JOURNAL OF

PSYCHIATRIC

RESEARCHJournal of Psychiatric Research 42 (2008) 259–267

www.elsevier.com/locate/jpsychires

Course of cognitive functioning during the stabilizationphase of schizophrenia

Stefan Klingberg a,*, Andreas Wittorf a, Stephanie Sickinger a,Gerhard Buchkremer a, Georg Wiedemann b

a Department of Psychiatry and Psychotherapy, University of Tuebingen, Osianderstrasse 24, D-72076 Tubingen, Germanyb Department of Psychiatry and Psychotherapy, University of Frankfurt, Germany

Received 27 September 2006; received in revised form 16 January 2007; accepted 2 February 2007

Abstract

The present study aimed at examining the longitudinal course of neuropsychological impairments in schizophrenia patients during thestabilization phase of the illness.

Cognitive functioning of 151 schizophrenia patients was assessed at baseline, 9-month, and 15-month follow-up with a comprehensivebattery of cognitive tests. Cognitive performance of 40 matched controls was also examined at baseline and follow-up in order to controlfor effects of repeated testing.

We found significant improvements in memory, attention, and global cognitive functioning from baseline to 9-month follow-up.Abstraction was stable at a relatively normal level. Global cognitive functioning remained at 9-month follow-up one standard deviationbelow normative level. Improvements in patients’ cognitive performance between the 9-month and the 15-month follow-up were fewerand less pronounced.

The present study implies that schizophrenia is a static encephalopathy with trait and state dependent cognitive components partic-ularly in the attention and memory domain. The statistically and clinically significant cognitive improvements should be ground for clin-ical optimism.� 2007 Elsevier Ltd. All rights reserved.

Keywords: Schizophrenia; Neuropsychology; Cognitive functioning; Follow-up

1. Introduction

There is an ongoing debate whether or not cognitivedecline is an inevitable characteristic of schizophrenia.Cognitive deficits are increasingly considered as essentialin schizophrenic disorders. There is convincing evidencethat secondary memory, executive functions, and attentionare impaired in schizophrenia (Goldberg and Gold, 1995;Heinrichs and Zakzanis, 1998; Weickert et al., 2000). It ishypothesized now that cognitive deficits represent a sepa-

0022-3956/$ - see front matter � 2007 Elsevier Ltd. All rights reserved.

doi:10.1016/j.jpsychires.2007.02.001

* Corresponding author. Tel.: +49 7071 29 82330; fax: +49 7071 294141.

E-mail address: stefan.klingberg@med.uni-tuebingen.de (S. Kling-berg).

rate domain of the illness (Green et al., 2002). There is evi-dence that cognitive impairments develop during theprodromal phase. Already in the first episode of psychosisimpairments may be as severely as in chronic schizophrenia(Bilder et al., 2000; Hoff et al., 1992; Saykin et al., 1994).

However, the characteristics of the course of theseimpairments are less clear. Longitudinal studies aim at dis-criminating stable dysfunctions (traits) from episode-related (state) deficits (Rund, 1998). Several follow-upstudies reported stability or at least no deterioration ofneuropsychological deficits (Rund, 1998; Hoff et al., 1999,2005; Heaton et al., 2001; Eyler Zorrilla et al., 2000; Hydeet al., 1994; DeLisi et al., 1995; Hughes et al., 2003; Nopo-ulos et al., 1994; Addington et al., 2005). These findingssupport the view of schizophrenia as a static encephalopa-thy. In this view schizophrenia is associated with cognitive

260 S. Klingberg et al. / Journal of Psychiatric Research 42 (2008) 259–267

impairment that begins at the time of or even before onsetof psychopathological symptoms and remains stable overtime even during symptom-free periods.

Other findings support the view of schizophrenia as adegenerative neuropsychiatric disorder. This is character-ized by onset in young adulthood followed by a length per-iod of gradual cognitive decline. This view is supported bystudies applying MRI (Mathalon et al., 2001) and in stud-ies including patients with late-life schizophrenia (Harveyet al., 1999a,b; Fucetola et al., 2000). Finally, several stud-ies show results indicating improvement in cognitive func-tioning over time (Sweeney et al., 1991; Nopoulos et al.,1994; Albus et al., 2002; Gold et al., 1999; Hoff et al.,1999, 2005; Bilder et al., 2000; Hughes et al., 2003).Improvement could be explained in the framework of statedependency with a limited stable deficit over time and addi-tional impairment during acute phases of illness.

Put together, the results of longitudinal studies assessingcognitive impairments remain controversial or heteroge-neous (Albus et al., 2002; Kurtz, 2005; Gold et al., 1999;Bilder et al., 2000). Contradictory findings in the literaturecan be partially explained by methodological problems.Rund (1998) and Albus et al. (2002) claim, that most ofthe studies which assess the course of cognitive perfor-mance in schizophrenia have methodological shortcomingsand confounding variables (e.g. reliability and validity ofdiagnoses, medication effects, medication compliance,practice and learning effects, and dropouts) that have tobe considered before general conclusions can be drawn.Furthermore, missing control groups, brief follow-up inter-vals, and non-comprehensive neuropsychological testingare limiting factors (Heaton et al., 2001). Even age, dura-tion of illness, initial neuropsychological impairment,improvement or deterioration in clinical status, and emer-gence of antipsychotic induced dyskinesia may have aninfluence on the results.

The objective of the present study is to investigate thecourse of cognitive impairments in patients with schizo-phrenia spectrum disorders. By means of repeated assess-ment of test performance with control for possibleconfounding variables this study aims to clarify whethercognitive functions improve, deteriorate or remain stableduring the stabilization phase of the illness.

2. Method

2.1. Patients

Between April 1998 and June 2001, 169 in-patients whomet DSM-IV criteria for schizophrenia or schizoaffectivedisorder were consecutively recruited as part of a combinedpsychotherapy and neuropsychology study at TuebingenUniversity Hospital, Department of Psychiatry and Psy-chotherapy, in Germany. All patients were admitted tohospital due to an acute episode of their illness. Diagnoseswere determined by the German version of the StructuredClinical Interview for DSM-IV Axis I Disorders (SCID-I;

Wittchen et al., 1997). All patients gave written informedconsent to participate in the study, which was approvedpositively by the local ethics committee. Patients wereselected on the basis of the following inclusion criteria:(1) stabilization phase of illness after an acute phase (i.e.symptom reduction), and (2) ages between 18 and 60 years.Exclusion criteria for neuropsychological testing were asfollows: (1) lifetime history of substance dependence orsubstance abuse (DSM-IV/SCID-I) during the last monthbefore recruitment, (2) neurologic disease or damage, (3)medical illnesses that may interfere with cognitive function,(4) history of head injury with loss of consciousness greaterthan 5 min, (5) mental retardation (IQ below 80 accordingto the MWT-B (Lehrl, 1992), a German multiple-choicevocabulary test measuring the premorbid intellectual level),and (6) insufficient German language skills. The diagnosisof two patients had to be changed later to a bipolar affec-tive disorder with psychotic symptoms. These two patientswere excluded from the analysis. Additional 16 patientsrefused to participate in the neuropsychological examina-tion. Thus, test data of 151 patients are available at base-line (t1). The mean interval from admission to hospital tobaseline assessment was 22 days (SD = 22 days). Thus,baseline assessment took place after an individually opti-mized pharmacological treatment had initiated for approx-imately three weeks.

Retests of the patient sample took place on an averageof 9 months (268 days; t2) and 15 months (447 days; t3)after baseline assessment. At t2 n = 100 and at t3 n = 83patients were available. At the retests the same cognitivemeasures were applied. The majority of testing sessionstook place in the afternoon. However, we did not makeefforts to exactly keep constant the time of testing for eachsingle patient.

2.2. Control group

With the aim of obtaining a healthy standardizationsample and to control for practice effects a control groupwas recruited. In order to attain a matching sample we ran-domly selected 40 cases out of our patient group. Matchingcriteria for the normal controls were age (±3 years), gen-der, and education (elementary school, secondary school,or high school). We recruited these 40 normal controlsthrough advertisements in the catchment area of the hospi-tal. Beyond the matching criteria normal controls had tofulfill the following inclusion criteria: (1) no history of psy-chotic or affective disorders (DSM-IV/SCID-I), and (2)currently no taking of psychotropic medications. Addition-ally, controls qualified as non-vulnerable individuals, asthey did not present any history of psychotic or affectivedisorders among their first-degree relatives. Exclusion crite-ria for the normal controls were identical with those ofpatients’.

Controls were retested (t2/c) on an average of 14 months(418 days) after t1/c. 27 of 40 controls participated in theretest examination, 13 refused to participate.

S. Klingberg et al. / Journal of Psychiatric Research 42 (2008) 259–267 261

2.3. Demographic and clinical characteristics

Table 1 shows the demographic and clinical characteris-tics of the two groups of probands. Patients and controlsshowed no significant differences with regard to age, gen-der, and education.

Table 1Demographic and clinical characteristics of subjects

Agea M (SD)Genderb

FemaleMale

Educationc

Elementary schoolSecondary schoolHigh school

Diagnoses (DSM-IV/SCID-I)Schizophrenia

Paranoid typeUndifferentiated typeDisorganized typeCatatonic typeResidual type

Schizoaffective disorderDepressive typeBipolar type

PANSS standard-scales (according to Kay et al., 1987)Positive-syndrome, mean item score (SD)RangeSum score (SD)Negative-syndrome, mean item score (SD)Range sum score (SD)General score, mean item score (SD)RangeSum score (SD)Total score, mean item score (SD)RangeSum score (SD)

First episode patientsAge at onset of illness (first psychotic symptom) M (SD)Number of previous hospitalizations Md/M (SD)Duration of previous hospitalizations (weeks) Md/M (SD)Antipsychotics (NL) at day of baseline testing

Patients treated with atypical NL onlyPatients treated with standard NL onlyPatients treated with combinationPatients without any NLCPE at day of testing M (SD)

Lifetime duration of antipsychotic treatment (months) M (SD)Extrapyramidal side-effects (EPS-sumscore) M (SD)Patients with co-medication

AnticholinergicsBenzodiazepinesAntidepressantsMood stabilizers

Medication complianceCompliant n (%)Non-compliant n (%)

PANSS: Positive and Negative Syndrome Scale; CPE: Chlorpromazine-Equiva t-Test.b Fisher’s exact test.c v2-Test.

Schizophrenia subtypes (DSM-IV/SCID-I) of thepatient sample are listed in Table 1. Clinical symptomassessment in patients had to be completed within twoweeks prior to neuropsychological testing. The interviewersused the Positive and Negative Syndrome Scale (PANSS,Kay et al., 1987). Table 1 shows the ranges for the mean

Patients (n = 151) Controls(n = 40)

p

33.6 (10.3) 33.3 (9.7) 0.850

78 (51.7%) 20 (50.0%) 0.86173 (48.3%) 20 (50.0%)

43 (28.5%) 7 (17.5%) 0.35956 (37.1%) 18 (45.0%)52 (34.4%) 15 (37.5%)

92 (60.9%)17 (11.3%)11 (7.3%)5 (3.3%)9 (6.0%)

7 (4.6%)10 (6.6%)

2.1 (0.7)1.0–4.414.8 (5.0)2.3 (1.0)1.0–5.1 16.1 (7.1)1.9 (0.4)1.0–3.030.4 (7.1)2.1 (0.5)1.0–3.561.3 (14.4)47 (31.1%)25.5 (7.9)2.0/3.1 (4.2)10.0/32.2 (51.0)

57 (37.7%)55 (36.6%)31 (20.5%)8 (5.3%)610 (364)48.5 (76.1)3.1 (3.6)

47 (31.1%)72 (47.7%)30 (19.9%)14 (9.3%)

116 (76.8%)35 (23.2%)

alents; Md: Median.

262 S. Klingberg et al. / Journal of Psychiatric Research 42 (2008) 259–267

item scores along with the sum scores for the PANSSscales. The moderate level of the PANSS scores impliesthat patients were neuropsychologically assessed at thebeginning of their stabilization phase.

At t1 all patients except eight were treated with antipsy-chotic medication. Antipsychotic medication was pre-scribed according to clinical requirements. Dosage wastransformed into chlorpromazine-equivalents (CPE). Anti-psychotic dosage had to be stable during the last seven daysbefore neuropsychological testing. However, in 27 cases thedosage had to be increased in order to improve the symp-tomatic status. Therefore, we computed correlationsbetween the increase of dosage and the neuropsychologicalfactor score. As there were no significant correlations wedid not exclude these 27 patients from further analyses.Approximately one-third of the patients received atypicalantipsychotics only. Table 1 gives a summary of the vari-ables of the antipsychotic medication.

As changes of symptoms and antipsychotic medicationare likely to occur over the follow-up period and couldhave an influence on the change of neuropsychologicalfunctioning we included a confounder analysis in Section3. Between t1 and t2 no specific interventions with regardto cognitive functioning (e.g. cognitive remediation) wereapplied.

2.4. Measures

The following battery of tests was administered to assessneuropsychological functions that have been found to beimpaired in schizophrenic patients: Computerized Wiscon-sin Card Sorting Test (WCST; Heaton et al., 1993);Degraded Stimulus Continuous Performance Test (dsCPT;Nuechterlein and Asarnow, 1996); Trail Making Test A/B(TMT; Reitan, 1992); Digit-Symbol and Digit-Span fromthe German version of the Wechsler Adult IntelligenceScale (WAIS; Tewes, 1994); Rey Complex Figure Test(RCFT; Meyers and Meyers, 1995); Verbal Fluency (Horn,1983); and the German version of the Rey Auditory VerbalLearning Test with a paralleled version (AVLT; Heubrock,1992). At t2 and t3, parallel versions of AVLT wereapplied. Parallel versions of the other tests were not avail-able. The sequence of test application was always the same:(1) AVLT, (2) RCFT, (3) Verbal Fluency, (4) Digit-Sym-bol, (5) Digit Span, (6) TMT, (7) WCST, and (8) dsCPT.Since the implementation of the dsCPT was delayed dueto measures of standardization we only were able to admin-ister this test to a subgroup of 98 patients. Completion ofthe test battery took approximately 75–90 min. The testswere applied by a trained psychological assistant with morethan 10 years of experience in conducting psychologicaltesting, supervised by a Ph.D. level senior clinical psychol-ogist or by master’s level clinical psychologists. We con-ducted a principal components analysis (PCA) over thecomplete neuropsychological data sets of the presentpatient sample, which was followed by orthogonal (Vari-max) rotation. The PCA extracted three components,

which accounted for 59% of variance. We interpreted thethree factors as representing the following constructs. Fac-tor 1 (39.2% of total variance): memory; factor 2 (10.1%):attention; and factor 3 (9.6%): abstraction. To calculateneuropsychological factor scores (function scores) raw testscores of all probands were first transformed to standardequivalents (z scores) using the means and standard devia-tions of a healthy control group. All standard scores werecomputed with higher values indicating better perfor-mance. Factor scores were created by averaging z scoreswithin each empirical domain. Details of the PCA proce-dure and the construction of the factor scores are describedelsewhere (Klingberg et al., 2006).

2.5. Statistics

We analyzed data in different stages. Firstly, with regardto all test raw scores we computed t-tests for independentsamples for comparisons between groups (patients vs. con-trols) and t-tests for dependent samples for comparisonsbetween assessments (t1–t2; t2–t3). This stage of analysiswas designed to present raw data in detail.

In a second stage we aimed at providing overview overthe data. For baseline (t1) and first follow-up assessment(t2) all patients’ raw scores were converted to z-scoresbased on the means and standard deviations of the controlgroup at baseline (t1) and follow-up (t2). Thus, z-scores ofpatients at t2 will not be confounded by the effect ofrepeated testing. We then computed average factor z-scoresand compared the patients’ performance at t1 with perfor-mance at t2 using t-tests for dependent samples. In addi-tion, we excluded patients with relapse for this analysis inorder to rule out any influence of a psychotic episode onthe change of neuropsychological functioning. For thispurpose, relapse has been defined as increase of 6 pointson the PANSS positive or negative syndrome scale.

In a third stage, multiple regression analyses as well asPearson correlations were conducted to investigate poten-tially confounding variables for the change of cognitivefunctioning in the patient sample from t1 to t2 with posi-tive difference scores indicating improvement.

Data analyses were done using SPSS for windows, ver-sion 13.0. Level of significance follows the usual conven-tion (p < 0.05 and p < 0.01). According to thecontroversial findings in the literature, we abstained fromtesting any directed hypotheses and conducted two-tailedsignificance tests. As a consequence, our results have tobe interpreted as explorative and not as confirmatoryhypotheses tests. This is also the reason why we abstainfrom corrections for multiple comparisons.

3. Results

3.1. Test raw scores

Table 2 gives an overview of neuropsychological func-tioning of patients (p) and controls (c) at the different

Table 2Neuropsychological tests and raw scores of patients and controls

Test Supposed neuropsychologicalfunction

Variables subjected to analyses Patients Controls t-Test

t1/p t2/p t3/p t1/c t2/c t1/p–t2/p

t2/p–t3/p

t1/p–t1/c

t2/p–t2/c

t1/c–t2/c

n = 151 n = 100 n = 83 n = 40 n = 27 n = 100n = 83 n = 151/40

n = 100/27

n = 27

Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) p p p p p

Memoryb

AVLT (Heubrock,1992)

Secondary verbal memory Trial (T)1 4.96 (1.88) 6.44 (1.83) 6.89 (1.76) 8.23 (1.97) 7.93 (2.0) <0.001 0.062<0.001 <0.001 0.228

T5 9.44 (2.97) 12.1 (2.45) 12.6 (2.4) 14.3 (1.14) 14.0 (1.52) <0.001 0.180<0.001 <0.001 0.527PT1–5 37.9 (10.9) 48.8 (10.25) 52.6 (10.0) 60.4 (6.78) 59.6 (8.36) <0.001 <0.001<0.001 <0.001 0.829

T7 (delay) 6.80 (3.46) 9.86 (3.55) 10.2 (3.63) 13.5 (1.91) 13.3 (2.28) <0.001 0.892<0.001 <0.001 0.919

RCFT (Meyers andMeyers, 1995)

Delayed visual memory Delayed recall 14.2 (7.3) 19.5 (7.25) 22.4 (6.33) 22.8 (5.63) 25.0 (6.45) <0.001 <0.001<0.001 <0.001 0.018

Abstractionb

WCST (Heatonet al., 1993)

Executive functioning:abstraction, concept formation,problem solving

Trials administered, % preservativeerrors, categories completed, failure tomaintain set

110.0 (21.6) 103.0 (22.2) 98.7 (22.6) 96.8 (20.2) 85.6 (16.5) 0.001 0.076 0.001 <0.001 0.003

17.8 (11.2) 13.8 (10.3) 12.5 (10.5) 12.1 (5.58) 8.89 (3.63) 0.003 0.460<0.001 <0.001 0.0124.10 (2.24) 4.98 (1.66) 5.01 (1.92) 5.58 (1.17) 5.78 (0.80)<0.001 0.476<0.001 0.001 0.0460.97 (1.08) 1.25 (1.42) 1.04 (1.39) 0.55 (0.99) 0.52 (0.70) 0.245 0.216 0.028 <0.001 0.284

Attentionb

Trail making test(Reitan, 1992)

Psychomotor, scanning, complexattention

Trail A (time in s) 41.9 (20.7) 31.3 (13.3) 27.3 (11.4) 26.0 (6.33) 22.9 (4.5) <0.001 0.010<0.001 <0.001 0.025

Trail B (time in s) 105.5 (65.2) 67.0 (40.0) 67.8 (33.8) 53.2 (11.4) 53.3 (14.2) <0.001 0.034<0.001 <0.001 0.469

Digit-symbol(WAIS; Tewes,1994)

Psychomotor, concentration Number correctly assigned symbols 41.8 (11.7) 51.8 (12.4) 55.8 (13.4) 62.5 (9.99) 68.5 (8.6) <0.001 <0.001<0.001 <0.001 0.001

Digit-span (WAIS;Tewes, 1994)

Immediate verbal memory,working memory

Forward 7.67 (2.06) 8.18 (2.09) 7.99 (2.08) 8.10 (2.04) 9.5 (2.34) 0.273 0.397 0.244 0.005 <0.001

Backward 5.44 (2.19) 7.01 (1.93) 7.42 (2.23) 8.30 (2.40) 8.81 (2.47)<0.001 0.031<0.001 <0.001 0.322

dsCPTa

(Nuechterleinand Asarnow,1996)

Vigilance, psychomotor Sensitivity d’, reaction time hits (in ms) 2.35 (1.04) 2.86 (1.03) 2.96 (1.08) 3.35 (0.97) 3.33 (1.10) 0.002 0.026<0.001 0.055 0.699

569.7 (86.6) 520.6 (83.3) 492.6 (57.7) 463.6 (48.3) 462.7 (50.8) <0.001 0.001<0.001 0.001 0.749

Verbal fluency(Horn, 1983)

Processing speed, workingmemory, psychomotor

Number words 29.6 (10.1) 33.1 (9.87) 35.8 (10.7) 38.5 (8.00) 40.8 (8.52) <0.001 0.138<0.001 <0.001 0.017

WCST: Wisconsin Card Sorting Test; dsCPT: Degraded Stimulus Continuous Performance Test, AVLT: Rey Auditory-Verbal Learning Test; RCFT: Rey Complex Figure Test.a Subgroup of patients: t1: n = 98; t2: n = 65; t3::n = 68.b Neuropsychological variables are organized according to our factor analysis (Klingberg et al., 2006).

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264 S. Klingberg et al. / Journal of Psychiatric Research 42 (2008) 259–267

points in time together with t-tests for independent anddependent samples to analyze the between group differ-ences (t1/p–t1/c, t2/p–t2/c) and changes within the groupsof patients (t1/p–t2/p, t2/p–t3/p) and controls (t1/c–t2/c).Between t1 and t2 patients show a significant improvementregarding most of the cognitive variables with only fewexceptions (WCST-failure to maintain set; digit span for-ward). In contrast, improvements in patients’ scoresbetween t2 and t3 as well as in controls between t1 andt2 are fewer and less pronounced. In both cases only 8 of17 analyzed scores are significantly improved. Controlsscored higher at both assessments (t1, t2) than patientswith the exception of digit span forward at t1 anddsCPT-sensitivity at t2.

3.2. Factor scores

Fig. 1 shows the three neuropsychological factor scoresand the total scores of patients at t1 and t2. Data are pre-sented as box plots to indicate the variability of the under-lying cognitive functions. The patients’ scores at t1 arestandardized by the scores of controls at t1, the patients’scores of t2 are standardized by the scores of controls att2. Fig. 1 gives only data of patients who did not relapsebetween t1 and t2 (n = 82). The scores of t1 and t2 werecompared using t-tests for dependent samples. The stan-dardized factor scores memory (t = �15.43) and attention(t = �4.34) as well as the total score (t = �8.19) demon-strate a significant (each p < 0.01) increase between t1

Fig. 1. Box plots of neuropsychological factor scores at t1 and t2,standardized by controls, controlled for repeated testing, only patientswithout relapse, n = 82.

and t2. Abstraction (t = 1.55, p = 0.125) shows no signifi-cant change.

3.3. Analysis of confounders

3.3.1. DropoutThe major analysis of this paper includes the 82 retested

patients without relapse of initial 151 patients. In order tocontrol for systematic bias we compared the baseline scoresof these 82 participating patients and the remaining 69patients. There was no significant difference between thesegroups regarding the neuropsychological factor scores pre-sented in Fig. 1 (total score: z = �1.66 vs. z = �1.84,p = 0.29; attention: z = �1.49 vs. z = �1.79, p = 0.11;memory: z = �2.70 vs. z = �2.80, p = 0.65; abstraction:z = �0.80 vs. z = �0.92, p = 0.56).

3.3.2. Case history and clinical data

Baseline case history data and symptom changes couldbe responsible for changes in cognitive functioning. There-fore, we investigated whether change of cognitive function-ing between t1 and t2 is correlated with case history data.We computed multiple regression analyses with forwardstepwise variable selection. All variables presented in Table1 (sample description) as well as symptom change scores(PANSS positive and negative syndrome) between t1 andt2 were included as independent variables. The differencescores (simple change scores, Dt2 � t1) of the three cogni-tive factors and the total score were the dependent vari-ables. In total, only few of the case history and clinicalvariables (Table 1) showed significant association withthe cognitive change scores. Longer lifetime duration ofantipsychotic treatment correlated with better course ofthe factor score memory (coefficient b = 0.365; t = 3.0;p = 0.004). Furthermore, higher EPS sum scores at t1/p(coefficient b = 0.315; t = 2.55; p = 0.014) as well as aimproved positive-syndrome from t1/p to t2/p (coefficientb = �.262; t = �2.125; p = 0.038) correlated with bettercourse of the factor score abstraction from t1/p to t2/p.Better medication compliance at t1/p (coefficientb = �.308; t = �2.506; p = 0.015) as well as higher EPSsum score at t1/p (coefficient b = 0.290; t = 2.366;p = 0.022) were associated with better course of global cog-nitive functioning (total score).

3.3.3. Baseline cognitive functioning and change of cognitivefunctioning

We analyzed whether the level of cognitive functioningat t1/p was associated with the change of functioning after9 months within each cognitive domain. We computedPearson correlations between the factor score at t1/p andthe difference score (score at t2/p � score at t1/p) andfound significant correlations within each cognitivedomain: attention: r = 0.33, p = 0.002; memory: r = 0.43,p < 0.001; abstraction: r = 0.30, p = 0.006; and total score:r = 0.30, p = 0.006. In each case, worse functioning wasassociated with more improvement.

S. Klingberg et al. / Journal of Psychiatric Research 42 (2008) 259–267 265

3.3.4. Changes in dosage of antipsychotic medication

Finally, we analyzed the influence of antipsychotic med-ication on the change of cognitive functioning. We com-puted the cumulated dosage of antipsychotic medicationthroughout the 9-month stabilization phase as well as thedifference of the mean monthly antipsychotic dosage att2/p compared to t1/p. Pearson correlations between thesevariables and the change of the neuropsychological factorscores showed no significant correlation.

4. Discussion

The present study aimed at examining the course of cog-nitive functioning of schizophrenia patients during the sta-bilization phase in a longitudinal design. The major resultis that patients showed significant improvement of mem-ory, attention, and global cognitive functioning over the9-month follow-up period. Abstraction remained stableon a relatively normal level over this period. A major meth-odological strength of this analysis is that not only thepatients but also the healthy controls have been retested.Otherwise, changes in test scores might generally be influ-enced by effects of repeated testing. This effect has to becontrolled for by also testing the controls twice and stan-dardizing patient’s retest performance by using the con-trol’s retest performance. Thus, the resulting changes oftest scores are not confounded by effects of repeatedtesting.

In order to interpret the longitudinal course of cognitivefunctioning a number of critical issues have to be takeninto account: diagnostic criteria, the effect of drugs, learn-ing effects, the time interval, and drop out (Rund, 1998;Albus et al., 2002; Heaton et al., 2001).

First, in order to assure reliability and validity of diag-nosis we applied the German Version of the StructuredClinical Interview for DSM-IV Axis I disorders.

Second, the effect of drugs on cognitive performance,especially antipsychotic medication as well as anticholiner-gic drugs, are not controlled for in most studies. Antipsy-chotics apparently improve some cognitive functions anddeteriorate others (Rund et al., 1997). In this study, weanalyzed the dosage of antipsychotics and found no evi-dence for an association with changes in cognitive func-tioning. The cumulated dosage throughout thestabilization phase did not correlate with the change ofcognitive functions. In addition, we considered whetherthe lifetime duration of antipsychotic treatment was associ-ated with cognitive functioning and found correlation withmemory, but not for the other domains. Moreover, bettermedication compliance at baseline correlated with betterglobal cognitive functioning. Thus, antipsychotic medica-tion does not seem to have a clear disadvantage regardingcognition in our study. However, this is no confirmatoryevidence but merely an explorative result. To analyzelong-term effects of medication requires sophisticateddesigns. Only randomized controlled trials with cognitivefunctioning as endpoint and two different intervention

strategies are adequate to show different treatment effects(Keefe et al., 2004). Therefore, we decided to conduct aseparate analysis on this issues which will be describedelsewhere.

Third, the dropout of patients in longitudinal studies is aserious problem, because these patients may have experi-enced a different course of cognitive function than patientswho were retested. Dropouts might have displayed a cogni-tive decline. In order to control for systematic bias we com-pared baseline cognitive functioning of the retested patientswithout relapse with those patients who relapsed ordropped out within the follow-up period. The groups didnot differ significantly. However, the fact that cognitivefunctioning at baseline was comparable does not necessar-ily imply that the cognitive changes also are comparable.Thus, the bias resulting from drop out was only partiallycontrolled for.

Fourth, a shortcoming of some follow-up studies is thatreports give insufficient information about the stage of ill-ness of the tested individuals (Rund, 1998; Heaton et al.,2001). In this study, we tested the patients at the beginningof the stabilization phase. The follow-up period of eightmonths is long enough to detect cognitive changes over thisphase. As our focus was on stabilization conditions weexcluded patients with relapses.

Fifth, the question whether cognitive changes depend oncertain clinical characteristics is unclear yet. Existing stud-ies suggest that variables like dyskinesia, age, duration ofillness, and initial neuropsychological impairment mayhave an influence on the course of cognitive functioning(Heaton et al., 2001). Results from our regression analysesshowed no predictive value of age and duration of illnesson the cognitive course. In contrast to other findings EPSat the initial testing was associated with better course ofcognitive functioning. However, as patients should receiveindividually optimized medication, changes of prescriptionoccurred in case of severe side effects. Thus, extrapyramidalsymptom assessed cross-sectionally at baseline cannot beregarded as influencing the course of functioning.

At baseline, patients are most severely impaired in mem-ory functioning as has been found in the majority of studies(Heinrichs and Zakzanis, 1998). One might speculate thatmotivational or compliance related factors might be a rea-son. Further, it could be stated that our control groupshowed a specifically high performance regarding memory.However, those factors are unlikely to affect only memorytests and not attention or abstraction tests. Improvementsin this domain might also partly be attributed to a regres-sion to the mean effect as memory deficits persist at follow-up at the same level as attention and global cognitive func-tioning deficits. A further hypothesis relates to the phase ofillness of this sample. Memory dysfunctions might be worsein the acute and in the stabilization phase than in the stablephase of the illness. Longitudinally, patients showed themost pronounced improvement in the memory domain.Since we controlled for practice effects, these improvementscan be ascribed to effects of a psychophysical recovery. In

266 S. Klingberg et al. / Journal of Psychiatric Research 42 (2008) 259–267

conclusion, we assume that the course of cognitive func-tioning is different between the cognitive domains withmemory showing delayed improvement in the stabilizationphase.

Regarding attention, patients were moderately impairedat baseline as has to be expected according to the literature.The significant improvement during the follow-up periodcan also be interpreted as a recovery effect. Attention def-icits seem to persist at the same level as the memory defi-cits, i.e. approximately at a median of �1 SD.

Regarding abstraction, patients were only weaklyimpaired at baseline and improved only slightly but not sig-nificantly during the follow-up interval. This lack of signif-icant improvement might be due to a ceiling effect. Wefound no reason why abstraction was astonishingly well-preserved in our patient sample. With regard to the WCSTperformance literature is very heterogeneous. Saykin et al.(1991) for example also found the WCST performance intheir sample of schizophrenia patients to be relativelyunimpaired. The review of Velligan and Bow-Thomas(1999) states, that deficits in executive functioning affect40–95% of individuals with this disorder. Thus, this reviewunderlines the enormous heterogeneity of executive func-tions in schizophrenia.

We found evidence that cognitive changes occurredmainly in the stabilization phase. The inspection of rawscores indicates considerable change between baseline and9-month follow-up but only to a lesser extent between 9-and 15-month follow-up. However, as the 15-month fol-low-up has not been controlled for repeated testing thesedata have to be interpreted cautiously.

Our longitudinal study discriminated stable dysfunc-tions (trait) from episode-related (state) deficits. Bothmemory and attention deficits, as well as global cognitivefunctioning comprise a state and a trait component. Thetrait component can be assumed to be approximately �1SD. These cognitive deficits can be characterized as inter-mediate factors. That is, they are more prominent in acuterphases of the illness but do not completely disappear dur-ing remission. The present data imply that schizophreniais a static encephalopathy with trait and state dependentcognitive components particularly in the attention andmemory domain. Our findings are consistent with thoseof Rund (1998) who found no support for hypothesizinga degenerative process in schizophrenia in his review.

A limitation of our study is the fact that patients andcontrols were tested at different points in time. Controlswere retested on an average of 14 months after baselinewhile the retests of the patients took place on an averageof 9 and 15 months respectively. Since longer intervalsmight be accompanied by lessened practice effects, wecannot exclude the possibility that at the first retest prac-tice effects in the patient group were not completely neu-tralized. Since controls were retests just once, it cannotbe ruled out that improvements in patients’ scoresbetween the first (t2) and the second (t3) retest areresults of practice effects.

In conclusion, we found that the course of cognitive func-tioning is different between the cognitive domains. Memoryfunctions improved considerably but remained impaired. Incontrast, abstraction was surprisingly unaffected. Globalcognitive performance remained approximately one stan-dard deviation below normative level. When interpretingthese results, it has to be taken into account that at baseline25% of our patients showed cognitive functioning in the nor-mal range. At follow-up even more than 50% of our patientsreached a normal level of global cognitive functioning. Thus,in a considerable amount of cases schizophrenia is notaccompanied by clinically significant cognitive impairment.This is in accordance with Rund et al. (2006) who state thatschizophrenia may exist in the context of preservedcognition.

The statistically and clinically significant cognitiveimprovements found in our study can be viewed as a resultof the recovery from the illness. On the background of thecorrelation of cognitive functioning and functional out-come (Green et al., 2000) our data on the course of cogni-tive functioning during the stabilization phase ofschizophrenia should be ground for clinical optimism.

Conflict of interest

All authors declare that they have no conflicts ofinterest.

Contributors

Stefan Klingberg (S.K.), Georg Wiedemann (G.W.) andGerhard Buchkremer (G.B.) were the applicants of thestudy and were responsible for the study design and proto-col. SK and Andreas Wittorf (A.W.) conducted statisticalanalyses and wrote the manuscript. Stephanie Sickingerperformed literature searches.

Role of funding source

The funding sources had no further role in study design;in the collection, analysis and interpretation of data; in thewriting of the report; and in the decision to submit thepaper for publication.

Acknowledgements

This study was supported by the German ResearchFoundation (DFG), Project No. DFG Wi 1523, KL1179, and by the research support program of the univer-sity hospital of Tuebingen (fortuene), Project Nos. 594-0-0 and 594-0-1.

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