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
AHFS/Drugs.com	monograph
MedlinePlus	a694015
Pregnancy cat.	C
Legal status	℞ Prescription only
Routes	Oral and extended-release intramuscular injection
Pharmacokinetic data
Bioavailability	70% (oral)
Metabolism	Hepatic (CYP2D6-mediated)
Half-life	3–20 hours
Excretion	Urinary
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	eMolecules & PubChem
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) (Risperdal, and generics) is a second-generation^[1] or atypical antipsychotic. It is used to treat schizophrenia (including adolescent schizophrenia), schizoaffective disorder, the mixed and manic states associated with bipolar disorder, and irritability in people with autism. It is associated with 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 and first released in 1994.^[3]

Medical uses[link]

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. 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]

Availability[link]

Risperdal (risperidone) 4 mg tablets (UK)

Janssen's patent on Risperdal 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 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.

Adverse effects[link]

The severity of adverse effects often depends on the dosage. Risperidone has been associated with weight gain.^[10] Other common side effects include akathisia, sedation, dysphoria, insomnia, elevated prolactin level, low blood pressure, high blood pressure, muscle stiffness, muscle pain, tremors, hypersalivation, constipation, and stuffy nose. 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+). Other skin conditions have also been reported, including rash, xerosis (dry skin), acne vulgaris, alopecia (hair loss), and seborrhea. 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. Also heart arrythmia, bradycardia and heart palpitations often occur.

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.

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

Patients with dementia[link]

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]

Discontinuation[link]

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 over-rapid reduction in dosage. However, despite increasing demand for safe and effective antipsychotic withdrawal protocols or dose-reduction schedules, no specific guidelines with proven safety and efficacy are currently available. Some have suggested using the Ashton Manual [2], originally developed for benzodiazapine withdrawal. Support groups such as The Icarus Project [3], and other online forums 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 nausea, emesis, lightheadedness, diaphoresis, dyskinesia, orthostasis, 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] Complicated and long-lasting rebound insomnia symptoms can also occur after withdrawing from antipsychotics.^{[citation needed]}

Pharmacology[link]

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-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.

• 5-HT_1A serotonin receptors antagonist (Ki = 420nM)^[24]
• 5-HT_1D serotonin receptors antagonist (Ki = 100nM)^[25]
• 5-HT_2A serotonin receptors antagonist (Ki = 0.16nM)^[24]
• 5-HT_2C receptors antagonist (Ki = 26nM)^[25]
• 5-HT₇ irreversible antagonist^[26]
• D₁ dopaminergic receptors (Ki = 536 nM)^[24]
  • D1 receptor antagonist
  • D5 receptor antagonist
• D₂ dopaminergic receptors (Ki = 3.13 nM)
  • D2 receptor antagonist
  • D3 receptor antagonist
  • D4 receptor antagonist
• α₁ adrenergic antagonist (Ki = 0.8 nM)
  • α1A
  • α1B
  • α1D subtypes
• α₂ adrenergic antagonist (Ki = 7.54 nM)
  • α2A
  • α2B
  • α2C subtypes
• 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.

Pharmacodynamics[link]

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 also has additional effects as well:

Dopamine receptors - Main target that this drug possess are the D1 and D2 family receptors. Risperidone may induce the "Parkinsonian gait" and tremors associated with diminished dopaminergic activity in the Substantia nigra.

Serotonin receptors - Anxiolytic and anti-aggressive properties. As well as inability to achieve orgasm. May also increase appetite leading to significant weight gain. Decreased extrapyramidal symptoms are also seen in patients. Side effets may include depression and anxiety disorders.

Alpha α1 adrenergic receptors - Diminished action of epinephrine and norepinephrine, which accounts for 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 alpha 2 receptors. Also possesses anti-aggressive properties.

Histamine H1 receptors - Accounting for sedation and inability to maintain vigilance. This may also lead to weight gain.

Even though this medication possess similar effects to other typical and atypical antipsychotics, it does not possess affinity for the Muscarinic acetylcholine receptors

Controversy, lawsuits and settlements[link]

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.

Brand names[link]

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^[1] and several other countries, Risperdal or Ridal in New Zealand and Venezuela, Sizodon, Riscalin or Risdone in India, Rispolept in Eastern Europe and Russia, Zepidone in Nigeria, Riperidone in South Korea, Risperidona in Spain, Apexidone in Egypt, Rissar in Macedonia and Serbia and Belivon or Rispen elsewhere.

References[link]

External links[link]

Psychiatry portal

• 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)