Dr. Jack McClellan examines commonly prescribed antipsychotic medications.

Dr. Jack McClellan’s desire to improve care for children with psychiatric problems is taking him down two important research paths. One thrust of his research — studying the safety and usefulness of current antipsychotic medications — points to the need for better therapies. The other — searching for genetic causes of schizophrenia — could someday lead to more effective diagnostic and treatment strategies for that disease.

Comparing efficacy and side effects

New Meds 220x180Approximately one out of every 100 American children is taking an antipsychotic medicine. Despite this widespread practice, there are few studies supporting the use of these agents in pediatric populations. McClellan, a child psychiatrist at Seattle Children’s, co-led a study that revealed limitations with current medicines.

This National Institutes of Mental Health–funded project — Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS) study — compared the long-term effectiveness and tolerability of two newer widely used antipsychotic agents, risperidone and olanzapine, to an older medication, molindone.

Before the study, new antipsychotic medicines were considered superior to older ones because they were thought to have fewer side effects. That led doctors to prescribe those drugs for a wider range of psychiatric problems — not just for schizophrenia but for mood, behavior and aggression disorders. As a result, use of the newer antipsychotic agents in children has increased at least sixfold since 2000.

Newer isn’t better

TEOSS demonstrated that olanzapine and risperidone have significant side effects that limit their use. While molidone can cause symptoms similar to Parkinson disease, the two new drugs can cause explosive weight gain — up to 15 pounds in eight weeks — and put young people at risk for diabetes and heart disease. The study also found the new drugs are no more useful than the old drugs at reducing psychotic symptoms — and each is useful in only a fraction of cases.

Although most children taking antipsychotic medications do not have a psychotic illness, the results of TEOSS — in particular the safety concerns — are relevant to all youth taking these agents. The weight gain many children experience is substantial and has important lifelong health consequences. These findings raise important public health questions as to whether antipsychotic agents should be so widely used in the pediatric age group.

Distinct individual genetic mutations

McClellan’s other research focus involves the identification of rare genetic mutations that cause schizophrenia. Prior to this research, it was widely thought there were common genetic mutations responsible for most cases of schizophrenia.

McClellan's findings imply that, in most cases, schizophrenia in each person is the result of a different genetic cause... thus changing the entire focus of schizophrenia genetic research. However, McClellan and his colleagues conducted a study showing people with schizophrenia were several times more likely than healthy people to have rare duplications or deletions that disrupted a gene, and in each case, the mutation was different.

These findings imply that, in most cases, schizophrenia in each person is the result of a different genetic cause. Subsequent research by several different researchers has replicated these findings, thus changing the entire focus of schizophrenia genetic research.

“We’ve learned that most people with schizophrenia have different individual mutations. Therefore, the medications we are currently using are not specific to the genetic cause,” says McClellan, a member Seattle Children’s Research Institute’s Center for Clinical and Translational Research. “The existing medications hit many biological pathways in hopes of hitting the pathway that is causing the illness in that one person.”

That’s a problem because — as McClellan’s study of antipsychotic medications suggests — existing medications often miss the pathway causing the illness and cause side effects by disrupting other pathways.

“If we can identify the critical biological pathways involved with schizophrenia,” McClellan says, “it will be the first step toward developing new therapies that target those pathways to make treatment more effective and less likely to cause side effects.”