Correlates of insight in first episode psychosis

Schizophrenia Research 70 (2004) 187 – 194 www.elsevier.com/locate/schres

Correlates of insight in first episode psychosis Matcheri S. Keshavan a,*, Jonathan Rabinowitz b, Goedele DeSmedt c, Phillip D. Harvey d, Nina Schooler e a

Department of Psychiatry, Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA b School of Social Work, Bar-Ilan University, Ramat Gan, Israel c International Clinical Research and Development, Janssen Research Foundation, Beerse, Belgium d Department of Psychiatry, Mt. Sinai School of Medicine, New York, NY, USA e Psychiatry Research, Long Island Jewish Medical Center, New Hyde Park, NY, USA Received 15 August 2003; received in revised form 7 November 2003; accepted 12 November 2003 Available online 25 January 2004

Abstract Impaired insight is common in schizophrenia and may be related to poor treatment adherence. Few studies have examined the clinical and neurocognitive correlates of insight in early schizophrenia. Early course schizophrenia, schizoaffective, and schizophreniform disorder patients (n = 535) were studied. The Positive and Negative Symptom Scale (PANSS) was used to assess psychopathology, and a broad range of neuropsychological functions was assessed. Using hierarchical stepwise multiple regression analyses, we examined the association of clinical, neurocognitive, and premorbid measures with the level of insight. Impaired insight was associated with overall symptomatology, including positive, negative, and general psychopathology and with deficits in cognitive functioning. In descending order of robustness, the significant variables were PANSS general psychopathology ( p < 0.0001), Rey Auditory Verbal Learning Test ( p < 0.0004), Clinical Global Impression ( p < 0.005), PANSS positive ( p < 0.007), and premorbid adjustment—general subscale ( p = 0.02). Among the PANSS general psychopathology items, unusual thought content was most robustly associated with impaired insight ( p < 0.00000). Insight impairment is very common in early schizophrenia, and appears to be associated with a broad range of psychopathology and deficits in multiple cognitive domains. These observations suggest that deficits in insight may be related to a generalized dysfunction of neural networks involved in memory, learning, and executive functions. D 2003 Elsevier B.V. All rights reserved. Keywords: Insight; First episode; Psychosis

1. Introduction Over the past several years, there has been a great deal of interest in the topic of insight among clinical * Corresponding author. UPMC Health System-Western Psychiatric Institute and Clinic, Room 984, 3811 O’Hara Street, Pittsburgh, PA 15213, USA. Tel.: +1-412-624-2794; fax: +1-412-624-1459. E-mail address: [email protected] (M.S. Keshavan). 0920-9964/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2003.11.007

researchers in psychotic disorders (Amador and David, 1998). Insight into psychotic illness is multidimensional, and involves several aspects of clinical psychopathology and cognition. Several studies have examined clinical correlates of insight among chronic schizophrenic patients, but the findings have been generally inconsistent particularly in reference to correlations with symptom severity (Buckley et al., 2001). Poor insight has been associated with female gender (Peralta

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and Cuesta, 1998), poorer functioning (Dickerson et al., 1997), premorbid impairment (Debowska et al., 1998), prolonged illness duration (Drake et al., 2000), and low levels (Carroll et al., 1999; Moore et al., 1999) or high levels (Collins et al., 1997) of depression. Impaired insight has been found to be correlated with positive symptoms (Amador et al., 1994; Baier et al., 2000; Kim et al., 1997), negative and disorganized but not positive symptoms (Cuesta et al., 1998), negative as well as positive symptoms (Debowska et al., 1998; Kemp and Lambert, 1995), or with neither positive nor negative symptoms (Schwartz and Petersen, 1999). This variability in research findings may be at least partially explained on the basis of small sample sizes, different phases of the illness being studied, heterogeneous samples, inappropriate statistical methods, and nonrandom sampling (Schwartz, 2000). Although for years poor insight in schizophrenia has been explained on the basis of various psychological phenomena, such as denial and willful preference for psychosis, recent studies suggest that insight deficits may reflect neurocognitive impairments perhaps due to prefrontal and parietal lobe dysfunctions. It has been proposed that schizophrenia-related impairment in insight might be similar to anosognosia seen in neurological illnesses (Amador and David, 1998). Some studies show a relationship between impaired insight and neurocognition (Mohamed et al., 1999), but others do not (Carroll et al., 1999; McCabe et al., 2002). Such inconsistencies again might be related to variable methodology, particularly small sample sizes and varying populations and phases of illness studied (Smith et al., 2000). Attitudes towards treatment and insight into the illness may vary during the course of the illness; it is therefore important to examine course-specific patterns and correlates of insight in schizophrenia. Only a few studies to our knowledge have examined first episode psychotic patients (Drake and Lewis, 2003; Mintz et al., 2003). Studies of this population allow us to examine the association between insight, symptomatology, and neurocognition without the potential confounds of illness chronicity. We examined the relationships between insight, clinical measures (positive, negative symptoms, general psychopathology, and Clinical Global Impression), premorbid adjustment, age of onset, illness duration, and cognitive performance on a variety of tasks tapping into attention,

memory, and executive functions—known to be impaired in schizophrenia (Elvevag and Goldberg, 2000).

2. Methods The data for this study were collected as part of a multicenter trial sponsored by the Janssen Research Foundation titled ‘‘Double-blind evaluation of risperidone vs. haloperidol on the long-term morbidity of early psychotic patients’’ (RIS-INT 35) conducted in 11 countries. Since the languages differed across the sites, a systematic procedure (Harvey et al., 2003) was used to ensure that the translations of all of the tests were valid. Briefly, a local expert was identified in each country where English was not the language of assessment. This expert assisted in the translation of the instructions and test stimuli, with these translations then confirmed by backtranslation. The data set at baseline included 535 subjects (155 females and 380 males; age 16– 45 years) with a DSM-IV diagnosis of schizophrenia (n = 264), schizophreniform (n = 231), or schizoaffective disorder (n = 40). To be eligible, the patient had to have the diagnosis of schizophrenia, schizophreniform, or schizoaffective disorder for less than a year, and must have received 12 weeks or less of lifetime exposure to antipsychotic medication. Patients with a diagnosis of axis I psychiatric disorder other than the above, those with a current substance use disorder, those with significant medical illness, pregnant women, and those with mental retardation were excluded. Threequarters of the sample were white (n = 400), 12% (n = 64) were black, 3% (n = 17) were Hispanic, 2% (n = 11) were Oriental, and 8% (n = 43) were from assorted other groups. Fourteen percent (n = 76) of the sample had no high school education, 26.6% (n = 141) had some high school education, 21.5% (n = 114) completed high school, 29.9% (n = 159) completed some post high school education, and 7.7% (n = 41) completed college. All subjects provided written informed consent after full description of the study. The Institutional Review Boards of each of the participating sites approved the study. Psychopathology was quantified using the Positive and Negative Symptom Scale (PANSS) (Kay et al., 1987). The PANSS provides total, positive symptoms,

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negative symptoms, and general psychopathology scale scores. The Lack of Insight and Judgment item of the PANSS general psychopathology subscale provides quantified (1 – 7 from absent to extreme) information on insight at baseline prior to institution of treatment. Overall severity of illness was rated using the Clinical Global Impression (CGI) scale. Premorbid adjustment was assessed using the Premorbid Adjustment Scale (PAS) (Cannon-Spoor et al., 1982). PAS determines premorbid functioning during four periods: childhood, early adolescence, late adolescence, and adulthood. Cognitive assessments were also conducted at baseline, prior to initiation of study treatment, and included abstraction and concept flexibility (Wisconsin Card Sorting Test, WCST; categories, total errors), verbal fluency, memory (Wechsler Memory Scale— Revised visual reproduction immediate and delayed; Rey Auditory Verbal Learning Test, RVLT; learning trials 1 – 5), and attention/psychomotor speed (the Computerized Continuous Performance Test, CPT d’ total, and the Wechsler Adult Intelligence Scale— Revised (WAIS-R) Digit Symbol, raw score). To further examine the relationship between cognitive function and level of insight, we also obtained a

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composite cognitive measure by adding the z-scores of the cognitive measures. Patients were divided into aggregate groups on the basis of their level of insight and comparisons were made between the resulting groups on demographic (education, sex, age, and age of first symptoms), premorbid, clinical (PANSS, CGI, and diagnosis), and cognitive measures using General Linear Model (GLM) MANOVA testing for linear and nonlinear effects. A separate model was used for each domain because there was a high correlation between variables (e.g., the various cognitive measures). The significant variables in each domain were entered into a stepwise multiple regression to identify the variables, which independently explained more of the variance. A final stepwise regression model that included the variables found to be significant in each domain was run.

3. Results Almost 12% of the patients (n = 62) had no impairment in insight, 12.4% (n = 66) had ‘‘minimal’’ impairment, 20.9% (n = 111) had ‘‘mild impairment,’’ 31.4% (n = 167) had ‘‘moderate impairment,’’ 13.7%

Table 1 Comparison of means (S.E.) of cognitive measures by level of insight Level of insight CPT d’ (high to low) total

RVLT learning trials 1 – 5

WMS-R VR WMS-R VR VF category VF letter delayed recall immediate recall fluency— fluency— total score total score total score total score

WAIS-R DS WCST WCST raw score categories total errors

1 n= 2 n= 3 n= 4 n= 5 n= 6 Mean n= Combined significance Linear Quadratic

0.85 (0.09) 58 0.87 (0.09) 56 0.80 (0.06) 105 0.81 (0.06) 145 0.65 (0.07) 59 0.64 (0.10) 44 0.1910

46.33 (1.45) 60 44.41 (1.45) 64 43.09 (1.16) 106 41.74 (1.01) 158 39.31 (1.67) 68 36.61 (1.83) 49 0.0002

30.53 (0.95) 60 28.25 (1.11) 63 26.53 (0.84) 107 25.38 (0.89) 154 25.43 (1.24) 65 21.92 (1.55) 50 0.0014

33.23 (0.90) 60 32.22 (0.80) 64 31.05 (0.64) 107 31.25 (0.62) 157 29.61 (1.07) 67 28.30 (1.07) 50 0.0093

37.83 (1.49) 60 40.61 (1.65) 64 36.66 (1.08) 108 36.97 (0.89) 157 34.87 (1.39) 68 32.35 (1.39) 49 0.0023

29.38 (1.49) 60 31.83 (1.59) 63 30.15 (1.12) 108 30.19 (0.94) 157 28.00 (1.40) 68 25.28 (1.49) 50 0.0309

46.88 (1.67) 59 46.16 (1.74) 63 42.85 (1.31) 108 42.92 (1.2) 157 42.40 (1.70) 68 39.69 (1.74) 49 0.1425

4.82 (0.21) 60 4.59 (0.24) 58 4.09 (0.21) 102 3.99 (0.18) 150 3.56 (0.29) 63 2.86 (0.34) 44 0.0000

35.33 (2.64) 60 36.34 (3.03) 58 42.33 (2.42) 102 43.53 (2.06) 150 48.33 (3.37) 63 57.13 (3.82) 46 0.0000

0.0210 0.372

0.0000 0.567

0.0000 0.960

0.0003 0.834

0.0006 0.126

0.0131 0.014

0.0107 0.865

0.0000 0.272

0.0000 0.105

Overall significance on the multivariate test: F = 1.67, df = 45, 2145, p = 0.0035. CPT = Continuous Performance Test; RVLT = Rey Verbal Learning Test; VF = Verbal Fluency; WMS-RVR—Wechsler Memory Scale— Revised, Visual Reproduction; WCST = Wisconsin Card Sorting Test.

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Fig. 1. The relation between the composite cognitive measure and insight showing a strong linear trend.

(n = 73) had ‘‘moderate –severe impairment,’’ 9.4% (n = 50) had ‘‘severe’’ impairment, and three patients had ‘‘extreme’’ impairment in insight. For the purposes of the analysis, the last two groups were combined (50 + 3). There was a significant linear difference in cognitive functioning, symptomatology, and premorbid functioning by level of insight in a MANOVA model presented in Table 1. shows the analysis of the cognitive variables. There were significant linear differences on seven of the nine cognitive measures; specifically, there were differences on the cognitive assessments of abstraction and concept flexibility (Wisconsin Card Sorting Test, WCST; categories, total errors), verbal fluency, memory (Wechsler Memory Scale—Revised visual reproduction immediate and delayed; and the Rey Auditory Verbal Learning Test, RVLT; learning trials 1– 5) but not on the two measures of attention/psychomotor speed [Computerized Continuous Performance Test, CPT d’ total, and

the Wechsler Adult Intelligence Scale—Revised (WAIS-R) Digit Symbol, raw score]. The relationship between the composite cognitive measure and insight (Fig. 1) showed a strong linear trend (combined significance, df = 5, 523, F = 5.11, p < 0.0001; linear term, df = 1, F = 24.45, p < 0.0001; deviation from linearity, df = 4, F = 0.39, p = 0.82), suggesting that less insight is associated with lower cognitive functioning. Stepwise linear regression of the significant cognitive variables found that when used together, the significant measures were the Rey Auditory Verbal Learning Test (learning trials 1 – 5) (standardized coefficient = 0.18, t = 3.74, p = 0.0002) and WCST (categories, total errors) (standardized coefficient = 0.156, t = 3.17, p = 0.002). There was a significant linear association between insight and the three PANSS subscales (positive, negative, and general psychopathology) and the CGI in a MANOVA presented in Table 2. Including

Table 2 Comparison of means (S.E.) of symptom measures by level of insight Level of insight (high to low)

Sample size

Positive and Negative Symptom Scale General psychopathology

Negative

Positive

1 2 3 4 5 6 Combined significance Linear Quadratic

62 66 111 167 73 53

31.66 (1.24) 36.79 (1.26) 37.96 (0.80) 42.76 (0.67) 45.47 (1.15) 49.43 (1.15) 0.0000 0.0000 0.9688

16.84 (0.86) 20.18 (0.81) 20.16 (0.54) 22.37 (0.56) 23.62 (0.87) 25.94 (0.87) 0.0000 0.0000 0.9899

16.02 (0.73) 16.83 (0.67) 19.41 (0.46) 21.40 (0.46) 22.45 (0.70) 25.02 (0.70) 0.0000 0.0000 0.6574

Multivariate test: F = 8.03, df = 20, 2100, p = 0.0000. CGI = Clinical Global Impression scale.

CGI

3.87 (0.13) 4.05 (0.13) 4.24 (0.08) 4.59 (0.06) 4.88 (0.09) 5.25 (0.09) 0.0000 0.0000 0.1705

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Table 3 Comparison of means (S.E.) of Premorbid Adjustment Scale by level of insight Level of insight Childhood Early adolescence Late adolescence Adulthood General (high to low) (up to age 11 years) (ages 12 – 15 years) (ages 16 – 18 years) (age 19 years and above)

Average premorbid (by mean)

1 Mean n= 2 Mean n= 3 Mean n= 4 Mean n= 5 Mean n= 6 Mean n= Combined significance Linear Quadratic

0.24 (0.02) 62 0 (0) 65 0.28 (0.015) 110 0.29 (0.01) 167 0.28 (0.02) 72 0.30 (0.03) 52 0.2995

0.27 (0.02) 62 0.28 (0.02) 65 0.33 (0.015) 110 0.34 (0.01) 167 0.33 (0.02) 72 0.35 (0.03) 52 0.1013

0.34 (0.02) 60 0.37 (0.03) 65 0.38 (0.02) 110 0.41 (0.01) 166 0.40 (0.03) 71 0.41 (0.03) 50 0.3943

0.39 (0.03) 55 0.37 (0.04) 56 0.39 (0.02) 97 0.45 (0.02) 149 0.42 (0.03) 63 0.46 (0.04) 46 0.1352

0.33 (0.02) 62 0.38 (0.02) 65 0.41 (0.02) 110 0.43 (0.01) 167 0.44 (0.02) 72 0.50 (0.03) 52 0.0000

0.31 (0.02) 62 0.34 (0.02) 65 0.36 (0.01) 110 0.39 (0.01) 167 0.37 (0.02) 72 0.40 (0.02) 52 0.0131

0.0209 0.8157

0.0087 0.6261

0.0542 0.5912

0.0333 0.6385

0.0000 0.8971

0.0004 0.9379

Multivariate test: F = 1.52, df = 30, 2295, p = 0.035.

three PANSS subscales and the CGI in a stepwise linear regression, we found that the significant measures were general psychopathology (standardized coefficient = 0.29, t = 5.65, p < 0.00001), CGI (standardized coefficient = 0.14, t = 2.78, p < 0.006), and PANSS positive subscale (standardized coefficient = 0.15, t = 2.72, p < 0.007). In view of the strong relation between PANSS general psychopathology subscale and insight, we conducted a multiple regression of all items from this scale with insight item as the dependent variable. Unusual thought content (G9) showed the highest predictive value (b = 0.31, p < 0.00000), followed by uncooperativeness (b = 0.20, p < 0.00000). On the Premorbid Adjustment Scale, we found a significant association of general premorbid functioning scales, but not by specific age groups in a MANOVA presented in Table 3. There were no significant linear associations between insight and age (linear F = 0.10, df = 1, p = 0.75), age of onset (linear F = 1.69, p = 0.19, df = 1), or education (linear F = 0.27, df = 1, p = 0.61), and no significant difference was seen between males and females ( F = 0.22, df = 1, p = 0.64). A final stepwise linear regression model of the significant variables from each domain found that all of the variables found significant in each domainspecific model were significant in the final model as

well with the exception of WCST categories and total errors. In descending order, the variables in the model were PANSS general (standardized coefficient = 0.27, t = 5.13, p < 0.0001), CGI (standardized coefficient = 0.15, t = 2.84, p = 0.005), RVLT learning test (learning trials 1 –5) (standardized coefficient = 0.14, t = 3.56, p < 0.0004), PANSS positive (standardized coefficient = 0.15, t = 2.70, p < 0.007), and Premorbid Adjustment Scale—General (standardized coefficient = 0.09, t = 2.35, p = 0.02). All of the variables together accounted for 30% of the variance (R2 = 0.296) in insight.

4. Discussion Our findings suggest that impaired insight is very common in first episode schizophrenia and schizoaffective patients; significant impairments were seen in nearly two-thirds of the patients. Very few studies have examined insight in first episode patients (Fennig et al., 1996; Thompson et al., 2001). Thompson et al. (2001) compared first episode patients to multiepisode patients and found that the former group had less awareness of illness than the latter. This suggests that insight may improve during the illness following the first episode. Longitudinal prospective studies are needed to verify such state-

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related change, and the factors that may underlie the acquisition of insight. While several studies have examined the relationship between insight and cognitive performance, the literature has been somewhat inconsistent. Some have failed to find a relationship between poor insight and global cognitive functioning (Cuesta and Peralta, 1994; Dickerson et al., 1997; Kemp and David, 1996; Smith et al., 2000). However, these studies are difficult to interpret because of low statistical power (Cuesta and Peralta, 1994), the use of only global cognitive performance (Kemp and David, 1996), or an exclusive focus to examine prefrontally mediated cognitive functions (Lysaker and Bell, 1994; Young et al., 1993; Young et al., 1998). Additionally, most previous studies examining the relation between insight and neurocognition have examined chronic or multiepisode patients. However, Drake and Lewis (2003) found an association between perseverative errors on WCST and poor insight, even in a relatively small sample of early course (within 5 years of onset) psychotic patients. In our study, we examined the relationship between insight and a broad range of cognitive functions in a large homogeneous group of early course patients. While cognitive performance measures reflecting prefrontal functions (such as WCST and CPT) were significantly correlated with impaired insight, cognitive measures that may reflect the functioning of other brain regions such as the temporal lobe (RVLT learning test) were more strongly correlated with insight. This suggests that impaired insight in schizophrenia may be mediated by a broad range of cognitive dysfunctions caused by a distributed neuronal network disorder involving the association cortex structures (Andreasen et al., 1999; McCarley et al., 1999; Pearlson et al., 1996). While a recent study has suggested that poor insight is associated with specific frontal regions (Flashman et al., 2001) as well as overall reductions in brain volume (Flashman et al., 2000), other brain regions have to be examined as well. Our data showed robust relationships between insight impairment and all three domains of PANSS psychopathology (positive, negative, and general). This contrasts with previous studies as discussed earlier, which have tended to find relationships one or other (Amador et al., 1994; Cuesta et al., 1998; Debowska et al., 1998; Kemp and Lambert, 1995;

Kim et al., 1997). Studies finding no relationships between psychopathology and insight tend to have comprised of relatively small sample sizes (Flashman et al., 2001; Laroi et al., 2000; McEvoy et al., 1996), suggesting the possibility that negative findings may be related to low statistical power to detect subtle effects. Additionally, first episode patients who have high levels of both insight impairments as well as symptomatology may offer sufficient variance and are better suited to find the predicted relationships between psychopathology and insight. Interestingly, among the PANSS general psychopathology items, unusual thought content (G9) was most highly associated with insight. This is not surprising since the G9 item has been found to be closely related to the positive and disorganized symptom factor in schizophrenia (Brazo et al., 1996). Unusual thought processes may lead to impairments in insight either by a pattern of denial or misattribution of the symptom experiences; it remains to be determined whether this path to insight is related to, or independent of, symptom unawareness that may be mediated by cognitive impairments (Lysaker et al., 2003). Thus, cognitive impairment specifically on measures of abstraction and concept flexibility, verbal fluency, as well as symptomatology and poor premorbid functioning are associated with poor insight early in the course of schizophrenia. Insight in schizophrenia is important because of its implications for treatment adherence. Nonadherence occurs in over 80% among schizophrenia patients (Corrigan et al., 1990) and is particularly prominent in first episode patients (Novak-Grubic and Tavcar, 1999). Early psychoeducation (Pekkala and Merinder, 2001) and psychotherapeutic interventions such as motivational interviewing (Bustillo et al., 2001; Kemp et al., 1998) can improve treatment adherence in schizophrenia. However, not all studies confirm the efficacy of psychosocial treatments in improving treatment adherence in schizophrenia (O’Donnell et al., 2003); clearly, impaired insight as well as cognitive deficits are among the well-known predictors of poor treatment adherence. Knowledge of the prevalence and correlates of impaired insight at illness onset can guide the clinical approach and also provide the framework for later reassessment of the degree of treatment-related change. Poor insight in patients with unusual thought content and delu-

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sions may potentially improve with cognitive behavioral techniques (Turkington et al., 2002); on the other hand, patients with illness unawareness related to impaired cognitive function might have improvements in insight with cognitive remediation treatments (Bell et al., 2001; Hogarty and Flesher, 1999). However, one cannot be too optimistic about the effectiveness of such treatments, since many factors, including structural and functional brain alterations, are likely to be involved in the pathogenesis of insight deficits. Pharmacological interventions that may address cognitive impairments are also worth considering in our efforts to improve insight. The possibility that novel antipsychotics may have differential therapeutic effects on insight is also worth examining in large-scale clinical trials. The strengths of this study include the large sample size and the choice of early course schizophrenia patients. Limitations include the cross-sectional nature of this data analyses and the use of data from a single item on PANSS to ascertain the level of insight, making it difficult to tease apart the correlates of the different dimensions of insight. However, our findings are meaningful for clinicians in practice who need to make brief global assessments of insight and judgment. Further, the fact that there were a number of differential correlations with level of insight argues against the interpretation that this single item is not reliable enough to identify variation in insight levels. Future studies need to separately examine the correlates of the specific components of impaired insight (i.e., unawareness and misattribution) (McEvoy et al., 1996; McGorry and McConville, 2000) in schizophrenia. Also needed are longitudinal evaluations of staterelated changes in insight and their relation to impaired cognition.

Acknowledgements This work was supported by the Janssen Research Foundation (RIS-INT 35). The authors would like to thank Michael Davidson, Robin Emsley, and Patrick McGorry for their advice as well as all the principal investigators of the RIS-INT 35 Study, Janssen Research Foundation, International Clinical Research and Development (Beerse, Belgium) for their contribution to the data collected.

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References Amador, X., David, A., 1998. Insight and Psychosis Oxford Univ. Press, New York, NY. Amador, X.F., Flaum, M., Andreasen, N.C., Strauss, D.H., Yale, S.A., Clark, S.C., et al., 1994. Awareness of illness in schizophrenia and schizoaffective and mood disorders. Arch. Gen. Psychiatry 51, 826 – 836. Andreasen, N.C., Nopoulos, P., O’Leary, D.S., Miller, D.D., Wassink, T., Flaum, M., 1999. Defining the phenotype of schizophrenia: cognitive dysmetria and its neural mechanisms. Biol. Psychiatry 46, 908 – 920 (see comments). Baier, M., DeShay, E., Owens, K., Robinson, M., Lasar, K., Peterson, K., et al., 2000. The relationship between insight and clinical factors for persons with schizophrenia. Arch. Psychiatr. Nurs. 14, 259 – 265. Bell, M., Bryson, G., Greig, T., Corcoran, C., Wexler, B.E., 2001. Neurocognitive enhancement therapy with work therapy: effects on neuropsychological test performance. Arch. Gen. Psychiatry 58, 763 – 768. Brazo, P., Ribeyre, J.M., Petit, M., Dollfus, S., 1996. Identification by typological analysis of distinct groups of schizophrenic patients. Applicability of a disorganized schizophrenia subtype. Encephale 22, 165 – 174. Buckley, P.F., Hasan, S., Friedman, L., Cerny, C., 2001. Insight and schizophrenia. Comp. Psychiatry 42, 39 – 41. Bustillo, J.R., Lauriello, J., Horan, W.P., Keith, S.J., 2001. The psychosocial treatment of schizophrenia: an update. Am. J. Psychiatry 158, 163 – 175. Cannon-Spoor, E., Potkin, S.G., Wyatt, R.J., 1982. Measurement of premorbid adjustment in chronic schizophrenia. Schizophr. Bull. 8, 470 – 484. Carroll, A., Fattah, S., Clyde, Z., Coffey, I., Owens, D.G., Johnstone, E.C., 1999. Correlates of insight and insight change in schizophrenia. Schizophr. Res. 35, 247 – 253. Collins, A.A., Remington, G.J., Coulter, K., Birkett, K., 1997. Insight, neurocognitive function and symptom clusters in chronic schizophrenia. Schizophr. Res. 27, 37 – 44. Corrigan, P.W., Liberman, R.P., Engel, J.D., 1990. From noncompliance to collaboration in the treatment of schizophrenia. Hosp. Community Psychiatry 41, 1203 – 1211. Cuesta, M.J., Peralta, V., 1994. Lack of insight in schizophrenia. Schizophr. Bull. 20, 359 – 366. Cuesta, M.J., Peralta, V., Zarzuela, A., 1998. Psychopathological dimensions and lack of insight in schizophrenia. Psychol. Rep. 83, 895 – 898. Debowska, G., Grzywa, A., Kucharska-Pietura, K., 1998. Insight in paranoid schizophrenia—its relationship to psychopathology and premorbid adjustment. Comp. Psychiatry 39, 255 – 260. Dickerson, F.B., Boronow, J.J., Ringel, N., Parente, F., 1997. Lack of insight among outpatients with schizophrenia. Psychiatr. Serv. 48, 195 – 199. Drake, R.J., Lewis, S.W., 2003. Insight and neurocognition in schizophrenia. Schizophr. Res. 62, 165 – 173. Drake, R.J., Haley, C.J., Akhtar, S., Lewis, S.W., 2000. Causes and consequences of duration of untreated psychosis in schizophrenia. Br. J. Psychiatry 177, 511 – 515.

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Elvevag, B., Goldberg, T.E., 2000. Cognitive impairment in schizophrenia is the core of the disorder. Crit. Rev. Neurobiol. 14, 1 – 21. Fennig, S., Everett, E., Bromet, E.J., Jandorf, L., Fennig, S.R., Tanenberg-Karant, M., et al., 1996. Insight in first-admission psychotic patients. Schizophr. Res. 22, 257 – 263. Flashman, L.A., McAllister, T.W., Andreasen, N.C., Saykin, A.J., 2000. Smaller brain size associated with unawareness of illness in patients with schizophrenia. Am. J. Psychiatry 157, 1167 – 1169. Flashman, L.A., McAllister, T.W., Johnson, S.C., Rick, J.H., Green, R.L., Saykin, A.J., 2001. Specific frontal lobe subregions correlated with unawareness of illness in schizophrenia: a preliminary study. J. Neuropsychiatry Clin. Neurosci. 13, 255 – 257. Harvey, P.D., Artiola i Fortuny, L., Vester-Blockland, E., De Smedt, G., 2003. Cross-national cognitive assessment in schizophrenia clinical trials: a feasibility study. Schizophr. Res. 59, 243 – 251. Hogarty, G.E., Flesher, S., 1999. Practice principles of cognitive enhancement therapy for schizophrenia. Schizophr. Bull. 25, 693 – 708. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13, 261 – 276. Kemp, R., David, A., 1996. Psychological predictors of insight and compliance in psychotic patients. Br. J. Psychiatry 169, 444 – 450. Kemp, R.A., Lambert, T.J., 1995. Insight in schizophrenia and its relationship to psychopathology. Schizophr. Res. 18, 21 – 28. Kemp, R., Kirov, G., Everitt, B., Hayward, P., David, A., 1998. Randomised controlled trial of compliance therapy. 18-Month follow-up. Br. J. Psychiatry 172, 413 – 419. Kim, Y., Sakamoto, K., Kamo, T., Sakamura, Y., Miyaoka, H., 1997. Insight and clinical correlates in schizophrenia. Comp. Psychiatry 38, 117 – 123. Laroi, F., Fannemel, M., Ronneberg, U., Flekkoy, K., Opjordsmoen, S., Dullerud, R.et al., , 2000. Unawareness of illness in chronic schizophrenia and its relationship to structural brain measures and neuropsychological tests. Psychiatry Res. 100, 49 – 58. Lysaker, P., Bell, M., 1994. Insight and cognitive impairment in schizophrenia. Performance on repeated administrations of the Wisconsin Card Sorting Test. J. Nerv. Ment. Dis. 182, 656 – 660. Lysaker, P.H., Lancaster, R.S., Davis, L.W., Clements, C.A., 2003. Patterns of neurocognitive deficits and unawareness of illness in schizophrenia. J. Nerv. Ment. Dis. 191, 38 – 44. McCabe, R., Quayle, E., Beirne, A.D., Anne Duane, M.M., 2002. Insight, global neuropsychological functioning, and symptomatology in chronic schizophrenia. J. Nerv. Ment. Dis. 190, 519 – 525. McCarley, R.W., Wible, C.G., Frumin, M., Hirayasu, Y., Levitt, J.J.,

Fischer, I.A., et al., 1999. MRI anatomy of schizophrenia. Biol. Psychiatry 45, 1099 – 1119. McEvoy, J.P., Hartman, M., Gottlieb, D., Godwin, S., Apperson, L.J., Wilson, W., 1996. Common sense, insight, and neuropsychological test performance in schizophrenia patients. Schizophr. Bull. 22, 635 – 641. McGorry, P.D., McConville, S.B., 2000. Insight in psychosis. Harv. Ment. Health Lett. 17, 3 – 5. Mintz, A.R., Dobson, K.S., Romney, D.M., 2003. Insight in schizophrenia: a meta-analysis. Schizophr. Res. 61, 75 – 88. Mohamed, S., Fleming, S., Penn, D.L., Spaulding, W., 1999. Insight in schizophrenia: its relationship to measures of executive functions. J. Nerv. Ment. Dis. 187, 525 – 531. Moore, O., Cassidy, E., Carr, A., O’Callaghan, E., 1999. Unawareness of illness and its relationship with depression and selfdeception in schizophrenia. Eur. Psychiatry 14, 264 – 269. Novak-Grubic, V., Tavcar, R., 1999. Treatment compliance in firstepisode schizophrenia. Psychiatr. Serv. 50, 970 – 971 (letter; comment). O’Donnell, C., Donohoe, G., Sharkey, L., Owens, N., Migone, M., Harries, R., et al., 2003. Compliance therapy: a randomised controlled trial in schizophrenia. BMJ 327, 834. Pearlson, G.D., Petty, R.G., Ross, C.A., Tien, A.Y., 1996. Schizophrenia: a disease of heteromodal association cortex? Neuropsychopharmacology 14, 1 – 17. Pekkala, E., Merinder, L., 2001. Psychoeducation for Schizophrenia. In The Cochrane Library, Oxford. Peralta, V., Cuesta, M.J., 1998. Factor structure and clinical validity of competing models of positive symptoms in schizophrenia. Biol. Psychiatry 44, 107 – 114. Schwartz, R.C., 2000. Insight and suicidality in schizophrenia: a replication study. J. Nerv. Ment. Dis. 188, 235 – 237. Schwartz, R.C., Petersen, S., 1999. The relationship between insight and suicidality among patients with schizophrenia. J. Nerv. Ment. Dis. 187, 376 – 378. Smith, T.E., Hull, J.W., Israel, L.M., Willson, D.F., 2000. Insight, symptoms, and neurocognition in schizophrenia and schizoaffective disorder. Schizophr. Bull. 26, 193 – 200. Thompson, K.N., McGorry, P.D., Harrigan, S.M., 2001. Reduced awareness of illness in first-episode psychosis. Comp. Psychiatry 42, 498 – 503. Turkington, D., Kingdon, D., Turner, T., 2002. Effectiveness of a brief cognitive – behavioural therapy intervention in the treatment of schizophrenia. Br. J. Psychiatry 180, 523 – 527. Young, D.A., Davila, R., Scher, H., 1993. Unawareness of illness and neuropsychological performance in chronic schizophrenia. Schizophr. Res. 10, 117 – 124. Young, D.A., Zakzanis, K.K., Bailey, C., Davila, R., Griese, J., Sartory, G., et al., 1998. Further parameters of insight and neuropsychological deficit in schizophrenia and other chronic mental disease. J. Nerv. Ment. Dis. 186, 44 – 50.