Atypical Antipsychotics and Hyperglycemia - April 2004

The Food and Drug Administration (FDA) has concluded that the labeling for all atypical antipsychotics should be revised to highlight the potential for diabetes, weight gain, and dyslipidemia. The information has been summarized by a consensus panel (Diabetes Care 2004; 27:596-601). Severe hyperglycemia, including ketosis, has been documented in patients receiving this class of medications. Clozapine and olanzapine have been most clearly associated with these effects, while risperidone and quetiapine have produced discrepant results. Aripiprazole and ziprasidone are associated with little or no diabetes, but have not been used as extensively as the other agents implicated. It is difficult to define a causal relationship in this complex patient population, since the baseline risk of diabetes may be elevated. Patients with established diabetes (or with risk factors such as a family history or obesity) should be monitored closely for changes in glucose control. Measurement of fasting blood glucose at the beginning of therapy and periodic monitoring during therapy are recommended. A "Dear Healthcare Professional" letter has been mailed by the manufacturers of some atypical antipsychotics to alert clinicians to these issues.

Additional information may be found at http://www.fda.gov/medwatch/SAFETY/2004/safety04.htm, last accessed April 12, 2004.

May cause orthostasis; an increased incidence of cerebrovascular events has been associated with risperidone use in elderly demented patients. Use with caution in patients with cardiovascular diseases (eg, heart failure, history of myocardial infarction or ischemia, cerebrovascular disease, conduction abnormalities). Use caution in patients receiving medications for hypertension (orthostatic effects may be exacerbated) or in patients with hypovolemia or dehydration. May alter cardiac conduction (low risk relative to other neuroleptics); life-threatening arrhythmias have occurred with therapeutic doses of neuroleptics.

May cause anticholinergic effects (confusion, agitation, constipation, xerostomia, blurred vision, urinary retention); therefore, they should be used with caution in patients with decreased gastrointestinal motility, urinary retention, BPH, xerostomia, or visual problems. Conditions which also may be exacerbated by cholinergic blockade include narrow-angle glaucoma (screening is recommended) and worsening of myasthenia gravis. Relative to other neuroleptics, risperidone has a low potency of cholinergic blockade.

May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is low relative to other neuroleptics, and is dose dependent). May be associated with neuroleptic malignant syndrome (NMS). May cause hyperglycemia; in some cases may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. Use with caution in patients with diabetes or other disorders of glucose regulation; monitor for worsening of glucose control.

Frequency not defined: Gastrointestinal: Dysphagia, esophageal dysmotility

>10%:

Central nervous system: Insomnia, agitation, anxiety, headache, extrapyramidal symptoms (dose dependent), dizziness (I.M. injection)

Gastrointestinal: Weight gain

Respiratory: Rhinitis (I.M. injection)

1% to 10%:

Cardiovascular: Hypotension (especially orthostatic), tachycardia

Central nervous system: Sedation, dizziness (oral formulation), restlessness, dystonic reactions, pseudoparkinsonism, tardive dyskinesia, neuroleptic malignant syndrome, altered central temperature regulation, nervousness, fatigue, somnolence, hallucination, tremor, hypoesthesia, akathisia

Dermatologic: Photosensitivity (rare), rash, dry skin, seborrhea, acne

Endocrine & metabolic: Amenorrhea, galactorrhea, gynecomastia, sexual dysfunction

Gastrointestinal: Constipation, GI upset, xerostomia, dyspepsia, vomiting, abdominal pain, nausea, anorexia, diarrhea, weight changes

Genitourinary: Polyuria

Neuromuscular & skeletal: Myalgia

Ocular: Abnormal vision

Respiratory: Rhinitis (oral formulation), cough, sinusitis, pharyngitis, dyspnea

<1%: Diabetes mellitus, hyperglycemia

Postmarketing and/or case reports (limited): Stroke, transient ischemic attack (TIA), anaphylactic reaction

Antihypertensives: Risperidone may enhance the hypotensive effects of antihypertensive agents

Carbamazepine: Plasma concentrations of risperidone and 9-hydroxyrisperidone were decreased by ~50% with concomitant use. The dose of risperidone may need to be titrated accordingly when carbamazepine is added or discontinued.

Clozapine: Decreases clearance of risperidone, increasing its serum concentrations

CYP2D6 inhibitors: May increase the levels/effects of risperidone. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.

Levodopa: At high doses (>6 mg/day), risperidone may inhibit the antiparkinsonian effect of levodopa; avoid this combination when high doses are used

Metoclopramide: May increase extrapyramidal symptoms (EPS) or risk.

Valproic acid: Generalized edema has been reported as a consequence of concurrent therapy (case report)

Ethanol: Avoid ethanol (may increase CNS depression).

Herb/Nutraceutical: Avoid kava kava, gotu kola, valerian, St John's wort (may increase CNS depression).

Absorption:

Oral: Rapid and well absorbed; food does not affect rate or extent

Injection: <1% absorbed initially; main release occurs at ~3 weeks and is maintained from 4-6 weeks

Distribution: Vd: 1-2 L/kg

Protein binding, plasma: Risperidone 90%; 9-hydroxyrisperidone: 77%

Metabolism: Extensively hepatic via CYP2D6 to 9-hydroxyrisperidone (similar pharmacological activity as risperidone); N-dealkylation is a second minor pathway

Bioavailability: Solution: 70%; Tablet: 66%; orally-disintegrating tablets are bioequivalent to tablets

Half-life elimination: Active moiety (risperidone and its active metabolite 9-hydroxyrisperidone)

Oral: 20 hours (mean)

Extensive metabolizers: Risperidone: 3 hours; 9-hydroxyrisperidone: 21 hours

Poor metabolizers: Risperidone: 20 hours; 9-hydroxyrisperidone: 30 hours

Injection: 3-6 days; related to microsphere erosion and subsequent absorption of risperidone

Time to peak, plasma: Oral: Risperidone: Within 1 hour; 9-hydroxyrisperidone: Extensive metabolizers: 3 hours; Poor metabolizers: 17 hours

Excretion: Urine (70%); feces (15%)

Oral:

Children and Adolescents:

Pervasive developmental disorder (unlabeled use): Initial: 0.25 mg twice daily; titrate up 0.25 mg/day every 5-7 days; optimal dose range: 0.75-3 mg/day

Autism (unlabeled use): Initial: 0.25 mg at bedtime; titrate to 1 mg/day (0.1 mg/kg/day)

Schizophrenia (unlabeled use): Initial: 0.5 mg once or twice daily; titrate as necessary up to 2-6 mg/day

Bipolar disorder (unlabeled use): Initial: 0.5 mg; titrate to 0.5-3 mg/day

Tourette's disorder (unlabeled use): Initial: 0.5 mg; titrate to 2-4 mg/day

Adults:

Schizophrenia: Recommended starting dose: 0.5-1 mg twice daily; slowly increase to the optimum range of 3-6 mg/day; may be given as a single daily dose once maintenance dose is achieved; daily dosages >10 mg does not appear to confer any additional benefit, and the incidence of extrapyramidal symptoms is higher than with lower doses

Bipolar mania: Recommended starting dose: 2-3 mg once daily; if needed, adjust dose by 1 mg/day in intervals 24 hours; dosing range: 1-6 mg/day

Elderly: A starting dose of 0.25-1 mg in 1-2 divided doses, and titration should progress slowly. Additional monitoring of renal function and orthostatic blood pressure may be warranted. If once-a-day dosing in the elderly or debilitated patient is considered, a twice daily regimen should be used to titrate to the target dose, and this dose should be maintained for 2-3 days prior to attempts to switch to a once-daily regimen.

I.M.: Adults: Schizophrenia (Risperdal® Consta™): 25 mg every 2 weeks; some patients may benefit from larger doses; maximum dose not to exceed 50 mg every 2 weeks. Dosage adjustments should not be made more frequently than every 4 weeks.

Note: Oral risperidone (or other antipsychotic) should be administered with the initial injection of Risperdal® Consta™ and continued for 3 weeks (then discontinued) to maintain adequate therapeutic plasma concentrations prior to main release phase of risperidone from injection site.

Dosing adjustment in renal impairment: Oral: Starting dose of 0.25-0.5 mg twice daily; clearance of the active moiety is decreased by 60% in patients with moderate to severe renal disease compared to healthy subjects.

Dosing adjustment in hepatic impairment: Oral: Starting dose of 0.25-0.5 mg twice daily; the mean free fraction of risperidone in plasma was increased by 35% compared to healthy subjects.

Oral: Oral solution can be mixed with water, coffee, orange juice, or low-fat milk, but is not compatible with cola or tea. May be administered with or without food.

Risperdal® M-Tabs™ should not be removed from blister pack until administered. Using dry hands, place immediately on tongue. Tablet will dissolve within seconds, and may be swallowed with or without liquid. Do not split or chew.

I.M.: Risperdal® Consta™ should be administered into the upper outer quadrant of the gluteal area. Injection should alternate between the two buttocks. Do not combine two different dosage strengths into one single administration. Do not substitute any components of the dose-pack; administer with needle provided.

Temazepam (30 mg) can be used to treat risperidone-induced insomnia.

Aggression: In a randomized, double-blind, placebo-controlled study, 10 children and adolescents 6-14 years of age (mean: 9.2 ± 2.9 years) with conduct disorder and prominent aggressive behavior received risperidone in the following doses: Patients <50 kg: Initial: 0.25 mg once daily; doses were increased as needed by 0.25 mg/day increments each week to a maximum of 1.5 mg/day; patients 50 kg: Initial: 0.5 mg once daily; doses were increased as needed by 0.5 mg/day increments each week to a maximum of 3 mg/day; final dose: 0.75-1.5 mg/day; mean: 0.028 ± 0.004 mg/kg/day (Findling, 2000). In another randomized, double-blind, placebo-controlled study, 19 adolescents (mean age: 14 ± 1.5 years; 7 with borderline IQ and 6 with mild mental retardation) received initial risperidone doses of 0.5 mg twice daily; doses were increased as needed by 1 mg/day increments up to a planned maximum of 5 mg twice daily; final doses: Range: 1.5-4 mg/day (0.019-0.08 mg/kg/day); mean: 2.9 mg/day (0.044 mg/kg/day); the authors recommend the following initial doses for clinical practice: Patients <25 kg: 0.25 mg/day; patients 25 kg: 0.5 mg/day (Buitelaar, 2001).

In an open trial, 26 children and adolescents 10-18 years of age (mean: 15 ± 1.9 years) with a borderline IQ (n=19) or mild mental retardation (n=5) received initial risperidone doses of 0.5 mg/day; doses were increased by 0.5-1 mg/day increments every 3 days up to a planned maximum of 6 mg/day and given in twice daily doses; final dose: 0.5-4 mg/day; mean: 2.1 ± 1 mg/day (Buitelaar, 2000). Eleven children and adolescents 5.5-16 years of age (mean: 9.8 years) with mood disorders and aggressive behavior received risperidone in titrated doses in an open trial; final dose: 0.75-2.5 mg/day given in 2-3 divided doses (Schreier, 1998).

Autism: A multicenter double-blind, placebo-controlled trial of risperidone in children and adolescents 5-17 years of age (mean: 8.8 ± 2.7 years) with autism and serious behavioral problems demonstrated the short-term efficacy of risperidone for the treatment of aggression, tantrums, or self-injurious behavior. The following doses were used: Children 15-20 kg: Initial: 0.25 mg/day. Children 20-45 kg: Initial: 0.5 mg at bedtime on days 1-3 and 0.5 mg twice daily on day 4; dose was gradually increased in 0.5 mg increments to a maximum dose of 2.5 mg/day. Children >45 kg: Maximum dose: 3.5 mg/day; mean effective dose: 1.8 ± 0.7 mg/day (range: 0.5-3.5 mg/day) (McCracken, 2002).

In an open-labeled prospective study, 10 boys 4.5-10.8 years of age (mean: 7.2 ± 2.2 years) with autistic disorder were started on risperidone 0.5 mg/day; final dose: range: 1-2.5 mg/day (0.03-0.08 mg/kg/day); mean: 1.3 ± 0.5 mg/day (0.05 ± 0.2 mg/kg/day) (Nicolson, 1998). In an open clinical trial, 6 children 5-9 years of age (mean: 7.33 years) with autistic disorder were started on risperidone monotherapy 0.25 mg at bedtime; final dose: range: 0.75-1.5 mg/day (0.03-0.06 mg/kg/day); mean: 1.1 mg (0.04 mg/kg/day) (Findling, 1997).

Bipolar disorder: In a retrospective chart review, 28 children and adolescents 4-17 years of age (mean: 10.4 ± 3.8 years) were treated for bipolar disorder; optimal mean dose: 1.7 ± 1.3 mg/day (Frazier 1999).

Pervasive developmental disorders (PDDs): In a prospective open-labeled study, children and adolescents 5-18 years of age (mean 10.2 ± 3.7 years) were treated for PDDs (11 with autistic disorder) with initial doses of 0.5 mg at night; optimal dose: 1-4 mg/day (mean: 1.8 ± 1 mg/day) (McDougle, 1997). Fourteen children and adolescents 9-17 years of age (mean: 12.7 ± 4 years) were treated in an open case series, for PDDs (4 with autistic disorder) with initial doses of 0.25 mg twice daily; optimal dose: 0.75-1.5 mg/day given in divided doses (Fisman, 1996). In an open trial, 6 children and adolescents 7-14 years of age (mean: 10.7 ± 3.3 years) were treated for PDDs (5 with autistic disorder; all 6 with severe behavioral problems) with initial doses of 0.5 mg once or twice daily; optimal dose: 1-6 mg/day (mean 2.7 ± 2.2 mg/day) (Perry, 1997). Twenty children and adolescents (age: 8-17 years) with developmental disorders refractory to previous psychotropic agents were treated in an open clinical trial with risperidone; final doses: 1.5-10 mg/day; responders: 1-4 mg/day; nonresponders: 4.5-10 mg/day (Hardan, 1996).

Schizophrenia: In a prospective, open-labeled pilot study, 10 children and adolescents 11-18 years of age (mean: 15.1 years) were treated for schizophrenia with initial doses of 1 mg twice daily; final dose: Range: 4-10 mg/day (0.05-0.17 mg/kg/day); mean: 6.6 mg/day (0.095 mg/kg/day) (Armenteros, 1997). In a retrospective study, 16 children and adolescents 9-20 years of age (mean 14.9 ± 2.73 years) were treated for psychotic disorders with initial doses of 1 mg twice daily; optimal dose: 2-10 mg/day (mean 5.9 ± 2.8 mg/day) divided and given in 2-3 doses/day (Grcevich, 1996).

Tourette's syndrome: In a multicenter, double-blind, parallel-group comparative study, 50 patients 11-50 years of age were treated for Tourette's syndrome with risperidone versus pimozide; final dose: 0.5-6 mg/day (mean: 3.8 mg/day) (Bruggeman, 2001).

Seven children and adolescents 11-16 years of age (mean: 12.9 ± 1.9 years) were treated in a prospective open-labeled trial for chronic tic disorders (5 with Tourette's syndrome) with initial doses of 0.5 mg at bedtime; final dose: 1-2.5 mg/day (Lombroso, 1995). In a retrospective review, 28 children and adolescents 5-18 years of age (mean 11.1 ± 3.6 years) with Tourette's syndrome and aggressive behavior were treated with risperidone; final dose: 0.5-9 mg/day (mean: 2 mg/day) (Sandor, 2000).

Armenteros JL, Whitaker AH, Welikson M, et al, "Risperidone in Adolescents With Schizophrenia: An Open Pilot Study,"J Am Acad Child Adolesc Psychiatry, 1997, 36(5):694-700.

Bruggeman R, van der Linden C, Buitelaar JK, et al, "Risperidone Versus Pimozide in Tourette's Disorder: A Comparative Double-Blind Parallel-Group Study,"J Clin Psychiatry, 2001, 62(1):50-6.

Buitelaar JK, "Open-Label Treatment With Risperidone of 26 Psychiatrically-Hospitalized Children and Adolescents With Mixed Diagnoses and Aggressive Behavior,"J Child Adolesc Psychopharmacol, 2000, 10(1):19-26.

Buitelaar JK, van der Gaag RJ, Cohen-Kettenis P, et al, "A Randomized Controlled Trial of Risperidone in the Treatment of Aggression in Hospitalized Adolescents With Subaverage Cognitive Abilities,"J Clin Psychiatry, 2001, 62(4):239-48.

Findling RL, Maxwell K, and Wiznitzer M, "An Open Clinical Trial of Risperidone Monotherapy in Young Children With Autistic Disorder,"Psychopharmacol Bull, 1997, 33(1):155-9.

Findling RL, McNamara NK, Branicky LA, et al, "A Double-Blind Pilot Study of Risperidone in the Treatment of Conduct Disorder,"J Am Acad Child Adolesc Psychiatry, 2000, 39(4):509-16.

Fisman S and Steele M, "Use of Risperidone in Pervasive Developmental Disorders: A Case Series,"J Child Adolesc Psychopharmacol, 1996, 6(3):177-90.

Frazier JA, Meyer MC, Biederman J, et al, "Risperidone Treatment for Juvenile Bipolar Disorder: A Retrospective Chart Review,"J Am Acad Child Adolesc Psychiatry, 1999, 38(8):960-5.

Grcevich SJ, Findling RL, Rowane WA, et al, "Risperidone in the Treatment of Children and Adolescents With Schizophrenia: A Retrospective Study,"J Child Adolesc Psychopharmacol, 1996, 6(4):251-7.

Hardan A, Johnson K, Johnson C, et al, "Case Study: Risperidone Treatment of Children and Adolescents With Developmental Disorders,"J Am Acad Child Adolesc Psychiatry, 1996, 35(11):1551-6.

Lombroso PJ, Scahill L, King RA, et al, "Risperidone Treatment of Children and Adolescents With Chronic Tic Disorders: A Preliminary Report,"J Am Acad Child Adolesc Psychiatry, 1995, 34(9):1147-52.

McCracken JT, McGough J, Shah B, et al, "Risperidone in Children With Autism and Serious Behavioral Problems,"N Engl J Med, 2002, 347(5):314-21.

McDougle CJ, Holmes JP, Bronson MR, et al, "Risperidone Treatment of Children and Adolescents With Pervasive Developmental Disorders: A Prospective Open-Label Study,"J Am Acad Child Adolesc Psychiatry, 1997, 36(5):685-93.

Nicolson R, Awad G, and Sloman L, "An Open Trial of Risperidone in Young Autistic Children,"J Am Acad Child Adolesc Psychiatry, 1998, 37(4):372-6.

Perry R, Pataki C, Munoz-Silva DM, et al, "Risperidone in Children and Adolescents With Pervasive Developmental Disorder: Pilot Trial and Follow-Up,"J Child Adolesc Psychopharmacol, 1997, 7(3):167-79.

Sandor P and Stephens RJ, "Risperidone Treatment of Aggressive Behavior in Children With Tourette Syndrome,"J Clin Psychopharmacol, 2000, 20(6):710-2.

Schreier HA, "Risperidone for Young Children With Mood Disorders and Aggressive Behavior,"J Child Adolesc Psychopharmacol, 1998, 8(1):49-59.

Injection, microspheres for reconstitution, extended release (Risperdal® Consta™): 25 mg, 37.5 mg, 50 mg [supplied in a dose-pack containing vial with active ingredient in microsphere formulation, prefilled syringe with diluent, needle-free vial access device, and safety needle]

Solution, oral: 1 mg/mL (30 mL) [contains benzoic acid]

Tablet: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg

Tablet, orally disintegrating (Risperdal® M-Tabs™): 0.5 mg [contains phenylalanine 0.14 mg]; 1 mg [contains phenylalanine 0.28 mg]; 2 mg [contains phenylalanine 0.56 mg]

Acri AA and Henretig FM, "The Effects of Risperidone (Risperdal® - Janssen) In Overdose,"Clin Toxicol, 1995, 33(5):521.

American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity, "Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes,"Diabetes Care, 2004, 27(2):596-601.

Armenteros JL, Whitaker AH, Welikson M, et al, "Risperidone in Adolescents With Schizophrenia: An Open Pilot Study,"J Am Acad Child Adolesc Psychiatry, 1997, 36(5):694-700.

Borison RL, Pathiraja AP, Diamond BI, et al, "Risperidone: Clinical Safety and Efficacy in Schizophrenia,"Psychopharmacol Bull, 1992, 28(2):213-8.

Bruggeman R, van der Linden C, Buitelaar JK, et al, "Risperidone Versus Pimozide in Tourette's Disorder: A Comparative Double-Blind Parallel-Group Study,"J Clin Psychiatry, 2001, 62(1):50-6.

Buitelaar JK, "Open-Label Treatment With Risperidone of 26 Psychiatrically-Hospitalized Children and Adolescents With Mixed Diagnoses and Aggressive Behavior,"J Child Adolesc Psychopharmacol, 2000, 10(1):19-26.

Buitelaar JK, van der Gaag RJ, Cohen-Kettenis P, et al, "A Randomized Controlled Trial of Risperidone in the Treatment of Aggression in Hospitalized Adolescents With Subaverage Cognitive Abilities,"J Clin Psychiatry, 2001, 62(4):239-48.

Byerly MJ, Greer RA, and Evans DL "Behavioral Stimulation Associated With Risperidone Initiation,"Am J Psychiatry, 1995, 152(7):1096-7.

Cardoni AA, "Risperidone: Review and Assessment of Its Role in the Treatment of Schizophrenia,"Ann Pharmacother, 1995, 29(6):610-8.

Cohen LJ, "Risperidone,"Pharmacotherapy, 1994, 14(3):253-65.

Dave M, "Two Cases of Risperidone-Induced Neuroleptic Malignant Syndrome,"Am J Psychiatry, 1995, 152(8):1233-4.

Davis JM, Chen N, and Glick ID, "A Meta-Analysis of the Efficacy of Second-Generation Antipsychotics,"Arch Gen Psychiatry, 2003, 60(6):553-64.

Findling RL, Maxwell K, and Wiznitzer M, "An Open Clinical Trial of Risperidone Monotherapy in Young Children With Autistic Disorder,"Psychopharmacol Bull, 1997, 33(1):155-9.

Findling RL, McNamara NK, Branicky LA, et al, "A Double-Blind Pilot Study of Risperidone in the Treatment of Conduct Disorder,"J Am Acad Child Adolesc Psychiatry, 2000, 39(4):509-16.

Fisman S and Steele M, "Use of Risperidone in Pervasive Developmental Disorders: A Case Series,"J Child Adolesc Psychopharmacol, 1996, 6(3):177-90.

Frazier JA, Meyer MC, Biederman J, et al, "Risperidone Treatment for Juvenile Bipolar Disorder: A Retrospective Chart Review,"J Am Acad Child Adolesc Psychiatry, 1999, 38(8):960-5.

Gelders YG, "Thymosthenic Agents, a Novel Approach in the Treatment of Schizophrenia,"Br J Psychiatry Suppl, 1989, 5:33-6.

Goss JB, "Concomitant Use of Thioridazine With Risperidone,"Am J Health Syst Pharm, 1995, 52(9):1012.

Grcevich SJ, Findling RL, Rowane WA, et al, "Risperidone in the Treatment of Children and Adolescents With Schizophrenia: A Retrospective Study,"J Child Adolesc Psychopharmacol, 1996, 6(4):251-7.

Hardan A, Johnson K, Johnson C, et al, "Case Study: Risperidone Treatment of Children and Adolescents With Developmental Disorders,"J Am Acad Child Adolesc Psychiatry, 1996, 35(11):1551-6.

Heather GS and Vicas IM, "Risperidone Overdose: A Case Series,"Vet Hum Toxicol, 1994, 36:371.

Kumra S, Herion D, Jacobsen LK, et al, "Case Study: Risperidone-Induced Hepatotoxicity in Pediatric Patients,"J Am Acad Child Adolesc Psychiatry, 1997, 36(5):701-5.

Kuspis D, Dean B, and Krenzelok EP, "Risperidone Overdose Assessment,"Clin Toxicol, 1995, 33(5):552.

Lombroso PJ, Scahill L, King RA, et al, "Risperidone Treatment of Children and Adolescents With Chronic Tic Disorders: A Preliminary Report,"J Am Acad Child Adolesc Psychiatry, 1995, 34(9):1147-52.

McCracken JT, McGough J, Shah B, et al, "Risperidone in Children With Autism and Serious Behavioral Problems,"N Engl J Med, 2002, 347(5):314-21.

McDougle CJ, Holmes JP, Bronson MR, et al, "Risperidone Treatment of Children and Adolescents With Pervasive Developmental Disorders: A Prospective Open-Label Study,"J Am Acad Child Adolesc Psychiatry, 1997, 36(5):685-93.

Meylan C, Bondolfi G, Aubert AC, et al, "Reversible Neutropenia During a Cold: Possible Involvement of Risperidone? A Case Report,"Eur Neuropsychopharmacol, 1995, 5(1):1-2.

Nicolson R, Awad G, and Sloman L, "An Open Trial of Risperidone in Young Autistic Children,"J Am Acad Child Adolesc Psychiatry, 1998, 37(4):372-6.

Perry R, Pataki C, Munoz-Silva DM, et al, "Risperidone in Children and Adolescents With Pervasive Developmental Disorder: Pilot Trial and Follow-Up,"J Child Adolesc Psychopharmacol, 1997, 7(3):167-79.

Sandor P and Stephens RJ, "Risperidone Treatment of Aggressive Behavior in Children With Tourette Syndrome,"J Clin Psychopharmacol, 2000, 20(6):710-2.

Schreier HA, "Risperidone for Young Children With Mood Disorders and Aggressive Behavior,"J Child Adolesc Psychopharmacol , 1998, 8(1):49-59.

Singer S, Richards C, and Boland RJ, "Two Cases of Risperidone-Induced Neuroleptic Malignant Syndrome,"Am J Psychiatry, 1995, 152(8):1234.

Swanson CL Jr, Price WA, and McEvoy JP, "Effects of Concomitant Risperidone and Lithium Treatment,"Am J Psychiatry, 1995, 152(7):1096.

Tekell JL, Smith EA, and Silva JA, "Prolonged Erection Associated With Risperidone Treatment,"Am J Psychiatry, 1995, 152(7):1097.