Risperidone

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Risperidone
Risperidone.svg
Risperidone-3D-balls.png
Systematic (IUPAC) name
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
Clinical data
Trade names Risperdal, other
AHFS/Drugs.com monograph
MedlinePlus a694015
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Routes of
administration		 Oral (tablets and liquid form), IM
Pharmacokinetic data
Bioavailability 70% (oral)[1]
Metabolism Liver (CYP2D6 mediated to 9-hydroxyrisperidone)[1]
Biological half-life 20 hours (Oral), 3–6 days (IM)[1]
Excretion Urinary (70%) feces (14%)[1]
Identifiers
CAS Number 106266-06-2 YesY
ATC code N05AX08 (WHO)
PubChem CID: 5073
IUPHAR/BPS 96
DrugBank DB00734 YesY
ChemSpider 4895 YesY
UNII L6UH7ZF8HC YesY
KEGG D00426 YesY
ChEBI CHEBI:8871 YesY
ChEMBL CHEMBL85 YesY
Chemical data
Formula C23H27FN4O2
Molecular mass 410.485 g/mol
  • Cc1c(c(=O)n2c(n1)CCCC2)CCN3CCC(CC3)c4c5ccc(cc5on4)F
  • InChI=1S/C23H27FN4O2/c1-15-18(23(29)28-10-3-2-4-21(28)25-15)9-13-27-11-7-16(8-12-27)22-19-6-5-17(24)14-20(19)30-26-22/h5-6,14,16H,2-4,7-13H2,1H3 YesY
  • Key:RAPZEAPATHNIPO-UHFFFAOYSA-N YesY
  (verify)

Risperidone, sold under the trade name Risperdal among others, is an antipsychotic medication.[1] It is mainly used to treat schizophrenia, bipolar disorder, and irritability in people with autism. It is taken either by mouth or by injection into a muscle.[1] The injectable version is long acting and lasts for about two weeks.[2]

Common side effects include movement problems, sleepiness, trouble seeing, constipation, and increased weight.[1][3] 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.[1][2] In older people with psychosis as a result of dementia it may increase the risk of dying. It is unclear if it is safe for use in pregnancy. Risperidone is an atypical antipsychotic. Its mechanism of action is not entirely clear but believed to be related to its ability as a dopamine antagonist.[1]

Study of risperidone began in the late 1980s and it was approved for sale in the United States in 1993.[1][4] It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[5] It is available as a generic medication.[2] The wholesale price is between 0.01 and 0.60 USD per day as of 2014.[6] In the United States it costs between 3.30 and 10.00 USD per day for a typical dose.[1]

Medical uses

Risperidone is used for the treatment of schizophrenia, bipolar disorder also including behavior problems in autistic people.[7]

Schizophrenia

Risperidone is effective in treating the acute exacerbations of schizophrenia.[8][9]

Studies evaluating the utility of the oral form of risperidone for maintenance therapy have reached varying conclusions. A 2012 systematic review concluded that there is strong evidence that risperidone is more effective than all first generation antipsychotics other than haloperidol, but that evidence directly supporting its superiority to placebo is equivocal.[10] 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.[11] 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.[12]

Long-acting injectable formulations of antipsychotic drugs provide improved compliance with therapy and reduce relapse rates relative to oral formulations.[13][14] The efficacy of risperidone long acting injection appears to be similar to that of long acting injectable forms of first generation antipsychotics.[15]

Bipolar disorder

Second generation antipsychotics, including risperidone, are effective in the treatment of manic symptoms in acute manic or mixed exacerbations of bipolar disorder.[16][17][18] In children and adolescents, risperidone may be more effective than lithium or divalproex, but has more metabolic side effects.[19] As maintenance therapy, risperidone is effective for the prevention of manic episodes but not depressive episodes.[20] 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.[21]

Autism

Compared to placebo, risperidone treatment reduces certain problematic behaviors in autistic children, including aggression toward others, self-injury, temper tantrums, and rapid mood changes. The evidence for its efficacy appears to be greater than that for alternative pharmacological treatments.[22] Weight gain is an important adverse effect.[23][24] Some authors recommend limiting the use of aripiprazole to those with the most challenging behavioral disturbances in order to minimize the risk of drug-induced adverse effects.[25] Evidence for the efficacy of risperidone in autistic adolescents and young adults is less persuasive.[26]

Other uses

Risperidone has no benefit in the treatment of eating disorders or personality disorders.[27]

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.[27] Because of this increased risk of death, treatment of dementia-related psychosis with risperidone is not FDA approved.[28]

Adverse effects

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See also: List of adverse effects of risperidone

Drug interactions

  • Carbamazepine and other enzyme inducers may reduce plasma levels of risperidone.[29] 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.[30]
  • CYP2D6 inhibitors, such as SSRI medications, may increase plasma levels of risperidone.[29]
  • Since risperidone can cause hypotension, its use should be monitored closely when a patient is also taking anti-hypertensive medicines to avoid severe low blood pressure.[30]

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[31] 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.[32][33][34][35] 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.[36]

Dementia

Older people with dementia-related psychosis are at a higher risk of death if they take risperidone compared to those who do not. Most deaths are related to heart problems or infections.[30]

Pharmacology

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 (detained), who are refusing, or consenting patients who may have disorganized thinking and cannot remember to take their daily doses.[37]

Risperidone undergoes hepatic metabolism and renal excretion. Lower doses are recommended for patients with severe liver and kidney disease.[28]

Risperidone pharmacodynamics excluding D-amino acid oxidase inhibitation

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.[38]

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.[39]

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.[38]

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.[38]

Alpha α2 adrenergic receptors: Perhaps greater positive, negative, affective and cognitive symptom control.[40]

Histamine H1 receptors: effects on these receptors account for its sedation and reduction in vigilance. This may also lead to drowsiness and weight gain.[38]

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.

Receptor Binding Affinity (Ki [nM])[41] Action
5-HT1A 423 Antagonist
5-HT1B 14.9 Antagonist
5-HT1D 84.6 Antagonist
5-HT2A 0.17 Inverse agonist
5-HT2B 61.9 Inverse agonist
5-HT2C 12.0 Inverse agonist
5-HT5A 206 Antagonist
5-HT6 2,060 Antagonist
5-HT7 6.60 Irreversible (or pseudo-irreversible) antagonist[42]
D1 244 Antagonist
D2 3.57 Antagonist
D2S 4.73 Antagonist
D2L 4.16 Antagonist
D3 3.6 Inverse agonist
D4 4.66 Antagonist
D5 290 Antagonist
α1A 5.0 Antagonist
α1B 9.0 Antagonist
α2A 16.5 Antagonist
α2B 108 Antagonist
α2C 1.30 Antagonist
mAChRs >10,000 Negligible
H1 20.1 Inverse agonist
H2 120 Inverse agonist

Society and culture

Risperdal (risperidone) 4 mg tablets (UK)

Regulatory status

Risperidone was approved by the United States Food and Drug Administration (FDA) in 1994 for the treatment of schizophrenia.[43] 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 autistic children and adolescents.[44] 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.[45]

Availability

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 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.

The active metabolite of risperidone, paliperidone, is also used as an antipsychotic.

Lawsuits

On 11 April 2012, Johnson & Johnson and its subsidiary Janssen Pharmaceuticals Inc. were fined $1.2 billion by Judge Timothy Davis Fox of the Sixth Division of the Sixth Judicial Circuit of the U.S. state of Arkansas.[46] The jury found the companies had downplayed multiple risks associated with risperidone (Risperdal). The verdict was later reversed by the Arkansas State Supreme court.[47]

According to the Wall Street Journal on June 20, 2012, "Johnson & Johnson and the U.S. Justice Department [we]re 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." The fine ultimately imposed totaled $2.2 billion.[48]

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 off-label uses including for dementia, anger management, and anxiety.[49]

Names

Brand names include Risperdal, Risperdal Consta, Risperdal M-Tab, Risperdal Quicklets.

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ 2.0 2.1 2.2 Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ 7.0 7.1 Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  18. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  19. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  20. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  21. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  22. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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  25. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  26. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  27. ↑ 27.0 27.1 Lua error in package.lua at line 80: module 'strict' not found.
  28. ↑ 28.0 28.1 Lua error in package.lua at line 80: module 'strict' not found.
  29. ↑ 29.0 29.1 http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020272s065,020588s053,021444s041lbl.pdf
  30. ↑ 30.0 30.1 30.2 Risperdal [Package Insert]. Titusville, NJ: Janssen Pharmaceuticals; April 2014. http://www.janssenpharmaceuticalsinc.com/assets/risperdal.pdf Accessed November 2, 2014
  31. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  32. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  33. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  34. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  35. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  36. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  37. ↑ Antipsychotic Medications, About.com: Mental Health May 30, 2006
  38. ↑ 38.0 38.1 38.2 38.3 Brunton L, Chabner B, Knollman B. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Twelfth Edition. McGraw Hill Professional; 2010.
  39. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  40. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  41. ↑ 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
  42. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  43. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  44. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  45. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  46. ↑ "Companies belittled risks of Risperdal, slapped with huge fine", Los Angeles Times, 11 April 2012.
  47. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  48. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  49. ↑ Lua error in package.lua at line 80: module 'strict' not found.

External links

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