The lipidome in major depressive disorder: Shared genetic influence for ether-phosphatidylcholines, a plasma-based phenotype related to inflammation, and disease risk.

BACKGROUND: The lipidome is rapidly garnering interest in the field of psychiatry. Recent studies have implicated lipidomic changes across numerous psychiatric disorders. In particular, there is growing evidence that the concentrations of several classes of lipids are altered in those diagnosed with MDD. However, for lipidomic abnormalities to be considered potential treatment targets for MDD (rather than secondary manifestations of the disease), a shared etiology between lipid concentrations and MDD should be demonstrated. METHODS: In a sample of 567 individuals from 37 extended pedigrees (average size 13.57 people, range=3-80), we used mass spectrometry lipidomic measures to evaluate the genetic overlap between twenty-three biologically distinct lipid classes and a dimensional scale of MDD. RESULTS: We found that the lipid class with the largest endophenotype ranking value (ERV, a standardized parametric measure of pleiotropy) were ether-phosphodatidylcholines (alkylphosphatidylcholine, PC(O) and alkenylphosphatidylcholine, PC(P) subclasses). Furthermore, we examined the cluster structure of the twenty-five species within the top-ranked lipid class, and the relationship of those clusters with MDD. This analysis revealed that species containing arachidonic acid generally exhibited the greatest degree of genetic overlap with MDD. CONCLUSIONS: This study is the first to demonstrate a shared genetic etiology between MDD and ether-phosphatidylcholine species containing arachidonic acid, an omega-6 fatty acid that is a precursor to inflammatory mediators, such as prostaglandins. The study highlights the potential utility of the well-characterized linoleic/arachidonic acid inflammation pathway as a diagnostic marker and/or treatment target for MDD.

Genome-wide significant loci for addiction and anxiety.

BACKGROUND: Psychiatric comorbidity is common among individuals with addictive disorders, with patients frequently suffering from anxiety disorders. While the genetic architecture of comorbid addictive and anxiety disorders remains unclear, elucidating the genes involved could provide important insights into the underlying etiology. METHODS: Here we examine a sample of 1284 Mexican-Americans from randomly selected extended pedigrees. Variance decomposition methods were used to examine the role of genetics in addiction phenotypes (lifetime history of alcohol dependence, drug dependence or chronic smoking) and various forms of clinically relevant anxiety. Genome-wide univariate and bivariate linkage scans were conducted to localize the chromosomal regions influencing these traits. RESULTS: Addiction phenotypes and anxiety were shown to be heritable and univariate genome-wide linkage scans revealed significant quantitative trait loci for drug dependence (14q13.2-q21.2, LOD=3.322) and a broad anxiety phenotype (12q24.32-q24.33, LOD=2.918). Significant positive genetic correlations were observed between anxiety and each of the addiction subtypes (ρg=0.550-0.655) and further investigation with bivariate linkage analyses identified significant pleiotropic signals for alcohol dependence-anxiety (9q33.1-q33.2, LOD=3.054) and drug dependence-anxiety (18p11.23-p11.22, LOD=3.425). CONCLUSIONS: This study confirms the shared genetic underpinnings of addiction and anxiety and identifies genomic loci involved in the etiology of these comorbid disorders. The linkage signal for anxiety on 12q24 spans the location of TMEM132D, an emerging gene of interest from previous GWAS of anxiety traits, whilst the bivariate linkage signal identified for anxiety-alcohol on 9q33 peak coincides with a region where rare CNVs have been associated with psychiatric disorders. Other signals identified implicate novel regions of the genome in addiction genetics.

Depression in Mexican Americans with diagnosed and undiagnosed diabetes.

BACKGROUND: Depression and diabetes commonly co-occur; however, the strength of the physiological effects of diabetes as mediating factors towards depression is uncertain. METHOD: We analyzed extensive clinical, epidemiological and laboratory data from n = 2081 Mexican Americans aged 35-64 years, recruited from the community as part of the Cameron County Hispanic Cohort (CCHC) divided into three groups: Diagnosed (self-reported) diabetes (DD, n = 335), Undiagnosed diabetes (UD, n = 227) and No diabetes (ND, n = 1519). UD participants denied being diagnosed with diabetes, but on testing met the 2010 American Diabetes Association and World Health Organization definitions of diabetes. Depression was measured using the Center for Epidemiological Studies - Depression (CES-D) scale. Weighted data were analyzed using dimensional and categorical outcomes using univariate and multivariate models. RESULTS: The DD group had significantly higher CES-D scores than both the ND and UD (p ⩽ 0.001) groups, whereas the ND and UD groups did not significantly differ from each other. The DD subjects were more likely to meet the CES-D cut-off score for depression compared to both the ND and UD groups (p = 0.001), respectively. The UD group was also less likely to meet the cut-off score for depression than the ND group (p = 0.003). Our main findings remained significant in models that controlled for socio-demographic and clinical confounders. CONCLUSIONS: Meeting clinical criteria for diabetes was not sufficient for increased depressive symptoms. Our findings suggest that the 'knowing that one is ill' is associated with depressive symptoms in diabetic subjects.

Transcriptomics of cortical gray matter thickness decline during normal aging.

INTRODUCTION: We performed a whole-transcriptome correlation analysis, followed by the pathway enrichment and testing of innate immune response pathway analyses to evaluate the hypothesis that transcriptional activity can predict cortical gray matter thickness (GMT) variability during normal cerebral aging. METHODS: Transcriptome and GMT data were available for 379 individuals (age range=28-85) community-dwelling members of large extended Mexican American families. Collection of transcriptome data preceded that of neuroimaging data by 17 years. Genome-wide gene transcriptome data consisted of 20,413 heritable lymphocytes-based transcripts. GMT measurements were performed from high-resolution (isotropic 800 µm) T1-weighted MRI. Transcriptome-wide and pathway enrichment analysis was used to classify genes correlated with GMT. Transcripts for sixty genes from seven innate immune pathways were tested as specific predictors of GMT variability. RESULTS: Transcripts for eight genes (IGFBP3, LRRN3, CRIP2, SCD, IDS, TCF4, GATA3, and HN1) passed the transcriptome-wide significance threshold. Four orthogonal factors extracted from this set predicted 31.9% of the variability in the whole-brain and between 23.4 and 35% of regional GMT measurements. Pathway enrichment analysis identified six functional categories including cellular proliferation, aggregation, differentiation, viral infection, and metabolism. The integrin signaling pathway was significantly (p<10(-6)) enriched with GMT. Finally, three innate immune pathways (complement signaling, toll-receptors and scavenger and immunoglobulins) were significantly associated with GMT. CONCLUSION: Expression activity for the genes that regulate cellular proliferation, adhesion, differentiation and inflammation can explain a significant proportion of individual variability in cortical GMT. Our findings suggest that normal cerebral aging is the product of a progressive decline in regenerative capacity and increased neuroinflammation.

P-selectin Expression Tracks Cerebral Atrophy in Mexican-Americans.

BACKGROUND AND PURPOSE: We hypothesized that the P-selectin (SELP) gene, localized to a region on chromosome 1q24, pleiotropically contributes to increased blood pressure and cerebral atrophy. We tested this hypothesis by performing genetic correlation analyses for 13 mRNA gene expression measures from P-selectin and 11 other genes located in 1q24 region and three magnetic resonance imaging derived indices of cerebral integrity. METHODS: The subject pool consisted of 369 (219F; aged 28-85, average = 47.1 ± 12.7 years) normally aging, community-dwelling members of large extended Mexican-American families. Genetic correlation analysis decomposed phenotypic correlation coefficients into genetic and environmental components among 13 leukocyte-based mRNA gene expressions and three whole-brain and regional measurements of cerebral integrity: cortical gray matter thickness, fractional anisotropy of cerebral white matter, and the volume of hyperintensive WM lesions. RESULTS: From the 13 gene expressions, significant phenotypic correlations were only found for the P- and L-selectin expression levels. Increases in P-selectin expression levels tracked with decline in cerebral integrity while the opposite trend was observed for L-selectin expression. The correlations for the P-selectin expression were driven by shared genetic factors, while the correlations with L-selectin expression were due to shared environmental effects. CONCLUSION: This study demonstrated that P-selectin expression shared a significant variance with measurements of cerebral integrity and posits elevated P-selectin expression levels as a potential risk factor of hypertension-related cerebral atrophy.

Common genetic influences on depression, alcohol, and substance use disorders in Mexican-American families.

Multiple genetic and environmental factors influence the risk for both major depression and alcohol/substance use disorders. In addition, there is evidence that these illnesses share genetic factors. Although, the heritability of these illnesses is well established, relatively few studies have focused on ethnic minority populations. Here, we document the prevalence, heritability, and genetic correlations between major depression and alcohol and drug disorders in a large, community-ascertained sample of Mexican-American families. A total of 1,122 Mexican-American individuals from 71 extended pedigrees participated in the study. All subjects received in-person psychiatric interviews. Heritability, genetic, and environmental correlations were estimated using SOLAR. Thirty-five percent of the sample met criteria for DSM-IV lifetime major depression, 34% met lifetime criteria for alcohol use disorders, and 8% met criteria for lifetime drug use disorders. The heritability for major depression was estimated to be h(2) = 0.393 (P = 3.7 × 10(-6)). Heritability estimates were higher for recurrent depression (h(2) = 0.463, P = 4.0 × 10(-6)) and early onset depression (h(2) = 0.485, P = 8.5 × 10(-5)). While the genetic correlation between major depression and alcohol use disorders was significant (ρ(g) = 0.58, P = 7 × 10(-3)), the environmental correlation between these traits was not significant. Although, there is evidence for increased rates of depression and substance use in US-born individuals of Mexican ancestry, our findings indicate that genetic control over major depression and alcohol/substance use disorders in the Mexican-American population is similar to that reported in other populations.

Genetic control over the resting brain.

The default-mode network, a coherent resting-state brain network, is thought to characterize basal neural activity. Aberrant default-mode connectivity has been reported in a host of neurological and psychiatric illnesses and in persons at genetic risk for such illnesses. Whereas the neurophysiologic mechanisms that regulate default-mode connectivity are unclear, there is growing evidence that genetic factors play a role. In this report, we estimate the importance of genetic effects on the default-mode network by examining covariation patterns in functional connectivity among 333 individuals from 29 randomly selected extended pedigrees. Heritability for default-mode functional connectivity was 0.424 +/- 0.17 (P = 0.0046). Although neuroanatomic variation in this network was also heritable, the genetic factors that influence default-mode functional connectivity and gray-matter density seem to be distinct, suggesting that unique genes influence the structure and function of the network. In contrast, significant genetic correlations between regions within the network provide evidence that the same genetic factors contribute to variation in functional connectivity throughout the default mode. Specifically, the left parahippocampal region was genetically correlated with all other network regions. In addition, the posterior cingulate/precuneus region, medial prefrontal cortex, and right cerebellum seem to form a subnetwork. Default-mode functional connectivity is influenced by genetic factors that cannot be attributed to anatomic variation or a single region within the network. By establishing the heritability of default-mode functional connectivity, this experiment provides the obligatory evidence required before these measures can be considered as endophenotypes for psychiatric or neurological illnesses or to identify genes influencing intrinsic brain function.

Efficacy of Adderall and methylphenidate in attention deficit hyperactivity disorder: a reanalysis using drug-placebo and drug-drug response curve methodology.

Because methylphenidate (MPH) is currently the most widely prescribed medication for attention deficit hyperactivity disorder (ADHD), several studies have used this as the touch-stone for evaluating the efficacy of a newer stimulant, Adderall. In a parallel-groups study of MPH (n = 20), Adderall (n = 20), and placebo (n = 18), Pliszka et al. (2000) reported that both medications were superior to placebo in improving parent, teacher, and clinician ratings of ADHD and associated behaviors. Compared with MPH, Adderall led to significantly more improvements in teacher and clinician ratings. The present study extends these results by addressing the issue of clinical significance using drug-placebo and drug-drug response curve analyses of the same data. The goal of this method is to answer the following questions about drug-placebo or drug-drug differences: Is the effect clinically meaningful? What does the effect tell us about individual responses? Is the effect due to symptom improvement, the prevention of worsening, or both? Our results show that the efficacy of Adderall to improve functioning is seen throughout the full range of improvement scores. In contrast, MPH showed a substantial effect for "mildly" and "much improved" but not for "very much improved." Our analyses also show that both Adderall and MPH prevent worsening of symptoms. They further suggest that, compared with the Conners Teacher Rating Scale, the Clinical Global Impressions scale may be more sensitive to improvements at the "well end" of the spectrum of functioning.

Validation of the Interview Module for Intermittent Explosive Disorder (M-IED) in children and adolescents: a pilot study.

We identified a subset of impulsive, aggressive children as having symptoms that met criteria for Intermittent Explosive Disorder (IED) using the Interview Module for Intermittent Explosive Disorder (M-IED). The M-IED was administered to 34 children and adolescents between the ages of 10 and 17. These data provide initial evidence for the M-IED as a useful instrument in the diagnosis of IED in adolescents. The M-IED displayed a high level of inter-rater reliability and adequate test-retest reliability. Construct validity was supported by the fact that the subjects with IED symptomatology had significantly more lifetime aggression, oppositionality, inattention and hyperactivity/impulsivity compared to community controls. In addition, the subjects with IED symptomatology had a significantly greater number of episodes of lifetime physical aggression and documented episodes of aggression while in residential treatment compared to psychiatric controls. The subjects with IED symptomatology had a greater number of positive screening questions for DSM-IV diagnoses using the Swanson, Nolan and Pelham questionnaire (SNAP-IV), particularly those related to IED and posttraumatic stress disorder than psychiatric controls.

Suicidal ideation in Hispanic and mixed-ancestry adolescents.

This survey examined differences in suicidal ideation, depressive symptomatology, acculturation, and coping strategies based on ethnicity. The author gathered data from a self-report questionnaire administered to students in an ethnically diverse middle school (grades 6-8, N= 158). Hispanic (predominantly Mexican American) and mixed-ancestry adolescents displayed significantly higher risk of suicidal ideation compared to Anglo peers, even when socioeconomic status, age, and gender were controlled for. Suicidal ideation was associated with depressive symptoms, family problems, lower levels of acculturation, and various coping strategies. Using multivariate analysis, Hispanic ancestry, depressive symptoms, family problems, and the use of social coping remained in the model.

A double-blind, placebo-controlled study of Adderall and methylphenidate in the treatment of attention-deficit/hyperactivity disorder.

OBJECTIVE: While Adderall has been available for the treatment of attention-deficit/hyperactivity disorder (ADHD) for several years, there are few controlled studies comparing it to methylphenidate. METHOD: Fifty-eight children with ADHD (mean age 8.1 +/- 1.4 years) were randomly assigned to receive placebo, methylphenidate, or Adderall in a double-blind, parallel-group design for 3 weeks. Dosage was adjusted at the end of weeks 1 and 2 via an algorithm based on teacher and parent ratings. Final doses were 12.5 +/- 4.1 mg/day for Adderall and 25.2 +/- 13.1 mg/day for methylphenidate. Teacher and parent ratings, as well as the psychiatrist's Clinical Global Impression (CGI), were the final outcome measures at the end of week 3. RESULTS: Both medications were superior to placebo at reducing inattentive and oppositional symptoms in the classroom and on the CGI. Adderall produced significantly more improvements on teacher ratings and the CGI than methylphenidate, although the algorithm may have limited dosing in the methylphenidate group. Seventy percent of children in the Adderall group were given medication once a day, compared with 15% of the subjects receiving methylphenidate. CONCLUSIONS: Adderall compared favorably to methylphenidate, and the behavioral effects of Adderall appear to persist longer than those of methylphenidate after individual doses.

An open trial of venlafaxine in the treatment of attention-deficit/hyperactivity disorder in children and adolescents.

A 5-week open trial of venlafaxine was conducted in 16 children and adolescents (mean age 11.6 years) with attention-deficit/hyperactivity disorder (ADHD) in order to estimate the appropriate dosage range and to determine the extent of side effects. Subjects were evaluated using a structured clinical interview and a computerized diagnostic assessment, and subjects diagnosed with ADHD and without comorbid depression were asked to enter the study. Conners Parent Rating Scale (CPRS) and Conners Continuous Performance Test (CPT) were performed at baseline and at the end of the 5-week trial. Two subjects were lost to follow-up. Of the remaining 14 patients, 7 subjects displayed a decrease of at least one standard deviation from their baseline on one of the CPRS subscale scores and had subjective reports from parents of improved behavior. There were no statistically significant effects of venlafaxine on reaction times or on the number of commission and omission errors on CPT. Three ADHD subjects displayed a worsening of their hyperactivity and required discontinuation of venlafaxine, and nausea led to drug discontinuation in 1 patient. The mean daily dose of venlafaxine was 60 mg (1.4 mg/kg), administered 2-3 divided doses, there were no effects on blood pressure or heart rate. In this sample, low doses of venlafaxine appeared to be effective in reducing behavioral but not cognitive symptoms of ADHD in 7 of 16 children and adolescents (44%), and adverse effects were not tolerable in 4 of 16 patients (25%). These preliminary results suggest that venlafaxine may aggravate symptoms of hyperactivity, consistent with the behavioral activation reported with fluoxetine and sertraline in children.