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Risperidone

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Risperidone
Clinical data
Trade namesRisperdal,Risperdal Consta,Risperdal M-Tab,Risperdal Quicklets
AHFS/Drugs.comMonograph
MedlinePlusa694015
Pregnancy
category
  • C
Routes of
administration		Oral (tablets and liquid form), IM
ATC code
Legal status
Legal status
  • US: WARNING[1]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability70% (oral)
MetabolismHepatic (CYP2D6-mediated)
Elimination half-life20 hours
ExcretionUrinary
Identifiers
  • 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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.114.705 Edit this at Wikidata
Chemical and physical data
FormulaC23H27FN4O2
Molar mass410.485 g/mol g·mol−1
3D model (JSmol)
  • 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 checkY
  • Key:RAPZEAPATHNIPO-UHFFFAOYSA-N checkY
  (verify)

Risperidone (/r[invalid input: 'i-']ˈsp[invalid input: 'air'][invalid input: 'i-']d[invalid input: 'oh']n/ ri-SPAIR-i-dohn) (trade name Risperdal, and generics) is a potent antipsychotic drug which is mainly used to treat schizophrenia (including adolescent schizophrenia), schizoaffective disorder, the mixed and manic states associated with bipolar disorder, and irritability in people with autism.

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

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

The drug was developed by Janssen-Cilag, subsidiary of Johnson & Johnson, and first released in 1994.[5] Today many generic versions are available.

Medical uses

Risperidone is used for the treatment of schizophrenia, bipolar disorder and behavior problems in people with autism.[6] A 2010 Cochrane review found a slight benefit during the first few weeks of treatment of schizophrenia however raised concerns regarding bias favoring risperidone.[7] In autism, however, it does not improve conversational ability or social erectile dysfuction skills, and does not appear to reduce obsessive behavior in most autistic people.[6] social erectile dysfuction skills Like other atypical antipsychotics, risperidone has been used to treat anxiety disorders, such as obsessive-compulsive disorder, severe, treatment-resistant depression with or without psychotic features, Tourette syndrome, disruptive behavior disorders in children, and eating disorders, among others.[citation needed] There however is no benefit in eating disorders or personality disorders.[8]

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]

Adverse effects

The severity of adverse effects often depends on the dosage. Risperidone has been associated with weight gain.[10] Other common side effects include akathisia, anxiety, sedation, dysphoria, insomnia, elevated prolactin level, low blood pressure, high blood pressure, muscle stiffness, muscle pain, tremors, hypersalivation, constipation, and stuffy nose.[medical citation needed] In addition, risperidone treatment causes photosensitivity, and patients should be warned to avoid prolonged exposure to the sun or to use effective sunscreen (SPF 15+).[medical citation needed] Other skin conditions have also been reported, including rash, xerosis (dry skin), acne vulgaris, alopecia (hair loss), and seborrhea.[medical citation needed] At high doses, skin hyperpigmentation may also occur.[11]

Many antipsychotics are known to cause hyperprolactinemia, which may lead to hypogonadism-induced osteoporosis, galactorrhoea (unexpected female breast-milk production), gynaecomastia (male breast development), irregular menstruation and sexual dysfunction.[medical citation needed]

Neuroleptic malignant syndrome has been reported with risperidone, with at least two fatal cases reported.[medical citation needed] Tardive dyskinesia, an irreversible movement disorder, has also been reported with risperidone.[12]

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[13] Due to compensatory changes at dopamine, serotonin, adrenergic and histamine receptor sites in the central nervous system, withdrawal symptoms can occur during abrupt or reduction in dosage that is too quick. Support groups provide resources and social support for those attempting to discontinue antipsychotics and other psychiatric medications. Withdrawal symptoms reported to occur after discontinuation of antipsychotics include sleeplessness for several days, nausea, emesis, lightheadedness, diaphoresis, dyskinesia, orthostatic hypotension, tachycardia, nervousness, dizziness, headache, excessive non-stop crying, and anxiety.[14][15] 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.[16][17][18][19] 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.[20]

Pharmacology

Specific receptors of risperidone
  • 5-HT1A serotonin receptors antagonist (Ki = 420nM)[21]
  • 5-HT1D serotonin receptors antagonist (Ki = 100nM)[22]
  • 5-HT2A serotonin receptors antagonist (Ki = 0.16nM)[21]
  • 5-HT2C receptors antagonist (Ki = 26nM)[22]
  • 5-HT7 irreversible antagonist[23]
  • D1 dopaminergic receptors (Ki = 536 nM)[21]
    • D1 receptor antagonist
    • D5 receptor antagonist
  • D2 dopaminergic receptors (Ki = 3.13 nM)
    • D2 receptor antagonist
    • D3 receptor inverse agonist
    • D4 receptor antagonist
  • α1 adrenergic antagonist; all subtypes (Ki = 0.8 nM)
  • α2 adrenergic antagonist; all subtypes (Ki = 7.54 nM)
  • H1 histamine receptor antagonist (Ki = 2.23 nM)

The main action of an antipsychotic (regardless of typical or atypical) is to decrease the action of dopamine and/or epinephrine and norepinephrine levels in the brain.

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 is unique among most other atypicals in that it has high affinity for the D2 receptor (also known as 'tight binding') whereas most other atypicals have 'loose binding' of the D2 receptor. 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. As a result of decreased dopaminergic levels in the brain, risperidone possesses effects similar to those of haloperidol.

It reaches peak plasma levels quickly, regardless of whether it is administered as a liquid or pill. Risperidone is metabolized fairly quickly, so the potential for nausea subsides usually in two to three hours. However, the active metabolite, 9-hydroxy-risperidone, which has similar pharmacodynamics to risperidone, remains in the body for much longer, and has been developed as an antipsychotic in its own right, called paliperidone.

An 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.[24] Doses range from 12.5 to 50 mg given as an intramuscular injection once every two weeks.

Risperidone acts on the following receptors:

Dopamine receptors — The targets of this drug are 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 induce sexual side effects and weight gain, associated with increased prolactin secretion. Side effects may also include depression and anxiety disorders. At considerable higher doses, the drug appears to block the Substantia nigra dopamine pathway; therefore inducing extrapyramidal and Parkinson-like symptoms such as tremors and walking "hunched over". Anticholinergic medications such as Benztropine or Diphenhydramine may be prescribed as an adjunct to counteract the motor side effects.

Serotonin receptors — anxiolytic, sedative and antipsychotic properties. It may also increase appetite, leading to significant weight gain. Improvement of extrapyramidal symptoms and sexual side effects are also seen in patients. Risperidone also possesses antidepressant properties associated with decreased activity of 5HT2A and 5HT7 receptors.[citation needed] Blocked action of the 5-HT2A relieves hallucinations, psychosis and delusional disorder, while the other receptors are associated with considerable weight gain and possible decrease in body temperature. Risperidone does not bind to 5-HT3 receptors despite its high affinities with Serotonin neurons.

Alpha α1 adrenergic receptors — Its diminished action of epinephrine and norepinephrine accounts for its sedation, anxiolytic effects, and smooth muscle relaxation. Vasodilation and decrease in blood pressure also take effect.

Alpha α2 adrenergic receptors — decreased extrapyramidal symptoms; increased sympathetic tone is associated with the blocked action of the adrenergic α2 receptors. Also, it possesses antidepressant properties.[citation needed]

Histamine H1 receptors — effects on these receptors account for its sedation and reduction in vigilance. This may also lead to drowsiness and weight gain. Sexual side effects may also arise.

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

Regulatory status

Risperidone was approved by the United States Food and Drug Administration (FDA) in 1993 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

Risperdal (risperidone) 4 mg tablets (UK)

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 Janssen Pharmaceutical's "authorized generic pharmaceutical". The drug is currently marketed in India under several brand names including Risperdal, Risdon and Sizodon.

Lawsuits

On 11 April 2012, Johnson & Johnson and its subsidiary, Janssen Pharmaceuticals Inc., were fined about $1.2 billion 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]

Brand names

It is sold under the trade name Risperdal in the Netherlands, United States, Canada, Australia, United Kingdom, Portugal, Spain, Israel, Turkey, New Zealand, Saudi Arabia, Venezuela, Ireland and several other countries, Risperdal or Ridal in New Zealand and Venezuela, Sizodon, Riscalin, Risdone, Riswel in India, Rispolept in Eastern Europe and Russia, Zepidone in Nigeria, Riperidone in South Korea, Rozidal in Malaysia, Risperidona in Spain, Apexidone in Egypt, Rissar in Macedonia and Serbia, Torendo Q in Slovenia, Russian federation and Serbia, Belivon or Rispen elsewhere.

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 21249678, please use {{cite journal}} with |pmid=21249678 instead.
  3. ^ Hasnain, M (2012 Jul). "Weight gain and glucose dysregulation with second-generation antipsychotics and antidepressants: a review for primary care physicians". Postgraduate medicine. 124 (4): 154–67. PMID 22913904. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  4. ^ USA. "Risperidone — PubMed Health". Ncbi.nlm.nih.gov. Retrieved 2012-03-23.
  5. ^ Risperdal (risperidone) at naminh.org/resources (web archive)
  6. ^ a b "Respiridone". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
  7. ^ Rattehalli RD, Jayaram MB, Smith M (2010). "Risperidone versus placebo for schizophrenia". Cochrane Database Syst Rev (1): CD006918. doi:10.1002/14651858.CD006918. PMID 20091611.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Maher AR, Theodore G (2012). "Summary of the comparative effectiveness review on off-label use of atypical antipsychotics". J Manag Care Pharm. 18 (5 Suppl B): S1–20. PMID 22784311. {{cite journal}}: Unknown parameter |month= ignored (help)
  9. ^ Maher AR, Theodore G (2012). "Summary of the comparative effectiveness review on off-label use of atypical antipsychotics". J Manag Care Pharm. 18 (5 Suppl B): S1–20. PMID 22784311. {{cite journal}}: Unknown parameter |month= ignored (help)
  10. ^ Newcomer JW (2005). "Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review". CNS Drugs. 19 (Suppl 1): 1–93. PMID 15998156.
  11. ^ Risperdal (risperidone) package insert. Titusville, NJ: Janssen Pharmaceutica Products, L.P.; 2010 Aug.
  12. ^ Hong KS, Cheong SS, Woo JM, Kim E (1999). "Risperidone-induced tardive dyskinesia". Am J Psychiatry. 156 (8): 1290. PMID 10450277. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ BMJ Group, ed. (2009). "4.2.1". British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. p. 192. ISBN 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. {{cite book}}: Check |isbn= value: length (help); Unknown parameter |month= ignored (help)
  14. ^ Kim, DR.; Staab, JP. (2005). "Quetiapine discontinuation syndrome". Am J Psychiatry. 162 (5): 1020. doi:10.1176/appi.ajp.162.5.1020. PMID 15863814. {{cite journal}}: Unknown parameter |month= ignored (help)
  15. ^ Michaelides, C.; Thakore-James, M.; Durso, R. (2005). "Reversible withdrawal dyskinesia associated with quetiapine". Mov Disord. 20 (6): 769–70. doi:10.1002/mds.20427. PMID 15747370. {{cite journal}}: Unknown parameter |month= ignored (help)
  16. ^ Chouinard, G.; Jones, BD. (1980). "Neuroleptic-induced supersensitivity psychosis: clinical and pharmacologic characteristics". Am J Psychiatry. 137 (1): 16–21. PMID 6101522. {{cite journal}}: Unknown parameter |month= ignored (help)
  17. ^ Miller, R.; Chouinard, G. (1993). "Loss of striatal cholinergic neurons as a basis for tardive and L-dopa-induced dyskinesias, neuroleptic-induced supersensitivity psychosis and refractory schizophrenia". Biol Psychiatry. 34 (10): 713–38. doi:10.1016/0006-3223(93)90044-E. PMID 7904833. {{cite journal}}: Unknown parameter |month= ignored (help)
  18. ^ Chouinard, G.; Jones, BD.; Annable, L. (1978). "Neuroleptic-induced supersensitivity psychosis". Am J Psychiatry. 135 (11): 1409–10. PMID 30291. {{cite journal}}: Unknown parameter |month= ignored (help)
  19. ^ Seeman, P.; Weinshenker, D.; Quiron, R.; Srivastava, LK.; Bhardwaj, SK.; Grandy, DK.; Premont, RT.; Sotnikova, TD.; Boksa, P. (2005). "Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis". Proc Natl Acad Sci U S A. 102 (9): 3513–8. doi:10.1073/pnas.0409766102. PMC 548961. PMID 15716360. {{cite journal}}: Unknown parameter |month= ignored (help)
  20. ^ Moncrieff, J. (2006). "Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse". Acta Psychiatr Scand. 114 (1): 3–13. doi:10.1111/j.1600-0447.2006.00787.x. PMID 16774655. {{cite journal}}: Unknown parameter |month= ignored (help)
  21. ^ a b c Alan F. Schatzberg, Charles B. Nemeroff. "The American Psychiatric Publishing textbook of psychopharmacology". American Psychiatric Pub, 2009, p. 629.
  22. ^ a b Atypicality of Atypical Antipsychotics
  23. ^ Smith C, Rahman T, Toohey N, Mazurkiewicz J, Herrick-Davis K, Teitler M (2006). "Risperidone irreversibly binds to and inactivates the h5-HT7 serotonin receptor". Mol. Pharmacol. 70 (4): 1264–70. doi:10.1124/mol.106.024612. PMID 16870886. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  24. ^ Antipsychotic Medications, About.com: Mental Health May 30, 2006
  25. ^ "Electronic Orange Book". Food and Drug Administration. 2007. Retrieved 2007-05-24. {{cite web}}: Unknown parameter |month= ignored (help)
  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 Disord. 38 (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.
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