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March 2008

Topiramate for Alcohol Dependence
Topiramate (Topamax) has been found to be beneficial in treating alcohol dependence.

Early Intervention for Schizophrenia: A Role for Antidepressants?
Antidepressants may reduce the transition from a prodrome of pre-psychosis to schizophrenia in vulnerable individuals.

In Brief
Duloxetine Approved for GAD; Depression in Parkinson’s Disease; Asthma Linked to Psychiatric Disorder

Adjunctive Antipsychotics for MDD
Patients with treatment-resistant major depressive disorder may benefit from the addition of second-generation antipsychotics to an antidepressant medication regimen.

Antipsychotics in Youth with Schizophrenia
Early-onset schizophrenia-spectrum disorder requires long-term antipsychotic treatment, but children and adolescents are sensitive to antipsychotic side effects and should be monitored carefully.

Antipsychotics in Youth with Schizophrenia

March 2008

Only about 1% of adults with schizophrenia have a first onset of psychotic symptoms before age 13 years.1 The incidence then increases sharply between ages 12 and 14 years. As many as one-third of adults with schizophrenia have early-onset schizophrenia-spectrum (EOSS) disorder, defined as onset of psychotic symptoms before age 18 years, which requires long-term antipsychotic medication treatment. Kumra and coauthors conducted a literature search of clinical trials of antipsychotics in children and adolescents with EOSS disorder and identified 10 double-blind clinical trials that included at least 15 subjects.1

As in adults, second-generation agents have a reduced propensity in children to cause adverse motor side effects and prolactin elevations compared with first-generation agents. Adolescents might be more vulnerable than adults, however, to a number of other side effects of these medications, including weight gain, metabolic disturbances, elevated prolactin, and sedation. Nonadherence to treatment is common among youth with schizophrenia, and weight gain is often the reason. The authors found no good treatment guidelines to address treatment-emergent obesity, diabetes, or hyperlipidemia in children or adolescents treated with second-generation antipsychotics. Possible antidotes that have been discussed include metformin (Glucophage and others), orlistat (Xenical), amantadine (Symmetrel and others), and sibutramine (Meridia), but none has been studied sufficiently.

Open-label studies of clozapine (Clozaril and others) have found it to be effective for both positive and negative symptoms as well as aggressive outbursts in EOSS disorder. It has been demonstrated to be superior to olanzapine (Zyprexa) in reducing negative symptoms in treatment-refractory EOSS disorder but not as consistently superior in improving overall clinical outcome.

In independent work, Sporn and associates describe 54 children and adolescents who had treatment-refractory childhood-onset schizophrenia, defined as the first episode of psychosis before a 13th birthday, and were enrolled in studies involving double-blind or open-label clozapine treatment.2 Subjects were followed for up to 6 years.

Sporn et al found that the best predictor of a positive response to clozapine in this young, treatment-resistant population was the ratio of plasma concentrations of N-desmethylclozapine to clozapine. A majority of clinical improvement occurred by 6 weeks, and 6-week response was the best predictor of long-term outcome. Nonetheless, of nine children who were nonresponders at 6 weeks, five went on to subsequently show response. The authors suggest that clozapine is an appropriate treatment for children and adolescents with early-onset schizophrenia who have failed two previous trials of antipsychotics. Monitoring of white blood cell counts should be the same as for adults: weekly for the first 6 months and biweekly thereafter. Children appear to have a higher rate of adverse effects than adults, suggesting the need for close monitoring. In the authors' study, neutropenia occurred in 6% of subjects (versus 1% to 2% for adults), and akathisia occurred in 15% (versus 3% for adults).

Early-onset schizophrenia is a severe condition. Among today's therapeutic options, antipsychotic drugs are almost always required for long-term treatment. In more difficult cases, clozapine should be tried and given at least a few months to determine response. Children and adolescents are sensitive to the adverse effects of antipsychotics and require careful clinical and laboratory monitoring.

1Kumra S, Oberstar JV, Sikich L, Findling RL, McClellan JM, Vinogradov S, Schulz SC: Efficacy and tolerability of second-generation antipsychotics in children and adolescents with schizophrenia. Schizophrenia Bull 2008;34:60–71.

2Sporn AL, Vermani A, Greenstein DK, Bobb AJ, Spencer EP, Clasen LS, Tossell JW, Stayer CC, Gochman PA, Lenane MC, Rapoport JL, Gogtay N: Clozapine treatment of childhood-onset schizophrenia: Evaluation of effectiveness, adverse effects, and long-term outcome. Schizophrenia Bull 2007;46:1349–1356.