Avoidant personality disorder increases the detection of first degree relatives affected by a schizophrenia spectrum diagnosis

80 in the treatment of schizophrenia has been demonstrated by combining the c~1-antagonist, prazosin, with haloperidol to produce superior effects similar to those of atypical antipsychotics. Genetic mutations in the C~lA-adrenoceptor may contribute to the dysfunction observed in schizophrenia, and may affect antipsychotic response. To test this hypothesis, we investigated an amino acid substitution (Arg492Cys) in the 3rd intracellular loop of this g-protein coupled receptor that may alter receptor signal transmission. To test this hypothesis, a total of 123 subjects receiving antipsychotic treatment (110 with schizophrenia, 14 with schizo-affective disorder) and 224 controls, all from northern Spain, were genotyped. Treatment response was assessed prospectively using the Positive And Negative Symptoms Scale (PANSS) and the Global Assessment Scale (GAS). No clear differences were observed between the different groups suggesting that this polymorphism does not have a significant role in either antipsychotic treatment or the aetiology of psychosis.

ASSOCIATION STUDY OF DYSBINDIN GENE (DTBN1) BFAI POLYMORPHISM IN SCHIZOPHRENIA V. De Luca,* R Muglia, M. Masliis, G. Wong, J. L. K e n n e d y

Neurogenetics, Centrefor Addcition and Mental Health, Toronto, ON, Canada Genome-wide linkage scans have provided some replicating evidence for involvement of the region of 6p24-21 in susceptibility to schizophrenia. Recent studies have implicated that the gene DTNBP1 (the human orthologue of the mouse dyshindin gene) in this region is strongly associated with schizophrenia. The purported function of the dysbindin gene in brain development is consistent with the neurodevelopmental hypothesis of schizophrenia. In a case-control association study we investigated the BfaI polymorphism (SNP 909706: an A to G transition) located in intron 1 of the DTNBP1 gene. Our pilot sample size consists of 30 schizophi'enics diagnosed via SCID interview and DSM-1V criteria. These cases are matched with 30 healthy controls for age, gender and ethnicity. The BfaI polymorphism is not associated with schizophrenia in this l~ilot sample (allelewise)~2=1.62, ldf, p=0.27; genotypewise Z~=2.58, 2df, p=0.27). We are cun'ently testing a larger sample of case-controls and a sample of triad families consisting of schizophrenia probands and both parents. In view of the positive genome scan data on 6p and the previously reported strong statistical results for DTNBP1, this gene remains of high interest in schizophrenia. Larger samples and more markers need to be typed at this locus to provide haplotype information and thus a more detailed test of this candidate gene.

COHERENCE OF CO-FAMILIAL PHENOTYPES IN SCHIZOPHRENIA: CRANIOFACIAL DYSMORPHOLOGY, THOUGHT DISORDER, AND SMOOTH PURSUIT EYE MOVEMENTS C. K. Deutsch,* D. L. Levy, E. A. Lauer, O. Krastoshevsky, E. Saunders, M. J. Coleman, S. E Price, S. Matthysse, R S. H o l z m a n

Psychobiology Program, Shriver Center, Waltham, MA, USA We have identified in previous studies three phenotypes that are statistically overrepresented among schizophrenic probands and their relatives: (1) embryologically-derived measures of craniofacial dysmorphology, (2) thought disorder assessed using the TDI, and (3)

7. Genetics, Clinical impairment of smooth pursuit eye movements (SPEM). Among firstdegree relatives, these co-familial traits are more prevalent than schizophrenia itself, and may constitute alternative manifestations of the same pathogenic process(es) that gives rise to psychiatric symptomatology. Our approach to dysmorphology diagnosis combines objective quantitative measures with biological interpretation based on embryologic factors. Both brain and face develop from common primordia (anlagen) and are shaped simultaneously by shared morphogenetic forces. Thus, untoward genetic or teratogenic influences on brain development can also disrupt the formation of craniofacial features. The purpose of this study is to determine the extent to which dysmorphology in schizophenia (here, derivatives of the interface of frontonasal and maxillary primordia) relate to TDI and SPEM scores. We report that dysmorphology and TDI scores are positively correlated among schizophrenic probands; thus, patients who have more anomalies along this embryologic juncture are more severely thought- disordered. This pattern also applies to their firstdegree relatives. However, there is no correlation between dysmorphology and SPEM among schizophrenic probands and relatives. Further, dysmorphology scores were uncorrelated with either behavioral phenotype in contrast groups of bipolar probands and their relatives. Because frontonasal-maxillary dysmorphology predicts specific regions of brain pathogenesis, its correlation with the TDI may advance the biological interpretation of thought disorder. Additionally, these phenotypes may combine with psychiatric diagnoses to boost the power to detect genetic linkage in schizophrenia. (Supported by NIMH: PO1 MH31154, RO1 MH49487, and ROI MH20892.)

AVOIDANT PERSONALITY DISORDER INCREASES THE DETECTION OF FIRST DEGREE RELATIVES AFFECTED BY A SCHIZOPHRENIA SPECTRUM DIAGNOSIS D. L. Fogelson,* K. H. Nuechterlein, R. A. Asarnow, K. L. Subotnik, D. L. Payne, K. C. Jacobson, M. C. Neale, K. S. Kendler

Department of Psychiatry and Biobehavioral Sciences, University of CaliJbrnia Los Angeles, Los Angeles, CA, USA The detection of relatives (Rels) of schizophrenia (Sz) probands who are affected by a Sz spectrum diagnosis (SzSD) allows delineation of an extended phenotype that may be helpful for establishing patterns of famihal transmission. Accepted SzSDs include: Sz, Sz-affective disorder, atypical psychosis, & Sz-typal & paranoid personality disorders. Avoidant Personality Disorder (APD) has been suggested to be a SzSD. APD would increase our detection of Rels "affected by a SzSD if it shows increased rates even when not co-morbid with another SzSD. We examined ifAPD shows heightened rates among Sz Rels, increases the detection of Rels affected by a SzSD, and has an unusual symptom structure. 1° relatives 18 years & older of probands with adult onset Sz (AOS), childhood onset Sz (COS), attention deficit disorder (ADHD), & of adult and child community control probands (ACC & CCC) were blindly interviewed using the DIS, PSE, & SCID. Diagnoses were made using direct interview, family history, & medical records. The risk for APD (see APD frequency Table) using logistic regression corrected for clustering within families, 1 tailed tests, shows: including co-morbid SzSD, (1+2) vs. (3+4), P=.00045; (1+2) vs. (5), P=.046; with no co-morbid SzSD, (1+2) vs. (3+4), P=.0038; (1+2) vs. (5), P=. 13. APD appears 71% of the time (25/35 cases, groups l&2) outside the presence of a SzSD. No significant differences were found between groups in dimen-

International Congress on Schizophrenia Research 2003

7. Genetics, Clinical

81

sional scores on individual SCID items or in the number of times an item was rated as present. We have replicated findings that 1° Rels of probands with COS & AOS are at increased risk for APD compared to 1° Rels of ADHD and ACC & CCC groups. This finding holds for APD outside the presence of a SzSD compared to the ACC & CCC groups but not to the ADHD control group. This pattern suggests that APD should be included as a SzSD, but its familial ties may not be wholly specific to Sz. The absence of sx structure differences suggests it is the same disorder across groups. Since APD appears 71% of the time outside the presence of other SzSD, it increases the detection of Rels affected by a SzSD. NoAPD APD(casesfilcludcCo-morbidSzSD APD(noCo-morbidity) 1-AOS

259

23

16

2-COS

84

12

9

3-ACC

120

3

2

4-CCC

121

2

2

5~ADHD

192

11

9

PSYCHOMETRIC RELATIONSHIPS OF INSIGHT IN PATIENTS WITH SCHIZOPHRENIA WHO C O M M I T S V I O L E N T ACTS L. Friedman,* D. Hrouda, S. Noffsinger, R Resnick, R E Buckley The MIND Institute, Albuquerque, NM, USA Lack of insight into illness is a core and most common characteristic of schizophrenia. Relationships between psychopothology, cognitive status and insight are complex. Impaired insight has variously been associated with more pronounced positive and negative symptoms, depressive symptoms, and with cognitive deficits. Impaired insight has also been hypothesized as the functional analogue for schizophrenia of the anosgnosic syndromes which are observed in patient with organic lesions affecting the parietal lobes. These relationships were examined here in a cohort of 122 patient with DSM-IV schizophrenia who committed violent acts. When compared to a community sample (n=l 11) of nonviolent schizophrenic patients, violent patients were more symptomatic (PANSS total score 73 + 19 v's 61 + 16, P < 0.0001) and exhibited poor insight (PANNS insight item 4.3 + 1.8 v's 2.7 + 1.7, P < 0.0001)Violent patients also showed significant insight deficits when compared with nonviolent patient on the SUMD. However, both groups had comparable cognitive perform~mce on Trials A & B and MMSE. Violent patients also exhibited poor [forensic] insight into the legal relationship to their illness, as measured on the Eisner scale. However, overall the correlations between Eisner and SUMD scales were weak, indicating a relative dissonance between 'illness insight' and 'forensic insight' in violent patients with schizophrenia. Funded by the Theodore and Vada Stanley Foundation

CHILDHOOD BEHAVIOUR IN A 22Q DELETION SYNDROME SUBTYPE OF SCHIZOPHRENIA M. Gheorghiu,* E. Chow, A. S. Bassett Clinical Genetics Research Program, Centre CotAddiction and Mental Health, Toronto, ON, Canada A high proportion of individuals with 22q Deletion Syndrome (22qDS) develop psychotic illnesses, primarily schizophrenia (SZ). Individuals with 22qDS may therefore be considered a genetic high

risk group for schizophrenia. Measures of childhood behaviour may be helpful in determining precursors of schizophrenia. We used the Childhood Behavioral Checklist (CBCL), a standard measure that quantifies problematic emotions and behaviours in childhood through adolescence. Parents completed the CBCL for the 4-15 year age period (always pre-onset of psychosis) for 22 individuals with 22qDS (10 22qDS-SZ and 12 with no psychosis (22qDS-NP)) and 6 controls with a congenital heart defect. We compared the groups on the eight CBCL syndrome scale scores. Within the 22qDS group there were no significant differences on any scale. However, the 22qDS-SZ and 22qDS-NP groups were significantly different from the control group on the following scales: withdrawn (p=0.004; p=0.001, respectively), anxiety (p<0.0001, p=0.0016, respectively), attention (p=0.001, p=0.003 respectively) and thought (p=0.03 for 22qDS-SZ, only a trend for 22qDS-NP p=0.09) scales. The results show that irrespective of psychosis status, the two 22qDS groups have similar emotional and behavioural profiles in childhood and adolescence on the CBCL in this study. However, the results also indicate that their profile is significantly different from that of individuals who do not have 22qDS: 22qDS patients showed more emotional and behavioural problems than individuals with a congenital heart defects. The results suggest that the CBCL may not be useful as a tool to help predict precursors of psychotic disorders in subjects with 22qDS.

THE NEURODEVELOPMENTAL HYPOTHESIS IN SCHIZOPHRENIA: D E F I N I N G A C O M P O S I T E PHENOTYPE D. Gourion,* M. O. Krebs INSERM El17, INSERM, Paris, France Background: Schizophrenia is a complex heritable disease with both genetic and environmental factors. Compelling evidences suggest that neurodevelopmental disruption could predispose to schizophrenia, and that Neurological Soft-Signs(NSS) and Minor Physical Anomalies (MPAs) are frequently found in patients with schizophrenia and their non psychotic relatives. Co-assessment of NSS and MPAs could lead to the validation of a composite phenotype based on a combination of developmental markers, especially interesting as a quantitative phenotype in extensive genetic studies of schizophrenia. Material and Methods: First, we studied the intrafamilial variance of NSS and MPAs in order to determine their familiality within 18 nuclear families. Secondary, a sample of 76 non-psychotic first degree relatives was dichotomized between presumed- and non-presumed- carriers for the genetic vulnerability to schizophrenia. Were defined as presumed carriers the parents who had a first or second degree family history of schizophrenia in their ascendants and/or collateral. NSS were assessed using a validated scale (Krebs et al, 2000), including 23 items and five consistent factors. MPAs were assessed in six body areas using a standardized scale (41 items) derived from the Waldrop's scale (Gourion et aI., 2001). Results: We performed intrafamilial variances for NSS and MPAs. NSS were significantly transmitted within families (Intra-Class Coefficient = 0.64; p=0.02), but not MPAs (ICC=-0.10; NS). A multivariate analysis of NSS and MPAs in the non psychotic relative sample showed that presumed carriers had more NSS than non presumed carriers (MANCOVA; p<0.001 for the total score and p<0.05 for motor coordination and integration subscores) and a discriminant function analyses (DFA) incorporating NSS and MPAs yielded a single function that significantly separated the groups (p=0.004) and that correctly classified 71.4% of the non psychotic relatives. Conclusion: There seemed therefore to be a difference in the transmission of NSS and MPAs in

International Congress on Schizophrenia Research 2003