Risperidone
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| Systematic (IUPAC) name | |
| 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 |
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| Clinical data | |
| Trade names | Risperdal |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a694015 |
| Pregnancy cat. | C |
| Legal status | ℞ Prescription only |
| Routes | Oral (tablets and liquid form), IM |
| Pharmacokinetic data | |
| Bioavailability | 70% (oral) |
| Metabolism | Hepatic (CYP2D6-mediated) |
| Half-life | 20 hours |
| Excretion | Urinary |
| Identifiers | |
| CAS number | 106266-06-2  |
| ATC code | N05AX08 |
| PubChem | CID 5073 |
| IUPHAR ligand | 96 |
| DrugBank | DB00734 |
| ChemSpider | 4895 |
| UNII | L6UH7ZF8HC |
| KEGG | D00426 |
| ChEBI | CHEBI:8871 |
| ChEMBL | CHEMBL85 |
| Chemical data | |
| Formula | C23H27FN4O2 |
| Mol. mass | 410.485 g/mol |
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Risperidone (/rɨˈspɛərɨdoʊn/ 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.[1] It is a dopamine antagonist possessing antiserotonergic, antiadrenergic and antihistaminergic properties.
Side effects of risperidone include significant weight gain and metabolic problems, as well as tardive dyskinesia and neuroleptic malignant syndrome. Risperidone and other antipsychotics also increase the risk of death in patients with dementia.[2]
The drug was developed by Janssen-Cilag, subsidiary of Johnson & Johnson, and first released in 1994.[3] Today many generic versions are available.
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[edit] Medical uses
Risperidone is used for the treatment of schizophrenia, bipolar disorder and behavior problems in people with autism.[4] In autism, however, it does not improve conversational ability or social skills, and does not appear to reduce obsessive behavior in most autistic people.[4]
Due to its strong serotonin, dopaminergic, and adrenergic antagonism, risperidone was approved by the United States Food and Drug Administration (FDA) in 1993 for the treatment of schizophrenia.[5] 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.[6] 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.[7] Like other atypical antipsychotics, risperidone has also been used off-label for the treatment of 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. In two small studies, risperidone was reported to successfully treat the symptoms of phencyclidine psychosis due to acute intoxication[8] and chronic use.[9]
[edit] 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 is also available as paliperidone IM injections (a risperidone derivative). This injection is given 12 times a year on the same day each month, and is longer-lasting and has better adherence in the community than Consta.
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.
[edit] Adverse effects
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This section needs additional citations for verification. (February 2013) |
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] Irritability, aggression, sleep disorders and eating disorders are also common due to the blocking action of serotonin and dopamine that risperidone produces.[medical citation needed] Also heart arrythmia, bradycardia and heart palpitations often occur.[medical citation needed]
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]
[edit] Patients with dementia
Clinical tests conducted in Canada[13] and the United Kingdom[14] have indicated the use of antipsychotic medications such as risperidone in people with dementia, such as those suffering from Alzheimer's disease, have been linked to higher incidences of death. In addition to a higher rate of death, patients with dementia taking antipsychotics are susceptible to serious side effects, including stroke.[15]
[edit] Discontinuation
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[16] 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.[17][18] 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.[19][20][21][22] 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.[23]
[edit] Pharmacology
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.
- 5-HT1A serotonin receptors antagonist (Ki = 420nM)[24]
- 5-HT1D serotonin receptors antagonist (Ki = 100nM)[25]
- 5-HT2A serotonin receptors antagonist (Ki = 0.16nM)[24]
- 5-HT2C receptors antagonist (Ki = 26nM)[25]
- 5-HT7 irreversible antagonist[26]
- D1 dopaminergic receptors (Ki = 536 nM)[24]
- D2 dopaminergic receptors (Ki = 3.13 nM)
- 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)
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.[27] Doses range from 12.5 to 50 mg given as an intramuscular injection once every two weeks.
[edit] Pharmacodynamics
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. Because of the risk of developing pre-existing Parkinson's disease as a result of decreased dopaminergic levels in the brain, risperidone possesses effects similar to those of haloperidol. It is a highly potent dopaminergic antagonist for the treatment of schizophrenia and bipolar disorder. However, the risk of extrapyramidal symptoms are decreased only slightly because of the antagonism of the serotonin and α2 adrenergic receptors. 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 and the limbic pathways 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"
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 possesses also antidepressant properties associated with decreased activity of 5HT2A and 5HT7 receptors.[citation needed]
Alpha α1 adrenergic receptors — Its diminished action of epinephrine and norepinephrine accounts for its sedation, anxiolytic effects, and smooth muscle relaxation.
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.
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.
[edit] Controversy, lawsuits and settlements
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]
[edit] 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.
[edit] References
- ^ Komossa, K.; Rummel-Kluge, C.; Schwarz, S.; Schmid, F.; Hunger, H.; Kissling, W.; Leucht, S. (2011). Risperidone versus other atypical antipsychotics for schizophrenia. In Komossa, Katja. "Cochrane Database of Systematic Reviews". Cochrane database of systematic reviews (Online) (1): CD006626. doi:10.1002/14651858.CD006626.pub2. PMID 21249678.
- ^ USA. "Risperidone — PubMed Health". Ncbi.nlm.nih.gov. Retrieved 2012-03-23.
- ^ Risperdal (risperidone) at naminh.org/resources (web archive)
- ^ a b "Respiridone". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
- ^ "Electronic Orange Book". Food and Drug Administration. April 2007. Retrieved 2007-05-24.
- ^ "FDA approves the first drug to treat irritability associated with autism, Risperdal" (Press release). FDA. October 6, 2006. Retrieved 2009-08-14.
- ^ 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.
- ^ AJ Giannini, GL Colapietro, DK Cook (1996). "Risperidone therapy in phencyclidine intoxication". Society for Neuroscience Abstracts 22 (77.12).
- ^ Gabbert JF, Giannini AJ (April 1997). "Clinical Therapeutic Conference: dopaminergic/serotonergic actions of phencyclidine as a model for schizophreniform psychosis". Am J Ther 4 (4): 159–63. doi:10.1097/00045391-199704000-00008. PMID 10423606.
- ^ Newcomer JW (2005). "Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review". CNS Drugs 19 (Suppl 1): 1–93. PMID 15998156.
- ^ Risperdal (risperidone) package insert. Titusville, NJ: Janssen Pharmaceutica Products, L.P.; 2010 Aug.
- ^ Hong KS, Cheong SS, Woo JM, Kim E (August 1999). "Risperidone-induced tardive dyskinesia". Am J Psychiatry 156 (8): 1290. PMID 10450277.
- ^ Gardner, Amanda (May 27, 2008). "Antipsychotics Dangerous for Elderly With Dementia". Washington Post. Retrieved 14 July 2011.
- ^ "Avoid antipsychotic drugs for elderly, experts urge, after death risk study". CBC News. January 9, 2009. Retrieved 14 July 2011.
- ^ "Statement Regarding Treatment of Behavioral and Psychiatric Symptoms of Alzheimer’s Disease". Alzheimer's Association.
- ^ BMJ Group, ed. (March 2009). "4.2.1". British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. p. 192. ISBN 0260-535X Check
|isbn=value (help). "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." - ^ Kim, DR.; Staab, JP. (May 2005). "Quetiapine discontinuation syndrome". Am J Psychiatry 162 (5): 1020. doi:10.1176/appi.ajp.162.5.1020. PMID 15863814.
- ^ Michaelides, C.; Thakore-James, M.; Durso, R. (Jun 2005). "Reversible withdrawal dyskinesia associated with quetiapine". Mov Disord 20 (6): 769–70. doi:10.1002/mds.20427. PMID 15747370.
- ^ Chouinard, G.; Jones, BD. (Jan 1980). "Neuroleptic-induced supersensitivity psychosis: clinical and pharmacologic characteristics". Am J Psychiatry 137 (1): 16–21. PMID 6101522.
- ^ 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 Psychiatry 34 (10): 713–38. doi:10.1016/0006-3223(93)90044-E. PMID 7904833.
- ^ Chouinard, G.; Jones, BD.; Annable, L. (NoFv 1978). "Neuroleptic-induced supersensitivity psychosis". Am J Psychiatry 135 (11): 1409–10. PMID 30291.
- ^ Seeman, P.; Weinshenker, D.; Quiron, R.; Srivastava, LK.; Bhardwaj, SK.; Grandy, DK.; Premont, RT.; Sotnikova, TD. et al. (Mar 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.
- ^ 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 Scand 114 (1): 3–13. doi:10.1111/j.1600-0447.2006.00787.x. PMID 16774655.
- ^ a b c Alan F. Schatzberg, Charles B. Nemeroff. "The American Psychiatric Publishing textbook of psychopharmacology". American Psychiatric Pub, 2009, p. 629.
- ^ a b Atypicality of Atypical Antipsychotics
- ^ Smith C, Rahman T, Toohey N, Mazurkiewicz J, Herrick-Davis K, Teitler M (October 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.
- ^ Antipsychotic Medications, About.com: Mental Health May 30, 2006
- ^ Companies belittled risks of Risperdal, slapped with huge fine
- ^ "NY AG: Janssen pays $181M over drug marketing". The Seattle Times. 30 August 2012.
[edit] External links
- Drugs.com Professional information on risperidone
- Drugs.com Consumer information on risperidone
- Janssen L.P. official web site on Risperdal (risperidone)
- PubChem Substance Summary: Risperidone National Center for Biotechnology Information.
- U.S. National Library of Medicine: Drug Information Portal — Risperidone
- Janssen-Ortho: Product Monograph: Risperdal Tablet (Last updated on June 30, 2008)
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