Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder.

Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed health problems, prior pharmacological treatments, and polygenic scores (PGS) has potential to inform risk stratification. We examined self-reported SB and ideation using the Columbia Suicide Severity Rating Scale (C-SSRS) among 3,942 SCZ and 5,414 BPI patients receiving care within the Veterans Health Administration (VHA). These cross-sectional data were integrated with electronic health records (EHRs), and compared across lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. PGS were constructed using available genomic data for related traits. Genome-wide association studies were performed to identify and prioritize specific loci. Only 20% of the veterans who reported SB had a corroborating ICD-9/10 EHR code. Among those without prior SB, more than 20% reported new-onset SB at follow-up. SB were associated with a range of additional clinical diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking initiation, suicide attempt, and major depressive disorder were associated with SB. The GWAS for SB yielded no significant loci. Among individuals with a diagnosed mental illness, self-reported SB were strongly associated with clinical variables across several EHR domains. Analyses point to sequelae of substance-related and psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in health records, underscoring the value of regular screening with direct, in-person assessments, especially among high-risk individuals.

Genome-wide association study of cognitive performance in U.S. veterans with schizophrenia or bipolar disorder.

Cognitive impairment is a frequent and serious problem in patients with various forms of severe mental illnesses (SMI), including schizophrenia (SZ) and bipolar disorder (BP). Recent research suggests genetic links to several cognitive phenotypes in both SMI and in the general population. Our goal in this study was to identify potential genomic signatures of cognitive functioning in veterans with severe mental illness and compare them to previous findings for cognition across different populations. Veterans Affairs (VA) Cooperative Studies Program (CSP) Study #572 evaluated cognitive and functional capacity measures among SZ and BP patients. In conjunction with the VA Million Veteran Program, 3,959 European American (1,095 SZ, 2,864 BP) and 2,601 African American (1,095 SZ, 2,864 BP) patients were genotyped using a custom Affymetrix Axiom Biobank array. We performed a genome-wide association study of global cognitive functioning, constructed polygenic scores for SZ and cognition in the general population, and examined genetic correlations with 2,626 UK Biobank traits. Although no single locus attained genome-wide significance, observed allelic effects were strongly consistent with previous studies. We observed robust associations between global cognitive functioning and polygenic scores for cognitive performance, intelligence, and SZ risk. We also identified significant genetic correlations with several cognition-related traits in UK Biobank. In a diverse cohort of U.S. veterans with SZ or BP, we demonstrate broad overlap of common genetic effects on cognition in the general population, and find that greater polygenic loading for SZ risk is associated with poorer cognitive performance.

A unique gene expression signature associated with serotonin 2C receptor RNA editing in the prefrontal cortex and altered in suicide.

Editing of the pre-mRNA for the serotonin receptor 2C (5-HT2CR) by site-specific adenosine deamination (A-to-I pre-mRNA editing) substantially increases the functional plasticity of this key neurotransmitter receptor and is thought to contribute to homeostatic mechanisms in neurons. 5-HT2CR mRNA editing generates up to 24 different receptor isoforms. The extent of editing correlates with 5-HT2CR functional activity: more highly edited isoforms exhibit the least function. Altered 5-HT2CR editing has been reported in postmortem brains of suicide victims. We report a comparative analysis of the connections among 5-HT2CR editing, genome-wide gene expression and DNA methylation in suicide victims, individuals with major depressive disorder and non-psychiatric controls. The results confirm previous findings of an overrepresentation of highly edited mRNA variants (which encode hypoactive 5-HT2CR receptors) in the brains of suicide victims. A large set of genes for which the expression level is associated with editing was detected. This signature set of editing-associated genes is significantly enriched for genes that are involved in synaptic transmission, genes that are preferentially expressed in neurons, and genes whose expression is correlated with the level of DNA methylation. Notably, we report that the link between 5-HT2CR editing and gene expression is disrupted in suicide victims. The results suggest that the postulated homeostatic function of 5-HT2CR editing is dysregulated in individuals who committed suicide.

The neurobiology of aggression and violence.

Aggression and violence represent a significant public health concern and a clinical challenge for the mental healthcare provider. A great deal has been revealed regarding the neurobiology of violence and aggression, and an integration of this body of knowledge will ultimately serve to advance clinical diagnostics and therapeutic interventions. We will review here the latest findings regarding the neurobiology of aggression and violence. First, we will introduce the construct of aggression, with a focus on issues related to its heterogeneity, as well as the importance of refining the aggression phenotype in order to reduce pathophysiologic variability. Next we will examine the neuroanatomy of aggression and violence, focusing on regional volumes, functional studies, and interregional connectivity. Significant emphasis will be on the amygdala, as well as amygdala-frontal circuitry. Then we will turn our attention to the neurochemistry and molecular genetics of aggression and violence, examining the extensive findings on the serotonergic system, as well as the growing literature on the dopaminergic and vasopressinergic systems. We will also address the contribution of steroid hormones, namely, cortisol and testosterone. Finally, we will summarize these findings with a focus on reconciling inconsistencies and potential clinical implications; and, then we will suggest areas of focus for future directions in the field.

Schizotypal personality disorder: a current review.

The study of schizotypal personality disorder (SPD) is important clinically, as it is understudied, challenging to treat, often under-recognized or misdiagnosed, and associated with significant functional impairment. SPD also represents an intermediate schizophrenia-spectrum phenotype, and therefore, can provide a better understanding of the genetics, pathogenesis, and treatment of related psychotic illnesses. In this review we discuss recent findings of SPD related to epidemiology and functional impairment, heritability and genetics, working memory and cognitive impairments, social-affective disturbances, and neurobiology. Additionally, we examine the challenges associated with treating patients with SPD, as well as clinical recommendations. Finally, we address future directions and areas in need of further exploration.

Personality disorders, attachment and psychodynamic psychotherapy.

While attachment has been a fruitful and critical concept in understanding enduring individual templates for interpersonal relationships, it does not have a well-understood relationship to personality disorders, where impairment of interpersonal functioning is paramount. Despite the recognition that attachment disturbances do not simply reflect nonoptimal caretaking environments, the relationship of underlying temperamental factors to these environmental insults has not been fully explored. In this paper we provide an alternate model for the role of neurobiological temperamental factors, including brain circuitry and neuropeptide modulation, in mediating social cognition and the internalization and maintenance of attachment patterns. The implications of these altered attachment patterns on personality disorders and their neurobiological and environmental roots for psychoanalytically based treatment models designed to ameliorate difficulties in interpersonal functioning through the medium of increased access to mature forms of mentalization is discussed.

The genetics of functional disability in schizophrenia and bipolar illness: Methods and initial results for VA cooperative study #572.

Given the prominence of cognitive impairments and disability associated with schizophrenia and bipolar disorder, substantial interest has arisen in identifying determinants of the diseases and their features. Genetic variation has been linked to skills that underlie disability ("functional capacity" or FC), highlighting need for understanding of these relationships. We describe the design and methods of a large, multisite, observational study focusing on the genetics of functional disability in schizophrenia and bipolar disorder, presenting initial data on recruitment, and characterization of the sample. Known as Veterans Affairs (VA) Cooperative Studies Program (CSP)#572, this study is recruiting, diagnosing, and assessing U.S. Veterans with either schizophrenia or bipolar I disorder. Assessments include neuropsychological (NP) testing, FC, suicidality, and co-morbid conditions such as posttraumatic stress disorder (PTSD). A sample of "psychiatrically healthy" Veterans from another project serves as a comparison group. An interim total of 8,140 participants (42.1% schizophrenia) have been recruited and assessed as of September 30, 2013, with 9 months of enrollment remaining and with a target sample size of 9,500. Veterans with schizophrenia were more likely to never have married, whereas lifetime PTSD and suicidality were more common in the bipolar veterans. Performance on the FC measures and NP tests was consistent with previous results, with mean t-scores of 35 (-1.5 SD) for schizophrenia and 41 (-0.9 SD) for the bipolar Veterans. This large population is representative of previous studies in terms of patient performance and co-morbidities. Subsequent genomic analyses will examine the genomic correlates of performance-based measures. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

The neurobiology of empathy in borderline personality disorder.

We present a neurobiological model of empathic dysfunction in borderline personality disorder (BPD) to guide future empirical research. Empathy is a necessary component of interpersonal functioning, involving two distinct, parallel neural networks. One form of empathic processing relies on shared representations (SR) of others' mental states, while the other is associated with explicit mental state attribution (MSA). SR processing is visceral and automatic, contributing to attunement, but also emotional contagion. MSA processing contributes to deliberate, perspectival forms of empathic understanding. Empathic dysfunction in BPD may involve hyper-reactivity of SR networks and impairment of MSA networks. Nevertheless, this empathic dysfunction is subtle, but contributes to interpersonal difficulties. Interaction between genetic factors and traumatic attachment stressors may contribute to development of BPD, with painful attachment insecurity and disorganization affecting SR and MSA network functioning. Future avenues for BPD research will include developmental assessment of attachment and neurobiological functioning under varying conditions.

Serotonin transporter availability in physically aggressive personality disordered patients: associations with trait and state aggression, and response to fluoxetine.

RATIONALE: Characterizing the neuroanatomical basis of serotonergic abnormalities in severe, chronic, impulsive aggression will allow for rational treatment selection, development of novel therapeutics, and biomarkers to identify at-risk individuals. OBJECTIVES: The aim of this study is to identify associations between regional serotonin transporter (5-HTT) availability and trait and state aggression, as well as response to the anti-aggressive effects of fluoxetine. METHODS: We examined 5-HTT availability using positron emission tomography (PET) imaging with [11C]DASB in personality disordered patients with current physical intermittent explosive disorder (IED; n = 18), and healthy comparison participants (HC; n = 11), in the anterior cingulate cortex (ACC), amygdala (AMY), ventral striatum (VST), and midbrain (MID). After PET imaging, IED patients were treated with fluoxetine 20 mg daily (n = 9) or placebo (n = 6) for 12 weeks. Trait and state aggression, trait callousness, and childhood trauma were assessed. RESULTS: In IED patients, trait aggression was positively associated with [11C]DASB binding in the ACC and VST; covarying for trait callousness and childhood trauma enhanced these correlations. Baseline state aggression was positively correlated with ACC [11C]DASB in IED patients. Greater baseline VST [11C]DASB binding predicted greater decreases in state aggression with fluoxetine treatment. CONCLUSIONS: Consistent with prior reports, ACC 5-HTT is related to trait aggression, and adjusting for factors related to proactive (callousness) and reactive (childhood trauma) aggression subtypes further resolves this relationship. Novel findings of the study include a better understanding of the association between regional 5-HTT availability and state aggression, and the involvement of VST 5-HTT with trait aggression, and with the anti-aggressive effects of fluoxetine.

Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder.

Objective: Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed mental and physical health problems, prior pharmacological treatments, and aggregate genetic factors has potential to inform risk stratification and mitigation strategies. Methods: In this study of 3,942 SCZ and 5,414 BPI patients receiving VA care, self-reported SB and ideation were assessed using the Columbia Suicide Severity Rating Scale (C-SSRS). These cross-sectional data were integrated with electronic health records (EHR), and compared by lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. Polygenic scores (PGS) for traits related to psychiatric disorders, substance use, and cognition were constructed using available genomic data, and exploratory genome-wide association studies were performed to identify and prioritize specific loci. Results: Only 20% of veterans who self-reported SB had a corroborating ICD-9/10 code in their EHR; and among those who denied prior behaviors, more than 20% reported new-onset SB at follow-up. SB were associated with a range of psychiatric and non-psychiatric diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking, suicide attempt, and major depressive disorder were also associated with attempt and ideation. Conclusions: Among individuals with a diagnosed mental illness, a GWAS for SB did not yield any significant loci. Self-reported SB were strongly associated with clinical variables across several EHR domains. Overall, clinical and polygenic analyses point to sequelae of substance-use related behaviors and other psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in clinical settings, underscoring the value of regular screening based on direct, in-person assessments, especially among high-risk individuals.

Frontotemporal thalamic connectivity in schizophrenia and schizotypal personality disorder.

Schizotypal personality disorder (SPD) resembles schizophrenia, but with attenuated brain abnormalities and the absence of psychosis. The thalamus is integral for processing and transmitting information across cortical regions and widely implicated in the neurobiology of schizophrenia. Comparing thalamic connectivity in SPD and schizophrenia could reveal an intermediate schizophrenia-spectrum phenotype to elucidate neurobiological risk and protective factors in psychosis. We used rsfMRI to investigate functional connectivity between the mediodorsal nucleus (MDN) and pulvinar, and their connectivity with frontal and temporal cortical regions, respectively in 43 healthy controls (HCs), and individuals in the schizophrenia-spectrum including 45 psychotropic drug-free individuals with SPD, and 20 individuals with schizophrenia-related disorders [(schizophrenia (n = 10), schizoaffective disorder (n = 8), schizophreniform disorder (n = 1) and psychosis NOS (n = 1)]. Individuals with SPD had greater functional connectivity between the MDN and pulvinar compared to individuals with schizophrenia. Thalamo-frontal (i.e., between the MDN and rostral middle frontal cortex) connectivity was comparable in SPD and HCs; in SPD greater connectivity was associated with less symptom severity. Individuals with schizophrenia had less thalamo-frontal connectivity and thalamo-temporal (i.e., pulvinar to the transverse temporal cortex) connectivity compared with HCs. Thalamo-frontal functional connectivity may be comparable in SPD and HCs, but abnormal in schizophrenia, and that this may be protective against psychosis in SPD.

Cingulate and temporal lobe fractional anisotropy in schizotypal personality disorder.

BACKGROUND: Consistent with the clinical picture of milder symptomatology in schizotypal personality disorder (SPD) than schizophrenia, morphological studies indicate SPD abnormalities in temporal lobe regions but to a much lesser extent in prefrontal regions implicated in schizophrenia. Lower fractional anisotropy (FA), a measure of white-matter integrity within prefrontal, temporal, and cingulate regions has been reported in schizophrenia but has been little studied in SPD. AIMS: The study aim was to examine temporal and prefrontal white matter FA in 30 neuroleptic-naïve SPD patients and 35 matched healthy controls (HCs). We hypothesized that compared with HCs, SPD patients would exhibit lower FA in temporal lobe and anterior cingulum regions but relative sparing in prefrontal regions. METHOD: We acquired diffusion tensor imaging (DTI) in all participants and examined FA in the white matter underlying Brodmann areas (BAs) in dorsolateral prefrontal (BAs 44, 45, and 46), temporal lobe (BAs 22, 21, and 20), and cingulum (BAs 25, 24, 31, 23, and 29) regions with a series of analyses using multivariate analysis of variance. RESULTS: Compared with HCs, the SPD group had significantly lower FA in the left temporal lobe but not prefrontal regions. In the cingulum, FA was lower in the SPD group in the posterior regions (BAs 31 and 23), higher in the anterior (BA 25) regions and lower overall in the right but not the left cingulum. Among the SPD group, lower FA in the cingulum was associated with more severe negative symptoms (e.g., odd speech). CONCLUSIONS: Similar to schizophrenia, our results indicate cingulum-temporal lobe FA abnormalities in SPD and suggest that cingulum abnormalities are associated with negative symptoms.

Evidence-based pharmacotherapy for personality disorders.

Patients with personality disorders are prescribed psychotropic medications with greater frequency than almost any other diagnostic group. Prescribing practices in these populations are often based on anecdotal evidence rather than rigorous data. Although evidence-based psychotherapy remains an integral part of treatment, Axis II psychopathology is increasingly conceptualized according to neurobiological substrates that correspond to specific psychopharmacological strategies. We summarize the best available evidence regarding medication treatment of personality disordered patients and provide optimal strategies for evidence-based practice. Most available evidence is concentrated around borderline and schizotypal personality disorders, with some additional evidence concerning the treatment of avoidant and antisocial personality disorders. Although maladaptive personality symptoms respond to antidepressants, antipsychotics, mood stabilizers, and other medications, evidence-based pharmacotherapy is most useful in treating circumscribed symptom domains and induces only partial improvement. Most available evidence supports use of medication in reducing impulsivity and aggression, characteristic of borderline and antisocial psychopathology. Efforts have also begun to reduce psychotic-like symptoms and improve cognitive deficits characteristic of schizotypy. Indirect evidence is also provided for psychopharmacological reduction of social anxiety central to avoidant personality disorder. Evidence-based practice requires attention to domains of expected clinical improvement associated with a medication, relative to the potential risks. The development of future rational pharmacotherapy will require increased understanding of the neurobiological underpinnings of personality disorders and their component dimensions. Increasing efforts to translate personality theory and social cognitive neuroscience into increasingly specific neurobiological substrates may provide more effective targets for pharmacotherapy.

Eye tracking performance and the boundaries of the schizophrenia spectrum.

In order to investigate the nature of the eye tracking impairment in schizophrenia spectrum we measured pursuit gain with a constant velocity target using a quantitative (RMS error in pursuit gain) and, on an exploratory basis, a qualitative (quality of tracking) measure. We utilized a sample consisting of three clinically characterized groups: patients with schizophrenia (SZ), their first degree non-psychotic relatives, subjects with schizotypal personality disorder (SPD), and healthy volunteers (HV). Thirty three SZ patients, 19 SPD subjects, 66 non-psychotic relatives (all clinically assessed for schizophrenia spectrum psychopathology--DSM-IIIR) and 18 HV were evaluated using an infrared eye tracking system. Targets were constant velocity trapezoids at 5°/s (slow) and 16°/s (fast). The quality of the eye tracking was independently evaluated by at least two raters (ICC: 0.92). The RMS measures at the two velocities (quantitative measure) and the quality of the tracking obtained for each velocity were entered separately into a two factor repeated measures ANOVA, with velocity and diagnosis as the independent measures. For the quantitative ratings (RMS error), a significant effect for velocity was found, with all subjects performing worse at the higher velocity, but there was no significant velocity by diagnosis interaction. In addition, an overall significant effect for diagnosis was found in the four-group ANOVA. In post hoc multiple comparison tests, SZ subjects performed significantly worse from the HV and the relatives. SPD subjects were not different from patients with schizophrenia (or from any group--and their performance was intermediate between the HV and the SZ). Relatives of the patients with schizophrenia were different from SZ subjects, but not different from SPD or HV subjects. Similar results were obtained in the exploratory qualitative ratings. Clinical symptoms did not correlate significantly with quantitative or qualitative performance in any group. We have found that the performance of SPD subjects is intermediate between that of patients with schizophrenia and the healthy volunteers in both qualitative and quantitative (exploratory) measures. Indeed, SPD subjects comprise the only group not statistically different from schizophrenic patients in quantitative or qualitative ratings.

Attitudes toward borderline personality disorder: a survey of 706 mental health clinicians.

OBJECTIVE: We sought to determine attitudes toward patients with borderline personality disorder (BPD) among mental health clinicians at nine academic centers in the United States. METHODS: A self-report questionnaire was distributed to 706 mental health clinicians, including psychiatrists, psychiatry residents, social workers, nurses, and psychologists. RESULTS: The study showed that most clinicians consider BPD a valid diagnosis, although nearly half reported that they preferred to avoid these patients. The clinician's occupational subgroup was significantly related to attitude. Staff nurses had the lowest self-ratings on overall caring attitudes, while social workers had the highest. Social workers and psychiatrists had the highest ratings on treatment optimism. Social workers and psychologists were most optimistic about psychotherapy effectiveness, while psychiatrists were most optimistic about medication effectiveness. Staff nurses had the lowest self-ratings on empathy toward patients with BPD and treatment optimism.DiscussionNegative attitudes persist among clinicians toward BPD, but differ among occupational subgroups. Overall, caring attitudes, empathy, and treatment optimism were all higher among care providers who had cared for a greater number of BPD patients in the past 12 months. CONCLUSION: These findings hold important implications for clinician education and coordination of care for patients with BPD.

Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans.

BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world's population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572. METHODS: We performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date. RESULTS: Our primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P < 10-30) and African American (P < .0005) participants in CSP #572. CONCLUSIONS: We have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations.

An attachment perspective on borderline personality disorder: advances in gene-environment considerations.

Accumulating evidence points to severe relationship dysfunction as the core epigenetic expression of borderline personality disorder (BPD). In adulthood, BPD is typified by disorganization within and across interpersonal domains of functioning. When interacting with their infants, mothers with BPD show marked withdrawal and frightening or frightened behavior, leading to disorganized infant-mother attachments. Linked to both infant disorganization and BPD is a maternal state of mind typified by unresolved mourning regarding past loss or trauma. Early risk factors for BPD in adulthood include maternal withdrawal in infancy and separation of 1 month or more from mother in the first 5 years of life. Likely contributing biological factors include genes linked to dopamine, serotonin, the hypothalamic-pituitary-adrenal axis, and neuropeptides. The complex gene-environment picture emerging confers risk or protection against BPD pathology in ways consistent with infants varying biological sensitivity to context. This line of research may refine early risk assessment and preventive mental health services.

Psychometric properties of a short form of the Affective Lability Scale (ALS-18).

Psychometric properties of a short form of the Affective Lability Scale (ALS) that was developed in a nonclinical sample (i.e., undergraduate students) were examined in a sample of people diagnosed with Cluster B DSM-IV Axis II personality disorders (n=236), other personality disorders (n=180), and healthy comparison participants (n=164). The total score of the ALS-18 score correlated strongly with the original 54-item scale (r = .97) and aspects of convergent and discriminant validity of the ALS-18 subscales (Anxiety/Depression, Depression/Elation, and Anger) were evaluated using self-report measures of affective and psychosocial functioning in the domains of affect intensity, anxiety, anger, and minimization/denial. Clinical utility of the scale was also demonstrated; participants diagnosed with Cluster B personality disorders reported higher affective lability scores, and healthy control participants reported lower scores, relative to individuals with Cluster A or Cluster C personality disorders (p's < .001). Confirmatory factor analyses were conducted and demonstrated reasonably good fit to the data but future research is needed to test the three factor substructure of the ALS-18 against alternative factor models in samples that include clinical and non-clinical participants.

Amphetamine-induced striatal dopamine release in schizotypal personality disorder.

RATIONALE: Previous research has suggested that schizotypal personality disorder (SPD), a condition that shares clinical and cognitive features with schizophrenia, may be associated with elevated striatal dopamine functioning; however, there are no published studies of dopamine release within subregions of the striatum in SPD. OBJECTIVES: To characterize dopamine release capacity in striatal subregions and its relation to clinical and cognitive features in SPD. METHODS: We used positron emission tomography with [11C]raclopride and an amphetamine challenge to measure dopamine D2-receptor availability (binding potential, BPND), and its percent change post-amphetamine (∆BPND) to index amphetamine-induced dopamine release, in subregions of the striatum in 16 SPD and 16 healthy control participants. SPD participants were evaluated with measures of schizotypal symptom severity and working memory. RESULTS: There were no significant group differences in BPND or ∆BPND in any striatal subregion or whole striatum. Among SPD participants, cognitive-perceptual symptoms were associated at trend level with ∆BPND in the ventral striatum, and disorganized symptoms were significantly negatively related to ∆BPND in several striatal subregions. CONCLUSIONS: In contrast to previous findings, SPD was not associated with elevated striatal dopamine release. However, in SPD, there was a moderate positive association between ventral striatal dopamine release and severity of cognitive-perceptual symptoms, and negative associations between striatal dopamine release and severity of disorganized symptoms. Future larger scale investigations that allow for the separate examination of subgroups of participants based on clinical presentation will be valuable in further elucidating striatal DA functioning in SPD.

The effects of age and sex on cognitive impairment in schizophrenia: Findings from the Consortium on the Genetics of Schizophrenia (COGS) study.

Recently emerging evidence indicates accelerated age-related changes in the structure and function of the brain in schizophrenia, raising a question about its potential consequences on cognitive function. Using a large sample of schizophrenia patients and controls and a battery of tasks across multiple cognitive domains, we examined whether patients show accelerated age-related decline in cognition and whether an age-related effect differ between females and males. We utilized data of 1,415 schizophrenia patients and 1,062 healthy community collected by the second phase of the Consortium on the Genetics of Schizophrenia (COGS-2). A battery of cognitive tasks included the Letter-Number Span Task, two forms of the Continuous Performance Test, the California Verbal Learning Test, Second Edition, the Penn Emotion Identification Test and the Penn Facial Memory Test. The effect of age and gender on cognitive performance was examined with a general linear model. We observed age-related changes on most cognitive measures, which was similar between males and females. Compared to controls, patients showed greater deterioration in performance on attention/vigilance and greater slowness of processing social information with increasing age. However, controls showed greater age-related changes in working memory and verbal memory compared to patients. Age-related changes (η2p of 0.001 to .008) were much smaller than between-group differences (η2p of 0.005 to .037). This study found that patients showed continued decline of cognition on some domains but stable impairment or even less decline on other domains with increasing age. These findings indicate that age-related changes in cognition in schizophrenia are subtle and not uniform across multiple cognitive domains.