Neuropsychological correlates of symptom profiles in first episode schizophrenia

Schizophrenia Research 71 (2004) 323 – 330 www.elsevier.com/locate/schres

Neuropsychological correlates of symptom profiles in first episode schizophrenia Sara Lucas a, Dianne Fitzgerald a, M. Antoinette Redoblado-Hodge a,*, Josephine Anderson a, Mark Sanbrook b, Anthony Harris c,d, John Brennan a a

Department of Child and Adolescent and Family Psychiatry, Westmead Hospital, Institute Road, Westmead NSW 2145, Australia b Department of Psychological Medicine, Nepean Hospital, Australia c Discipline of Psychological Medicine, University of Sydney, Australia d Prevention Early Intervention and Recovery Service, Western Sydney Area Health Service, Australia Received 10 February 2004; received in revised form 19 March 2004; accepted 19 March 2004 Available online 30 April 2004

Abstract This paper aimed to examine the relationship between the trichotomous symptom structure of psychopathology and neuropsychological functioning in young people with first episode schizophrenia (FES), most of whom were receiving atypical antipsychotic medication. This was with a view to providing insight into the underlying pathophysiology of the clinical symptoms of schizophrenia. Fifty-three young people (aged 13 – 25 years) with FES participated in the study. Subjects completed a comprehensive clinical and neuropsychological examination. Cognitive domain scores were correlated with composite scores relating to Disorganisation, Psychomotor Poverty and Reality Distortion. A significant association was identified between Disorganisation and Verbal Acquisition, Verbal Recall and Cognitive Flexibility. There were no significant associations between cognitive domains and either Reality Distortion or Psychomotor Poverty, nor with measures of depressive symptomatology. The present study provides preliminary evidence that symptoms associated with the Disorganisation factor are significantly associated with cognitive deficits suggesting impaired frontal – temporal functioning. Differences between the current findings and those of similar research may reflect the effects of different medication regimes, as well as the absence of illness chronicity. D 2004 Elsevier B.V. All rights reserved. Keywords: First episode schizophrenia; Reality Distortion; Disorganisation; Psychomotor Poverty

1. Introduction Neuropsychological studies of individuals with schizophrenia have found considerable variability in * Corresponding author. Tel.: +61-2-9845-6577; fax: +61-29891-5690. E-mail address: [email protected] (M.A. Redoblado-Hodge). 0920-9964/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2004.03.006

the severity and pattern of cognitive deficits (Addington et al., 2003; Bilder et al., 2000; Hoff et al. 1992; Mohamed et al., 1999), reflecting in part the clinical heterogeneity of the disorder. Attempts to reduce the clinical complexity of schizophrenia have focused on grouping symptoms into domains of psychopathology, which are thought to reflect separate underlying pathophysiological processes (Buchanan and Carpenter, 1994). Of these, Liddle’s (Liddle, 1987a, 1989)

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three -syndrome model of Reality Distortion (delusions and hallucinations), Disorganisation (thought disorder, inappropriate affect.) and Psychomotor Poverty (poverty of speech, flat affect, decreased spontaneous movement) has found consistent support from subsequent factor analytic studies (Bilder et al., 1985; Peralta et al., 1992; Thompson and Meltzer, 1993; Norman et al., 1997). Liddle postulated that the three syndromes reflected discrete patterns of cerebral malfunction, with Psychomotor Poverty associated with left prefrontal dysfunction, Disorganisation with right prefrontal dysfunction and Reality Distortion with temporal lobe abnormalities. Further, examination of this relationship in 47 patients with chronic schizophrenia confirmed an association between Psychomotor Poverty and decreased abstract reasoning, and between Disorganisation and impaired attention and new learning. However, Reality Distortion failed to reveal significant associations with neuropsychological impairment (Liddle, 1987b). Subsequent attempts to replicate these findings in chronic schizophrenia populations have provided mixed results, with some studies corroborating Liddle’s findings (Baxter and Liddle, 1998; Niewenstein et al., 2001), whereas others have yielded contrary results (Williams, 1996; Norman et al., 1997; O’Leary et al., 2000; Malla et al., 2001). This disparity in findings may reflect methodological variability between studies, and also raises the question of whether findings from chronic schizophrenia populations reflect primary effects related to the illness itself, or secondary effects of long-term conventional antipsychotic treatment (which has been shown to have detrimental effects on cognition) (Sharma, 1999; Harvey and Keefe, 2001). As a consequence, recent studies have focused on the neuropsychological correlates of symptoms in first episode psychosis (FEP). However, findings remain mixed due to differences in sample selection, phase of illness (acute or stabilised) and range of cognitive functions assessed. For instance, Verdoux et al. (1999) employed a positive – negative symptom dichotomy, and found a significant association between positive symptoms and poor verbal fluency, but no correlation between negative symptoms and cognition in a sample of 34 FEP patients with a broad range of diagnoses. In contrast, a recent study of 94 FES subjects in

remission from acute symptoms and prescribed atypical antipsychotics, revealed several significant correlations between Psychomotor Poverty and deficits in speed of information processing, memory, visuospatial abilities and executive functions. No associations were found between Disorganisation or Reality Distortion syndromes and cognitive functioning (Bilder et al., 2000). An earlier attempt to examine relationships between cognitive function and positive, negative and Disorganisation symptoms in 60 recent-onset adolescent patients found that only symptoms of Disorganisation and depression significantly correlated with executive functioning (Van der Does et al., 1993), whereas more recently, Joyce et al. (2002) failed to identify any significant results between the threesyndrome model and tests of executive functioning in a sample of FES patients. In summary, previous research into the neuropsychological correlates of symptoms provides a confusing picture which has been confounded by the effects of medication (typical versus. atypical antipsychotics), chronicity of illness, depressive symptoms, population sample bias and phase of illness (acute Vvs. stabilised). To address these problems, the present study aimed to examine the relationships between the trichotomous symptom structure and a wide selection of neuropsychological domains in an ecologically valid sample of young individuals with FES, either unmedicated or receiving atypical antipsychotic medication.

2. Method 2.1. Participants Participants were recruited as part of the Western Sydney First Episode Psychosis Project. Inclusion criteria for entry into the project were: (1). age from 13 to 25 years inclusive; (2). first contact with mental health services with psychotic symptoms (prior contact for non-psychotic problems was acceptable); (3). presence of psychotic symptoms as defined by hallucinations, delusions, formal thought disorder or prominent negative symptoms present for a minimum of 3three days. Exclusion criteria included: (1). treatment with electroconvulsive therapy in the six 6 months prior to referral;, (2). gross neurological disease;, (3). devel-

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opmental delay (IQ < 75); or a (4). history of head injury causing unconsciousness for at least one1 hour. The 53 participants included in the present study consisted of those diagnosed with either schizophrenia (n = 41), schizophreniform disorder (n = 11) or schizoaffective disorder (n = 1) according to the Diagnostic and Statistical Manual of Mental Disorders—Fourth Edition (APA, 1994), by consensus of at least three fully qualified psychiatrists. At the time of assessment, 47 (89%) individuals were prescribed atypical antipsychotics with a mean chlorpromazineequivalent dose of 269 mg/day (S.D. = 192 mg/day), and 6 were not prescribed any antipsychotic medication. Chlorpromazine -equivalents were calculated using Lambert, (1999) methodology. Of those prescribed antipsychotic medication, 4 (9%) participants were also prescribed a mood stabiliser [(Llithium [(n = 2) and Ssodium Vvalproate ([n = 2)]). In addition, 7 (13%) participants were receiving an antidepressant (5 SSRI, 2 tricyclic), 1 (2%) was prescribed benzodiazepines and 3 (6%) were taking low dose anticholinergics (benztropine) in conjunction with antipsychotic medication. Table 1 presents the demographic details of the patient group. Normative data from 31 healthy control subjects was obtained during the same period that clinical patients were assessed, and collected under the same conditions. Control subjects within the age and educational level range of the clinical group were recruited from local high schools, vocational education centres and a firstyear undergraduate psychology course. In addition to the exclusion criteria applicable to FEP subjects, conTable 1 Demographic and clinical characteristics for the first episode schizophrenia (FES) group FES Mean

S.D.

Age (years) Education (years) Estimated premorbid IQa

19.1 10.8 96.9

3.3 2.0 11.5

PANSS scores Positive scale Negative scale General scale Calgary depression scale Young mania rating scale

17.6 19.0 39.4 4.8 9.3

5.8 5.5 8.5 3.8 6.3

a

Wide Range Achievement Test, 3rd Edition—Standard Score.

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trol subjects were excluded if they reported any personal or family history of mental illness. The healthy control group’s cognitive performance on neuropsychological assessment was used as an ecologically and culturally valid normative data set, against which to calculate z-scores for the clinical group. 2.2. Measures The presence and severity of psychotic symptoms was evaluated by interview, using the Positive and Negative Syndrome Scale (PANSS; Kay et al., 1986). Symptom clusters for Psychomotor Poverty, Disorganisation and Reality Distortion were calculated by summing the appropriate PANSS item scores, according to the method derived by Harris et al. (1999). The following items were combined for each symptom cluster: Psychomotor Poverty: blunted affect, emotional withdrawal, social withdrawal, poor rapport, lack of spontaneity. Disorganisation: conceptual disorganisation, grandiosity, excitement, lack of abstract thinking. Reality Distortion: suspiciousness, delusions, hostility, hallucinatory behaviour. The Calgary Depression Scale (Addington et al., 1990) was also administered to provide information on depressive symptomatology. Comprehensive neuropsychological evaluation was also undertaken. Selected measures from individual tests included in the battery were grouped into 10 cognitive domains based on findings from previous meta-analytic research (Heinrichs and Zakzanis, 1998) and a priori assessment of content validity. Table 2 displays the neurocognitive tests administered and the individual measures included in each cognitive domain. Due to the age range of participants in the study, child ( < 16 years 11 months) and adult (>16 years 11 months) versions of individual tests within the neuropsychological battery were administered as appropriate. To limit the confounding effects of acute symptomatology and conceptual disorganisation on test performance, assessments were commenced when FES patients had achieved stabilisation of acute symptoms, as indicated by a score of less than < 5

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Table 2 Neuropsychological domains Domain

Tests

Current intellectual ability

Full scale IQ score [Wechsler Adult Intelligence Scale, 3rd edition (WAIS-III) (Wechsler, 1997a) or Wechsler Intelligence Scale for Children (WISC-III) (Wechsler, 1991)] Hits [Conners’ Continuous Performance Test (CPT) Conners, 1995] d’ (CPT) Digits forward (span) (WAIS-III/WISC-III) Failure to maintain set [Wisconsin Card Sorting Test (WCST) (Heaton et al., 1993)] Working memory index score [Wechsler Memory Scale, 3rd edition (WMS-III) (Wechsler, 1997b)] or freedom from distractibility index score (WISC-III) Logical memory I (WMS-III; Wechsler, 1997b) or stories I (Children’s memory scale (CMS); Cohen, 1997) Trials 1 – 5 total score [Rey Auditory Verbal Learning Test (RAVLT) (Spreen and Strauss, 1998)] Logical memory II (WMS-III) or stories II (CMS) Trial 7 (RAVLT) 30 min delayed recall [Rey Complex Figure Test (RCFT) (Spreen and Strauss, 1998)] Faces II (WMS-III or CMS) Block design (WAIS-III or WISC-III) RCFT copy score Preservative errors (WCST) Number of categories achieved (WCST) Trail making test—Part B (Spreen and Strauss, 1998) FAS total score [Controlled oral word association test (Spreen and Strauss, 1998)] Animal fluency (Spreen and Strauss, 1998) Trail-making test—Part A (Spreen and Strauss, 1998) Processing speed index (WAIS-III or WISC-III)

Attention/ vigilance

Working memory

Verbal acquisition

Verbal recall

Visual recall

Visuospatial ability Cognitive flexibility

Verbal fluency

Speeded visuomotor processing

on the ‘conceptual disorganisation’ item of the PANSS’ positive subscale. In the case of voluntary inpatients, assessments were conducted as close to discharge as possible. In order to ensure reliability of associations between levels of symptomatology and cognitive functioning, the neuropsychological battery was generally administered within 1 –2 days of symptom ratings, with a maximum time interval of 14 days. Tests were administered by Master’s level neuropsychologists and psychologists, and given in the same order to all subjects. The battery of tests was typically

completed in one session of 3– 4 hours duration, with rest breaks given as needed. All tests were administered and scored according to published standardised instructions. 2.3. Statistical analyses In order to calculate composite scores for each cognitive domain, the healthy control group data was divided into two age brackets ( < 16:11 and >16:11 years) and mean raw scores for individual tests were calculated for both age groups. On tests where higher scores indicated impairment, scores were transformed (reverse-scored) so that high scores always indicated better functioning. Composite scores for each cognitive domain were calculated for FES participants by converting individual raw scores to standardised zscores based on the age-appropriate control group mean scores. zZ-scores were then summed and averaged across tests in each domain, to provide a single score. The syndrome scores for the three-factor model were correlated with scores from the cognitive domains using Pearson’s two-tailed correlations. Corrections for multiple comparisons were applied using the Bonferroni method [(critical p ([0.05/33)] = < 0.002]). Fisher’s z-tests were used to compare syndromes and their respective correlations with specific cognitive domains. In order to examine the contribution of depressive symptoms to neuropsychological test performance, scores for the PANSS depression item and Calgary Depression Scale were also correlated with the cognitive domains. All analyses were carried out using Statistical Package for Social Sciences, version 10.0 (SPSS, 2001).

3. Results Results of the correlational analyses are shown in Table 3 for the three-factor model. Psychomotor Poverty and Reality Distortion produced no significant relationships with cognitive functioning after Bonferroni corrections for multiple comparisons ( p < 0.002). However, Disorganisation was significantly associated with poorer performance on verbal

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Table 3 Correlations between the cognitive domains and the three-factor symptom clusters

Current intellectual abilities Premorbid intellectual abilities Attention/vigilance Working memory Verbal acquisition Verbal recall Visual recall Visuospatial abilities Cognitive flexibility Verbal fluency Speeded processing

Psychomotor poverty

Disorganisation

r

r

p 0.26 0.06 0.03 0.16 0.13 0.18 0.24 0.29 0.11 0.21 0.14

0.059 0.6665 0.822 0.262 0.354 0.191 0.082 0.033 0.423 0.133 0.322

Reality distortion p

0.38 0.32 0.30 0.20 0.45* 0.45* 0.37 0.38 0.44* 0.22 0.17

0.001 0.001 0.007 0.005 0.001 0.001 0.007 0.005 0.001 0.116 0.219

r

p 0.18 0.22 0.10 0.21 0.12 0.14 0.14 0.07 0.05 0.04 0.01

0.196 0.121 0.494 0.136 0.404 0.326 0.329 0.633 0.730 0772 0.997

* p < 0.002 (with Bonferroni corrections for multiple comparisons).

acquisition (r = 0.45), verbal recall (r = 0.45) and cognitive flexibility (r = 0.42). These correlations account for between 18% and 20% of variance, which is indicative of small to medium effect sizes. Neither of the depression measures used in the study (PANSS depression item and Calgary Depression Scale total score) produced any significant correlations with the cognitive domains (see Table 4). Fisher’s z-test revealed a significant difference between Disorganisation and Reality Distortion syndromes in terms of their associations with the verbal acquisition ( p < 0.05), verbal recall ( p < 0.05) and cognitive flexibility ( p < 0.05) domains. In contrast, there was no significant difference between the relationships for these three cognitive domains and Psychomotor Poverty and Disorganisation. Table 4 Correlations between cognitive domains and measures of depression Calgary depression scale Current intellectual abilities Premorbid intellectual abilities Attention/vigilance Working memory Verbal acquisition Verbal recall Visual recall Visuospatial abilities Cognitive flexibility Verbal fluency Speeded processing

0.26 0.19 0.12 0.10 0.20 0.20 0.02 0.06 0.15 0.06 0.14

PANSS depression 0.22 0.21 0.08 0.09 0.07 0.16 0.04 0.13 0.09 0.16 0.02

4. Discussion This study examined the relationship between neuropsychological functioning and the three-factor symptom profile in first episode schizophrenia (FES). There was a significant association between the Disorganisation factor and verbal acquisition (r = 0.45), verbal recall (r = 0.45) and cognitive flexibility (r = 0.42) similar to the findings of Liddle (1987b), Liddle and Morris (1991), O’Leary et al. (2000) and Moritz et al. (2001) . These relationships account for between 18% and 20% of variance, which represents small to medium effect sizes. Comparison between syndromes revealed similar relationships with Psychomotor Poverty and Disorganisation, and the differential pattern of associations between Reality Distortion and Disorganisation. These results reflect similar substrates in Disorganisation and Psychomotor Poverty (prefrontal cortex) and different substrate in Reality Distortion (medial temporal lobe) as found in Liddle et al.’s (1992) cerebral blood flow study. Verdoux et al.’s (1999) study differed primarily in terms of the breakdown of psychotic symptoms into the two-factor rather than three-factor model. Thus, we cannot directly compare results. It is possible though that the Disorganisation items loading on the positive symptom factor were responsible for the correlation with verbal fluency. The present results may differ from those of other first episode studies due to differences in phase of illness at time of testing. Bilder et al. (2000) speculated

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that testing subjects in the acute phase of illness may confound state and trait neuropsychological effects. Research into the longitudinal course of the symptomatology of schizophrenia emphasises that symptom domains enter a stable pattern of regular fluctuation that may taper in acuity after 2– 5 years (Birchwood et al., 1998). This raises the possibility that the relationships found between cognitive functioning and symptoms may represent more transient effects (given that participants in both studies were assessed within 6 months of their first episode). The issue of when to test is difficult to resolve. Delaying testing for too long means the relationship of symptomatology to neuropsychological performance does not reflect the early stages of illness, and fluctuation of symptoms means not all patients are in remission at 6 months. Disorganisation has been recognised as a stable, longitudinal symptom domain and characterised as one of the traditional subtypes of the disorder—hebephrenia. Nonetheless, assessment during severe cognitive disorganisation will be affected by the acuity of symptoms. Thus, using a threshold level of symptoms rather than an arbitrary period of time was seen as preferable in this study. Further examination of the stability of the relationship between symptoms and cognitive functioning in the early stages of illness is important, and will be explored as part of our longitudinal follow up of the present cohort. Another possible explanation for the inconsistent results across studies is the difference in both medication type and dosage (Sharma, 1999; Harvey and Keefe, 2001). For instance, there is a large discrepancy between the chlorpromazine-equivalent dosage levels in the current study (269 mg/day) and those reported by Bilder et al. (2000; 712 mg/day). The significantly higher dose of typical antipsychotics in the latter study may have produced associations that were influenced by medication interactions with symptoms. In other studies including those of Bilder et al. (2000), Verdoux et al. (1999) and Van der Does et al. (1993), many subjects were either taking conventional antipsychotic or anticholinergic medication which have known adverse effects on cognition. This may have influenced the association between symptoms and cognition. In contrast, no participants in the present study were taking conventional antipsychotics, and only three were prescribed anticholinergic medication.

Reality Distortion results were comparable to previous research findings which have failed to identify relationships between hallucinations and delusions, and neuropsychological deficits (Liddle, 1987b; Liddle and Morris, 1991; Bilder et al., 2000). Contrary to previous studies of chronic schizophrenia, there was no association between Psychomotor Poverty and cognitive functioning in the present study. This was not due to low levels of negative symptoms as the current sample demonstrated higher mean negative subscale scores on the PANSS relative to the positive subscale. As indicated earlier, this may be due to the medication regime of atypical antipsychotic medication used (including some individuals on no antipsychotic medication), given the results of Moritz et al. (2001) discussed earlier. The possibility that depressive symptoms may have confounded the results was considered, given that depression has consistently been found to affect cognitive functioning (Cassens et al., 1990; Veiel, 1997). However, two separate measures of depression (PANSS depression item and Calgary Depression Scale score) failed to produce any significant relationships with any of the cognitive domains used in the present study. This may be due to low levels of depressive symptomatology in the present sample, given that only 22% of subjects (n = 21) scored above the clinical cut off score of 8 for significant depressive symptomatology on the Calgary Depression Scale (Addington et al., 1990). Nevertheless, it suggests that depressive symptoms may not relate to the cognitive dysfunction observed, and that psychotic symptoms are the main factor associated with such dysfunction in young people with FES. Some authors have suggested that the trichotomous division of symptoms in schizophrenia is flawed because of its simplicity and the limited range of symptomatology that it encompasses (Stuart et al., 1999). Certainly, the structure of symptomatology in schizophrenia is varied, being determined as much by the symptoms placed into the analysis, the number of subjects and the mode of analysis, at a minimum. These studies emphasise that the Reality Distortion factor is the least stable, frequently breaking down into two or more factors. This inherent instability may reflect an inadequate model of psychopathology. However, the validity of such criticism can only be

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tested via studies such as these that examine the fit of the data with external factors and eventually with underlying pathological mechanisms. Given the burgeoning research into the structure of psychotic symptomatology (White et al., 1997), a contrasting and more robust model may become apparent in the future. Despite these unresolved theoretical issues, the current study has provided several methodological improvements on previous research such as the use of an ecologically valid sample of young FES patients; the employment of a threshold level of symptomatology (conceptual disorganisation) to standardise the assessment procedure; the inclusion of only participants who were either unmedicated or prescribed atypical antipsychotics; and specific examination of the effects of depression. Although further research is warranted to clarify the nature of the cognitive correlates of symptom profiles in FES and their stability in the early stages of this illness, the present study provides preliminary evidence that symptoms loading on the Disorganisation factor are significantly associated with impaired frontal – temporal functioning, both of which may represent core features of schizophrenia that are present at the earliest manifestations of the illness. Concurrent validity from studies examining brain functioning by electrophysiological and neuroanatomical means also needs to be established. Clinically, these findings suggest that young people with FES who appear to have a significant degree of disorganised symptoms may be at greater risk of cognitive dysfunction, and ultimately poorer outcome (Green, 1996; Green et al., 2000). This remains to be seen by researching the longitudinal relationships between these factors.

Acknowledgements The authors thank Dr. Wayne Reid and Ms. Susanne Meares for their substantial contributions to the development and implementation of this study, and Dr. Anne Taylor, Dr. Mark Kneebone, Dr. Martyn Patfield, Dr. Megan Chambers and Ms. Susan Coleman for their assistance and cooperation. This research was supported by a grant from the Centre for Mental Health (NSW Health, Australia).

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