Risperidone

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Risperidone
Risperidone2D1.svg
Risperidone3Dan.gif
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
Clinical data
Trade names Risperdal,Risperdal Consta,Risperdal M-Tab,Risperdal Quicklets
AHFS/Drugs.com monograph
MedlinePlus a694015
Pregnancy cat.
Legal status
Routes Oral (tablets and liquid form), IM
Pharmacokinetic data
Bioavailability 70% (oral)[1]
Metabolism Hepatic (CYP2D6 mediated to 9-hydroxyrisperidone)[1]
Half-life 20 hours (Oral), 2.9–6 days (IM) [1]
Excretion Urinary (70% (adults), 4.3% (children), 7.4% (adolescents)), faecal (14%) [1]
Identifiers
CAS number 106266-06-2 YesY
ATC code N05AX08
PubChem CID 5073
IUPHAR ligand 96
DrugBank DB00734
ChemSpider 4895 YesY
UNII L6UH7ZF8HC YesY
KEGG D00426 YesY
ChEBI CHEBI:8871 YesY
ChEMBL CHEMBL85 YesY
Chemical data
Formula C23H27FN4O2 
Mol. mass 410.485 g/mol
 YesY (what is this?)  (verify)

Risperidone (/rɨˈspɛərɨdn/ 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 is a second-generation atypical antipsychotic.[2] It is a dopamine antagonist possessing anti-serotonergic, anti-adrenergic and anti-histaminergic 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 to 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 autistic people.[7]

Schizophrenia[edit]

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[edit]

Second generation antipsychotics, including risperidone, are effective in the treatment of maniac symptoms in acute maniac 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, aripiprazole is effective for the prevention of maniac episodes but not depression.[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[edit]

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[edit]

Risperidone provides 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[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.[30] 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.[31][32][33][34] 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.[35]

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 (detained), who are refusing, or consenting patients who may have disorganized thinking and cannot remember to take their daily doses.[36]

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

Risperidone belongs as a chemical structure to a new antipsychotic medication chemical group called "benzioxazoles".

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.[37]

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.[38]

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.[37]

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.[37]

Alpha α2 adrenergic receptors: Perhaps greater positive, negative, affective and cognitive symptom control.[39]

Histamine H1 receptors: effects on these receptors account for its sedation and reduction in vigilance. This may also lead to drowsiness and weight gain.[37]

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])[40] 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 antagonist[2]
D1 244 Antagonist
D2 3.57 Antagonist
D2S 4.73 Antagonist
D2L 4.16 Antagonist
D3 14.7 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[edit]

Seized Risperdal (risperidone) 4 mg tablets (UK)

Regulatory status[edit]

Risperidone was approved by the United States Food and Drug Administration (FDA) in 1994 for the treatment of schizophrenia.[41] 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.[42] 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.[43]

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 $1.2 billion by Judge Timothy Davis Fox of the Sixth Division of the Sixth Judicial Circuit of the U.S. state of Arkansas.[44] The jury found the companies had downplayed multiple risks associated with risperidone (Risperdal). The verdict was later reversed by the Arkansas State Supreme court.[45]

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.[46]

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.[47]

In 2012, Johnson & Johnson settled a lawsuit claiming that Risperdal caused hundreds of male patients to grow breast tissue.[48]

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External links[edit]