Chemistry:Risperidone

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Short description: Antipsychotic medication
Risperidone
Risperidone.svg
Risperidone-3D-balls.png
Clinical data
Trade namesRisperdal, Okedi, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa694015
License data
Pregnancy
category
  • AU: C
Routes of
administration		By mouth, intramuscular, subcutaneous
Drug classAtypical antipsychotic[2]
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability70% (by mouth)[2]
MetabolismLiver (CYP2D6 mediated to 9-hydroxyrisperidone)[2]
Elimination half-life20 hours (by mouth), 3–6 days (IM)[2]
ExcretionUrinary (70%) feces (14%)[2]
Identifiers
CAS Number
PubChem CID
PubChem SID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
Chemical and physical data
FormulaC23H27FN4O2
Molar mass410.493 g·mol−1
3D model (JSmol)
  (verify)

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.[6]

Common side effects include severe depression, movement problems, sleepiness, dizziness, trouble seeing, constipation, and increased weight.[2][7] 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][6] In older people with psychosis as a result of dementia, it may increase the risk of death.[2] It is unknown if it is safe for use in pregnancy.[2] Its mechanism of action is not entirely clear, but is believed to be related to its action as a dopamine and serotonin antagonist.[2]

Study of risperidone began in the late 1980s and it was approved for sale in the United States in 1993.[2][8][4] It is on the World Health Organization's List of Essential Medicines.[9] It is available as a generic medication.[6] In 2020, it was the 138th most commonly prescribed medication in the United States, with more than 4 million prescriptions.[10][11]

Medical uses

Risperidone is mainly used for the treatment of schizophrenia, bipolar disorder, and irritability associated with autism.[12]

Schizophrenia

Risperidone is effective in treating psychogenic polydipsia and the acute exacerbations of schizophrenia.[13][14]

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.[15] 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.[16] 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.[17] A 2011 Cochrane review compared risperidone with other atypical antipsychotics such as olanzapine for schizophrenia:[18]

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.[18]

Long-acting injectable formulations of antipsychotic drugs provide improved compliance with therapy and reduce relapse rates relative to oral formulations.[19][20] The efficacy of risperidone long-acting injection appears to be similar to that of long-acting injectable forms of first-generation antipsychotics.[21]

Bipolar disorder

Second-generation antipsychotics, including risperidone, are effective in the treatment of manic symptoms in acute manic or mixed exacerbations of bipolar disorder.[22][23][24] In children and adolescents, risperidone may be more effective than lithium or divalproex, but has more metabolic side effects.[25] As maintenance therapy, long-acting injectable risperidone is effective for the prevention of manic episodes but not depressive episodes.[26] 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.[27]

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.[28] The evidence for its efficacy appears to be greater than that for alternative pharmacological treatments.[29] Weight gain is an important adverse effect.[4][30] 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.[31] Evidence for the efficacy of risperidone in autistic adolescents and young adults is less persuasive.[32]

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.[33] Because of this increased risk of death, treatment of dementia-related psychosis with risperidone is not FDA approved and carries a black box warning.[4] 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.[34][35]

Other uses

Risperidone has demonstrated clinical benefit as an augmentation agent in the management of (unipolar) non-psychotic treatment-resistant depression alongside antidepressant treatment.[36] 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.[37]

Risperidone has shown promise in treating therapy-resistant obsessive-compulsive disorder, when serotonin reuptake inhibitors alone are not sufficient.[38]

Risperidone has proven to be effective in treatment with attention deficit hyperactivity disorder especially in cases of aggression[39][40] or with another mental condition.[41]

Risperidone has not demonstrated a benefit in the treatment of eating disorders or personality disorders, except for limited evidence in schizotypal personality disorder.[33]

Forms

Available forms of risperidone include tablet, oral dissolving tablet, oral solution, and powder and solvent for suspension for injection.[42]

Adverse effects

Common side effects include movement problems, sleepiness, dizziness, trouble seeing, constipation, and increased weight.[2][7] 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][6] 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.[43][44] Atypical antipsychotics, however, are associated with a greater amount of weight gain and other metabolic side effects.[45][44]

Drug interactions

  • Carbamazepine and other enzyme inducers may reduce plasma levels of risperidone.[4] 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.[4]
  • CYP2D6 inhibitors, such as SSRI medications, may increase plasma levels of risperidone and those medications.[4]
  • 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.[4]
  • Risperidone and its metabolite paliperidone are reduced in efficacy by P-glycoprotein inducers such as St John's wort.[46][47]

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[48]

Dementia

Older people with dementia-related psychosis are at a higher risk of death.[4]

Pharmacology

Pharmacodynamics

Risperidone[49]
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[50]
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
mACh >10,000 Negligible

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.[51]

It has been 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.[52]

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. It has "tight binding" properties, which means it has a long half-life. 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.[51]

Serotonin receptors: Most important pharmalogical function is to compensate dopamine blocking.

Alpha α1 adrenergic receptors: This action accounts for the orthostatic hypotensive effects and perhaps some of the sedating effects of risperidone.[51]

Alpha α2 adrenergic receptors: Risperidone's action at these receptors may cause greater positive, negative, affective, and cognitive symptom control.[53]

Histamine H1 receptors: effects on these receptors account for its sedation and reduction in vigilance. This may also lead to drowsiness and weight gain.[51]

Voltage-gated sodium channels: Because it accumulates in synaptic vesicles, Risperidone inhibits voltage-gated sodium channels at clinically used concentrations.[54]

Pharmacokinetics

Risperidone undergoes hepatic metabolism and renal excretion. Lower doses are recommended for patients with severe liver and kidney disease.[4] The active metabolite of risperidone, paliperidone, is also used as an antipsychotic.[55][unreliable medical source?]

v · d · e 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 [56]
Clopentixol decanoate Sordinol Depot Typical Viscoleob 50–600 mg/1–4 weeks 4–7 days ? 19 days 9.0 [57]
Flupentixol decanoate Depixol Typical Viscoleob 10–200 mg/2–4 weeks 4–10 days 8 days 17 days 7.2–9.2 [57][58]
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 [59][60][61]
Fluphenazine enanthate Prolixin Enanthate Typical Sesame oil 12.5–100 mg/1–4 weeks 2–3 days 4 days ? 6.4–7.4 [60]
Fluspirilene Imap, Redeptin Typical Watera 2–12 mg/1 week 1–8 days 7 days ? 5.2–5.8 [62]
Haloperidol decanoate Haldol Decanoate Typical Sesame oil 20–400 mg/2–4 weeks 3–9 days 18–21 days 7.2–7.9 [63][64]
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 [65]
Pipotiazine palmitate Piportil Longum Typical Viscoleob 25–400 mg/4 weeks 9–10 days ? 14–21 days 8.5–11.6 [58]
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 intramuscular injection. Footnotes: a = Microcrystalline or nanocrystalline aqueous suspension. b = Low-viscosity vegetable oil (specifically 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 Food and Drug Administration (FDA) in 1993 for the treatment of schizophrenia.[66] 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.[67] 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.[68] On 22 August 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.

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.[69] The applicant for this medicinal product is Laboratorios Farmacéuticos Rovi, S.A.[69] Risperidone was approved for medical use in the European Union in February 2022.[5][70]

Lawsuits

In April 2012, Johnson & Johnson (J&J) and its subsidiary Janssen Pharmaceuticals Inc. were fined $1.2 billion for downplaying multiple risks associated with risperidone.[71] The verdict was later reversed by the Arkansas state supreme court.[72]

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.[73]

In November 2013, J&J was fined $2.2 billion for illegally marketing risperidone for use in people with dementia.[74]

In 2015, Steven Brill wrote an investigative journalism piece about J&J in The Huffington Post focused on J&J's marketing of risperidone.[75][76]

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.[77] In October 2019, a jury awarded a Pennsylvania man $8 billion in a verdict against J&J.[78]

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.[79]

References

  1. ↑ 1.0 1.1 1.2 Drugs.com International trade names for risperidone Page accessed 15 March 2016
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 "Risperidone". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/risperidone.html. 
  3. ↑ "Risperdal Consta 25 mg powder and solvent for prolonged-release suspension for injection - Summary of Product Characteristics (SmPC)". 6 December 2018. https://www.medicines.org.uk/emc/product/1690/smpc. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 "Risperdal- risperidone tablet Risperdal M-Tab- risperidone tablet, orally disintegrating Risperdal- risperidone solution". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e117c7e-02fc-4343-92a1-230061dfc5e0. 
  5. ↑ 5.0 5.1 "Okedi EPAR". 15 December 2021. https://www.ema.europa.eu/en/medicines/human/EPAR/okedi. 
  6. ↑ 6.0 6.1 6.2 6.3 Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. 2015. pp. 434–435. ISBN 9781284057560. 
  7. ↑ 7.0 7.1 "Weight gain and glucose dysregulation with second-generation antipsychotics and antidepressants: a review for primary care physicians". Postgraduate Medicine 124 (4): 154–67. July 2012. doi:10.3810/pgm.2012.07.2577. PMID 22913904. 
  8. ↑ The American Psychiatric Publishing textbook of psychopharmacology (4th ed.). Washington, D.C.: American Psychiatric Pub.. 2009. pp. 627. ISBN 9781585623099. https://books.google.com/books?id=Xx7iNGdV25IC&pg=PA627. 
  9. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  10. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  11. ↑ "Risperidone - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Risperidone. 
  12. ↑ "Respiridone". https://www.drugs.com/monograph/risperidone.html. 
  13. ↑ "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet 382 (9896): 951–62. September 2013. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019. 
  14. ↑ "The psychopharmacology algorithm project at the Harvard South Shore Program: an update on schizophrenia". Harvard Review of Psychiatry 21 (1): 18–40. 2013. doi:10.1097/HRP.0b013e31827fd915. PMID 23656760. 
  15. ↑ "Schizophrenia". BMJ Clinical Evidence 2012. June 2012. PMID 23870705. 
  16. ↑ "Mid-term and long-term efficacy and effectiveness of antipsychotic medications for schizophrenia: a data-driven, personalized clinical approach". The Journal of Clinical Psychiatry 72 (12): 1616–27. December 2011. doi:10.4088/JCP.11r06927. PMID 22244023. 
  17. ↑ "Risperidone versus placebo for schizophrenia". The Cochrane Database of Systematic Reviews 2016 (12): CD006918. December 2016. doi:10.1002/14651858.CD006918.pub3. PMID 27977041. PMC 6463908. http://eprints.whiterose.ac.uk/134704/1/Rattehalli_et_al_2016_Cochrane_Database_of_Systematic_Reviews.pdf. Retrieved 27 November 2018. 
  18. ↑ 18.0 18.1 "Risperidone versus other atypical antipsychotics for schizophrenia". The Cochrane Database of Systematic Reviews (1): CD006626. January 2011. doi:10.1002/14651858.CD006626.pub2. PMID 21249678. 
  19. ↑ "Oral versus depot antipsychotic drugs for schizophrenia--a critical systematic review and meta-analysis of randomised long-term trials". Schizophrenia Research 127 (13): 83–92. April 2011. doi:10.1016/j.schres.2010.11.020. PMID 21257294. 
  20. ↑ "Systematic review of long-acting injectables versus oral atypical antipsychotics on hospitalization in schizophrenia". Current Medical Research and Opinion 30 (8): 1643–55. August 2014. doi:10.1185/03007995.2014.915211. PMID 24730586. 
  21. ↑ "Comparative effectiveness of risperidone long-acting injectable vs first-generation antipsychotic long-acting injectables in schizophrenia: results from a nationwide, retrospective inception cohort study". Schizophrenia Bulletin 41 (3): 627–36. May 2015. doi:10.1093/schbul/sbu128. PMID 25180312. 
  22. ↑ "Efficacy of second generation antipsychotics in treating acute mixed episodes in bipolar disorder: a meta-analysis of placebo-controlled trials". Journal of Affective Disorders 150 (2): 408–14. September 2013. doi:10.1016/j.jad.2013.04.032. PMID 23735211. 
  23. ↑ "New treatment guidelines for acute bipolar mania: a critical review". Journal of Affective Disorders 140 (2): 125–41. October 2012. doi:10.1016/j.jad.2011.10.015. PMID 22100133. 
  24. ↑ "Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials". Neuropsychopharmacology 36 (2): 375–89. January 2011. doi:10.1038/npp.2010.192. PMID 20980991. 
  25. ↑ "Pharmacotherapy of bipolar disorder in children and adolescents: an update". Revista Brasileira de Psiquiatria 35 (4): 393–405. 2013. doi:10.1590/1516-4446-2012-0999. PMID 24402215. 
  26. ↑ "Maintenance therapies in bipolar disorders". Bipolar Disorders 14 (Suppl 2): 51–65. May 2012. doi:10.1111/j.1399-5618.2012.00992.x. PMID 22510036. 
  27. ↑ "Long-acting injectable antipsychotics for the maintenance treatment of bipolar disorder". CNS Drugs 26 (5): 403–20. May 2012. doi:10.2165/11631310-000000000-00000. PMID 22494448. 
  28. ↑ "Risperidone for autism spectrum disorder". The Cochrane Database of Systematic Reviews 2010 (1): CD005040. January 2007. doi:10.1002/14651858.CD005040.pub2. PMID 17253538. 
  29. ↑ "Efficacy and tolerability of pharmacotherapy options for the treatment of irritability in autistic children". Clinical Medicine Insights. Pediatrics 8: 17–30. 2014. doi:10.4137/CMPed.S8304. PMID 24932108. 
  30. ↑ "Efficacy of risperidone in managing maladaptive behaviors for children with autistic spectrum disorder: a meta-analysis". Journal of Pediatric Health Care 26 (4): 291–9. 2012. doi:10.1016/j.pedhc.2011.02.008. PMID 22726714. 
  31. ↑ "A systematic review of medical treatments for children with autism spectrum disorders". Pediatrics 127 (5): e1312–21. May 2011. doi:10.1542/peds.2011-0427. PMID 21464191. 
  32. ↑ "Medications for adolescents and young adults with autism spectrum disorders: a systematic review". Pediatrics 130 (4): 717–26. October 2012. doi:10.1542/peds.2012-0683. PMID 23008452. 
  33. ↑ 33.0 33.1 "Summary of the comparative effectiveness review on off-label use of atypical antipsychotics". Journal of Managed Care Pharmacy 18 (5 Suppl B): S1–20. June 2012. doi:10.18553/jmcp.2012.18.s5-b.1. PMID 22784311. 
  34. ↑ "Risperidone: Revised PBS restrictions for behavioural and psychological symptoms of dementia" (in en). 19 March 2020. https://www.nps.org.au/radar/articles/risperidone-revised-pbs-restrictions-for-behavioural-and-psychological-symptoms-of-dementia. 
  35. ↑ "Antipsychotics and other drug approaches in dementia care | Alzheimer's Society" (in en). 13 August 2021. https://www.alzheimers.org.uk/about-dementia/treatments/drugs/antipsychotic-drugs. 
  36. ↑ "A randomized, placebo-controlled trial of risperidone augmentation for patients with difficult-to-treat unipolar, non-psychotic major depression". J Psychiatr Res 43 (3): 205–14. January 2009. doi:10.1016/j.jpsychires.2008.05.003. PMID 18586273. 
  37. ↑ "Adjunctive atypical antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of life, and safety outcomes". PLOS Med 10 (3): e1001403. 2013. doi:10.1371/journal.pmed.1001403. PMID 23554581. 
  38. ↑ "Antipsychotic augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: a meta-analysis of double-blind, randomized, placebo-controlled trials". The International Journal of Neuropsychopharmacology 16 (3): 557–74. April 2013. doi:10.1017/S1461145712000740. PMID 22932229. 
  39. ↑ "Risperidone treatment in 12 children with developmental disorders and attention-deficit/hyperactivity disorder". Primary Care Companion to the Journal of Clinical Psychiatry 7 (5): 221–224. 2005. doi:10.4088/pcc.v07n0502. PMID 16308577. 
  40. ↑ "Risperidone augmentation for treatment-resistant aggression in attention-deficit/hyperactivity disorder: a placebo-controlled pilot study". Journal of the American Academy of Child and Adolescent Psychiatry 46 (5): 558–565. May 2007. doi:10.1097/chi.0b013e3180323354. PMID 17450046. 
  41. ↑ "Risperidone treatment for ADHD in children and adolescents with bipolar disorder". Neuropsychiatric Disease and Treatment 4 (1): 203–207. February 2008. doi:10.2147/ndt.s1992. PMID 18728799. 
  42. ↑ Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press http://www.medicinescomplete.com [Accessed on 2 February 2020]
  43. ↑ "Second-generation antipsychotics and extrapyramidal adverse effects". BioMed Research International 2014: 656370. 2014. doi:10.1155/2014/656370. PMID 24995318. 
  44. ↑ 44.0 44.1 "First- and Second-Generation Antipsychotics in Children and Young Adults: Systematic Review Update". Comparative Effectiveness Reviews (184): ES–24. March 2017. Report 17-EHC001-EF. Bookshelf ID: NBK442352. PMID 28749632. "Compared with FGAs, SGAs may decrease the risk for experiencing any extrapyramidal symptom (EPS). FGAs probably cause lower gains in weight and BMI.". 
  45. ↑ "Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis". The Lancet. Psychiatry 7 (1): 64–77. January 2020. doi:10.1016/S2215-0366(19)30416-X. PMID 31860457. 
  46. ↑ "The brain entry of risperidone and 9-hydroxyrisperidone is greatly limited by P-glycoprotein". The International Journal of Neuropsychopharmacology 7 (4): 415–419. December 2004. doi:10.1017/S1461145704004390. PMID 15683552. 
  47. ↑ "Gauging the clinical significance of P-glycoprotein-mediated herb-drug interactions: comparative effects of St. John's wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics". Molecular Nutrition & Food Research 52 (7): 772–779. July 2008. doi:10.1002/mnfr.200700081. PMID 18214850. 
  48. ↑ BMJ Group, ed (March 2009). "4.2.1". British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. pp. 192. "Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse." 
  49. ↑ "PDSP Datatbase". National Institute of Mental Health. ChapelHill (NC): University of North Carolina. http://pdsp.med.unc.edu/pdsp.php. 
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Further reading

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