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DRUG RECORD

 

RISPERIDONE

OVERVIEW
Risperidone

 

Introduction

Risperidone is an atypical antipsychotic that is used widely in the treatment of mania and schizophrenia.  Risperidone therapy is associated with serum aminotransferase elevations and in rare instances has been linked to clinically apparent acute liver injury.

 

Background

Risperidone (ris per' i done) is a benzisoxazole derivative which appears to act as a dopamine type 2 (D2) and serotonin (5-HT2) receptor antagonist.  Risperidone is indicated for treatment of schizophrenia and as monotherapy or combination therapy for acute manic or mixed episodes of bipolar I disorder in adults.  Risperidone is also used for management of irritability with autistic disorder in children and adolescents.  Risperidone was approved for use in the United States in 1993 and it is still widely used.  Risperidone is available as tablets of 0.25, 0.5, 1, 2, 3 and 4 mg generically and under the brand name of Risperdal.  Oral solutions for pediatric use are available as are orally disintegrating tablets and formulations for parenteral administration.  The typical initial dose in adults is 1 mg once or twice daily, with increase in dose to as high as 8 mg daily based upon indications, efficacy and tolerance.  Common side effects include somnolence, fatigue, restlessness, dizziness, dry mouth, increased saliva, constipation, increased appetite and weight gain.

 

Hepatotoxicity

Liver test abnormalities may occur in up to 30% of patients on long term therapy with risperidone, usually arising within the first 8 weeks of treatment.  The ALT elevations are usually mild, transient and may resolve even with continuation of medication.  Instances of more marked ALT and alkaline phosphatase elevations, with or without symptoms and with or without jaundice, have also been reported.  The onset of injury typically occurs within a few days of starting risperidone and resolves rapidly with stopping.  Instances of acute liver injury with jaundice arising several months and even years after starting risperidone have also been reported.  The pattern of serum enzyme elevations is typically cholestatic, but cases with hepatocellular and mixed patterns have also been described.  Immunoallergic manifestations (rash, fever, eosinophilia) are rare; a case of autoimmune hepatitis apparently triggered by risperidone therapy was been published, but most cases do not have autoimmune features.

 

Mechanism of Injury

The mechanism by which risperidone causes serum ALT elevations is not known.  Risperidone is extensively metabolized by the cytochrome P450 system (CYP 2D6) to its active metabolite.  Some instances of liver injury may be due to nonalcoholic fatty liver disease caused by weight gain that occurs in at least one-quarter of treated patients and can be as much as 30 kg, generally during the first 1 to 2 years of therapy.  In large series, however, the minor ALT elevations that occur on therapy have not correlated well with weight gain.

 

Outcome and Management

The serum aminotransferase elevations that occur on risperidone therapy are usually self-limited and often do not require dose modification or discontinuation of therapy.  No instances of acute liver failure or vanishing bile duct syndrome have been attributed to risperidone.  A single case of autoimmune hepatitis due to risperidone has been published.  There may be some cross reactivity to liver injury between risperidone and quetiapine, but usually not with clozapine and olanzapine.

 

Drug Class:  Antipsychotic Agents

 

Other Drugs in the Subclass, Atypicals:  Aripiprazole, Clozapine, Olanzapine, Quetiapine, Ziprasidone


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PRODUCT INFORMATION
Risperidone

 

REPRESENTATIVE TRADE NAMES
Risperidone – Generic, Risperdal®

 

DRUG CLASS
Antipsychotic Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Risperidone 106266-06-2 C23-H27-F-N4-O2 Risperidone Chemical Structure

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REFERENCES
Risperidone

 

References Last Updated: 10 January 2014

  1. Meyer JM. Pharmacotherapy of psychosis and mania. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman.s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 417-56.  (Textbook of pharmacology and therapeutics).

  2. Larry D. Hepatotoxicity of psychotropic drugs and drugs of abuse. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 2nd ed. New York: Informa Healthcare USA, 2007, pp. 507-26.  (Review of hepatotoxicity of psychiatric agents mentions that at least 10 cases of liver injury have been ascribed to risperidone, some with steatosis and weight gain and others with acute clinical jaundice).

  3. Risperidone for chronic schizophrenia. Med Lett Drugs Ther 1994; 36: 33-4. PubMed Citation  (Brief review of efficacy and safety of risperidone shortly after its approval in the United States; common side effects are asthenia, sedation and difficulty concentrating, orthostatic hypotension and weight gain; no mention of liver injury).

  4. Fuller MA, Simon MR, Freedman L. Risperidone-associated hepatotoxicity. J Clin Psychopharmacol 1996; 16: 84-5. PubMed Citation  (Two cases; 64 year old man developed jaundice 6 weeks after starting risperidone [bilirubin 16.1 mg/dL, ALT 297 U/L, Alk P 119 U/L], resolving upon stopping; 68 year old woman developed lethargy 1 year after starting risperidone [bilirubin 0.7 mg/dL, ALT 341 U/L, Alk P 174 U/L], resolving rapidlly upon stopping).

  5. Kumra S, Herion D, Jacobsen LK, Briguglia C, Grothe D. Case study: risperidone-induced hepatotoxicity in pediatric patients. J Am Acad Child Adolesc Psychiatry 1997; 36: 701-5. PubMed Citation  (Retrospective review of 13 children on risperidone; 2 developed elevated ALT levels [108 and 144 U/L] with weight gain [16 and 5 kg] on long term risperidone [7 and 17 months], resolution on stopping risperidone even without much weight loss).

  6. Geller WK, Zuiderwijk PB. Risperidone-induced hepatotoxicity? J Am Acad Child Adolesc Psychiatry 1998; 37: 246-7. PubMed Citation  (Letter disagreeing with comments of Kumra [1997], arguing against routine ALT monitoring for patients on risperidone).

  7. Landau J, Martin A. Is liver function monitoring warranted during risperidone treatment? J Am Acad Child Adolesc Psychiatry 1998; 37: 10: 1007-8. PubMed Citation  (Overweight 13 year old girl found to have ALT elevations [164 U/L] 3 days after starting risperidone and steatohepatitis on biopsy; no values before starting therapy).

  8. Benazzi F. Risperidone-induced hepatotoxicity. Pharmacopsychiatry 1998; 31: 241. PubMed Citation  (25 year old woman treated with increasing doses of risperidone [to 6 mg/day] had 20 kg weight gain and fatigue; ALT rose from 13 [pre] to 277 U/L [month 4] without jaundice and fell to normal 1 month after stopping drug).

  9. Phillips EJ, Liu BA, Knowles SR. Rapid onset of risperidone-induced hepatotoxicity. Ann Pharmacother 1998; 32: 843-4. PubMed Citation  (81 year old man developed jaundice within 2 days of starting risperidone [bilirubin 3.6 mg/dL, ALT 101 U/L, Alk P 244 U/L], resolving 2 weeks after stopping).

  10. Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, Weiden PJ. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999; 156: 1686-96. PubMed Citation  (Systematic review of 81 articles on weight change with antipsychotics, using change after 10 weeks to compare agents: clozapine +5.7, olanzapine +4.2, chlorpromazine +4.2, quetiapine +2.5, risperidone +1.7, loxapine +0.6, haloperidol +0.5, ziprasidone +0.3, molindone -0.1, and pimozide -2.7 kilograms).

  11. Whitworth AB, Liensberger D, Fleischhacker WW. Transient increase of liver enzymes induced by risperidone: two case reports. J Clin Psychopharmacol 1999; 19: 475-6. PubMed Citation  (Two cases; 22 year old man had ALT elevation [106 U/L] 16 days after starting risperidone,which improved with lowering dose from 6 to 5 mg/day; 19 year old man had ALT elevation [43 U/L] which fell to normal despite continuing risperidone therapy).

  12. Szigethy E, Wiznitzer M, Branicky LA, Maxwell K, Findling RL. Risperidone-induced hepatotoxicity in children and adolescents? A chart review study. J Child Adolesc Psychopharmacol 1999; 9: 93-8. PubMed Citation  (Retrospective study of 38 children and adolescents on risperidone for ~15 months; only 1 had ALT elevation [46 U/L], degree of surveillance unclear; abstract only).

  13. Conley RR. Conley RR. Risperidone side effects. J Clin Psychiatry 2000; 61 Suppl 8: 20-3. PubMed Citation  (Review of side effects of risperidone, but no mention of hepatotoxicity or ALT elevations).

  14. Krebs S, Dormann H, Muth-Selbach U, Hahn EG, Brune K, Schneider HT. Risperidone-induced cholestatic hepatitis. Eur J Gastroenterol Hepatol 2001; 13: 67-9. PubMed Citation  (37 year old man developed rises in ALT [140 U/L] and GGT [260 U/L] within days of starting risperidone, that continued on haloperidol [ALT 100 U/L] and olanzapine [ALT 160 U/L]; peak bilirubin 1.6 mg/dL; biopsy showed “cholestatic hepatitis”; tests fell to normal ~1 month after discontinuation).

  15. Cordeiro Q Jr, Elkis H. Pancreatitis and cholestatic hepatitis induced by risperidone. J Clin Psychopharmacol 2001; 21: 529-30. PubMed Citation  (32 year old man developed abdominal pain and jaundice 1 week after starting risperidone [bilirubin 2.8 mg/dL, ALT 366 U/L, Alk P 367 U/L, amylase 1617 U/L], resolving rapidly with stopping).

  16. Dumortier G, Cabaret W, Stamatiadis L, Saba G, Benadhira R, Rocamora JF, Aubriot-Delmas B, et al. [Hepatic tolerance of atypical antipsychotic drugs]. Encephale 2002; 28: 542-51. PubMed Citation  (Review of literature on liver injury due to atypical antipsychotics).

  17. Mouradian-Stamatiadis L, Dumortier G, Januel D, Delmas BA, Cabaret W. Liver function tests during treatment with antipsychotic drugs: a case series of 23 patients. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 1409-11. PubMed Citation  (23 hospitalized patients on atypical antipsychotics, 6 had ALT or AST elevations by day 14, ALT 48-158 U/L, 2 on risperidone, 2 on olanzapine and one on amisulpride; 1 on risperidone required discontinuation).

  18. Haberfellner EM, Honsig T. Nonalcoholic steatohepatitis: a possible side effect of atypical antipsychotics. J Clin Psychiatry 2003; 64: 851. PubMed Citation  (Three patients with weight gain [24-26 kg] had ALT elevations [47-91 U/L] on olanzapine or risperidone for ~4 years; ultrasound suggested fatty liver).

  19. Prior TI, Baker GB. Interactions between the cytochrome P450 system and the second-generation antipsychotics. J Psychiatry Neurosci 2003; 28: 99-112. PubMed Citation  (Review of the interactions of the atypical antipsychotics with the P450 system; clozapine is metabolized by CYP1A2 and 3A4 and possibly 2C9 and 2D6; risperidone by CYP2D6 and possibly 3A4; olanzapine by CYP1A2 and possibly 2D6; quetiapine and ziprasidone by CYP3A4).

  20. Bender S, Grohmann R, Engel RR, Degner D, Dittmann-Balcar A, Ruther E. Severe adverse drug reactions in psychiatric inpatients treated with neuroleptics. Pharmacopsychiatry 2004; 37(Suppl 1): S46-53. PubMed Citation  (Severe adverse drug reactions among 35,293 inpatients; adverse events more common with atypicals [0.5-0.9%] than typical antipsychotic agents [0.02-0.2%], increased liver enzymes was the most common adverse reaction to olanzapine, 4th in frequency to clozapine, 6th to haloperidol, 7th to risperidone; no mention of hepatitis or acute liver failure).

  21. Holtmann M, Kopf D, Mayer M, Bechtinger E, Schmidt MH. Risperidone-associated steatohepatitis and excessive weight-gain. Pharmacopsychiatry 2003; 36: 206-7. PubMed Citation  (17 year old woman had significant weight gain [35 kg] and ALT elevations [108 U/L] on clozapine that worsened when switched to risperidone; ultrasound showed hypo-echogenicity suggestive of fatty liver; ALT levels decreased after stopping risperidone and a weight loss of 5 kg).

  22. Choice of an antipsychotic. Med Lett Drugs Ther 2003; 45: 102-4. PubMed Citation  (Risperidone is a second generation antipsychotic with the highest rate of galactorrhea, gynecomastia and sexual dysfunction; no mention of liver injury).

  23. Aman MG, Arnold LE, McDougle CJ, Vitiello B, Scahill L, Davies M, McCracken JT, et al. Acute and long-term safety and tolerability of risperidone in children with autism. J Child Adolesc Psychopharmacol 2005; 15: 869-84. PubMed Citation  (8 week trial of risperidone vs placebo in 101 children and adolescents; ALT levels rose to >2 times ULN in 2 risperidone- vs no placebo-recipients).

  24. Llinares Tello F, Hernández Prats C, Bosacoma Ros N, Pérez Martínez E, Climent Grana E, Navarro Polo JN, Ordovás Baines JP. Acute cholestatic hepatitis probably associated with risperidone. Int J Psychiatry Med 2005; 35: 199-205. PubMed Citation  (64 year old man developed rising serum enzymes between days 2 and 5 of risperidone treatment [bilirubin 0.5 mg/dL, ALT 186 U/L, Alk P 1326 U/L], values falling to near normal 2 weeks after stopping).

  25. Radzik J, Grotthus B, Leszek J. [Disorder of liver functions in a schizophrenic patient after long-term risperidone treatment—case report]. Psychiatr Pol 2005; 39: 309-13. PubMed Citation  (51 year old man developed jaundice after 4 years of risperidone therapy [bilirubin 2.5 mg/dL, AST 49 U/L, normal Alk P and GGT], possibly representing Gilbert syndrome and minor AST elevations from risperidone; unclear whether abnormalities resolved on stopping).

  26. Pae CU, Lim HK, Kim TS, Kim JJ, Lee CU, Lee SJ, Lee C, et al. Naturalistic observation on the hepatic enzyme changes in patients treated with either risperidone or olanzapine alone. Int Clin Psychopharmacol 2005; 20: 173-6. PubMed Citation  (Retrospective analysis found ALT elevations more common among 145 patients on olanzapine [25%] than 298 on risperidone [13%] and particularly >3 times ULN [7.6% vs 2.8%]; no instances of jaundice or hepatitis).

  27. Esposito D, Brocvielle H, Becquemont L, Hardy P, Chouinard G, Corruble E. Risperidone-induced immunoallergic hepatitis. Am J Psychiatry 2005; 162: 1984. PubMed Citation  (28 year old man developed enzyme elevations 7 weeks and symptoms 8 weeks after starting risperidone [bilirubin normal, ALT 522 U/L], resolving within 3 weeks of stopping; smooth muscle antibody positive).

  28. Legaz Huidobro ML, González Carro P, Pérez Roldán F, Soto Fernández S, de Pedro Esteban A, Cuesta Domínguez R. [Autoimmune hepatitis after risperidone-induced cholestatic hepatitis]. Gastroenterol Hepatol 2005; 28: 135-6. Spanish. PubMed Citation  (36 year old woman developed jaundice 10 days after starting risperidone [bilirubin rising from 15 to 29 mg/dL, ALT 818 U/L, Alk P 627 U/L, ANA of 1:320]; ALT continued to rise for 3 weeks [peak 1185 U/L] and prednisone was started with rapid response, but relapse [ALT 843 U/L, ANA 1:1280] when corticosteroids stopped, biopsy showing features of autoimmune hepatitis which was again controlled by prednisone and later with azathioprine alone).

  29. Perlis RH, Baker RW, Zarate CA Jr, Brown EB, Schuh LM, Jamal HH, Tohen M. Olanzapine versus risperidone in the treatment of manic or mixed States in bipolar I disorder: a randomized, double-blind trial. J Clin Psychiatry 2006; 67: 1747-53. PubMed Citation  (Trial of 3 weeks of olanzapine [n=165] vs risperidone [n=164] for bipolar illness; greater weight gain [16% vs 4%] and ALT elevations [mean increase 15.7 U/L vs 1 U/L] with olanzapine).

  30. Rettenbacher MA, Baumgartner S, Eder-Ischia U, Edlinger M, Graziadei I, Hofer A, Huber R, et al. Association between antipsychotic-induced elevation of liver enzymes and weight gain: a prospective study. J Clin Psychopharmacol 2006; 26: 500-3. PubMed Citation  (Prospective study of 67 patients started on atypical antipsychotics [10 on risperidone]; ALT elevations were more frequent in 14 patients who gained >7% of body weight than in 53 who did not [50% vs 19%] and mean changes in ALT, AST and GGT were greater; all were transient, asymptomatic and not associated with bilirubin elevations).

  31. Wright TM, Vandenberg AM. Risperidone- and quetiapine-induced cholestasis. Ann Pharmacother 2007; 41: 1518-23. PubMed Citation  (30 year old man developed jaundice after 8 years of therapy with risperidone and lithium [bilirubin 4.7 mg/dL, ALT 99 U/L, Alk P 267 U/L], resolving with change of risperidone to ziprasidone, but recurring 3 weeks after starting quetiapine, after tolerating olanzapine).

  32. Atasoy N, Erdogan A, Yalug I, Ozturk U, Konuk N, Atik L, Ustundag Y. A review of liver function tests during treatment with atypical antipsychotic drugs: a chart review study. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 1255-60. PubMed Citation  (Retrospective analysis on 194 patients on atypical antipsychotics; ALT >3 times ULN occurred in 27%, often in first month; among 29 receiving risperidone, 28% had ALT elevations, but elevations were modest and none >3 times ULN).

  33. Sikich L, Frazier JA, McClellan J, Findling RL, Vitiello B, Ritz L, Ambler D, et al. Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study. Am J Psychiatry 2008; 165: 1420-31. PubMed Citation  (Prospective trial of molindone [1st generation antipsychotic agent] vs olanzapine or risperidone [2nd generation agents] for schizophrenia in 199 youths found similar rates of efficacy [34-50%], but more weight gain [mean 6.1 kg] and ALT elevations with olanzapine).

  34. Erdogan A, Atasoy N, Akkurt H, Ozturk D, Karaahmet E, Yalug I, Yalug K, et al. Risperidone and liver function tests in children and adolescents: a short-term prospective study. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 849-57. PubMed Citation  (Among 120 children and adolescents prospectively followed for one month on risperidone therapy, 52.5% had mild ALT elevations, but only 1 subject had ALT >3 times ULN [ALT 225 U/L, Alk P 641 U/L, bilirubin 0.4 mg/dL], resolving with discontinuation; no correlation with weight gain, which occurred in 57%).

  35. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H,
    Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation  (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008; several antidepressants [duloxetine, sertaline, fluoxetine, amitryptilline], but none of the atypical antipsychotic agents were implicated).

  36. Torrent C, Amann B, Sanchez-Moreno J, Colom F, Feinares M, Comes M, Rosa AR, et al. Weight gain in bipolar disorder: pharmacological treatment as a contributing factor. Acta Psychiatr Scand 2008; 118: 4-18. PubMed Citation  (Review of frequency of weight gain in patients treated for bipolar disorders, most weight gain occurred with clozapine and olanzapine, but some weight gain also with quetiapine, risperidone, lithium, valproate and gabapentin; not with aripiprazole, ziprasidone, carbamazepine or lamotrigine).

  37. Parsons B, Allison DB, Loebel A, Williams K, Giller E, Romano S, Siu C. Weight effects associated with antipsychotics: a comprehensive database analysis. Schizophr Res 2009; 110:103-10. PubMed Citation  (Analysis of weight gain in 21 placebo controlled trials [~3300 patients]; average monthly weight gain in pounds was +0.1 with placebo, +0.8 olanzapine, 0.6 risperidone, -0.3 ziprasidone; a 5% increase in weight occurred after one year in 13% of placebo, 39% haloperidol, 20% ziprasidone, 45% risperidone and 60% olanzapine treated subjects).

  38. Paulzen M, Orfanos S, Gründer G. Remission of drug-induced hepatitis after switching from risperidone to paliperidone. Am J Psychiatry 2010; 167: 351-2. PubMed Citation  (43 year old woman with schizophrenia developed jaundice on risperidone and clozapine therapy [bilirubin not given, ALT 75 U/L, Alk P 6 times ULN], improving on switching from risperidone to paliperidone and lowering clozapine dosage).

  39. Lin CH, Kuo CC, Chou LS, Chen YH, Chen CC, Huang KH, Lane HY. A randomized, double-blind comparison of risperidone versus low-dose risperidone plus low-dose haloperidol in treating schizophrenia. J Clin Psychopharmacol 2010; 30: 518-25. PubMed Citation  (Controlled trial of 6 weeks of risperidone alone vs lower dose risperidone and haloperidol in 88 patients with schizophrenia; no change in mean ALT or AST levels in either group and no mention of hepatotoxicity).

  40. Erdogan A, Karaman MG, Ozdemir E, Yurteri N, Tufan AE, Kurcer MA. Six months of treatment with risperidone may be associated with nonsignificant abnormalities of liver function tests in children and adolescents: a longitudinal, observational study from Turkey. J Child Adolesc Psychopharmacol 2010; 20: 407-13. PubMed Citation  (Among 102 children or adolescents [ages 2-18 years] treated with risperidone for more than 6 months, serum enzyme elevations occurred in 38%, but were usually transient and mild and isolated Alk P elevations only; only one child had ALT rise above twice normal [ALT 225 U/L, GGT 27 U/L, bilirubin 0.5 mg/dL], which resolved within one month of stopping; weight gain averaged 5.5 kg at 6 months).

  41. Karaman MG, Erdoğan A, Tufan E, Yurteri N, Ozdemir E, Ankarali H. Liver function tests in children and adolescents receiving risperidone treatment for a year: a longitudinal, observational study from Turkey. Int J Psychiatry Clin Pract 2011; 15: 204-8. PubMed Citation  (Among 100 children or adolescents treated with risperidone for more than 6 months, liver tests were abnormal in 21%, but none had symptoms and only one child had an ALT level above 3 times ULN, which resolved rapidly upon stopping).

  42. Copur M, Erdogan A. Risperidone rechallenge for marked liver function test abnormalities in an autistic child. Recent Pat Endocr Metab Immune Drug Discov
    2011; 5: 237-9. PubMed Citation  (5 year old boy with atuism was found to have elevations in serum enzymes during risperidone therapy, which resolved on stopping but did not recur when risperidone was restarted).

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Risperidone
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