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First generation antipsychotic drugs as effective as newer ones in some children

September 15, 2008

CHAPEL HILL - Nearly every child who receives an antipsychotic medicine is first prescribed one of the second-generation, or "atypical" drugs, such as olanzapine and risperidone. However, there has never been evidence that these drugs are more effective than the older, first-generation medications.

Now a study from the University of North Carolina at Chapel Hill School of Medicine suggests that molindone, a first-generation drug, is as effective as the newer ones and should be used as a first line of therapy in some children with schizophrenia or schizoaffective disorder.

"People thought the second-generation drugs were superior because they had no side effects. We found that molindone works as well as newer drugs, and in some cases it's safer," said Lin Sikich, M.D., associate professor in the department of psychiatry at UNC and lead author of the study, titled the Treatment of Early-Onset Schizophrenia Spectrum Disorders Study.

"The guidelines are going to have to be rewritten because of this study," Sikich said. A report of the study is published Monday in the Sept. 15, 2008 edition of the American Journal of Psychiatry. Co-author Jeffrey Lieberman, M.D., led the earlier CATIE trial at UNC, a landmark study that compared antipsychotic medications in adults. Lieberman is now at Columbia University Medical Center.

The study is the largest head-to-head trial comparing the newer drugs, which became available in the 1990s, to the older ones, which have been around since the 1950s.

Between 2002 and 2006 the study randomly assigned 119 people aged 8 to 19 years to receive molindone, olanzapine or risperidone over an eight-week period at four sites: UNC; McLean Hospital and Cambridge Health Alliance at Harvard Medical School; Seattle Children's Hospital and the University of Washington; and Case Western Reserve University.

A decline in symptoms was similar across the three medications. But the drugs caused very different types of side effects, Sikich said. Both olanzapine and risperidone were associated with significant weight gain and could put young patients at risk of developing heart disease and diabetes. In fact, the National Institute of Mental Health, which sponsored the study, halted recruitment into the olanzapine arm of the study because of the weight gain problem and the resulting increase in cholesterol and glucose levels.

"Olanzapine should not be a first-line therapy in adolescents," Sikich said.

Both the older "typical" antipsychotics and newer "atypical" ones block dopamine receptors in the brain, but the newer drugs also interact with serotonin receptors and cause fewer muscle side effects, including stiffness, muscle cramps, restlessness and involuntary movements. With some older drugs, the involuntary movements can lead to permanent physical disabilities.

There were more reported cases of restlessness with molindone treatment than with either of the two newer treatments. Participants treated with molindone were also required to receive another drug, benztropine, to decrease muscle cramps and stiffness.

Brandon Constantineau, 18, of Wilmington, N.C., enrolled in the TEOSS study about four years ago. He was initially prescribed olanzapine but quickly began gaining weight, ultimately adding more than 45 pounds over 36 weeks. He was switched to molindone and gained about 8 pounds over the next 31 weeks and saw improvements similar to those with olanzapine. But, probably as a result of being on olanzapine, Sikich said, Brandon developed fatty liver disease and was ultimately prescribed two other medications.

Brandon's case also highlights two other points Sikich makes in the study: the benefits of proper diagnosis and the need for more effective medications.

"He was treated when he was very young, about 3, for ADHD," said Brandon's father, Richard Constantineau. But medications and other therapies didn't help, and Brandon grew violent.

"At the point when we went to see Dr. Sikich, when Brandon was 14, I was getting phone calls from the school because he was making threats against teachers," said Brandon's mother, Darlene Wilson. This coincided with violent threats against his parents and, Brandon said, "at one point in time I thought I was seeing angels with halos and wings, like in the Bible."

A psychiatrist Brandon had been seeing was not helpful, Wilson said, so a pediatrician referred them to Sikich.

Late diagnosis is a common problem with many children who develop early onset schizophrenia or schizoaffective disorder, and the diseases usually develop more severely when they begin in childhood, Sikich said.

Brandon is now doing well on an even newer drug, ziprasidone. But in the TEOSS trial only half of all of the participants responded to any medication.

"Medications make a vast difference in peoples' lives, but we need better treatment options," Sikich said. The trial will next compare outcomes after a one-year course of treatment.

Brandon and his family appreciate first-hand the challenges and advances.

"It's working well for him and we need to enjoy the good times, because it's not always good times," Wilson said. "We just have to enjoy what we have right now."

University of North Carolina School of Medicine