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February 2010

Second-Generation Antipsychotics: New Information
Second-generation antipsychotics differ from each other, offering options for patients.

Cognitive Effects of Antipsychotic Drugs: Are All Created Equal?
First- and second-generation antipsychotics appear comparable in their ability to lessen cognitive dysfunction associated with schizophrenia.

In Brief
Long-acting Injectable Olanzapine Approved in US; High-potency Cannabis May Increase Risk of Psychosis

Olanzapine and Sertraline Combined for Psychotic Depression
In a short-term trial, sertraline (Zoloft and others) combined with olanzapine (Zyprexa) was more efficacious than olanzapine plus placebo for psychotic depression in both young and elderly patients.

Cognitive Effects of Antipsychotic Drugs: Are All Created Equal?

February 2010

Patients with schizophrenia tend to have lower cognitive performance on standardized psychometric tests than people without schizophrenia. Cognitive impairment, which is now considered a core symptom of the illness,1 often appears before the onset of psychosis, persists throughout a patient’s life even when psychosis is in remission, and is correlated with functional outcomes.2 The extent of a patient’s cognitive impairment predicts ability to cope successfully with everyday activities, including work, socializing, and independent living.1

When second-generation antipsychotics were introduced into clinical practice, many believed they had enhanced abilities to improve cognitive function compared with first-generation agents. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study found that cognitive performance improved with all antipsychotics studied—the second-generation agents olanzapine (Zyprexa), quetiapine (Seroquel), and risperidone (Risperdal and others), and the first-generation agent perphenazine (Trilafon and others).3 However, there were no statistically significant differences among the benefits associated with each agent.

More recently, Davidson et al tested the cognitive effects of four second-generation antipsychotics and the first-generation agent haloperidol (Haldol and others) in the European First-Episode Schizophrenia Trial (EUFEST).2 Investigators studied 498 patients with schizophreniform disorder or first-episode schizophrenia. Subjects were randomly assigned in an open-label design to take haloperidol, 1 to 4 mg/day; amisulpride,* 200 to 800 mg/day; olanzapine, 5 to 20 mg/day; quetiapine 200 to 750 mg/day; or ziprasidone (Geodon), 40 to 160 mg/day. A cognitive test battery was administered at baseline and at a 6-month follow-up evaluation.

Unlike response rates, which were higher in subjects treated with the second-generation antipsychotics than in those taking haloperidol (see “Second-Generation Antipsychotics: New Information,” this issue, page 7), cognitive test scores between baseline and follow-up improved comparably among patients taking all five medicines. There were no statistically significant differences. A weak correlation was observed between the degree of cognitive improvement and the overall symptom improvement in the Positive and Negative Syndrome Scale scores.

In a separate study, Brown and others examined prenatal exposure to infection as an etiologic mechanism of cognitive dysfunction in schizophrenia.4 Serologically documented maternal infection during pregnancy with influenza or toxoplasmosis predicted executive dysfunction in offspring who developed schizophrenia. The parasite that causes toxoplasmosis cannot cross the placenta, leading scientists to assume that the damage to the developing fetal brain is caused by elevated maternal IgG antibody to toxoplasma. Children born to mothers infected with influenza or toxoplasmosis who developed schizophrenia had poorer executive function than those with schizophrenia whose mothers did not have one of these infections during pregnancy.

It has become increasingly clear that cognitive dysfunction is a major burden for people who suffer from schizophrenia. To the extent that they improve schizophrenia symptoms overall, antipsychotic agents appear to lessen cognitive dysfunction associated with this disorder. There is no apparent difference among antipsychotic drugs—whether first- or second-generation. Given the high likelihood that schizophrenia can be caused by multiple insults to the developing brain, maternal infection during pregnancy might increase the liability to executive dysfunction once schizophrenia appears in offspring.

*Not available in the United States.

1Goldberg TE, Gomar JJ: Targeting cognition in schizophrenia research: From etiology to treatment. Am J Psychiatry 2009;166:631-634.

2Davidson M, Galderisi S, Weiser M, Werbeloff N, Fleischhacker WW, Keefe RS, Boter H, Keet IPM, Prelipceanu D, Rybakowski JK, Libiger J, Hummer M, Dollfus S, López-Ibor JJ, Hranov LG, Gaebel W, Peuskens J, Lindefors N, Riecher-Rössler A, Kahn RS: Cognitive effects of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: A randomized, open-label clinical trial (EUFEST). Am J Psychiatry 2009;166:675-682.

3Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209-1223.

4Brown AS, Vinogradov S, Kremen WS, Poole JH, Deicken RF, Penner JD, Mckeague IW, Kochetkova A, Kern D, Schaefer CA: Prenatal exposure to maternal infection and executive dysfunction in adult schizophrenia. Am J Psychiatry 2009;166:683-690.