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Longitudinal studies of cognition in schizophrenia: Meta-analysis

  • Andrei Szöke (a1), Anca Trandafir (a1), Marie-Estelle Dupont (a2), Alexandre Méary (a1), Franck Schürhoff (a1) and Marion Leboyer (a1)...



A wide range of cognitive deficits have been demonstrated in schizophrenia, but their longitudinal course remains unclear.


To bring together all the available information from longitudinal studies of cognitive performance in people with schizophrenia.


We carried out a meta-analysis of 53 studies. Unlike previous reviewers, we included all studies (regardless of the type of medication), analysed each variable separately and compared results with data from controls.


Participants with schizophrenia showed a significant improvement in most cognitive tasks. The available data for controls showed, with one exception (the Stroop test), a similar or greater improvement. Performance in semantic verbal fluency remained stable in both individuals with schizophrenia and controls.


Participants with schizophrenia displayed improvement in most cognitive tasks, but practice was more likely than cognitive remediation to account for most of the improvements observed. Semantic verbal fluency may be the best candidate cognitive endophenotype.

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Corresponding author

Dr Andrei Szöke, Service de Psychiatrie Adulte, Hôpital Albert Chenevier, 40 rue de Mesly, 94000 Créteil, France. Email:


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Longitudinal studies of cognition in schizophrenia: Meta-analysis

  • Andrei Szöke (a1), Anca Trandafir (a1), Marie-Estelle Dupont (a2), Alexandre Méary (a1), Franck Schürhoff (a1) and Marion Leboyer (a1)...
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The jury is still out � waiting for new data not new analyses!

Andrei Sz�, MD
17 April 2009

Balanza-Martinez et al. made a detailed review of our article (Szoke et al, 2008) and also provided several suggestions for future research.

Although we agree with the authors that the conclusions of our article are by no means definitive, we disagree with them on the followingimportant issues.

First, Balanza-Martinez et al. suggest that our “meta-analysis (…) more likely overestimates the potential for cognitive improvement” as compared with other reviews (the authors cite as an example the review done by Rund (Rund, 1989)). On the contrary, we think that the comparison of results in schizophrenic subjects with controls, which is an original feature of our review, has a sobering effect as it points out that “practice (is) more likely than cognitive remediation to account for most of the improvements observed”. On the other hand reviews (such as the one cited earlier), in which performances in schizophrenic subjects are not compared with those of controls, could mistake improvement in results for improvement in cognitive abilities.

Second, commenting on the methods we used in our meta-analysis, Balanza-Martinez et al. criticize three of our options:

-The inclusion of studies with a test-retest duration under 1 year;

-The inclusion of open trials (especially clozapine trials);

-The fact that we did not differentiate between “first-episode, chronic and geriatric patients”.

As such, the cited authors suggest that it would be better to limit the analyses to a subset of the available data assuming, without formally testing, that some of the studies’ characteristics significantly influenceresults.

At the time we made our analysis there were only 11 studies with morethan a year test-retest interval and only four of them reported data for acontrol group. It was not possible to limit our analysis only to this subset of studies, let alone further exclude studies or separately analysesubgroups of studies.

Instead, we chose to include all methodological sound studies and test the role of potentially confounding variables (including test-retest interval). By using this method, we limited the loss of important available information. It is our belief that we could not gain more insight from less data.

As we report in our article, only 2 variables, out of the 17 tested, showed a larger improvement in studies with shorter test-retest intervals.Thus, for the vast majority of variables, excluding studies with shorter test-retest intervals would lead to an unjustified loss of information.

Third, Balanza-Martinez et al. consider that their suggestions may lead to results “more helpful for clinicians, patients and caregivers”. Wethink that limiting the analysis to studies with large test-retest intervals (which usually have high attrition rates) or excluding the more naturalistic, open trials would achieve just the contrary.

In conclusion, although we agree with Balanza-Martinez et al. that the conclusions of our meta-analysis are not definitive, we also consider that to improve our knowledge on the subject we need new data, not new analyses in subsets of (the same) data.


1. Szöke A, Trandafir A, Dupont ME, Méary A, Schürhoff F, Leboyer M. (2008) Longitudinal studies of cognition in schizophrenia: meta-analysis. British Journal of Psychiatry, 192, 248-257.

2. Rund BR. (1989) A review of longitudinal studies of cognitive functions in schizophrenia patients. Schizophr Bulletin, 24, 425-435.
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Conflict of interest: None Declared

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Longitudinal course of cognition in schizophrenia - the jury is still out!

Vicent Balanz�-Mart�nez, Associate Professor of Psychiatry and Psychological Medicine
19 March 2009

In their meta-analysis(1), Szöke et al. found significant improvements in most neuropsychological variables, along with well-known potential practice effects, and also that semantic verbal fluency holds promise as a suitable cognitive endophenotype in schizophrenia. We acknowledge that this review is a step forward, attempting to merge and quantify the evidence from both naturalistic observational studies(2) and clinical trials(3).

We agree with the authors that the current literature is limited by the virtual absence of healthy control groups. Since only 9 out of 53 studies reported longitudinal neurocognitive data for controls, it is difficult to disentangle whether patients´ cognitive changes are true improvements or confounded by the non-specific effects of practice-relatedlearning(4). The use of healthy subjects from test-retest studies (´external controls´) is also problematic and the parallel assessment of controls would rule out the possibility that patients´ apparent cognitive stability is not deterioration in disguise, as the authors accurately suggest.

In addition, we would like to highlight other critical issues that may limit the conclusions. Firstly, the authors´ choice to lower the minimum study duration to one month led to the median test-retest intervalbeing only 4 months, which is shorter than the recommended trial duration to evaluate cognitive changes, e.g. at least 6 months(5). This also may have biased the review towards short-term clinical trials intended to improve cognitive deficits, especially with second-generation antipsychotics. Had a more stringent and clinically relevant 1-year follow-up cut-off(2) been used, only 24 out of 53 studies would have been reviewed. Secondly, approximately half of the 20 clinical trials previously reviewed(3) are open, and these are mostly clozapine trials of treatment-resistant patients. Significant associations between cognitive change and change in negative symptoms are more likely to occur in these studies than in naturalistic follow-up studies(5). Thirdly, we feel the authors missed an opportunity to include the distinction between first-episode, chronic, and geriatric patients as a potential moderator variable. This could have contributed to a better understanding of the probably complex cognitive pathways during the lifespan.

Despite the number of longitudinal neurocognitive reports, less is known than was originally supposed about the course of cognition in schizophrenia. Only a small subset (n=4) of longitudinal reports have compared these neurocognitive pathways with those of healthy controls overat least one year. When reviews(2) are not focused on the neurocognitive effects of antipsychotics, stable long-term performances and, in some cases, cognitive gains could be expected, thus offering a rather pessimistic picture for cognitive enhancement. This approach seems more useful for understanding the long-term natural history of cognition in schizophrenia. Conversely, this meta-analysis(1) relies on short-term data, mostly from clinical trials(3), and therefore more likely overestimates the potential for cognitive improvement.

In sum, it would be misleading if the conclusions were regarded as a major leap forward instead of as tentative hypotheses awaiting further investigation. Since the possibility remains that the current findings aremore valuable to researchers, a new meta-analysis that takes into consideration these and other limitations might be more helpful for clinicians, patients and caregivers.


1. Szöke A, Trandafir A, Dupont ME, Méary A, Schürhoff F, Leboyer M. Longitudinal studies of cognition in schizophrenia: meta-analysis. Br J Psychiatry. 2008;192(4):248-57.

2. Rund BR. A review of longitudinal studies of cognitive functions in schizophrenia patients. Schizophr Bull. 1998;24(3):425-35.

3. Woodward ND, Purdon SE, Meltzer HY, Zald DH. A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. Int J Neuropsychopharmacol. 2005; 8(3): 457-72.

4. Goldberg TE, Goldman RS, Burdick KE, Malhotra AK, Lencz T, Patel RC, Woerner MG, Schooler NR, Kane JM, Robinson DG. Cognitive improvement after treatment with second generation antipsychotic medications in first-episode schizophrenia: is it a practice effect? Arch Gen Psychiatry. 2007;64(10):1115-22.

5. Buchanan RW, Davis M, Goff D, Green MF, Keefe RS, Leon AC, Nuechterlein KH, Laughren T, Levin R, Stover E, Fenton W, Marder SR. A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia. Schizophr Bull 2005; 31(1):5-19.
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Conflict of interest: None Declared

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How long is longitudinal

Ahmed S huda, Consultant, Early Intevention in Psychosis
25 April 2008

One of the authors' aims was to distinguish if cognitive deficits were progressive. They used studies which retested after at least one month. The means for half of the studies included retesting occurred btween 1-4 months but with a few "outliers" pulling the mean to 12 months.This is a relatively short period of time to deterimine if cognitive deficits are progressive. The data supplement did not state the period of time between tests for the studies. It suggests there were few studies included with retesting beyond 12 months.

I think we can accept the autohrs' conclusions of improvement in cognitive testing. However we have to add the further caveat that this seems to be in the short term only (12 months or less given the likley paucity of data from after this period included in the study).

This paper can not address the issue of whether schizophrenia is associated with progressive cognitve deficits in the long term as it does not include enough studies with time between tests measured in years/ decades.

For example:V. S. Gabrovska-Johnson et al (2003),"Right-hemisphere encephalopathy in elderly subjects with schizophrenia: evidence from neuropsychological and brain imaging studies" Psychopharmacology Volume 169, p. 367-375 found evidence of neurocognitive deficits in elderly patients with schizophreniathat were different than those found in Alzheimer's disease.

Perhaps the authors' were too restrictive in their entry criteria andexcluded a lot of the longer term studies.

It would be unfortunate if the authors' study was to be referenced infuture as proof that there is no long term cognitive deteriotation in schizophrenia.
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