A five-year followup study of deficit and nondeficit schizophrenia

A five-year followup study of deficit and nondeficit schizophrenia

Schizophrenia Research 49 (2001) 253±260 www.elsevier.com/locate/schres A ®ve-year followup study of de®cit and nonde®cit schizophrenia C. Tek*, B. ...

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Schizophrenia Research 49 (2001) 253±260

www.elsevier.com/locate/schres

A ®ve-year followup study of de®cit and nonde®cit schizophrenia C. Tek*, B. Kirkpatrick, R.W. Buchanan Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland, Baltimore, MD 21246, USA Received 23 June 2000; revised 25 August 2000; accepted 31 August 2000

Abstract Previous studies have suggested that de®cit schizophrenia is a stable subtype of schizophrenia, and that patients with the de®cit schizophrenia have different course of illness from other people with schizophrenia. We tested the ability of the de®cit/ nonde®cit categorization to predict clinical features at ®ve years' followup in a group of chronically ill outpatients. Outpatients categorized into de®cit …N ˆ 46† and nonde®cit …N ˆ 174† schizophrenia were assessed at an average of ®ve years after the categorization was made. Raters making the followup assessments were blind to the initial categorization. At followup, the de®cit patients had poorer quality of life, poorer social and occupational function, and more severe negative symptoms. Despite these differences, de®cit patients were less distressed (as measured by depressive mood, anxiety, and guilt), and they did not have more severe hallucinations, delusions, thought disorder. These differences could not be attributed to demographic differences. The group differences in quality of life and level of psychosocial function remained signi®cant after accounting for the severity of baseline negative symptoms. These ®ndings con®rm that patients with the de®cit schizophrenia have a set of relatively stable clinical features that are associated with poor outcome. q 2001 Elsevier Science B.V. All rights reserved. Keywords: De®cit schizophrenia; Delusions; Nonde®cit schizophrenia

1. Introduction Schizophrenia is a highly heterogeneous disorder in terms of such clinical features as risk factors, longterm course, symptom pro®les, and treatment response. There is also substantial variation in biological correlates, ranging from brain volume size to postmortem neuropathology (Carpenter et al., 1999). This heterogeneity has prompted researchers to propose several putative subtypes of schizophrenia, and has raised the possibility that there are multiple pathophysiological processes within schizophrenia

* Corresponding author. Tel.: 11-410-402-7604; fax: 11-410402-7198. E-mail address: [email protected] (C. Tek).

(Andreasen and Olsen, 1982; Crow 1985; Carpenter et al., 1988). De®cit schizophrenia represents one such putative subtype. These patients are characterized by the presence of idiopathic enduring negative symptoms (Carpenter et al., 1988). The de®cit/ nonde®cit categorization has a high degree of stability, with good test±retest and interrater reliability (Kirkpatrick et al., 1989; Fenton and McGlashan, 1992; Amador et al., 1999). The validity of the de®cit schizophrenia is also supported by the demonstration of distinctive clinical features and biological correlates. Patients with the de®cit schizophrenia have been reported to differ from other patients with schizophrenia in terms of risk factors (Waltrip et al., 1997; Kirkpatrick et al., 1998, 2000), family history of schizophrenia

0920-9964/01/$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S 0920-996 4(00)00146-8

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(Dollfus et al., 1996), functional and structural imaging variables (Tamminga et al., 1992; Buchanan et al., 1993; Carpenter et al., 1999; Heckers et al., 1999; Kirkpatrick et al., 1999), neurocognitive measures (Buchanan et al., 1994, 1997; Bustillo et al., 1997), an association with eye tracking disorder (Thaker et al., 1989; Ross et al., 1996, 1997), and response to treatment (Kopelowicz et al., 1997; Buchanan et al., 1998). These differences are not attributable to the severity of other disease variables such as the duration of illness, the severity of positive psychotic symptoms, or comorbidity with substance abuse and depression (Carpenter et al., 1988; Kirkpatrick et al., 1993, 1994, 1996a,b,c; Fenton and McGlashan, 1994). Two previous studies have also found the de®cit categorization predicted subsequent course. Fenton and McGlashan (1994) found that at an average of 19 years' followup, de®cit patients had signi®cantly poorer outcome than other schizophrenia patients, despite a similar severity of delusions, hallucinations, and thought disorder. The de®cit/nonde®cit categorization in those patients was made retrospectively from chart records when they were inpatients at Chestnut Lodge, which at the time of their admission was a tertiary care center for severely ill patients. In the second study, the clinical features that were characteristic of de®cit vs. nonde®cit outpatients were found to be stable at one to two and one half years' followup (Kirkpatrick et al., 1993, 1994). In the present study, we extended our study of predictive validity of the de®cit categorization in schizophrenia. In contrast with Chestnut Lodge study (Fenton and McGlashan, 1994), the de®cit/ nonde®cit categorization was performed prospectively, at a time when the patients were stable and at an outpatient clinic. We hypothesized that at followup, de®cit patients would show the characteristic pro®le of symptoms that had been previously reported (Buchanan et al., 1990; Kirkpatrick et al., 1993, 1994): (1) more severe negative symptoms, despite (2) the presence of less severe dysphoric symptoms, and (3) positive psychotic symptoms that were less severe or did not differ from those of nonde®cit patients. We also hypothesized that the de®cit patients would have poorer quality of life and functional outcome.

2. Method Subjects of the study were all patients admitted to the Maryland Psychiatric Research Center Outpatient Program between 1988 and 2000 who met DSM-III(R) criteria for schizophrenia, who were categorized as de®cit or nonde®cit schizophrenia, and who had at least one BPRS rating at least six months following their index assessment. The diagnosis of schizophrenia was based on a best-estimate diagnostic conference, attended by all clinicians in the clinic, at which all available information was used for making the diagnosis, including direct assessment, family informants, structured interviews, and past medical records. Patients with an organic brain disorder, mental retardation, a history of severe head trauma, or signi®cant drug abuse were not included. The patients were subtyped (by BK and/or RWB) into de®cit …N ˆ 46† and nonde®cit …N ˆ 174† groups using the Schedule for the De®cit Syndrome (SDS), a semi-structured interview of documented reliability in this population (kappa ˆ 0.73; Kirkpatrick et al., 1989). The SDS provides speci®c criteria for assessing the presence and duration of negative symptoms, as well as the distinction between primary and secondary negative symptoms. Ratings other than the SDS were done prior to initiation of this study, and without any formal information about de®cit/nonde®cit categorization. Using the date of the de®cit/nonde®cit categorization as the baseline, items from the last Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1961) administered in the course of the patients' tenure in the clinic were used to measure negative, dysphoric, and positive psychotic symptoms. BPRS ratings were used only if they were completed at least six months after the SDS categorization was made, and the patient had been judged by the patient's primary therapist to be in a period of clinical stability or relative remission at the time of the rating. (All patients were outpatients at the time of this rating.) These therapists were doctorate or masters' level clinicians who had been trained extensively on use of these scales, and had participated in monthly interrater reliability exercises. All assessments were done with the written informed consent of patients under protocols approved by the appropriate institutional review board.

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Negative symptoms were quanti®ed using the ªanergiaº factor from the BPRS, which consists of the sum of the items for emotional withdrawal, motor retardation, and blunted affect. Because of the results of many previous factor analyses of the symptoms of schizophrenia, the conceptual disorganization item was considered separately from the sum of the hallucinatory behavior and unusual thought content items in multivariate analyses (Andreasen and Olsen, 1982; Liddle 1987; Arndt et al., 1991; Peralta et al., 1992; Minas et al., 1992; Silver et al., 1993; Buchanan and Carpenter, 1994). Because of previous ®ndings that de®cit patients are less suspicious than other schizophrenia patients, the suspiciousness item was also considered separately (Kirkpatrick et al., 1996b). Dysphoria was quanti®ed using the sum of the anxiety, guilt feelings, and depressive mood items. The BPRS-based variables were log-transformed to approximate a normal distribution. Where available, the last Quality of Life Scale (QLS; Heinrichs et al., 1984) and Level of Function Scale (LOF; Hawk et al., 1975) scores, if obtained in the same clinical stability period within one year of the followup BPRS, were also examined. These were also completed by the patients' primary therapists. As in the case with the BPRS extensive training and monthly reliability exercises was the standard in our clinic during the period of the study. The LOF focuses on objective observation of major areas of functioning like social contacts, employment, self-care, etc. The QLS is more focused on patient's subjective perception of various aspects of their life, as rated by the interviewer. As an example, where having full time employment receives a high rating for the related item in the LOF, to receive a similarly high rating in QLS patient needs to be satis®ed with his/her work situation as well. Two important aspects of functioning from the LOF were considered separately: useful employment (item 3a) and ability to meet own basic needs (item 5). Both were dichotomized for analysis, to re¯ect full time employment vs. all other, and adequate ability for self-care vs. all other, respectively. Adequate ability for self-care was de®ned as scores of 3 and 4 at item 5 of LOF, which corresponds to needing minimal or no help with basic needs like feeding self, keeping clean, etc. Antipsychotic medication doses at the time of followup BPRS ratings were converted to a common

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metric using the conversion system developed by Schooler (Schooler, 1993 and personal communication). The metric in terms of chlorpromazine equivalence is, 1 ˆ 300 mg or less, 2 ˆ 301±599 mg; 3 ˆ 600±999 mg; and 4 ˆ 1000 mg or more. To assess the predictive validity of the de®cit/ nonde®cit schizophrenia diagnosis, multiple regression analyses were conducted using LOF and QLS total scores as dependent variables. Age, gender, the de®cit/nonde®cit categorization (as a 0/1 variable), current hallucinations 1 delusions, negative symptom and conceptual organization scores were used as independent variables. The rationale of including main symptom factors is to be able to delineate the predictive power of the de®cit schizophrenia diagnosis independent from the current severity of illness, which may negatively affect outcome measures. Another possible confounding factor for outcome measures would be the chronicity of illness as well as how early the disease started (Davidson and McGlashan, 1997). Also, the duration of followup for the subject was covering a range of 12 years. To control for these, we added age of onset in the analysis as another independent variable. A further analysis was also conducted in a subgroup of patients who had had BPRS ratings made within one month of the de®cit/nonde®cit categorization. Multiple regression was used with QLS and LOF total scores as dependent variables and age, sex, de®cit/nonde®cit categorization (as a 0/1 variable), baseline hallucinations 1 delusions, negative symptom, and conceptual organization scores as the independent variables. The aim of this ®nal analysis was to compare the predictive validity of the diagnosis of de®cit schizophrenia, which emphasizes the primary enduring negative symptoms, to BPRS measured negative symptoms, which theoretically includes both primary and secondary negative symptoms. We also explored if the de®cit categorization has any advantage over positive symptom measures for prediction of future outcome. 3. Results De®cit …N ˆ 46† and nonde®cit …N ˆ 174† categorizations were available for 220 patients. For 143 patients (66% of total; 41 de®cit and 102 nonde®cit) a

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Table 1 Sociodemographic characteristics of the patients

Age (mean years) Sex (male) Race (White) Education (mean years) Followup period b (mean years) a b

De®cit (N ˆ 46)

Nonde®cit (N ˆ 174)

Statistic

Pa

35.8 (SD ˆ 8.1) 38 (82.6%) 27 (58.7%) 11.5 (SD ˆ 2.2) 5.93 (SD ˆ 4.0)

36.5 (SD ˆ 8.6) 107 (61.5%) 113 (64.9%) 12.7 (SD ˆ 2.3) 4.67 (SD ˆ 3.5)

t ˆ 20:52 x2 ˆ 7:22 x2 ˆ 2:05 t ˆ 23:34 t ˆ 1:76

NS , 0.008 NS , 0.002 NS

NS means p values above 0.05. Of all patients, 12.6% were followed up less than 1 year, and 16.1% were followed up more than 9 years.

followup BPRS at least six months after the categorization was available. Of these 143, 125 patients had a followup LOF and 114 had a followup QLS. There were no signi®cant differences between the whole sample and the followup sample in terms of any sociodemographic or clinical variables including de®cit/ nonde®cit categorization (data not shown). The demographic and symptomatic variables for the patients with de®cit and nonde®cit schizophrenia at followup are presented in Tables 1 and 2. De®cit schizophrenia was signi®cantly more common among men than women (26.2 vs. 10.7%), and the nonde®cit patients had on average completed 1.2 more years of education; this difference was also signi®cant. However, patients with de®cit and nonde®cit schizophrenia did not differ signi®cantly relative to age, race, socioeconomic status of the patient's household of origin, or the age of onset of illness. Antipsychotic medication doses and percentage of

atypical antipsychotic use (52.2% in de®cit group vs. 40.3% in the nonde®cit group) were comparable in the two groups. The followup BPRS ratings were conducted on average 5.0 …SD ˆ 3:7† years, LOF ratings were conducted 5.3 …SD ˆ 3:5† years, and QLS ratings were conducted 5.3 …SD ˆ 3:6† years after the initial de®cit/nonde®cit categorization. At followup, the severity of conceptual disorganization, hallucinations 1 delusions, and suspiciousness did not differ signi®cantly different between de®cit and nonde®cit patients. However, the de®cit patients had signi®cantly more severe negative symptoms at followup (mean difference 3.3 points on a 21-point scale,t ˆ 6:85; df ˆ 53:6; p , 0:0001). This difference could not be attributable to greater dysphoria scores (Table 2), which were lower in the de®cit group. Despite the lesser severity of dysphoric symptoms

Table 2 Clinical characteristics of the patients at followup (N ˆ 143 except for LOF …N ˆ 125† and QLS …N ˆ 114†) Mean (SD)

Age of onset of illness Hallucinations/delusions Conceptual disorganization Suspiciousness Negative symptoms Dysphoria Level of function Quality of life Antipsychotic medication b a b

De®cit

Nonde®cit

21.57 (6.82) 4.90 (2.99) 1.83 (1.26) 2.05 (1.80) 8.32 (3.41) 4.88 (2.80) 16.06(5.44) 42.61 (19.66) 2.78 (1.09)

22.14 (6.56) 5.55 (3.58) 1.89 (1.46) 2.45 (1.85) 5.04 (2.17) 6.24 (3.47) 20.93 (7.65) 69.53 (26.18) 2.75 (1.14)

Statistic

Pa

t ˆ 20:45 t ˆ 21:09 t ˆ 20:26 t ˆ 21:18 t ˆ 6:85 t ˆ 22:23 t ˆ 23:45 t ˆ 25:57 t ˆ 0:13

NS NS NS NS , 0.0001 , 0.03 , 0.002 , 0.0001 NS

NS means p values above 0.05. In terms of chlorpromazine equivalence; 1 ˆ 300 mg or less, 2 ˆ 301±599 mg, 3 ˆ 600±999 mg, 4 ˆ 1000m g or more.

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Table 3 Predictors of level of function and quality of life at followup Variable Level of function (N ˆ 125, df ˆ 5) Age Sex Age of onset Current hallucinations/delusions Current conceptual disorganization Current negative symptoms De®cit syndrome Quality of life (N ˆ 114, df ˆ 5) Age Sex Age of onset Current hallucinations/delusions Current negative symptoms Current conceptual disorganization De®cit syndrome a

T

Pa

Partial r

0.14 0.24 1.88 22.26 24.12

NS NS NS 0.026 0.000

0.14 0.02 0.19 20.22 20.38

22.84 22.43

0.006 0.017

20.27 20.24

0.76 0.32 0.92 22.37 23.75 22.22

NS NS NS 0.020 0.000 0.029

0.06 0.03 0.09 20.24 20.36 20.22

23.67

0.000

20.35

NS means p values above 0.05.

and a similar severity of positive psychotic symptoms, the de®cit patients had signi®cantly worse functioning than the nonde®cit patients as measured by the LOF and QLS scores (Table 2). They were also signi®cantly less likely to have fulltime employment (8.1 vs. 30.5%, x2 ˆ 7:26; df ˆ 1; p , 0:01). The difference in the percentage of patients in each group who were adequately caring for their basic needs was not signi®cant (78 vs. 91%, respectively, for the de®cit and nonde®cit groups). The results of the multiple regression analyses of LOF and QLS scores for the followup group are presented in Table 3. Current hallucinations 1 delusions, conceptual disorganization, current negative symptoms and the baseline de®cit/nonde®cit categorization were all signi®cant predictors of LOF scores; the de®cit patients had poorer function. The results for QLS scores were similar, as current hallucinations 1 delusions, conceptual disorganization, current negative symptoms and baseline de®cit/ nonde®cit categorization were all signi®cant predictors of quality of life. The subgroup …N ˆ 47† for whom both a baseline BPRS as well as followup QLS and LOF ratings were available, was representative of the followup group relative to clinical and sociodemographic variables,

except for a higher percentage of de®cit patients in the followup group (36.2 vs. 20.9%, x2 ˆ 5:00; df ˆ 1; p , 0:03). Two of the baseline patients were not present in the followup group. The mean time between the de®cit categorization and the followup ratings for this group was: 5.2 years …SD ˆ 3:4 years† for the LOF and 5.1 years …SD ˆ 3:5† for the QLS. In the multiple regression analysis with these 47 patients, QLS at ®ve-year followup was predicted by the de®cit categorization …t ˆ 3:12; df ˆ 6, p ˆ 0:012† but not any other baseline symptom measures, including negative symptoms. LOF total scores at ®ve year followup were predicted by de®cit/nonde®cit categorization …t ˆ 22:53; df ˆ 6; p ˆ 0:016† and baseline conceptual disorganization scores …t ˆ 22:53; df ˆ 6; p ˆ 0:016† but not by the negative or positive symptom scores at the baseline. 4. Discussion In a study of outpatients, we found that ®ve years after the de®cit/nonde®cit categorization was made, de®cit patients differed on a number of features when compared to other patients with chronic schizophrenia. They continued to exhibit more severe

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negative symptoms, and had poorer quality of life and global level of function. In addition, a smaller percentage of de®cit patients had full time employment. These differences in outcome could not be accounted for by more severe positive psychotic symptoms, or by greater anxiety, depressive mood, or guilt feelings in the group with de®cit schizophrenia. The differences in function and quality of life were signi®cant after controlling for the variance due to main schizophrenia symptom factors including combination of primary and secondary negative symptoms, age of onset, and demographic features. In an analysis of a subgroup of our sample who were evaluated at baseline, the diagnosis of de®cit schizophrenia predicted subsequent quality of life and level of function after an average of ®ve years, but baseline negative symptoms broadly de®ned did not. An important limitation of our ®ndings is that the ratings that were used were made in the course of the patients' tenure in the clinic. This introduced the possibility of bias due to differences in dropouts in the groups with de®cit and nonde®cit schizophrenia. However, the demographic and clinical features of the followup groups were very similar to all of the clinic's patients who had been categorized, and at both baseline and followup the de®cit and nonde®cit groups were similar relative to demographic variables, and positive psychotic symptoms. In addition, accounting for the variance due to demographic variables and psychotic symptoms did not change the pattern of our results. In addition, the groups clinical features and our results were similar to the Chestnut Lodge study (Fenton and McGlashan, 1992). In our analysis of a subgroup of patients for whom a baseline BPRS was available, negative symptoms did not predict subsequent function, although the diagnosis of de®cit schizophrenia did. In the diagnosis of de®cit schizophrenia, the emphasis is on trait rather than state negative symptoms, and on a primary (or idiopathic) abulia or loss of motivation rather than negative symptoms that are secondary to such causes as depression or medication side effects. The clinical rating scales that are commonly used in the study of schizophrenia are not designed to make the distinction between transitory versus enduring, or primary versus secondary negative symptoms (Carpenter et al., 1999). Another limitation is our use of BPRS anergia factor as a negative symptom measure. However, this

subscore is shown to be highly correlated with other negative symptom scales (Czobor et al., 1991; Welham et al., 1999). There are other studies which have found the presence of de®cit schizophrenia and negative symptoms more broadly de®ned have important differences in how patients are categorized, and in clinical and neurobiological correlates (Fenton and McGlashan, 1992; Kirkpatrick et al., 1993, 1996b, 1998, 2000). Our results are consistent with previous studies of the disease course of de®cit versus nonde®cit patients. Fenton and McGlashan (1994) assessed inpatients an average of 19 years after their index admission to Chestnut Lodge, a tertiary care center. The de®cit categorization was highly stable, and associated with poorer global outcome. De®cit patients had also had suicidal thoughts less frequently, despite their poorer outcome; presumably, like our patients, they were less depressed and anxious. In our previous, smaller study of outpatients with an average followup of 2.5 years, we also found de®cit patients continued to have more severe negative symptoms and less dysphoria, but not more severe psychotic symptoms than did nonde®cit patients (Kirkpatrick et al., 1993). De®cit patients appear to differ in function from other people with schizophrenia throughout most of life. Long prior to the onset of psychosis, de®cit patients are more isolated (Kirkpatrick, 1997), and have poorer global function (Buchanan et al., 1990; Kirkpatrick et al., 1996a,b). The onset of their illness is also more insidious (Fenton and McGlashan, 1994). If more severe positive and negative psychotic symptoms, anxiety/depression, or drug abuse cannot account for the poorer function of de®cit patients, previous studies suggest certain other factors may (Kirkpatrick et al., 1993, 1996b,c). De®cit patients have a fairly widespread impairment in cognitive function, compared to other patients with chronic schizophrenia (Buchanan and Carpenter, 1994; Buchanan et al., 1994, 1997; Bustillo et al., 1997; Thaker et al., 1989; Heckers et al., 1999). Also, by de®nition, de®cit patients are less motivated, and this should contribute to poorer function. Our ®ndings add to the growing body of evidence that the diagnosis of de®cit schizophrenia has predictive validity, relative to course of illness, neurobiological variables, and psychosocial functioning. Broader de®nitions of negative symptoms appear to

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be less sensitive to these group differences. These differences between patients with de®cit and nonde®cit schizophrenia have important implications not only for research purposes, but also for intervention and services planning for schizophrenic populations. Acknowledgements Supported in part by PHS grant MH-40279-13 and R25-MH-60487. References Amador, X.F., Kirkpatrick, B., Buchanan, R.W., Carpenter Jr., W.T., Marcinko, L., Yale, S.A., 1999. Stability of the diagnosis of de®cit syndrome in schizophrenia. Am. J. Psychiatry 156, 637±639. Andreasen, N.C., Olsen, S., 1982. Negative v positive schizophrenia. De®nition and validation. Arch. Gen. Psychiatry 39, 789±794. Arndt, S., Alliger, R.J., Andreasen, N.C., 1991. The distinction of positive and negative symptoms. The failure of a two-dimensional model. Br. J. Psychiatry 158, 317±322. Buchanan, R.W., Kirkpatrick, B., Heinrichs, D.W., Carpenter Jr., W.T., 1990. Clinical correlates of the de®cit syndrome of schizophrenia. Am. J. Psychiatry 147, 290±294. Buchanan, R.W., Breier, A., Kirkpatrick, B., Elkashef, A., Munson, R.C., Gellad, F., Carpenter, W.T., 1993. Structural abnormalities in de®cit vs. nonde®cit schizophrenia. Am. J. Psychiatry 150, 59±65. Buchanan, R.W., Carpenter, W.T., 1994. Domains of psychopathology: an approach to the reduction of heterogeneity in schizophrenia. J. Nerv. Ment. Dis. 182, 193±204. Buchanan, R.W., Strauss, M.E., Kirkpatrick, B., Holstein, C., et al., 1994. Neuropsychological impairments in de®cit vs. nonde®cit forms of schizophrenia. Arch. Gen. Psychiatry 51, 804±811. Buchanan, R.W., Strauss, M.E., Breier, A., Kirkpatrick, B., Carpenter Jr., W.T., 1997. Attentional impairments in de®cit and nonde®cit forms of schizophrenia. Am. J. Psychiatry 154, 363±370. Buchanan, R.W., Breier, A., Kirkpatrick, B., Ball, P., Carpenter Jr., W.T., 1998. Positive and negative symptom response to clozapine in schizophrenic patients with and without the de®cit syndrome. Am. J. Psychiatry 155, 751±760. Bustillo, J.R., Thaker, G., Buchanan, R.W., Moran, M., Kirkpatrick, B., Carpenter, W.T., 1997. Visual information-processing impairments in de®cit and nonde®cit schizophrenia. Am. J. Psychiatry 154, 647±654. Carpenter Jr., W.T., Heinrichs, D.W., Wagman, A.M., 1988. De®cit and nonde®cit forms of schizophrenia: the concept. Am. J. Psychiatry 145, 578±583. Carpenter Jr., W.T., Arango, C., Buchanan, R.W., Kirkpatrick, B., 1999. De®cit psychopathology and a paradigm shift in schizophrenia research. Biol. Psychiatry 46, 352±360.

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