In an open-label trial our group conducted with 11 children age 10 to 18 years who had gained weight while taking atypical antipsychotics, metformin decreased lipid levels and body mass index but not significantly. I’ve followed these children in my practice, however, and all those who continued taking metformin over a period of months lost weight.
Antipsychotics in children with schizophrenia:
TEOSS study adds to debate about efficacy and tolerability
TEOSS study adds to debate about efficacy and tolerability
The 5-year National Institute of Mental Health-funded Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) trial began with an ambitious goal: to compare the efficacy and safety of 1 typical and 2 atypical antipsychotics in children age 8 to 19 with schizophrenia. The primary hypothesis was that atypical agents would show greater efficacy and tolerability when given for 8 weeks. Instead, the atypical agents showed no greater efficacy, and adverse effects occurred with all 3 antipsychotics. Because the trial was designed for 168 subjects but enrolled 119, it may not have been adequately powered to detect differences among the 3 agents.
Medications: Most of the 116 children who received medications were severely ill with psychotic symptoms when randomly assigned to 1 of the 3 antipsychotics for 8 weeks of double-blind treatment. Administration began at the lowest dose in a set range and usually was increased to midrange within 10 to 14 days. Dosing remained flexible within these ranges:
- molindone, 10 to 140 mg/d (mean endpoint dose 59.9 mg/d)
- olanzapine, 2.5 to 20 mg/d (mean endpoint dose 11.4 mg/d)
- risperidone, 0.5 to 6 mg/d (mean endpoint dose 2.8 mg/d).
Benztropine, ≥1 mg/d, was given to all patients treated with molindone, 14% of those treated with olanzapine, and 34% of those treated with risperidone to prevent or manage akathisia.
Efficacy: Two criteria defined treatment response: a Clinical Global Impression improvement score of 1 or 2 and a ≥20% reduction in baseline Positive and Negative Syndrome Scale (PANSS) score. Tolerability outcomes included neurologic side effects, weight changes, laboratory analyses, vital signs, ECG, serious adverse events, and treatment discontinuation. Extrapyramidal symptoms were monitored with involuntary movement and akathisia scales.
Observed PANSS total score by week of treatment
Mean Positive and Negative Symptom Scale (PANSS) total scores of observed cases during each week of the TEOSS trial. Minimum possible PANSS score is 30; scores >60 typically are viewed as problematic.
Among the 70 patients who completed treatment (25 of 40 with molindone, 17 of 35 olanzapine, and 28 of 41 with risperidone), more than one-half failed to achieve an adequate response. Response rates were 50% with molindone, 34% with olanzapine, and 46% with risperidone. The atypical antipsychotics did not show greater efficacy than molindone, and mean reductions in psychotic symptoms were modest (20% to 34% on the PANSS). Mean medication doses were midrange and considered moderate.
Tolerability: Sedation, irritability, and anxiety were frequent adverse events. Patients receiving molindone reported significantly higher rates of akathisia (P < .0008). Those receiving olanzapine reported significantly higher rates of weight gain (P < .0001) and were the only group with increased lipid and insulin serum levels and liver function tests. Patients in the risperidone group reported significantly higher rates of constipation (P < .021) and were the only group that experienced elevated serum prolactin.
Source: Sikich L, Frazier JA, McClellan J, et al. Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizoaffective disorder: findings from the Treatment of Early-Onset Schizophrenia Spectrum disorders (TEOSS) study. Am J Psychiatry. 2008;165:1420-1431
Choosing antipsychotics
DR. KOWATCH: Let’s say you’re seeing psychosis in a 12-year-old whom you think is schizophrenic, and he or she has not yet received an antipsychotic. What are your top 3 treatment choices?
DR. FRAZIER: The first agent I usually select is risperidone. We have the most data on the use of this atypical antipsychotic in children and adolescents, and most psychotic children I see do better with a bit more D2 blockade than some of the other atypicals provide. That said, I remain concerned about risperidone’s side effects—such as weight gain and increased serum prolactin—so my usual second-line agent is aripiprazole.
Prodromal symptoms of early-onset psychotic disorder
I became interested in the complicated overlap between pervasive developmental disorders spectrum and psychotic disorders early in my training. More is known about prodromal symptoms in adolescents and adults than in children.
A group in the Netherlands5 compared 32 adolescents with severe early deficits in affect regulation, anxiety, disturbed social relationships, and thought disorder (characterized as “multiple complex developmental disorder” [MCDD]) with 80 adolescents with prodromal psychotic symptoms who met criteria for “at-risk mental state” (ARMS). Three-quarters of the children with MCDD (78%) were found to meet criteria for ARMS, and the 2 groups showed similar schizotypal traits, disorganization, and prodromal symptoms.
Signs of progression to psychosis and schizophrenia in children typically include:
- change in personality
- decrease in functioning or decline in ability to perform at school
- unusual thoughts or behaviors
- crippling anxiety
- supersensitivity to stress.
With experience, the clinician can more clearly differentiate the prodromal signs of psychosis from normal childhood behaviors. Children who are psychotic often don’t make good eye contact. When you try to engage them in discussion about hearing voices, they’re inattentive and internally preoccupied.
Normal vs psychotic children. You want a child in the latency age to have a rich fantasy life. If they do not, that raises concerns. Both normal and psychotic children sometimes say an imaginary friend told them something. Normal children eventually will admit this friend is imaginary. When children are psychotic, especially at an early age, you can’t pull them out of thinking about the imaginary friend, and they can’t distinguish fantasy from reality. Psychotic children also hear imaginary friends talking to them much more often.
Normal children usually are not afraid of their imaginary friends, whereas psychotic children—particularly adolescents—often are afraid of the voices they hear. However, if a psychotic child has heard voices from a young age, the voices aren’t always ego-dystonic. The girl I mentioned at the beginning of this article likes having the voices around. In fact, she gets uncomfortable when the voices are quiet.—Jean A. Frazier, MD