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August 2008

High-Dose Olanzapine in Treatment-Resistant Schizophrenia
For some treatment-resistant patients with schizophrenia, high-dose olanzapine might be a better option than clozapine.

Increased Stroke Risk in Schizophrenia Patients
Patients with schizophrenia appear to have an increased risk of stroke, and the risk may be higher for women than for men.

Tamoxifen for Mania?
Through inhibition of protein kinase C, tamoxifen may benefit patients with mania and merits further study.

In Brief
Genetic Variations in Patients with Schizophrenia; Zonisamide for Weight Loss in Bipolar Disorder; Music Therapy for Stroke Recovery

NMS in Children and Adolescents
The neuroleptic malignant syndrome is a risk in children and adolescents treated with second-generation antipsychotics.

Options for SSRI-Resistant Depression in Adolescents
In a study by Brent et al, depressed adolescents who did not respond sufficiently to an SSRI benefited from switching to a different antidepressant and cognitive behavioral therapy.

NMS in Children and Adolescents

August 2008

The neuroleptic malignant syndrome (NMS), an adverse event associated with antipsychotic treatment, is comprised of motor rigidity and other extrapyramidal signs, hyperthermia, altered mental state (from confusion through delirium), autonomic instability (including blood pressure and pulse changes), and laboratory abnormalities, such as increased serum creatine phosphokinase and elevated white blood cell counts. The mechanism of NMS remains obscure but is commonly attributed to dopamine D2 receptor blockade. Recent studies estimate the incidence as 0.01% to 0.02% of adults treated with antipsychotic drugs.1 Many believe the incidence of NMS with second-generation agents may be lower than with first-generation antipsychotics, but comparative data are sparse. Nonetheless, case reports link all available second-generation agents with NMS.

Second-generation antipsychotics have substantially eclipsed traditional agents in adults. The same is true in pediatric patients, for whom antipsychotics are prescribed for bipolar, pervasive developmental, disruptive behavior, tic, and eating disorders. The US Food and Drug Administration (FDA) recently approved risperidone (Risperdal and others) to treat irritability in autistic children, aged 5 through 16 years; schizophrenia in patients aged 13 to 17; and manic and mixed episodes in patients with bipolar I disorder, aged 10 to 17. Similarly, aripiprazole (Abilify) has received FDA-approved labeling for the treatment of schizophrenia in patients aged 13 to 17, and for the acute treatment of manic and mixed episodes in patients aged 10 to 17 with bipolar I disorder.

NMS exists in children, but details are few. One review of 77 NMS cases in children and adolescents treated with first-generation antipsychotics found little difference in the clinical presentation and course of NMS between children and adults, with fever, tachycardia, and rigidity being the cardinal NMS features.2 NMS cases often involved the use of multiple antipsychotic drugs. As in adults, there is a worrisome mortality rate. Croarkin and colleagues conducted a literature review to compile published information on antipsychotics in young patients.1

The authors located 20 published cases of purported NMS in patients aged 11 to 18 years. Sixteen of the patients were male. Diagnoses included schizophrenia, psychotic disorder not otherwise specified, bipolar disorder, major depressive disorder with psychotic features, and pervasive development disorder not otherwise specified. Associated antipsychotics were clozapine (Clozaril and others), risperidone, olanzapine (Zyprexa), ziprasidone (Geodon), and aripiprazole. Only 3 patients were being treated with multiple second-generation antipsychotics, but 11 were taking at least one other psychotropic medication concomitantly. Half the patients had had a prior episode of extrapyramidal reactions. No patient died.

Croarkin et al conclude that NMS is a risk in children and adolescents treated with second-generation antipsychotics. The presentation is similar to that observed in adults. Although a majority of published cases involve male patients, it is unclear from adult studies whether gender is, in fact, a risk factor. This review suggests that polypharmacy, recent medication changes, and prior episodes of extrapyramidal signs may be risk factors in pediatric patients taking antipsychotics.

In adults, high ambient temperatures and dehydration may be risk factors both for the development of NMS and for a fatal outcome.3 Caregivers should be alerted to these factors and advised to observe children treated with antipsychotics for alterations in mental status, motor function, or body temperature. Should these or other signs of NMS occur, the child requires urgent medical attention.

1Croarkin PE, Emslie GJ, Mayes TL: Neuroleptic malignant syndrome associated with atypical antipsychotics in pediatric patients. J Clin Psychiatry, in press.

2Silva RR, Munoz DM, Alpert M, Permutter IR, Diaz J: Neuroleptic malignant syndrome in children and adolescents. J Am Acad Child Adolesc Psychiatry 1999;38:187-194.

3Gelenberg AJ, Bellinghausen B, Wojcik JD, Falk WE, Sachs GS: A prospective survey of neuroleptic malignant syndrome in a short-term psychiatric hospital. Am J Psychiatry 1988;145:517-518.