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1.  Improving the Understanding of the Link between Cognition and Functional Capacity in Schizophrenia and Bipolar Disorder 
Schizophrenia research  2015;169(0):121-127.
Deficits in cognitive functioning are related to functional disability in people with serious mental illness. Measures of functional capacity are commonly used as a proxy for functional disabilities for cognitive remediation programs, and robust linear relationships between functional capacity and cognitive deficits are frequently observed. This study aimed to determine whether a curvilinear relationship better approximates the association between cognitive functioning and functional capacity.
Two independent samples were studied. Study 1: Participants with schizophrenia (n=435) and bipolar disorder (n=390) aged 18–83 completed a neuropsychological battery and a performance-based measure of functional capacity. Study 2: 205 participants with schizophrenia (age range=39–72) completed a brief neuropsychological screening battery and a performance-based measure of functional capacity. For both studies, linear and quadratic curve estimations were conducted with cognitive performance predicting functional capacity scores.
Significant linear and quadratic trends were observed for both studies. Study 1: In both the schizophrenia and bipolar participants, when cognitive composite z-scores were >0 (indicating normal to above normal performance), cognition was not related to functional capacity. Study 2: When neuropsychological screening battery z-scores were >−1 (indicating low average to average performance), cognition was not related to functional capacity.
These results illustrate that in cognitively normal adults with serious mental illness, the relationship between cognitive function and functional capacity is relatively weak. These findings may aid clinicians and researchers determine who may optimally benefit from cognitive remediation programs, with greater benefits possibly being achieved for individuals with cognitive deficits relative to individuals with normal cognition.
PMCID: PMC4681671  PMID: 26427917
2.  Current Smoking is Associated with Worse Cognitive and Adaptive Functioning in Serious Mental Illness 
Acta psychiatrica Scandinavica  2015;131(5):333-341.
Cigarette smoking is highly prevalent among people with bipolar disorder or schizophrenia. Few studies have examined whether smoking history is associated with adaptive functioning among individuals diagnosed with these serious mental illnesses.
In a large relatively homogenous cohort of patients with either bipolar disorder (n=363) or schizophrenia (n=400), we investigated the association between cigarette smoking status, intensity, and cumulative exposure and performance on a comprehensive battery of neurocognitive, functional capacity, informant-rated functional measures. The associations were adjusted for variation in sociodemographic indicators, psychopathologic symptoms, and substance use.
There was an average of 12 pack years of smoking across the sample. People with schizophrenia reported double the rate of current smoking compared to patients with bipolar disorder. Adjusting for demographic covariates, current smokers had worse composite cognitive functioning and poorer functional outcome than past or never smokers. There were no significant differences between never and past smokers, and these effects were evident in both bipolar disorder and schizophrenia.
Current smokers with either schizophrenia or bipolar disorder evidence worse cognitive and adaptive functioning functional outcome, even when demographic covariates are considered.
Significant Outcomes
Patients with schizophrenia had double the rate of smoking compared to patients with bipolar disorder
Current smoking was negatively associated with cognitive functioning, functional capacity, and informant reported functional outcomes in both patients with schizophrenia and bipolar disorder, after adjusting for sociodemographic covariates
The study was cross-sectional and so causal associations cannot be inferred
Tobacco use was assessed with a self-report instrument
The sample was relatively homogenous and high function and may not generalize to ethnically diverse or more symptomatic samples
PMCID: PMC4400207  PMID: 25559296
Cognition; Neuropsychology; Schizophrenia; Psychosis; Bipolar Disorder; Nicotine
3.  Association of obesity and treated hypertension and diabetes with cognitive ability in bipolar disorder and schizophrenia 
Bipolar disorders  2014;16(4):422-431.
People with bipolar disorder or schizophrenia are at greater risk for obesity and other cardio-metabolic risks, and several prior studies have linked these risks to poorer cognitive ability. In a large ethnically homogenous outpatient sample, we examined associations among variables related to obesity, treated hypertension and/or diabetes, and cognitive abilities in these two patient populations.
In a study cohort of outpatients with either bipolar disorder (n = 341) or schizophrenia (n = 417), we investigated the association of self-reported body mass index and current use of medications for hypertension or diabetes with performance on a comprehensive neurocognitive battery. We examined sociodemographic and clinical factors as potential covariates.
Patients with bipolar disorder were less likely to be overweight or obese than patients with schizophrenia, and also less likely to be prescribed medication for hypertension or diabetes. However, obesity and treated hypertension were associated with worse global cognitive ability in bipolar disorder (as well as with poorer performance on individual tests of processing speed, reasoning/problem-solving, and sustained attention), with no such relationships observed in schizophrenia. Obesity was not associated with symptom severity in either group.
Although less prevalent in bipolar disorder compared to schizophrenia, obesity was associated with substantially worse cognitive performance in bipolar disorder. This association was independent of symptom severity and not present in schizophrenia. Better understanding of the mechanisms and management of obesity may aid in efforts to preserve cognitive health in bipolar disorder.
PMCID: PMC4047181  PMID: 24725166
bipolar disorder; diabetes; health risk factors; hypertension; neuropsychology; obesity; psychosis
4.  Infection and Inflammation in Schizophrenia and Bipolar Disorder: A Genome Wide Study for Interactions with Genetic Variation 
PLoS ONE  2015;10(3):e0116696.
Inflammation and maternal or fetal infections have been suggested as risk factors for schizophrenia (SZ) and bipolar disorder (BP). It is likely that such environmental effects are contingent on genetic background. Here, in a genome-wide approach, we test the hypothesis that such exposures increase the risk for SZ and BP and that the increase is dependent on genetic variants. We use genome-wide genotype data, plasma IgG antibody measurements against Toxoplasma gondii, Herpes simplex virus type 1, Cytomegalovirus, Human Herpes Virus 6 and the food antigen gliadin as well as measurements of C-reactive protein (CRP), a peripheral marker of inflammation. The subjects are SZ cases, BP cases, parents of cases and screened controls. We look for higher levels of our immunity/infection variables and interactions between them and common genetic variation genome-wide. We find many of the antibody measurements higher in both disorders. While individual tests do not withstand correction for multiple comparisons, the number of nominally significant tests and the comparisons showing the expected direction are in significant excess (permutation p=0.019 and 0.004 respectively). We also find CRP levels highly elevated in SZ, BP and the mothers of BP cases, in agreement with existing literature, but possibly confounded by our inability to correct for smoking or body mass index. In our genome-wide interaction analysis no signal reached genome-wide significance, yet many plausible candidate genes emerged. In a hypothesis driven test, we found multiple interactions among SZ-associated SNPs in the HLA region on chromosome 6 and replicated an interaction between CMV infection and genotypes near the CTNNA3 gene reported by a recent GWAS. Our results support that inflammatory processes and infection may modify the risk for psychosis and suggest that the genotype at SZ-associated HLA loci modifies the effect of these variables on the risk to develop SZ.
PMCID: PMC4363491  PMID: 25781172
5.  Reciprocal duplication of the Williams-Beuren syndrome deletion on chromosome 7q11.23 is associated with schizophrenia 
Biological psychiatry  2013;75(5):371-377.
Several copy number variants (CNVs) have been implicated as susceptibility factors for schizophrenia (SZ). Some of these same CNV also increase risk for autism spectrum disorders (ASD), suggesting an etiologic overlap between these conditions. Recently, de novo duplications of a region on chromosome 7q11.23 were associated with ASD. The reciprocal deletion of this region causes Williams-Beuren syndrome (WBS).
We assayed an Ashkenazi Jewish cohort of 554 SZ cases and 1014 controls for copy number variation (CNV), using a high-density genome-wide array. An excess of large rare and de novo CNV were observed, including a 1.4 Mb duplication on chromosome 7q11.23 identified in two unrelated patients. To test whether this 7q11.23 duplication is also associated with SZ, we obtained data for 14,387 SZ cases and 28,139 controls from seven additional studies with high-resolution genome-wide CNV detection. We performed a meta-analysis, correcting for study population of origin, to assess whether the 7q11.23 duplication is associated with SZ.
We find duplications at 7q11.23 in 11 of 14,387 SZ cases with only 1 in 28,139 controls (unadjusted odds ratio, 21.52, 95% CI: 3.13-922.6, p-value 5.5×10-5; adjusted odds ratio 10.8, 95% CI: 1.46-79.62, p-value 0.007). Of three SZ duplication carriers with available detailed retrospective data, all show social anxiety and language delay premorbid to SZ onset, consistent with both human studies and animal models of the 7q11.23 duplication.
We have identified a new CNV associated with SZ. Reciprocal duplication of the Williams syndrome deletion at chromosome 7q11.23 confers an approximately 10-fold increase in risk for SZ.
PMCID: PMC3838485  PMID: 23871472
Schizophrenia; 7q11.23 duplication syndrome; Psychiatric genetics; Schizophrenia genetics; Autism; Williams-Beuren syndrome
6.  Prediction of Real World Functional Disability in Chronic Mental Disorders: A Comparison of Schizophrenia and Bipolar Disorder 
The American journal of psychiatry  2010;167(9):1116-1124.
Schizophrenia (SZ) and Bipolar Disorder (BD) are associated with multidimensional disability. This study examined differential predictors of functional deficits between the disorders.
Community dwelling individuals with SZ (N=161) or BD (N=130) were administered neuropsychological tests, symptom measures, performance-based social and adaptive (i.e., everyday-living skills) functional competence measures, and rated on domains of real-world functioning: 1) Community and Household activities, 2) Work skills, and 3) Interpersonal relationships. We used confirmatory path analysis to find the best fitting models to examine the direct and indirect (as mediated by competence) prediction of the three domains of real-world functioning.
In all models for both groups, neurocognition’s relationship with outcomes was largely mediated by competence. Symptoms were negatively associated with outcomes but unassociated with competence, with the exception of depression, which was a direct and mediated (through social competence) predictor in BD. In both groups, neurocognition was related to Activities directly and through a mediated relationship with adaptive competence. Work Skills were directly and indirectly (through mediation with social competence) predicted by neurocognition in SZ and entirely mediated by adaptive and social competence in BD. Neurocognition was associated with Interpersonal Relationships directly in the SZ group, and mediated by social competence in both groups.
Although there was greater disability in SZ, neurocognition predicted worse functioning in all outcome domains in both disorders. Our study supports the shared role of neurocognition in BD and SZ in producing disability, with predictive differences between disorders observed in domain-specific effects of symptoms and social and adaptive competence.
PMCID: PMC3694770  PMID: 20478878
7.  Linkage analysis of plasma dopamine β-hydroxylase activity in families of patients with schizophrenia 
Human genetics  2011;130(5):635-643.
Dopamine β-hydroxylase (DβH) catalyzes the conversion of dopamine to norepinephrine. DβH enters the plasma after vesicular release from sympathetic neurons and the adrenal medulla. Plasma DβH activity (pDβH) varies widely among individuals, and genetic inheritance regulates that variation. Linkage studies suggested strong linkage of pDβH to ABO on 9q34, and positive evidence for linkage to the complement fixation locus on 19p13.2-13.3. Subsequent association studies strongly supported DBH, which maps adjacent to ABO, as the locus regulating a large proportion of the heritable variation in pDβH. Prior studies have suggested that variation in pDβH, or genetic variants at DβH, associate with differences in expression of psychotic symptoms in patients with schizophrenia and other idiopathic or drug-induced brain disorders, suggesting that DBH might be a genetic modifier of psychotic symptoms. As a first step toward investigating that hypothesis, we performed linkage analysis on pDβH in patients with schizophrenia and their relatives. The results strongly confirm linkage of markers at DBH to pDβH under several models (maximum multipoint LOD score, 6.33), but find no evidence to support linkage anywhere on chromosome 19. Accounting for the contributions to the linkage signal of three SNPs at DBH, rs1611115, rs1611122, and rs6271 reduced but did not eliminate the linkage peak, whereas accounting for all SNPs near DBH eliminated the signal entirely. Analysis of markers genome-wide uncovered positive evidence for linkage between markers at chromosome 20p12 (multi-point LOD = 3.1 at 27.2 cM). The present results provide the first direct evidence for linkage between DBH and pDβH, suggest that rs1611115, rs1611122, rs6271 and additional unidentified variants at or near DBH contribute to the genetic regulation of pDβH, and suggest that a locus near 20p12 also influences pDβH.
PMCID: PMC3193571  PMID: 21509519
8.  Sensitivity and Specificity of the UCSD Performance-based Skills Assessment (UPSA-B) for Identifying Functional Milestones in Schizophrenia 
Schizophrenia research  2011;132(2-3):165-170.
Schizophrenia is a highly debilitating illness that often results in disruption to independent living and employment. However, “gold standard” methods of assessing functional abilities to achieve these milestones are still lacking. In a sample of 367 individuals with schizophrenia, we examined the sensitivity and specificity of the Brief UCSD Performance-based Skills Assessment (UPSA-B) to predict both residential and employment status. Of all individuals residing independently, 75.9% scored 78 or above on the UPSA-B, and of all individuals not residing independently, 59% scored below 78 on the UPSA-B. Of individuals who were employed, 73.9% scored above 82 on the UPSA-B, and of those not employed, 57.8% scored below 82. These results expand upon both the population base and functional milestones with which the UPSA-B is validated, although future work should examine whether the UPSA-B can be used as a decision aid in the likelihood of success in a longitudinal study, such as at critical transitions (post-hospitalization, cessation of supported housing).
PMCID: PMC3195873  PMID: 21843926
Psychosis; Functional Capacity; Functioning; Employment; Independence; Well-being
9.  Replication of an association of a common variant in the Reelin gene (RELN) with schizophrenia in Ashkenazi Jewish women 
Psychiatric genetics  2010;20(4):184-186.
A single nucleotide polymorphism (rs7341475) in RELN has recently been shown to be associated with schizophrenia (SZ) in an Ashkenazi Jewish (AJ) case-control study specifically in women by Shifmen et al. We have replicated this association in women in another large independent AJ collection (721 cases, 259 female; 1455 controls, 834 female) and confirmed that it applies to both SZ and schizoaffective disorder. Further, we explore the effects of this polymorphism through quantitative trait loci (QTL) analysis of 9 SZ related factors providing information on sex-specific genotype-phenotype correlations.
PMCID: PMC2901865  PMID: 20431428
Schizophrenia; Reelin; Association; Endophenotype; Sex-specific; Ashkenazi; Jewish
10.  Relationship of the Brief UCSD Performance-based Skills Assessment (UPSA-B) to multiple indicators of functioning in people with schizophrenia and bipolar disorder 
Bipolar disorders  2010;12(1):45-55.
This study assessed the relationship between multiple indicators of ‘real-world’ functioning and scores on a brief performance-based measure of functional capacity known as the Brief University of California San Diego (UCSD) Performance-based Skills Assessment (UPSA-B) in a sample of 205 patients with either serious bipolar disorder (n = 89) or schizophrenia (n = 116).
Participants were administered the UPSA-B and assessed on the following functional domains: (i) independent living status (e.g., residing independently as head of household, living in residential care facility); (ii) informant reports of functioning (e.g., work skills, daily living skills); (iii) educational attainment and estimated premorbid IQ as measured by years of education and Wide Range Achievement Test reading scores, respectively; and (iv) employment.
Better scores on the UPSA-B were associated with greater residential independence after controlling for age, diagnosis, and symptoms of psychopathology. Among both bipolar disorder and schizophrenia patients, higher UPSA-B scores were significantly related to better informant reports of functioning in daily living skills and work skills domains. Greater estimated premorbid IQ was associated with higher scores on the UPSA-B for both schizophrenia and bipolar disorder participants. Participants who were employed scored higher on the UPSA-B when controlling for age and diagnosis, but not when controlling for symptoms of psychopathology.
These data suggest the UPSA-B may be useful for assessing capacity for functioning in a number of domains in both people diagnosed with schizophrenia and bipolar disorder.
PMCID: PMC2846793  PMID: 20148866
employment; functional capacity; functional outcome; independence; severe; mental illness

Results 1-10 (10)