Risperidone

Risperidone
Names
Trade namesRisperdal, others[1]
IUPAC name
  • 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
Clinical data
Drug classAtypical antipsychotic[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
    Routes of
    use    		By mouth (tablets and liquid form), intramuscular injection
    Defined daily dose5 mg (by mouth)[3]
    2.7 mg (intramuscular)[3]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa694015
    Legal
    License data
    Legal status
    Pharmacokinetics
    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]
    Chemical and physical data
    FormulaC23H27FN4O2
    Molar mass410.493 g·mol−1
    3D model (JSmol)
    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 checkY
    • Key:RAPZEAPATHNIPO-UHFFFAOYSA-N checkY

    Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic.[2] It is used to treat schizophrenia, bipolar disorder, and irritability associated with autism.[2] It is taken either by mouth or by injection into a muscle.[2] The injectable version is long-acting and lasts for about two weeks.[4] When the unpublished literature is included, benefits are lower and harms are greater than when only the published literature is looked at.[5]

    Common side effects include movement problems, sleepiness, dizziness, trouble seeing, constipation, and increased weight.[2][6] 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][4] In older people with psychosis as a result of dementia, it may increase the risk of dying.[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 antagonist 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][7][8] It is on the World Health Organization's List of Essential Medicines.[9] It is available as a generic medication.[4] The wholesale price in the developing world is between US$0.01 and US$0.60 per day as of 2014.[10] The cost for a typical month of medication in the United States is between US$100−200 as of 2015.[4] In 2020, it was the 138th most commonly prescribed medication in the United States, with more than 4 million prescriptions.[11][12]

    Medical uses

    Risperidone is mainly used for the treatment of schizophrenia, bipolar disorder, and irritability associated with autism.[13] When the unpublished literature is included, benefits are lower and harms are higher than when only the published literature is looked at.[5]

    Schizophrenia

    Risperidone is effective in treating the acute exacerbations of schizophrenia.[14][15] A 2013 study compared 15 antipsychotic drugs in treating schizophrenia. Risperidone was ranked fourth, 11% more effective than paliperidone (fifth), 20–23% more effective than haloperidol, quetiapine, and aripiprazole, and 36% less effective than clozapine (first).[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.[16] 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.[17] 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.[18] A 2011 Cochrane review compared risperidone with other atypical antipsychotics such as olanzapine for schizophrenia:[19]

    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 drawing firm conclusions difficult.[19]

    Long-acting injectable formulations of antipsychotic drugs provide improved compliance with therapy and reduce relapse rates relative to oral formulations.[20][21] The efficacy of risperidone long-acting injection appears to be similar to that of long acting injectable forms of first generation antipsychotics.[22]

    Bipolar disorder

    Second-generation antipsychotics, including risperidone, are effective in the treatment of manic symptoms in acute manic or mixed exacerbations of bipolar disorder.[23][24][25] In children and adolescents, risperidone may be more effective than lithium or divalproex, but has more metabolic side effects.[26] As maintenance therapy, long-acting injectable risperidone is effective for the prevention of manic episodes but not depressive episodes.[27] 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.[28]

    Autism

    Compared to placebo, risperidone treatment reduces certain problematic behaviors in autistic children, including aggression toward others, self-injury, meltdowns, and rapid mood changes.[29] The evidence for its efficacy appears to be greater than that for alternative pharmacological treatments.[30] Weight gain is an important adverse effect.[8][31] 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.[32] Evidence for the efficacy of risperidone in autistic adolescents and young adults is less persuasive.[33]

    Other uses

    Risperidone has shown promise in treating therapy-resistant obsessive–compulsive disorder, when serotonin reuptake inhibitors are not sufficient.[34]

    Risperidone has not demonstrated a benefit in the treatment of eating disorders or personality disorders.[35]

    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.[35] Because of this increased risk of death, treatment of dementia-related psychosis with risperidone is not FDA approved.[8]

    Forms

    Available forms of risperidone include tablet, oral dissolving tablet, oral solution, and powder and solvent for suspension for injection.[36]

    Dosage

    The defined daily dose is 5 mg for the tablets and oral liquid, and 2.7 mg for the injection.[3] The initial dose may vary from 1 mg twice per day to 3 mg twice per day in adults in adults.[37] In older people, those with kidney problems, and those with liver problems smaller doses should be used.[37] For an episode of acute psychosis at least 3 months of treatment is recommended while for chronic psychosis at least a year is recommended.[37] When stopping, this should be done gradually.[37]

    Side effects

    See also: List of adverse effects of risperidone
    Risperidone induced skin breakdown

    Common side effects include movement problems, sleepiness, dizziness, trouble seeing, constipation, and increased weight.[2][6] 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][4] In older people with psychosis as a result of dementia, it may increase the risk of dying.[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.[38][39] Atypical antipsychotics however are associated with a greater amount of weight gain.[39]

    Interactions

    • Carbamazepine and other enzyme inducers may reduce plasma levels of risperidone.[8] 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.[8]
    • CYP2D6 inhibitors, such as SSRI medications, may increase plasma levels of risperidone and those medications.[8]
    • 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.[8]
    • Risperidone and it's metabolite paliperidone are reduced in efficacy by P-glycoprotein inducers such as St John's wort[40][41]

    Discontinuation

    The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[42] 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.[43][44][45][46] 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 as the public.[47]

    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.[8]

    Pharmacology

    Pharmacodynamics

    See also: Atypical antipsychotic § Pharmacodynamics, and Antipsychotic § Comparison of medications
    Risperidone[48]
    SiteKi (nM)Action
    5-HT1A423Antagonist
    5-HT1B14.9Antagonist
    5-HT1D84.6Antagonist
    5-HT2A0.17Inverse agonist
    5-HT2B61.9Inverse agonist
    5-HT2C12.0Inverse agonist
    5-HT5A206Antagonist
    5-HT62,060Antagonist
    5-HT76.60Irreversible
    antagonist[49]
    α1A5.0Antagonist
    α1B9.0Antagonist
    α2A16.5Antagonist
    α2B108Antagonist
    α2C1.30Antagonist
    D1244Antagonist
    D23.57Antagonist
    D2S4.73Antagonist
    D2L4.16Antagonist
    D33.6Inverse agonist
    D44.66Antagonist
    D5290Antagonist
    H120.1Inverse agonist
    H2120Inverse agonist
    mACh>10,000Negligible
    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.[50]

    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.[51]

    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.[50]

    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.[50]

    Alpha α2 adrenergic receptors: Perhaps greater positive, negative, affective and cognitive symptom control.[52]

    Histamine H1 receptors: effects on these receptors account for its sedation and reduction in vigilance. This may also lead to drowsiness and weight gain.[50]

    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.[8] The active metabolite of risperidone, paliperidone, is also used as an antipsychotic.[53]

    Pharmacokinetics of long-acting injectable antipsychotics
    MedicationBrand nameClassVehicleDosageTmaxt1/2 singlet1/2 multiplelogPcRef
    Aripiprazole lauroxilAristadaAtypicalWatera441–1064 mg/4–8 weeks24–35 days ?54–57 days7.9–10.0
    Aripiprazole monohydrateAbilify MaintenaAtypicalWatera300–400 mg/4 weeks7 days ?30–47 days4.9–5.2
    Bromperidol decanoateImpromen DecanoasTypicalSesame oil40–300 mg/4 weeks3–9 days ?21–25 days7.9[54]
    Clopentixol decanoateSordinol DepotTypicalViscoleob50–600 mg/1–4 weeks4–7 days ?19 days9.0[55]
    Flupentixol decanoateDepixolTypicalViscoleob10–200 mg/2–4 weeks4–10 days8 days17 days7.2–9.2[55][56]
    Fluphenazine decanoateProlixin DecanoateTypicalSesame oil12.5–100 mg/2–5 weeks1–2 days1–10 days14–100 days7.2–9.0[57][58][59]
    Fluphenazine enanthateProlixin EnanthateTypicalSesame oil12.5–100 mg/1–4 weeks2–3 days4 days ?6.4–7.4[58]
    FluspirileneImap, RedeptinTypicalWatera2–12 mg/1 week1–8 days7 days ?5.2–5.8[60]
    Haloperidol decanoateHaldol DecanoateTypicalSesame oil20–400 mg/2–4 weeks3–9 days18–21 days7.2–7.9[61][62]
    Olanzapine pamoateZyprexa RelprevvAtypicalWatera150–405 mg/2–4 weeks7 days ?30 days–
    Oxyprothepin decanoateMeclopinTypical ? ? ? ? ?8.5–8.7
    Paliperidone palmitateInvega SustennaAtypicalWatera39–819 mg/4–12 weeks13–33 days25–139 days ?8.1–10.1
    Perphenazine decanoateTrilafon DekanoatTypicalSesame oil50–200 mg/2–4 weeks ? ?27 days8.9
    Perphenazine enanthateTrilafon EnanthateTypicalSesame oil25–200 mg/2 weeks2–3 days ?4–7 days6.4–7.2[63]
    Pipotiazine palmitatePiportil LongumTypicalViscoleob25–400 mg/4 weeks9–10 days ?14–21 days8.5–11.6[56]
    Pipotiazine undecylenatePiportil MediumTypicalSesame oil100–200 mg/2 weeks ? ? ?8.4
    RisperidoneRisperdal ConstaAtypicalMicrospheres12.5–75 mg/2 weeks21 days ?3–6 days–
    Zuclopentixol acetateClopixol AcuphaseTypicalViscoleob50–200 mg/1–3 days1–2 days1–2 days4.7–4.9
    Zuclopentixol decanoateClopixol DepotTypicalViscoleob50–800 mg/2–4 weeks4–9 days ?11–21 days7.5–9.0
    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.

    Society and culture

    Risperdal (risperidone) 4 mg tablets (UK)

    Cost

    The wholesale price in the developing world is between US$0.01 and US$0.60 per day as of 2014.[10] The cost for a typical month of medication in the United States is between US$100−200 as of 2015.[4] In 2020, it was the 138th most commonly prescribed medication in the United States, with more than 4 million prescriptions.[64][65]

    • Risperidone costs (US)
      Risperidone costs (US)
    • Risperidone prescriptions (US)
      Risperidone prescriptions (US)

    Regulatory 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] 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.[68]

    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.[69] The jury found the companies had downplayed multiple risks associated with risperidone (Risperdal). The verdict was later reversed by the Arkansas State Supreme court.[70]

    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.[71]

    In November 2013, J&J was fined $2.2 billion for illegally marketing risperidone for use in people with dementia.[72]

    In 2015, Steven Brill posted a 15-part investigative journalism piece on J&J in The Huffington Post, called "America's most admired lawbreaker", which was focused on J&J's marketing of risperidone.[73][74]

    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.[75] In October, 2019, a jury awarded a Pennsylvania man $8 billion in a verdict against J&J.[76]

    Names

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

    References

    1. 1 2 3 Drugs.com International trade names for risperidone Archived 2016-03-18 at the Wayback Machine Page accessed March 15, 2016
    2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 "Risperidone". The American Society of Health-System Pharmacists. Archived from the original on 2 December 2015. Retrieved 1 December 2015.
    3. 1 2 3 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 6 August 2020. Retrieved 26 August 2020.
    4. 1 2 3 4 5 6 Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. pp. 434–435. ISBN 9781284057560.
    5. 1 2 Hodkinson, A; Heneghan, C; Mahtani, KR; Kontopantelis, E; Panagioti, M (25 August 2021). "Benefits and harms of Risperidone and Paliperidone for treatment of patients with schizophrenia or bipolar disorder: a meta-analysis involving individual participant data and clinical study reports". BMC medicine. 19 (1): 195. doi:10.1186/s12916-021-02062-w. PMID 34429113.
    6. 1 2 Hasnain M, Vieweg WV, Hollett B (July 2012). "Weight gain and glucose dysregulation with second-generation antipsychotics and antidepressants: a review for primary care physicians". Postgraduate Medicine. 124 (4): 154–67. doi:10.3810/pgm.2012.07.2577. PMID 22913904.
    7. ↑ Schatzberg, Alan F; Nemeroff, Charles B (2009). The American Psychiatric Publishing textbook of psychopharmacology (4th ed.). Washington, D.C.: American Psychiatric Pub. p. 627. ISBN 9781585623099.
    8. 1 2 3 4 5 6 7 8 9 "Risperdal- risperidone tablet Risperdal M-Tab- risperidone tablet, orally disintegrating Risperdal- risperidone solution". DailyMed. Archived from the original on 30 April 2017. Retrieved 31 December 2019.
    9. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
    10. 1 2 "Risperidone". International Drug Price Indicator Guide. Archived from the original on 22 January 2018. Retrieved 2 December 2015.
    11. ↑ "The Top 300 of 2020". ClinCalc. Archived from the original on 18 March 2020. Retrieved 7 October 2022.
    12. ↑ "Risperidone - Drug Usage Statistics". ClinCalc. Archived from the original on 29 April 2017. Retrieved 7 October 2022.
    13. ↑ "Respiridone". The American Society of Health-System Pharmacists. Archived from the original on 13 April 2011. Retrieved 3 April 2011.
    14. 1 2 Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM (September 2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet. 382 (9896): 951–62. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019.
    15. ↑ Osser DN, Roudsari MJ, Manschreck T (2013). "The psychopharmacology algorithm project at the Harvard South Shore Program: an update on schizophrenia". Harvard Review of Psychiatry. 21 (1): 18–40. doi:10.1097/HRP.0b013e31827fd915. PMID 23656760.
    16. ↑ Barry SJ, Gaughan TM, Hunter R (June 2012). "Schizophrenia". BMJ Clinical Evidence. 2012. PMC 3385413. PMID 23870705.
    17. ↑ Glick ID, Correll CU, Altamura AC, Marder SR, Csernansky JG, Weiden PJ, Leucht S, Davis JM (December 2011). "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. doi:10.4088/JCP.11r06927. PMID 22244023.
    18. ↑ Rattehalli RD, Zhao S, Li BG, Jayaram MB, Xia J, Sampson S (December 2016). "Risperidone versus placebo for schizophrenia" (PDF). The Cochrane Database of Systematic Reviews. 12: CD006918. doi:10.1002/14651858.CD006918.pub3. PMC 6463908. PMID 27977041. Archived (PDF) from the original on 28 January 2019. Retrieved 27 November 2018.
    19. 1 2 Komossa K, Rummel-Kluge C, Schwarz S, Schmid F, Hunger H, Kissling W, Leucht S (January 2011). "Risperidone versus other atypical antipsychotics for schizophrenia". The Cochrane Database of Systematic Reviews (1): CD006626. doi:10.1002/14651858.CD006626.pub2. PMC 4167865. PMID 21249678.
    20. ↑ Leucht C, Heres S, Kane JM, Kissling W, Davis JM, Leucht S (April 2011). "Oral versus depot antipsychotic drugs for schizophrenia--a critical systematic review and meta-analysis of randomised long-term trials". Schizophrenia Research. 127 (1–3): 83–92. doi:10.1016/j.schres.2010.11.020. PMID 21257294.
    21. ↑ Lafeuille MH, Dean J, Carter V, Duh MS, Fastenau J, Dirani R, Lefebvre P (August 2014). "Systematic review of long-acting injectables versus oral atypical antipsychotics on hospitalization in schizophrenia". Current Medical Research and Opinion. 30 (8): 1643–55. doi:10.1185/03007995.2014.915211. PMID 24730586.
    22. ↑ Nielsen J, Jensen SO, Friis RB, Valentin JB, Correll CU (May 2015). "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. doi:10.1093/schbul/sbu128. PMC 4393684. PMID 25180312.
    23. ↑ Muralidharan K, Ali M, Silveira LE, Bond DJ, Fountoulakis KN, Lam RW, Yatham LN (September 2013). "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. doi:10.1016/j.jad.2013.04.032. PMID 23735211.
    24. ↑ Nivoli AM, Murru A, Goikolea JM, Crespo JM, Montes JM, González-Pinto A, García-Portilla P, Bobes J, Sáiz-Ruiz J, Vieta E (October 2012). "New treatment guidelines for acute bipolar mania: a critical review". Journal of Affective Disorders. 140 (2): 125–41. doi:10.1016/j.jad.2011.10.015. PMID 22100133.
    25. ↑ Yildiz A, Vieta E, Leucht S, Baldessarini RJ (January 2011). "Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials". Neuropsychopharmacology. 36 (2): 375–89. doi:10.1038/npp.2010.192. PMC 3055677. PMID 20980991.
    26. ↑ Peruzzolo TL, Tramontina S, Rohde LA, Zeni CP (2013). "Pharmacotherapy of bipolar disorder in children and adolescents: an update". Revista Brasileira de Psiquiatria. 35 (4): 393–405. doi:10.1590/1516-4446-2012-0999. PMID 24402215.
    27. ↑ Gitlin M, Frye MA (May 2012). "Maintenance therapies in bipolar disorders". Bipolar Disorders. 14 Suppl 2: 51–65. doi:10.1111/j.1399-5618.2012.00992.x. PMID 22510036.
    28. ↑ Gigante AD, Lafer B, Yatham LN (May 2012). "Long-acting injectable antipsychotics for the maintenance treatment of bipolar disorder". CNS Drugs. 26 (5): 403–20. doi:10.2165/11631310-000000000-00000. PMID 22494448.
    29. ↑ Jesner, O. S.; Aref-Adib, M.; Coren, E. (24 January 2007). "Risperidone for autism spectrum disorder". The Cochrane Database of Systematic Reviews (1): CD005040. doi:10.1002/14651858.CD005040.pub2. ISSN 1469-493X. PMID 17253538.
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