First- and Second-Generation Antipsychotics ....

CME Released: 06/26/2009; Valid for credit through 06/26/2010

From Medscape Medical News CME

EUFEST: First- and Second-Generation Antipsychotics Equal in Improving Cognition in Schizophrenia CME

News Author: Pauline Anderson CME Author: Charles P. Vega, MD, FAAFP

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June 26, 2009 — The latest results from the European First Episode Schizophrenia Trial (EUFEST) show that when it comes to improving cognition in patients with schizophrenia, there is little difference between antipsychotic agents.

The randomized trial shows that a relatively low dose of haloperidol, a first-generation antipsychotic, performed essentially as well as 4 second-generation antipsychotics, including amisulpride (Solian, Sanofi-Aventis), olanzapine (Zyprexa, Lilly), quetiapine (Seroquel, AstraZeneca), and ziprasidone (Geodon, Pfizer) in moderately improving cognition among patients experiencing a first episode of schizophrenia.

The study helps solve the question of which category of antipsychotic medications best address impaired cognition, which affects a significant proportion of individuals with schizophrenia. The study addresses some of the limitations of earlier related research in that it included younger patients and used low-dose haloperidol.

While the study provides an improved picture of the effect of antipsychotics on cognition, it likely will not have a major impact on clinical practice, according to the study's lead author, Michael Davidson, MD, from Sheba Medical Center, in Ramat Gan, Israel.

The study is published in the June issue of the American Journal of Psychiatry.

Modest Improvement Across the Board

The multicenter study included 49 sites in Europe and Israel and assessed 498 first-episode patients aged 18 to 40 years who had experienced psychosis for less than 2 years, had been exposed to antipsychotic drugs for less than 2 weeks during the preceding year, and had less than 6 weeks of total lifetime exposure to antipsychotic drugs.

Patients who are often excluded from efficacy studies — for example, those with substance-abuse issues — were included in this study.

Subjects were assigned to receive haloperidol at a dose of 1 to 4 mg/day or 1 of 4 second-generation antipsychotics. The medications used in the study were selected because they are the most commonly prescribed antipsychotics, said Dr. Davidson.

Researchers administered 5 cognitive tests to measure recall, dexterity, processing speed, concentration, and visual perception. Motor skills were included to help assess the effect of haloperidol on cognitive performance.

The researchers developed a composite score that represented the mean of the patients' results on all 5 neurocognitive tests. A higher score indicated a better performance.

The final analysis included 286 patients (mean age, 25.73 years) for whom there were data on at least 3 of these 5 cognitive tests. At baseline, the mean composite score for these participants was 0.04.

Of these 286 patients, 29% were antipsychotic naive, 24.5% had taken a first-generation antipsychotic, and 46.5% had been treated with a second-generation drug.

At the end of the 6-month study, there were modest improvements in cognitive composite scores in all 5 groups. The mean composite scores were 0.36 for haloperidol, 0.46 for olanzapine, 0.50 for quetiapine, 0.35 for amisulpride, and 0.44 for ziprasidone.

The study found that a poorer baseline composite score predicted greater cognitive improvement.

CATIE Results Confirmed

The scores of patients who were antipsychotic naive before baseline testing did not differ significantly from those of patients who had previously received such drug treatment.

Controlling for trial site, years of education, and baseline alcohol and substance use did not significantly change these results.

It is unclear why some patients with schizophrenia develop cognitive impairment while others do not, said Dr. Davidson.

These results provide a clearer picture of the comparison between first- and second-generation antipsychotics, he added. Past research indicated that second-generation drugs are superior, but many of those studies used relatively high doses of haloperidol, included small study samples, or were funded by companies that manufacture antipsychotics, he said.

While the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study also found about the same level of cognitive improvement among patients taking first-or second-generation agents, it, too, had some limitations.

The CATIE study used perphenazine instead of the more commonly prescribed haloperidol as the comparison first-generation agent and included older, chronically ill patients who may be less likely to reap the cognitive-enhancing benefits of second-generation antipsychotics.

Bursting the Bubble

Asked by Medscape Psychiatry to comment on the study, Jeffrey Lieberman, MD, chair of psychiatry at the Columbia University College of Physicians and Surgeons and director of the New York State Psychiatric Institute, said he was not surprised by the findings given similar results from CATIE.

The CATIE results "seemed to burst the bubble, the illusion of superiority on cognition" for second-generation drugs, he said.

Previous studies had shown that first- and second-generation antipsychotics did not differ in terms of symptoms, and now, this latest study shows no difference in terms of cognition, said Dr. Lieberman. "To me, that says that whatever claim there is of superiority is really of a limited nature."

Using haloperidol instead of perphenazine as a comparison drug should not make much of a difference to results, he said. "They're both first-generation drugs, which means they're the same pharmacologically."

One concern he had, however, was the possible bias of measuring cognition when some patients may still have been acutely psychotic. "They [the authors] say there was no correlation, but nevertheless it makes me wonder whether the moderate improvement in cognition associated with all treatments, not just second-generation treatments, was to some, or a large, degree related just to the general improvement in the symptoms of the patient."

Dr. Davidson has received 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. Disclosures for the coauthors are listed in the article.

Am J Psychiatry. 2009;166:675-682. Abstract

Clinical Context

Cognitive deficits are commonly encountered among patients with schizophrenia, and a previous review by Green, which appeared in the March 1996 issue of the American Journal of Psychiatry, examined the effects of these deficits on patient function. Among specific types of neurocognitive deficits, patient deficiencies in verbal memory and vigilance had the most profound impact on their daily lives. Higher degrees of negative symptoms of schizophrenia corresponded with worse social functioning. However, psychotic symptoms were not significantly associated with functional outcomes in this review.

It has been suggested that newer, second-generation antipsychotics vs older agents may reduce the risk for cognitive deficits among patients with schizophrenia, but this issue remains controversial. The current study uses an open-label design to examine the effects of antipsychotic medications on cognitive function in a setting which approximates that of most clinical practice.

Study Highlights

Patients eligible for study participation were between the ages of 18 and 40 years who met formal criteria for schizophrenia or schizophreniform disorder. All participants had experienced the onset of psychosis in the 2 years before entry into the study, and those who had received 6 weeks or more of lifetime treatment with an antipsychotic medication were excluded from study participation.

Participants were randomly assigned to receive treatment with one of the following medications: haloperidol 1 to 4 mg/day, amisulpride 200 to 800 mg/day, quetiapine 200 to 750 mg/day, olanzapine 5 to 20 mg/day, or ziprasidone 40 to 160 mg/day. The dosage was left to the discretion of the treating clinician, and the concomitant use of other psychiatric medications was permitted during the trial.

Cognitive testing included a verbal learning test, a trail-making test to examine complex visual scanning and the ability to shift strategy, a pegboard test to examine motor function, and a coding test to examine processing speed and concentration.

Testing was completed at baseline and after 6 months of treatment.

The main outcome of the study was the comparison between haloperidol and the 4 second-generation antipsychotic medications on the composite score of the 5 cognitive tests.

498 participants underwent randomization, and 286 individuals provided data at baseline and 6 months. Patients who dropped out of the study were slightly less educated and had slightly lower cognitive scores vs those who completed the trial.

The mean age of participants was 25 years. More than half of the study cohort consisted of men, and more than 95% of participants were Caucasian.

Cognitive testing scores improved in all 5 antipsychotic treatment groups during the study period, with no difference between different treatment groups in either the mean composite score or scores on individual cognitive tests.

Treatment with antipsychotic medications before entry into the study did not alter the main study conclusion.

A lower baseline cognitive score was mildly associated with a greater improvement during the 6-month trial period. However, the presence of substance abuse, the use of anticholinergic medication, and the severity of schizophrenia did not significantly affect cognitive function.

Cognitive function was weakly related to reduction in the symptoms of schizophrenia.