New Findings in Early-Onset Schizophrenia

The Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) study, funded by the NIMH, was a multicenter, controlled treatment trial of children and adolescents.¹ The aim of the TEOSS study was to compare the efficacy and safety of risperidone and olanzapine with that of a traditional antipsychotic agent-molindone.

In this double-blind, parallel-group study, patients were randomized to receive risperidone, olanzapine, or molindone for 8 weeks followed by a 44-week, double-blind maintenance phase for responders. A total of 119 children and adolescents were randomized in the study. The results of the study, which should be reported in the near future, will provide needed information about the safety and tolerability of antipsychotic medications in youths with schizophrenia spectrum disorders.

The clinical characteristics of this large sample were recently reported and provide important information about the demographics and severity of illness in children and adolescents with early-onset schizophrenia and schizoaffective disorder.² The mean age of onset of illness was 11.1 years. At the time of enrollment, the mean age of the patients was 13.8 years. The sex distribution was 66% male and 34% female. The racial breakdown was 62% white, 31% African Amer-ican, 3.4% Asian, 2.5% mixed, and 0.8% Pacific Islander. The average IQ of the sample was 93. Most of the youths lived with their family, 4% were hospitalized, and 7% lived in a group home or residential facility.

Before the current diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder, the youths had a wide range of lifetime diagnoses, which included attention-deficit/hyperactivity disorder (28%), mood disorders (25%), anxiety disorders (19%), and conduct and oppositional defiant disorders (16%). The youths had been treated previously with antipsychotics (50%), antidepressants (42%), stimulants (32%), or mood stabilizers (21%). Nearly half of the youths had at least 1 previous psychiatric hospitalization. Fifteen percent of them had a history of suicide attempts. Twenty-five percent of the youths had a history of legal problems or aggression. Physical and sexual abuse (23%) and neglect (14%) were common. The youths had a high rate of psychotic symptoms, mood symptoms, anxiety symptoms, behavioral problems, and impairment in overall functioning, as well as social and school functioning.

The authors concluded that compared with adults who have schizophrenia, these youths with early-onset schizophrenia spectrum disorders were more severely ill and had significantly more negative and positive psychotic symptoms.

Treatment with risperidone
Risperidone is the first atypical antipsychotic that has been approved by the FDA for the treatment of schizophrenia in adolescents aged 13 to 17.³ Two controlled trials 6 to 8 weeks in duration supported the efficacy and safety of risperidone for this use.⁴ In a double-blind, placebo-controlled trial, adolescents were randomized to 1 of 3 treatment groups: placebo, risperidone 1 to 3 mg/d, or risperidone 4 to 6 mg/d.

The patients in both risperidone groups demonstrated a statistically and clinically significant decrease in psychotic symptoms (according to Positive and Negative Syndrome Scale [PANSS] scores) compared with placebo.

The most common adverse effects were extrapyramidal symptoms, dizziness, hypertonia, somnolence, agitation, and anxiety. The group treated with the higher dosage of risperidone experienced more extrapyramidal symptoms, hypertonia, and dizziness than those who received the lower dosage. A clinically significant increase (more than 7%) in body weight was found in 15% of adolescents who received risperidone 1 to 3 mg/d and in 16% of those who received risperidone 4 to 6 mg/d. The mean increase in prolactin was 26 ng/mL in the low-dose group and 41 ng/mL in the high-dose group. There was a small mean increase in fasting glucose levels from baseline to end point in the higher-dose risperidone group.

Further research
A number of multicenter, double-blind, placebo-controlled trials of other atypical antipsychotics are under way or were recently reported. The efficacy of olanzapine was examined in 107 adolescents with schizophrenia in a double-blind, placebo-controlled trial.⁵ The mean dosage of olanzapine was 11.1 mg/d. Olanzapine-treated adolescents had significant improvements on the Brief Psychiatric Rating Scale for Children and Clinical Global Impression-Severity scale compared with the placebo group. However, there were no significant differences in response rates between olanzapine-treated patients (38%) and placebo-treated patients (26%).

Adverse events that were significantly more common in olanzapine-treated patients were increased weight (4.3 kg compared with 0.1 kg in the placebo group) and somnolence. There also was a significant increase at end point in fasting triglyceride levels in olanzapine-treated patients.

In a 6-week, double-blind, placebo-controlled trial of 302 adolescents with schizophrenia, youths were randomized to receive placebo or a fixed dose of 10 or 30 mg of aripiprazole.⁶ Patients who received the 10-mg dose and those who received the 30-mg dose both showed significant differences on the PANSS total score compared with those who received placebo at end point. The most common adverse events associated with aripiprazole were extrapyramidal disorder, somnolence, and headache. The incidence of clinically significant weight gain (more than 7% increase) in the aripiprazole-treated patients was 4.8% (10 mg) and 6% (30 mg) compared with 1% for those who received placebo. Mean prolactin levels were decreased in the aripiprazole-treated patients.⁷

Some youths with early-onset schizophrenia fail to respond to treatment with an atypical antipsychotic. It is important to determine what medication should be used in treatment-refractory, early-onset schizophrenia. A recent 12-week study compared clozapine with high-dose olanzapine (up to 30 mg/d) in 39 children and adolescents aged 10 to 18 with schizophrenia who were resistant or intolerant to 2 antipsychotics.⁸ A higher response rate was reported with clozapine than with olanzapine (66% vs 33%). Clozapine-treated patients had a greater reduction in negative symptom scores than did the olanzapine-treated patients. However, there was significant weight gain and metabolic abnormalities with both medications.

 

References:

References

1.

McClellan J, Sikich L, Findling RL, et al. Treatment of early-onset schizophrenia spectrum disorders (TEOSS): rationale, design, and methods.

J Am Acad Child Adolesc Psychiatry.

2007;46:969-978.

2.

Frazier JA, McClellan J, Findling RL, et al. Treatment of early-onset schizophrenia spectrum disorders (TEOSS): demographic and clinical characteristics.

J Am Acad Child Adolesc Psychiatry.

2007;46:979-988.

3.

FDA News. FDA approves Risperdal for two psychiatric conditions in children and adolescents. August 22, 2007. Available at:

http://www.fda.gov/bbs/topics/NEWS/2007/NEW01686.html

. Accessed January 14, 2008.

4.

FDA. Summaries of medical and clinical pharmacology reviews of pediatric studies 2007. Available at:

http://www.fda.gov/cder/pediatric/Summaryreview.htm

. Accessed January 14, 2008.

5.

Kryzhanovskaya L, Schultz C, McDougle CJ, et al. A double-blind, placebo-controlled study of olanzapine in adolescents with schizophrenia. New Research Poster presented at: the Annual Meeting of the American Psychiatric Association; May 20-25, 2006; Toronto.

6.

Robb AS, Auby P, Nyilas M, et al, Efficacy of aripiprazole in the treatment of adolescents with schizophrenia. Poster presented at: the Annual Meeting of the American Psychiatric Association; May 19-24, 2007; San Diego.

7.

Findling RL, Nyilas M, Auby P, et al. Tolerability of aripiprazole in the treatment of adolescents with schizophrenia. Poster presented at: the Annual Meeting of the American Psychiatric Association; May 19-24, 2007; San Diego.

8.

Kumra S, Kranzler H, Gerbino-Rosen G, et al. Clozapine and "high-dose" olanzapine in refractory early-onset schizophrenia: a 12-week randomized and double-blind comparison.

Biol Psychiatry.

2008;63: 524-529.