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Risperidone

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Risperidone
Clinical data
Trade namesRisperdal, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa694015
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth (tablets and liquid form), IM
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: WARNING[2]Rx-only
Pharmacokinetic data
Bioavailability70% (oral)[3]
MetabolismLiver (CYP2D6 mediated to 9-hydroxyrisperidone)[3]
Elimination half-life20 hours (Oral), 3–6 days (IM)[3]
ExcretionUrinary (70%) feces (14%)[3]
Identifiers
  • 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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
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, sold under the trade name Risperdal among others, is an antipsychotic medication.[3] It is mainly used to treat schizophrenia, bipolar disorder, and irritability in autistic people.[3] It is taken either by mouth or by injection into a muscle.[3] The injectable version is long acting and lasts for about two weeks.[4]

Common side effects include movement problems, sleepiness, trouble seeing, constipation, and increased weight.[3][5] 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.[3][4] In older people with psychosis as a result of dementia, it may increase the risk of dying.[3] It is unclear if it is safe for use in pregnancy.[3] Risperidone is an atypical antipsychotic.[3] Its mechanism of action is not entirely clear, but is believed to be related to its action as a dopamine antagonist and serotonin antagonist.[3]

Study of risperidone began in the late 1980s and it was approved for sale in the United States in 1993.[3][6] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[7] It is available as a generic medication.[4] The wholesale price in the developing world is between 0.01 and 0.60 USD per day as of 2014.[8] The cost for a typical month of medication in the United States is between 100 and 200 USD as of 2015.[4]

Medical uses

Risperidone is mainly used for the treatment of schizophrenia, bipolar disorder, and irritability associated with autism.[9]

Schizophrenia

Risperidone is effective in treating the acute exacerbations of schizophrenia.[10][11] A 2013 study compared 15 antipsychotic drugs in treating schizophrenia. Risperidone was ranked fourth, 11% more effective than paliperidone (5th), 20-23% more effective than haloperidol, quetiapine, and aripiprazole, and 36% less effective than clozapine (1st).[12]

Studies evaluating the utility of risperidone by mouth 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.[13] 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.[14] A 2016 Cochrane review suggests that risperidone reduces the overall symptoms of schizophrenia, but firm conclusions are difficult to make due to very low quality evidence. Data and information are scarce, poorly reported and probably biased in favour of risperidone, with about half of the included trials developed by drug companies. The article raises concerns regarding the serious side effects of risperidone, such as parkinsonism.[15] A 2011 Cochrane review compared risperidone with other atypical antipsychotics such as olanzapine for schizophrenia:[16]

Summary
Risperidone seems to produce somewhat more extrapyramidal side effects and clearly more prolactin increase than most other atypical antipsychotics. It may also differ from other compounds in the occurrence of other adverse effects such as weight gain, metabolic problems, cardiac effects, sedation and seizures. Nevertheless, the large proportion of participants leaving studies early and incomplete reporting of outcomes makes it difficult to draw firm conclusions.[16]

Long-acting injectable formulations of antipsychotic drugs provide improved compliance with therapy and reduce relapse rates relative to oral formulations.[17][18] The efficacy of risperidone long acting injection appears to be similar to that of long acting injectable forms of first generation antipsychotics.[19]

Bipolar disorder

Second generation antipsychotics, including risperidone, are effective in the treatment of manic symptoms in acute manic or mixed exacerbations of bipolar disorder.[20][21][22] In children and adolescents, risperidone may be more effective than lithium or divalproex, but has more metabolic side effects.[23] As maintenance therapy, long-acting injectable risperidone is effective for the prevention of manic episodes but not depressive episodes.[24] 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.[25]

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.[26] Weight gain is an important adverse effect.[27][28] Some authors recommend limiting the use of risperidone and aripiprazole to those with the most challenging behavioral disturbances in order to minimize the risk of drug-induced adverse effects.[29] Evidence for the efficacy of risperidone in autistic adolescents and young adults is less persuasive.[30]

Other uses

Risperidone has shown promise in treating therapy resistant obsessive–compulsive disorder, when serotonin reuptake inhibitors are not sufficient.[31]

Risperidone has not demonstrated a benefit in the treatment of eating disorders or personality disorders.[32]

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.[32] Because of this increased risk of death, treatment of dementia-related psychosis with risperidone is not FDA approved.[33]

Adverse effects

See also: List of adverse effects of risperidone

Drug interactions

  • Carbamazepine and other enzyme inducers may reduce plasma levels of risperidone.[34] 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.[35]
  • CYP2D6 inhibitors, such as SSRI medications, may increase plasma levels of risperidone.[34]
  • 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.[35]

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[36] 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.[37][38][39][40] 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.[41]

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.[35]

Pharmacology

Pharmacodynamics

See also: Atypical antipsychotic § Pharmacodynamics, and Antipsychotic § Comparison of medications
Risperidone[42]
Site Ki (nM) 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[43]
α1A 5.0 Antagonist
α1B 9.0 Antagonist
α2A 16.5 Antagonist
α2B 108 Antagonist
α2C 1.30 Antagonist
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
H1 20.1 Inverse agonist
H2 120 Inverse agonist
mAChTooltip Muscarinic acetylcholine receptor >10,000 Negligible
Risperidone pharmacodynamics excluding D-amino acid oxidase inhibition

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 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. 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.[44]

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.[45]

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, with 70-fold selectivity for the D2 family. 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.[44]

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.[44]

Alpha α2 adrenergic receptors: Perhaps greater positive, negative, affective and cognitive symptom control.[46]

Histamine H1 receptors: effects on these receptors account for its sedation and reduction in vigilance. This may also lead to drowsiness and weight gain.[44]

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.

Pharmacokinetics

Risperidone undergoes hepatic metabolism and renal excretion. Lower doses are recommended for patients with severe liver and kidney disease.[33] The active metabolite of risperidone, paliperidone, is also used as an antipsychotic.[47]

Society and culture

Risperdal (risperidone) 4 mg tablets (UK)

Regulatory status

Risperidone was approved by the United States Food and Drug Administration (FDA) in 1993 for the treatment of schizophrenia.[48] 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.[49] 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. 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.[50]

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). It is available under many brand names worldwide.[1]

Risperidone is available as a tablet, an oral solution, and an ampule, which is a depot injection.[1]

Lawsuits

On 11 April 2012, Johnson & Johnson (J&J) 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.[51] The jury found the companies had downplayed multiple risks associated with risperidone (Risperdal). The verdict was later reversed by the Arkansas State Supreme court.[52]

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 and paliperidone for off-label uses including for dementia, anger management, and anxiety.[53]

In November 2013, J&J was fined $2.2 billion for illegally marketing risperidone for use in people with dementia.[54]

J&J has faced numerous civil lawsuits on behalf of children who were prescribed risperidone who grew breasts (a condition called gynecomastia); as of July 2016 there were about 1,500 cases in Pennsylvania state court in Philadelphia, and there had been a February 2015 verdict against J&J with $2.5 million awarded to a man from Alabama, a $1.75M verdict against J&J that November, and in 2016 a $70 million verdict against J&J.[55]

In 2015, Steven Brill posted a 15-part investigative journalism piece on J&J in Huffington Post, called "America's most admired lawbreaker", which was focused on J&J's marketing of risperidone.[56][57]

Names

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

References

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