Risperidone

Effects

Overview

Risperidone (also known as Risperdal) is an atypical antipsychotic medication of the benzisoxazole chemical class. Risperidone is prescribed for bipolar disorder, autism, and psychotic disorders, such as in schizophrenia. It is sometimes used as a sedative to reduce the effects of psychedelics like LSD and to induce sleepiness. Benzodiazepines are also used for this purpose. PW

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.[1][2][3] WP

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.[1][3][4] WP

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 2023, it was the 176th most commonly prescribed medication in the United States, with more than 2 million prescriptions.[1][2][3][5–8] WP

History

Legal status

• Australia: Risperidone is available only through prescription. PW⚠ PsychonautWiki itself has flagged this text: citation needed.
• Germany: Risperidone is a prescription medicine, according to Anlage 1 AMVV.[9] PW
• Switzerland: Risperidone is listed as a "Abgabekategorie B" pharmaceutical, which requires a prescription.[10] PW
• United Kingdom: Risperidone is available only through prescription. PW⚠ PsychonautWiki itself has flagged this text: citation needed.
• United States: Risperidone is available only through prescription. PW⚠ PsychonautWiki itself has flagged this text: citation needed.

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.[11][12][13] WP

In December 2021, the Committee for Medicinal Products for Human Use of the European Medicines Agency 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.[14][15][16] WP

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.[17][18] WP

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.[19] WP

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.[20] WP

In 2015, Steven Brill wrote an investigative journalism piece about J&J in The Huffington Post focused on J&J's marketing of risperidone.[21][22] WP

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.[23][24][25] WP

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.[26] WP

Risperidone is available as a tablet, an oral solution, and an ampule, which is a depot injection.[26] WP

Brand names include Risperdal, Risperdal Consta, Risperdal M-Tab, Risperdal Quicklets, Risperlet, Okedi, and Perseris.[27] WP

Pharmacology

Pharmacodynamics

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.[28] WP

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.[29] WP

Risperidone acts on the following receptors: WP

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.[28] WP

Alpha α₁ adrenergic receptors: This action accounts for the orthostatic hypotensive effects and perhaps some of the sedating effects of risperidone.[28] WP

Alpha α₂ adrenergic receptors: Risperidone's action at these receptors may cause greater positive, negative, affective, and cognitive symptom control.[30] WP

Histamine H₁ receptors: effects on these receptors account for its sedation and reduction in vigilance. This may also lead to drowsiness and weight gain.[28] WP

5-HT2A receptor: Risperidone’s atypicality is relatively strong in terms of its binding preference for 5-HT2A receptors over dopamine D2 receptors. However, clozapine is generally considered stronger in this regard. Clozapine differs in that it has lower overall receptor affinity compared to some other atypical antipsychotics, but still maintains an approximate 4-fold higher affinity for 5-HT2A receptors relative to D2 receptors. WP

Among three atypical antipsychotics often noted for significant 5-HT2A receptor blockade (risperidone, olanzapine, and clozapine), risperidone shows the highest degree of receptor occupancy in a dose-dependent comparison. At approximately 20 mg risperidone and 6 mg olanzapine, reported receptor occupancies are around 93–95%, respectively. Clozapine ranks third when compared using chlorpromazine equivalents.[31][32][33] WP

Voltage-gated sodium channels: Because it accumulates in synaptic vesicles, Risperidone inhibits voltage-gated sodium channels at clinically used concentrations.[34] WP

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.[5][35] WP⚠ Wikipedia itself has flagged this text: unreliable medical source?.

Chemistry

Formula

C23H27FN4O2 PC

CAS number

106266-06-2 PC

Molar mass (g/mol)

410.5 PC

IUPAC name (computed by PubChem)

3-[2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one PC

SMILES

CC1=C(C(=O)N2CCCCC2=N1)CCN3CCC(CC3)C4=NOC5=C4C=CC(=C5)F PC

InChIKey

RAPZEAPATHNIPO-UHFFFAOYSA-N PC

PubChem CID

5073

Pop culture

No references added yet.

References

1. Other Risperidone
2. Other Schatzberg AF, Nemeroff CB. The American Psychiatric Publishing textbook of psychopharmacology. 2009
3. Other Hamilton R. Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. 2015
4. Journal / agency Hasnain M, Vieweg WV, Hollett B. Weight gain and glucose dysregulation with second-generation antipsychotics and antidepressants: a review for primary care physicians. Postgraduate Medicine. July 2012. doi:10.3810/pgm.2012.07.2577 · PMID 22913904
5. Journal / agency Risperdal- risperidone tablet Risperdal M-Tab- risperidone tablet, orally disintegrating Risperdal- risperidone solution
6. Other World Health Organization model list of essential medicines: 21st list 2019. 2019
7. Other The Top 300 of 2023
8. Other Risperidone Drug Usage Statistics, United States, 2014 - 2023
9. Other Anlage 1 AMVV - Einzelnorm
10. Other https://compendium.ch/product/81388-risperdal-filmtabl-0-5-mg
11. Journal / agency Electronic Orange Book. April 2007
12. Journal / agency FDA approves the first drug to treat irritability associated with autism, Risperdal. 6 October 2006
13. Journal / agency Scahill L. How do I decide whether or not to use medication for my child with autism? Should I try behavior therapy first?. Journal of Autism and Developmental Disorders. July 2008. doi:10.1007/s10803-008-0573-7 · PMID 18463973
14. Journal / agency Okedi: Pending EC decision. 15 December 2021
15. Journal / agency Okedi EPAR. 15 December 2021
16. Other Okedi Product information
17. Other Muskal M. Companies belittled risks of Risperdal, slapped with huge fine. 11 April 2012
18. Other Thomas K. Arkansas Court Reverses $1.2 Billion Judgment Against Johnson & Johnson. 20 March 2014
19. Other NY AG: Janssen pays $181M over drug marketing. 30 August 2012
20. Other Johnson & Johnson to Pay More Than $2.2 Billion to Resolve Criminal and Civil Investigations. 4 November 2013
21. Other Ashbrook T. Johnson & Johnson And The Big Lies Of Big Pharma. 22 September 2015
22. Other Brill S. America's Most Admired Lawbreaker. September 2015
23. Other Feeley J. J&J Hit With $70 Million Risperdal Verdict Over Male Breasts. 1 July 2016
24. Other Jury says J&J must pay $8 billion in case over male breast growth linked to Risperdal. 9 October 2019
25. Other Stempel J. Judge slashes $8 billion Risperdal award against Johnson & Johnson to $6.8 million. 2020-01-17
26. Other Drugs.com International trade names for risperidone Page accessed 15 March 2016. link 2
27. Journal / agency Risperidone: MedlinePlus Drug Information
28. Other Brunton L, Chabner B, Knollman B. Goodman and Gilman's The Pharmacological Basis of Therapeutics, Twelfth Edition. McGraw Hill Professional; 2010
29. Journal / agency Abou El-Magd RM, Park HK, Kawazoe T, Iwana S, Ono K, Chung SP, Miyano M, Yorita K, Sakai T, Fukui K. The effect of risperidone on D-amino acid oxidase activity as a hypothesis for a novel mechanism of action in the treatment of schizophrenia. Journal of Psychopharmacology. July 2010. doi:10.1177/0269881109102644 · PMID 19329549
30. Journal / agency Hecht EM, Landy DC. Alpha-2 receptor antagonist add-on therapy in the treatment of schizophrenia; a meta-analysis. Schizophrenia Research. February 2012. doi:10.1016/j.schres.2011.11.030 · PMID 22169246
31. Journal / agency Kessler RM, Ansari MS, Riccardi P, Li R, Jayathilake K, Dawant B, Meltzer HY. Occupancy of striatal and extrastriatal dopamine D2/D3 receptors by olanzapine and haloperidol. Neuropsychopharmacology. 2005. doi:10.1038/sj.npp.1300836 · PMID 16123775
32. Journal / agency Nyberg S, Eriksson B, Oxenstierna G, Halldin C, Farde L. Suggested minimal effective dose of risperidone based on PET-measured D2 and 5-HT2A receptor occupancy in schizophrenic patients. The American Journal of Psychiatry. 1999. doi:10.1176/ajp.156.6.869 · PMID 10360125
33. Journal / agency Seeman P. Clozapine, a Fast-Off-D2 Antipsychotic. ACS Chemical Neuroscience. 2013. doi:10.1021/cn400189s · PMID 24219174 · PMC3894721
34. Journal / agency Brauner JM, Hessler S, Groemer TW, Alzheimer C, Huth T. Risperidone inhibits voltage-gated sodium channels. European Journal of Pharmacology. April 2014. doi:10.1016/j.ejphar.2014.01.062 · PMID 24508524
35. Harm reduction site The DrugBank database

Text and values on this page are quoted from PsychonautWiki (CC BY-SA 4.0), Wikipedia (CC BY-SA 4.0), PubChem (public domain). Each value links to the exact revision it came from.