Risperidone

Risperidone

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.	B3 (AU) C (US)
Legal status	Prescription Only (S4) (AU) POM (UK) ℞-only (US)
Routes	Oral (tablets and liquid form), IM
Pharmacokinetic data
Bioavailability	70% (oral)[1]
Metabolism	Hepatic (CYP2D6-mediated) [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 Y
ATC code	N05AX08
PubChem	CID 5073
IUPHAR ligand	96
DrugBank	DB00734
ChemSpider	4895 Y
UNII	L6UH7ZF8HC Y
KEGG	D00426 Y
ChEBI	CHEBI:8871 Y
ChEMBL	CHEMBL85 Y
Chemical data
Formula	C23H27FN4O2
Mol. mass	410.485 g/mol
SMILES Cc1c(c(=O)n2c(n1)CCCC2)CCN3CCC(CC3)c4c5ccc(cc5on4)F
InChI 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 Y Key:RAPZEAPATHNIPO-UHFFFAOYSA-N Y
Y (what is this?)  (verify)

Risperidone (/rɨˈspɛərɨdoʊn/ ri-SPAIR-i-dohn) (trade name Risperdal, and generics) is an atypical 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 type 2 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 from 1988-1992 as an improvement from the typical antipsychotic, subsidiary of Johnson & Johnson, and first approved by the FDA 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 but the article raised concerns regarding bias favoring risperidone.^[7] In autism, however, it does not improve conversational ability or social skills, and does not appear to reduce obsessive behavior in most autistic people.^[6]

Risperidone provides no benefit in the treatment of 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.^[8]

Adverse effects

Sources:^[1][9][10]

Note: The percentages provided next to these adverse effects is the incidence of them according to DrugPoint.^[1]

Common (≥1%)

• Rash (oral, adults, 1% to 4%; pediatrics, up to 11% ; IM, less than 4%)
• Hyperprolactinaemia (risperidone is probably the most notorious antipsychotic for causing hyperprolactinaemia via its potent blockade of D2 receptors expressed on the lactotrophic cells of the pituitary)^[11] (oral, adults, less than 1%; pediatrics, 49% to 87% ; IM, less than 4%)
• Weight gain (causes less weight gain than clozapine, olanzapine and zotepine, around as much weight gain as quetiapine and more weight gain than amisulpride, aripiprazole, lurasidone, asenapine and ziprasidone)^[11] (oral, adult, 8.7% to 20.9%; pediatric, 14% to 32.6% ; IM, adult, 8% to 10%)
• Constipation (oral, 8% to 21% ; IM, 5% to 7%)
• Diarrhoea (oral, 1% to 8% ; IM, less than 4%)
• Excessive Salivation (oral, 1% to 10% ; IM, 1% to 4%)
• Increased appetite (oral, adult, more than 5%; pediatric, 4% to 47% ; IM, 4%)
• Indigestion (oral, 2% to 10% ; IM, 6%)
• Nausea (oral, 4% to 16% ; IM, 3% to 4%)
• Vomiting (oral, 10% to 25% ; IM, less than 4%)
• Upper abdominal pain (oral, adult, more than 5%; pediatric, 13% to 16%)
• Xerostomia (oral, 4% to 15% ; IM, up to 7%)
• Akathisia (oral, up to 10% ; IM, 4% to 11%)
• Dizziness (oral, 4% to 16% ; IM, 3% to 11%)
• Dyspnoea
• Asthenia
• Agitation
• Urinary incontinence
• Arthralgia
• Myalgia
• Epistaxis
• Somnolence (oral, adult, 3% to 6%; pediatric, 8% to 29% )
• Sleep disturbances
• Dose-dependent extrapyramidal side effects such as dystonia (oral, adult, 3% to 5%; pediatric, 2% to 6% ; IM, adult, less than 4%), tremor (oral, 2% to 12% ; IM, 3% to 24%) and Parkinsonism (oral, 6% to 28% ; IM, 8% to 15%)
• Blurred vision (oral, 1% to 7% ; IM, 2% to 3%)
• Anxiety (oral, up to 16% IM, less than 4%)
• Cough (oral, adults, 2%; pediatrics, 24% ; IM, 2% to 4%)
• Nasal congestion (oral, adult, 4% to 6%; pediatric, 13%)
• Nasopharyngitis (oral, adult, 3% to 4%; pediatric, 21%)
• Pain in the throat (oral, adult, more than 5%; pediatric, 3% to 10%)
• Upper respiratory tract infection (oral, 2% to 8% ; IM, 2% and 6%)
• Fatigue (oral, adult, 1% to 3%; pediatric, 18% to 42% ; IM, 3% to 9%)
• Generalised pains (IM, 1% to 4%)
• Gynecomastia^[12]
• Galactorrhea^[13]

Rare

• Prolonged QT interval
• Sudden cardiac death
• Syncope (oral, up to 1% ; IM, up to 2%)
• Diabetic ketoacidosis
• Hypothermia
• Pancreatitis
• Agranulocytosis
• Neutropenia
• Leukopenia
• Thrombocytopenia
• Thrombotic thrombocytopenic purpura
• Stroke (oral, less than 5% ; IM, less than 4%)
• Seizure (oral, 0.3% ; IM, 0.3%)
• Tardive dyskinesia (oral, less than 5% ; IM, less than 4%)
• Priapism
• Pulmonary Embolism
• Neuroleptic Malignant Syndrome (oral, adults, less than 1%; pediatrics, less than 5%)
• Anorexia
• Hypoaesthesia
• ECG
• Impaired concentration
• Sexual dysfunction
• Angioedema
• Intestinal obstruction
• Oedema
• Hyponatraemia

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.^[14] 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.^[15][16] 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.^{[17][18][19][20]} 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.^[21]

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. It has actions at several 5-HT (serotonin) receptor subtypes. These are 5-HT_2C, linked to weight gain, 5-HT_2A, linked to its antipsychotic action and relief of some of the extrapyramidal side effects experienced with the typical neuroleptics.^[23]

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.

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.^[25]

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 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.^[23]

Serotonin receptors: Its action at these receptors may be responsible for its lower extrapyramidal side effect liability (via the 5-HT_2A/2C receptors) and improved negative symptom control compared to typical antipsychotics such as haloperidol for instance. Its antagonistic actions at the 5-HT_2C 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.^[23]

Alpha α2 adrenergic receptors: Perhaps greater positive, negative, affective and cognitive symptom control.^[26]

Histamine H1 receptors: effects on these receptors account for its sedation and reduction in vigilance. This may also lead to drowsiness and weight gain.^[23]

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

Seized 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.^[27] 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.^[28] 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.^[29]

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.

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.^[30] 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.^[31]

In 2012, Johnson & Johnson settled a lawsuit claiming that Risperdal caused hundreds of male patients to grow breast tissue. Additionally, Johnson & Johnson face many claims that consumers were misled by both marketing and product packaging of Risperdal.^[13]

In 2013, Johnson and Johnson settled out of court for a fine of $2.2 billion in response to allegations that they used illegal marketing techniques to encourage deliberate overmedication of children, elderly and mentally disabled.^[32]

See also

• Paliperidone

References

External links

Wikimedia Commons has media related to Risperidone.

• Janssen L.P. official web site on Risperdal (risperidone)
• PubChem Substance Summary: Risperidone—National Center for Biotechnology Information.
• Drug Information Portal—Risperidone—U.S. National Library of Medicine
• Janssen-Ortho: Product Monograph: Risperdal Tablet (Last updated on June 30, 2008)