Skip to main content Accessibility help


  • Access
  • Cited by 38


      • Send article to Kindle

        To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

        Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

        Find out more about the Kindle Personal Document Service.

        Cognitive effectiveness of olanzapine and risperidone in first-episode psychosis
        Available formats

        Send article to Dropbox

        To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

        Cognitive effectiveness of olanzapine and risperidone in first-episode psychosis
        Available formats

        Send article to Google Drive

        To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

        Cognitive effectiveness of olanzapine and risperidone in first-episode psychosis
        Available formats
Export citation



Cognitive impairment in schizophrenia-spectrum disorders is highly prevalent and notably influences functional outcomes.


To characterise the cognitive effectiveness of second-generation antipsychotic drugs.


One hundred consecutive and previously unmedicated patients with first-episode schizophrenia-spectrum disorders were admitted. Seventy-seven completed baseline, 1-month and 6-month psychopathological and neuropsychological assessments. Patients were randomised to risperidone or olanzapine treatment. Four final treatment allocation groups were defined since patients continued treatment in their normal setting: risperidone, olanzapine, mixed and no-antipsychotic groups.


There were no differences in cognitive effectiveness between the four treatment groups. Reliable change index methods demonstrated that nearly a half of patients showed an improvement in Global Cognitive Score at the 6-month assessment. Improvement on the neuropsychological tests ranged from 17 to 54%.

A strong predictor of cognitive response was poor performance on baseline neuropsychological tests; response was moderately influenced by a low premorbid scholastic performance and IQ.


Cognitive improvement related to second-generation antipsychotic drugs appeared within the first 4 weeks of treatment and persisted at 6 months irrespective of treatment group. Greater cognitive dysfunction at baseline and lower premorbid cognitive background predicted cognitive improvement in our sample.


The Navarrás Government provided funding for implementation of the study (grants 946/2005 and 55/2007).

Declaration of interest


Cognitive impairment is a prevalent feature in patients with schizophrenia Reference Heinrichs and Zakzanis1Reference Kraus and Keefe5 that greatly influences functional outcomes. Reference Green6,Reference Green7 Both global deficit and impairments in attention, memory and executive functions are commonly found in schizophrenia.

A renewed interest in the amelioration of cognitive deficits of schizophrenia arose with the new antipsychotic drugs. Earlier reviews suggested that first-generation antipsychotic drugs did not improve cognitive performance in schizophrenia, Reference Cuesta, Peralta and Zarzuela8Reference King13 although studies concluded that low doses of typical antipsychotics seem to have favourable cognitive effects. Reference Weickert and Goldberg14Reference Sharma18 Moreover, two recent contributions reduce the strength of the argument for cognitive efficacy of antipsychotic drugs. First, the CATIE study concluded that the cognitive improvement related to either first- or second-generation antipsychotics was significant, but smaller than previously reported. Reference Keefe, Bilder, Davis, Harvey, Palmer and Gold17 Second, it was recently suggested that part of this improvement in patients with first-episode schizophrenia was similar to the practice effect observed in healthy controls. Reference Goldberg, Goldman, Burdick, Malhotra, Lencz and Patel19

The present study was a naturalistic, randomly assigned and non-commercially funded study aimed at assessing the cognitive outcome at 6 months in a sample of drug-naive patients with first-episode psychosis. The primary goal was to compare cognitive function between four treatment conditions: patients receiving either risperidone or olanzapine; patients who changed their initial atypical antipsychotic; and patients who did not receive antipsychotics in the last 3 months of the study. As a secondary goal, this study aimed to investigate individual prognostic indicators of a good cognitive response irrespective of treatment group.



A total of 100 consecutive, drug-naive patients with first-episode psychosis were evaluated. Inclusion criteria were:

  1. (a) patients aged 16–65 years

  2. (b) an acute episode at study intake that met DSM–IV–TR 20 criteria for schizophrenia and other psychotic disorders

  3. (c) no previous exposure to antipsychotics

  4. (d) provided written informed consent and able to take part in neuropsychological assessment.

Patients with a history of serious medical or neurological disease, head injury, intellectual disability or drug dependence were excluded from the study.

All study aims and procedures were fully explained to participants and their families before they signed a written consent form; the study was approved by the institutional review board.

Study design and procedures

This was a longitudinal and naturalistic study, which comprised comprehensive psychopathological and neuropsychological assessments at three points: baseline, 1-month and 6-month follow-up. All patients underwent the Comprehensive Assessment of Symptoms and History interview. Reference Andreasen, Flaum and Arndt21 A DSM–IV–TR diagnosis was reached by clinical consensus between the two senior researchers (M.J.C. and V.P.).

Two psychiatrists (E.G.J. and M.S.C.) assessed the psychopathological and cognitive status of patients in such a way that each was masked to the assessment of the other and to the treatment received by patients. Good interrater reliability coefficients for psychopathological assessments (κ=0.80–0.98) were achieved by the two psychiatrists.

Once baseline assessments were completed on the first day of admission, participants were randomly assigned to receive either risperidone (n=56) or olanzapine (n=44) treatment. Patients initially received a low dose (2.5 mg for risperidone, 5 mg for olanzapine), which was gradually titrated up while active symptoms were present. Patients were followed in their natural treatment environment and treatment decisions after initial randomisation were made by treating psychiatrists.

Of the 100 patients, 23 withdrew during the course of the study (11 and 12 individuals at 1-month and 6-month assessments respectively) (Fig. 1). Final drug allocation groups were as follows: risperidone group, n=29; olanzapine group, n=22; mixed group (those patients who needed to change their initial antipsychotic to another atypical antipsychotic), n=16; and no-antipsychotic group (those patients who did not receive antipsychotic drugs in the last 3 months of follow-up), n=10.

Fig. 1 Flow of participants through the study. a. Patients who needed to change their initial antipsychotic to another. b. Patients who did not receive antipsychotic drugs in the last 3 months of follow-up.

Doses of the atypical antipsychotics were transformed to chlorpromazine equivalents (mg). Reference Woods22 Patients received either biperidene or benzodiazepines if needed by indication of the treating psychiatrists.

Drug adherence was assured by collecting information independently from patients, families and the attending psychiatrist at every point of assessment. Surveillance by close relatives is one of most accurate methods of measuring adherence. Reference Osterberg and Blaschke23

Neuropsychological assessment

Participants were assessed by means of a comprehensive neuropsychological battery measuring attention, executive function, information processing, and memory. Neuropsychological tests included: Verbal Fluency Reference Reitan and Wolfson24 (number of animals evoked in 1 min); Trail Making Test – form B Reference Reitan and Wolfson24 (number of seconds to complete the task); Wechsler Memory Scale (WMS); Reference Wechsler25 and four tasks of the COGLAB computerised neuropsychological battery: Reference Spaulding, Garbin and Dras26,Reference Penn, Van Der Does, Spaulding, Garbin and Linszen27 a reaction time task (that included Redundancy-Associated Deficit (RAD), a vigilance and span of apprehension task (Asarnow's test, which included Total Hits and Total False Alarms), a visual backward masking task (iconic memory test), and the Wisconsin Card Sorting Test (WCST; Perseverative Errors and Total Trials).

Exploratory factor analyses of the 14 cognitive measures at each assessment point were done to obtain a Global Cognitive Score (GCS) and to normalise different scales of measurements. Exploratory factor analyses resulted in four factors (eigenvalue =1), although an inspection of the three Scree test plots revealed that only one factor achieved the greater percentage of explained variance. Thus, reduction to a one-factor solution was carried out and baseline, 1-month and 6-month GCS variables were saved. Oblimin rotation was chosen to allow factors to be correlated, as it occurs usually among cognitive measures. Reference Hair, Black, Babin, Anderson and Tatham28

General IQ was ascertained by means of the Spanish version of a non-verbal IQ test (TONI-2 Test). Reference Brown, Sherbenou and Johnsen29

Statistical analysis

To compare demographic and clinical characteristics between groups, one-way repeated measures ANOVA and chi-squared test were applied. Logarithmic transformation or z-transformations were applied to non-normally distributed variables.

Testing occasion was the within-group factor (baseline, 1 month and 6 months) and treatment assignment was the between-group factor (risperidone, olanzapine, mixed and no-antipsychotic groups). Repeated measures ANCOVA was also performed for each cognitive variable using baseline neuropsychological assessments, biperidene and antipsychotic mean doses (chlorpromazine equivalents in mg) as covariates. Tukey's Honestly Significant Difference test was performed for post hoc analysis between diagnostic groups.

We also calculated two forms of the reliable change index (RCI), Reference Jacobson and Truax30 which is a group of statistical techniques used in many areas of medicine to help determine when an individual's performance on a neuropsychological test has changed from a previous assessment with the same test. The index provides information about whether people have changed sufficiently that the change is unlikely to be due to simple measurement unreliability. Formulas for RCI–simple (RCI–s) and RCI–practice (RCI–p) are shown in the online supplement to this paper.


Demographic and clinical characteristics of treatment groups

No differences in clinical or epidemiological variables at baseline were found between those patients who withdrew (n=23, 23%) and those who completed the study (n=77, 77%) except for years of education (t=2.36, d.f.=98, P<0.020) (Table 1). The subsequent results refer to those who completed the three assessments (n=77).

Table 1 Demographic, clinical and pharmacological characteristics of the sample at baseline

Risperidone (n = 29) Olanzapine (n = 22) Mixed (n = 16) No antipsychotic drug (n = 10) Total (n = 77) Statistic (P)
    Male 22 16 9 6 53 χ2 = 2.37 (0.5)
    Female 7 6 7 4 24
Age, years: mean (s.d.) 26.7 (7.44) 32.73 (11.8) 30.13 (10.86) 34.10 (8.86) 30.09 (10) F = 2.27 (0.087)a
Age at onset, years: mean (s.d.) 24.99 (7.57) 31.5 (11.8) 26.63 (9.17) 29.89 (9.93) 27.83 (9.78) F = 2.16 (0.099)a
Duration of illness, years: mean (s.d.) 0.84 (1.47) 0.61 (0.9) 1.74 (3.12) 2.10 (3.65) 1.13 (2.2) F = 1.67 (0.179)a
Years of education, mean (s.d.) 13.83 (3.52) 15 (4.61) 12.38 (4.36) 14.30 (3.23) 13.92 (4.04) F = 1.35 (0.263)a
Parent's years of education, mean (s.d.) 8.83 (3.38) 7.76 (2.27) 7.03 (1.81) 8.20 (3.73) 8.07 (2.90) F = 1.46 (0.233)a
Scholastic performance,b n (%)
    Excellent 3 (10) 1 (5) 0 1 (10) 5 (6) χ2 = 13.56 (0.330)
    Good 3 (10) 4 (18) 2 (13) 3 (30) 12 (16)
    Medium 12 (41) 10 (45) 4 (25) 4 (40) 30 (39)
    Low 8 (28) 6 (27) 10 (63) 1 (10) 25 (32)
    Failing 3 (10) 1 (5) 0 1 (10) 5 (6)
GAF—P, mean (s.d.) 76.07 (17.71) 80.14 (12.54) 73.94 (21.45) 82.30 (17.04) 77.60 (17.11) F = 0.72; (0.540)a
Current IQ (TONI-2), mean (s.d.) 96.9 (17.85) 92.5 (18.94) 96.06 (18.35) 99.10 (20.74) 95.75 (18.41) F = 0.37; (0.776)a
DSM—IV—TR diagnosis, n (%)
    Schizophrenia 16 (55) 6 (27) 7 (44) 4 (40) 33 (43) χ2 = 21.47; (0.122)
    Schizoaffective disorder 1 (3) 1 (5) 2 (13) 2 (20) 6 (8)
    Brief psychotic disorder 6 (21) 7 (32) 4 (25) 1 (10) 18 (23)
    Schizophreniform disorder 6 (21) 3 (14) 3 (19) 0 12 (16)
    Delusional disorder 0 4 (19) 0 2 (20) 6 (8)
    Atypical psychosis 0 1 (5) 0 1 (10) 2 (3)
Benzodiazepines, n (%) 22 (76) 16 (73) 13 (81) 9 (90) 60 (78)

The four treatment groups did not differ in most epidemiological, clinical and diagnostic variables. However, the risperidone group had significantly higher scores for psychotic syndrome than the olanzapine group; the no-antipsychotic group had significantly higher scores than the risperidone group for depressive syndrome; and the risperidone and mixed groups showed significantly higher scores for disorganisation syndrome than the olanzapine group at baseline (online Table DS1). Patients in the risperidone group received higher antipsychotic doses at 6-month but not at 1-month assessment and they were treated more often with anticholinergic drugs (37.93%) than either the mixed (18.75%) or olanzapine and no-antipsychotic groups (0%) (Table 2).

Table 2 Clinical and pharmacological characteristics of the sample at 1-month and 6-month assessment

Risperidone (n = 29) Olanzapine (n = 22) Mixed (n = 16) No antipsychotic drug (n = 10) Total (n = 77) Statistic (P)
1-month assessment
Chlorpromazine equivalent dose, mg: mean (s.d.) 303.44 (136.23) 215.90 (96.83) 290.62 (174.13) 227.50 (134.08) 265.90 (138.30) F=2.19 (0.096)a
    Dose, mg: mean (s.d.) 3.33 (1.15) 0 0 0 3.33 (1.15) F=1.60 (0.195)a
    Patients, n (%) 3 (10) 0 0 0 3 (4)
Benzodiazepines, n (%) 29 (100) 17 (77) 16 (100) 9 (90) 71 (92)
6-month assessment
DSM—IV—TR diagnosis, n (%)
    Schizophrenia 23 (79) 10 (45) 10 (63) 4 (40) 47 (61) χ2=26.12 (0.097)
    Schizoaffective disorder 2 (7) 2 (9) 3 (19) 2 (20) 9 (12)
    Acute psychosis 3 (10) 5 (23) 2 (13) 1 (10) 11 (14)
    Schizophreniform disorder 1 (3) 1 (5) 1 (6) 0 3 (4)
    Delusional disorder 0 4 (18) 0 2 (20) 6 (8)
    Atypical psychosis 0 0 0 1 (10) 0
Chlorpromazine equivalent dose, 212.93 145.45 288.09 0 206.28 F=6.04 (0.001)a,b
mg: mean (s.d.) (143.24) (72.22) (334.14) (190.06)
    Dose, mg: mean (s.d.) 3.63 (0.81) 0 4 (0) 0 3.71 (0.72) F=5.02 (0.003)a,c
    Patients, n (%) 11 (38) 0 3 (19) 0 14 (18)
Benzodiazepines, n (%) 26 (90) 21 (95) 14 (88) 0 71 (92)

Neuropsychological test results

No significant main effects on neuropsychological tests and on the GCS were found for any of the four groups. Cognitive performance showed significant improvement over time on most neuropsychological tests irrespective of the treatment group, with the exception of performance on three tasks: reaction time, RAD and Asarnow Total False Alarms (Table 3). The mixed group showed greater improvement than the other three groups on WMS Associated Learning (group × time interaction: F=2.63, d.f.=3.63, P=0.044).

Table 3 Reliable change index (95%) simple and practice frequencies for each neuropsychological test

Cognitive test Patients, n RCI—s/RCI—p Worsening, n (%) RCI—s/RCI—p Stable, n (%) RCI—s/RCI—p Improvement, n (%) RCI—s/RCI—p
Verbal fluencya 77/77 35 (45.45)/39 (50.64) 0 (0)/0 (0) 42 (54.54)/38 (49.35)
Trail Making Test—Ba 77/77 50 (64.93)/48 (62.33) 2 (2.59)/1 (1.29) 25 (32.46)/28 (36.36)
Wechsler Memory Scale
    Total 76/76 40 (52.63)37 (46.68) 0 (0)/1 (1.31) 36 (47.36)/38 (50.00)
    Logical memory 77/77 35 (45.45)/41 (53.24) 5 (6.49/1 (1/29) 37 (48.05)/35 (45.45)
    Digital memory 77/77 36 (46.75/45 (58.44) 0 (0)/0 (0) 41 (53.24)/32 (41.55)
    Visual reproduction 77/77 41 (53.24)/40 (51.94) 1 (1.29)/2 (2.59) 35 (45.45)/35 (45.45)
    Paired associated learning 77/77 44 (57.14)/37 (48.05) 1 (1.29)/2 (2.59) 32 (41.55)/38 (49.35)
    Reaction time 77/75 45 (58.44)/39 (52.00) 2 (2.59)/1 (1.33) 30 (38.96)/35 (46.66)
    RAD (reaction time) 77/75 40 (51.94)/39 (52.00) 4 (5.19)/1 (1.33) 33 (42.85)/35 (46.66)
    Backward Masking Total 75/73 44 (58.66)/37 (50.68) 2 (2.66)/3 (4.10) 29 (38.66)/33 (45.20)
    WCST Perseverative Errors 76/74 44 (57.89)/37 (50.00) 4 (5.26)1 (1.35) 28 (36.84)/36 (48.64)
    WCST Total Trials 76/74 50 (65.78)/40 (54.05) 3 (3.94)/0 (0) 23 (30.26)/34 (45.94)
    Asarnow Total Hits 75/73 45 (60.00)/41 (56.16) 2 (2.66)/1 (1.36) 28 (37.33)/31 (42.46)
    Asarnow Total False Alarms 75/73 49 (65.33)/28 (38.35) 13 (17.33)/0 (0) 13 (17.33)/45 (61.64)
    Global Cognitive Scoreb 74/72 39 (52.70)/38 (52.77) 0 (0)/1 (1.38) 35 (47.29)/33 (45.83)

After including antipsychotic and biperidene doses at the 6-month point with baseline neuropsychological results as covariates on repeated measures ANCOVA analyses, most effects for time vanished. Only the effects for time on WCST Total Trials (F=6.29, d.f.=1, P=0.015) and Asarnow Total Hits (F=12.47, d.f.=1, P=0.001) remained statistically significant.

The significant findings of both ANOVA and ANCOVA did not exceed the required P-value level of the Bonferroni correction (P=0.003, for 16 sets of repeated measures of ANOVA or ANCOVA), except for Asarnow Total Hits.

Reliable change index scores

Reliable change indices for the whole sample demonstrated great variation in individual patterns over time across neuropsychological tests, although both indices (simple and practice) showed similar scores. Specifically, the percentages of patients who improved on neuropsychological tests and GCS ranged from 17.33% on Asarnow False Alarms to 54.54% on Verbal Fluency (Table 3).

The RCI–s and RCI–p results for the GCS demonstrated that 35 (47.29%) and 33 (45.83%) patients respectively showed a statistically meaningful improvement (or reliable improvement) and that 39 (52.70%) and 38 (52.77%) patients respectively displayed a lower change than expected at 6-month follow-up. However, there were no individual patients performing below their own baseline performance at the 6-month assessment on any cognitive measures.

Reliable worsening and stable patterns should be interpreted with caution since they do not represent patients definitively showing a deteriorating outcome, rather those patients who did not reach significant statistical changes as shown in online Fig. DS1.

To characterise the cognitive improvement of our patients, two sets of stepwise regression procedures were set for demographic and clinical variables in which the indices of neuropsychological tests and of GCS were introduced as ‘dummy’ dependent variables (improvement v. stable and no-improvement patients) (see footnote of online Table DS2 for a description of variables entered into the regression analyses). Moreover, in order to gain greater insight into patients' cognitive performance, it was necessary to account for both ceiling effects of cognitive measures and for patients' performance within normal ranges on neuropsychological tests by including baseline performance on each test and baseline GCS together with the above demographic and clinical variables for both RCI–s and RCI–p.

Patients with a cognitive response were strongly influenced by poor performance on neuropsychological tests at baseline (online Table DS2). The premorbid scholastic performance and current IQ were moderate predictors of cognitive improvement; high baseline psychopathological scores (disorganisation and psychotic syndrome scores), treatment variables (lower 6-month chlorpromazine equivalent doses) and 6-month DSM–IV–TR diagnosis were slight, but also significant predictors. Treatment status was not included in these patients' profiles in the regression analyses.


In the present study, we followed the treatment effects of atypical antipsychotic drugs on neurocognitive performance in a drug-naive patient sample with first-episode schizophrenia-spectrum disorders over 6 months in a naturalistic setting.

Three main conclusions can be drawn from this study. First, no differences in cognitive effectiveness were found between the four treatment groups. Second, 30% of the total sample showed an improvement in GCS at 6 months and showed improvement on the 14 neuropsychological tests ranging from 17 to 54%. Finally, the clinical profile at the individual level was strongly influenced by poor cognitive performance at baseline and moderately influenced by low premorbid scholastic performance and low IQ. Female gender, young age and low antipsychotic doses at the 6-month assessment also contributed marginally to a better cognitive improvement profile at the individual level.

Levels of cognitive impairment and rates of global cognitive improvement in our patients were in keeping with previous studies at initial disease presentation. Reference Saykin, Shtasel, Gur, Kester, Mozley and Stafiniak31Reference Townsend and Norman34 Our results can also be applied to non-drug-naive patients with first-episode psychosis since no differences were evident between studies comparing drug-naive and non-naive patients in first-episode psychosis. Reference Mohamed, Paulsen, O'Leary, Arndt and Andreasen35,Reference Riley, McGovern, Mockler, Doku, OCeallaigh and Fannon36

It is usually taken for granted that cognitive improvement is a direct effect of antipsychotic drugs; however, any longitudinal cognitive change (either improvement or worsening) in schizophrenia might come from at least three sources: patient-related factors, neuropsychological assessment and treatment effects.

Patient-related factors

The pattern of cognitive impairment in patients with schizophrenia is likely to be a function of the heterogeneity within the disorder itself. Reference Goldstein and Shemansky37 To homogenise the population as much as possible for differences in illness-phase, Reference González-Blanch, Alvarez-Jiménez, Rodríguez-Sánchez, Pérez-Iglesias, Vázquez-Barquero and Crespo-Facorro38 we only included drug-naive patients with a first episode. Moreover, based on the current lack of definitive validation for any psychosis subtype, Reference Peralta and Cuesta39 we chose a broad approach by including schizophrenia-spectrum disorders. Nevertheless, the analysis from the statistical procedures performed only on patients with schizophrenia demonstrated that there were no great differences compared with the entire sample.

One of the most important determinants of neuropsychological performance is premorbid scholastic performance. Premorbid intra-individual intellectual performance variability has been associated with the risk of developing schizophrenia, Reference Reichenberg, Weiser, Rapp, Rabinowitz, Caspi and Schmeidler40 and low premorbid intellectual achievement may also be an early manifestation of the illness. Reference Cannon, Caspi, Moffit, Harrington, Taylor and Murray41 New to this study was that lower premorbid IQ predicted cognitive improvement over 6 months. This implies that patients with greater ‘cognitive reserve’, who are already experiencing cognitive changes related to schizophrenia, perform within normal limits until acute impairment is severe. Likewise, patients with lower cognitive reserve are less able to compensate for cognitive deficits; consequently, they are prone to develop greater cognitive dysfunction related to the acute episode and show a wider range of intra-individual variability on standard clinical cognitive testing.

Neuropsychological issues in the assessment of cognitive improvement

Accurate interpretations of the neuropsychological test findings are based on the premise that each test is reasonably free of measurement error, practice effects and that tests are not prone to floor and ceiling effects. In our study, the reliable change index method (both simple and practice) was used as a statistical technique to account for the reliability of intra-individual score changes. As was reported for patients with stable schizophrenia, Reference Heaton, Temkin, Dikmen, Avitable, Taylor and Marcotte42 we found larger-than-expected percentages of patients with schizophrenia-spectrum disorders classified as cognitively changed on 6-month retest assessments. In this regard, although reliable change index methods allowed us to delineate cut-off points for cognitive improvement in neuropsychological tests, cognitive decline and cognitively stable patterns are better interpreted as ‘lower performance than predicted’. Moreover, after inspection of the baseline and 6-month plots of our 14 neuropsychological measures, we determined that our results were not subject to floor or ceiling effects.

Antipsychotic drug effects on cognitive performance

There were no significant differences in cognitive effectiveness among the four treatment groups over the 6 months of treatment. These results added support to studies reporting that atypical antipsychotic drugs produced significant improvement in neurocognition, Reference Woodward, Purdon, Meltzer and Zald16,Reference Keefe, Sweeney, Gu, Hamer, Perkins and McEvoy43,Reference Cuesta, Peralta and Zarzuela44 although with a smaller effect than previously reported. Reference Green7,Reference Keefe, Bilder, Davis, Harvey, Palmer and Gold17

To account for practice effects Reference Goldberg, Goldman, Burdick, Malhotra, Lencz and Patel19 we did not include a healthy control group but we employed differences in neuropsychological tests between the 1-month assessment, when patients were clinically stable, and the 6-month assessment to derive our RCI–p. The latter is in agreement with the findings of Heaton et al, Reference Heaton, Temkin, Dikmen, Avitable, Taylor and Marcotte42 who found large standard errors in patients with schizophrenia, suggesting that results from normative populations might not be appropriate for them. The RCI–p and RCI–s results were similar, and nearly a half of our patients with schizophrenia-spectrum disorders (47.29 and 45.83%, RCI–s and RCI–p respectively) showed an improvement in GCS, irrespective of treatment allocation.

Moreover, since cognitive improvement was not only seen on tests more prone to practice effect – such as those involving a large speed component, requiring an infrequently practised response or those involving learning Reference Lezak45 – it seemed feasible in all 14 neuropsychological measures that cognitive improvement was not only due to practice, but was also a direct drug effect. There could also be an effect of the ‘acute episode’, but linear estimations by means of multiple regressions showed that variations in psychopathological syndrome scores only accounted for a small amount of the explained variance and not in all neuropsychological measures (Table 3). It seems unlikely that a placebo effect would only show an improvement between baseline and the 1-month assessment; however, it showed an effect that lasted for 6 months, even for the no-antipsychotic group and in a naturalistic setting.

An unexpected finding of our study was the lack of great differences in cognitive improvement between patients receiving atypical antipsychotic drugs and patients without antipsychotic drugs after the first 3 months of follow-up. This finding suggests that cognitive enhancement related to antipsychotic drugs in patients with first-episode schizophrenia-spectrum disorder might be apparent in the first weeks of treatment and might last for at least 6 months, irrespective of subsequent treatment.

Relevance of cognitive impairment at baseline for cognitive improvement

Individual improvement for each neuropsychological measure on the basis of RCI methods revealed that the higher the cognitive impairment at baseline assessment, the greater the rate of improvement with treatment. However, when individual profiles were compared between patients who showed improvement and worsening on the RCI, we discovered a limitation to this method: those who began with high scores could not demonstrate improvement because of a ceiling effect related to the capacity of being able to improve on neuropsychological tests beyond normal limits. These patients performing well at the beginning continued doing well during follow-up, and as a consequence, their cognitive change was clearly inferior to those starting at very low levels of performance.

The insight gleaned from our results will help guide future studies, which should be focused at the individual level in order to differentiate any potential factors contributing to the cognitive heterogeneity of our patients. Moreover, an added effort should be made to provide tools for clinicians to interpret and manage changes in cognitive functioning at the individual level such as RCI methods.


Some caution is warranted owing to the small sample in the no-antipsychotic group, which might have led to our study being underpowered to detect real differences on cognitive performance in relation to other treatment groups. However, ANCOVA has been repeatedly demonstrated to be one of the most powerful methods of analysis for randomised comparative trials Reference Vickers46 and statistical power usually increases with repeated measures designs in situations where large individual differences are expected. Reference Allison, Allison, Faith, Paultre and Pi-Sunyer47


We thank all participants and support staff that made this study possible. We are also grateful to Manel Salamero for his advice on statistical analysis.


1 Heinrichs, RW, Zakzanis, KK. Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology 1998; 12: 426–45.
2 Saykin, AJ, Gur, RC, Gur, RE, Mozley, PD, Mozley, LH, Resnick, SM, et al. Neuropsychological function in schizophrenia. Selective impairment in memory and learning. Arch Gen Psychiatry 1991; 48: 618–24.
3 Cuesta, MJ, Peralta, V, Caro, F, de Leon, J. Schizophrenic syndrome and Wisconsin Card Sorting Test dimensions. Psychiatry Res 1995; 58: 4551.
4 Heaton, RK, Gladsjo, JA, Palmer, BW, Kuck, J, Marcotte, TD, Jeste, DV. Stability and course of neuropsychological deficits in schizophrenia. Arch Gen Psychiatry 2001; 58: 2432.
5 Kraus, MS, Keefe, RSE. Cognition as an outcome measure in schizophrenia. Br J Psychiatry 2007; 191 (suppl 50): s4651.
6 Green, MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 1996; 153: 321–30.
7 Green, MF. Cognition, drug treatment, and functional outcome in schizophrenia: a tale of two transitions. Am J Psychiatry 2007; 164: 992–4.
8 Cuesta, MJ, Peralta, V, Zarzuela, A. Illness duration and neuropsychological impairments in schizophrenia. Schizophr Res 1998; 33: 141–50.
9 Heaton, RK, Crowley, TJ. Effects of psychiatry disorders and their somatic treatments on neuropsychological test results. In Handbook of Clinical Neuropsychology (eds Filskov, SB, Boll, TJ): 481525. Wiley, 1981.
10 Medalia, A, Gold, J, Merriam, A. The effect of neuroleptics on neuropsychological test results of schizophrenics. Arch Clin Neuropsychol. 1988; 3: 249–71.
11 Spohn, HE, Strauss, ME. Relation of neuroleptic and anticholinergic medication to cognitive fuctions in schizophrenia. J Abnorm Psychol 1989; 98: 367–80.
12 Cassens, G, Inglis, AK, Appelbaum, PS, Gutheil, TG. Neuroleptics: effects on neuropsychological function in chronic schizophrenic patients. Schizophr Bull 1990; 16: 477–99.
13 King, DJ. The effect of neuroleptics on cognitive and psychomotor function. Br J Psychiatry 1990; 157: 799811.
14 Weickert, TW, Goldberg, TE. First- and second-generation antipsychotic medication and cognitive processing in schizophrenia. Curr Psychiatry Rep 2005; 7: 304–10.
15 Mishara, AL, Goldberg, TE. A meta-analysis and critical review of the effects of conventional neuroleptic treatment on cognition in schizophrenia: opening a closed book. Biol Psychiatry 2004; 55: 1013–22.
16 Woodward, ND, Purdon, SE, Meltzer, HY, Zald, DH. A meta-analysis of cognitive change with haloperidol in clinical trials of atypical antipsychotics: dose effects and comparison to practice effects. Schizophr Res 2007; 89: 211–24.
17 Keefe, RS, Bilder, RM, Davis, SM, Harvey, PD, Palmer, BW, Gold, JM, et al. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry 2007; 64: 633–47.
18 Sharma, T. Cognitive effects of conventional and atypical antipsychotics in schizophrenia. Br J Psychiatry 1999; 174 (suppl 38): s4451.
19 Goldberg, TE, Goldman, RS, Burdick, KE, Malhotra, AK, Lencz, T, Patel, RC, et al. Cognitive improvement after treatment with second-generation antipsychotic medications in first-episode schizophrenia: is it a practice effect? Arch Gen Psychiatry 2007; 64: 1115–22.
20 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th edn, text revision) (DSM–IV–TR). APA, 2000.
21 Andreasen, NC, Flaum, M, Arndt, S. The Comprehensive Assessment of Symptoms and History (CASH). An instrument for assessing diagnosis and psychopathology. Arch Gen Psychiatry 1992; 49: 615–23.
22 Woods, SW. Chlorpromazine equivalent doses for the newer atypical antipsychotics. J Clin Psychiatry 2003; 64: 663–67.
23 Osterberg, L, Blaschke, T. Adherence to medication. N Engl J Med 2005; 353: 487–97.
24 Reitan, RM, Wolfson, D. The Halstead-Reitan Neuropsychological Test Battery: Theory and Clinical Interpretation. Neuropsychology Press, 1985.
25 Wechsler, DA. Standarized memory scale for clinical use. J Psychology 1945; 19: 8795.
26 Spaulding, W, Garbin, CP, Dras, SR. Cognitive abnormalities in schizophrenic patients and schizotypal college students. J Nerv Ment Dis 1989; 177: 717–28.
27 Penn, DL, Van Der Does, W, Spaulding, W, Garbin, CP, Linszen, D, et al. Information processing and social cognitive problem solving in schizophrenia. J Nerv Ment Dis 1993; 181: 1320.
28 Hair, JF, Black, B, Babin, B, Anderson, RE, Tatham, RL. Multivariate Data Analysis (6th edn). Pearson Prentice Hall, 2005.
29 Brown, L, Sherbenou, RJ, Johnsen, SK. TONI-2 Test de Inteligencia No Verbal. TEA Ediciones, 1995.
30 Jacobson, NS, Truax, P. Clinical significance: a statistical approach to defining meaningful change in psychotherapy research. J Consult Clin Psychol 1991; 59: 12–9.
31 Saykin, AJ, Shtasel, DL, Gur, RE, Kester, DB, Mozley, LH, Stafiniak, P, et al. Neuropsychological deficits in neuroleptic naive patients with first-episode schizophrenia. Arch Gen Psychiatry 1994; 51: 124–31.
32 Bilder, RM, Goldman, RS, Robinson, D, Reiter, G, Bell, L, Bates, JA, et al. Neuropsychology of first-episode schizophrenia: initial characterization and clinical correlates. Am J Psychiatry 2000; 157: 549–59.
33 Lee, SM, Chou, YH, Li, MH, Wan, FJ, Yen, MH. Effects of antipsychotics on cognitive performance in drug-naive schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 1101–7.
34 Townsend, LA, Norman, RM. Course of cognitive functioning in first episode schizophrenia spectrum disorders. Expert Rev Neurother 2004; 4: 61–8.
35 Mohamed, S, Paulsen, JS, O'Leary, D, Arndt, S, Andreasen, N. Generalized cognitive deficits in schizophrenia: a study of first-episode patients. Arch Gen Psychiatry 1999; 56: 749–54.
36 Riley, EM, McGovern, D, Mockler, D, Doku, VC, OCeallaigh, S, Fannon, DG, et al. Neuropsychological functioning in first-episode psychosis – evidence of specific deficits. Schizophr Res 2000; 43: 4755.
37 Goldstein, G, Shemansky, WJ. Influences on cognitive heterogeneity in schizophrenia. Schizophr Res 1995; 18: 5969.
38 González-Blanch, C, Alvarez-Jiménez, M, Rodríguez-Sánchez, JM, Pérez-Iglesias, R, Vázquez-Barquero, JL, Crespo-Facorro, B. Cognitive functioning in the early course of first-episode schizophrenia spectrum disorders: timing and patterns. Eur Arch Psychiatry Clin Neurosci 2006; 256: 364–71.
39 Peralta, V, Cuesta, MJ. A dimensional and categorical architecture for the classification of psychotic disorders. World Psychiatry 2007; 6: 36–7.
40 Reichenberg, A, Weiser, M, Rapp, MA, Rabinowitz, J, Caspi, A, Schmeidler, J, et al. Pre-morbid intra-individual variability in intellectual performance and risk for schizophrenia: a population-based study. Schizophr Res 2006; 85: 4957.
41 Cannon, M, Caspi, A, Moffit, TE, Harrington, H, Taylor, A, Murray, RM, et al. Evidence for early-childhood, pan-developmental impairment specific to schizophreniform disorder: results from a longitudinal birth cohort. Arch Gen Psychiatry 2002; 59: 449–56.
42 Heaton, RK, Temkin, N, Dikmen, S, Avitable, N, Taylor, MJ, Marcotte, TD, et al. Detecting change: a comparison of three neuropsychological methods, using normal and clinical samples. Arch Clin Neuropsychol 2001; 16: 7591.
43 Keefe, RS, Sweeney, JA, Gu, H, Hamer, RM, Perkins, DO, McEvoy, JP, et al. Effects of olanzapine, quetiapine, and risperidone on neurocognitive function in early psychosis: a randomized, double-blind 52-week comparison. Am J Psychiatry 2007; 164: 1061–71.
44 Cuesta, MJ, Peralta, V, Zarzuela, A. Effects of olanzapine and other antipsychotics on cognitive function in chronic schizophrenia: a longitudinal study. Schizophr Res 2001; 48: 1728.
45 Lezak, MD. Neuropsychological Assessment (3rd edn). Oxford University Press, 1995.
46 Vickers, AJ. How many repeated measures in repeated measures designs? Statistical issues for comparative trials. BMC Med Res Methodol 2003; 3: 22.
47 Allison, DB, Allison, RL, Faith, MS, Paultre, F, Pi-Sunyer, FX. Power and money: designing statistically powerful studies while minimizing financial costs. Psychol Methods 1997; 2: 2033.