Comparable reliability and acceptability of telepsychiatry and face-to-face psychiatric assessments in the emergency room setting.

OBJECTIVE: This study aims to compare the reliability and acceptability of psychiatric interviews using telepsychiatry and face-to-face modalities in the emergency room setting. METHODS: In this prospective observational feasibility study, psychiatric patients (n = 38) who presented in emergency rooms between April and June 2020, went through face-to-face and videoconference telepsychiatry interviews in a non-randomised varying order. Interviewers and a senior psychiatry resident who observed both interviews determined diagnosis, recommended disposition and indication for involuntary admission. Patients and psychiatrists completed acceptability post-assessment surveys. RESULTS: Agreement between raters on recommended disposition and indication for involuntary admission as measured by Cohen's kappa was 'strong' to 'almost perfect' (0.84/0.81, 0.95/0.87 and 0.89/0.94 for face-to-face vs. telepsychiatry, observer vs. face-to-face and observer vs. telepsychiatry, respectively). Partial agreement between the raters on diagnosis was 'strong' (Cohen's kappa of 0.81, 0.85 and 0.85 for face-to-face vs. telepsychiatry, observer vs. face-to-face and observer vs. telepsychiatry, respectively).Psychiatrists' and patients' satisfaction rates, and psychiatrists' perceived certainty rates, were comparably high in both face-to-face and telepsychiatry groups. CONCLUSIONS: Telepsychiatry is a reliable and acceptable alternative to face-to-face psychiatric assessments in the emergency room setting. Implementing telepsychiatry may improve the quality and accessibility of mental health services.Key pointsTelepsychiatry and face-to-face psychiatric assessments in the emergency room setting have comparable reliability.Patients and providers report a comparable high level of satisfaction with telepsychiatry and face-to-face modalities in the emergency room setting.Providers report a comparable level of perceived certainty in their clinical decisions based on telepsychiatry and face-to-face psychiatric assessments in the emergency room setting.

Expansion of the GRIA2 phenotypic representation: a novel de novo loss of function mutation in a case with childhood onset schizophrenia.

Childhood-onset schizophrenia (COS) is a rare form of schizophrenia with an onset before 13 years of age. There is rising evidence that genetic factors play a major role in COS etiology, yet, only a few single gene mutations have been discovered. Here we present a diagnostic whole-exome sequencing (WES) in an Israeli Jewish female with COS and additional neuropsychiatric conditions such as obsessive-compulsive disorder (OCD), anxiety, and aggressive behavior. Variant analysis revealed a de novo novel stop gained variant in GRIA2 gene (NM_000826.4: c.1522 G > T (p.Glu508Ter)). GRIA2 encodes for a subunit of the AMPA sensitive glutamate receptor (GluA2) that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. GluA2 subunit mutations are known to cause variable neurodevelopmental phenotypes including intellectual disability, autism spectrum disorder, epilepsy, and OCD. Our findings support the potential diagnostic role of WES in COS, identify GRIA2 as possible cause to a broad psychiatric phenotype that includes COS as a major manifestation and expand the previously reported GRIA2 loss of function phenotypes.

[IDENTIFYING PREDICTORS OF MENTAL HEALTH SERVICES CONSUMPTION IN ISRAEL].

INTRODUCTION: The budget for health services in Israel was recently increased to cover mental health. It was suggested to divide funds for psychiatric hospitalization between the HMOs based on their share of insured members. For ambulatory care, it was suggested to add risk adjustment based on age only to the capitation formula used for allocating health care funds. This simplistic measure encourages risk selection and discrimination of costly individuals. AIMS: To identify predictors of mental health services consumption in Israel, in order to implement them in the capitation formula. METHODS: Data were gathered on 27,446 individuals hospitalized in psychiatric wards in Israel in 2012-2013, and 6115 outpatients treated during this period in one mental health clinic. The association between demographic and clinical variables with services consumption was studied. RESULTS: The average annual expenses per person on mental health were NIS 50,000 for hospitalization, NIS 1,700 for ambulatory care and NIS 7,000 for all services. Adult age and schizophrenia spectrum diagnoses predicted increased expenditure on all services. Being a male, single, Jewish and living in the economic periphery predicted increased expenditure mainly on hospitalization. Regression analysis using these variables explained up to 30% of variance. CONCLUSIONS: It is possible to predict, at least partially, mental health consumption in Israel based on clinical and demographic variables. DISCUSSION: Limitations of the study call or re-analysis using full databases, which are available only to the state authorities. Predictors of mental health consumption in Israel can be used for the risk adjustment of allocating funds for services.

Genetic insights into childhood-onset schizophrenia: The yield of clinical exome sequencing.

Childhood-onset schizophrenia (COS) is a rare form of schizophrenia with an onset prior to 13 years of age. Although genetic factors play a role in COS etiology, only a few causal variants have been reported to date. This study presents a diagnostic exome sequencing (ES) in 37 Israeli Jewish families with a proband diagnosed with COS. By implementing a trio/duo ES approach and applying a well-established diagnostic pipeline, we detected clinically significant variants in 7 probands (19 %). These single nucleotide variants and indels were mostly inherited. The implicated genes were ANKRD11, GRIA2, CHD2, CLCN3, CLTC, IGF1R and MICU1. In a secondary analysis that compared COS patients to 4721 healthy controls, we observed that patients had a significant enrichment of rare loss of function (LoF) variants in LoF intolerant genes associated with developmental diseases. Taken together, ES could be considered as a valuable tool in the genetic workup for COS patients.

Oxytocin and vasopressin genes are significantly associated with schizophrenia in a large Arab-Israeli pedigree.

We have previously studied the genetics of schizophrenia in a large inbred Arab-Israeli pedigree and found evidence for linkage on chromosome 20p13. This locus harbours four strong candidate genes for schizophrenia: atractin (ATRN), pantonate-kinase2 (PANK2), oxytocin (OXT) and arginine-vasopressin (AVP). In this study we further explored the association of these genes with schizophrenia in the pedigree and searched for the disease-causing variants. A mutation screening of affected individuals from the pedigree was performed by using intensive sequencing in these four genes of interest. Then, we studied the prevalence of the identified variants in all family members (n=56) as well as in Arab-Israeli nuclear families (n=276) and a Jewish case-control sample (n=545). We also studied the possible functional role of these variants by examining their association with gene expression in the brain (n=104). We identified seven genetic variants in the OXT-AVP cluster in affected individuals from the pedigree. Three of these variants were significantly associated with schizophrenia in this pedigree. A 7-SNP haplotype was also significantly associated with disease. We found significant association of some of these variants in the two samples from the general population. Expression data analysis showed a possible functional role of two of these variants in regulation of gene expression. Involvement of OXT and AVP in the aetiology of schizophrenia has been suggested in the past. This study demonstrates, for the first time, a significant genetic association of these neuropeptides with schizophrenia and strongly supports this hypothesis.

DOCK4 and CEACAM21 as novel schizophrenia candidate genes in the Jewish population.

It is well accepted that schizophrenia has a strong genetic component. Several genome-wide association studies (GWASs) of schizophrenia have been published in recent years; most of them population based with a case-control design. Nevertheless, identifying the specific genetic variants which contribute to susceptibility to the disorder remains a challenging task. A family-based GWAS strategy may be helpful in the identification of schizophrenia susceptibility genes since it is protected against population stratification, enables better accounting for genotyping errors and is more sensitive for identification of rare variants which have a very low frequency in the general population. In this project we implemented a family-based GWAS of schizophrenia in a sample of 107 Jewish-Israeli families. We found one genome-wide significant association in the intron of the DOCK4 gene (rs2074127, p value=1.134×10⁻7) and six additional nominally significant association signals with p<1×10⁻5. One of the top single nucleotide polymorphisms (p<1×10⁻5) which is located in the predicted intron of the CEACAM21 gene was significantly replicated in independent family-based sample of Arab-Israeli origin (rs4803480: p value=0.002; combined p value=9.61×10⁻8), surviving correction for multiple testing. Both DOCK4 and CEACAM21 are biologically reasonable candidate genes for schizophrenia although generalizability of the association of DOCK4 with schizophrenia should be investigated in further studies. In addition, gene-wide significant associations were found within three schizophrenia candidate genes: PGBD1, RELN and PRODH, replicating previously reported associations. By application of a family-based strategy to GWAS, our study revealed new schizophrenia susceptibility loci in the Jewish-Israeli population.

Identification of new schizophrenia susceptibility loci in an ethnically homogeneous, family-based, Arab-Israeli sample.

While the use of population-based samples is a common strategy in genome-wide association studies (GWASs), family-based samples have considerable advantages, such as robustness against population stratification and false-positive associations, better quality control, and the possibility to check for both linkage and association. In a genome-wide linkage study of schizophrenia in Arab-Israeli families with multiple affected individuals, we previously reported significant evidence for a susceptibility locus at chromosome 6q23.2-q24.1 and suggestive evidence at chromosomes 10q22.3-26.3, 2q36.1-37.3 and 7p21.1-22.3. To identify schizophrenia susceptibility genes, we applied a family-based GWAS strategy in an enlarged, ethnically homogeneous, Arab-Israeli family sample. We performed genome-wide single nucleotide polymorphism (SNP) genotyping and single SNP transmission disequilibrium test association analysis and found genome-wide significant association (best value of P=1.22×10(-11)) for 8 SNPs within or near highly reasonable functional candidate genes for schizophrenia. Of particular interest are a group of SNPs within and flanking the transcriptional factor LRRFIP1 gene. To determine replicability of the significant associations beyond the Arab-Israeli population, we studied the association of the significant SNPs in a German case-control validation sample and found replication of associations near the UGT1 subfamily and EFHD1 genes. Applying an exploratory homozygosity mapping approach as a complementary strategy to identify schizophrenia susceptibility genes in our Arab Israeli sample, we identified 8 putative disease loci. Overall, this GWAS, which emphasizes the important contribution of family based studies, identifies promising candidate genes for schizophrenia.

Callous-Unemotional Traits and Face-Emotion Recognition as Mediators in Conduct Problems of Children With ADHD.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is associated with increased risk for conduct problems (CP), as well as with callous-unemotional traits (CUt) and lower accuracy in face emotional recognition (FER). It is unclear, however, whether CUt and low accuracy in FER contribute to the risk for CP in ADHD. The present study investigated the possibility of such contribution. METHODS: This pilot study's participants included 31 children aged 7-17 years, diagnosed with ADHD, and treated in a psychiatric outpatient clinic. The parents rated their children on the ADHD Rating Scale, Inventory of Callous-Unemotional Traits, and the Child Behavior Checklist-Conduct Problems scale. Participants completed the Hebrew version of the children's Reading the Mind in the Eyes Test (cRMET)-a Theory of Mind measure. A bootstrapped multiple mediator model was used, adjusting for age and gender. RESULTS: ADHD symptoms were associated with CP. This association was not mediated by CUt or cRMET. CUt was associated with CP independent of ADHD symptom severity. CONCLUSIONS: ADHD symptoms and CUt both should be considered when assessing risk for CP and devising a treatment plan, in children with ADHD. Current results did not confirm the hypothesis that cRMET and CUt mediate between ADHD symptoms and CP. More studies employing larger samples, longitudinal design, and other emotion recognition measures are needed.

Elevated brain-derived cell-free DNA among patients with first psychotic episode - a proof-of-concept study.

Schizophrenia is a common, severe, and debilitating psychiatric disorder. Despite extensive research there is as yet no biological marker that can aid in its diagnosis and course prediction. This precludes early detection and intervention. Imaging studies suggest brain volume loss around the onset and over the first few years of schizophrenia, and apoptosis has been proposed as the underlying mechanism. Cell-free DNA (cfDNA) fragments are released into the bloodstream following cell death. Tissue-specific methylation patterns allow the identification of the tissue origins of cfDNA. We developed a cocktail of brain-specific DNA methylation markers, and used it to assess the presence of brain-derived cfDNA in the plasma of patients with a first psychotic episode. We detected significantly elevated neuron- (p=0.0013), astrocyte- (p=0.0016), oligodendrocyte- (p=0.0129), and whole brain-derived (p=0.0012) cfDNA in the plasma of patients during their first psychotic episode (n=29), compared with healthy controls (n=31). Increased cfDNA levels were not correlated with psychotropic medications use. Area under the curve (AUC) was 0.77, with 65% sensitivity at 90% specificity in patients with a psychotic episode. Potential interpretations of these findings include increased brain cell death, disruption of the blood-brain barrier, or a defect in clearance of material from dying brain cells. Brain-specific cfDNA methylation markers can potentially assist early detection and monitoring of schizophrenia and thus allow early intervention and adequate therapy.

Fine mapping of AHI1 as a schizophrenia susceptibility gene: from association to evolutionary evidence.

In previous studies, we identified a locus for schizophrenia on 6q23.3 and proposed the Abelson helper integration site 1 (AHI1) as the candidate gene. AHI1 is expressed in the brain and plays a key role in neurodevelopment, is involved in Joubert syndrome, and has been recently associated with autism. The neurodevelopmental role of AHI1 fits with etiological hypotheses of schizophrenia. To definitively confirm our hypothesis, we searched for associations using a dense map of the region. Our strongest findings lay within the AHI1 gene: single-nucleotide polymorphisms rs11154801 and rs7759971 showed significant associations (P=6.23E-06; P=0.84E-06) and haplotypes gave P values in the 10E-8 to 10E-10 range. The second highest significant region maps close to AHI1 and includes the intergenic region between BC040979 and PDE7B (rs2038549 at P=9.70E-06 and rs1475069 at P=6.97E-06), and PDE7B and MAP7. Using a sample of Palestinian Arab families to confirm these findings, we found isolated signals. While these results did not retain their significance after correction for multiple testing, the joint analysis across the 2 samples supports the role of AHI1, despite the presence of heterogeneity. Given the hypothesis of positive selection of schizophrenia genes, we resequenced a 11 kb region within AHI1 in ethnically defined populations and found evidence for a selective sweep. Network analysis indicates 2 haplotype clades, with schizophrenia-susceptibility haplotypes clustering within the major clade. In conclusion, our data support the role of AHI1 as a susceptibility gene for schizophrenia and confirm it has been subjected to positive selection, also shedding light on new possible candidate genes, MAP7 and PDE7B.

[Impairment status and related predictors for adults hospitalized as children in a psychiatric ward in Israel].

BACKGROUND: The few studies that exist on long term outcome of psychiatric hospitalization of children show poor prognosis. OBJECTIVES: To study the level of functioning of adults who were hospitalized as children in a psychiatric ward in Israel and to identify prognosis predictors. METHODS: The study population consisted of all 1654 people who had been hospitalized in a psychiatric hospital in Israel and whose age at the time of the study was 21 years and above. For each subject, demographic and clinical data were extracted from a national case registry and data on disability benefits were retrieved from another file in the Ministry of Health. RESULTS: Only 8% of the study subjects were married, 8.3% died (3.5 times more in men compared to the general population), and 21% received disability benefits. More than half of the people who were hospitalized as children were rehospitalized during the follow-up (43% as adults). Younger age at first hospitalization was associated with a longer cumulative duration of hospitalization, while an older age was associated with a greater number of hospitalizations and a higher rate of eligibility for disability benefits. Diagnosis at first hospitalization was associated with all measures of functioning in adulthood. Diagnosis of an "organic" or severe psychiatric disorder was associated with poor prognosis. Longer duration of first hospitalization was associated with a higher rate of death and eligibility for disability benefits. CONCLUSIONS: This study shows poor prognosis for adults who were hospitalized in child psychiatry wards and calls for long-term prospective and controlled studies.

Evidence for association of the GLI2 gene with tardive dyskinesia in patients with chronic schizophrenia.

Tardive dyskinesia (TD) occurs in approximately 20% of patients exposed to long-term antipsychotic treatment and may be influenced by genetic predisposition, in addition to clinical risk factors. In this study, we implemented a two-step approach to identify susceptibility genes for TD. First, we performed a secondary analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) genome-wide association study (GWAS) dataset to identify candidate genes for TD severity. A total of 327 schizophrenia patients treated with antipsychotics who participated in the CATIE trial were included in a TD severity GWAS (approximately 495,000 SNPs). Cases were defined as demonstrating involuntary movements of a mild degree in two or more body regions or of a moderate to severe degree in at least one body region on at least two separate evaluations, whereas controls were completely free of abnormal involuntary movement on all evaluations. Using logistic regression and controlling for population stratification and relevant clinical risk factors, none of the associated SNPs reached GWAS significance; however, several promising SNPs were identified for follow-up investigation. In the second step, we performed an association study of the top 25 SNPs in an independent sample of 170 Jewish, Israeli, schizophrenia patients (retrospective, cross-sectional design). Association of the SNP rs3943552 T allele in the GLI2 gene with TD was observed in a subsample of Ashkenazi Jewish patients (N = 96, P = 0.018; P = 6.2 × 10⁻5 in the CATIE sample). The GLI2 gene encodes a transcription factor that participates in the development of the dopaminergic system during embryogenesis. Taken together, our findings support a possible contribution of GLI2 to TD susceptibility.

Psychiatric and cognitive profile in Anderson-Fabry patients: a preliminary study.

Anderson-Fabry disease (AFD) is an X-linked inherited lysosomal storage disorder disease caused by a deficiency in the activity of the alpha-galactosidase enzyme. We investigated neuropsychological and psychiatric function in AFD patients. We studied 16 AFD patients, aged 7 to 61 years. Intelligence, language, vision-spatial abilities, memory, sensorimotor abilities, and attention and executive functions were tested with a computerized test battery as well as standard paper and pencil tests. The results were compared to known age-based norms. In addition, all patients were screened for lifelong DSM-IV Axis-I and Axis-II psychiatric diagnoses, and 4 were interviewed by a psychiatrist. Performance on most cognitive measures was within average range. All measures of information processing speed were significantly reduced, as were some measures of executive functions. Ten out of 16 patients met DSM-IV criteria for Axis I or Axis II diagnoses at some point in their lives. This preliminary study delineates a psychiatric and cognitive phenotype in AFD patients and contributes to the growing field of characterizing behavioral phenotypes of patients with genetic diseases. We suggest that psychiatric and neuro-psychological evaluation be included in the patient's evaluation.

Why do young women smoke? VII COMT as a risk modifying gene for Nicotine dependence - role of gene-gene interaction, personality, and environmental factors.

OBJECTIVES: Catechol-O-methyltransferase (COMT) may be a risk modifying gene for Nicotine dependence (ND) rather than a direct susceptibility gene for this phenotype. Brain nicotinic cholinergic receptors modulate dopaminergic transmission, and several variants within the neighboring CHRNA5-CHRNA3 genes have been associated with ND. Therefore, it is biologically reasonable to study the interactive contribution of COMT and the CHRNA5 and CHRNA3 genes to ND. METHODS: Using a case-control sample of 90 young, Israeli, Jewish female smokers (FTND ≥ 4) and 108 controls (FTND = 0 during heaviest period of smoking), we studied association with ND of 8 COMT tagging SNPs, their interaction with tagging CHRNA5-A3 SNPs and the role of background, personality, and environmental factors. RESULTS: None of the COMT SNPs were associated directly with ND. In pairwise interaction analysis of SNPs from the two loci (COMT SNP-CHRNA5-CHRNA3 SNP), the interaction of intronic COMT SNP, rs9332377, with CHRNA3 3'UTR SNP rs660652 was significantly associated with ND (p = 0.0005), withstanding correction for multiple testing. CONCLUSION: Addition of the genetic interaction variable into a model of non-genetic ND predictors [parental smoking, novelty seeking (NS), and lifetime history of trauma], substantially increases the percentage of ND variance explained by the model, as well as the percentage of cases correctly identified by it.

Toward risk adjustment in mental health in Israel: calculation of risk adjustment rates from large outpatient and inpatient databases.

BACKGROUND: In 2015, mental health services were added to the Israeli National Health Insurance package of services. As such, these services are financed by the budget which is allocated to the Health Plans according to a risk adjustment scheme. An inter-ministerial team suggested a formula by which the mental health budget should be allocated among the Health Plans. Our objective in this study was to develop alternative rates based on individual data, and to evaluate the ones suggested. METHODS: The derivation of the new formula is based on our previous study of all psychiatric inpatients in Israel in the years 2012-2013 (n = 27,446), as well as outpatients in one psychiatric clinic in the same period (n = 6115). Based on Ministry of Health and clinic data we identified predictors of mental health services consumption. Age, gender, marital status and diagnosis were used as risk adjusters to calculate the capitation rates for outpatient care and inpatient care, respectively. All prices of services were obtained from the Ministry of Health tariffs. These rates were modified to include non-users using restricted models. RESULTS: The mental health capitation scales are typically "humped" with regard to age. The rates for ambulatory care varied from a minimum 0.19 of the average consumption for males above the age of 85 to a maximum of 1.93 times the average for females between the ages of 45-54. For inpatient services the highest rate was 409.25 times the average for single, male patients with schizophrenia spectrum diagnoses, aged 45-54. The overall mental health scale ranges from 2.347 times the average for men aged 45-54, to 0.191 for women aged 85+. The modified scale for the entire post-reform package of benefits (including both mental health care and physical health care) is increasing with age to 4.094 times the average in men aged over 85. The scale is flatter than the pre-reform scale. CONCLUSIONS: The risk adjustment rates calculated for outpatient care are substantially different from the ones suggested by the inter-ministerial team. The inpatient rates are new, and indicate that for patients with schizophrenia, a separate risk-sharing arrangement might be desirable. Adopting the rates developed in this analysis would decrease the budget shares of Clalit and Leumit with their relatively older populations, and increase Maccabi and Meuhedet's shares. Future research should develop a risk-adjustment scheme which covers directly both mental and physical care provided by the Israeli Health Plans, using their data.

The association of non-suicidal self-injurious and suicidal behaviors with religiosity in hospitalized Jewish adolescents.

Religiosity may be a potent protective factor against self-injurious and suicidal behaviors. However, no previous study has addressed this relationship in adolescent psychiatric population. This study aimed to examine the association between religiosity and non-suicidal self-injurious (NSSI) and suicidal behaviors, among hospitalized Jewish adolescents. This is a cross-sectional study of 60 hospitalized Jewish adolescents in two mental health centers. They were evaluated for religiosity, NSSI, and suicidal behaviors. The following religiosity measures were found to be protective against NSSI: a higher degree of adherence to religious practices (extrinsic measure) (beta = -0.083, p = .006), a higher level of belief in religious principles (intrinsic measure) (beta = -0.063, p = .008) and a self-reported higher religious affinity (χ2 = 7.64, p = .022). The severity of suicidal ideation inversely correlated with the extrinsic measure (standardized beta = -0.2, t = -2.5, p = .015) and with self-reported degree of religious affinity (analysis of variance, F = 3.5, p = .035). History of transition in religious affinity was associated with worse suicidal ideation (3.77 ± 1.8 vs. 2.26 ± 1.99, t = -3.25, p = .004) and with suicide attempts (OR = 3.89 (95% CI: 1.08 - 14.03), p = .004); however, these relationships were mediated by history of abuse. This study provides first evidence of a protective effect of some religiosity measures on NSSI and suicidal behaviors in hospitalized Jewish adolescents.

Commentary: seclusion and mechanical restraint of psychiatric patients in Israel - an update.

Recently, Miodownik et al. reported in this journal the results of a study on seclusion and mechanical restraint of psychiatric patients in Israel (Isr J Health Policy Res 8:9, 2019). The study was a retrospective examination over a year of one inpatient ward in a psychiatric hospital. They found negative associations between length of use of coercive measures and the diagnosis of schizophrenia, being single, and the presence of academic nurses. Positive associations were found between length of use of coercive measures and the use of antipsychotic medications, violence towards oneself, and the use of restraint compared to seclusion. Interesting and important as they are, these results were obtained from data gathered in 2014. As the authors note, since then there has been a dramatic change in the official policy of the Israeli Ministry of Health on this topic and in the practice of seclusion and mechanical restraint in Israel. This commentary reviews and comments on the current situation.

Genome-wide linkage scan, fine mapping, and haplotype analysis in a large, inbred, Arab Israeli pedigree suggest a schizophrenia susceptibility locus on chromosome 20p13.

Linkage and association studies in schizophrenia have repeatedly drawn attention to several chromosomal regions and to genes within them. Conflicting patterns of association and the lack of a clear functional significance of the associated variants limit the interpretation of these results. The use of rare pedigrees, where genes with a major effect cause the disorder, has been proven beneficial in studies of other complex disorders. Our objective was to use this advantage by performing a genome wide linkage analysis for schizophrenia in a large, multiplex Israeli Arab pedigree. We genotyped 346 microsatellite markers in 24 pedigree members affected with schizophrenia spectrum disorders and 32 unaffected relatives. Two-point linkage analysis with SUPERLINK demonstrated a LOD score of 2.47 for D20S116 on chromosome 20p13 under an autosomal dominant mode of inheritance. Further fine mapping yielded a two-point LOD score of 2.56 for the adjacent marker D20S193 and narrowed down the linked region to 2-5 cM. A haplotype containing the markers D20S193, D20S889, and D20S116, 0.7 Mb in length, was found to be shared by most affected pedigree members. Genotyping of 43 SNPs in the interval supported these results with a multipoint LOD score of 2.7 around D20S193. We were also able to better define the boundaries of the shared haplotype which contains strong candidate genes for schizophrenia. Our study exemplifies the power of rare and unique pedigrees in drawing attention to novel regions for genetic studies of schizophrenia.