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This review compares the main brain abnormalities in schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and 22q11.2 Deletion Syndrome (22q11DS) determined by ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) consortium investigations. We obtained ranked effect sizes for subcortical volumes, regional cortical thickness, cortical surface area, and diffusion tensor imaging abnormalities, comparing each of these disorders relative to healthy controls. In addition, the studies report on significant associations between brain imaging metrics and disorder-related factors such as symptom severity and treatments. Visual comparison of effect size profiles shows that effect sizes are generally in the same direction and scale in severity with the disorders (in the order SZ > BD > MDD). The effect sizes for 22q11DS, a rare genetic syndrome that increases the risk for psychiatric disorders, appear to be much larger than for either of the complex psychiatric disorders. This is consistent with the idea of generally larger effects on the brain of rare compared to common genetic variants. Cortical thickness and surface area effect sizes for 22q11DS with psychosis compared to 22q11DS without psychosis are more similar to those of SZ and BD than those of MDD; a pattern not observed for subcortical brain structures and fractional anisotropy effect sizes. The observed similarities in effect size profiles for cortical measures across the psychiatric disorders mimic those observed for shared genetic variance between these disorders reported based on family and genetic studies and are consistent with shared genetic risk for SZ and BD and structural brain phenotypes.

Aims Young people with attenuated psychotic symptoms (APS), brief intermittent psychosis, and/or genetic risk and functional deterioration are at high risk for developing psychotic disorders. In a prior trial, family-focused therapy for clinical high risk youth (FFT-CHR) was more effective than brief psychoeducation in reducing APS severity over 6 months. This 7-site trial will compare the efficacy of FFT-CHR to a psychoeducational and supportive intervention (enhanced care) on APS and social functioning in CHR individuals over 18 months. Methods Participants (N = 220, ages 13-25 years) with a CHR syndrome will be randomly assigned to FFT-CHR (18 1-h sessions of family psychoeducation and communication/problem-solving skills training) or enhanced care (3 1-h family psychoeducational sessions followed by 5 individual support sessions), both given over 6 months. Participants will rate their weekly progress during treatment using a mobile-enhanced online platform. Family communication will be assessed in a laboratory interactional task at baseline and post-treatment. Independent evaluators will assess APS (primary outcome) and psychosocial functioning (secondary outcome) every 6 months over 18 months. Results We hypothesize that, compared to enhanced care, FFT-CHR will be associated with greater improvements in APS and psychosocial functioning over 18 months. Secondarily, improvements in family communication over 6 months will mediate the relationship between treatment condition and primary and secondary outcomes over 18 months. The effects of FFT-CHR are predicted to be greater in individuals with higher baseline risk for psychosis conversion. Conclusions Results of the trial will inform treatment guidelines for individuals at high risk for psychosis.

Atypical antipsychotics (AT) and stress are related to weight gain in individuals with severe mental illness. This cross-sectional study examines AT use, stressful life events, and baseline weight in a sample of youth at clinical high risk for psychosis. Results showed that dependent and desirable life events moderated the relationship between AT use and weight after controlling for demographic factors and selective serotonin reuptake inhibitor antidepressant (AD) use. The relation of AD and weight was explored as a secondary analysis and showed no relation between AD use and weight. Further, stress did not moderate the relationship between AD medication and weight after controlling for antipsychotic use. Results suggest that stress exposure may exacerbate the relationship between ATs and increased weight in clinical high-risk populations. Findings have implications for the development of interventions to address psychosocial factors that worsen or buffer the adverse effects of antipsychotic medication on weight.

Aim On average, there is a 10% to 12% likelihood of developing a psychotic disorder solely based on being at familial high risk. However, the introduction of the criteria for clinical high risk (CHR) of psychosis suggested for CHR individuals, 20% to 30% will go on to develop a full-blown psychotic illness within 3 years. Several studies suggest a role for family history in conversion to psychosis among those at CHR. However, we know very little about those who meet the CHR criteria and have a positive family history for psychosis compared to those at CHR with no known family history. The aim of this study was to compare these 2 groups on demographics, clinical symptoms, social and role functioning, IQ, environmental factors and conversion to psychosis. Method A total of 762 participants met criteria for being at CHR, 119 of whom had a family history (CHR + FH) and 643 without (CHR-FH). Groups were compared on attenuated symptoms, role and social functioning, IQ, past trauma, perceived discrimination and cannabis use. Survival analysis was used to compare groups on conversion rates. Results There were no major differences between the groups in symptoms, functioning, IQ, cannabis use or in the rate of conversion between the groups. The CHR + FH group reported increased amounts of early trauma. Conclusion There is a possibility that CHR + FH individuals believe that it is more difficult for them to cope with circumstances such as abuse or potential abuse. Future research on this subject should investigate family environment and its role in conversion to psychosis among CHR + FH individuals.

Aim There is an interest in the transition to psychosis for those at clinical high risk of developing psychosis. This transition is typically determined by a change in severity of the attenuated symptoms as they reach a psychotic level. However, any concomitant change in the content of such symptoms has not been examined. The current study aimed to examine potential qualitative changes in the symptom content from a clinical high-risk state to a first episode of psychosis. Methods Sixty-seven individuals, who had been identified as meeting the attenuated psychotic syndrome based on the Structured Interview of Psychosis-Risk Syndromes and who later developed a full-blown psychosis were included in the study. Comprehensive clinical vignettes were written and raters were trained using the Content of Attenuated Psychotic Symptoms codebook to code for the presence of specific symptom content found within the attenuated psychotic symptoms of unusual thought content, suspicious ideas, grandiose ideas and perceptual abnormalities. Results Two main changes in symptom content from baseline to conversion were observed. First, content that was vague and lacked intensity progressed to being more specific, concrete and severe. Second, new symptoms appeared whose onset occurred for the first time at conversion. Conclusion A change in symptom content should be monitored by clinicians, as changes in content may be indications of a possible transition to psychosis.

Objective Magnetic resonance imaging (MRI) studies in bipolar I disorder (BD-I) suggest that lithium is associated with increased volumes of cortico-limbic structures. However, more rigorous control of confounding factors is needed to obtain further support for this hypothesis. The aim of the present study was to assess differences in brain volumes among long-term lithium-treated BD-I patients, unmedicated BD-I patients, and healthy controls. Methods This was a cross-sectional study with 32 euthymic BD-I patients (16 on lithium monotherapy for a mean of 180 months, and 16 receiving no medication for at least the 2 months prior to the study) and 20 healthy controls. Patients were euthymic (Hamilton Depression Rating Scale [HDRS]

Objective Lovastatin has been shown to reverse learning deficits in a mouse model of Neurofibromatosis Type 1 (NF1), a common monogenic disorder caused by a mutation in the Ras‐MAPK pathway and associated with learning disabilities. We conducted a randomized double‐blind placebo‐controlled trial to assess lovastatin's effects on cognition and behavior in patients with NF1. Method Forty‐four NF1 patients (mean age 25.7+/−11.6 years; 64% female) were randomly assigned to 14 weeks of lovastatin (N = 23; maximum dose of 80 mg/day for adult participants and 40 mg/day for children) or placebo (N = 21). Based on findings in the mouse model, primary outcome measures were nonverbal learning and working memory. Secondary outcome measures included verbal memory, attention, and self/parent‐reported behavioral problems, as well as tolerability of medication. Participants also underwent neuroimaging assessments at baseline and 14 weeks, to determine whether neural biomarkers were associated with treatment response. Linear mixed models assessed for differential treatment effects on outcome measures. Results Twelve participants dropped from the study prior to completion (8 placebo, 4 lovastatin), resulting in 32 completers (15 placebo, 17 lovastatin). Lovastatin was well‐tolerated, with no serious adverse events. Differential improvement favoring lovastatin treatment was observed for one primary (working memory; effect size f 2 = 0.70, P < 0.01) and two secondary outcome measures (verbal memory, f 2 = 0.19, P = 0.02, and adult self‐reported internalizing problems, f 2 = 0.26, P = 0.03). Exploratory moderator analyses revealed that higher baseline neural activity in frontal regions was associated with larger treatment effects. Interpretation These preliminary results suggest beneficial effects of lovastatin on some learning and memory functions, as well as internalizing symptoms in patients with NF1.

Aim High rates of anxiety have been observed in youth at clinical high risk (CHR) of developing psychosis. In CHR, anxiety often co-occurs with depression, and there is inconsistent evidence on anxiety in relation to transition to psychosis. The aim of this study was to examine: (i) the prevalence of anxiety disorders in individuals at CHR; (ii) clinical differences between those with and without anxiety; and (iii) the association of baseline anxiety with later transition to psychosis. Methods The sample consisted of 765 CHR individuals and 280 healthy controls. CHR status was determined with the Structured Interview of Prodromal Syndromes, mood and anxiety diagnoses with the Structured Clinical Interview for DSM-IV Disorders, and severity of anxiety with the Social Interaction Anxiety Scale and Self-Rating Anxiety Scale. Results In the CHR sample, 51% met criteria for an anxiety disorder. CHR participants had significantly more anxiety diagnoses and severity than healthy controls. Anxiety was correlated to attenuated psychotic and negative symptoms in CHR and those with an anxiety disorder demonstrated more suspiciousness. CHR participants with obsessive–compulsive disorder (OCD) exhibited more severe symptomatology than those without OCD. An initial presentation of anxiety did not differ between those who did or did not transition to psychosis. Conclusions In this large sample of individuals at CHR, anxiety is common and associated with more severe attenuated psychotic symptoms. Treatment not only to prevent or delay transition to psychosis but also to address presenting concerns, such as anxiety, is warranted.

Neurofibromatosis type I (NF1) is a genetic disorder caused by mutations in the neurofibromin 1 gene at locus 17q11.2. Individuals with NF1 have an increased incidence of learning disabilities, attention deficits, and autism spectrum disorders. As a single-gene disorder, NF1 represents a valuable model for understanding gene-brain-behavior relationships. While mouse models have elucidated molecular and cellular mechanisms underlying learning deficits associated with this mutation, little is known about functional brain architecture in human subjects with NF1. To address this question, we used resting state functional connectivity magnetic resonance imaging (rs-fcMRI) to elucidate the intrinsic network structure of 30 NF1 participants compared with 30 healthy demographically matched controls during an eyes-open rs-fcMRI scan. Novel statistical methods were employed to quantify differences in local connectivity (edge strength) and modularity structure, in combination with traditional global graph theory applications. Our findings suggest that individuals with NF1 have reduced anterior-posterior connectivity, weaker bilateral edges, and altered modularity clustering relative to healthy controls. Further, edge strength and modular clustering indices were correlated with IQ and internalizing symptoms. These findings suggest that Ras signaling disruption may lead to abnormal functional brain connectivity; further investigation into the functional consequences of these alterations in both humans and in animal models is warranted.

Impaired temporal processing has historically been viewed as a hallmark feature of attention deficit hyperactivity disorder. Recent evidence suggests temporal processing deficits may also be characteristic of autism spectrum disorder (ASD). However, little is known about the factors that impact temporal processing in children with ASD. The purpose of this study was to assess the effects of co-morbid attention problems, working memory (WM), age, and their interactions, on time reproduction in youth with and without ASD. Twenty-seven high-functioning individuals with ASD and 25 demographically comparable typically developing individuals (ages 9-17; 85% male) were assessed on measures of time reproduction, auditory WM, and inattention/hyperactivity. The time reproduction task required depression of a computer key to mimic interval durations of 4, 8, 12, 16, or 20 sec. Mixed effects regression analyses were used to model accuracy and variability of time reproduction as functions of diagnostic group, interval duration, age, WM, and inattention/hyperactivity. A significant group by age interaction was detected for accuracy, with the deficit in the ASD group being greater in younger children. There was a significant group by WM interaction for consistency, with the effects of poor WM on performance consistency being more pronounced in youth with ASD. All participants tended to underestimate longer interval durations and to be less consistent for shorter interval durations; these effects appeared more pronounced in those who were younger or who had poorer WM performance. Inattention/hyperactivity symptoms in the ASD group were not related to either accuracy or consistency. This study highlights the potential value of temporal processing as an intermediate trait of relevance to multiple neurodevelopmental disorders.

Aim Little is known about the role of expressed emotion (EE) in early symptom expression in individuals at clinical high risk (CHR) for psychosis. In patients with established schizophrenia, the effects of EE on clinical outcomes have purportedly varied across racial/ethnic groups, but this has not yet been investigated among CHR patients. Furthermore, studies have traditionally focused upon caregiver levels of EE via interview-based ratings, whereas the literature on patient perceptions of caregiver EE on psychosis symptoms is relatively limited. Methods Linear regression models were conducted to examine the impact of criticism and perceived warmth in the family environment, from the CHR patient's perspective, on positive and negative symptom expression in non-Latino white (NLW; n = 38) and Latino (n = 11) adolescents and young adults at CHR for developing psychosis. Results Analyses examining the sample as a whole demonstrated that perceived levels of maternal criticism were negatively associated with negative CHR symptomatology. Additional analyses indicated that race/ethnicity moderated the relationship between criticism/warmth and clinical symptomatology. We found evidence of a contrasting role of patient perceived criticism and warmth depending upon the patient's race/ethnicity. Conclusion Family processes shown to impact the course of schizophrenia among NLWs may function differently among Latino than NLW patients. These findings have important implications for the development of culturally appropriate interventions and may aid efforts to improve the effectiveness of mental health services for diverse adolescents and young adults at CHR for psychosis. Given the small sample size of this study, analyses should be replicated in a larger study before more definitive conclusions can be made.

Author(s): Alderman, T; Addington, J; Bearden, C; Cannon, TD; Cornblatt, BA; McGlashan, TH; Perkins, DO; Seidman, LJ; Tsuang, MT; Walker, EF; Woods, SW; Cadenhead, KS | Abstract: Aim: Examining ethnically related variables in evaluating those at risk for psychosis is critical. This study investigated sociodemographic and clinical characteristics of Latino versus non-Latino clinical high-risk (CHR) subjects and healthy control (HC) subjects in the first North American Prodrome Longitudinal Study. Methods: Fifty-six Latino CHR subjects were compared to 25 Latino HC and 423 non-Latino CHR subjects across clinical and demographic variables. Thirty-nine of the 56 CHR subjects completed at least one subsequent clinical evaluation over the 2.5-year period with 39% developing a psychotic illness. Characteristics of Latino CHR subjects who later converted to psychosis ('converters') were compared to those who did not ('non-converters'). Results: Latino CHR subjects were younger than non-Latino CHR subjects and had less education than Latino HC subjects and non-Latino CHR counterparts. Latino CHR converters had higher scores than Latino non-converters on the Structured Interview for Prodromal Syndromes total negative symptoms that were accounted for by decreased expression of emotion and personal hygiene/social attentiveness subsections. Latino CHR converters scored lower on the global functioning:social scale, indicating worse social functioning than Latino non-converters. Conclusion: Based on this sample, Latino CHR subjects may seek treatment earlier and have less education than non-Latino CHR subjects. Deficits in social functioning and impaired personal hygiene/social attentiveness among Latino CHR subjects predicted later psychosis and may represent important areas for future study. Larger sample sizes are needed to more thoroughly investigate the observed ethnic differences and risk factors for psychosis in Latino youth.

Multisite longitudinal neuroimaging designs are used to identify differential brain structural change associated with onset or progression of disease. The reliability of neuroanatomical measurements over time and across sites is a crucial aspect of power in such studies. Prior work has found that while within-site reliabilities of neuroanatomical measurements are excellent, between-site reliability is generally more modest. Factors that may increase between-site reliability include standardization of scanner platform and sequence parameters and correction for between-scanner variations in gradient nonlinearities. Factors that may improve both between- and within-site reliability include use of registration algorithms that account for individual differences in cortical patterning and shape. In this study 8 healthy volunteers were scanned twice on successive days at 8 sites participating in the North American Prodrome Longitudinal Study (NAPLS). All sites employed 3 Tesla scanners and standardized acquisition parameters. Site accounted for 2 to 30% of the total variance in neuroanatomical measurements. However, site-related variations were trivial (

Aim There is a wealth of evidence suggesting that patients with schizophrenia tend to respond to life stressors using less effective coping skills, which are in turn related to poor outcome. However, the contribution of coping strategies to outcome in youth at clinical high risk (CHR) for developing psychosis has not been investigated.

Velo-cardio-facial syndrome (VCFS; 22q11.2 deletion syndrome) results from a genetic mutation that increases risk for Autism Spectrum Disorder (ASD). We compared Theory of Mind (ToM) skills in 63 individuals with VCFS (25% with an ASD diagnosis) and 43 typically developing controls, and investigated the relationship of ToM to reciprocal social behavior. We administered a video-based task to assess mentalizing at two sites University of California, Los Angeles (UCLA) and State University of New York (SUNY) Upstate Medical University. The videos depicted interactions representing complex mental states (ToM condition), or simple movements (Random condition). Verbal descriptions of the videos were rated for Intentionality (i.e. mentalizing) and Appropriateness. Using Repeated Measures analysis of variance (ANOVA), we assessed the effects of VCFS and ASD on Intentionality and Appropriateness, and the relationship of mentalizing to Social Responsiveness Scale (SRS) scores. Results indicated that individuals with VCFS overall had lower Intentionality and Appropriateness scores than controls for ToM but not for Random scenes. In the SUNY sample, individuals with VCFS, both with and without ASD, performed more poorly than controls on the ToM condition; however, in the UCLA sample, only individuals with VCFS without ASD performed significantly worse than controls on the ToM condition. Controlling for site and age, performance on the ToM condition was significantly correlated with SRS scores. Individuals with VCFS, regardless of an ASD diagnosis, showed impairments in the spontaneous attribution of mental states to abstract visual stimuli, which may underlie real-life problems with social interactions. A better understanding of the social deficits in VCFS is essential for the development of targeted behavioral interventions.

Impulsivity is a multifaceted construct that can be conceptualized as a predisposition to react toward stimuli in a rapid and unplanned manner without regard to negative consequences (1). Increased impulsivity is considered a dimension of mania (2) and may underlie a number of behaviors commonly observed in symptomatic individuals with bipolar disorder, including risky sexual behaviors, indiscriminant spending, reckless driving, and increased suicidal ideation (3). Although the degree of impulsivity is associated to some degree with acute manic symptomatology (4), several studies report persistent elevation of impulsive traits in remitted or minimally symptomatic patients (5–8), raising the possibility that impulsivity may be a trait marker for the illness. In addition, family, twin and adoption studies show that increased impulsivity is heritable (9–12), suggesting that impulsive behavior is under genetic control. Unaffected relatives of patients with bipolar disorder have impairment in cognitive tasks thought to involve aspects of impulsivity, particularly response inhibition (13, 14), which is also reflected in shared abnormalities between bipolar disorder patients and their relatives in brain function (15) and functional connectivity (16) within neural networks involved in inhibitory control. Collectively, these findings suggest that increased impulsivity may be part of familial risk for the illness. However, familial resemblance in self-reported impulsivity in family members discordant for bipolar disorder has not yet been investigated. We used the Barratt Impulsiveness Scale, version 11 (BIS-11) (17) to examine self-reported attentional, motor, and non-planning dimensions of impulsivity in bipolar probands and their clinically unaffected siblings [see Stanford et al. (18) for a review]. The BIS-11 differs from performance-based or cognitive measures of impulsivity as scores reflect self-rated behaviors rather than discrete cognitive processes and thus may be closer to psychiatric symptomatology. Our primary aim was to test whether familial risk for bipolar disorder impacts on attentional, non-planning and response inhibition scales of the BIS-11. A secondary aim was to examine the real-world implications of increased impulsivity in bipolar disorder patients and their unaffected relatives. There are severe clinical and public health ramifications of impulsive behavior; for example, impulsivity is associated with early experimentation with drugs and liability to developing a substance use disorder (19), and its behavioral manifestations include violent criminality (20). To the extent that behavioral measures of impulsivity can be shown to be risk factors or endophenotypes for bipolar disorder, it is possible that these measures can be used to help disentangle the complex genetic architecture of bipolar disorder. We hypothesized that both euthymic individuals with bipolar disorder and their clinically unaffected siblings would have higher levels of trait impulsivity compared to healthy subjects, and that siblings would evidence impulsivity levels intermediate between those of healthy controls and bipolar I disorder probands. Additionally, in order to assess the functional implications of impulsiveness, we examined the association of BIS-11 scores with psychosocial functioning and criminal history in bipolar I disorder patients, their siblings, and controls.

Bipolar disorder is a chronic illness with substantial psychosocial and occupational morbidity. Several studies have shown that, after a manic episode, the majority of patients with bipolar disorder continue to exhibit significant impairment in role functioning, despite symptomatic recovery (1–6). A recent review of outcome studies concluded that 57–65% of patients with bipolar disorder were unemployed (as compared to 6% of the general population), and up to 80% were considered to have at least partial vocational disability following syndromal recovery from a first-lifetime manic or mixed episode (7). It is generally believed that the depressive pole of bipolar disorder is more consistently and strongly associated with functional disability (8, 9) than is the hypomanic/manic pole (10, 11). However, one of the few large-scale outcome studies of first-episode mania found that while the majority of patients (72%) had achieved symptomatic recovery within two years of their initial hospitalization, less than half (43%) had achieved functional recovery, defined as regaining one’s premorbid occupational and residential status (6). Despite its prevalence and cost in both personal and societal terms, the reasons for persistent work disability in patients with bipolar disorder remain unclear. Factors other than mood symptoms may contribute to poor occupational functioning (12, 13). In particular, there is increasing evidence that impairment in specific cognitive domains, i.e., executive function, verbal memory, attention, and processing speed, persists in some patients with bipolar disorder even during periods of euthymia [(14); (see 15, 16 for meta-analyses)]. Impairments in executive functioning, verbal memory, and speed of processing have been consistently associated with poorer functional outcome in schizophrenia (17–19). There is also mounting evidence that cognitive impairment in these domains may contribute to functional disability in bipolar disorder patients (20–24). A recent review of the literature concluded that in the majority of studies (six out of eight) of euthymic patients with bipolar disorder, poorer cognitive function was associated with worse functional outcome, even after controlling for residual mood symptoms, age, and other clinical variables (25). However, most of these studies used very general measures of functional outcome, such as the Global Assessment of Functioning (GAF) (26), which does not separate clinical symptom severity from functional status in the rating of level of overall functioning. Additionally, the relationship between neurocognitive impairment and the ability to resume normal occupational functioning after an acute manic episode resolves has rarely been studied (27). To our knowledge, only one prior study has examined changes in neurocognitive function over time as a predictor of outcome in bipolar disorder patients (28). In this study, positive changes in composite neurocognitive performance over one year emerged as a significant predictor of improved functioning (as assessed by the GAF) over the follow-up period. The purpose of this study was to assess the cross-sectional and prospective longitudinal association between neurocognition and occupational function in subjects with bipolar disorder who had recently achieved symptomatic recovery following a manic episode. Using the Life Functioning Questionnaire (LFQ) (29), a gender-neutral measure of occupational function that assesses both quality and quantity of work impairment, we sought to answer the following questions: (i) Does neurocognitive function at the time of symptomatic recovery from a manic episode differentiate patients who achieve occupational recovery from those who do not? (ii) In those who do not achieve occupational recovery concurrently with symptomatic recovery, does neurocognitive function at the time of symptomatic recovery predict short-term occupational recovery? (iii) Is change in cognitive function, either globally or in specific domains, associated with short-term occupational recovery? Given prior findings, in both patients with schizophrenia and bipolar disorder, which indicate deficits in executive functions, verbal memory, and speed of processing are associated with poor functional outcome, we hypothesized that better baseline neurocognitive function in these domains would be associated with concurrent occupational recovery, and that cognitive improvement in these domains over time would be associated with occupational recovery over the follow-up period.

Hispanics are now the largest ethnic-minority group in the United States, making up 15% of the population with over 46 million people (www.census.gov). As with other racial/ethnic groups, the leading mental health diagnoses among individuals of Mexican origin born in the U.S. are depression and alcohol and/or other substance use disorders (Alegria et al., 2008). Relatively little is known about potential differences in the pathophysiologic mechanisms of these mental illnesses in the Mexican-American population. Improving our understanding of the genetic and environmental factors that increase risk for mood and substance use disorders in this underserved ethnic minority could lead to better clinical care for Mexican-Americans. Despite clinical and etiological heterogeneity, there is increasing evidence that liability for major depressive disorder and liability for alcohol/substance use disorders is under genetic control. Numerous studies document the heritability of major depressive disorder at roughly 0.40 (Kendler et al., 2006; Kendler et al., 2001; Kendler et al., 1993). Similarly, the heritability of alcohol use disorders ranges from 0.40–0.60 (Goldman et al., 2005; Grant et al., 2009; Kendler et al., 1997) and the heritability for illicit drug use disorders is 0.30–0.80 (Goldman et al., 2005; Kendler et al. 2006, Tsuang et al., 1996), suggesting similar levels of genetic influence on major depression and alcohol and drug disorders (Bienvenu et al., 2010). However, Hispanics have not been adequately represented in behavioral or molecular genetic studies of these common psychiatric illnesses (Oquendo et al., 2010). The under-representation of Mexican American individuals in these studies, and in the genetic repositories maintained by the National Institute of Mental Health and the National Institute on Drug Abuse, may reflect explicit attempts by investigators to minimize population stratification, or may be an unintended consequence of selecting symptomatically homogeneous samples, as ethnic groups like Hispanics may have subtle differences in clinical presentation (Kleinman 2004). In either case, one potential consequence of the under-representation of the largest ethnic minority in the United States in genetic studies of major depression and alcohol/substance use disorders is the inability to elucidate genetic and environmental vulnerabilities specific for this population. Lifetime comorbidity between drug and alcohol use disorders and major depression has been consistently observed in clinical and epidemiological samples (Grant and Harford 1995; Hasin et al., 2007; Kessler et al., 1997; Regier et al., 1990; Schuckit et al., 1997). This pattern of comorbidity may be at least partly attributable to shared genetic factors (Kendler et al., 2003; Prescott et al., 2000). While there is significant phenotypic heterogeneity in the expression of these disorders, it is possible that more clinically homogeneous subtypes, particularly those with more severe clinical course (multiple episodes and/or early onset), may have a higher genetic loading (Kendler et al., 1993; Kendler et al., 1999; Weissman et al., 1988) and therefore may be more amenable to gene discovery (Levinson 2006; Levinson et al., 2007). In this context, it is possible that identifying common genetic factors between alcohol and substance use disorders and major depression could reduce the heterogeneity of each phenotype, thereby improving the potential for determining the risk genes for these common mental illnesses. In this manuscript, we report on the prevalence and phenomenology of major depression and coexisting alcohol/substance use disorders, in a community-based, ascertained sample of Mexican-American families, consisting of 1,122 persons. Our goals are (1) to estimate the heritability of major depressive disorder, alcohol and drug use disorders in Mexican-American families and (2) to examine evidence for pleiotropy between substance disorders and depression. In addition, we examined clinical subtypes of major depression (e.g. recurrent major depression, early onset major depression, recurrent-early onset major depression), with the expectation that early onset and recurrence of major depression would be associated with relatively stronger genetic control than more broadly defined DSM-IV major depression (Levinson 2006; McGuffin et al., 1996; McGuffin et al., 2003).

Although studies have consistently found that individuals with bipolar disorder exhibit wide-spread neurocognitive dysfunction during acute episodes of mania (1) and depression (2), the discovery that these deficits endure during periods of euthymia raises the possibility that cognitive impairments may be associated with the core pathophysiology of the illness rather than being secondary to mood symptoms (3, 4). During euthymia, patients with bipolar disorder exhibit deficits in several cognitive domains, including executive function (5, 6), declarative memory (7–9), and sustained attention (10–12). Some cognitive deficits appear to be influenced by the same genes that predispose the illness (13), suggesting that cognitive impairment is closely linked to the etiology of bipolar disorder. Yet despite the potential trait-like qualities of cognitive impairments in bipolar disorder, performance on certain neurocognitive measures appears to vary with mood state. Indeed, Goldberg and colleagues (14) reported that while psychiatric symptoms in schizophrenia patients accounted for less than 5% of variance in neuropsychological testing, affective symptoms accounted for 30% of variance in individuals with bipolar disorder. While Martinez-Aran and colleagues (15) found that bipolar disorder patients were similarly impaired on measures of executive function and declarative memory, regardless of mood state, only the acutely ill subjects were impaired on measures of attention and processing speed. Further, Clark and Goodwin (16) found that while discrimination during an attention task is impaired in both depressed and manic patients, only manic patients make significantly more false positive errors. Together, these data suggest that while impairments in some cognitive domains may result from acute affective state, other neuropsychological deficits appear to be present regardless of symptom status. To assess fully the relationship between affective symptoms and cognitive functioning, serial neuropsychological assessments on the same individuals are needed (17). However, very few within-subject longitudinal studies have been conducted in bipolar disorder patients, and most of these involve a pharmacological treatment (4, 15), making it difficult to determine whether cognitive changes are due to treatment effects or are secondary to changes in severity of mood symptoms. In addition, few studies to date have included healthy comparison subjects, making it difficult to determine whether observed cognitive changes over time are more than would be expected as a function of practice effects (18). Here, we administered a neuropsychological battery to subjects at baseline and at a follow-up session approximately three months later. Participants included individuals with bipolar disorder recruited from community mental health centers in San Antonio, TX, and demographically matched healthy volunteers. Although patients displayed a range of mood symptomatology at both assessments, all were clinically stable outpatients living either independently or with family members, and did not experience changes in medication status over the assessment interval. Based on prior work, we hypothesized that specific cognitive measures, such as attention, will be sensitive to mood fluctuations in individuals with bipolar disorder, while performance on tests assessing executive functioning and declarative memory will remain stable over time.

Brooks JO III, Bearden CE, Hoblyn JC, Woodard SA, Ketter TA. Prefrontal and paralimbic metabolic dysregulation related to sustained attention in euthymic older adults with bipolar disorder. Bipolar Disord 2010: 12: 866–874. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objective: Reports of sustained attention deficits in the euthymic phase of bipolar disorder have been variable, and have yet to be related to cerebral metabolism. In the present study, we evaluated relationships between cognitive performance deficits and resting cerebral metabolism in euthymic older adults with bipolar disorder. Methods: Sixteen older (mean age 58.7 years) euthymic outpatients with bipolar disorder (10 type I, 6 type II; 44% female) and 11 age-matched healthy controls received resting positron emission tomography with 18fluorodeoxyglucose and, within 10 days, the Conners’ Continuous Performance Test-II, a commonly used measure of sustained attention and inhibitory control. Results: Bipolar disorder patients had significantly more omission errors (z = 2.53, p = 0.01) and a trend toward more commission errors (z = 1.83, p

Bipolar disorder is associated with persistent declarative memory disturbances, but the neural basis of these deficits is not well understood. We used fMRI to investigate brain activity during performance on a face-name paired associate task, which allows for the dissociation of encoding and recall-related memory processes. Fifteen clinically remitted bipolar I disorder patients and 24 demographically matched healthy comparison subjects were scanned during task performance. At the voxel level, bipolar patients showed reduced cortical activation, relative to controls, in multiple task-related brain regions during encoding. During recognition, bipolar patients under-activated left hippocampal and parahippocampal regions, despite adequate task performance. Region of interest analyses indicated that, during encoding, bipolar patients had greater bilateral dorsolateral prefrontal (DLPFC) activity than healthy subjects. In contrast, during recognition patients showed hypo-activation relative to controls in the right, but not the left, DLPFC. Although hippocampal activity did not differ between groups during encoding, bipolar patients failed to activate hippocampal regions to the same extent as healthy subjects during recognition. Finally, while better task performance was associated with recognition-related hippocampal activity in healthy subjects, bipolar patients showed an inverse relationship between task performance and hippocampal activity. Remitted bipolar patients over-engaged dorsolateral prefrontal regions when learning face-name pairs, but relative hypoactivation in both prefrontal and medial temporal regions during recognition. These findings suggest a neural basis for the long-term memory deficits consistently observed in patients with bipolar disorder; further, as these patterns appear in symptomatically remitted patients, they are unlikely to be an artifact of mood symptoms.

Obstetric complications (OCs) are an integral component of a neural diathesis-stress model of schizophrenia, which posits that early brain lesions interacting with later neuroendocrine, neurodevelopmental and psychosocial factors result in the eventual presentation of clinical signs and symptoms of psychosis1,2. In support of this theory, several studies have observed that a history of OCs is associated with earlier onset and a poorer course of illness3,4. Although these investigations have provided evidence for OCs as a general putative marker, to date there has been little research aimed at determining if OCs confer a greater risk for conversion to psychotic disorders among clinical high-risk populations. Such ultra-high-risk (UHR) individuals exhibit a cluster of subthreshold psychotic symptoms, consistent with a prodromal syndrome, and have a roughly 35% rate of conversion to psychotic disorder over 2 years5. If OCs are associated with conversion among UHR populations, this pattern would suggest a link between early neurodevelopmental insults and subsequent neuromaturational events thought to be related to the developmental pathogenesis of psychotic disorders during adolescence/early adulthood. Recent research suggests that early pharmacological and psychosocial interventions with UHR individuals can potentially improve the course of illness, or even prevent onset of psychosis6. Therefore, it has become priority to identify risk-markers that define those UHR individuals who are at the highest risk. In the present study, high-risk individuals were assessed for a history of OCs and their diagnostic status was followed for a period of two-years. We hypothesized that a history of OCs would be associated with greater severity of symptomatology and a greater risk for conversion.

There is growing evidence that at least a proportion of patients with bipolar disorder have significant cognitive impairments, even during periods of symptomatic remission (1–5). Working memory—defined as the temporary maintenance and manipulation of information—is among the most severely affected cognitive domains (1, 6, 7), with the level of deficit rising with increasing task difficulty (8). Both structural and functional abnormalities have been reported in bipolar patients in brain regions relevant for working memory function, including the dorsolateral prefrontal cortex (PFC), anterior cingulate cortex (ACC), and medial temporal lobe (MTL) (9–11). Most theoretical models of working memory distinguish between manipulation and maintenance processes, highlighting that these processes are differentially served by prefrontal regions, with dorsolateral prefrontal regions and superior parietal regions being differentially involved in the manipulation of information (12–14), and ventrolateral prefrontal regions in the maintenance of information (14). Recently, we developed a novel delayed-non-match-to-sample (DNMS) working memory task that highlights maintenance processes with separate conditions requiring the use of distinct mnemonic strategies to facilitate performance. Specifically, the task includes a condition that emphasizes the use of contextual information to organize familiar stimuli (‘familiarity condition’) and a condition where using holistic representations of novel stimuli (‘novelty condition’) is advantageous. While the former has been linked to prefrontal activation (15–17), the latter is thought to be associated more closely with MTL function (18). Previously, we employed this task behaviorally in a moderately symptomatic sample of patients with bipolar disorder and found that bipolar patients had deficits consistent with organizational dysfunction and poor detection of novel information relative to healthy controls (19). Although these results imply prefrontal and medial temporal dysfunction in bipolar disorder, direct assessment of neurophysiologic differences during task performance is necessary. In the current experiment, we used functional magnetic resonance imaging (fMRI) to examine activity in remitted patients with bipolar I disorder and demographically matched healthy comparison subjects while performing our working memory task (19). We focused on patients in symptomatic remission to ensure that between-group neurophysiologic differences during task performance were not due to confounding effects of current mood symptoms. Thus, the present design allowed assessment of trait-related functional abnormalities within prefrontal and medial temporal regions. Consistent with the notion of working memory network dysfunction, particularly with regard to maintenance processes, implied by our prior behavioral findings utilizing this paradigm (19), we hypothesized that remitted patients with bipolar disorder would exhibit reduced neural activity compared to healthy subjects in prefrontal regions during the familiarity condition, and in MTL regions during the novelty condition.

Aim: This study investigated the behavioural correlates of caregiver attitudes among parents of youth at risk for psychosis and with recent-onset psychotic symptoms. Methods: Forty adolescents identified as ultra-high-risk (UHR) for psychosis using the Structured Interview for Prodromal Syndromes, and their primary caregivers, participated in the Family Interaction Task (FIT), a 10-minute discussion of meaningful shared experiences that allowed families to demonstrate supportive as well as conflict-engaging behaviour. At the same assessment, caregivers were administered the Camberwell Family Interview (CFI). We examined cross-sectional relationships between these measures, as well as their association with youth symptom severity and functioning at 4-month follow-up. Results: As predicted, caregivers who provided more positive remarks regarding their UHR and recent-onset adolescents during the CFI were also more likely to exhibit constructive behaviour during the FIT. Similarly, CFI critical comments were positively associated with caregivers' conflict-engaging behaviour during the FIT. Parents' positive remarks predicted a decrease in negative symptoms, and parent warmth predicted an increase in social functioning at follow-up assessment. Conclusions: The ability to maintain a constructive attitude and approach towards youth predicted symptomatic and functional improvement, and may be a teachable skill.

Aim: In this study, we investigate the feasibility and acceptability of a 9-month psychoeducational multi-family group (PMFG) intervention for adolescents who are at ultra-high–risk (UHR) for developing psychosis. Methods: The treatment programme was adapted from those previously shown to be effective in patients with established psychotic illness, but emphasizes content relevant to adolescence and to a pre-onset phase of illness. Results: Participants report that psychoeducational presentations are highly useful, they attend the PMFG group sessions regularly and report feeling comfortable in meetings and benefiting from them, and adolescents demonstrate improvement in symptoms and functional outcome. Conclusions: This study was not a randomized controlled trial and multiple interventions were introduced simultaneously; thus, changes in outcome cannot be attributed to the PMFG intervention per se. Nonetheless, these results establish the acceptability of PMFG to adolescents and families, and encourage further research into the potential positive impact of PMFG with this at-risk population.

Background: Although bipolar disorder and schizophrenia have long been viewed as distinct illnesses, there is growing evidence that these two complex diseases share some common genes, which may manifest as overlapping neuropsychological impairments. Although working memory dysfunction has been proposed to be central to the pathophysiology of schizophrenia, it has received less attention in studies of bipolar disorder. Method: We applied measures of working memory to patients with schizophrenia (n = 15), patients with schizoaffective disorder (n = 15), patients with psychotic (n = 11) and non-psychotic (n = 15) bipolar disorder, and demographically matched healthy subjects (n = 32), in order to determine the extent to which these groups show common or unique impairments. Results: While patients with bipolar disorder (with and without psychotic features) and those with schizophrenia/schizoaffective disorder were impaired on backward digit span, only patients with a lifetime history of psychotic features, regardless of diagnosis, were impaired on spatial delayed response task. Conclusions: Backward digit span performance is comparable in bipolar disorder and schizophrenia, and may be an appropriate endophenotypic marker that cuts across diagnostic categories. In contrast, spatial working memory performance clearly distinguishes non-psychotic bipolar disorder patients from patients with functional psychosis.

Objectives: To present a comprehensive review of the existing neuropsychological and neuroimaging literature on bipolar affective disorder. This review critically evaluates two common conceptions regarding the neuropsychology of bipolar disorder: 1) that, in contrast to schizophrenia, bipolar affective disorder is not associated with general cognitive impairment independent of illness episodes, and 2) relative right hemisphere (RH) dysfunction is implicated in bipolar illness patients, supported by reports of relatively greater impairment in visuospatial functioning, lateralization abnormalities, and mania secondary to RH lesions. Methods: The major computerized databases (Medline and PSYCInfo) were consulted in order to conduct a comprehensive, integrated review of the literature on the neuropsychology and neuroanatomy of bipolar disorder. Articles meeting specified criteria were included in this review. Results: In a critical evaluation of the above notions, this paper determines that: 1) while there is little evidence for selective RH dysfunction, significant cognitive impairment may be present in bipolar illness, particularly in a subgroup of chronic, elderly or multiple-episode patients, suggesting a possible toxic disease process, and 2) the underlying functional correlate of these cognitive deficits may be white matter lesions (‘signal hyperintensities’) in the frontal lobes and basal ganglia, regions critical for executive function, attention, speeded information processing, learning and memory, and affect regulation. While this hypothesized neural correlate of cognitive impairment in bipolar disorder is speculative, preliminary functional neuroimaging evidence supports the notion of frontal and subcortical hypometabolism in bipolar illness. Conclusions: The etiology of the structural brain abnormalities commonly seen in bipolar illness, and their corresponding functional deficits, remains unknown. It is possible that neurodevelopmental anomalies may play a role, and it remains to be determined whether there is also some pathophysiological progression that occurs with repeated illness episodes. More research is needed on first-episode patients, relatives of bipolar probands, and within prospective longitudinal paradigms in order to isolate disease-specific impairments and genetic markers of neurocognitive function in bipolar disorder.