Persistent negative symptoms in first-episode schizophrenia: A prospective three-year follow-up study

Schizophrenia Research 133 (2011) 22–28

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Persistent negative symptoms in first-episode schizophrenia: A prospective three-year follow-up study W.C. Chang ⁎, Christy L.M. Hui, Jennifer Y.M. Tang, Gloria H.Y. Wong, May M.L. Lam, Sherry K.W. Chan, Eric Y.H. Chen Department of Psychiatry, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong

a r t i c l e

i n f o

Article history: Received 12 April 2011 Received in revised form 22 August 2011 Accepted 9 September 2011 Available online 2 October 2011 Keywords: Persistent primary negative symptoms Stability First-episode schizophrenia Course Outcome

a b s t r a c t Background: Negative symptoms are a core feature of schizophrenia. The evolution and trajectory of primary negative symptoms were under-studied. We aimed at evaluating the prevalence and stability of primary negative symptoms, and factors associated with persistent primary negative symptoms in a first-episode sample. Method: Ninety-three Hong Kong Chinese aged 18 to 55 years presenting with first-episode schizophreniaspectrum disorder were studied. Data on premorbid adjustment, socio-demographics, and baseline clinical and cognitive profiles were obtained. Psychopathological and vocational reassessments were conducted at 12, 24 and 36 months. Primary negative symptoms were defined as the presence of clinically significant negative symptoms excluding depression and extra-pyramidal signs. Results: At baseline, 25.8% of subjects exhibited primary negative symptoms. A quarter of patients had their initial primary negative symptoms status retained 12 months after treatment initiation. In both Year 2 and Year 3 of study period, around 70% of subjects had their primary negative symptoms status maintained for 12 months. At the end of three-year follow-up, 23.7% were categorized as having persistent primary negative symptoms. Male sex, unemployment at intake, prolonged duration of untreated psychosis, poorer premorbid academic and social functioning, poorer insight and worse vocational outcome were found to be associated with persistent primary negative symptoms. Conclusion: Clinical status of primary negative symptoms in first-episode schizophrenia-spectrum disorder was unstable in the initial year of treatment. Baseline symptom assessment may not reliably predict development of persistent primary negative symptoms. Studying negative symptoms should take into account the longitudinal perspective, especially in the early course of psychotic disorders. © 2011 Elsevier B.V. All rights reserved.

1. Introduction Negative symptoms have long been considered as the core feature of schizophrenia (Kraepelin, 1919; Bleuler, 1950), and constitute a discrete psychopathological dimension separate from reality distortion, disorganization and cognitive impairment (Liddle, 1987; Lenzenweger and Dwokin, 1996; Harvey et al., 2006). Unlike positive symptoms, negative symptoms remain an unmet therapeutic need, and are associated with poor functional outcome (Bowie et al., 2006; Ventura et al., 2009) and limited response to pharmacotherapy (Murphy et al., 2006). It is hypothesized that deficit syndrome characterized by primary enduring negative symptoms independent of paranoid social withdrawal, depression, drug-induced extra-pyramidal signs and environmental deprivation may represent a putative subtype of schizophrenia (Carpenter et al., 1988). A substantial body of evidence demonstrated that deficit schizophrenia displayed distinctive clinical and neurobiological profiles,

⁎ Corresponding author. Tel.: +852 22554486; fax: +852 28551345. E-mail address: [email protected] (W.C. Chang). 0920-9964/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2011.09.006

and was correlated with poor prognosis relative to non-deficit schizophrenia (Kirkpatrick et al., 2001). Hence, it is suggested that examining this clinically more homogeneous subgroup may facilitate unraveling the pathophysiology of schizophrenia. Thus far, the majority of studies examining primary negative symptoms focused on chronic patients who were on long-term medications. Conversely, research on first-episode sample provides unique opportunity in at least three ways. First, the trajectory of primary negative symptoms can be thoroughly assessed right from the onset of psychosis. Second, confounding effects of illness chronicity and longstanding exposure to antipsychotic treatment can be minimized. Third, factors associated with development of persistent primary negative symptoms may be identified, thereby facilitating an early detection and intervention of these debilitating symptoms. In fact, longitudinal investigation of persistent negative symptoms was identified in NIMH-initiated consensus development conference as an important area for future research (Kirkpatrick et al., 2006). Despite its profound implications in research and clinical practice, only a few first-episode studies have been conducted in this respect. Among those studies that examined first-episode population, many

W.C. Chang et al. / Schizophrenia Research 133 (2011) 22–28

relied on retrospective data (Fenton and McGlashan, 1994; Makinen et al., 2010) or single cross-sectional assessment without taking into consideration the stability of primary negative symptoms (Kirkpatrick et al., 1996; Gerbaldo et al., 1997). For those studies which adopted prospective design, their lengths of follow-up ranged from 6 to 18 months only (Mayerhoff et al., 1994; Subotnik et al., 1998; Edwards et al., 1999; Malla et al., 2004). As clinical picture is fluid in the initial phase of psychotic illness, such a short follow-up interval is unlikely to capture adequately the evolution of primary negative symptoms. In this article, we presented a longitudinal three-year prospective follow-up study in a representative cohort of Chinese patients having first-episode schizophrenia-spectrum disorder in Hong Kong with an aim to: 1. examine the prevalence and stability of primary negative symptoms; 2. compare three-year outcomes between subjects with persistent primary negative symptoms and those without, and 3. identify any factors associated with development of persistent primary negative symptoms. 2. Method 2.1. Subjects Participants were recruited from both outpatient and inpatient psychiatric units that provide service for a catchment area in Hong Kong with a population of approximately 1.3 million. A total of 138 patients aged 18 to 55 years who were consecutively diagnosed as first-episode DSM-IV (American Psychiatric Association, 1994) schizophrenia, schizophreniform disorder or schizoaffective disorder were included. Patients with known neurological disorder or moderate to severe learning disability were excluded from the study. Each subject was assessed at baseline and was followed up for 3 years. Of the initial cohort, 93 subjects completed the three-year follow-up, 40 defaulted, four committed suicide and one died of medical disease. There were no significant differences between completers and non-completers on socio-demographics, DUP and baseline symptom ratings. Patients in this study were initially treated with low-dose first generation antipsychotic medications. Among 93 subjects, 48 were first assessed in medication-naïve state, and the rest were evaluated within 7 days of starting antipsychotic treatment. The current study was part of a prospective three-year follow-up study in first-episode schizophrenia-spectrum disorder and findings regarding neurological soft signs and cognitive predictors of relapse have been reported elsewhere (Chen et al., 2005a, 2005b). The study was approved by local institutional review board and all of the subjects gave written informed consent before participation. 2.2. Assessments 2.2.1. Diagnostic ascertainment Diagnostic assignment was based on longitudinal approach taking into consideration that diagnostic change may take place over time (Chang et al., 2009). The three-year diagnosis of each subject was determined according to DSM-IV criteria using all available information encompassing the whole follow-up period including the Chinesebilingual Structured Clinical Interview for DSM-IV (Axis I, Patient version) (CB-SCID-I/P; So et al., 2003) administered at baseline and at 3 years, informant histories and medical records. Previous validation study showed that CB-SCID-I/P yielded reliable DSM-IV diagnoses in Chinese patients with psychotic disorders (So et al., 2003). Independent diagnostic assessments on a subset of sample (n= 38) demonstrated satisfactory concordance rate of 86%. 2.2.2. Premorbid functioning Premorbid functioning was measured with the Premorbid Adjustment Scale (PAS; Cannon-Spoor et al., 1982) based on information obtained via interviews with patients and relatives. We divided the

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PAS score into academic and social domains as primary measures of premorbid adjustment (Larsen et al., 2004). We only included childhood (≤11 years) and early adolescence (12–15 years) periods for assessment to avoid any possible confounding with early symptoms because the onset of prodrome and psychosis usually occur in late adolescence and early adulthood (Crumlish et al., 2009). An overall score for each of two premorbid functioning domains was computed by averaging the ratings for the relevant subscales in both childhood and early adolescence (score range 0 to 1, higher score indicates lower functioning). 2.2.3. Baseline evaluation The Interview for the Retrospective Assessment of the Onset of Schizophrenia (IRAOS; Hafner et al., 1992) was administered to determine duration of untreated psychosis (DUP), age and mode of onset of psychosis. DUP was defined as the time interval between the onset of positive psychotic symptoms and treatment initiation. Positive symptoms were assessed using Positive and Negative Syndrome Scale (PANSS; Kay et al., 1987) with intra-class correlation coefficient (ICC) being 0.83 for positive symptoms subscale. High Royds Evaluation of Negativity Scale (HEN; Mortimer et al., 1989) was employed to measure negative symptoms. It comprises six subscales and 18 items which are rated along an anchored five-point severity scale (range 0–4, higher score indicates more severe negative symptoms). Validation of HEN for use in Chinese schizophrenia patients has previously been reported (Chen et al., 1996). ICCs for the subscales ranged from 0.74 (Thought) to 0.85 (Speech). In this study, we only included four of the six subscales, i.e., Affect, Behavior, Speech and Functioning subscales for analysis as the remaining two, namely Thought and Appearance subscales were more related to disorganization dimension. Montgomery–Asberg Depression Rating Scale (MADRS; Montgomery and Asberg, 1979) and Simpson-Angus Scale (SAS; Simpson and Angus, 1970) were used to assess depression and extra-pyramidal signs, respectively. Measures of cognitive functions comprised logical memory test (Wechsler Memory Scale Revised, WMS-R-HK; Hong Kong Psychological Society, 1989), visual reproduction test (WMS-R-HK), forward digit span (Wechsler Adult Intelligence Scale, WAIS-R-HK; Hong Kong Psychological Society, 1989), semantic category fluency and Modified Wisconsin Card Sorting Test (MWCST; Nelson, 1976). General verbal intelligence was estimated using information subscale from the WAIS-R-HK. 2.2.4. Follow-up assessment Clinical interview and psychopathological re-evaluation including PANSS, HEN, MADRS and SAS were conducted to each subject at 12, 24 and 36 months. Symptom ratings were ascertained on the basis of both interviews and medical records, and investigators were blind to previous ratings. Data on length of hospitalizations, vocational functioning, treatment adherence and chlorpromazine (CPZ) equivalence of antipsychotic medications of each subject were also obtained. 2.3. Data analysis 2.3.1. Criteria for primary negative symptoms Clinically significant negative symptoms were regarded as being present if total score on Affect, Behavior or Speech subscale in HEN was ≥6, or if total score on Functioning subscale was ≥8. Absence of depression and extra-pyramidal signs were defined as MADRS total score b16 (Tollefson et al., 1998) and SAS mean score b0.3 (Simpson and Angus, 1970), respectively. Patients who met criteria for clinically significant negative symptoms together with an exclusion of depression and extra-pyramidal signs were considered as having primary negative symptoms. 2.3.2. Statistical analysis The prevalence of primary negative symptoms at baseline, 12, 24 and 36 months were determined. Stability or prospective consistency

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W.C. Chang et al. / Schizophrenia Research 133 (2011) 22–28

of primary negative symptoms status across follow-up interval was also calculated. In this study, prospective consistency was defined as the proportion of subjects exhibiting primary negative symptoms at baseline who persisted to have these symptoms at subsequent followup assessment. Patients were categorized into two groups according to their primary negative symptoms status in the third year (12-month interval) of follow-up: (1) subjects with persistent primary negative symptoms across Year 3 (Persistent PN group) and (2) subjects without persistent primary negative symptoms across Year 3. Group differences with regard to premorbid adjustment, baseline variables, treatment characteristics, and three-year clinical and vocational outcomes were analyzed using chi-square test and independent t-test as appropriate. DUP was log-transformed due to its skewed distribution and standardized z-scores for cognitive functions were computed for analyses. Those premorbid and baseline variables that were significantly associated with Persistent PN group were then entered into stepwise logistic regression analysis to determine which factors independently predicted development of persistent primary negative symptoms at the end of three-year follow-up. The level of statistical significance for all analyses were set at p b 0.05. 3. Results 3.1. Characteristics of the sample The 93 subjects were predominantly single (74.2%) and 45.2% were male. The mean age of the sample at intake was 31.2 years (S.D.= 9.6; range: 18 to 55 years) and the average educational level was 10.54 years (S.D.= 2.9). The median DUP of the sample was 180 days and the mean was 473.7 days (S.D.= 786.4; range: 2 to 3650 days). Diagnoses for the cohort were schizophrenia (n = 75), schizophreniform disorder (n =13) and schizoaffective disorder (n = 5). 3.2. Prevalence and stability of primary negative symptoms The prevalence of primary negative symptoms at different time points along the three-year follow-up period ranged from 24.7% to 33.3%. Table 1 summarizes the findings on prospective consistency (stability) of primary negative symptoms status across the study period. Twenty-five percent (n = 6) of patients had their initial primary negative symptoms persisted at 12 months. Sixteen subjects (69.9%) who were categorized as having primary negative symptoms at 12 months maintained this clinical status upon reassessment at 24 months. Similarly, 71% of subjects presenting with primary negative symptoms at 24 months continued to exhibit these symptoms at Table 1 Prospective consistency of primary negative symptoms in first-episode schizophreniaspectrum disorder across the follow-up period. Follow-up interval

Baseline to Year 1 (12-months) Baseline to Year 2 (24-months) Baseline to Year 3 (36-months) Year 1 to Year 2 (12-months) Year 1 to Year 3 (24-months) Year 2 to Year 3 (12-months)

No. of subjects with persistent primary negative symptoms, n (%)

Prospective consistency of primary negative symptoms, (%)

6 (6.5)

25.0

4 (4.3)

16.7

4 (4.3)

16.7

16 (17.2)

69.6

12 (12.9)

52.2

22 (23.7)

71.0

36 months. The three-year prospective consistency of primary negative symptoms was 16.7%.

3.3. Premorbid functioning and baseline characteristics As shown in Table 2, there were no significant differences between subjects with and without persistent primary negative symptoms over the last 12 months of follow-up (Year 3) with respect to baseline psychopathological ratings and cognitive functions. Patients with persistent primary negative symptoms across Year 3 (Persistent PN group) were significantly more likely to be male, unemployed at intake, to have longer DUP and poorer premorbid functioning in both academic and social domains. Table 2 Premorbid adjustment and baseline characteristics of subjects with and without persistent primary negative symptoms at the end of three-year follow-up. Variables of interest

Subjects with persistent primary negative symptoms in Year 3 (n = 22)

Baseline socio-demographics Age at entry, 30.8 mean (SD) Male sex, n (%) 15 Single, n (%) 19 Years of education, 10.0 mean (SD) Unemployed, n (%) 14 Premorbid adjustment PAS academic domain, mean (SD) PAS social domain, mean (SD)

Subjects without persistent primary negative symptoms in Year 3 (n = 71)

Statistics p (χ²/t, df) value

(2.5)

31.4 (1.1)

0.3, 91

0.79

(68.2) (86.4) (2.8)

27 (38.0) 50 (70.4) 10.7 (2.9)

6.2 2.2 1.0, 91

0.013 0.14 0.32

(66.7)

28 (39.4)

4.9

0.027

0.4 (0.1)

0.3 (0.1)

− 2.8, 85 0.006

0.5 (0.1)

0.3 (0.2)

− 3.2, 86 0.002

35 (49.3)

1.8

Baseline clinical characteristics Onset with 4 weeks, 7 n (%) Log DUP, mean (SD) 5.8 18.5 PANSS positive symptom score, mean (SD) 4.8 PANSS insight score (item G12), mean (SD) HEN total score, 13.2 mean (SD) MADRS total score, 8.0 mean (SD) SAS total score, 1.5 mean (SD) Baseline cognitive variables Logical memory, − 0.9 mean (SD) Visual reproduction, − 0.8 mean (SD) Forward digit span, − 0.4 mean (SD) Semantic fluency, − 0.5 mean (SD) MWCST perseverative − 1.9 error, mean (SD) − 0.1 WAIS-R-HK Information subscale, mean (SD)

(31.8)

0.18

− 2.2, 82 0.032 1.3, 91 0.21

(1.2) (4.6)

4.7 (1.8) 20.1 (5.7)

(1.4)

4.9 (1.3)

0.3, 91

0.79

(11.6)

13.7 (11.4)

0.2, 91

0.87

(10.7)

10.2 (12.2)

0.8, 91

0.45

(3.2)

0.3 (1.0)

(0.9)

− 0.9 (1.0)

0.1, 91

0.92

(1.4)

− 0.5 (1.4)

0.7, 91

0.50

(1.2)

0.1 (0.8)

2.3, 91

0.27

(1.1)

− 0.7 (0.9)

0.5, 91

0.63

(2.3)

− 1.1 (1.8)

1.5, 88

0.14

(1.1)

0.4 (1.0)

0.8, 91

0.45

− 1.8, 91 0.94

Abbreviation: PAS = Premorbid Adjustment Scale, DUP = Duration of untreated psychosis, PANSS = Positive and Negative Syndrome Scale, HEN = High Royds Evaluation of Negativity Scale, MADRS = Montgomery–Asberg Depression Rating Scale, SAS = Simpson and Angus Scale, MWCST = Modified Wisconsin Card Sorting Test, WAIS-R-HK = Wechsler Adult Intelligence Scale Revised Cantonese version, Hong Kong.

W.C. Chang et al. / Schizophrenia Research 133 (2011) 22–28

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Table 3 Treatment and outcome characteristics of subjects with and without persistent primary negative symptoms at the end of three-year follow-up. Variables of interest Treatment characteristics Baseline CPZ equivalence, mean (SD) On anticholinergic medicationa at baseline, n (%) Year 3 CPZ equivalence, mean (SD) On second generation antipsychoticb at Year 3, n (%) On anticholingeric medication at Year 3, n (%) Good treatment adherencec, n (%) Clinical outcome at Year 3 PANSS positive symptoms score, mean (SD) PANSS delusion (item P1), mean (SD) PANSS hallucination (item P3), mean (SD) PANSS conceptual disorganization (item P2), mean (SD) PANSS insight (item G12), mean (SD) HEN total score, mean (SD) MADRS total score, mean (SD) SAS total score, mean (SD) Length of hospitalizations in 3 years, month, mean (SD) Vocational outcome Full-time employment in 3 years, month, mean (SD) Full-time employment in year 3, months, mean (SD) Sustained full-time employment for at least 8 months in 3 years, n (%)

Subjects with persistent primary negative symptoms in Year 3 (n = 22)

Subjects without persistent primary negative symptoms in Year 3 (n = 71)

Statistics (χ²/t, df)

163.4 (251.1) 7 (31.8)

170.0 (474.3) 13 (18.3)

0.09, 91 1.8

0.95 0.18

249.4 (427.7) 7 (31.8)

228.0 (250.4) 11 (15.5)

− 0.3, 91 2.9

0.77 0.09

12 (54.5)

34 (47.9)

3.0

0.59

13 (59.1)

52 (73.2)

2.0

0.15

9.6 (3.6)

9.1 (3.7)

− 0.6, 91

0.53

1.6 (1.0)

1.6 (1.2)

0.06, 91

0.95

1.7 (1.2)

1.5 (1.0)

− 0.9, 91

0.36

1.5 (1.1)

1.3 (0.7)

− 0.6, 91

0.56

4.1 (1.4)

2.8 (1.5)

− 3.5, 91

0.001

6.8 1.3 0.9 0.9

− 7.1, 91 0.08, 91 0.84, 91 − 2.8, 91

b0.001 0.94 0.41 0.07

23.8 (8.1) 1.3 (2.4) 0.5 (0.9) 2.5 (3.7)

(10.3) (2.8) (2.4) (1.7)

p value

4.3 (8.6)

16.5 (14.9)

3.6, 91

b0.001

1.2 (2.8)

5.9 (5.6)

3.8, 91

b0.001

42 (59.2)

8.9

5 (22.7)

0.003

Abbreviations: CPZ = Chlorpromazine, PANSS = Positive and Negative Syndrome Scale, HEN = High Royds Evaluation of Negativity Scale, MADRS = Montgomery–Asberg Depression Rating Scale, SAS = Simpson and Angus Scale. a Anticholinergic medication referred to benzhexol. b 18 out of 93 subjects took second generation antipsychotic (SGA) medications at Year 3, with 2 on clozapine, 5 on olanzapine and 11 on risperidone. The remaining were treated with first generation antipsychotic (FGA) medications. c Subjects were considered as having good treatment adherence if they took more than 70% of prescribed medication (assessed on the basis of reports from both subjects and their relatives; Chen et al., 2005b).

3.4. Treatment and outcome characteristics

4. Discussion

Differences between subjects who had persistent primary negative symptoms across Year 3 and those who did not in terms of treatment and outcome characteristics are presented in Table 3. Patients in Persistent PN group had poorer insight, more prominent negative symptoms as expected and worse vocational outcome. They spent significantly less time in full-time employment and were less likely to achieve sustained full-time work for at least eight consecutive months over three years than those without persistent primary negative symptoms.

Our study showed that around one-fourth (25.8%) of subjects presenting with first-episode schizophrenia-spectrum disorder had primary negative symptoms at initial assessment. Stability of primary negative symptoms was low in the first year of treatment and was greatly increased in subsequent follow-up. At the end of the threeyear follow-up, 23.7% were found to display persistent primary negative symptoms.

3.5. Predictors of persistent primary negative symptoms We employed stepwise logistic regression analysis to identify variables obtained at initial assessment that predicted development of persistent primary negative symptoms at the end of the three-year follow-up. Those premorbid and baseline variables that were found to be significantly associated with Persistent PN group in bivariate analyses, namely sex, DUP, occupational status at entry, premorbid academic and social functional domains were included in the regression model. Premorbid academic functioning and DUP were found to remain in the final equation, though only the former significantly predicted persistent primary negative symptoms (Table 4).

Table 4 Logistic regression analysis for predictors of persistent primary negative symptoms in Year 3. Variables in the equation

B

S.E.

Wald

df

Sig.

Exp (B)

95% C.I for Exp (B)

PAS academic domain Log DUP Constant

7.01

3.30

4.51

1

0.034

1108.18

1.72–715059.49

0.37 − 6.05

0.21 1.77

3.02 11.71

1 1

0.078 0.001

1.45

0.96–2.17

Final model: Nagelkerke R2 = 0.202, χ² = 9.719, p b 0.01 Abbreviations: PAS = Premorbid Adjustment Scale; DUP = Duration of untreated psychosis; PAS social domain, sex, occupational status at baseline, which entered the stepwise logistic regression model, were excluded as predictors of persistent primary negative symptoms in Year 3 after analysis.

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W.C. Chang et al. / Schizophrenia Research 133 (2011) 22–28

Previous review suggested that the prevalence of deficit syndrome in first-episode population was around 15% (Kirkpatrick et al., 2001). However, discrepant findings were observed which may partly be due to methodological variations. First of all, varying definitions and measurements of primary negative symptoms have been applied across studies. Broadly speaking, three different methods were used to define primary negative symptoms or deficit syndrome including the proxy measure (Proxy for the Deficit Syndrome, PDS; Kirkpatrick et al., 1993) (Kirkpatrick et al., 1996; Subotnik et al., 1998; Makinen et al., 2010), negative symptom scale (Husted et al., 1992; Mayerhoff et al., 1994; Edwards et al., 1999; Malla et al., 2004), and Schedule for Deficit Syndrome (SDS; Kirkpatrick et al., 1989) (Gerbaldo et al., 1997) or its modified criteria (Fenton and McGlashan, 1994). Case identification by PDS was based on an equation using items from symptom scales (Kirkpatrick et al., 1993). However, PDS neither differentiates primary from secondary negative symptoms nor incorporates longitudinal evaluation. Although SDS has been shown to reliably classify patients with deficit syndrome (Kirkpatrick et al., 1989), it was mostly applied in chronic samples and the enduring nature of negative symptoms was based on retrospective assessment. For those studies that employed negative symptom scale, some investigators did not consider confounding effects from depression and extra-pyramidal signs (Husted et al., 1992). Secondly, majority of these studies recruited first-admission (Fenton and McGlashan, 1994; Mayerhoff et al., 1994; Kirkpatrick et al., 1996; Gerbaldo et al., 1997; Subotnik et al., 1998; Makinen et al., 2010) rather than first-contact-to-treatment sample (Husted et al., 1992; Edwards et al., 1999; Malla et al., 2004), thereby introducing bias by excluding patients who had milder illness without requiring hospitalization at initial presentation. Furthermore, lengths of followup of those few prospective studies were less than 2 years which would be too short to capture adequately the evolution of primary negative symptoms in the early phase of illness (Mayerhoff et al., 1994; Subotnik et al., 1998; Edwards et al., 1999; Malla et al., 2004). In fact, our results on prevalence of persistent primary negative symptoms over the first year of follow-up (6.5%) were consistent with two previous prospective studies using negative symptom scale together with exclusion of depression and extra-pyramidal signs in case identification which revealed that 3.8% (Edwards et al., 1999) and 4% (Mayerhoff et al., 1994) of first-episode sample had 1year and 6-month persistent primary negative symptoms, respectively. Based on our findings on prevalence and the change of stability of primary negative symptoms status in first-episode schizophreniaspectrum disorder, two plausible interpretations could be suggested. First, the clinical status of primary negative symptoms in the first year of treatment was unstable, thus baseline cross-sectional measure of negative symptoms may not reliably predict the development of persistent primary negative symptoms. Second, primary negative symptoms gradually stabilized and were more likely to become persistent 12 months after treatment initiation. In this regard, the first year of treatment may potentially be a therapeutic window within which early and intensive intervention incorporating both optimal pharmacological and psychosocial treatments might reduce the risk of evolving into deficit syndrome. In fact, one previous study found that delay in intensive psychosocial treatment was associated with worse outcome on negative symptoms in first-episode schizophrenia (de Haan et al., 2003). Some other researchers also demonstrated that integrated treatment including social skill training, family intervention and intensive case management significantly reduced negative symptoms level 2 years after first psychotic episodes (Thorup et al., 2005). Due to the scarcity of existing data, further research is needed to confirm our preliminary findings, to identify treatment components specific to primary negative symptoms, and most importantly, to examine the prognostic significance of early and intensive intervention in this potential “critical period” in preventing emergence of deficit symptoms.

Consistent with prior reports, we found that male sex (Roy et al., 2001), prolonged DUP (Edwards et al., 1999; Malla et al., 2004) and poorer premorbid adjustment (Mayerhoff et al., 1994; Edwards et al., 1999; Malla et al., 2004) were associated with persistent primary negative symptoms. In logistic regression analysis, premorbid academic functioning was found to predict persistent primary negative symptoms at the end of the follow-up. Our results thus agreed with another study which revealed that good school performance at teenage predicted less persistent negative symptoms (Makinen et al., 2010), and previous reports which demonstrated that poor scholastic achievement was significantly related to the severity of negative symptoms (Johnstone et al., 1995; Brill et al., 2009). Concerning baseline clinical features, there were no significant differences in positive, negative and depressive symptom levels between subjects with persistent primary negative symptoms and those without. Similar to one previous study (Malla et al., 2004), we also failed to find any differences in baseline cognitive functions between the two groups. Literature indicated that cross-sectional relationship between negative symptoms and cognitive deficits was at best moderate and results on longitudinal correlation between these two domains were inconsistent (Harvey et al., 2006). A recent meta-analysis showed that although deficit patients performed more poorly on cognitive tests, most were non-significant and effect size for those turned to be significant was small, and was mainly related to social cognition (Cohen et al., 2007). Additionally, fluidity of clinical symptoms in the early stage of illness may contribute to lack of relationship between persistent primary negative symptoms and baseline cognitive dysfunctions in our first-episode sample. We replicated findings of earlier reports that patients with persistent primary negative symptoms had poorer insight (Trotman et al., 2011) and worse vocational functioning (Fenton and McGlashan, 1994; Tek et al., 2001). However, no significant differences between the two groups in terms of three-year outcomes on positive symptoms, depression and extra-pyramidal signs were observed. Hence, we confirmed previous results that patients with persistent primary negative symptoms had poorer functional outcome. Further, our findings lent support to the validity of operational criteria we used for defining Persistent PN group which had clinical profiles comparable to that of deficit syndrome reported in the literature (Cohen et al., 2010). The study results have to be interpreted considering the following methodological limitations. First, similar to other existing negative symptom scales, ratings on avolition and asociality domains in HEN overlapped with functional outcome measure as scores of these symptom items primarily derived from reports of performance deficits (Blanchard et al., 2011). Second, SDS, a gold standard instrument for ascertaining deficit syndrome, was not used in this study. Nonetheless, it should be noted that categorization of deficit case by SDS relied on cross-sectional assessment and retrospective data. Future research on longitudinal course of primary negative symptoms should incorporate both SDS and prospective assessments with negative symptom scale that has addressed the limitations of current instruments (Blanchard et al., 2011; Kirkpatrick et al., 2011). Third, it needs to be acknowledged that it is difficult to reliably distinguish between primary and secondary negative symptoms (Flaum and Andreasen, 1995), particularly in first-episode population (Edwards et al., 1999). The operational definition applied in this study may also exclude those patients who had concurrent idiopathic negative symptoms and prominent extra-pyramidal signs or depression from being correctly classified as having primary negative symptoms. Fourth, our final sample comprised slightly more females (54.8%) than males, which was in contrary to many (Marshall et al., 2005), but not all first-episode studies (Ucok et al., 2004; Oosthuizen et al., 2005) showing male preponderance, and thus may limit generalizability of our results. One possible reason was that we recruited patients aged from 18 to 55 years with a relatively older mean age of

W.C. Chang et al. / Schizophrenia Research 133 (2011) 22–28

entry (31.2 years), therefore it may be more likely for female schizophrenia patients to be included in our study as literature showed that females had an older age of illness onset than males and a second (though smaller) peak age of onset at 40s (Hafner et al., 1993; Castle et al., 1998). Fifth, although subjects were studied for 3 years, a greater length of follow-up is required to clarify whether the frequency and stability of primary negative symptoms increase further with illness progression. In conclusion, our results indicated that primary negative symptoms of first-episode schizophrenia-spectrum disorder fluctuated considerably in the initial year of treatment and the severity of negative symptoms at baseline is not an accurate predictor of development of persistent primary negative symptoms. Stability of primary negative symptoms significantly increased 1 year after treatment initiation and persistent primary negative symptoms were associated with male sex, poorer premorbid adjustment, prolonged DUP, lower level of insight and worse vocational functioning. Owing to limited data on the evolution of primary negative symptoms in the early stage of illness, more prospective research in first-episode sample or subjects with at-risk mental state should be conducted to further clarify the longitudinal course of primary negative symptoms which will in turn facilitate early detection and intervention of these debilitating symptoms. Role of funding source This work was supported by grant 21500.10202404 from the Research Grants Council of Hong Kong.

Contributors Author E.Y.H.C designed the study. Author W.C.C managed literature search and statistical analysis, and wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interest Author E.Y.H.C. has participated in the paid advisory board for Otsuka, has received educational grant support from Janssen-Cilag, and has received research funding from AstraZeneca, Janssen-Cilag, Eli Lilly, Sanofi-Aventis and Otsuka; Author M.M.L.L has done consultancy for Otsuka and Eli Lilly. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Acknowledgments We thank all the coordinating clinicians and staff from the psychiatric inpatient and outpatient units, as well as the medical records department at the Queen Mary Hospital for their kind assistance. We are also grateful to the individuals who participated in the study.

References American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th edition. American Psychiatric Association, Washington DC. Blanchard, J.J., Kring, A.M., Horan, W.P., Gur, R., 2011. Toward the next generation of negative symptom assessments: the collaboration to advance negative symptom assessment in schizophrenia. Schizophr. Bull. 37, 291–299. Bleuler, E., 1950. Dementia Praecox or the Group of Schizophrenias. International Universities Press, New York. Bowie, C.R., Reichenberg, A., Patterson, T.L., Heaton, R.K., Harvey, P.D., 2006. Determinants of real-world functional performance in schizophrenia subjects: correlations with cognition, functional capacity, and negative symptoms. Am. J. Psychiatry 163, 418–425. Brill, N., Levine, S.Z., Reichenberg, A., Lubin, G., Weiser, M., Rabinowitz, J., 2009. Pathways to functional outcomes in schizophrenia: the role of premorbid functioning, negative symptoms and intelligence. Schizophr. Res. 110, 40–46. Cannon-Spoor, H.E., Potkin, S.G., Wyatt, R.J., 1982. Measurement of premorbid adjustment in chronic schizophrenia. Schizophr. Bull. 8, 470–484. Carpenter Jr., W.T., Heinrichs, D.W., Wagman, A.M.I., 1988. Deficit and nondeficit forms of schizophrenia: the concept. Am. J. Psychiatry 145, 578–583. Castle, D., Sham, P., Murray, R., 1998. Differences in distribution of ages of onset in males and females with schizophrenia. Schizophr. Res. 33, 179–183. Chang, W.C., Pang, S.L.K., Chung, D.W.S., Chan, S.S.M., 2009. Five-year stability of ICD-10 diagnoses among Chinese patients presented with first-episode psychosis in Hong Kong. Schizophr. Res. 115, 351–357. Chen, E.Y.H., Lam, L.C.W., Chen, R.Y.L., Nguyen, D.G.H., 1996. Negative symptoms, neurological signs and neuropsychological impairments in 204 Hong Kong Chinese patients with schizophrenia. Br. J. Psychiatry 168, 227–233.

27

Chen, E.Y.H., Hui, C.L.M., Chan, R.C.K., et al., 2005a. A 3-year prospective study of neurological soft signs in first-episode schizophrenia. Schizophr. Res. 75, 45–54. Chen, E.Y.H., Hui, C.L.M., Dunn, E.L.W., et al., 2005b. A prospective 3-year longitudinal study of cognitive predictors of relapse in first-episode schizophrenic patients. Schizophr. Res. 77, 99–104. Cohen, A.S., Saperstein, A.M., Gold, J.M., Kirkpatrick, B., Carpenter Jr., W.T., Buchanan, R.W., 2007. Neuropsychology of the deficit syndrome: new data and meta-analysis of findings to date. Schizophr. Bull. 33, 1201–1212. Cohen, A.S., Brown, L.A., Minor, K.S., 2010. The psychiatric symptomatology of deficit schizophrenia: a meta-analysis. Schizophr. Res. 118, 122–127. Crumlish, N., Whitty, P., Clark, M., et al., 2009. Beyond the critical period: longitudinal study of 8-year outcome in first-episode non-affective psychosis. Br. J. Psychiatry 194, 18–24. de Haan, L., Linszen, D.H., Lenior, M.E., de Win, E.D., Gorsira, R., 2003. Duration of untreated psychosis and outcome of schizophrenia: delay in intensive psychological treatment versus delay in treatment with antipsychotic medication. Schizophr. Bull. 29, 341–348. Edwards, J., McGorry, P.D., Waddell, F.M., Harrigan, S.M., 1999. Enduring negative symptoms in first-episode psychosis: comparison of six methods using follow-up data. Schizophr. Res. 40, 147–158. Fenton, W.S., McGlashan, T.H., 1994. Antecedents, symptom progression, and long-term outcome of the deficit syndrome of schizophrenia. Am. J. Psychiatry 151, 351–356. Flaum, M., Andreasen, N., 1995. The reliability of distinguishing primary versus secondary negative symptoms. Compr. Psychiatry 36, 421–427. Gerbaldo, H., Georgi, K., Pieschl, D., 1997. The deficit syndrome in first-admission patients with psychotic and non-psychotic disorders. Eur. Psychiatry 12, 53–57. Hafner, H., Riecher-Rossler, A., Hambrecht, M., et al., 1992. IRAOS: an instrument for the assessment of onset and early course of schizophrenia. Schizophr. Res. 6, 209–223. Hafner, H., Riecher-Rossler, A., Van der Heiden, W., Maurer, K., Fatkenheuer, B., Loffler, W., 1993. Generating and testing a causal explanation of the gender difference in age at first onset of schizophrenia. Psychol. Med. 23, 925–940. Harvey, P.D., Koren, D., Reichenberg, A., Bowie, C.R., 2006. Negative symptoms and cognitive deficits: what is the nature of their relationship? Schizophr. Bull. 32, 250–258. Hong Kong Psychological Society, 1989. The Wechsler Adult Intelligence Scale-Revised. (Cantonese version) Hong Kong Psychological Society, Hong Kong. Husted, J.A., Beiser, M., Iacano, W.G., 1992. Negative symptoms and the early course of schizophrenia. Psychiatry Res. 43, 215–222. Johnstone, E.C., Frith, C.D., Lang, F.H., Owens, D.G.C., 1995. Determinants of the extremes of outcome in schizophrenia. Br. J. Psychiatry 167, 604–609. Kay, S.R., Opler, L.A., Fiszbein, A., 1987. Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr. Bull. 13, 261–276. Kirkpatrick, B., Buchanan, R.W., McKenney, P.D., Alphs, L.D., Carpenter Jr., W.T., 1989. The schedule for the deficit syndrome: an instrument for research in schizophrenia. Psychiatry Res. 30, 119–123. Kirkpatrick, B., Buchanan, R.W., Breier, A., Carpenter Jr., W.T., 1993. Case identification and stability of the deficit syndrome of schizophrenia. Psychiatry Res. 47, 47–56. Kirkpatrick, B., Ram, R., Bromet, E., 1996. The deficit syndrome in the Suffork County Mental Health Project. Schizophr. Res. 22, 119–126. Kirkpatrick, B., Buchanan, R.W., Ross, D.E., Carpenter Jr., W.T., 2001. A separate disease within the syndrome of schizophrenia. Arch. Gen. Psychiatry 58, 165–171. Kirkpatrick, B., Fenton, W.S., Carpenter Jr., W.T., Marder, S.R., 2006. The NIMH-MATRICS consensus statement on negative symptoms. Schizophr. Bull. 32, 214–219. Kirkpatrick, B., Strauss, G.P., Nguyen, L., et al., 2011. The Brief Negative Symptom Scale: psychometric properties. Schizophr. Bull. 37, 300–305. Kraepelin, E., 1919. Dementia Praecox and Paraphrenia. Livingstone, Edinburgh. Larsen, T.K., Friis, S., Haahr, U., et al., 2004. Premorbid adjustment in first-episode nonaffective psychosis: distinct patterns of pre-onset course. Br. J. Psychiatry 185, 108–115. Lenzenweger, M.F., Dwokin, R.H., 1996. The dimensions of schizophrenia phenomenology. Br. J. Psychiatry 168, 432–440. Liddle, P.F., 1987. The symptoms of chronic schizophrenia: a re-examination of the positive– negative dichotomy. Br. J. Psychiatry 151, 145–151. Makinen, J., Miettunen, J., Jaaskelainen, E., Veijola, J., Isohanni, M., Koponen, H., 2010. Negative symptoms and their predictors in schizophrenia within the Northern Finland 1966 Birth Cohort. Psychiatry Res. 178, 121–125. Malla, A.K., Norman, R.M.G., Takhar, J., et al., 2004. Can patients at risk for persistent negative symptoms be identified during their first episode of psychosis? J. Nerv. Ment. Dis. 192, 455–463. Marshall, M., Lewis, S., Lockwood, A., Drake, R., Jones, P., Croudace, T., 2005. Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: a systematic review. Arch. Gen. Psychiatry 62, 975–983. Mayerhoff, D.I., Loebel, A.D., Alvir, J.M.J., et al., 1994. The deficit state in first-episode schizophrenia. Am. J. Psychiatry 151, 1417–1422. Montgomery, S.A., Asberg, M.A., 1979. A new depression scale designed to be sensitive to change. Br. J. Psychiatry 134, 382–389. Mortimer, A.M., McKenna, P.J., Lund, C.E., Mannuzza, S., 1989. Rating of negative symptoms using the High Royds Evaluation of Negativity (HEN) Scale. Br. J. Psychiatry 155 (Suppl. 7), 89–91. Murphy, B.P., Chung, Y.C., Park, T.W., McGorry, P.D., 2006. Pharmacological treatment of primary negative symptoms in schizophrenia: a systematic review. Schizophr. Res. 88, 5–25. Nelson, H.E., 1976. A modified card sorting test sensitive to frontal lobe defects. Cortex 12, 313–324. Oosthuizen, P., Emsley, R.A., Keyter, N., Niehaus, D.J.H., Koen, L., 2005. Duration of untreated psychosis and outcome in first-episode psychosis: perspective from a developing country. Acta Psychiatr. Scand. 111, 214–219.

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Roy, M., Maziade, M., Labbe, A., Merette, C., 2001. Male gender is associated with deficit schizophrenia: a meta-analysis. Schizophr. Res. 47, 141–147. Simpson, G.M., Angus, J.W., 1970. A rating scale for extrapyramidal side effects. Acta Psychiatr. Scand. 212, 11–19 (suppl.). So, E., Kam, I., Leung, C.M., Chung, D., Liu, Z., Fong, S., 2003. The Chinese-bilingual SCID-I/P Project: stage 1: reliability for mood disorders and schizophrenia. Hong Kong J. Psychiatry 13, 7–18. Subotnik, K.L., Nuechterlein, K.H., Ventura, J., Green, M.F., Hwang, S.S., 1998. Prediction of the deficit syndrome from initial deficit symptoms in the early course of schizophrenia. Psychiatry Res. 80, 53–59. Tek, C., Kirkpatrick, B., Buchanan, R.W., 2001. A five-year followup study of deficit and nondeficit schizophrenia. Schizophr. Res. 49, 253–260. Thorup, A., Petersen, L., Jeppesen, P., et al., 2005. Integrated treatment ameliorates negative symptoms in first-episode psychosis: results from the Danish OPUS trial. Schizophr. Res. 79, 95–105.

Tollefson, G.D., Sanger, T.M., Lu, Y., Thieme, M.E., 1998. Depressive signs and symptoms in schizophrenia: a prospective blinded trial of olanzapine and haloperidol. Arch. Gen. Psychiatry 55, 250–258. Trotman, H.D., Kirkpatrick, B., Compton, M.T., 2011. Impaired insight in patients with newly diagnosed nonaffective psychotic disorders with and without deficit features. Schizophr. Res. 127, 100–106. Ucok, A., Polat, A., Genc, A., Cakir, S., T, N., 2004. Duration of untreated psychosis may predict acute treatment response in first-episode schizophrenia. J. Psychiatr. Res. 38, 163–168. Ventura, J., Hellemann, G.S., Thames, A.D., Koellner, V., Nuechterlein, K.H., 2009. Symptoms as mediators of the relationship between neurocognition and functional outcome in schizophrenia: a meta-analysis. Schizophr. Res. 113, 189–199.