Childhood psychopathological antecedents in early onset schizophrenia

European Psychiatry 20 (2005) 309–314 http://france.elsevier.com/direct/EURPSY/

Original article

Childhood psychopathological antecedents in early onset schizophrenia F. Muratori a,*, F. Salvadori b, G. D’Arcangelo b, V. Viglione b, L Picchi b a

b

University of Pisa, Pisa, Italy Division of Child Neuropsichiatry, Scientific Institute Stella Maris, Calambrone, Pisa, Italy Received 1 September 2004; accepted 21 March 2005

Abstract Objective. – To describe the premorbid state of early onset schizophrenia (EOS). Methods. – Twenty-three adolescents with EOS were compared to a healthy control group (CG) and to a group of anorexic patients (AG). The premorbid state was studied through the CBCL and the data obtained were analyzed using ANOVA’s and t-test. Results. – During the premorbid period EOS showed significantly higher scores on all scales, relative to the CG, and only on some scales (social, thought and attention problems, and school competencies) relative to the AG. Conclusions. – Children who develop first episode psychosis during adolescence differ from children with normal development. The premorbid internalizing state is common to AG but social competencies and school problems are the most affected areas in EOS when compared to the AG. It is hypothesized that both EOS and AG can be considered as the expression of a previous vulnerability. © 2005 Elsevier SAS. All rights reserved. Keywords: Adolescence; Schizophrenia; Child behavior checklist; Premorbid state

1. Introduction Schizophrenia occurring before the age of 18 is defined as ‘early onset schizophrenia’ (EOS). It represents 10% of total schizophrenia [34] and the majority of youth with EOS display an insidious onset which, differently from the abrupt onset, occurs over a period of deteriorating functioning lasting more than 4 weeks. Full-blown symptomatology is formed by the appearance of positive and negative symptoms in a subject free of these symptoms before the first-episode psychosis [3]. Although reliability and validity of the diagnosis may be reasonably satisfactory during the acute phase, problems arise as far as other phases are concerned. In particular the beginning of the prodromal phase, that is the period immediately preceding the development of overt psychotic symptoms, is not always easy to date in EOS where lifelong premorbid abnormalities are usual [36]. In fact several lines of evidence suggest that behavioral and cognitive problems may be already present before the prodromal phase. The presence * Corresponding author. Present address: c/o IRCCS Stella Maris, Via dei Giacinti, 2, 56018 Calambrone, Pisa, Italy. Tel.: +39 050 886 292; fax: +39 050 886 247. E-mail address: [email protected] (F. Muratori). 0924-9338/$ - see front matter © 2005 Elsevier SAS. All rights reserved. doi:10.1016/j.eurpsy.2005.03.004

of these premorbid lifelong problems, which rarely reach a clinical level, confirm schizophrenia as a neurodevelopmental disorder [35] with subtle impairments before the full psychiatric disorder will be manifested. Among premorbid problems, evidence for motor [33,16,17] or language [21] developmental impairments have emerged in a large set of literature but data are sometime conflicting [7]. Cognitive impairment and difficult school performances [22,24,18], reduction of social skill and poor relationships [12,8,2], behavioral abnormalities and social withdrawal [26] can precede by some years the onset of schizophrenia and have long been known as a vulnerability index for schizophrenia. The definition of the premorbid characteristics of EOS could potentially inform current efforts to identify populations at risk for schizophrenia, and it would allow treatment interventions to begin before the frank onset of psychotic symptoms [37]. Besides, research on interventions on people who manifest high risk indicators prior to the development of the illness have generated controversial findings about the probability of success vs. the probability of unintended negative consequences [19,29]. The aim of the present study was to investigate the features of the premorbid state in EOS; it will be reached by means of two types of comparison: with a group of healthy

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adolescents, and with a psychiatric control group (CG). As a psychiatric CG, we have chosen anorexia nervosa because it appears as a new clinical pattern of symptoms in a subject who, before the onset of the illness, had never needed psychiatric help; as a second instance, anorexia is now considered, as EOS, an illness with a developmental vulnerability. While the first comparison will permit us to identify a population at risk for a mental health disorder, the comparison with the anorexic group (AG) will permit us to overcome the lack of evidence of premorbid specificity for schizophrenia. We expected to find significant differences in the premorbid state between EOS and the other two groups.

Table 1 Demographic and clinical features of the three groups EOS (n = 23) Age upon entry into study a Age of onset Male (%) b Full scale IQ Family status (%) Intact One parent Out of home Socioeconomic status (%) Upper/middle Lower a

2. Methods 2.1. Subjects The sample was composed of 23 adolescents (14 females and nine males) hospitalized, over a 3-year period, in the adolescent inpatient ward at the Division of Child and Adolescent Neuropsychiatry, a suburban public academic hospital providing care to patients of all socioeconomic levels, because of a first-episode psychosis later diagnosed as EOS. The mean age was 15.3 years (S.D.: 1.8; range 12–18) and mean lag time from onset of first psychotic symptoms to age of hospitalization was 2 months (range: 15 days to 4 months). Most subjects had a prodrome (defined as the period of deteriorating functioning just prior the full onset of syndrome) of 6 months or less. No subjects had substance abuse histories before the onset of psychosis. The average length of stay in the hospital for the first-episode was 1 month. We have excluded patients affected by mental retardation or neurological disease. One year after first-episode psychosis, during one of the regular appointments for the therapeutic outpatients program, subjects were reclassified, by means of the Schedule for Affective Disorders and Schizophrenia for School Aged Children (KSADS-P) as patients with Schizophrenia (subjects with a diagnosis of Bipolar Disorder were excluded). At this time the mean age of patients was 16.4 years (S.D.: 1.7; range 13–18.9). The study of the premorbid state included the constitution of two CGs: 1) a healthy group (CG), composed of 23 subjects (14 F and nine M; mean age: 15 years; S.D.: 1.24; range 13–17) with normal development and attending a local secondary school; 2) a clinical group (AG), composed of 23 subjects (21 F and two M; mean age: 14.7 years; S.D.: 2.34; range 10–18) referred to the same ward because of anorexia nervosa. The diagnosis of anorexia was made using eating attitude test (EAT) and KSADS-P which also permitted us to exclude any associated psychotic disorder in this psychiatric group. Demographic and clinical characteristics of the three groups are reported in Table 1. If inclusion criteria were satisfied, parents of eligible participants (and youths, once out of the acute episode) were informed about the research project and signed informed con-

b

16.4 ± 1.7 15.3 ± 1.8 39.1 83.6 ± 10.0

AG (n = 23) CG (n = 23) 14.7 ± 2.34 15 ± 1.4 13.5 ± 1.9 8.7 39.1 103.1 ± 6.9

92.3 8.7 0

95,7 4,3 0

95.7 4.3 0

87 13

91.3 8.7

91.3 8.7

F = 4.39; t = –2.40; P < .05 (EOS vs. AG). v2 = 5.8; P < .01.

sent was obtained. The local Ethics Committee has approved the research project. 2.2. Measures The acute phase was evaluated during the first hospitalization through the schedule for positive symptoms (SAPS) and the schedule for negative symptoms (SANS) [4,5]. These measures are composed of six-point items, regarding the main group of positive and negative symptoms, and were used by a trained child psychiatrist to evaluate symptomatology during a standard clinical interview. To determine the categorical diagnosis an independent trained child psychiatrist, blind to other clinical information, interviewed the adolescent and the parents separately using the K-SADS-P [11], a semistructured psychiatric interview according to the DSM-IIIR diagnostic criteria. Subjects of the two clinical groups received a psychological test including the WISC-III-R [30]. For the evaluation of the premorbid state we administered two forms of the child behavior checklist (CBCL): one concerning behavioral problems during the first 3 years of life (CBCL 2–3); the other concerning child problems within the 4–11 age period. This way we captured social and behavioral problems on the CBCL from three time frames: during the first 3 years of life, from ages 4 to 11, and at the time of visit. All the interviews were filled out by the mother. To exclude any possible overlap of the prodromal phase with the premorbid symptoms, we invited the parents to fill the 4–11 CBCL referring to the childhood period ending 1 year before evidence of full blown psychotic or anorexic symptomatology. CBCL [1] is a parent-form questionnaire composed of questions about social competencies and behavioral problems. From the row scores three summary scores (total problem (TP); internalizing; externalizing), eight syndrome scores, a total score for social competencies and three partial scores: Activity (including items about sports, hobbies, housework); Social (including items about the participation in social organizations); School (mainly academic performances) are obtained. For every score the cut-off between normal, border-

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Table 2 CBCL premorbid state (age range 4–11) in the three groups and comparisons CBCL Social competences Total Activities Social School Syndrome scales Withdrawn Somatic complaints Anxious/depressed Social problems Thought problems Attention problems Delinquent behavior Aggressive behavior Summary scales Internalizing Externalizing TP

EOS Mean (S.D.)

AG Mean (S.D.)

CG Mean (S.D.)

ANOVA

EOS vs. CG

EOS vs. AG

32.23 (7.41) 34.00 (7.91) 37.08 (7.83) 41.09 (9.49)

37.73 (7.15) 36.00 (6.12) 41.17 (8.64) 47.65 (6.91)

39.47 (4.53) 35.28 (4.06) 45.39 (6.63) 50.30 (4.10)

F = 7.08 b F = 0.58 ns F = 6.60 b F = 9.87 c

T = –3.82 b T = –0.66 ns T = –3.88 c T = –4.19 c

T = –2.50 a T = –0.95 ns T = –1.68 ns T = –2.66 b

65.57 (13.43) 56.52 (8.47) 62.17 (11.78) 65.39 (13.43) 58.48 (10.99) 62.57 (11.85) 56.09 (6.80) 51.65 (3.11)

63.43 (11.97) 58.13 (8.04) 62.74 (11.88) 57.74 (7.80) 52.39 (5.13) 54.39 (5.65) 55.96 (6.01) 53.48 (4.86)

52.04 (4.10) 50.91 (2.64) 50.78 (1.65) 50.17 (0.58) 50.00 (0) 50.30 (0,88) 50.22 (0.85) 50.00 (0)

F = 10.71 c F = 6.91 b F = 11.12 c F = 16.54 c F = 8.96 c F = 15.54 c F = 9.33 c F = 6.27 b

T = 4.62 c T = 3.03 b T = 4.59 c T = 5.43 c T = 3.69 c T = 4.95 c T = 4.11 c T = 2.55 b

T = 0.57 ns T = –0.66 ns T = –0.16 ns T = 2.37 a T = 2.40 a T = 2.99 b T = 0.07 ns T = –1.52 ns

62.26 (12.28) 47.57 (8.03) 57.57 (11.59)

61.17 (13.37) 50.70 (9.44) 56.00 (12.20)

41.65 (8.58) 35.78 (4.17) 35.30 (7.87)

F = 23.02 c F = 24.96 c F = 30.85 c

T = 6.6 c T = 6.24 c T = 7.62 c

T = 0.29 ns T = –1.21 ns T = 0.45 ns

a

P < 0.05. P < 0.01. c P < 0.001, t-test (df = 44), ANOVA (df = 36).

b

line and clinical range has been detected through the study of a huge normative sample. Its retrospective use has already been used by Baum and Walker [6] and Rossi et al. [25]. For this study the CBCL items were changed to the past tense as proposed by Baum and Walker. We adopted the cut-off score that distinguishes clinical cases from borderline and normal ones (values higher then 63 for summary scales, higher then 67 for syndrome scales, and lower then 37 for competency scale, mean worse clinical picture). To check for possible differences between the three groups at the two age-periods (2–3 and 4–11) ANOVAs was performed, using the group as the independent factor and CBCL scores as the dependent variables. Then the post hoc t-test (two-tailed, probability level P < 0.05) was used to contrast schizophrenic group with the other ones. The data were analyzed with SPSS 9.0 for Windows.

3. Results 3.1. Sample characteristics Demographic and clinical comparison between groups showed no statistical differences except for the higher rate of female and for the lower age upon entry into study in the AG. As expected KSADS-P showed a comorbidity of anorexia with depression and/or anxiety disorders in 80% of cases. The mean value of EAT-40 for this group was 45 (S.D.: 12; range 33–70). For EOS group SANS and SAPS showed: hallucinations (mainly auditory type) in 70% of patients; delusion in 91% (mainly persecutory type); bizarre, repetitive and aggressive behaviors in 55%; positive formal thought such as derailment and illogicality in 52%; negative symptoms (flat-

tening affect, alogy, poverty of speech, poor relationship, apathy and abuly) in 80%. On the basis of the prevalence of positive or negative symptoms, we have identified two clinical subtypes: positive subtype (13 cases) and negative subtype (10 cases); we included the 12 cases with a mixed subtype into one of the two main subgroups on the basis of the clinical judgment. 3.2. Premorbid state At the age period 4–11 years (Table 2) ANOVAs showed significant effect for the diagnostic group. Post hoc t-test comparisons indicated that EOS showed significantly higher mean scores than CG on all summary and syndrome scales, even if no mean score was in the clinical range. The EOS showed, relative to the AG, significantly higher mean scores on social problems, thought problems, attention problems and school competencies; for the other syndrome scales some significantly differences were found only on some item as reported on Table 3. At the age period 2–3 years (Table 4), EOS did not show any pathological mean score. Nevertheless, while no significant differences were present compared to the AG, significant differences appeared in all scales relative to the CG. EOS showed a long term stability of CBCL profile types: at the 2–3 age period an internalizing profile prevalently under the threshold (mean score: 58.47) was present; at the 4–11 age period the mean internalizing score (62.26) reached clinical significance; during the first-episode psychoses the internalizing score was more consistent (73.13) and it became the main dimension in CBCL broad profile (TP: 71.13; externalizing: 59.70).

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Table 3 CBCL premorbid state (age range 4–11): differences in the internalizing dimension between EOS and AG CBCL (item) Withdrawn Shy (75) Stares (80) Underactive (102) Somatic complaints Headaches (56b) Anxious/depressed Perfect (32) Selfconscious (71)

EOS Mean (S.D.)

AG Mean (S.D.)

P

1.39 (0.66) 0.35 (0.71) 0.78 (0.79)

0.91 (0.73) 0.00 (00) 0.13 (0.34)

t = 2.33 a t = 2.34 a t = 3.6 c

0.22 (0.42)

0.74 (0.62)

t = –3.34 b

0.22 (0.6) 0.96 (0.83)

0.61 (0.78) 0.52 (0.59)

t = –1.9 a t = 2.05 a

a

P < 0.05. P < 0.01. c P < 0.001.

b

As far as the number of cases with a TP in clinical range during the two premorbid periods is concerned, while for CG no subject was in clinical range, for EOS eight cases, during the age period 4–11, and four cases, during the age period 2–3 years, were in clinical range; comparing positive vs. negative subtypes, two out of 13 positive cases had a pathological TP on 4–11 CBCL, and six out of 10 negative cases had a pathological TP on 4–11 CBCL: this difference was significant [v2(1) = 4.92; P > 0.05] which means that more negative cases had a clinical premorbid state as indicated by worse TP on CBCL. Moreover all the four cases with a TP in clinical range during the age period 2–3 showed a negative subtype of EOS. The comparison of CG with the 15 EOS with a TP in nonclinical range during the age period 4–11, showed the maintenance of significant differences on all summary and syndrome scales with higher scores for the EOS.

4. Discussion Our findings are consistent with studies that underline the importance of alterations of the premorbid functioning in

patients with adult [2,20,31] or adolescent [18] onset schizophrenia. Although the study has the limitations of a retrospective study we underline that, differently from many previous studies, the examined age periods were relatively recent in time, so that mother’s memories were more able to differentiate the premorbid behavior of their child from both the prodromal and frankly morbid ones. In our study mothers have filled out the questionnaires at the earliest stage of the illness of their child so that the recall bias due to the duration of illness is extremely reduced. The many significant differences in all the behavioral problems investigated by the CBCL make children who develop schizophrenia during adolescence, different from healthy subjects. Otherwise before the onset of the psychotic or eating disorder, all children are equally filled by a premorbid psycopathology which makes these two groups different from healthy subjects. The internalizing constellation, expressed in our sample by the long term stability of internalizing profile, may index a more generally vulnerable child at risk for adolescent psychiatric disorders. In fact Cannon et al. [9] has signaled that childhood premorbid emotional difficulties are associated with a range of adult psychiatric disorders and that they indicate a common pathway to the development of a range of different disorders. However, this does not mean that EOS and AG are comparable before the onset of the illness. In fact those who later develop EOS look qualitatively different from children who will develop an eating disorder because of the major problems in the areas of social, thought and attention, and in school performances; it is possible to suggest that difficulties in these areas are specific in predating the emergence of the first-episode psychosis, and that they do not represent only a correlate or a sequelae of the illness. Moreover, even if internalizing total and syndrome scores does not show any significant differences, the internalizing dimension is qualitatively different as far as some items are concerned; subjects with EOS appear more shy, underactive and hypersensitive, and they stare more frequently, while subjects with anorexia, as expected, appear perfectionist and with

Table 4 CBCL premorbid state (age range 2–3) in the three groups and comparisons CBCL Syndrome scales Withdrawn Somatic complaints Sleep problems Anxious/depressed Delinquent behavior Aggressive behavior Summary scales Internalizing Externalizing TP a

EOS Mean (S.D.)

AG Mean (S.D.)

CG Mean (S.D.)

ANOVA

EOS vs. CG

EOS vs. AG

60.21 (11.91) 56.79 (8.57) 56.53 (7.60) 63.16 (14.47) 52.26 (4.54) 51.53 (3.13)

55.43 (6.91) 55.17 (6.85) 55.04 (5.98) 61.22 (10.94) 50.26 (0.86) 52.48 (3.81)

50.70 (2.60) 50.70 (2.48) 51.39 (3.46) 50.39 (1.16) 50.04 (0.21) 50.00 (0)

F = 7.81 b F = 5.36 b F = 4.45 a F = 10.00 c F = 4.81 a F = 4.48 a

T = –3.42 b T = –2.99 b T = –2.72 a T = –3.84 c T = –2.13 a T =–2.12 a

T = 1.55 ns T = 0.68 ns T = 0.71 ns T = 0.49 ns T = 1.89 ns T = –0.87 ns

58.47 (18.03) 43.47 (11.31) 50.74 (17.36)

55.17 (13.01) 44.17 (8.85) 49.61 (10.64)

39.74 (7.87) 35.48 (5.32) 36.13 (7.16)

F = 12.39 c F = 6.99 b F =10.01 c

T = –4.21 c T = –2.83 b T = –3.43 b

T = 0.688 ns T = –0.22 ns T = 0.26 ns

P < 0.05. P < 0.01. c P < 0.001, t-test (df = 44), ANOVA (df = 36).

b

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more somatic problems. Moreover, considering the high rate of depression in the AG, we suggest that the premorbid withdrawal in EOS could have a specific different quality as far as depression is considered, and that social isolation in children who later develop EOS is different from a non-specific antecedent for a broad spectrum of emotional disturbance. The finding of significant differences on social problem scale is congruent with studies showing that premorbid behavior of individuals who develop schizophrenia is marked by a tendency to seclusion and lack of sociability [6,20,10]. More recently Hans et al. [13] have indicated that social problems: 1) characterize the premorbid state of EOS, 2) could have a specific role in adolescent onset of schizophrenia, 3) extend beyond the onset of psychopathology, 4) may reflect vulnerability to schizophrenic disorders. Our finding regarding specific difficulties in school performances requires further comment. In fact two large Finnish studies [8,15] did not find any significant predictive power of school performances except in a non-academic domain [8]. An explanation of our conflicting finding could be related to the adolescent onset of our sample with respect to the adulthood onset which is usually considered a less severe type of schizophrenia. They confirm the idea that more precocious the onset of schizophrenia is, the more severe and persistent is the premorbid developmental impairment [9]. Our results are consistent with previous reports of a poorer premorbid functioning in subjects with more severe symptoms as reflected by the prevalence of negative symptoms [25,14,23]. They also seem to confirm the existence of the two clusters signaled by Rossi et al. [25]: cluster I, composed of patients showing early slight behavioral problems increasing progressively over the years; and cluster II, composed of patients characterized by the presence already during childhood of more severe behavioral problems. Our results show that children who during adolescence develop EOS are burdened by a broad symptomatology which reach clinical significance in about one third of cases. We can consider our eight cases with a childhood TP in clinical range during the ages 4–11 as belonging to cluster II. It seems however of interest that also the two thirds of our cases with a TP score in non-clinical range belonging to cluster I have, during the 4–11 age period, significantly higher scores on all summary and syndrome scales than healthy children. We can observe an analogous picture in the 2–3 age period where, though most children are not in the clinical range, there are however significant differences from the non-clinical subjects; moreover, the absence of significant differences in this age period between subjects who develop schizophrenia and subjects who develop an eating disorder shows again these two samples as very similar and characterized for the presence of a common internalizing premorbid symptomatology. The absence in the CBCL 2–3 of the four scales able to differentiate premorbid state in the 4–11 age period for subjects who later develop EOS or AN does not permit us to explore these characteristics at this very early age. Some limitations in this study should be noted. First, sample size is a problem for this area of research. EOS is

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relatively uncommon and small sample sizes are a problem throughout literature [18]. Furthermore our findings regard a specific population of adolescents with schizophrenia characterized by a severe first-episode psychosis needing hospitalization, and by no association with substance use, which is now considered influential for the onset of some cases of schizophrenia [27]. Second, the choice of patients with anorexia as a reference psychiatric group could be questionable for the little phenomenological overlap and because it is not well matched by sex. Nevertheless the similar pathways of the two syndromes, characterized by a full-blown symptomatology preceded by a prodromal syndrome and a longlife subthreshold premorbid state, could be a strong point of our study which shows similarities and differences between two separate clinical groups opening the avenue to specificity of premorbid vulnerability to different diseases. Thirdly, only retrospective parent report was used. On the contrary, many studies of this kind have used ratings of premorbid functioning performed only by clinicians [28]. We need studies using different informants (parents, teachers, clinicians), as well as new studies using direct inspection of children through home movies as a new source of information [32], which together may shed light on premorbid period of EOS. Notwithstanding these limitations, our study reveals how EOS begins in adolescence with a symptomatology which has its roots in previous behavioral problems. Even if they rarely reach the clinical threshold, children who develop schizophrenia during adolescence are different from healthy children for the higher behavioral problems rate. Moreover the fact that also children who later develop anorexia show a higher behavioral problems rate than the healthy group deserves attention. In fact it seems to indicate that both these disorders of adolescence represent the expression of a crisis which happens in the contest of a constitutional fragility characterized by an internalizing pattern. Despite the fact that prevention of schizophrenia is a complex and problematic issue and that we need more research to improve our knowledge about risk indicators, our study proposes, through an instrument which can be used for epidemiological studies, some premorbid features specific to schizophrenia and different from emotional difficulties found in anorexia. In particular we have carried out a deeper investigation into social withdrawal which appears an early manifestation of negative symptoms currently considered the core feature of schizophrenia.

References [1]

[2]

[3]

Achenbach TM. Manual for the child behavior checklist/4–18 and 1991 profile. Burlington: University of Vermont, Department of Psychiatry; 1991. Amminger GP, Rock D, Roberts S. Relationship between childhood behavioral disturbance and later schizophrenia in the New York High Risk Project. Am J Psychiatry 1999;156(4):525–30. Andreasen NC. Positive vs. negative schizophrenia: a critical evaluation. Schizophr Bull 1995;11:380–9.

314 [4] [5] [6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14] [15]

[16]

[17]

[18]

F. Muratori et al. / European Psychiatry 20 (2005) 309–314 Andreasen NC. The scale for the assessment of positive symptoms. Iowa City, IA: The University of Iowa; 1984. Andreasen NC. The scale for the assessment of negative symptoms. Iowa City, IA: The University of Iowa; 1984. Baum KM, Walker EF. Childhood behavioral precursors of adult symptom dimensions in schizophrenia. Schizophr Res 1995;16(2): 111–20. Cannon M, Walsh E, Hollis C, Kargin M, Taylor E, Murray RM, et al. Predictors of later schizophrenia and affective psychosis among attendees at a child psychiatry department. Br J Psychiatry 2001;178: 420–6. Cannon M, Jones P, Huttunen MO, Tanskanen A, Huttunen T, RabeHesketh S, Murray RM. School performance in Finnish children and later development of schizophrenia: a population-based longitudinal study. Arch Gen Psychiatry 1999;56(5):457–63. Cannon M, Caspi A, Moffitt TE, Harrington H, Taylor A, Murray RM, et al. Evidence for early-childhood, pan-developmental impairment specific to schizophreniform disorder: results from a longitudinal birth cohort. Arch Gen Psychiatry 2002;59(5):449–56. Cannon M, Jones P, Gilvarry CM, Rifkin L, Mckenzie K, Foerster A, et al. Premorbid social functioning in schizophrenia and bipolar disorder: similarities and differences. Am J Psychiatry 1997;154: 1544–50. Chambers W, Puig Antich J, Hirsch M, Paez P, Ambrosini P, Tabrizi M, et al. The assessment of affective disorders in children and adolescent by semistructured interviews: test retest reliability of the Kiddie-Sads. Arch Gen Psychiatry 1985;42:696–702. Done DJ. Childhood antecedents of schizophrenia and affective illness: social adjustment at ages 7 and 11. Br Med J 1994;309:699– 703. Hans SL, Auerbach JG, Asarnov JR, Styr B, Marcus J. Social adjustment of adolescents at risk for schizophrenia: the Jerusalem Infant Development Study. J Am Acad Child Adolesc Psychiatry 2000; 39(11):1406–14. Hollis C. Child and adolescent schizophrenia. A case study of premorbid developmental impairments. Br J Psychiatry 1995;166:489–95. Isohanni M, Makikyro T, Moring J, Rasanen P, Hakko H, Partanen U, et al. A comparison of clinical and research DSM-III-R diagnoses of schizophrenia in a Finnish national birth cohort. Soc Psychiatry Psychiatr Epidemiol 1997;32(5):303–8. Jones P, Rodgers B, Murray R, Marmot M. Child developmental risk factors for adult schizophrenia in the British 1946 birth cohort. Lancet 1994;344:1398–402. Karp BI, Garvey M, Jacobsen LK, Frazier JA, Hamburger SD, Bedwell JS, et al. Abnormal neurologic maturation in adolescents with early-onset schizophrenia. Am J Psychiatry 2001;158(1):118–22. McClellan J, Breiger D, McCurry C, Hlastala SA. Premorbid functioning in early-onset psychotic disorders. J Am Acad Child Adolesc Psychiatry 2003;42(6):666–72.

[19] McGorry PD, Jackson HJ. The recognition and management of early psychosis. Cambridge, UK: Cambridge Univerity Press; 1999. [20] Neumann CS, Grimes K, Walker EF, Baum K. Developmental pathways to schizophrenia: behavioral subtypes. J Abnorm Psychol 1995; 104(4):558–66. [21] Nicolson R, Lenane M, Singaracharlu S, Malaspina D, Giedd JN, Hamburger SD, et al. Premorbid speech and language impairments in childhood-onset schizophrenia: association with risk factors. Am J Psychiatry 2000;157(5):794–800. [22] Offord DR. School performance of adult schizophrenics, their siblings and age mates. Br J Psychiatry 1974;125:12–9. [23] Rabinowitz J, De Smedt G, Harvey PD, Davidson M. Relationship between premorbid functioning and symptom severity as assessed at first-episode psychosis. Am J Psychiatry 2002;159(12):2021–6. [24] Reiter G, Bilder RM, Freysisen P. Premorbid achievement in firstepisode schizophrenia. J Int Neuropsychol Sci 1995;1:157. [25] Rossi A, Pollice R, Daneluzzo E, Marinangeli MG, Stratta P. Behavioral neurodevelopment abnormalities and schizophrenic disorder: a retrospective evaluation with the childhood behavior checklist (CBCL). Schizophr Res 2000;44(2):121–8. [26] Tolbert HA. Psychoses in children and adolescents: a review. J Clin Psychiatry 1996;57:4–8. [27] Veen ND, Selten JP, van der Tweel I, Feller WG, Hoek HW, Kahn RS. Cannabis use and age at onset of schizophrenia. Am J Psychiatry 2004;161(3):501–6. [28] Vourdas A, Pipe R, Corrigall R, Frangou S. Increased developmental deviance and premorbid dysfunction in early onset schizophrenia. Scizophr Res 2003;1(62):13–22. [29] Warner R. The prevention of schizophrenia: what interventions are safe and effective? Schizophr Bull 2001;27(4):551–62. [30] Wechsler D. Manual for the Wechsler intellegence scale for children. 3rd ed. San Antonio, TX: Psychological Corporation; 1991. [31] Walker EF, Grimes KE, Davis DM, Smith AJ. Childhood precursors of schizophrenia: facial expressions of emotion. Am J Psychiatry 1993;50(11):1654–60. [32] Walker E, Lewine JR. Prediction of adult-onset schizophrenia from childhood home movies of the patients. Am J Psychiatry 1990;147(8): 1052–6. [33] Walker EF, Diforio D, Baum K. Developmental neuropathology and the precursors of schizophrenia. Acta Psychiatr Scand Suppl 1999; 395:12–9. [34] Werry JS, McClellan JM, Andrews LK. Clinical features and outcome of child and adolescent schizophrenia. Schizophr Bull 1994;20:619– 30. [35] Weinberger DR. Implication of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987;44:660–9. [36] Werry JS. Child and early adolescent schizophrenia: a review in the light of DSM III-R. J Autism Dev Disord 1992;22:610–4. [37] Yung AR, McGorry PD. Is pre-psychotic intervention realistic in schizophrenia and related disorders? Aust New Zealand J Psychiatry 1997;31:799–805.