Risperidone

Source: Wikipedia, the free encyclopedia.

Risperidone
Clinical data
Trade namesRisperdal, Okedi, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa694015
License data
Pregnancy
category
  • AU: C
subcutaneous
Drug classAtypical antipsychotic[2]
ATC code
Legal status
Legal status
9-hydroxyrisperidone)[2]
Elimination half-life20 hours (by mouth), 3–6 days (IM)[2]
ExcretionUrinary (70%) feces (14%)[2]
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
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)
A box of Rispolept (Risperidone) tablets

Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic[2] used to treat schizophrenia and bipolar disorder.[2] It is taken either by mouth or by injection (subcutaneous or intramuscular).[2] The injectable versions are long-acting and last for 2–4 weeks.[9]

Common side effects include severe depression,

serotonin antagonist.[2]

Study of risperidone began in the late 1980s and it was approved for sale in the United States in 1993.

generic medication.[9] In 2021, it was the 138th most commonly prescribed medication in the United States, with more than 4 million prescriptions.[13][14]

Medical uses

Risperidone is mainly used for the treatment of

autism.[15]

Schizophrenia

Risperidone is effective in treating psychogenic polydipsia and the acute exacerbations of schizophrenia.[16][17]

Studies evaluating the utility of risperidone by mouth for maintenance therapy have reached varying conclusions. A 2012 systematic review concluded that evidence is strong that risperidone is more effective than all first-generation antipsychotics other than haloperidol, but that evidence directly supporting its superiority to placebo is equivocal.[18] 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.[19] 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.[20] A 2011 Cochrane review compared risperidone with other atypical antipsychotics such as olanzapine for schizophrenia:[21]

Summary
Risperidone seems to produce somewhat more extrapyramidal side effects and clearly more prolactin increase than 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 drawing firm conclusions difficult.[21]

Long-acting injectable formulations of antipsychotic drugs provide improved compliance with therapy and reduce relapse rates relative to oral formulations.[22][23] The efficacy of risperidone long-acting injection appears to be similar to that of long-acting injectable forms of first-generation antipsychotics.[24]

Bipolar disorder

Second-generation antipsychotics, including risperidone, are effective in the treatment of manic symptoms in acute manic or mixed exacerbations of bipolar disorder.

divalproex, but has more metabolic side effects.[28] As maintenance therapy, long-acting injectable risperidone is effective for the prevention of manic episodes but not depressive episodes.[29] 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.[30]

Autism

Compared to placebo, risperidone treatment reduces certain problematic behaviors in autistic children, including aggression toward others, self-injury, challenging behavior, and rapid mood changes.[31] The evidence for its efficacy appears to be greater than that for alternative pharmacological treatments.[32] Weight gain is an important adverse effect.[7][33] 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.[34] Evidence for the efficacy of risperidone in autistic adolescents and young adults is less persuasive.[35]

Dementia

While antipsychotic medications such as risperidone have a slight benefit in people with dementia, they have been linked to higher incidence of death and stroke.[36] Because of this increased risk of death, treatment of dementia-related psychosis with risperidone is not FDA approved and carries a black box warning.[7] However, many other jurisdictions regularly use it to control severe aggression and psychosis in those with dementia when other non-pharmacological interventions have failed and their pharmaceutical regulators have approved its use in this population.[37][38]

Other uses

Risperidone has demonstrated clinical benefit as an augmentation agent in the management of (unipolar) non-psychotic treatment-resistant depression alongside antidepressant treatment.[39] Atypical antipsychotics, such as risperidone, are among the most common augments for antidepressant therapy. Such usage occurs "off-label" in most jurisdictions and the risk of adverse effects (e.g., weight gain, movement disorders) must be carefully weighed against the clinical benefit.[40]

Risperidone has shown promise in treating therapy-resistant

obsessive-compulsive disorder, when serotonin reuptake inhibitors alone are not sufficient.[41]

Risperidone has proven to be effective in treatment with attention deficit hyperactivity disorder especially in cases of aggression[42][43] or with another mental condition.[44]

Risperidone has not demonstrated a benefit in the treatment of eating disorders or personality disorders, except for limited evidence in schizotypal personality disorder.[36]

Forms

Available forms of risperidone include tablet, oral dissolving tablet, oral solution, and powder and solvent for suspension for injection.[45]

Adverse effects

See also: List of adverse effects of risperidone

Common side effects include movement problems, sleepiness, dizziness, trouble seeing, constipation, and increased weight.[2][10] About 9 to 20% of people gained more than 7% of the baseline weight depending on the dose.[2] 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.[2][9] In older people with psychosis as a result of dementia, it may increase the risk of death.[2]

While atypical antipsychotics appear to have a lower rate of movement problems as compared to typical antipsychotics, risperidone has a high risk of movement problems among the atypicals.[46][47] Atypical antipsychotics, however, are associated with a greater amount of weight gain and other metabolic side effects.[48][47]

Drug interactions

  • Carbamazepine and other enzyme inducers may reduce plasma levels of risperidone.[7] 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.[7]
  • SSRI medications, may increase plasma levels of risperidone and those medications.[7]
  • Since risperidone can cause hypotension, its use should be monitored closely when a patient is also taking antihypertensive medicines to avoid severe low blood pressure.[7]
  • Risperidone and its metabolite
    St John's wort.[49][50]

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[51]

Dementia

Older people with dementia-related psychosis are at a higher risk of death.[7]

Pharmacology

Pharmacodynamics

See also: Atypical antipsychotic § Pharmacodynamics, and Antipsychotic § Comparison of medications
Risperidone[52]
Site Ki (nM)
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[53]
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 has been classified as a "qualitatively atypical" antipsychotic agent with a relatively low incidence of

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.[54]

It has been found that

D-serine — the neurotransmitters) is inhibited by risperidone.[55]

Risperidone acts on the following receptors:

galactorrhoea, infertility, gynecomastia and, with chronic use reduced bone mineral density leading to breaks, all of which are associated with increased prolactin secretion.[54]

Serotonin receptors: Most important pharmalogical function is to compensate dopamine blocking.[medical citation needed
]

Alpha α1 adrenergic receptors: This action accounts for the orthostatic hypotensive effects and perhaps some of the sedating effects of risperidone.[54]

Alpha α2 adrenergic receptors: Risperidone's action at these receptors may cause greater positive, negative, affective, and cognitive symptom control.[56]

Histamine H1 receptors: effects on these receptors account for its sedation and reduction in vigilance. This may also lead to drowsiness and weight gain.[54]

Voltage-gated sodium channels: Because it accumulates in synaptic vesicles, Risperidone inhibits voltage-gated sodium channels at clinically used concentrations.[57]

Pharmacokinetics

Risperidone undergoes hepatic metabolism and renal excretion. Lower doses are recommended for patients with severe liver and kidney disease.[7] The active metabolite of risperidone, paliperidone, is also used as an antipsychotic.[58][unreliable medical source?]

Pharmacokinetics of long-acting injectable antipsychotics
Medication Brand name Class Vehicle Dosage Tmax t1/2 single t1/2 multiple logPc Ref
Aripiprazole lauroxil Aristada Atypical Watera 441–1064 mg/4–8 weeks 24–35 days ? 54–57 days 7.9–10.0
Aripiprazole monohydrate
 Abilify Maintena Atypical Watera 300–400 mg/4 weeks 7 days ? 30–47 days 4.9–5.2
Bromperidol decanoate Impromen Decanoas Typical Sesame oil 40–300 mg/4 weeks 3–9 days ? 21–25 days 7.9 [59]
Clopentixol decanoate
 Sordinol Depot Typical Viscoleob 50–600 mg/1–4 weeks 4–7 days ? 19 days 9.0 [60]
Flupentixol decanoate
 Depixol Typical Viscoleob 10–200 mg/2–4 weeks 4–10 days 8 days 17 days 7.2–9.2 [60][61]
Fluphenazine decanoate
 Prolixin Decanoate Typical Sesame oil 12.5–100 mg/2–5 weeks 1–2 days 1–10 days 14–100 days 7.2–9.0 [62][63][64]
Fluphenazine enanthate
 Prolixin Enanthate Typical Sesame oil 12.5–100 mg/1–4 weeks 2–3 days 4 days ? 6.4–7.4 [63]
Fluspirilene Imap, Redeptin Typical Watera 2–12 mg/1 week 1–8 days 7 days ? 5.2–5.8 [65]
Haloperidol decanoate Haldol Decanoate Typical Sesame oil 20–400 mg/2–4 weeks 3–9 days 18–21 days 7.2–7.9 [66][67]
Olanzapine pamoate
 Zyprexa Relprevv Atypical Watera 150–405 mg/2–4 weeks 7 days ? 30 days –
Oxyprothepin decanoate Meclopin Typical ? ? ? ? ? 8.5–8.7
Paliperidone palmitate
 Invega Sustenna Atypical Watera 39–819 mg/4–12 weeks 13–33 days 25–139 days ? 8.1–10.1
Perphenazine decanoate
 Trilafon Dekanoat Typical Sesame oil 50–200 mg/2–4 weeks ? ? 27 days 8.9
Perphenazine enanthate Trilafon Enanthate Typical Sesame oil 25–200 mg/2 weeks 2–3 days ? 4–7 days 6.4–7.2 [68]
Pipotiazine palmitate
 Piportil Longum Typical Viscoleob 25–400 mg/4 weeks 9–10 days ? 14–21 days 8.5–11.6 [61]
Pipotiazine undecylenate
 Piportil Medium Typical Sesame oil 100–200 mg/2 weeks ? ? ? 8.4
Risperidone Risperdal Consta Atypical
Microspheres
 12.5–75 mg/2 weeks 21 days ? 3–6 days –
Zuclopentixol acetate
 Clopixol Acuphase Typical Viscoleob 50–200 mg/1–3 days 1–2 days 1–2 days 4.7–4.9
Zuclopentixol decanoate
 Clopixol Depot Typical Viscoleob 50–800 mg/2–4 weeks 4–9 days ? 11–21 days 7.5–9.0
Note: All by
fractionated coconut oil with medium-chain triglycerides). c = Predicted, from PubChem and DrugBank
. Sources: Main: See template.
Risperdal (risperidone) 4 mg tablets (UK)

Society and culture

Legal status

Risperidone was approved by the United States

lithium
.

On 16 December 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Okedi, intended for the treatment of schizophrenia in adults for whom tolerability and effectiveness has been established with oral risperidone.[72] The applicant for this medicinal product is Laboratorios Farmacéuticos Rovi, S.A.[72] Risperidone was approved for medical use in the European Union in February 2022.[8][73]

Lawsuits

In April 2012,

Janssen Pharmaceuticals Inc. were fined $1.2 billion for downplaying multiple risks associated with risperidone.[74] The verdict was later reversed by the Arkansas state supreme court.[75]

In August 2012, J&J agreed to pay $181 million to 36 US states in order to settle claims that it had promoted risperidone and paliperidone for off-label uses including for dementia, anger management, and anxiety.[76]

In November 2013, J&J was fined $2.2 billion for illegally marketing risperidone for use in people with dementia.[77]

In 2015,

The Huffington Post focused on J&J's marketing of risperidone.[78][79]

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 $1.75 million verdict against J&J that November, and in 2016 a $70 million verdict against J&J.[80] In October 2019, a jury awarded a Pennsylvania man $8 billion in a verdict against J&J.[81]

Brand names

Janssen's patent on risperidone expired in December 2003, opening the market for cheaper generic versions from other companies, and Janssen's exclusive marketing rights expired in June 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]

Brand names include Risperdal, Risperdal Consta, Risperdal M-Tab, Risperdal Quicklets, Risperlet, Okedi, and Perseris.[82]

References

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Further reading

External links

Media related to Risperidone at Wikimedia Commons

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