Fine-mapping scan of bipolar disorder susceptibility loci in Latino pedigrees.

We previously identified bipolar disorder (BD) susceptibility loci on 8q24, 14q32, and 2q12-14 in a genome-wide nonparametric linkage screen in a Latino cohort. We now perform a fine mapping analysis using a dense map of additional SNPs to identify BD susceptibility genes within these regions. One thousand nine hundred and thirty-eight individuals with Latino ancestry (880 individuals with BD Type I or Schizoaffective, Bipolar Type) from 416 Latino pedigrees from the United States, Mexico, Costa Rica, and Guatemala were genotyped with 3,074 SNPs to provide dense coverage of the 8q24 (11.5 cM), 14q32 (7.5 cM), and 2q12-14 (6.5 cM) chromosomal loci. Single-marker association tests in the presence of linkage were performed using the LAMP software. The top linkage peak (rs7834818; LOD = 5.08, p = 3.30E - 5) and associated single marker (rs2280915, p = 2.70E - 12) were located within FBXO32 on 8q24. On chromosome 2, the top linkage peak (rs6750326; LOD = 5.06, p = 3.50E - 5) and associated single marker (rs11887088, p = 2.90E - 6) were located in intragenic regions near ACTR3 and DPP10. None of the additional markers in the region around chromosome 14q32 met significance levels for linkage or association. We identified six SNPs on 2q12-q14 and one SNP in FBXO32 on 8q24 that were significantly associated with BD in this Latino cohort.

Replication of genome-wide association study (GWAS) susceptibility loci in a Latino bipolar disorder cohort.

OBJECTIVES: Recent genome-wide association studies (GWASs) have identified numerous putative genetic polymorphisms associated with bipolar disorder (BD) and/or schizophrenia (SC). We hypothesized that a portion of these polymorphisms would also be associated with BD in the Latino American population. To identify such regions, we tested previously identified genetic variants associated with BD and/or SC and ancestral haploblocks containing these single nucleotide polymorphisms (SNPs) in a sample of Latino subjects with BD. METHODS: A total of 2254 Latino individuals were genotyped for 91 SNPs identified in previous BD and/or SC GWASs, along with selected SNPs in strong linkage disequilibrium with these markers. Family-based single marker and haplotype association testing was performed using the PBAT software package. Empirical P-values were derived from 10 000 permutations. RESULTS: Associations of eight a priori GWAS SNPs with BD were replicated with nominal (P≤.05) levels of significance. These included SNPs within nuclear factor I A (NFIA), serologically defined colon cancer antigen 8 (SDCCAG8), lysosomal associated membrane protein 3 (LAMP3), nuclear factor kappa B subunit 1 (NFKB1), major histocompatibility complex, class I, B (HLA-B) and 5'-nucleotidase, cytosolic II (NT5C2) and SNPs within intragenic regions microRNA 6828 (MIR6828)-solute carrier family 7 member 14 (SLC7A14) and sonic hedgehog (SHH)-long intergenic non-protein coding RNA 1006 (LINC01006). Of the 76 ancestral haploblocks that were tested for associations with BD, our top associated haploblock was located in LAMP3; however, the association did not meet statistical thresholds of significance following Bonferroni correction. CONCLUSIONS: These results indicate that some of the gene variants found to be associated with BD or SC in other populations are also associated with BD risk in Latinos. Variants in six genes and two intragenic regions were associated with BD in our Latino sample and provide additional evidence for overlap in genetic risk between SC and BD.

A national cohort study of the association between the polytrauma clinical triad and suicide-related behavior among US Veterans who served in Iraq and Afghanistan.

OBJECTIVES: We examined the association of posttraumatic stress disorder (PTSD), traumatic brain injury, and chronic pain-the polytrauma clinical triad (PCT)-independently and with other conditions, with suicide-related behavior (SRB) risk among Operation Enduring Freedom (OEF; Afghanistan) and Operation Iraqi Freedom (OIF) veterans. METHODS: We used Department of Veterans Affairs (VA) administrative data to identify OEF and OIF veterans receiving VA care in fiscal years 2009-2011; we used International Classification of Diseases, Ninth Revision, Clinical Modification codes to characterize 211652 cohort members. Descriptive statistics were followed by multinomial logistic regression analyses predicting SRB. RESULTS: Co-occurrence of PCT conditions was associated with significant increase in suicide ideation risk (odds ratio [OR] = 1.9; 95% confidence interval [CI]=1.5, 2.4) or attempt and ideation (OR=2.6; 95% CI=1.5, 4.6), but did not exceed increased risk with PTSD alone (ideation: OR=2.3; 95% CI=2.0, 2.6; attempt: OR=2.0; 95% CI=1.4, 2.9; ideation and attempt: OR=1.8; 95% CI=1.2, 2.8). Ideation risk was significantly elevated when PTSD was comorbid with depression (OR=4.2; 95% CI=3.6, 4.8) or substance abuse (OR=4.7; 95% CI = 3.9, 5.6). CONCLUSIONS: Although PCT was a moderate SRB predictor, interactions among PCT conditions, particularly PTSD, and depression or substance abuse had larger risk increases.

A genome-wide linkage scan of bipolar disorder in Latino families identifies susceptibility loci at 8q24 and 14q32.

A genome-wide nonparametric linkage screen was performed to localize Bipolar Disorder (BP) susceptibility loci in a sample of 3757 individuals of Latino ancestry. The sample included 963 individuals with BP phenotype (704 relative pairs) from 686 families recruited from the US, Mexico, Costa Rica, and Guatemala. Non-parametric analyses were performed over a 5 cM grid with an average genetic coverage of 0.67 cM. Multipoint analyses were conducted across the genome using non-parametric Kong & Cox LOD scores along with Sall statistics for all relative pairs. Suggestive and significant genome-wide thresholds were calculated based on 1000 simulations. Single-marker association tests in the presence of linkage were performed assuming a multiplicative model with a population prevalence of 2%. We identified two genome-wide significant susceptibly loci for BP at 8q24 and 14q32, and a third suggestive locus at 2q13-q14. Within these three linkage regions, the top associated single marker (rs1847694, P = 2.40 × 10(-5)) is located 195 Kb upstream of DPP10 in Chromosome 2. DPP10 is prominently expressed in brain neuronal populations, where it has been shown to bind and regulate Kv4-mediated A-type potassium channels. Taken together, these results provide additional evidence that 8q24, 14q32, and 2q13-q14 are susceptibly loci for BP and these regions may be involved in the pathogenesis of BP in the Latino population.

Suggestive evidence for association between L-type voltage-gated calcium channel (CACNA1C) gene haplotypes and bipolar disorder in Latinos: a family-based association study.

OBJECTIVES: Through recent genome-wide association studies (GWASs), several groups have reported significant association between variants in the calcium channel, voltage-dependent, L-type, alpha 1C subunit (CACNA1C) and bipolar disorder (BP) in European and European-American cohorts. We performed a family-based association study to determine whether CACNA1C is associated with BP in the Latino population. METHODS: This study included 913 individuals from 215 Latino pedigrees recruited from the USA, Mexico, Guatemala, and Costa Rica. The Illumina GoldenGate Genotyping Assay was used to genotype 58 single-nucleotide polymorphisms (SNPs) that spanned a 602.9-kb region encompassing the CACNA1C gene including two SNPs (rs7297582 and rs1006737) previously shown to associate with BP. Individual SNP and haplotype association analyses were performed using Family-Based Association Test (version 2.0.3) and Haploview (version 4.2) software. RESULTS: An eight-locus haplotype block that included these two markers showed significant association with BP (global marker permuted p = 0.0018) in the Latino population. For individual SNPs, this sample had insufficient power (10%) to detect associations with SNPs with minor effect (odds ratio = 1.15). CONCLUSIONS: Although we were not able to replicate findings of association between individual CACNA1C SNPs rs7297582 and rs1006737 and BP, we were able to replicate the GWAS signal reported for CACNA1C through a haplotype analysis that encompassed these previously reported significant SNPs. These results provide additional evidence that CACNA1C is associated with BP and provides the first evidence that variations in this gene might play a role in the pathogenesis of this disorder in the Latino population.

A case control study of the implementation of change model versus passive dissemination of practice guidelines for compliance in monitoring for metabolic syndrome.

We developed an intervention to improve compliance with guidelines for monitoring metabolic syndrome and compared compliance prior to intervention and three times post-intervention at three community mental health clinics in Texas. One test clinic received intervention and two other clinics served as controls. Fifty random charts were reviewed from each clinic for three specific, 1-2 weeks periods over the course of 18 months. There were significant improvements in the ordering of labs, the presence of lab results in the chart, and documentation of blood pressure, body mass index and waist circumference in the intervention clinic over time in comparison to the control clinics. Documented evidence of physician action with respect to out of range values remained low. Metabolic monitoring is a multi-step process. Removing barriers, creating specific procedures, and dedicating staff resources can improve compliance with monitoring.

Barriers to, and strategies for, starting a long acting injection clinic in a community mental health center.

As many as 50% of patients with schizophrenia do not take oral antipsychotic medications as prescribed, yet long acting injections are rarely utilized. Community agencies that serve this population are often over-burdened and poorly funded. There are negative attitudes on the part of both physicians and consumers about injections. Transportation and logistics are often problematic. We describe the unique opportunity provided by the need for bi-weekly or monthly injections to establish a recovery-oriented group around injection visits. Our approach discusses methods and resources to help overcome some of the common barriers by establishing advocates within the agency, establishing necessary infrastructure, providing education for consumers, providers, and staff, sharing information about successful outcomes with clinic staff and working through billing issues. We also recommend public advocacy on the part of the clinic and consumers to work with state funding sources to change regulations that may limit appropriate clinical care.

Association of serotonin transporter promoter gene polymorphism (5-HTTLPR) with depression in Costa Rican schizophrenic patients.

Depression and suicidal behavior are frequently observed in patients with schizophrenia. The serotonin transporter protein regulates serotonergic signaling at synapses and is encoded by a single gene (SLC6A4; Locus Link ID: 6532), located at 17q11.1-q12 with two polymorphic variants (the short and the long allele). The short allele of serotonin transporter gene has been associated with depression and suicidality in individuals who suffered negative life events and with depression in individuals with chronic psychosis.. Subjects were recruited from a genetic study of schizophrenia conducted in Costa Rica. The authors replicated their previous research, using a more narrow phenotype (only schizophrenic subjects) and a more ethnically homogenous sample (only Costa Rican schizophrenic individuals who were not included in the previous study). The authors hypothesized that subjects with at least one copy of the serotonin transporter promoter gene polymorphism (5-HTTLPR) "s" allele would have a greater history of lifetime depression and suicidability rate than those who had an "l/l" genotype. The authors analyzed 155 subjects with a DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) diagnosis of schizophrenia (73% male, age at interview 38.3, SD = 11.23). The genotype distribution was "ss" 58 (37%), "sl" 69 (45%), and "ll" 28 (18%). In the secondary analysis, the authors explored association of the "s" allele with lifetime history of suicide behavior in 173 subjects (18 more subjects than primary analysis because schizophrenic individuals were included regardless of history of depression). The authors found that subjects carrying at least one short allele had a significant increased lifetime risk for depressive syndromes (chi(2) = 5.4, df = 1, P = 0.02; odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.15-6.3). No association was found for suicidal behavior in the same sample (chi(2) = 0.928, P = 0.629). In conclusion, the genotype at the 5-HTTLPR promoter polymorphic locus increases the risk of developing major depression but not suicidal behavior during the course of the schizophrenia in these patients. Due to the small sample size, these results should be followed by definitive replication.

Social and clinical comparison between schizophrenia and bipolar disorder type I with psychosis in Costa Rica.

INTRODUCTION: Schizophrenia (SC) and bipolar disorder (BP) are two of the most severe and incapacitating mental disorders. It has been questioned whether these two conditions designate distinct illnesses with different etiologies or whether they represent different ends of a clinical spectrum with a common etiology. MATERIALS AND METHODS: This study compares social and clinical characteristics of 84 SC and 84 BP subjects from the Costa Rican Central Valley (CRCV) using information from the DIGS, FIGS and psychiatric records. Each of these subjects had a best estimate lifetime consensus diagnosis of either bipolar type I or SC. RESULTS: Subjects with SC differed from subjects with BP in social adjustment measures like marital and employment status, and number of children. Both groups were very similar in years of education, age of onset of their illness, history of other psychiatric co-morbidities, and treatment received. DISCUSSION: The high percentage of psychosis in the BP group (97.6%) may largely explain the similarities found between groups in their clinical characteristics. CONCLUSION: The differences in social and functional decline support the original dichotomy described by Kraepelin based on chronicity and periodicity between these two psychotic disorders.

Heritability of age of onset of psychosis in schizophrenia.

Schizophrenia is a genetically complex illness with heterogeneous clinical presentation, including variable age of onset. In this study, the heritability, or proportion of variation in age of onset of psychotic symptoms due to genetic factors, was estimated using a maximum likelihood method. The subjects were 717 members of families with more than one member affected with schizophrenia from Mexican and Central American populations. Age of onset of psychosis was determined by best-estimate consensus diagnosis based on the Diagnostic Interview for Genetic Studies, Family Interview for Genetic Studies, and each subject's medical records. Mean age of onset was 21.44 years (SD 8.07); 20.55 years for males (SD 6.90), and 22.67 for females (SD 9.34). Variance components were estimated using a polygenic model in the SOLAR software package. The sex of the participant was a significant covariate (P = 0.010) accounting for 0.02 of the total variance in age of onset. The heritability of age of onset of psychosis was 0.33 (SE = 0.09; P = 0.00004). These findings suggest that genetic factors significantly contribute to the age of onset of psychotic symptoms in individuals with schizophrenia and that sex influences this trait as well.

APOE-epsilon3 and APOE-219G haplotypes increase the risk for schizophrenia in sibling pairs.

To investigate the role of the apolipoprotein E (APOE) gene in schizophrenia, the authors analyzed 60 families with this mental disorder. An association in the presence of linkage test (APL) and haplotypes analysis were undertaken using the APL v1.1 software. A global allelic transmitted was significant for APOE-epsilon3 (chi(2)=6.24, p=0.01); this allele is mainly carried by female patients (chi(2)=8.33, p=0.003), whereas APOE-219G is preferentially transmitted in males (p=0.02). Furthermore, our results show that haplotypes APOE-epsilon3/APOE-219G are associated with schizophrenia (chi(2)=11.61, p=0.01). These results provide evidence that the APOE gene may play a significant role in the etiology of schizophrenia in the Mexican population.

Diagnosis of schizophrenia in latino populations: a comparison of direct interview and consensus based multi-source methods.

We determined the rates of agreement between diagnoses, using the Diagnostic Interview for Genetic Studies (DIGS) and diagnoses arrived at, using additional sources of information, to establish whether there are differences in agreement between direct interview diagnoses at US and non-US sites in comparison best estimate consensus process and to identify diagnoses that could increase diagnostic error when only the DIGS is used. DIGS diagnoses were compared with consensus diagnoses that used the same DIGS interview, plus Family Interview for Genetic Studies (FIGS) and review of medical records in 342 psychotic subjects. We found similar numbers of subjects diagnosed with schizophrenia (225 by direct interview, and 232 by consensus process). The majority of those "misdiagnosed" by direct interview had mood disorder by the consensus. Over 10% of the total subjects diagnosed by direct interview as not meeting criteria for schizophrenia had schizophrenia by consensus. There were no statistically significant differences between countries (US vs. non-US sites) in the agreement rate between direct interview diagnosis and consensus diagnosis. In conclusion, a final best-estimate process is essential to make diagnostic distinctions and to reduce diagnostic misclassifications for both research studies and in clinical practice.

Methionine sulfoxide reductase: a novel schizophrenia candidate gene.

Methionine sulfoxide reductase (MSRA) is an antioxidant enzyme implicated in protection against oxidative stress and protein maintenance. We have previously reported the association of marker D8S542, located within the MSRA gene, with schizophrenia in the Central Valley of Costa Rica (CVCR). By performing fine mapping analysis, we have now identified a potential three-marker at risk haplotype within MSRA in the same CVCR sample, with a global P-value slightly above nominal significance (P = 0.0526). By sequencing the MSRA gene in individuals carrying this haplotype, we identified a novel 4-base pair deletion 1,792 bases upstream of the MSRA transcription start site. This deletion was significantly under-transmitted to schizophrenia patients in the CVCR sample (P = 0.0292) using FBAT, and this was replicated in a large independent sample of 321 schizophrenia families from the Hispanic population (P = 0.0367). These findings suggest a protective effect of the deletion against schizophrenia. Further, MSRA mRNA levels were significantly lower in lymphoblastoid cell lines of individuals homozygous for the deletion compared to carriers of the normal allele (P = 0.0135), although significance was only evident when genotypes were collapsed. This suggests that the deleted sequence may play a role in regulating MSRA expression. In conclusion, this work points towards MSRA as a novel schizophrenia candidate gene. Further studies into the mechanisms by which MSRA is involved in schizophrenia pathophysiology may shed light into the biological underpinnings of this disorder.

The epsin 4 gene is associated with psychotic disorders in families of Latin American origin.

This study attempted to replicate evidence for association of the Epsin 4 gene (which encodes enthoprotin, a protein involved in vesicular transport) to schizophrenia in a new sample of families segregating schizophrenia drawn from the Latin American population. 1,423 subjects (767 with a history of psychosis) from 337 Latino families were genotyped using three single nucleotide polymorphisms (SNPs) spanning the Epsin 4 gene. A family based association test was utilized to test for association of these SNPs to the phenotypes of psychosis and schizophrenia. Haplotypes defined by these three SNPs showed significant association to the phenotype of psychosis in this sample (global p value=0.014, bi-allelic p value=0.047). Variation in the Epsin 4 gene is significantly associated with psychotic disorder in this Latino population. This provides additional support for the involvement of enthoprotin in the pathogenesis of schizophrenia and other psychotic disorders.

Cannabinoid receptor 1 gene (CNR1) and susceptibility to a quantitative phenotype for hebephrenic schizophrenia.

Functional alterations of components of the endogenous cannabinoid system, in particular of the cannabinoid receptor 1 protein (CB1), are hypothetical contributors to many of the symptoms seen in schizophrenia. Variants within the cannabinoid receptor 1 gene (CNR1) have been shown to be directly associated with the hebephrenic form of schizophrenia in a Japanese population. This finding, however, has yet to be replicated. In the present study we sought to study the same (AAT)n-repeat microsatellite of the CNR1 gene which showed association to hebephrenic schizophrenia in Japan, and to investigate whether this microsatellite showed association to a hebephrenic type of schizophrenia in a family-based association study in a population of the Central Valley of Costa Rica. The Lifetime Dimensions of Psychosis Scale and a best estimate consensus process were utilized to identify subjects with schizophrenia who had an elevated lifetime dimensional score for negative and disorganized symptoms, which we used as a proxy for "hebephrenia." Using the Family Based Association Test we found association of these hebephrenic subjects and the (AAT)n-repeat marker of the CNR1 (multi-allelic P = 0.0368). Our hypothesis that an association with the (AAT)n-repeat marker of CNR1 would not be found with the more general type of schizophrenia was also confirmed. Schizophrenic subjects with prominent lifetime scores for disorganization and negative symptoms (dimension for hebephrenia) are associated with the CNR1 gene and present a type of symptomatology that resembles chronic cannabinoid-induced psychosis. The current finding points to the possibility of different genetic and pathophysiologic mechanisms underlying different types of schizophrenia.

Malic enzyme 2 and susceptibility to psychosis and mania.

Previous studies have identified a putative gene locus for both schizophrenia and bipolar disorder in the chromosome 18q21 region. To identify candidate genes associated with these disorders we completed fine mapping analyses (using microsatellite markers) in 152 families from the Central Valley of Costa Rica (CVCR) (376 total subjects, 151 with a history of psychosis, 97 with a history of mania). Microsatellite analyses showed evidence of association at two contiguous markers, both located at the same genetic distance and spanning approximately 11 known genes. In a corollary gene expression study, one of these genes, malic enzyme 2 (ME2), showed levels of gene expression 5.6-fold lower in anterior cingulate tissue from post-mortem bipolar brains. Subsequent analysis of individual SNPs in strong linkage disequilibrium with the ME2 gene revealed one SNP and one haplotype associated with the phenotype of psychosis in the CVCR sample. ME2 interacts directly with the malate shuttle system, which has been shown to be altered in schizophrenia and bipolar disorder, and has roles in neuronal synthesis of glutamate and gamma-amino butyric acid. The present study suggests that genetic variation in or near the ME2 gene is associated with both psychotic and manic disorders, including schizophrenia and bipolar disorder.

A novel missense mutation in the transmembrane domain of neuregulin 1 is associated with schizophrenia.

BACKGROUND: Although genetic factors are known to play an important role in schizophrenia, the identification of genes involved in this disorder has remained elusive. The neuregulin 1 gene is among the few candidate genes to have been implicated in schizophrenia susceptibility in several populations. However, no causal mutations within this gene have been identified. METHODS: In attempts to identify polymorphisms within the neuregulin 1 gene, we performed DNA sequencing using 12 subjects with a history of psychosis from the Central Valley of Costa Rica. DNA genotyping and association studies were then performed in an extended cohort of 142 affected individuals and their relatives from the same population. RESULTS: We identified a novel missense mutation (Val to Leu) in exon 11, which codes for the transmembrane region of the neuregulin 1 protein. Association analysis by the Family Based Association Test (FBAT) revealed that this mutation is associated with psychosis (p = .0049) and schizophrenia (p = .0191) in this population. CONCLUSIONS: We report the finding of a missense mutation in the neuregulin 1 gene associated with schizophrenia. Additional analyses of an independent sample as well as detailed functional studies should be performed to determine the relevance of this novel polymorphism to the pathophysiology of schizophrenia.

Linkage disequilibrium analyses in the Costa Rican population suggests discrete gene loci for schizophrenia at 8p23.1 and 8q13.3.

Linkage studies using multiplex families have repeatedly implicated chromosome 8 as involved in schizophrenia etiology. The reported areas of linkage, however, span a wide chromosomal region. The present study used the founder population of the Central Valley of Costa Rica and phenotyping strategies alternative to DSM-IV classifications in attempts to further delimitate the areas on chromosome 8 that may harbor schizophrenia susceptibility genes. A linkage disequilibrium screen of chromosome 8 was performed using family trios of individuals with a history of psychosis. Four discrete regions showing evidence of association (nominal P values less than 0.05) to the phenotype of schizophrenia were identified: 8p23.1, 8p21.3, 8q13.3 and 8q24.3. The region of 8p23.1 precisely overlaps a region showing strong evidence of linkage disequilibrium for severe bipolar disorder in Costa Rica. The same chromosomal regions were identified when the broader phenotype definition of all individuals with functional psychosis was used for analyses. Stratification of the psychotic sample by history of mania suggests that the 8q13.3 locus may be preferentially associated with non-manic psychosis. These results may be helpful in targeting specific areas to be analyzed in association-based or linkage disequilibrium-based studies, for researchers who have found evidence of linkage to schizophrenia on chromosome 8 within their previous studies.

Identification of circadian gene variants in bipolar disorder in Latino populations.

BACKGROUND: Variations in circadian genes can impact biological rhythms. Given the rhythm disturbances that characterize bipolar disorder (BD), genes encoding components of molecular clocks are good candidate genes for the illness. METHODS: A family based association analysis of circadian gene single nucleotide polymorphisms (SNPs) and BD was conducted in Latino pedigrees. 884 individuals from 207 pedigrees (473BP phenotype and 411 unaffected family members) were genotyped. Family based single marker association testing was performed. Ancestral haplotypes (SNPs found to be in strong LD defined using confidence intervals) were also tested for association with BD. RESULTS: Multiple suggestive associations between circadian gene SNPs and BD were noted. These included CSNK1E (rs1534891, p=0.00689), ARNTL (rs3789327, p=0.021172), CSNK1D (rs4510078, p=0.022801), CLOCK (rs17777927, p=0.031664). Individually, none of the SNPs were significantly associated with BD after correction for multiple testing. However, a 4-locus CSNK1E haplotype encompassing the rs1534891 SNP (Z-score=2.685, permuted p=0.0076) and a 3-locus haplotype in ARNTL (Z-score=3.269, permuted p=0.0011) showed a significant association with BD. LIMITATIONS: Larger samples are required to confirm these findings and assess the relationship between circadian gene SNPs and BD in Latinos. CONCLUSIONS: The results suggest that ARNTL and CSKN1E variants may be associated with BD. Further studies are warranted to assess the relationships between these genes and BD in Latino populations.

A randomized single-blind pilot study of compensatory strategies in schizophrenia outpatients.

In a previous study, we found that cognitive adaptation training (CAT)--a manual-driven program of environmental supports designed to bypass cognitive deficits--improved multiple domains of outcome in schizophrenia patients recently discharged from a State psychiatric facility. The present study examined the efficacy of CAT in a sample of patients who had been in the community at least 3 months. Forty-five medicated schizophrenia patients were randomly assigned for 9 months to one of three conditions: (1) CAT, (2) a condition that controlled for therapist time and provided environmental changes unrelated to cognitive deficits, or (3) follow-up only. Comprehensive assessments were conducted every 3 months by blinded raters. Results of repeated measures analyses of covariance for mixed models indicated that patients participating in CAT had better adaptive function and quality of life, and fewer positive symptoms than those in the two non-CAT conditions. Results indicate that compensatory strategies may improve various outcomes in schizophrenia outpatients.