Cognitive Effects of Antipsychotic Drugs in First-Episode Schizophrenia and Schizophreniform Disorder: A Randomized, Open-Label Clinical Trial (EUFEST)

Participants (N=498) were 18- to 40-year-old patients who met DSM-IV criteria for schizophrenia or schizophreniform disorder, confirmed using the Mini-International Neuropsychiatric Interview–Plus (30), and were recruited at 50 sites in 13 European countries and Israel.

Inclusion criteria were 1) recent onset of psychosis with <2 years between the onset of positive symptoms and recruitment into the trial; 2) <2 weeks exposure to antipsychotic drugs during the preceding year, and 3) <6 weeks lifetime exposure to antipsychotic drugs. Data were obtained on demographics, diagnoses, severity of psychopathology (Positive and Negative Syndrome Scale [PANSS] [31], Clinical Global Impression [CGI] Scale [32] ), and extrapyramidal symptoms (St. Hans Rating Scale [33] ). The trial was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and national regulatory requirements.

Patients were randomly assigned via a centralized, computerized online randomization system to open-label treatment with haloperidol, 1 to 4 mg/day (N=103); amisulpride, 200 to 800 mg/day (N=104); olanzapine, 5 to 20 mg/day (N=105); quetiapine, 200 to 750 mg/day (N=104); or ziprasidone, 40 to 160 mg/day (N=82). (Ziprasidone was not available in all participating countries at all times throughout the trial, which explains the smaller number of patients in this arm.) At all times during the trial, the dose administered to patients was at the discretion of the treating physician, providing that it remained within the range permitted by the protocol. Mood stabilizers, benzodiazepines, antidepressants, and anticholinergics were allowed before and during the trial. Additional antipsychotics were not permitted.

The following five cognitive tests were administered:

Rey Auditory Verbal Learning Test . This assessment is a list learning task in which the participants are read a list of words and are then tested for what they have learned by recall. Five trials are administered, and the outcome measure is the total number of words recalled (34) .

Trail Making Test, Part A and Part B (two tests). These assessments are tests in which participants must first draw lines to connect consecutively numbered circles on one worksheet (Part A) and then connect the same number of consecutively numbered and lettered circles on another worksheet by alternating between the two sequences (Part B). The outcome measures are the time to complete the tests. These are tests of complex visual scanning, motor speed, and ability to shift strategy (35) .

Purdue Pegboard Test . This assessment is a task in which participants must place pegs in the holes of a board. It tests motor speed and motor coordination and is sensitive to subtle motor dysfunction, including extrapyramidal symptoms. The outcome measure is the number of pegs placed correctly within 30 seconds by the dominant hand drawn (36) .

Digit Symbol Coding . This assessment is a test in which the participant is allowed 120 seconds to move through a grid of 133 numbers (1 to 9) and pair them with the correct symbol by using a key consisting of nine symbol-digit pairs. The test is part of the WAIS-III (37) and measures symbolic representational abilities, visual motor skill/dexterity, processing speed, attention/concentration, visual perception of abstract stimuli, and short-term visual memory. The outcome measure is the number of correct symbols drawn within 120 seconds (37) .

The composite score, rather than the individual test scores, was assigned as the main outcome measure to increase statistical power. The five cognitive tests were selected based on practicality of administration for a large, multisite, international, multilingual, schizophrenia antipsychotic clinical trial. Motor abilities were emphasized in order to assess the effect of haloperidol on cognitive performance. All of the countries that participated had validated versions of the tests, except Bulgaria for the Rey Auditory Verbal Learning Test. Since lengthy testing is not always acceptable to patients, the tests selected represent a compromise between the comprehensiveness of the test battery and the desire to reduce the amount of missing data. The tests were administered at baseline and after 6 months of treatment (SD=3 weeks). For patients in whom the severity of psychosis at baseline was such that cognitive testing was not feasible, testing could be postponed until the end of the first month of the trial. The tests were administered by psychologists and psychiatrists trained at investigators meetings to administer the specified tests.

Of the 498 patients randomly assigned to one of the five trial drugs, 40 were missing baseline data and 172 completed ≤2 of the five neurocognitive tests at both time points and were therefore excluded from analyses using the composite score. The remaining 286 patients included in the analysis had valid data at baseline and again at 6 months for ≥3 of the five neurocognitive assessments. Analyses regarding each subtest included all patients who had valid data for the specific test at both baseline and the 6-month follow-up. Comparison of demographics and clinical characteristics between the group of 286 patients included in the composite score analyses and the group of 212 patients excluded from these analyses as a result of incomplete data revealed that excluded patients were less educated and had worse cognitive performance on two of the individual tests, but these differences were very small ( Table 1 ). Chi square tests revealed no differences in the distribution of gender and race between the group of included patients and the group of excluded patients. Before receiving trial medication, of the 286 patients included in the analyses, 29% were antipsychotic naive, 24.5% had received treatment with a first-generation antipsychotic drug, and 46.5% had received treatment with a second-generation antipsychotic drug. Comparisons among the patients randomly assigned to the five medication arms revealed no baseline differences on demographic characteristics ( Table 2 ). There were no differences in rates of extrapyramidal symptoms between the five study arms, except patients who were randomly assigned to haloperidol exhibited more akathisia (χ ² =9.77, df=4, p=0.04), but these differences were very small.

Before randomization to the trial medication, 11.2% of patients were already receiving anticholinergic drugs as treatment for extrapyramidal symptoms resulting from medications taken before the present study. During the 6-month period between randomization and follow-up, anticholinergic drugs were added to the treatment regimen of an additional 18.5% of the participating patients. At the time of the 6-month follow-up, the mean daily antipsychotic doses were as follows: 2.5 mg for haloperidol, 455 mg for amisulpride, 12 mg for olanzapine, 458 mg for quetiapine, and 98 mg for ziprasidone.

Change in the cognitive composite score from baseline to 6 months showed improvement in each of the five treatment groups (haloperidol: t=–3.43, df=51, p=0.001 [effect size=0.43]; olanzapine: t=–7.11, df=73, p<0.001 [effect size=0.56]; quetiapine: t=–6.25, df=59, p<0.001 [effect size=0.51]; ziprasidone: t=–4.75, df=44, p<0.001 [effect size=0.49]; and amisulpride: t=–4.15, df=54, p<0.001 [effect size=0.33]). There was no overall difference between the five treatment groups in the composite scores (F=0.56, df=4, 281, p=0.69) or individual tests (all p values >0.11) ( Table 3 ). Random effects analyses, including subjects with partial missing data, yielded similar results. A significant improvement in the cognitive composite score was seen over time (p<0.001), but there were no differences between the five study arms (p=0.42). Controlling for multiple comparisons using Bonferroni corrections, t tests comparing the change in the subtest scores from baseline to month 6 for haloperidol versus the four second-generation antipsychotic drugs (both separately and grouped together) revealed no significant differences.

Since there were no differences among the five treatment groups on the cognitive composite and subtest scores, presentation of the individual measures at baseline and the 6-month follow-up included all patients who had valid data for both time points collapsed across treatment groups ( Table 4 ). Change in the individual measures showed consistent improvement.

Changes in the effect size of the composite scores of patients who were drug naive before baseline testing did not differ significantly from that of patients who received drug treatment before baseline testing (effect size=0.37 [SD=0.58] versus effect size=0.45 [SD=0.65], p=0.31, respectively).

The analyses were repeated with trial site, years of education, and baseline alcohol and substance use included in the model. These covariates did not produce results that differed significantly from the unadjusted analyses.

A model of prediction of improvement in the cognitive composite score from baseline to 6 months suggested that a lower (worse) baseline composite score was a predictor of greater cognitive improvement (r ² =0.25, p<0.001). Drug and alcohol abuse, trial site, and PANSS subscale scores were not significant predictors of cognitive improvement. Similar results were found when examining each of the five study arms separately.

The Pearson correlations between change in the cognitive composite score from baseline to the 6-month follow-up and change in PANSS scores from baseline to the 6-month follow-up revealed negative correlations ( Table 5 ). These negative correlations indicated that cognitive improvement was associated with symptom amelioration, but the magnitude of these correlations was very small. Changes in the composite scores of the 53 patients for whom anticholinergic medications were added between the baseline and 6-month assessments did not differ from that of the rest of the patients (effect size=0.43 [SD=0.6] versus effect size=0.41 [SD=0.75], respectively).

Cox proportional hazards regression analyses suggested that change from baseline to 6 months in the cognitive composite score was not a significant predictor of time to discontinuation as a result of efficacy (p=0.99) or time to all-cause discontinuation (p=0.96). The results were unchanged when baseline covariates that were found previously to predict time to discontinuation were included (26) .

The present study compared cognitive performance in first-episode schizophrenia patients after 6 months of treatment with haloperidol, olanzapine, amisulpride, ziprasidone, or quetiapine. Compared with the results of baseline testing, cognitive scores improved moderately, with no differences among the five treatment groups. Lower (worse) baseline composite scores predicted greater cognitive improvement. Change in cognitive performance was weakly related to change in symptom scores.

Results of this randomized, open-label trial, reporting small advantages of second-generation antipsychotic drugs relative to first-generation antipsychotic drugs in terms of cognitive performance, differ from findings of some previous studies and meta-analyses (22 – 21) . A likely explanation for this difference might be the relatively high doses of haloperidol used in some, but not all, related studies (13) . High doses increase the risk of extrapyramidal symptoms and the use of anticholinergic medications, which in turn impair motor and cognitive speed. It is therefore possible that results of previous trials comparing second-generation antipsychotics with first-generation antipsychotics on cognitive functioning in schizophrenia in fact reflect the diminished propensity of second-generation antipsychotics to induce extrapyramidal symptoms rather than an intrinsic cognitive benefit of these new compounds. In the present trial, the mean daily dose of haloperidol was only 2.5 mg, which is a lower dose than that used in most other studies.

Results of the present trial are in agreement with the results of the CATIE schizophrenia trial, which reported cognitive improvements after 2, 6, and 18 months of treatment, relative to baseline, but no differences among treatment groups, with the exception of a slight advantage for perphenazine (26) . The larger effect sizes reported in the present study compared with that of the CATIE study could be attributable to the younger and less chronic population examined in our study. The magnitude of the improvement observed in the present study is similar to that reported in other studies of first-episode schizophrenia patients (15, 39, 40) . One single study (39) of first-episode patients reported a very small advantage of risperidone over haloperidol, but the advantage was extremely small and the dose of haloperidol was higher than the dose used in the present trial.

Part of the improvement in cognitive test scores between baseline and 6-month testing observed in the current study might have been a result of practice or placebo effects (41), such as prior exposure to the tests, familiarity, and procedural learning. This was demonstrated in a recent study, conducted by Goldberg et al. (23), in a sample of first-episode schizophrenia patients treated with second-generation antipsychotics as well as in a comparison sample of healthy subjects, reporting the same order of magnitude of improvement found in the present study (i.e., effect size=0.33). In the present trial, the changes between the baseline and 6-month assessments ranged from an effect size of 0.56 to 0.33, depending on the individual test. Although patients were tested more often in the study conducted by Goldberg et al. (23) than in the present study, it is still possible that at least part of the improvement observed in the current trial might have been the result of practice. Thus, the 6 months that elapsed between testing was sufficiently long and the effect size was sufficiently large to suggest that at least part of the effect was drug related and not practice related. It has also been suggested that first-generation antipsychotics, particularly haloperidol, might attenuate the practice effect (23) . However, this is not reported in the present study, since the cognitive improvement from a low dose of haloperidol was not significantly different from that of the second-generation antipsychotic drugs. Nevertheless, it is still conceivable that higher doses of haloperidol might exert a deleterious effect on cognitive performance (22) . Furthermore, these data do not support the contention that treatment with haloperidol plus anticholinergic drugs is equivalent to treatment with second-generation antipsychotics.

There are several limitations to the present study. First, a more comprehensive cognitive battery might have revealed different results. However, there is little biological rationale to assume that a particular cognitive task not assessed in our study might have preferentially been affected by one but not another of the five drugs tested. Second, because of the open-label design and the possibility that some investigators might have been convinced by results of previous trials reporting advantages of second-generation antipsychotics over first-generation antipsychotics in terms of cognitive performance, this might have led to an “expectation bias,” which could have conferred an advantage to the second-generation antipsychotic drugs over haloperidol (29) . However, this potential bias is not supported by the results. Third, since antipsychotics can be detected in both blood and the CNS for many days and weeks after discontinuation of treatment, it is conceivable that the effect of the antipsychotic drugs administered before baseline testing could have affected baseline cognitive performance. In the present trial, like in many other similar trials (42), some patients had very brief washout periods, others had no washout period, and a few patients who could not be tested off medication because of the severity of their psychosis were allowed to have baseline testing shortly after random assignment. However, this is unlikely to have affected the results, since there were no baseline differences in cognitive performances among the five treatment groups, nor were there differences between the group of patients who were drug naive before baseline testing and the group of patients who received drugs before baseline testing. Furthermore, the NIMH Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Task Force on the design of clinical trials to assess the cognitive effects of drug treatment (43) and other similar trials evaluating cognition in first-episode patients (42) suggests that the interference of severe psychosis with testing might not justify antipsychotic washout. Finally, it cannot be ruled out that a first-generation antipsychotic drug or a second-generation antipsychotic drug not included in the present trial, such as risperidone or clozapine, would have proved to be superior to the drugs tested.

Despite the limitations of the present study, as well as other similar studies, it is unlikely that different trial designs or different patient populations would help differentiate any of the currently marketed antipsychotic drugs in terms of cognitive benefits. First, the discovery platform common to all antipsychotic drugs for the last 50 years has been the same, and its target has been the reduction of psychotic symptoms, not cognitive improvement. Antipsychotic drugs are screened based on their preclinical in vitro and in vivo similarities to other antipsychotics already proven to ameliorate psychosis in humans. The proof of concept and the go-/no-go decisions in phases II and III clinical trials have been based on the antipsychotic properties of these drugs and not on their potential procognitive benefit. If second-generation antipsychotic drugs differ from first-generation antipsychotic drugs in areas other than adverse effect profile, they do so in terms of global effectiveness as reflected by the results of the trials conducted by Fleischhacker et al. (28) and Kahn et al. (29) .

The present study, similar to many other previous studies, found only very weak correlations between psychotic symptoms at baseline or improvement in psychotic symptoms and cognitive impairment at baseline or improvement in cognitive performance, further underlying the separation between the desired procognitive and antipsychotic effects. It is therefore not surprising that not a single antipsychotic drug distinguishes itself in terms of cognitive benefits.

Interestingly, individual trials, even the most pragmatic and independently funded trials, very rarely provide definitive answers to the clinical question they intend to address. This is particularly true when the debate is about the advantages and distinguishing characteristics of drugs aimed at the same indications but perceived as older versus newer generations of drugs. Neither the CATIE study (44) nor the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (45 – 50), a trial showing very little differences between diuretics compared with novel antihypertensive drugs, settled the debate or immediately and radically affected prescribing practices. It appears that only a continuous stream of quality publications in high-impact journals and educational efforts can alter established perceptions and affect prescribing practices (51) .

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 of this study represent the European First Episode Schizophrenia Trial (EUFEST). Received June 1, 2008; revisions received Sept. 21 and Oct. 29, 2008; accepted Dec. 22, 2008 (doi: 10.1176/appi.ajp.2008.08060806). From the Department of Psychiatry, Sheba Medical Center, Tel-Hashomer, Israel; Department of Psychiatry, University of Naples SUN, Naples, Italy; Department of Biological Psychiatry, Medical University of Innsbruck, Austria; Departments of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, N.C.; Department of Psychiatry, University of Medical Centre Utrecht, Rudolf Magnus Institute of Neuroscience, Utrecht, the Netherlands; AMC de Meren, Amsterdam; Carlo Davila Medical School, Bucharest, Romania; Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland; Department of Psychiatry, University Hospital Hradec Kralove, Czech Republic; Centre Hospitalier Universitaire, Centre Esquirol, Caen, France; Institute of Psychiatry and Mental Health, Hospital Clinico San Carlos, Madrid; Department of Psychiatry, University Hospital of Neurology and Psychiatry, St. Naum, Sofia, Bulgaria; Department of Psychiatry and Psychotherapy, Heinrich-Heine-University, Düesseldorf, Germany; University Psychiatric Centre, Katholieke Universiteit Leuven, Campus St. Jozef Kortenberg, Leuven, Belgium; Department of Clinical Neuroscience, Karolinska Institutet, Psychiatry Section, Stockholm; and Psychiatric Department, University Hospital Basel, Basel, Switzerland. Address correspondence to Dr. Davidson, Sheba Medical Center, Department of Psychiatry, Tel-Hashomer 52621, Ramat Gan, Israel; [email protected] (e-mail).

Dr. Davidson has received research grant support and/or travel support and/or speaker fees and/or consultant fees from JNJ, Pfizer, Lundbeck, Teva, BioLineRx, Eli Lilly, Sanofi-Aventis, Roche, Servier, and Tangent Data. Dr. Galderisi has received fees for educational programs from or served on the advisory boards of AstraZeneca, Innova-Pharma, Bristol-Myers Squibb, and Janssen-Cilag. Dr. Weiser has received research grant support and/or travel support from Eli Lilly, AstraZeneca, and Janssen-Cilag. Dr. Fleischhacker has received research grants from Bristol-Myers Squibb/Otsuka, Eli Lilly, Janssen-Cilag, and Servier; he has received honoraria for educational programs from AstraZeneca and Pfizer; he has received speaker’s fees from AstraZeneca, Bristol-Myers Squibb/Otsuka, Janssen-Cilag, and Pfizer; and he has served on the advisory boards and received honoraria from AstraZeneca, Bristol-Myers Squibb/Otsuka, Janssen-Cilag, Servier, and Wyeth. Dr. Keefe has received grant/research support from AstraZeneca and Eli Lilly; he has served as a consultant and/or on the advisory boards for Abbott, Acadia, BiolineRx, Bristol-Myers Squibb, Cephalon, Cortex, Dainippon Sumitomo Pharma, Eli Lilly, Johnson and Johnson, Lundbeck, Memory Pharmaceuticals, Merck, NeuroSearch, Orexigen, Pfizer, Roche, Sanofi-Aventis, Shering-Plough, Wyeth, and Xenoport; he has served as a speaker for Eli Lilly; and he also receives royalties for the Brief Assessment of Cognition, Brief Assessment of Cognition in Affective Disorders, Brief Assessment of Cognition in Schizophrenia, and of the subtests from these batteries that are a part of NIMH (MATRICS Consensus Battery). Dr. Keet has received honoraria for education programs from Eli Lilly. Dr. Rybakowski has served as a consultant or speaker for Adamed-Poland, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen-Cilag, Lundbeck, Organon, Pfizer, Sanofi-Aventis, and Servier. Dr. Libiger has received speaker’s honoraria, travel grants, or consultant fees from Eli Lilly, Bristol-Myers Squibb, Lundbeck, and Servier; he has also served on the advisory boards of Eli Lilly and Bristol-Myers Squibb, and he is a faculty member of the Lundbeck Institute (Lundbeck Neuroscience Foundation). Dr. Hummer has received speaker’s fees and financial support for visiting congresses from Janssen-Cilag, Sanofi-Aventis, Eli Lilly, Pfizer, AstraZeneca, and Bristol-Myers Squibb. Dr. López-Ibor is a member of the scientific committee of Fundacion Lilly (Spain), a Wyeth member of the Global Strategy Consultant Board, and board member of the Lundbeck Neuroscience Foundation; he has also attended several meetings financed by Eli Lilly, Bristol-Myers Squibb, GlaxoSmithKline, and Lundbeck. Dr. Hranov has received speaker’s honoraria from the National Association of General Practitioners in Bulgaria, Lundbeck, and Eli Lilly; he has received consultant’s honoraria from the National Drug Agency, GlaxoSmithKline, and Sanofi-Aventis; he has received sponsorship for congresses from Bristol-Myers Squibb, Pfizer, Janssen-Cilag, Sanofi-Aventis, and Lundbeck; and he has received investigator’s fees from Cephalon. Dr. Gaebel has served on the speaker’s bureaus for AstraZeneca GmbH, Janssen-Cilag GmbH, Eli Lilly, Deutschland GmbH, and Lundbeck GmbH; and he is a member of the advisory boards for Eli Lilly Deutschland GmbH, Janssen-Cilag GmbH. Dr. Peuskens has received consultant fees and research grants from and participated in clinical trials sponsored by AstraZeneca, Sanofi-Aventis, Eli Lilly, Pfizer, and Janssen-Cilag. Dr. Riechler-Rössler has served on the advisory boards of Janssen-Cilag and Eli Lilly; she has also received unconditional grants from Eli Lilly, Janssen-Cilag, AstraZeneca, Bristol-Myers Squibb, and Lundbeck. Dr. Kahn has received grants, honoraria for education programs, and/or served as a consultant for Astellas, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen-Cilag, Pfizer, Roche, and Sanofi-Aventis. Drs. Werbeloff, Boter, Prelipceanu, Dollfus, and Lindefors report no competing interests.

Funded by the European Group for Research in Schizophrenia, which received funding from AstraZeneca Pharmaceuticals, Pfizer, U.S. Pharmaceuticals Group, and Sanofi. These companies had no role in the study design, data collection, data analysis, data interpretation, writing of the article, or the decision to submit the article for publication.

The authors thank the patients who participated in this study.

This study is registered as an International Standard Randomized Controlled Trial EUFEST: #ISRCTN68736636.

Additional information about EUFEST is available in the data supplement accompanying the online version of this article.