EUFEST: Atypical Antipsychotics Offer No Advantage in Improving Cognitive Function in Schizophrenia

Janis Kelly

April 24, 2009

April 24, 2009 — Treatment with low-dose haliperidol or second-generation antipsychotics have the about the same moderate effect in improving cognitive function in patients with first-episode schizophrenia or schizophreniform disorder, the latest results from the European First Episode Schizophrenia Trial (EUFEST) suggest.

In a study published online April 15 in the American Journal of Psychiatry, Michael Davidson, MD, from Sheba Medical Center, in Tel-Hashomer, Israel, and colleagues suggest that the apparent advantage of the newer antipsychotics in previous studies was likely due to the use of higher doses of first-generation drugs as comparators, leading to impaired motor performance and the need for anticholinergic drugs, which themselves can impair cognitive performance.

"Our most important findings were that cognitive function improved in all 5 treatment groups and that there were no significant differences between any of the treatment groups," Dr. Davidson told Medscape Psychiatry.

Dr. Davidson also pointed out that the EUFEST data highlight the need for "a different class of drugs with different mechanisms of action" to improve cognition.

Magnitude of Improvement Did Not Differ

Cognitive impairment often develops before psychosis in patients with schizophrenia and is emerging as a potential target for intervention. EUFEST was designed to address a number of questions about treating patients with first-episode schizophrenia. This multicenter trial included sites in Israel, Italy, Austria, the United States, the Netherlands, Romania, Poland, the Czech Republic, France, Spain, Bulgaria, Germany, Belgium, Sweden, and Switzerland.

Investigators enrolled 498 patients with schizophreniform disorder or first-episode schizophrenia. They were randomized to open-label haloperidol (1 to 4 mg/day), amisulpride (Solian, Sanofi-Aventis), olanzapine (Zyprexa, Eli Lilly), quetiapine (Seroquel, AstraZeneca), or ziprasidone (Zeldox, Pfizer).

At baseline and after 6 months of treatment, cognitive function was assessed with the Rey Auditory Verbal Learning Test, the Trail-Making Test Parts A and B, the Wechsler Adult Intelligence Scale (WAIS) Digit Symbol Test, and the Purdue Pegboard Test.

At follow-up, all 5 groups had moderate but significant improvements in composite cognitive test scores compared with baseline, and "there were no overall differences among the treatment groups," the investigators report. Cognitive improvement was weakly related to symptom change.

"In summary, we found that antipsychotics, whether a low-dose of haloperidol or several second-generation antipsychotics, were associated with improvement on cognitive test performance in patients in the early stages of schizophrenia but that the magnitude of improvement among these drugs did not differ," the authors write.

Urgent Need for Better Drugs

Neil D. Woodward, PhD, from Vanderbilt University, in Nashville, Tennessee, told Medscape Psychiatry that the EUFEST study "fills an important gap in the literature by addressing several limitations of prior studies in the field and serves as further evidence that the relative benefits of atypical antipsychotic drugs on cognitive function are very modest at best."

"However," Dr. Woodward added, "this does not rule out the distinct possibility that atypical antipsychotic drugs — and typical antipsychotic drugs for that matter — may be important for treating cognitive impairment in the context of personalized medicine."

Dr. Woodward noted that a great deal of evidence indicates that cognitive function is at least as important to the long-term functional outcome of schizophrenia patients as clinical symptoms.

"Several aspects of outcome, including job tenure, are related to cognition," he said. "For this reason alone, treatment providers should consider evaluating patients' cognitive status using objective neuropsychological measures whenever possible. With respect to treatment effects, the EUFEST findings and the handful of studies that have examined drugs developed specifically for cognitive impairment clearly indicate that treatments with greater positive effects on cognition are urgently needed."

Dr. Davidson discloses research grant support, travel support, speaker fees, or consultant fees from Johnson & Johnson, Pfizer, Lundbeck, Teva, BioLineRx, Eli Lilly, Sanofi-Aventis, Roche, Servier, and Tangent Data.

Am J Psychiatry. Published online April 15, 2009. Abstract