voltage-gated sodium channels: Because it accumulates in synaptic vesicles, Risperidone inhibits voltage-gated sodium channels at clinically used concentrations.<ref>Template:Cite journal</ref>
PharmacokineticsEdit
Risperidone undergoes hepatic metabolism and renal excretion. Lower doses are recommended for patients with severe liver and kidney disease.<ref name="Risperdal FDA label" /> The active metabolite of risperidone, paliperidone, is also used as an antipsychotic.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>Template:Unreliable medical source
Template:Pharmacokinetics of long-acting injectable antipsychotics
Society and cultureEdit
Legal statusEdit
Risperidone was approved by the United States Food and Drug Administration (FDA) in 1993 for the treatment of schizophrenia.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>Template:Cite press release</ref> 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.<ref>Template:Cite journal</ref> 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.<ref name="Okedi: Pending EC decision">{{#invoke:citation/CS1|citation |CitationClass=web }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> Long-acting depot injectable risperidone was approved for medical use in the European Union in February 2022.<ref name="Okedi EPAR" /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
LawsuitsEdit
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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The verdict was later reversed by the Arkansas state supreme court.<ref>Template:Cite news</ref>
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.<ref>Template:Cite news</ref>
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.<ref>Template:Cite press release</ref>
In 2015, Steven Brill wrote an investigative journalism piece about J&J in The Huffington Post focused on J&J's marketing of risperidone.<ref>Template:Cite news</ref><ref>Template:Cite news</ref>
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.<ref>Template:Cite news</ref> 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.<ref name="Murray-8B-verdict">Template:Cite news</ref> 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.<ref name="Murray-6.8m-verdict">Template:Cite news</ref> 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.<ref name="Murray-8B-verdict" />
Brand namesEdit
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.<ref name=generics>Drugs.com International trade names for risperidone Template:Webarchive Page accessed 15 March 2016</ref>
Risperidone is available as a tablet, an oral solution, and an ampule, which is a depot injection.<ref name=generics/>
Brand names include Risperdal, Risperdal Consta, Risperdal M-Tab, Risperdal Quicklets, Risperlet, Okedi, and Perseris.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
ReferencesEdit
Further readingEdit
External linksEdit
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