A 3-year prospective study of neurological soft signs in first-episode schizophrenia

Schizophrenia Research 75 (2005) 45 – 54 www.elsevier.com/locate/schres

A 3-year prospective study of neurological soft signs in first-episode schizophrenia Eric Yu-Hai Chena,*, Christy Lai-Ming Huia, Raymond Chor-Kiu Chana,c, Eva Lai-Wah Dunnb, May Yin-King Miaob, Wai-Song Yeungb, Chi-Keung Wongb, Wah-Fat Chanb, Wai-Nang Tangb a

Department of Psychiatry, University of Hong Kong. Queen Mary Hospital, Pokfulam Road, Hong Kong b Department of Psychiatry, Pamela Youde Nethersole Eastern Hospital, Hong Kong c Department of Psychology, Sun Yat-Sen University, Guangzhou, China Received 12 August 2004; received in revised form 23 August 2004; accepted 6 September 2004 Available online 13 October 2004

Abstract Neurological soft signs are biological traits that underlie schizophrenia and are found to occur at higher levels in at-risk individuals. The expression of neurological soft signs may be modifiable during the onset of the first psychotic episode and the subsequent evolution of the illness and its treatment. This study investigates neurological soft signs in 138 patients with firstepisode schizophrenia and tracks the expression of motor soft signs in the following 3 years. For the 93 patients who have completed the 3-year follow-up, we find that neurological soft signs are stable in the 3 years that follow the first psychotic episode, and that neurological soft signs are already elevated at the presentation of first-episode psychosis in medication-naRve subjects. The level of neurological soft signs at clinical stabilization is lower for patients with a shorter duration of untreated psychosis. Although the quantity of neurological soft signs does not significantly change in the 3 years that follow the first episode, the relationship between neurological soft signs and negative symptoms does not become apparent until 1 year after the initial episode. A higher level of neurological soft signs is related to a lower educational level and an older age at onset, but the level of neurological soft signs does not predict the outcome in terms of relapse or occupational functioning. D 2004 Elsevier B.V. All rights reserved. Keywords: First-episode schizophrenia; Neurological soft signs; Longitudinal study

1. Introduction

* Corresponding author. Tel.: +852 28554488; fax: +852 28551345. E-mail address: [email protected] (E.Y.-H. Chen). 0920-9964/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2004.09.002

Neurological soft signs are nonlocalizing neurological abnormalities that are generally found to be more prevalent in schizophrenic patients (Heinrichs and Buchanan, 1988). They have been conceptualized as btarget featuresQ that mediate the biological

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Madsen et al., 1999; Sanders et al., 1994; Whitty et al., 2003; Schroder et al., 1992b; Table 1), which have identified increased levels of neurological soft signs in first-episode schizophrenia (and in other psychotic disorders), even in the medication-naRve state. Flyckt et al. (1999) compared the neurological signs in firstepisode and chronic patients, and found no significant difference. They concluded that the level of neurological soft signs that is identified at the first episode continues to be stable with time, but their conclusion is limited by the use of cross-sectional sampling. The possible progression of neurological soft signs needs to be more definitively addressed in a longitudinal study. To date, relatively few studies have provided longitudinal follow-up data on neurological soft signs in patients after their first episode (Dazzan and Murray, 2002). In the only study that involves a longer-term follow-up (beyond 18 months after the first episode), Madsen et al. (1999) measured neurological soft signs in a small sample of 18 schizo-

propensity for the development of psychosis (Tsuang and Faraone, 1999). Family studies have identified an increased level of neurological soft signs in the firstdegree relatives of schizophrenia patients compared with the healthy population (Chen et al., 2000; Kinney et al., 1986; Rossi et al., 1990). Longitudinal high-risk studies have also detected a modest increase in neurological soft signs in individuals who are at risk for psychosis (Fish, 1977; Lawrie et al., 2001; Marcus et al., 1985), which suggests that neurological soft signs are manifested early as a premorbid trait prior to the onset of illness. To understand the subsequent longitudinal evolution of neurological soft signs as the course of the illness and treatment unfolds, it is necessary to investigate neurological soft signs in the first psychotic episode and in the first few years of illness (Dazzan and Murray, 2002). Neurological soft signs in first-episode schizophrenia have been explored in a number of studies (Browne et al., 2000; Flyckt et al., 1999; Gupta et al., 1995; Table 1 Studies of neurological soft signs in first-episode schizophrenia References

Subjects at first admission

Subjects at follow-up

First-episode Medication Diagnosis patients (n) naRve (n) Keshavan et al., 2003

129

90

Whitty et al., 2003

97

33

Browne et al., 2000

56

35

Carr et al., 2000 Flyckt et al., 1999 Madsen et al., 1999

56 21

– 18

63

–

Gupta et al., 1995 Sanders et al., 1994

152

26

17

17

Schroder et al., 1992a,b

50

17

Healthy Follow-up control (n) period

90—Schizopehrnia; 93 30—other psychotic disorders Schizophrenia/ – schizophreniform disorder Schizophrenia/ – schizophreniform disorder Psychosis – Schizophrenia 55

–

–

NES

73

–

NES & CNE

–

–

NES & CNE

14.6 months 27 – –

– –

NES SNE

5 years

18

10

SNE

–

–

–

CASH

15

–

–

–

NES

34

–

–

–

Heidelberg scale

34—Schizophrenia; 20 29—other psychotic disordres Schizophrenia 117 Schizophrenia/ schizophreniform disorder Schizophrenia/ schizophreniform disorder

–

Instruments

First-episode Healthy patients (n) control (n)

6 months

–

NES, Neurological Evaluation Scale (Buchanan and Heinrichs, 1989); CNE, Condensed Neurological Examination (Rossi et al., 1990); SNE, Standard neurological examination; CASH, Comprehensive Assessment of Symptoms and History (Andreasen et al., 1992); Heidelberg Scale (Schroder et al., 1992a,b).

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phrenic patients at their first psychotic episode and at 5 years, and found that although there was no significant overall change, there was evidence of a progression of neurological soft signs in a subset of patients who had a family history of psychotic disorders and in patients with a nonremitting course. As the initial assessments in the study were carried out during the acute first psychotic episode, it is not known as to what extent the initial neurological soft signs that were measured were part of the acute psychotic state. In a shorter follow-up study, Whitty et al. (2003) reassessed first-episode patients after 6 months and found that there was a significant improvement in neurological soft signs, which suggests that neurological soft signs manifest statelike characteristics that vary with the clinical course. Likewise, in an earlier study, Schroder et al. (1992b) found that neurological soft signs in first-episode medication-naRve patients improved after treatment of the first psychotic episode. These studies highlight the importance of measuring neurological soft signs both before and after the treatment of the first psychotic episode to provide an informative baseline for further longitudinal tracking over the early course of the illness. They also suggest the need to follow patients beyond the initial treatment phase of the first episode into the next few years, so that observations can be made as to whether neurological soft signs evolve independently from the initial psychotic state. A more systematic longitudinal study could potentially be informative about the way in which the relationship between neurological soft signs and symptoms might evolve over time. Neurological soft signs have been found to be related to negative symptoms in a number of studies that involved chronic patients (Addington and Addington, 1991; Merriam et al., 1990; Mohr et al., 1996; Wong et al., 1997), but they have been reported to be related to positive symptoms in some first-episode studies (Browne et al., 2000; Whitty et al., 2003). The relationship between neurological soft signs and the duration of untreated psychosis, as well as clinical and functional outcome, could also be addressed in such a prospective study. In this study, we measure neurological soft signs in patients who presented initially with first-episode psychosis and then again after they have remitted from the psychotic episode. We subsequently track the level and correlates of the neurological soft signs for 3 years.

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Specifically, we address the following questions: (1) whether there is a progression in the level of neurological soft signs over time in the 3 years following a first psychotic episode, (2) whether the level of neurological soft signs improves after the treatment of the first psychotic episode, (3) whether the level of neurological soft signs is related to the duration of untreated psychosis (DUP), and (4) whether neurological soft signs are related to clinical variables and the outcome of the first psychotic episode.

2. Method 2.1. Sample The sample consisted of 138 consecutively diagnosed first-episode patients with schizophrenia, schizophreniform disorder, and schizoaffective disorder. Ninety-three patients completed the 3-year follow-up. The patients were between 18 and 55 years of age and came from a catchment area within Hong Kong with a population of 1.3 million. They were not recruited if they had had a previous psychotic episode (whether treated or not), if they had a known neurological condition, or if there was a history of special school attendance. The patients in this study were initially treated with low-dose conventional antipsychotics (less than 5 mg of haloperidol or equivalent). The study was approved by the relevant institutional review board, and all of the subjects gave written informed consent prior to participation. Subjects in the healthy control sample were 68 unpaid volunteers. They were screened with a structured questionnaire for the exclusion criteria. The patients were assessed at initial assessment, and then at the time of clinical stabilization (mean: 42.6 days after the initiation assessment) when no major change in the level of symptoms or treatment was anticipated. Subsequent assessments were carried out each year for a period of 3 years. The healthy control subjects were assessed once only. 2.2. Assessments 2.2.1. Diagnostic and clinical assessments Diagnoses were made according to DSM-IV criteria (American Psychiatric Association, 1994) based on

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clinical interviews, informant histories, and medical records. Symptoms were assessed using the Positive and Negative Symptom Scale (PANSS; Kay et al., 1988), and items were scored according to standardized instructions that are based on clinical interviews and medical records. The intraclass correlation coefficients were 0.83 for the PANSS positive subscale and 0.73 for the PANSS negative subscale. In addition, negative symptoms were assessed using the High Royds Evaluation of Negativity (HEN; Mortimer et al., 1989). Validation of the HEN for use in Chinese patients has previously been reported (Chen et al., 1997). The interrater reliability for the global scores in the HEN was 0.92. The intraclass correlation for the subscales ranged from 0.74 (thought) to 0.85 (speech). Extra-pyramidal signs were assessed with the Simpson Angus scale (Simpson and Angus, 1970), dyskinesia was assessed with the Abnormal Involuntary Movements Scale (AIMS; Guy, 1976), and akasthisia was assessed with the Barnes Akasthisia scale (Barnes, 1989). The duration of untreated psychosis (DUP) was evaluated using the Interview for the Retrospective Assessment of the Onset of Schizophrenia (IRAOS), and information about educational level and family history of psychiatric illness was also obtained through this assessment. The IRAOS is a semistructured instrument that is designed to capture detailed information that relates to onset and early symptoms, their time course and presentation (Hafner et al., 1992). The DUP was calculated as the onset date for the earliest psychotic symptom. Premorbid personality and adjustment were assessed by interviewing the parents of the patient using the premorbid schizoid and schizotypal trait (PSST) scale (Foerster et al., 1991) and an abridged version of the premorbid adjustment scale (PAS; Cannon et al., 1982), respectively. 2.2.2. Neurological soft signs The Cambridge Neurological Inventory (CNI) was used for the assessment of neurological soft signs (Chen et al., 1995). The CNI has been validated and used on both Caucasians and Chinese patients (Chen et al., 1995, 1996a,b; Chen and Chan, 2003). An abridged CNI soft signs assessment that consists of the motor coordination subscale was

adopted in this study. We focused on motor soft signs, as it has previously been found that the other major subcategory of neurological soft signs— sensory integration signs—significantly covary with a wide range of cognitive functions and may signify general cognitive impairment (Arango et al., 1999). In contrast, motor soft signs appear to be more related to a specific prefrontal and subcortical function and are arguably more discriminating in the diagnosis of schizophrenia and psychotic disorders (Schroder et al., 1995, 1998; Mohr et al., 1996; Boks et al., 2000). The motor coordination subscale tests for neurological soft signs that involve regularly paced repetitive movements. They include fingerthumb opposition, finger-thumb tapping, diadochokinesia, the fist-edge palm test, and the Ozeretsky test. In the data analysis, the item scores were collapsed into either babsentQ (which covered the normal or equivocal scale scores) or bpresentQ (which covered the abnormal or grossly abnormal scale scores). Items that could be scored on both the left and the right were each treated as independent scores. The interrater reliability for the motor soft signs scores was evaluated by comparing investigators’ ratings on a set of 15 videotaped CNI examinations and was found to be satisfactory (intraclass correlation, 0.93). 2.3. Data analysis Statistical analyses were carried out using the Statistical Package for Social Sciences (SPSS) version 11.51. The first comparison addressed whether there was an increase in motor soft signs in first-episode patients compared with the healthy controls, and both parametric (unpaired t-test) and nonparametric (Mann–Whitney U-test) comparisons were made. The second analysis addressed whether there was a longitudinal progression of neurological soft signs. A repeated measure ANOVA for motor soft signs scores with five within-subject levels (initial, stabilized, year one, year two, and year three) was used to establish whether there were significant changes in neurological soft signs over time. Finally, correlational analyses were carried out between the neurological soft signs scores and clinical parameters (symptom and side effect subscale scores).

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3. Results 3.1. Sample characteristics There were 42 men and 51 women, and their mean age was 31.2 (S.D.=9.6) years. The average duration of untreated psychosis (DUP) was 474 days (S.D.=768), and the average educational level was 10.54 (S.D.=2.9) years. The DSM-IV diagnoses for the sample were schizophrenia (n=75), schizophreniform disorder (n=13), and schizoaffective disorder (n=5). Forty-eight patients were first assessed in a medication-naRve state, and the rest were assessed within 7 days of starting a course of medication. A healthy control group that was matched for age, gender, and educational level was assessed. The control sample consisted of 22 men and 46 women with a mean age of 32 years (S.D.=8.4). There was no significant difference between the patients and control subjects in age, gender, or educational level. 3.2. Longitudinal stability of neurological soft signs in the 3 years following first-episode psychosis Motor soft signs at presentation, after stabilization of the first episode, and for the following 3 years are shown in Table 2. We further compared the initial levels of neurological soft signs and the 3-year follow-up levels of neurological soft signs using paired sample t-tests. We then divided the sample according to gender, family history of psychotic illness, and persistent positive symptoms (an improvement of more than 5 points on the positive symptoms subscale of the PANSS). There was no significant difference between the initial and 3-year follow-up levels of neurological soft signs in any of these subgroups. Table 2 Levels of motor soft signs scores in the 3 years following a first psychotic episode Initial presentation Clinical stabilization 1-year 2-year 3-year

Mean

S.D.

1.87 1.47 1.64 1.44 1.45

2.00 1.83 1.80 1.78 2.20

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A repeated measure analysis of variance was carried out with time as the within-subject factor. This revealed no significant time effect ( F=1.2, p=0.3, ns). To address the question of whether the level of neurological soft signs falls after treatment of the first psychotic episode, a within-subject comparison was carried out between the scores at the initial presentation and the scores after clinical stabilization. No significant difference was found. There was also no significant correlation between the changes in neurological soft signs scores and the changes in the positive and negative subscale scores and the total PANSS score. 3.3. Level of motor soft signs at the first episode The motor soft signs scores were compared between first-episode patients (1.79, S.D.=1.99) and control subjects (0.85, S.D.=1.34). Significant differences were found between the two groups (t=3.59, df=159, pb0.001), with a moderate effect size of 0.5. Nonparametric analysis (Mann–Whitney U-test) also confirmed a significant increase in motor soft signs in first-episode patients (z= 3.48, pb0.001). The results thus support the notion that motor soft signs are at an increased level in first-episode schizophrenia. As only 48 of the 93 initial assessments were conducted in a medication-naRve state (the rest were carried out shortly after the initiation of antipsychotic therapy), we further examined the subset of medication-naive patients (n=48). There was no difference in age, gender, or educational level between those who were medication-naRve and those who had started medication before the initial assessment. The total motor soft signs were still at an increased level in medication-naRve patients (1.56, S.D.=1.89) relative to the healthy controls (0.85, S.D.=1.34) in both the parametric (t=2.23, df=114, t=0.020) and nonparametric (z= 3.48, pb0.001) analyses. When a comparison was made between the medication-naRve and medicated patients, no significant difference was found between the two groups for motor soft signs. For signs that could be assessed bilaterally, there was no significant difference between the level of signs on the left and on the right (paired t-tests, ns). A further analysis that was restricted to those with a positive family history did not reveal a significant left–right difference. The prevalence and mean

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scores for individual motor soft signs are shown in Table 3. 3.4. Clinical and demographic correlates of motor soft signs 3.4.1. Demographic and premorbid factors A higher age at onset was modestly associated with an increased level of motor soft signs (r=0.27, p=0.007). A higher educational level was associated with a lower level of neurological soft signs (r= 0.38, p=0.0001). The levels of motor soft signs were not significantly different between the male and female subjects, and there was no significant relationship between the levels of neurological soft signs and premorbid personality and adjustments. Levels of motor soft signs in patients with a diagnosis of schizophrenia were not significantly different from those with diagnoses of schizoaffective and schizophreniform disorders. 3.4.2. Neurological soft signs and the duration of untreated psychosis (DUP) The sample was divided into those with a DUP of less than 1 month (n=24) and those with a DUP of Table 3 Mean scores and frequency (%) of individual motor soft signs in patients with first episode schizophrenia and healthy control subjects Healthy control (n=68)

Patients (n=93)

Mean

Mean S.D. (%) Z

S.D.

(%)

Mann–Whitney p

Finger-thumb opposition L 0.09 0.29 8.8 R 0.10 0.31 10.3

0.16 0.16

0.37 16.1 0.37 16.1

1.36 1.06

ns ns

Finger-thumb tapping L 0.01 0.12 1.5 R 0.01 0.12 1.5

0.06 0.09

0.25 0.28

6.5 8.6

1.53 1.94

ns 0.052

Diadochokinesia L 0.06 0.24 R 0.04 0.21

5.9 4.4

0.09 0.05

0.28 0.23

8.6 5.4

0.65 0.28

ns ns

Fist-edge palm test L 0.24 0.43 R 0.13 0.34

23.5 13.2

0.31 0.28

0.47 31.2 0.45 28.0

1.07 2.23

ns 0.026

Ozeretsky test 0.16 0.37

16.2

0.32

0.47 32.3

2.31

0.021

more than 1 month (n=69). Motor soft signs at initial presentation and after clinical stabilization were compared between the groups. Although there was no significant difference in the level of neurological soft signs at initial presentation, after clinical stabilization the level motor soft signs was significantly lower in patients with a shorter DUP (Mann–Whitney U-test, z= 2.4, p=0.016). 3.4.3. Relationship between neurological soft signs and clinical variables at different stages of the illness At initial presentation, there was no significant correlation between the levels of neurological soft signs and the levels of positive and negative symptoms, affective and obsessive compulsive symptoms, or measures of extra-pyramidal signs. The picture is similar upon clinical stabilization following medication. At the end of the first year, a moderate correlation with negative symptoms (thought subscale, r=0.29, p=0.01) emerged. By the second year, a wider range of negative symptoms was significantly correlated to motor coordination neurological soft signs. These included the behavior (r=0.28, p=0.005), speech (r=0.28, p=0.006), thought (r=0.27, p=0.009), and affect (r=0.26, p=0.01) subscales of the HEN. There were also modest correlations with the global HEN score (r=0.28, p=0.006) and the negative symptoms subscale scores of the PANSS (r=0.32, p=0.001). By year three, there were significant correlations with the HEN subscales of thought (r=0.21, p=0.04) and affect (r=0.25, p=0.014). 3.4.4. Neurological soft signs and outcome The relationship between neurological soft signs at the first psychotic episode (before and after treatment) and clinical outcome (symptoms, relapse, and vocational functioning) of the illness was explored. Patients were divided into two groups according to whether they had (n=37) or had not (n=55) experienced one or more relapses. The level of neurological soft signs was not significantly different between the two groups. Likewise, the patients were divided into two groups, one for those with a good vocational outcome and the other for those with a poor vocational outcome, according to whether they had achieved full-time employment for at least 8 months in the 3-year period. The two groups did not differ in

E.Y.-H. Chen et al. / Schizophrenia Research 75 (2005) 45–54

motor soft signs either before or after receiving treatment for the first psychotic episode. The presence of motor soft signs at the first episode also did not predict either positive or negative symptoms at the 3year follow-up.

4. Discussion In this prospective three-year longitudinal study of neurological soft signs in first-episode schizophrenia, the key findings are (1) that neurological soft signs remain stable over the first 3 years of the illness, (2) that levels of neurological soft signs are higher in medication-naive first-episode patients, (3) that patients with a short DUP have lower levels of neurological soft signs at the clinical stabilization stage, (4) that the association of neurological soft signs with negative symptoms is apparent by 1 year of illness, and (5) that initial neurological soft signs levels are related to age at onset and educational level but do not predict relapse or symptomatic and occupational outcome. We found that there was no obvious progression in the level of motor soft signs in the initial 3 years that followed the first psychotic episode. Although Madsen et al. (1999) reported longitudinal data on neurological soft signs in 18 patients and suggested the stability of the levels of neurological soft signs following the first episode of psychosis, the issue has not been investigated in a larger sample. This study provides further empirical data that suggest that levels of neurological soft signs remain stable for 3 years following the first psychotic episode. However, some aspects of the observations of Madsen et al. are not replicated in our study. In our sample, we found that patients with a family history of psychotic disorders did not show a deterioration in motor soft signs, nor did we find a deterioration in male patients or in those with unremitting positive symptoms. Apart from the involvement of a larger sample, this study differs from Madsen et al. in other important aspects. The bmotor systemQ signs in Madsen et al. involved a wider range of neurological abnormalities including extra-pyramidal signs. We found no evidence of an increase either in the entire sample or in comparable subgroups when we restricted our observation to core motor soft signs.

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The increase in neurological soft signs in medication-naRve first-episode psychosis patients is consistent with previous findings (Browne et al., 2000; Gupta et al., 1995; Sanders et al., 1994; Flyckt et al., 1999; Madsen et al., 1999; Schroder et al., 1992b). The observation is nevertheless important, as it rules out the concern that neurological soft signs are largely a consequence of antipsychotic treatment. Whitty et al. (2003) observed that following treatment of the first psychotic episode, there may be a reduction in the level of neurological soft signs, which suggests that processes that are associated with a state of psychosis might partly contribute to the expression of neurological soft signs. In their study, they applied two instruments—the Neurological Evaluation Scale (NES) and the Condensed Neurological Evaluation (CNE). Improvements were detected in the NES but not in the CNE. In this study, we do not detect a significant change in the level of motor soft signs between the first presentation and at stabilization of the first psychotic episode. In addition, we cannot identify a correlation between the change in scores for neurological soft signs and the change in scores for symptoms (positive, negative, or total PANSS scores). One potential difference between the two samples is the levels of positive symptoms. The positive symptom subscale score in the sample of Whitty et al. (23.5, S.D.=7.2) is higher than that in our sample (19.73, S.D.=5.45). Possible attentional impairments that are related to the psychotic state have been postulated to explain the relationship between neurological soft signs and positive symptoms. According to this stance, the presence of higher levels of psychotic symptoms in the study of Whitty et al. would have increased the extent to which neurological soft signs could be affected by positive symptoms. In our sample, the relative stability of neurological soft signs both before and after treatment of the first psychotic episode is highlighted, which reflects the traitlike characteristics of neurological soft signs, even in the first psychotic episode. The stability in the total neurological soft signs scores also needs to be considered in the light of changes in their associations. Although the relationship between neurological soft signs and negative symptoms is well documented in chronic patients (Addington and Addington, 1991; Malla et al., 1997;

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Mohr et al., 1996), such a relationship is not clear among first-episode patients (Flyckt et al., 1999). This study demonstrates the longitudinal unfolding of this relationship in the early course of the illness. The relationship between neurological soft signs and negative symptoms was not evident during the first psychotic episode and only became apparent after 1 year. We found that patients with a shorter DUP had a lower level of neurological soft signs after the clinical stabilization of the first episode. Previous first-episode studies have not been able to identify a relationship between the DUP and neurological soft signs in the first episode (Browne et al., 2000; Madsen et al., 1999). It is worth noting that in these studies, the assessment of neurological soft signs was carried out during acute first psychotic episodes. It is therefore possible that statelike factors influenced the expression of neurological soft signs in the acute psychotic period and served to mask the relationship with the DUP. In our sample, the relationship with the DUP was also not apparent during the initial assessment but was observable only after the clinical stabilization of the psychosis. The association between the levels of neurological soft signs and the DUP suggests that neurological soft signs could be regarded as possible markers for putative neurobiological processes that take place during the untreated psychotic state. Such an association does not, however, rule out the possibility that neurological soft signs designate a feature that leads to a long DUP, rather than vice versa. At initial presentation, the level of neurological soft signs is related to educational level and age at onset. The relationship between neurological soft signs and educational level has been noted in a number of studies (Cuesta et al., 1996; Mohr et al., 1996). Our findings confirm this relationship once again in a Chinese sample of first-episode patients. It is important to recognize that this relationship exists not only for schizophrenic patients, in whom one might speculate that an early manifestation of the disorder would lead to both educational underachievement and neurological soft signs, but also extends to other patient groups and normal healthy individuals (Mikkelsen et al., 1982; Quitkin et al., 1976). Therefore, there could be a more fundamental relationship between neurological soft signs and intelligence level beyond the specific effects of schizophrenia.

The relationship between neurological soft signs and age at onset is contentious. Previous studies are inconclusive, with some studies having reported correlations (Schroder et al., 1992a; Woods et al., 1986) and others failing to find such a relationship (Cuesta et al., 1996; Kolakowska et al., 1985). This study, which uses a cohort of first-episode patients, shows that patients with a higher age at onset have more neurological soft signs. We have previously identified a positive correlation between age and neurological soft signs in a cross-sectional study of mixed patients (Chen and Chan, 2003). The current finding that this relationship already exists in a firstepisode sample enables us to infer that the relationship is not confounded by illness duration and treatment. As in a number of previous studies, we found that neurological soft signs are not related to outcome measures, such as relapse or vocational performance. Our study uses a prospective longitudinal design and is therefore capable of addressing whether there is any predictive relationship between the early expression of neurological soft signs and the later outcome. We found that levels of neurological soft signs in the first psychotic episode do not predict the outcome in the following 3 years. In this study, the motor soft sign subscale from the Cambridge Neurological Inventory was used. The items that are represented in the subscale consist mainly of regular repetitive simple motor sequences. Similar items are included in the Neurological Evaluation Scale (NES), which has been adopted in some other studies (Arango et al., 1999; Buchanan and Heinrichs, 1989). We have chosen to focus on motor soft signs and their relative specificity in contrast to sensory neurological soft signs, which tend to covary with general cognitive function (Arango et al., 1999). This study provides longitudinal information on neurological soft signs after first-episode psychosis. What could not be addressed by this study is whether there is any increase in the expression of neurological soft signs around the prodrome period before they are observed in the first psychotic episode. Such change could be an early indication of an incipient psychosis and could be of value in early intervention efforts. This possibility, however, has to be addressed in longitudinal studies of high-risk individuals from a prepsychotic state to the development of psychosis.

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Acknowledgements This work was supported by grant 21500.10202404 from the Research Grant Council of Hong Kong. We are also grateful to the individuals who participated in the study.

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