Risperidone - Wikipedia, the free encyclopedia

4-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-piperidyl]ethyl]-3-methyl-2,6-diazabicyclo[4.4.0]deca-1,3-dien-5-one

Risperdal,Risperdal Consta,Risperdal M-Tab,Risperdal Quicklets

monograph

a694015

B3 (AU) C (US)

Prescription Only (S4)(AU)POM(UK)℞-only(US)

Oral (tablets and liquid form), IM

70% (oral)[1]

Hepatic (CYP2D6-mediated)to 9-hydroxyrisperidone[1]

20 hours (Oral), 2.9-6 days (IM) [1]

Urinary (70% [adults], 4.3% [children], 7.4% [adolescents]), faecal (14%) [1]

106266-06-2 Y

N05AX08

CID 5073

96

DB00734

4895 Y

L6UH7ZF8HC Y

D00426 Y

CHEBI:8871 Y

CHEMBL85 Y

C23H27FN4O2

410.485 g/mol

Cc1c(c(=O)n2c(n1)CCCC2)CCN3CCC(CC3)c4c5ccc(cc5on4)F

Risperidone (//ri-SPAIR-i-dohn) (trade name Risperdal, and generics) is an antipsychotic drug mainly used to treat schizophrenia (including adolescent schizophrenia), schizoaffective disorder, the mixed and manic states of bipolar disorder, and irritability in people with autism.

Risperidone belongs to the class of atypical antipsychotics which are second generation.[2] It is a dopamine antagonist possessing antiserotonergic, antiadrenergic and antihistaminergic properties.

Adverse effects of risperidone include significant weight gain and metabolic problems such as diabetes mellitus type 2,[3] as well as tardive dyskinesia and neuroleptic malignant syndrome. Risperidone and other antipsychotics also increase the risk of death in people with dementia.[4]

The drug was developed by Janssen-Cilag, subsidiary of Johnson & Johnson, from 1988-1992 as an improvement from the typical antipsychotic and first approved by the FDA in 1994.[5] Today many generic versions are available. It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[6]

Medical uses[edit]

Risperidone is used for the treatment of schizophrenia, bipolar disorder also including behavior problems in people with autism.[7] A 2010 Cochrane review found a slight benefit during the first few weeks of treatment of schizophrenia but the article raised concerns regarding bias favoring risperidone.[8] In autism it does not improve conversational ability or social skills, and does not appear to reduce obsessive behavior in most people with autism.[7]

Risperidone provides no benefit in the treatment of eating disorders or personality disorders.[9]

While antipsychotic medications such as risperidone have a slight benefit in people with dementia, they have been linked to higher incidences of death and stroke.[9] Because of this increased risk of death, treatment of dementia-related psychosis with risperidone is not FDA approved.[10]

Adverse effects[edit]

Drug interactions[edit]

Discontinuation[edit]

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[12] Due to compensatory changes at dopamine, serotonin, adrenergic and histamine receptor sites in the central nervous system, withdrawal symptoms can occur after cessation or abrupt reduction in dosage. These symptoms include sleeplessness, nausea, emesis, lightheadedness, diaphoresis, dyskinesia, orthostatic hypotension, tachycardia, nervousness, dizziness, headache, excessive crying, and anxiety.[13][14] Some have argued the additional somatic and psychiatric symptoms associated with dopaminergic super-sensitivity, including dyskinesia and acute psychosis, are common features of withdrawal in individuals treated with neuroleptics.[15][16][17][18] This has led some to suggest the withdrawal process might itself be schizomimetic, producing schizophrenia-like symptoms even in previously healthy patients, indicating a possible pharmacological origin of mental illness in a yet unknown percentage of patients currently and previously treated with antipsychotics. This question is unresolved, and remains a highly controversial issue among professionals in the medical and mental health communities, as well the public.[19]

Pharmacology[edit]

Pharmacokinetics

Risperidone is available as an oral tablet, oral dissolving tablet, or intramuscular injection.[7] The intramuscular preparation, marketed as Risperdal Consta, can be given once every two weeks. It is slowly released from the injection site. This method of administration may be used on sanctioned patients who are declining, or consenting patients who may have disorganized thinking and cannot remember to take their daily doses.[20]

Risperidone undergoes hepatic metabolism and renal excretion. Lower doses are recommended for patients with severe liver and kidney disease.[10]

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. It has actions at several 5-HT (serotonin) receptor subtypes. These are 5-HT2C, linked to weight gain, 5-HT2A, linked to its antipsychotic action and relief of some of the extrapyramidal side effects experienced with the typical neuroleptics.[21]

It was recently 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.[22]

Risperidone acts on the following receptors:

Dopamine receptors: This drug is an antagonist of the D1 (D1, and D5) as well as the D2 family (D2, D3 and D4) receptors. This drug has "tight binding" properties, which means it has a long half-life and 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, 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.[21]

Serotonin receptors: Its action at these receptors may be responsible for its lower extrapyramidal side effect liability (via the 5-HT2A/2C receptors) and improved negative symptom control compared to typical antipsychotics such as haloperidol for instance. Its antagonistic actions at the 5-HT2C receptor may account, in part, for its weight gain liability.

Alpha α1 adrenergic receptors: This action accounts for its orthostatic hypotensive effects and perhaps some of the sedating effects of risperidone.[21]

Alpha α2 adrenergic receptors: Perhaps greater positive, negative, affective and cognitive symptom control.[23]

Histamine H1 receptors: effects on these receptors account for its sedation and reduction in vigilance. This may also lead to drowsiness and weight gain.[21]

Though this medication possesses similar effects to other typical and atypical antipsychotics, it does not possess an affinity for the muscarinic acetylcholine receptors. In many respects, this medication can be useful as an "acetylcholine release-promoter" similar to gastrointestinal drugs such as metoclopramide and cisapride.

Society and culture[edit]

Regulatory status[edit]

Risperidone was approved by the United States Food and Drug Administration (FDA) in 1994 for the treatment of schizophrenia.[25] On August 22, 2007, risperidone was approved as the only drug agent available for treatment of schizophrenia in youths, ages 13–17; it was also approved that same day for treatment of bipolar disorder in youths and children, ages 10–17, joining lithium. 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. 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 children and adolescents with autism.[26] 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.[27]

Availability[edit]

Janssen's patent on risperidone expired on December 29, 2003, opening the market for cheaper generic versions from other companies, and Janssen's exclusive marketing rights expired on June 29, 2004 (the result of a pediatric extension).

Risperidone is available as a tablet, an oral solution, and an ampule, Risperdal Consta, which is a depot injection administered once every two weeks. It is also available as a wafer known in the United States and Canada as Risperdal M-Tabs and elsewhere as Risperdal Quicklets. Risperidone is also available as paliperidone IM injections (a risperidone derivative). This injection is given 12 times a year on the same day each month.

Risperidone became available as a generic drug in October 2008 from Teva Pharmaceuticals, Dr. Reddy's Laboratories, Inc. and Patriot Pharmaceutics. The Patriot generic is an authorized generic pharmaceutical. The drug is currently marketed in India under several brand names including Risperdal, Risdon and Sizodon.

Lawsuits[edit]

On 11 April 2012, Johnson & Johnson and its subsidiary, Janssen Pharmaceuticals Inc., were fined $ 1,200,000,000 by an Arkansas judge.[28] The jury found the companies had downplayed multiple risks associated with risperidone (Risperdal). The judge held that nearly 240,000 violations of the state's Medicaid fraud law had been committed. Each violation carried a fine of $5,000. The companies were also fined $11 million for more than 4,500 violations of the state’s deceptive practices laws.

According to an online report from the Wall Street Journal on June 20, 2012, "Johnson & Johnson and the Justice Department are close to settling a protracted investigation into the company’s promotion of the antipsychotic Risperdal, for what would be one of the highest sums to date in a drug-marketing case. The sides are trying to wrap together a number of lawsuits, state investigations and other probes of alleged illegal marketing, and are discussing a payment of $1.5 billion or higher."

In August 2012, Johnson & Johnson agreed to pay $181 million to 36 U.S. states in order to settle claims that it had promoted risperidone for non-approved uses including dementia, anger management, and anxiety.[29]

In 2012, Johnson & Johnson settled a lawsuit claiming that Risperdal caused hundreds of male patients to grow breast tissue. Additionally, Johnson & Johnson face many claims that consumers were misled by both marketing and product packaging of Risperdal.[30]

In 2013, Johnson and Johnson settled out of court for a fine of $2.2 billion in response to allegations that they used illegal marketing techniques to encourage deliberate overmedication of children, elderly and mentally disabled.[31]

References[edit]

1. ^ abcdTruven Health Analytics, Inc. DrugPoint® System (Internet) [cited 2013 Sep 18]. Greenwood Village, CO: Thomsen Healthcare; 2013.
2. ^ abKomossa K, Rummel-Kluge C, Schwarz S, Schmid F, Hunger H, Kissling W, Leucht S (Jan 19, 2011). "Risperidone versus other atypical antipsychotics for schizophrenia.". The Cochrane database of systematic reviews (1): CD006626. PMID 21249678. 
3. ^Hasnain M, Vieweg WV, Hollett B (July 2012). "Weight gain and glucose dysregulation with second-generation antipsychotics and antidepressants: a review for primary care physicians". Postgraduate medicine124 (4): 154–67. doi:10.3810/pgm.2012.07.2577. PMID 22913904. 
4. ^"Risperidone — PubMed Health". Ncbi.nlm.nih.gov. Retrieved 2012-03-23. [dead link]
5. ^Risperdal (risperidone) at naminh.org/resources (web archive)
6. ^"WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
7. ^ abc"Respiridone". The American Society of Health-System Pharmacists. Retrieved 3 April 2011. 
8. ^Rattehalli RD, Jayaram MB, Smith M (2010). "Risperidone versus placebo for schizophrenia". In Rattehalli, Ranganath. Cochrane Database Syst Rev (1): CD006918. doi:10.1002/14651858.CD006918. PMID 20091611. 
9. ^ abMaher AR, Theodore G (June 2012). "Summary of the comparative effectiveness review on off-label use of atypical antipsychotics". J Manag Care Pharm18 (5 Suppl B): S1–20. PMID 22784311. 
10. ^ ab"Risperdal Prescribing Information Label". Drugs@FDA: FDA Approved Drug Products. Jannsen Pharmaceuticals, Inc. Retrieved 17 April 2014. 
11. ^ abhttp://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020272s065,020588s053,021444s041lbl.pdf
12. ^BMJ Group, ed. (March 2009). "4.2.1". British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. p. 192. ISSN 0260-535X. "Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse." 
13. ^Kim DR, Staab JP (May 2005). "Quetiapine discontinuation syndrome". Am J Psychiatry162 (5): 1020. doi:10.1176/appi.ajp.162.5.1020. PMID 15863814. 
14. ^Michaelides C, Thakore-James M, Durso R (Jun 2005). "Reversible withdrawal dyskinesia associated with quetiapine". Mov Disord20 (6): 769–70. doi:10.1002/mds.20427. PMID 15747370. 
15. ^Chouinard G, Jones BD (1980). "Neuroleptic-induced supersensitivity psychosis: clinical and pharmacologic characteristics". Am J Psychiatry137 (1): 16–21. PMID 6101522. 
16. ^Miller R, Chouinard G (Nov 1993). "Loss of striatal cholinergic neurons as a basis for tardive and L-dopa-induced dyskinesias, neuroleptic-induced supersensitivity psychosis and refractory schizophrenia". Biol Psychiatry34 (10): 713–38. doi:10.1016/0006-3223(93)90044-E. PMID 7904833. 
17. ^Chouinard G, Jones BD, Annable L (Nov 1978). "Neuroleptic-induced supersensitivity psychosis". Am J Psychiatry135 (11): 1409–10. PMID 30291. 
18. ^Seeman P, Weinshenker D, Quirion R, Srivastava LK, Bhardwaj SK, Grandy DK, Premont RT, Sotnikova TD, Boksa P, El-Ghundi M, O'dowd BF, George SR, Perreault ML, Männistö PT, Robinson S, Palmiter RD, Tallerico T (Mar 2005). "Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis". Proc Natl Acad Sci U S A102 (9): 3513–8. doi:10.1073/pnas.0409766102. PMC 548961. PMID 15716360. 
19. ^Moncrieff J (Jul 2006). "Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse". Acta Psychiatr Scand114 (1): 3–13. doi:10.1111/j.1600-0447.2006.00787.x. PMID 16774655. 
20. ^Antipsychotic Medications, About.com: Mental Health May 30, 2006
21. ^ abcdBrunton L, Chabner B, Knollman B. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Twelfth Edition. McGraw Hill Professional; 2010.
22. ^Abou El-Magd RM, Park HK, Kawazoe T, Iwana S, Ono K, Chung SP, Miyano M, Yorita K, Sakai T, Fukui K (July 2010). "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 Psychopharmacology24 (7): 1055–1067. doi:10.1177/0269881109102644. PMID 19329549. 
23. ^Hecht EM, Landy DC. Alpha-2 receptor antagonist add-on therapy in the treatment of schizophrenia; a meta-analysis. Schizophrenia Research [Internet]. 2012 Feb [cited 2013 Oct 1];134(2–3):202–6. Available from: http://www.sciencedirect.com/science/article/pii/S0920996411006281
24. ^National Institute ofMental Health. PDSD Ki Database (Internet) [cited 2013 Aug 10]. ChapelHill (NC): University of North Carolina. 1998-2013. Available from: http://pdsp.med.unc.edu/pdsp.php
25. ^"Electronic Orange Book". Food and Drug Administration. April 2007. Retrieved 2007-05-24. 
26. ^"FDA approves the first drug to treat irritability associated with autism, Risperdal" (Press release). FDA. October 6, 2006. Retrieved 2009-08-14. 
27. ^Scahill L (2008). "How do I decide whether or not to use medication for my child with autism? should I try behavior therapy first?". J Autism Dev Disord38 (6): 1197–8. doi:10.1007/s10803-008-0573-7. PMID 18463973. 
28. ^Companies belittled risks of Risperdal, slapped with huge fine
29. ^"NY AG: Janssen pays $181M over drug marketing". The Seattle Times. 30 August 2012. 
30. ^http://allnurses.com/psychiatric-nursing/risperdal-gynecomastia-galactorrhea-74429.html
31. ^[1]

External links[edit]