Risk Factors for the Emergence of Psychotic Disorders in Adolescents

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one-third of all individuals with 22q11.2 deletion syndrome develop ...... Achenbach TM: Manual for the Child Behavior Checklist/4-18 and 1991 Profile.

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Risk Factors for the Emergence of Psychotic Disorders in Adolescents With 22q11.2 Deletion Syndrome Doron Gothelf, M.D. Carl Feinstein, M.D. Tracy Thompson, Ph.D. Eugene Gu Lauren Penniman, B.A. Ellen Van Stone, B.A. Hower Kwon, M.D. Stephan Eliez, M.D., Ph.D. Allan L. Reiss, M.D.

Objective: The 22q11.2 deletion syndrome is the most common known genetic risk factor for the development of schizophrenia. The authors conducted a longitudinal evaluation of adolescents with 22q11.2 deletion syndrome to identify early risk factors for the development of psychotic disorders. Method: Sixty children, 31 with 22q11.2 deletion syndrome and 29 comparison subjects with idiopathic developmental disability matched for age and IQ, underwent a baseline evaluation between 1998 and 2000; of these, 51 children (28 and 23 in the two groups, respectively) underwent follow-up evaluation between 2003 and 2005. A standardized comprehensive psychiatric, psychological, and adaptive functioning evaluation was conducted in both waves. Participants with 22q11.2 deletion syndrome were also genotyped for the catechol O-methyltransferase (COMT) Met/Val polymorphism and underwent magnetic resonance imaging scans.

Results: The two groups had similar baseline neuropsychiatric profiles. At follow-up, 32.1% of subjects with 22q11.2 deletion syndrome had developed psychotic disorders as compared with 4.3% of comparison subjects. In the 22q11.2 deletion syndrome group, baseline subthreshold psychotic symptoms interacted both with the COMT genotype and with baseline symptoms of anxiety or depression to predict 61% of the variance in severity of psychosis at follow-up evaluation. Lower baseline verbal IQ was also associated with more severe psychotic symptoms at follow-up evaluation. Conclusions: Genetic , cognitive, and psychiatric risk factors for the evolution of psychotic disorders in 22q11.2 deletion syndrome during adolescence were identified. Early intervention in the subgroup of children with subthreshold signs of psychosis and internalizing symptoms (especially anxiety symptoms) may reduce the risk of developing psychotic disorders during adolescence. (Am J Psychiatry 2007; 164:663–669)

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he 22q11.2 deletion syndrome, also known as velocardiofacial syndrome or DiGeorge syndrome, is the most common microdeletion genetic disorder known in human beings, occurring in at least 1:5,000 live births (1). It is caused by a microdeletion in the long arm of chromosome 22 and is associated with congenital malformations and cognitive deficits (1, 2). The 22q11.2 deletion syndrome is an appealing model for studying risk factors for the emergence of schizophrenia and other psychotic disorders, as one-third of all individuals with 22q11.2 deletion syndrome develop schizophrenia-like psychotic disorders (3, 4). From early childhood, abnormal behaviors and an increased rate of psychiatric disorders are already present in subjects with 22q11.2 deletion syndrome. While the schizophrenia-related psychotic disorders usually evolve only during late adolescence or early adulthood, children and adolescents with 22q11.2 deletion syndrome have a high frequency of nonpsychotic psychiatric disorders, including attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder, anxiety and affective disorders, autism, and obsessive-compulsive disorder (OCD)

(5–7). Some of these early abnormal neuropsychiatric symptoms could be premorbid signs for the later development of psychosis (8, 9). Cross-sectional studies of children with 22q11.2 deletion syndrome indicate that onethird to one-half of affected individuals demonstrate subsyndromal evidence of definite or suspected signs and symptoms of psychosis (5, 6). The purpose of this study was twofold. First, we sought to evaluate the psychiatric, behavioral, and adaptive developmental trajectories of individuals with 22q11.2 deletion syndrome in comparison with individuals with idiopathic developmental disability during the critical period from childhood and early adolescence to late adolescence and early adulthood. We predicted that significantly more individuals in the 22q11.2 deletion syndrome group would develop psychotic disorders than in the comparison group. Our second objective was to identify the profile of early risk factors for the development of psychotic disorders in 22q11.2 deletion syndrome. On the basis of our previous findings (3), we assumed that the catechol O-methyltransferase (COMT) low-activity allele (COMT

This article is discussed in an editorial by Dr. Kates on p. 547. Am J Psychiatry 164:4, April 2007

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PSYCHOSIS IN 22Q11.2 DELETION SYNDROME

Met) would predict the development of psychotic disorders by the time of the follow-up evaluation. On the basis of findings from the neuroimaging literature on schizophrenia in the general population (10, 11) and on 22q11.2 deletion syndrome (12, 13), we also hypothesized that abnormal prefrontal and temporal gray matter volumes at baseline would be associated with the development of psychotic disorders. Finally, we predicted that subjects with prodromal psychotic symptoms at the time of the first evaluation would be more likely to have developed a psychotic disorder at follow-up.

Method Subjects The baseline assessment, conducted between 1998 and 2000, included 31 children with 22q11.2 deletion syndrome and a comparison group of 29 children with idiopathic developmental disability matched for age, gender, and IQ. Recruitment and sample characteristics have been described elsewhere (6). The 22q11.2 deletion syndrome group included only children in whom the microdeletion was confirmed with a fluorescence in situ hybridization test. Similarly, absence of the 22q11 deletion was confirmed in all comparison subjects. A follow-up assessment of the initial sample, conducted between 2003 and 2005, included 28 children from the 22q11.2 deletion syndrome group (90.3%) and 23 from the developmental disability group (79.3%). Dropouts were due to the inability to locate subjects whose family had left the area (two from the 22q11.2 deletion syndrome group and four from the developmental disability group) or to subjects’ choosing not to participate in the followup evaluation (one from the 22q11.2 deletion syndrome group and two from the developmental disability group). In both groups, subjects who dropped out of the study were similar to their counterparts who participated in the follow-up evaluation in baseline age and severity of psychiatric symptoms (as measured by the Child Behavior Checklist—Parent Version [CBCL; 14]). Full-scale IQ scores tended to be lower in subjects who dropped out compared with those who participated at follow-up (57.0 [SD=17.4] versus 70.5 [SD=16.1] in the 22q11.2 deletion syndrome group and 68.3 [SD=21.8] versus 74.4 [SD=23.5] in the developmental disability group). There were no significant differences between the groups at follow-up in age at baseline assessment (mean=12.5 years [SD= 3.9] and mean=12.9 years [SD=3.3] for the 22q11.2 deletion syndrome and developmental disability groups, respectively), age at follow-up assessment (mean=17.4 years [SD=3.7] and mean=18.2 years [SD=3.8], respectively), gender distribution (males:females, 18:10 and 14:9, respectively), full-scale IQ (mean=70.5 [SD=16.1] and mean=74.3 [SD=23.6], respectively), and duration of parents’ education (mean=16.4 years [SD=2.2] and mean=17.1 years [SD= 3.0], respectively). The mean time between assessments was shorter for the 22q11.2 deletion syndrome group than for the developmental disability group (mean=4.8 years [SD=0.8] versus mean=6.0 years [SD=2.6], respectively). After providing a complete description of the study to the subjects and their parents, written informed consent was obtained at both assessments, under protocols approved by the institutional review board of Stanford University.

Genotype Blood samples were drawn from the 22q11.2 deletion syndrome group to determine genotype. The COMT Val108/158Met polymorphism (rs165688) was genotyped by polymerase chain

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reaction and restriction digestion according to standard techniques and was determined by NlaIII digestion (NlaIII+=Met, NlaIII–=Val) (15).

Neuropsychiatric, Adaptive Functioning, and Cognitive Assessments Interviewers at follow-up were blind to baseline evaluations and diagnoses. They were also blind to group status, although a minority of subjects in the 22q11.2 deletion syndrome group exhibited clinical features of the syndrome, such as dysmorphic facies and hypernasal speech. The baseline psychiatric evaluation included the following: 1. The Child Behavior Checklist—Parent Version. This instrument is a well-established and widely used questionnaire, both for typically developing children (14) and for children with developmental disabilities (16). The scale yields a total problem score and eight syndrome scores. 2. The computerized Diagnostic Inventory for Children and Adolescents (17), a DSM-IV-based structured interview that was administered by a child and adolescent psychiatrist to participants’ parents. 3. The screening-question portion of the parent version of the Schedule for Affective Disorders and Schizophrenia for SchoolAged Children—Present and Lifetime Version (K-SADS-PL) (18). If any screening item was positive, the full K-SADS-PL section on the relevant possible diagnosis was administered. In addition, a 3point psychosis scale was created on the basis of the K-SADS-PL psychosis scores. A score of 0 indicated no hallucinations or delusions; 1 indicated subthreshold (i.e., suspected or likely) hallucinations or delusions; and 2 indicated definite hallucinations or delusions. Each subject’s diagnostic information was reviewed by at least two of five child psychiatrists (D.G., C.F., H.K., S.E., and A.L.R.), and a consensus diagnosis based on DSM-IV criteria was made. The follow-up psychiatric evaluations were similar to the baseline evaluations but included some modifications because some of the subjects were young adults at follow-up. Thus, for subjects 19 years of age and older, we used the Adult Behavior Checklist (19), an adult version of the CBCL, also completed by parents. For the longitudinal analyses, we used six symptom scales and the internalizing and externalizing group scores, which are similar in the child and adult questionnaires. In addition, subjects over age 18 were evaluated with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) (20). All subjects were interviewed at follow-up by a child and adolescent psychiatrist, who completed the Brief Psychiatric Rating Scale (BPRS) based on his or her evaluation of the subject (21). The interview was extended to include the K-SADS-PL or SCID sections assessing psychosis. The interviewer also asked subjects to verify uncertain symptoms suggested by their parents (e.g., depressive, compulsive, or phobic symptoms). Adaptive behavior was assessed at both baseline and follow-up with the Vineland Adaptive Behavior Scales—Interview Edition (22), which were completed on the basis of interviews with the parents. Standard scores were calculated on the basis of the age-appropriate national standards up to the age of 19 years (22). For subjects above age 19, the norms of the upper age level were used (18 years and 8 months to 19 years), as suggested by the manual (22). For cognitive assessment, the Wechsler Intelligence Scale for Children, 3rd edition (23), was used for subjects age 17 and younger, and the Wechsler Adult Intelligence Scale, 3rd edition (24), for those above age 17.

Magnetic Resonance Imaging Protocol The 22q11.2 deletion syndrome group underwent magnetic resonance imaging (MRI) scans. Coronal images were acquired with a GE 1.5-T scanner (General Electric, Milwaukee) using a three-dimensional volumetric radiofrequency spoiled gradient echo pulse sequence with the following scan parameters: TR=35 Am J Psychiatry 164:4, April 2007

GOTHELF, FEINSTEIN, THOMPSON, ET AL. TABLE 1. Change in Psychiatric Morbidity Between Baseline and Follow-Up in Subjects With 22q11.2 Deletion Syndrome and Comparison Subjects With Idiopathic Developmental Disability Baseline Subjects With 22q11.2 Deletion Syndrome (N=28) Psychiatric Disorder Psychotic disordersa Attention deficit hyperactivity disorder Oppositional defiant disorder Anxiety disordersb Affective disorders

N 0 12 12 17 7

% 0.0 42.9 42.9 60.7 25.0

Follow-Up

Comparison Subjects With Developmental Disability (N=23) N 0 9 10 16 7

% 0.0 39.1 43.5 69.6 39.1

Subjects With 22q11.2 Deletion Syndrome (N=28) N 9 9 9 20 7

% 32.1 32.1 32.1 71.4 25.0

Comparison Subjects With Developmental Disability (N=23) N 1 8 6 9 5

% 4.3 34.8 26.1 39.1 21.7

a Fisher’s exact test, p=0.015. b In group-by-baseline-diagnostic-status

analysis, logistic regression with psychiatric status at follow-up as outcome variable and psychiatric diagnosis by group interaction as predictor, β=0.42, p=0.04.

msec, TE=6 msec, flip angle=45°, number of excitations=1, matrix size=256×192, field of view=24 cm 2, slice thickness=1.5 mm, 124 contiguous slices. MRI scans were imported into BrainImage (Stanford University, Stanford) for semiautomated whole-brain segmentation and quantification using previously described and validated methods (25) that produce volume measurements of gray matter, white matter, CSF, and total tissue for the whole brain and for the four cerebral lobes. The prefrontal cortex was defined as all frontal cortical gray matter lying anterior to a coronal plane intersecting the most anterior point of the genu of the corpus callosum (3, 26).

Data Analysis Pearson chi-square tests were used to assess the difference between groups in the frequency of psychiatric disorders at baseline. For between-groups comparisons of the change in frequency of psychiatric disorders from baseline to follow-up, logistic regressions were done for each psychiatric diagnosis. In each analysis, the diagnostic status at follow-up was the outcome variable, and baseline psychiatric diagnosis by group interaction was predictor. Unpaired t tests were used for between-groups comparison of baseline CBCL and Vineland Adaptive Behavior Scales subscale scores. Longitudinal change in CBCL and Vineland subscale scores was assessed by repeated-measures analyses of variance (ANOVAs) with group as the between-subjects factor and CBCL and Vineland subscale scores at baseline and follow-up as the within-subject factor. To clarify the interactions, we calculated the effect sizes (standardized mean differences) within each group. To further investigate significant interactions, we conducted post hoc pairwise t tests separately for the two groups. As the repeated-measures ANOVA was used 13 times, the significance threshold was corrected to an alpha of 0.004. For the longitudinal prediction of follow-up psychotic disorders and BPRS scores in 22q11.2 deletion syndrome, we used hierarchical/stepwise logistic and linear regressions.

Results Longitudinal Change in Psychiatric Morbidity There were no significant differences between the 22q11.2 deletion syndrome group and the developmental disability group at baseline in the frequency of any psychiatric disorder, and none of the participants had a psychotic disorder (Table 1). At follow-up, significantly more subjects with 22q11.2 deletion syndrome than comparison subjects fulfilled DSM-IV criteria for a psychotic disorder (p=0.01). The psychotic disorders in the 22q11.2 deletion syndrome group were schizophrenia or schizoafAm J Psychiatry 164:4, April 2007

fective disorder (N=6), schizophreniform disorder (N=2), and psychotic depression (N=1). One subject in the developmental disability group met criteria for psychotic depression. The 22q11.2 deletion syndrome group had a higher mean BPRS score at follow-up (35.7 [SD=12.5]) compared with the developmental disability group (28.0 [SD=7.1], t=2.7, df=49, p=0.01). The logistic regression showed that there was a significant effect of anxiety disorder status (presence or absence) at baseline by group interaction on anxiety disorder status at follow-up (p

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