The Maudsley Early-Onset Schizophrenia Study: cognitive function in adolescent-onset schizophrenia

Schizophrenia Research 65 (2003) 95 – 103 www.elsevier.com/locate/schres

The Maudsley Early-Onset Schizophrenia Study: cognitive function in adolescent-onset schizophrenia Eugenia Kravariti a,*, Robin G. Morris b, Sophia Rabe-Hesketh c, Robin M. Murray a, Sophia Frangou d a

Department of Psychiatry, Division of Psychological Medicine, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK b Neuropsychology Unit, Institute of Psychiatry, UK c Department of Biostatistics, Institute of Psychiatry, UK d Section of Neurobiology of Psychosis, Division of Psychological Medicine, Institute of Psychiatry, UK Received 28 October 2002; accepted 15 February 2003

Abstract The neuropsychological correlates of adolescent-onset schizophrenia have been investigated very little to date. We assessed intelligence, memory and executive function in 42 patients with adolescent-onset schizophrenia and 43 healthy control subjects. Cases showed impairments in most cognitive variables. Despite the overall similarity with the quantitative and qualitative performance characteristics of later-onset patients in the literature, their cognitive profile displayed a unique feature: modification of the usual pattern of thinking latencies in the Tower of London Task. After adjusting for potential confounders, no effect of illness duration, symptoms or medication dose on patient performance emerged. However, longer exposure to medication predicted a lower level of performance in aspects of attention, psychomotor processing speed and spatial working memory. Our data are not consistent with worse cognition or progression of neuropsychological impairment in adolescent-onset schizophrenia. D 2003 Elsevier Science B.V. All rights reserved. Keywords: Psychomotor; Schizophrenia; Cognition

1. Introduction Attempts to illuminate the aetiology and heterogeneity of schizophrenia have frequently focused on age of onset as an important key to elucidating the origins and complexity of the disorder (DeLisi, 1992). The reported severity and homogeneity of the early* Corresponding author. Tel.: +44-20-7-848-0331; fax: +44-207-701-9044. E-mail address: [email protected] (E. Kravariti).

onset type, in particular, might yield more marked and consistent neurobiological findings than would be expected from investigations of adult-onset schizophrenia (ADUOS) (Gordon et al., 1994). The few cognitive studies of adolescent-onset schizophrenia (ADOLOS) have produced inconsistent findings (Cornblatt et al., 1998; Erickson et al., 1984; Rund et al., 1998; Øie et al., 1998; Kravariti et al., in press; Morice and Ingram, 1983; Hoff et al., 1996; Basso et al., 1997). Recent-onset studies have provided little support for the notion that adolescent-

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onset is associated with more aberrant neuropsychological function than adult-onset (Cornblatt et al., 1998; Erickson et al., 1984; Rund et al., 1998; Øie et al., 1998; Kravariti et al., 2003). By contrast, the few existing studies of chronic ADOLOS have generally shown greater cognitive impairment than is found in ADUOS (Morice and Ingram, 1983; Hoff et al., 1996; Basso et al., 1997). These contradictory findings may be due to methodological confounders. A second possibility, however, is that ADOLOS is associated with greater progression of neuropsychological dysfunction than its adult-onset counterpart. We addressed this question in a sample of ADOLOS patients (n = 42) with a broad range of age and illness duration. In addition, we indirectly compared their performance characteristics to those established in ADUOS by using tasks which have yielded replicable findings in the latter disorder.

2. Method 2.1. Subjects 2.1.1. Patients with schizophrenia Forty-two subjects (n = 42) with an onset of DSMIV-defined schizophrenia (American Psychiatric Association, 1994) in adolescence (12 – 18 years, inclusive), and no evidence of other Axis I disorders, participated in the Maudsley Early-Onset Schizophrenia Study. Diagnoses were based on the Structured Clinical Interview for DSM-IV Axis I Disorders (First et al., 1997), on medical records and on information from family members and treating physicians. The above sources were also used to determine age of schizophrenia onset, which was defined as age of onset of positive symptoms. Potential recruits were excluded, if they had any of the following: (a) current neurological disorders or a family history of hereditary neurological disorders, (b) a history of head injury resulting in loss of consciousness for more than an hour, (c) a history of alcohol or substance abuse and (d) IQ < 70. The patients were aged 13– 57 years and had been ill for a mean period of 9 years. The percentages of cases receiving typical (haloperidol/fluphenazine/flupenthixol decanoate, trifluoperazine, chlorpromazine, pipothiazine, sulpiride), atypical (clozapine, olanza-

pine and risperidone), mixed and no medication were approximately 30%, 60%, 5% and 5%, respectively. Medication doses were converted into chlorpromazine equivalents according to the guidelines of the Clinical Handbook of Psychotropic Drugs, 10th ed. (Bezchlibnyk-Butler and Jeffries, 2000) and the Psychotropic Drug Directory 1998 (Bazire, 1998). Although a widely accepted method of establishing dose equivalence for atypical antipsychotics is not currently available, the conversion used was based on the affinity of these agents for the Dopamine 2 receptor (D2), as well as on their pharmacokinetic properties (Bezchlibnyk-Butler and Jeffries, 2000). This method closely resembles the one used for calculating chlorpromazine equivalents, which is based on the D2 affinity of typical antipsychotics. However, the dose equivalents of the atypical agents reported here are considered only approximations. Clinical symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987), and had been relatively stable in all patients for a minimum period of 6 months. Handedness was established using the Annett (1970) Handedness Questionnaire. Parental socio-economic status was assessed by the Standard Occupational Classification (Office of Population Censuses and Surveys, 1991), employing three condensed categories (1 = professional or managerial, 2 = skilled or partly skilled, 3 = unskilled or unemployed). 2.1.2. Healthy controls Forty-three healthy controls (n = 43) were recruited through local press advertisements. Their selection was subject to the same exclusion criteria used for the patient sample with the addition of a personal or family history of mental disorder. This was established on the basis of personal interviews. The patient and control groups were closely matched for age, gender, handedness and ethnic composition, but they differed in parental socio-economic status and years of education (Table 1). The latter variable was difficult to equate between the two groups, as adolescent-onset schizophrenia occurs at a time when scholastic, academic and vocational training are still incomplete. All subjects provided informed consent to participate in the study. Their characteristics are presented in Table 1.

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Table 1 Socio-demographic, handedness, clinical (patients only) and treatment (patients only) characteristics of the patient and control groups Variablea

Patients (n = 42)

Controls (n = 43)

Male/female (n) Age at testing: range/mean (S.D.) White/African (Caribbean)/Asian/Mixedb (n) Right-handed/left-handed/mixed-handedc (n) Years of education at testing: range/mean (S.D.)d Parental socio-economic statuse: 1/2/3 (n)d Years old at onset of positive symptoms: range/mean (S.D.) Years ill at testingf: range/mean (S.D.) Years on medication at testing: range/mean (S.D.) Chlorpromazine equivalents (mg/day): range/mean (S.D.) Positive symptoms scoreg: range/mean (S.D.) Negative symptoms scoreg: range/mean (S.D.) General psychopathology symptoms scoreg: range/mean (S.D.)

26/16 13.3 – 56.7/24.9 (11.3) 31/7/3/1 37/2/3 8 – 16/11.3 (1.7) 25/7/8 12.6 – 18.4/15.9 (1.4) 0.08 – 42.7/9.2 (11.4) 0.0 – 40.7/8.4 (11.1) 0.0 – 1445.0/344.8 (288.4) 7 – 30/13.3 (5.9) 7 – 29/15.4 (6.8) 16 – 65/31.9 (11.5)

24/19 13.5 – 55.0/24.6 (11.0) 29/6/3/5 35/1/7 9 – 20/12.7 (2.7) 22/18/2 N/a N/a N/a N/a N/a N/a N/a

a Patients and controls did not differ ( p > 0.05) in gender or ethnic distribution, handedness (chi-square test) or age at testing (independent samples t-test), but differed in parental socio-economic status (Fisher’s Exact Test = 0.01) and years of education (t = 2.82, p < 0.01). b To increase the cell count for the statistical analysis, the categories ‘Asian’ and ‘Mixed’ were collapsed into a single category of ‘Asian or Mixed’. c Assessed by the Annett (1970) Handedness Questionnaire. To increase the cell count for the statistical analysis, the categories ‘Lefthanded’ and ‘Mixed-handed’ were collapsed into a single category of ‘Left-handed or Mixed-handed’. d Patients and controls differed on this variable ( p V 0.01). e Assessed by the Standard Occupational Classification (Office of Population Censuses and Surveys, 1991), employing three condensed categories (1 = professional or managerial, 2 = skilled or partly skilled, 3 = unskilled or unemployed). f Illness duration was defined as number of months since onset of positive symptoms and, therefore, did not necessarily include periods of prodromal symptoms or negative symptoms. However, criterion C of DSM-IV (6 months of continuous signs of disturbance) was fulfilled in all cases. g Assessed by the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987), which yields a minimum score of 7 (symptoms absent) and a maximum score of 49 (positive and negative scales) or 112 (general psychopathology scale) (extreme symptoms).

2.2. Neuropsychological tests 2.2.1. Intelligence Full-Scale, Verbal and Performance IQs were measured by: (a) The Wechsler (1992) Intelligence Scale for Children—Third Edition UK (WISC-IIIUK): subjects 17 years old or younger (12 patients, 15 controls). (b) The Wechsler (1981) Adult Intelligence Scale—Revised (WAIS-R): subjects older than 17 years (30 patients, 28 controls). 2.2.2. Memory Verbal Memory, Visual Memory, General Memory, Attention/Concentration and Delayed Recall were assessed by the Wechsler (1987) Memory Scale— Revised (WMS-R). Subjects younger than 15 years (two patients, four controls) did not contribute to the

assessment of memory due to the lack of WMS-R normative data in younger adolescents, which did not allow the derivation of scaled scores. 2.2.3. Executive function The executive function variables assessed in the study have been described previously (Kravariti et al., 2003). They were derived from four experimental tasks, administered on an IBM-compatible lap top computer (model Extensa 600, Texas Instruments), fitted with an Intasolve touch-sensitive screen (model Sygnos CL-2010 TFT LCD). To both increase sensitivity for the detection of impairment and avoid ceiling effects, only data from the highest difficult levels were entered in the present analyses (Table 2). 1. Planning and problem solving were assessed by the Three-Dimensional Computerised Tower of London Test (3-D CTL Test) and Control (3-D CTL Control) tasks (Morris et al., 1993, 1995; Kravariti

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Table 2 Mean (S.D.) raw scores obtained by the patient and control groups on the cognitive variables Variable

Patients (n = 42)

Full-scale IQb,c Verbal IQb,c Performance IQb,c General memoryd Verbal memoryd Visual memoryd Delayed recalld Attention/concentrationd Moves above minimume Initial planning time (total seconds)e Subsequent planning time (total seconds)e Visual – motor speed (seconds per move)e Within-search errorsf Between-search errorsf Spatial strategy error scoref Trails A (total seconds)g Trails B (total seconds)g Motor speed/reaction time (total seconds)g Combined dual-task scoreh

91.6 96.5 87.8 85.7 85.0 95.6 88.4 89.2 2.7 7.3

(16.7)b/94.4 (10.8)c (14.8)b/96.5 (10.4)c (17.6)b/93.1 (12.8)c (18.1) (16.3) (17.4) (18.9) (15.3) (2.1) (5.9)

Coefficienta

Controls (n = 43) 105.9 (15.7)b/110.6 (11.0)c 104.5 (12.8)b/109.3 (11.2)c 106.2 (18.0)b/110.1 (12.6)c 111.0 (13.1) 107.6 (12.8) 112.7 (12.1) 111.8 (15.4) 99.9 (14.7) 1.0 (1.2) 14.1 (13.5)

14.3b/16.2c 8.0b/12.8c 18.5b/17.0c 24.5 22.1 15.9 23.2 7.1 1.7 6.7

Confidence interval (CI)a 1.4 3.0 4.2 16.6 15.0 7.5 14.3 0.6 2.5 1.0

to to to to to to to to to to

27.2b/10.5 to 22.0c 18.9b/7.1 to 18.5c 32.7b/10.3 to 23.7c 32.4 29.1 24.3 32.1 13.5 0.8 12.4

pa *b/***c nsb/***c **b/***c *** *** *** *** * *** *

7.2 (7.7)

6.4 (6.6)

1.5

5.3 to 2.3

ns

2.2 (0.8)

1.6 (0.3)

0.5

0.7 to

***

(1.1) (3.5) (3.8) (6.5) (9.0) (3.0)

0.6 5.5 2.6 4.8 7.2 2.3

1.2 to 0.1 8.2 to 2.8 4.3 to 1.0 8.7 to 1.0 12.7 to 1.7 4.1 to 0.6

ns *** ** * ** **

65.1 (7.1)

1.0

2.5 to 4.5

ns

1.4 9.6 19.4 12.7 26.0 18.3

(1.9) (6.3) (3.4) (10.2) (18.2) (4.4)

63.2 (11.0)

0.7 3.7 16.4 6.1 14.2 15.5

0.2

ns: p > 0.05. a The statistical analyses controlled for the group differences in education and socio-economic status. b Obtained from a subsample of 27 subjects (12 patients, 15 controls) who were administered the Wechsler (1992) Intelligence Scale for Children—Third Edition UK (WISC-IIIUK). c Obtained from a subsample of 58 subjects (30 patients, 28 controls) who were administered the Wechsler (1981) Adult Intelligence Scale—Revised (WAIS-R). d Assessed by the Wechsler (1987) Memory Scale—Revised (WMS-R) in subjects aged 15 years or older (n = 79) (40 patients, 39 controls). e Assessed by the Computerised Tower of London Test (CTL-T) and Control (CTL-C) tasks (Morris et al., 1993). The reported initial and subsequent planning times are adjusted for the group difference in visual – motor speed. Only data from the highest difficulty level (5) were included in the analysis. f Assessed by the Computerised Executive Golf task (Morris et al., 1999). Only data from the highest difficulty level (8) were included in the analysis. g Assessed by the Computerised Trail Making Test (Kravariti et al., 2003). The reported times (total seconds) to perform Trails A and B are adjusted for the group difference in Motor Speed/Reaction Time. Only data from the highest difficulty level (3) were included in the analysis. h Assessed by a modified version of the computerised Baddeley Working Memory Test (Baddeley et al., 1986). * p V 0.05. ** p V 0.01. *** p V 0.00.

et al., 2003). The 3-D CTL Test requires subjects to match a desired ball arrangement in a specified minimum number of moves by rearranging three coloured balls in three vertical columns. Individual differences in visual –motor speed are controlled for using the 3-D CTL Control task. This is identical in structure to the test condition, but lacks the planning component. Moves Above Minimum

(planning accuracy), Initial Planning Time (from problem presentation to first move), Subsequent Planning Time (from first move to solution) and Visual – Motor Speed (3-D CTL Control task) were analysed. 2. Spatial working memory was assessed by a selfordered searching paradigm, the Computerised Executive Golf Task (Feigenbaum et al., 1996;

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Morris et al., 1999; Kravariti et al., 2003). This requires subjects to search through ‘host holes’ on the screen to discover the target location of a golf ball. Once a ball has been placed in a hole during a trial (search), that hole cannot be used as a target on subsequent trials (searches), and subjects have to remember not to go back to these used locations. Within-Search Errors (number of returns to any searched location within a trial), Between-Search Errors (number of returns to any location occupied in a previous trial) and Strategy Error Score (degree of irregularity in the subject’s search paths) were analysed. 3. Sequencing and mental flexibility were assessed by the Computerised Trail Making Task, an experimental adaptation of the Trail Making Test (Army Individual Test Battery, 1944). This computerised version involves a 20-letter task equivalent to Trails A, and a 20-number/letter task equivalent to Trails B. A motor control condition is further used to separate the relative contributions of mental and motor speed/reaction time to the total performance times. 4. Divided Attention was assessed by a modified version of the Baddeley Working Memory Task (Baddeley et al., 1986), a paradigm devised to tap the integrity of the central executive (attentioncontroller) of working memory. The task requires subjects to perform motor tracking (a computerised task) and digit span (an auditory verbal working memory task) simultaneously at a difficulty level that is individually adjusted for baseline ability on each of the component tasks. Combined Dual-Task Score, an index of the ability to allocate attention to two simultaneously performed tasks, was analysed. 2.3. Statistical analysis The data were analysed using Intercooled Stata 7.0 for Windows (Rabe-Hesketh and Everitt, 2000). Group differences in neuropsychological function were examined by linear regression analyses using robust standard errors to safeguard against potential violations of the standard ANOVA assumptions. As the patient and control groups were not matched for parental socio-economic status and years of education, all analyses were performed controlling for these potential confounders.

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The effect of illness duration and other diseaserelated parameters (clinical symptoms, medication dose, medication duration) on the patients’ performance were examined in two sequential steps: (a) the effect of each variable of interest (illness duration, positive symptom score, negative symptom score, medication dose, medication duration) or potential confounder (age, gender, years of education) on the various outcome functions was individually examined in simple linear regression models; (b) variables showing significant effects on any outcome function were simultaneously entered in multiple regression analyses. These were performed using robust standard errors to safeguard against potential violations of the standard ANOVA assumptions. As we were mainly interested in the effect of each disease-related parameter on cognitive performance after controlling for the confounding effects of the remaining disease-related parameters, only the results of step 2 (multiple regression analyses) will be reported. The effect of illness duration on intelligence was examined in relation to WAIS-R data, as the WISCIIIUK had been uniformly administered to recently diagnosed subjects (illness duration < 2 years), and the two instruments are not directly comparable.

3. Results 3.1. Missing data All subjects completed the full range of age-appropriate tests, with the exception of one patient failing to complete the computerised executive function tasks. Parental socio-economic status could not be established for three subjects, as relevant information was not available. 3.2. Group differences in neuropsychological performance Table 2 presents the means and standard deviations of the raw scores obtained by the patient and control subjects in the various cognitive variables, and the results of the statistical group comparisons. Group differences surviving the Bonferroni correction for multiple comparisons are indicated with three asterisks (***) ( p V 0.001) in Table 2.

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Group differences at the 0.001 (Bonferroni), 0.01 or 0.05 levels of statistical significance were noted for 16 of the 19 variables examined (Table 2) (patients performed worse than controls in all 16 variables). No group differences were detected for Subsequent Planning Time, Within-Search Errors (immediate spatial memory), Combined Dual-Task Score (divided attention) or Verbal IQ (WISC-IIIUK only) (Table 2). 3.3. Effect of disease-related parameters on patient performance 3.3.1. Simple linear regression analyses (step 1) Illness duration, medication duration, positive symptom score, negative symptom score, age and years of education each showed significant effects on one or more neuropsychological variables and were, therefore, entered in the multiple regression analyses (step 2). Medication dose and gender showed no effects on any neuropsychological function and were, therefore, excluded from the multiple regression models (step 2). 3.3.2. Multiple linear regression analyses (step 2) After partialling out the effects of co-predictors, the only disease-related parameter to predict neuropsychological performance in the patient group was medication duration. The longer a patient had been exposed to antipsychotic treatment, the poorer his/her performance was on Attention/Concentration (coefficient = 1.9, CI: 3.5 to 0.3, p V 0.05), Visual – Motor Speed (coefficient = 0.2, CI: 0.1 to 0.3, p V 0.01), Within-Search Errors (coefficient = 0.3, CI: 0.1 to 0.6, p V 0.01), Between-Search Errors (coefficient = 0.8, CI: 0.3 to 1.4, p V 0.01), Trails A (coefficient = 1.3, CI: 0.2 to 2.4, p V 0.05) and Motor Speed/Reaction Time (coefficient = 0.6 CI: 0.1 to 1.2, p V 0.05). No other effect of any disease-related parameter reached or approached significance.

4. Discussion We reported findings from the largest sample of ADOLOS patients investigated to date using a comprehensive neuropsychological battery. The broad spectrum of age and illness duration in our cohort allowed us to explore whether cognitive impairment

progresses over the course of ADOLOS. This possibility was raised by the proposed severity of earlyonset schizophrenia, and the inconsistency of findings in the existing literature: No evidence in recent-onset studies has linked ADOLOS to worse cognition than is demonstrated in ADUOS (Cornblatt et al., 1998; Erickson et al., 1984; Rund et al., 1998; Øie et al., 1998; Kravariti et al., 2003), but studies of chronic patients have found worse performance in adolescentonset than adult-onset subjects (Morice and Ingram, 1983; Hoff et al., 1996; Basso et al., 1997). An appealing hypothesis accounting for this discrepancy is that the adolescent-onset form is associated with greater progression of neuropsychological impairment compared to later-onset schizophrenia. Two main findings in the present study suggested a lack of progression of neuropsychological impairment over the course of ADOLOS: Our statistical analyses failed to detect any correlation between cognitive performance and illness duration after partialling out the effects of age and accumulative medication exposure. In addition, a simple inspection of the WISCIIIUK and WAIS-R IQs obtained by our youngest (recent onset), and older (more chronic), ADOLOS patients, respectively, reveals, if anything, higher scores in the more chronic group. Although the two instruments are not directly comparable, they have been standardised on representative population samples and have similar psychometric properties. It is, therefore, unlikely that the older patients performed worse than the younger subjects. The patients’ quantitative characteristics in the standardised tests of the battery (WISC-III UK , WAIS-R, WMS-R) are similar to those reported in studies of later-onset schizophrenia. The six- to eightpoint decrement (relative to the normative mean) in Full-Scale IQ in the present study is comparable to the 10-point deficit derived from a synthesis of Wechsler intelligence data from adult schizophrenia studies (Winder, 1960). In addition, the WMS-R indexes of the ADOLOS cohort fell within the low average range (80 –89), with the exception of the (average) Visual Memory index (95.6). WMS(R) studies assessing memory function in adult-onset schizophrenia have mainly reported indexes in the borderline to low average range (70 – 89) (Bilder et al., 2000; Hawkins et al., 1997; Randolph et al., 1994; Gold et al., 1992; Wechsler, 1987), with the exception of an average

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Visual Memory index in a study by Hawkins et al. (1997). These indirect comparisons on Wechsler data do not support a greater deficit of intelligence and memory in ADOLOS (present study) compared to ADUOS (literature). However, only direct comparisons between the two types can definitively address this issue. Such a comparison was performed by Basso et al. (1997) in two groups of chronic patients, and found significantly worse performance in the adolescentonset sample. However, the latter authors included atypically high-functioning ADUOS patients in their study, which may have confounded their findings. Using non-Wechsler data, Morice and Ingram (1983) and Hoff et al. (1996) also reported significant effects of earlier age of onset on the cognitive performance of chronic patients. However, the results reported by Hoff et al. (1996) lost statistical significance after controlling for education. On the other hand, recent-onset studies of ADOLOS have provided both direct (Cornblatt et al., 1998) and indirect (Erickson et al., 1984; Rund et al., 1998; Øie et al., 1998; Kravariti et al., 2003) evidence that ADOLOS is not associated with more aberrant neuropsychological function than the adult-onset type. Combined with the findings of the present study, which involved a relatively balanced composition of recent-onset and chronic subjects, the existing evidence to date does not strongly support the case for a greater disruption of neuropsychological function in ADOLOS relative to ADUOS. The patients’ performance in the executive function battery was qualitatively similar to that displayed by later-onset patients in the schizophrenia literature. A pattern of impaired planning accuracy (moves above the minimum) and visual –motor processing time in the Tower of London task (Morris et al., 1995; Pantelis et al., 1997; Rushe et al., 1999; Hutton et al., 1998), preserved immediate spatial memory (within-search errors) but impaired spatial working memory (between-search errors) in structural analogues of the Executive Golf Task (Pantelis et al., 1997; Elliott et al., 1998; Hutton et al., 1998), impaired trail making performance (Levander et al., 1985; Himelhoch et al., 1996; McGrath et al., 1997; Mahurin et al., 1998), and intact concurrent-task monitoring by the central executive mechanism of working memory (Salame´ et al., 1998; Spindler et al., 1997; Granholm et al., 1996), has consistently been

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outlined in the in ADUOS literature and was replicated in the present study. The modification of the usual pattern of planning latencies in the Tower of London task differentiated our ADOLOS patients from later-onset subjects in the schizophrenia literature. Patients with ADUOS show unimpaired (Pantelis et al., 1997; Elliott et al., 1998) or slightly reduced (Hutton et al., 1998) initial planning time, combined with prolonged subsequent planning (Pantelis et al., 1997; Elliott et al., 1998; Hutton et al., 1998). These findings suggest inefficient use of initial thinking time (viewed in the light of compromised planning accuracy) and a compensatory attempt to correct incompletely formulated plans (Robbins et al., 1998). In contrast to this pattern, the patients of the present study showed reduced initial planning time (their time to plan move sequences was half that of the control group), but no prolongation of subsequent planning. In other words, they not only tended to spend insufficient time planning their problem solutions, but also failed to adjust their subsequent thinking latencies to the increased demands for corrective action. If not a chance finding, reduced thinking latencies in the Tower of London Task may primarily characterise earlier-onset schizophrenia, being indicative of greater impulsivity or self-monitoring deficits relative to the later-onset form. Medication dose did not exert a significant effect on neuropsychological performance either before or after introducing co-variates in the regression analyses. By contrast, the overall duration of a patient’s exposure to antipsychotic treatment was the strongest predictor of cognitive performance. This finding is interesting and highlights the importance of taking into account the accumulative effects of medication in future studies. Although the question of progression of neuropsychological dysfunction in ADOLOS was central to the present study, we addressed this issue using a cross-sectional design, which is limited methodologically. In addition, we examined linear effects of illness duration on quantitative summary indexes of individual cognitive functions. A longitudinal followup of patients with ADOLOS would be better suited to address the question of progression of neuropsychological impairment, and additionally, examine changes in patterns of performance in addition to changes in degree of impairment.

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In summary, the pattern of cognitive deficits observed in the ADOLOS cohort of the present investigation supports notions of neurobiological continuity with adult-onset schizophrenia, although a small modification of the cognitive pattern associated with ADUOS was also noted. No evidence of greater severity relative to ADUOS, or progression of neuropsychological dysfunction in ADOLOS, was provided by the present study. Our findings must be viewed in the light of the limitations imposed by a cross-sectional design. Future studies should place emphasis on a longitudinal investigation of cognition in ADOLOS, including ADUOS patients in their comparisons. Acknowledgements We are grateful to all the participants of this study. We also wish to thank the staff of the adolescent and adult units that referred patients to us, particularly the Bethlem, Woodside and Tycehurst adolescent units for their valuable help. This study was supported by a grant from the Stanley Foundation. References American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Association, Washington, DC. Annett, M., 1970. A classification of hand preference by association analysis. Br. J. Psychol. 61, 303 – 321. Army Individual Test Battery, 1944. Manual of Directions and Scoring. War Department, Adjutant General’s Office, Washington, DC. Baddeley, A., Logie, R., Bressi, S., Della Sala, S., Spinnler, H., 1986. Dementia and working memory. Q. J. Exp. Psychol., A 38, 603 – 618. Basso, M.R., Nasrallah, H.A., Olson, S.C., Bornstein, R.A., 1997. Cognitive deficits distinguish patients with adolescent- and adult-onset schizophrenia. Neuropsychiatry Neuropsychol. Behav. Neurol. 10, 107 – 112. Bazire, S., 1998. Psychotropic Drug Directory 1998: The Professionals’ Pocket Handbook and Aide Memoire. Mark Allen Publishing, Wilts. Bezchlibnyk-Butler, K.Z., Jeffries, J.J. (Eds.), 2000. Clinical Handbook of Psychotropic Drugs, 10th rev. ed. Hogrefe and Huber, Toronto, pp. 71 – 73. Bilder, R.M., Goldman, R.S., Robinson, D., Reiter, G., Bell, L., Bates, J.A., Pappadopoulos, E., Willson, D.F., Alvir, J.M., Woerner, M.G., Geisler, S., Kane, J.M., Lieberman, J.A., 2000. Am. J. Psychiatry 157, 549 – 559.

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