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1.  Independent Effects of 5' and 3' Functional Variants in the Serotonin Transporter Gene on Suicidal Behavior in the Context of Childhood Trauma 
Journal of psychiatric research  2013;47(7):900-907.
The serotonin transporter, encoded by the SLC6A4 gene, influences the synaptic actions of serotonin and is responsive to stress hormones. We hypothesized that 5-HTTLPR, a functional SLC6A4 promoter polymorphism, and two tightly-linked, putatively functional 3' UTR SNPs (rs3813034, rs1042173) might have independent effects on suicidal behavior in the context of childhood trauma (CT).
DNA and Childhood Trauma Questionnaire scores were available for a total of 474 African Americans, including 112 suicide attempters and 362 non-suicide attempters. Genotyping was performed for the triallelic 5-HTTLPR polymorphism, 14 SLC6A4 haplotype-tagging SNPs, and 186 ancestry informative markers.
There were independent G × E interactive effects of 5-HTTLPR (p=0.017) and the rs3813034-rs1042173 diplotype (p=0.011) on suicidal behavior. In individuals exposed to high CT the risk of suicide attempt was 0.52 in carriers of the low activity 5-HTTLPR variant and 0.32 in medium/high activity variant carriers. Likewise, CT exposed carriers of the major rs3813034-rs1042173 ATAT diplotype had an increased risk of suicidal behavior relative to the ATCG/CGCG diplotype carriers (0.40 vs 0.31). Neither the 5' nor the 3' functional variants had an effect in individuals without CT: suicide attempt risk = 0.12 – 0.22. In individuals exposed to high CT the prevalence of suicide attempt was 0.56 in carriers of both 5' and 3' risk variants, 0.39 in carriers of one risk variant and 0.25 in individuals without either risk variant.
Our findings suggest that the 5' and 3' SLC6A4 functional variants have independent effects on the risk for suicidal behavior in CT exposed individuals.
doi:10.1016/j.jpsychires.2013.03.007
PMCID: PMC3646970  PMID: 23558235
SLC6A4; 5-HTTLPR; substance dependence; rs3813034; rs1042173; suicide attempt
2.  Factors Associated With Recovery from Anorexia Nervosa 
Journal of psychiatric research  2013;47(7):972-979.
Previous studies of prognostic factors of anorexia nervosa (AN) course and recovery have followed clinical populations after treatment discharge. This retrospective study examined the association between prognostic factors—eating disorder features, personality traits, and psychiatric comorbidity—and likelihood of recovery in a large sample of women with AN participating in a multi-site genetic study. The study included 680 women with AN. Recovery was defined as the offset of AN symptoms if the participant experienced at least one year without any eating disorder symptoms of low weight, dieting, binge eating, and inappropriate compensatory behaviors. Participants completed a structured interview about eating disorders features, psychiatric comorbidity, and self-report measures of personality. Survival analysis was applied to model time to recovery from AN. Cox regression models were used to fit associations between predictors and the probability of recovery. In the final model, likelihood of recovery was significantly predicted by the following prognostic factors: vomiting, impulsivity, and trait anxiety. Self-induced vomiting and greater trait anxiety were negative prognostic factors and predicted lower likelihood of recovery. Greater impulsivity was a positive prognostic factor and predicted greater likelihood of recovery. There was a significant interaction between impulsivity and time; the association between impulsivity and likelihood of recovery decreased as duration of AN increased. The anxiolytic function of some AN behaviors may impede recovery for individuals with greater trait anxiety.
doi:10.1016/j.jpsychires.2013.02.011
PMCID: PMC3682792  PMID: 23535032
Eating disorders; anorexia nervosa; recovery; prognostic factors; personality; comorbidity
3.  Ketamine regulates the presynaptic release machinery in the hippocampus 
Journal of psychiatric research  2013;47(7):892-899.
In the search for new drug targets, that may help point the way to develop fast-acting treatments for mood disorders, we have explored molecular pathways regulated by ketamine, an NMDA receptor antagonist, which has consistently shown antidepressant response within a few hours of administration. Using Sprague-Dawley rats we investigated the effects of ketamine on the presynaptic release machinery responsible for neurotransmitter release at 1, 2 and 4 h as well as 7 days after administration of a single subanesthetic dose of ketamine (15 mg/kg). A large reduction in the accumulation of SNARE complexes was observed in hippocampal synaptic membranes after 1, 2 and 4 h of ketamine administration. In parallel, we found a selective reduction in the expression of the synaptic vesicle protein synaptotagmin I and an increase in the levels of synapsin I in hippocampal synaptosomes suggesting a mechanism by which ketamine reduces SNARE complex formation, in part, by regulating the number of synaptic vesicles in the nerve terminals. Moreover, ketamine reduced Thr286-phosphorylated αCaMKII and its interaction with syntaxin 1A, which identifies CaMKII as a potential target for second messenger-mediated actions of ketamine. In addition, despite previous reports of ketamine-induced inhibition of GSK-3, we were unable to detect regulation of its activity after ketamine administration. Our findings demonstrate that ketamine rapidly induces changes in the hippocampal presynaptic machinery similar to those that are obtained only with chronic treatments with traditional antidepressants. This suggests that reduction of neurotransmitter release in the hippocampus has possible relevance for the rapid antidepressant effect of ketamine.
doi:10.1016/j.jpsychires.2013.03.008
PMCID: PMC3678963  PMID: 23548331
Ketamine; SNARE; Synapsin; Synaptotagmin; CaMKII; Antidepressant
4.  Temporal sequencing of nicotine dependence and bipolar disorder in the national epidemiologic survey on alcohol and related conditions (NESARC) 
Journal of psychiatric research  2013;47(7):858-864.
Bipolar disorder (BD) and nicotine dependence (ND) often co-occur. However, the mechanisms underlying this association remain unclear. We aimed to examine, for the first time in a national and representative sample, the magnitude and direction of the temporal relationship between BD and ND; and to compare, among individuals with lifetime ND and BD, the sociodemographic and clinical characteristics of individuals whose onset of ND preceded the onset of BD (ND-prior) with those whose onset of ND followed the onset of BD (BD-prior). The sample included individuals with lifetime BD type I or ND (n=7958) from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC, n=43093). Survival analyses and logistic regression models were computed to study the temporal association between ND and BD, and to compare ND-prior (n=135) and BD-prior (n=386) individuals. We found that ND predicted the onset of BD and BD also predicted the onset of ND. Furthermore, the risk of developing one disorder following the other one was greatest early in the course of illness. Most individuals with lifetime ND and BD were BD-prior (72.6%). BD-prior individuals had an earlier onset of BD and a higher number of manic episodes. By contrast, ND-prior individuals had an earlier onset of both daily smoking and ND, and an increased prevalence of alcohol use disorder. In conclusion, ND and BD predict the development of each other. The phenomenology and course of ND and BD varied significantly depending on which disorder had earlier onset.
doi:10.1016/j.jpsychires.2013.03.012
PMCID: PMC3674324  PMID: 23582710
bipolar disorder; nicotine dependence; age of onset; smoking; epidemiology
5.  Efficacy and specificity of Social Cognitive Skills Training for outpatients with psychotic disorders 
Journal of psychiatric research  2011;45(8):1113-1122.
Psychosocial interventions that target social cognition show promise for enhancing the functional outcomes of people with psychotic disorders. This randomized controlled trial evaluated the efficacy and treatment-outcome specificity of a 24-session Social Cognitive Skills Training (SCST) that targets emotional processing, social perception, attributional bias, and mentalizing (or Theory of Mind). Sixty-eight stable outpatients with primary psychotic disorders were randomly assigned to one of four time- and group format-matched treatment conditions: (1) SCST, (2) computerized neurocognitive remediation, (3) standard illness management skills training, or (4) a Hybrid treatment that combined elements of SCST and neurocognitive remediation. The SCST group demonstrated greater improvements over time than comparison groups in the social cognitive domain of emotional processing, including improvement on measures of facial affect perception and emotion management. There were no differential benefits among treatment conditions on neurocognitive or clinical symptom changes over time. Results indicate that a targeted social cognitive intervention led to improvements in social cognition among outpatients with psychosis. Findings provide guidance for continued efforts to maximize the benefits of social cognitive interventions.
doi:10.1016/j.jpsychires.2011.01.015
PMCID: PMC4064828  PMID: 21377168
Schizophrenia; Psychosocial treatment; Social cognition; Skills training
6.  Sex differences of Gray Matter Morphology in Cortico-limbic-striatal Neural System in Major Depressive Disorder 
Journal of psychiatric research  2013;47(6):733-739.
Sex differences are observed in both epidemiological and clinical aspects of major depressive disorder (MDD). The cortico-limbic-striatal neural system, including the prefrontal cortex, amygdala, hippocampus, and striatum, have shown sexually dimorphic morphological features and have been implicated in the dysfunctional regulation of mood and emotion in MDD. In this study, we utilized a whole-brain, voxel-based approach to examine sex differences in the regional distribution of gray matter (GM) morphological abnormalities in medication-naïve participants with MDD. Participants included 29 medication-naïve individuals with MDD (16 females and 13 males) and 33 healthy controls (HC) (17 females and 16 males). Gray matter morphology of the cortico-limbic-striatal neural system was examined using voxel-based morphometry analyses of high-resolution structural magnetic resonance imaging scans. The main effect of diagnosis and interaction effect of diagnosis by sex on GM morphology were statistically significant (p<0.05, corrected) in the left ventral prefrontal cortex, right amygdala, right hippocampus and bilateral caudate when comparing the MDD and HC groups. Posthoc analyses showed that females with MDD had significant GM decreases in limbic regions (p<0.05, corrected), compared to female HC; while males with MDD demonstrated significant GM reduction in striatal regions, (p<0.05, corrected), compared to HC males. The observed sex-related patterns of abnormalities within the cortico-limbic-strial neural system, such as predominant prefrontal-limbic abnormalities in MDD females vs. predominant prefrontal-striatal abnormalities in MDD males, suggest differences in neural circuitry that may mediate sex differences in the clinical presentation of MDD and potential targets for sex-differentiated treatment of the disorder.
doi:10.1016/j.jpsychires.2013.02.003
PMCID: PMC3626116  PMID: 23453566
Major depressive disorder; Magnetic resonance imaging; Voxel-based morphometry; Caudate; Amygdala; Hippocampus
7.  Negative life stress and longitudinal hippocampal volume changes in older adults with and without depression 
Journal of psychiatric research  2013;47(6):829-834.
Major depressive disorder is associated with smaller hippocampal volumes but the mechanisms underlying this relationship are unclear. To examine the effect of environmental influences, we examined the relationship between self-reported stressors and two-year change in hippocampal volume. Seventy elderly nondepressed subjects and eighty-nine elderly depressed subjects were followed for two years. The number of negative stressful life events (nSLE), perceived stress levels, and cranial MRI were obtained at baseline and at the two-year assessment. For secondary analyses, subjects provided blood for 5-HTTLPR polymorphism genotyping. After controlling for covariates including presence or absence of depression, greater numbers of baseline nSLEs were significantly associated with greater baseline hippocampal volumes bilaterally. Greater numbers of baseline nSLEs were also associated with reduction in hippocampal volume over two years in the right but not the left hemisphere. Neither perceived stress levels nor changes in stress measures were significantly associated with hippocampal volume measures. However, in secondary analyses, we found that increases in perceived stress over time was associated with volume reduction of the left hippocampus, but only in 5-HTTLPR L/L homozygotes. Our findings suggest different short- and long-term effects of negative life stressors on hippocampal volumes in older adults. These effects appear independent on the presence or absence of depression. Furthermore, these effects may be moderated by genetic polymorphisms in key neurotransmitter systems. These novel findings have important implications for understanding environmental influences on brain aging.
doi:10.1016/j.jpsychires.2013.02.008
PMCID: PMC3622849  PMID: 23478048
depression; geriatric depression; late-life depression; genetic polymorphism; hippocampus; life events; stress; neuroimaging; serotonin transporter; longitudinal
9.  Increased Gsα within Blood Cell Membrane Lipid Microdomains in Some Depressive Disorders: An Exploratory Study 
Journal of psychiatric research  2013;47(6):706-711.
The stimulatory guanine nucleotide binding protein Gs couples many cellular receptors to adenylate cyclase, and the Gsα subunit activates all 9 isoforms of the adenylate cyclase catalytic unit to produce the enzyme product cyclicAMP or cAMP. In prefrontal cortex and cerebellum of unipolar depressive suicides, Rasenick and colleagues have found increased concentrations of Gsα in membrane lipid microdomains (Donati et al, 2008), where the ensconced Gsα is less likely to activate adenylate cyclase by receptor and postreceptor pathways (Allen et al, 2005 & 2009).
We report that a group of 7 depressed patients (DP-1) had (1) reduced activation of platelet receptor-stimulated adenylate cyclase by both prostaglandins E2 and D2 compared to controls, and (2) reduced postreceptor stimulation of adenylate cyclase by aluminum fluoride ion in both platelets and mononuclear leukocytes when compared to both another group of depressed patients (DP-2, n=17) and to controls (n=21). Our observations in the blood cells of the group DP-1 support the findings of Donati et al (2008), and they reflect the importance of this interaction between the activated Gsα subunit and membrane lipid microdomains in the pathophysiology and treatment of some major depressive disorders.
doi:10.1016/j.jpsychires.2013.02.005
PMCID: PMC3669544  PMID: 23490066
major depressive disorder; adenylate cyclase; Gsα subunit; membrane lipid rafts
10.  Deconstructing Negative Symptoms of Schizophrenia: Avolition-Apathy and Diminished Expression Clusters Predict Clinical Presentation and Functional Outcome 
Journal of psychiatric research  2013;47(6):783-790.
Background
Previous studies indicate that negative symptoms reflect a separable domain of pathology from other symptoms of schizophrenia. However, it is currently unclear whether negative symptoms themselves are multi-faceted, and whether sub-groups of patients who display unique negative symptom profiles can be identified.
Methods
A data-driven approach was used to examine the heterogeneity of negative symptom presentations in two samples: Study 1 included 199 individuals with schizophrenia assessed with a standard measure of negative symptoms and Study 2 included 169 individuals meeting criteria for deficit schizophrenia (i.e., primary and enduring negative symptoms) assessed with a specialized measure of deficit symptoms. Cluster analysis was used to determine whether different groups of patients with distinct negative symptoms profiles could be identified.
Results
Across both studies, we found evidence for two distinctive negative symptom sub-groups: one group with predominantly Avolition-Apathy (AA) symptoms and another with a predominantly Diminished Expression (DE) profile. Follow-up discriminant function analyses confirmed the validity of these groups. AA and DE negative symptom sub-groups significantly differed on clinically relevant external validators, including measures of functional outcome, premorbid adjustment, clinical course, disorganized symptoms, social cognition, sex, and ethnicity.
Conclusions
These results suggest that distinct subgroups of patients with elevated AA or DE can be identified within the broader diagnosis of schizophrenia and that these subgroups show clinically meaningful differences in presentation. Additionally, AA tends to be associated with poorer outcomes than DE, suggesting that it may be a more severe aspect of psychopathology.
doi:10.1016/j.jpsychires.2013.01.015
PMCID: PMC3686506  PMID: 23453820
Schizophrenia; Negative Symptoms; Avolition; Apathy; Emotion; Blunted Affect
11.  Major Depression Duration Reduces Appetitive Word Use: An Elaborated Verbal Recall of Emotional Photographs 
Journal of psychiatric research  2013;47(6):809-815.
Introduction
Major depressive disorder (MDD) is characterized by cognitive biases in attention, memory and language use. Language use biases often parallel depression symptoms, and contain over-representations of both negative emotive and death words as well as low levels of positive emotive words. This study further explores cognitive biases in depression by comparing the effect of current depression status to cumulative depression history on an elaborated verbal recall of emotional photographs.
Methods
Following a negative mood induction, fifty-two individuals (42 women) with partially-remitted depression viewed – then recalled and verbally described – slides from the International Affective Picture System (IAPS). Descriptions were transcribed and frequency of depression-related word use (positive emotion, negative emotion, sex, ingestion and death) was analyzed using the Linguistic Inquiry and Word Count program (LIWC).
Results
Contrary to expectations and previous findings, current depression status did not affect word use in any categories of interest. However, individuals with more than 5 years of previous depression used fewer words related to positive emotion (t(50) = 2.10, p = .04, (d = .57)), and sex (t(48) = 2.50, p = .013 (d = .81)), and there was also a trend for these individuals to use fewer ingestion words (t(50) = 1.95, p = .057 (d = .58)), suggesting a deficit in appetitive processing.
Conclusions
Our findings suggest that depression duration affects appetitive information processing and that appetitive word use may be a behavioral marker for duration related brain changes which may be used to inform treatment.
doi:10.1016/j.jpsychires.2013.01.022
PMCID: PMC3732741  PMID: 23510497
depression; remission; cognitive processes; appetitive; word use
12.  Resting State EEG Power and Coherence Abnormalities in Bipolar Disorder and Schizophrenia 
Journal of psychiatric research  2013;47(12):1893-1901.
Resting state electroencephalogram (EEG) abnormalities in schizophrenia and bipolar disorder patients suggest alterations in neural oscillatory activity. However, few studies directly compare these anomalies between patient groups, and none have examined EEG coherence. Therefore, this study investigated whether these electrophysiological characteristics differentiate clinical populations from one another, and from non-psychiatric controls. To address this question, resting EEG power and coherence were assessed in 76 bipolar patients (BP), 132 schizophrenia patients (SZ), and 136 non-psychiatric controls (NC). We conducted separate repeated-measures ANOVAs to examine group differences within seven frequency bands across several brain regions. BP showed significantly greater power relative to SZ at higher frequencies including Beta and Gamma across all regions. In terms of intra-hemispheric coherence, while SZ generally exhibited higher coherence at Delta compared to NC and BP, both SZ and BP showed higher coherence at Alpha1 and Alpha2. In contrast, BP and HC showed higher coherence within hemispheres compared to SZ at Beta 1. In terms of inter-hemispheric coherence, SZ displayed higher coherence compared to NC at temporal sites at both Alpha1 and Alpha2. Taken together, BP exhibited increased high frequency power with few disruptions in neural synchronization. In contrast, SZ generally exhibited enhanced synchronization within and across hemispheres. These findings suggest that resting EEG can be a sensitive measure for differentiating between clinical disorders.
doi:10.1016/j.jpsychires.2013.09.009
PMCID: PMC4015517  PMID: 24090715
resting state; EEG; power; neural synchronization; bipolar disorder; schizophrenia
13.  The involvement of 5-lipoxygenase activating protein in anxiety-like behavior 
Journal of psychiatric research  2013;47(5):694-698.
The 5-lipoxygenase is an enzyme widely expressed in the central nervous system, where its activity is dependent on the presence the 5-lipoxygenase activating protein (FLAP) for the formation of leukotrienes, potent bioactive lipid mediators. Emerging evidence has shown that the FLAP/leukotriene pathway may play a role in neuropsychiatric disease contexts.
In this study we investigated whether genetic deficiency of FLAP (FLAPKO) modulated some behavioral aspects in mice, and if this effect was age-dependent. While we observed that FLAPKO mice at 3 and 6 months of age did not different from wild type animals in the elevated plus maze, at 12 months of age they manifested a significant increase in the anxiety-like behavior. By contrast, we observed no differences between FLAPKO mice and their controls at any of the three ages considered when they were tested for working memory in the Y maze paradigm. Additionally, while we found that cFOS protein and message levels were reduced in the brains of animals lacking FLAP, no changes for other transcription factors were detected.
Taken together our findings suggest a novel role for FLAP in the pathogenesis of anxiety-like behavior. Future studies of FLAP neurobiology may be attractive for development of anxiolytic therapeutics.
doi:10.1016/j.jpsychires.2012.12.011
PMCID: PMC3594470  PMID: 23357209
Five-lipoxygenase activating protein (FLAP); animal models; behavior; anxiety
14.  Association of elevated cytokines with childhood adversity in a sample of healthy adults 
Journal of psychiatric research  2013;47(5):604-610.
Objective
Childhood trauma has been associated adult stress-related disorders. However, little is known about physiologic alterations in adults with a history of early life trauma that do not have current psychiatric or medical diagnoses. In this study, the relationships between childhood adversity and cytokine and C - reactive protein (CRP) levels in healthy adults were examined.
Method
Participants included men (n=18) and women (n=20) who did not meet DSM-IV criteria for Axis I psychiatric disorders or any major medical illness. Cytokine and CRP levels were obtained from baseline blood samples. Subjects completed the Early Trauma Inventory Self Report (ETI-SR). The primary outcomes included serum interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1β (IL1-β), and CRP levels. In addition, the mean numbers of traumatic experiences (sexual, physical, emotional, general, and the summed total) were measured.
Results
Significant positive associations were found between the total ETI score and IL-6 (p = 0.05), IL1-β (p < 0.05), and TNF-α (p = 0.01). Significant positive correlations were found between the number of general traumas and IL1-β (p < 0.05), TNF-α (p < 0.05), and IL-6 (p < 0.01). Neither the total number of traumas nor any of the trauma subscales were significantly associated with CRP levels.
Conclusions
The positive association between childhood trauma and basal cytokine levels supports the extant literature demonstrating the long-term impact of childhood trauma and stress on homeostatic systems. Importantly, this association was found in healthy adults, suggesting that these alterations may precede the development of significant stress-related psychiatric disorder or disease.
doi:10.1016/j.jpsychires.2013.01.008
PMCID: PMC3594625  PMID: 23415658
life stress; biological stress; innate immunity; cytokines; C-reactive protein
15.  The Association of Cardiac Vagal Control and Executive Functioning – Findings from the MIDUS Study 
Journal of psychiatric research  2013;47(5):628-635.
Cardiac Vagal Control (CVC), an index of parasympathetic contribution to cardiac regulation, has been linked to enhanced executive functioning (EF). However, findings to date have been based on small or unique samples. Additionally, previous studies assessed the CVC-EF link only during rest or recovery period from a cognitive challenge, but not during both states. In the present study, data on 817 socioeconomically diverse participants were obtained from the Midlife Development in the United States (MIDUS) study. As part of this study, participants completed cognitive tests, including EF, along with laboratory-based measures of CVC during rest and following recovery from a cognitive challenge. Regression analyses adjusting for respiratory rate revealed no effect of CVC at rest or during recovery on a global index of EF. However, exploratory post-hoc analyses of the components of the global EF index revealed a significant association between faster vagal recovery and better attention-switching and response inhibition abilities, as indexed by faster reaction time to the mixed SGST. This association remained significant after controlling for demographic, clinical (BMI, diseases and medications altering cardiac autonomic functioning, etc.), and health behavior covariates (Beta=.148, p=.010). Our findings suggest that future studies may need to investigate the links of CVC to specific EF abilities, rather than global measures of EF. Additionally, our results highlight the importance of assessing CVC during both rest and recovery from a cognitive challenge. The authors discuss the putative neurobiological underpinning of this link, as well as suggestions for future basic and clinical research.
doi:10.1016/j.jpsychires.2013.01.018
PMCID: PMC3594003  PMID: 23434176
16.  Comorbidity-independent Risk for Suicidality Increases with Bulimia Nervosa but not with Anorexia Nervosa 
Journal of psychiatric research  2013;47(5):617-621.
Background
Eating disorders are serious psychiatric illnesses with high levels of suicidality and high comorbidity. However, no study has established the extent to which suicidality is uniquely associated with eating disorders rather than attributable to comorbid mood, anxiety, or substance use disorders. The current study examined whether unique associations between eating disorders and suicidality exist and whether potential associations differ by eating disorder diagnosis.
Methods
Participants were women (n=364) from the second stage of a large epidemiological study examining eating and health related attitudes and behaviors. The Structured Clinical Interview for Axis I diagnoses (SCID-I) was used to determine lifetime psychiatric diagnoses and lifetime suicidality.
Results
A multiple regression model including eating and comorbid disorders indicated that bulimia nervosa (BN) was significantly associated with suicidality above and beyond risk predicted by comorbid disorders. No unique association was found for anorexia nervosa (AN) or eating disorder not otherwise specified while controlling for comorbidity.
Conclusions
BN is independently associated with suicidality, and findings emphasize the need to incorporate suicide risk assessment in standardized assessments of eating disorders.
doi:10.1016/j.jpsychires.2013.01.005
PMCID: PMC3594594  PMID: 23384941
eating disorders; suicidality; bulimia nervosa; anorexia nervosa; suicide; risk factors
17.  Subsyndromal Depression and Anxiety in Older Adults: Health Related, Functional, Cognitive and Diagnostic Implications 
Journal of psychiatric research  2013;47(5):599-603.
Subsyndromal depression in later life is common in primary care. Comorbid anxiety disorders could exacerbate the negative effect of subsyndromal depression on functioning, health-related quality of life, comorbidity and/or cognition. We examined anxiety disorders coexisting with subsyndromal depression in participants ≥ age 50 in an NIH trial of Problem Solving Therapy for Primary Care for indicated prevention of major depression. There were 247 participants, with Centers for Epidemiologic Studies - Depression scores ≥ 11. Participants could have multiple psychiatric diagnoses: 22% of the sample had no DSM IV diagnosis; 39% of the sample had only 1 DSM IV diagnosis; 28% had 2 diagnoses; 6% had 3 DSM IV diagnoses; 4% had 4 DSM IV diagnoses; and 1% had 5 diagnoses. Furthermore, 34% of participants had a current comorbid DSM IV diagnosis of a syndromal anxiety disorder. We hypothesized that those with subsyndromal depression, alone relative to those with coexisting anxiety disorders, would report better health-related quality of life, less disability, less medical comorbidity and less cognitive impairment. However, there were no differences in quality of life based on the SF 12 nor in disability based on Late Life Function and Disability Instrument scores. There were no differences in medical comorbidity based on the Cumulative Illness Scale-Geriatrics scale scores nor in cognitive function based on the Executive Interview (EXIT), Hopkins Verbal Learning Test-Revised and Mini Mental Status Exam. Our findings suggest that about one third of participants 50 years and older with subsyndromal depression have comorbid anxiety disorders; however, this does not appear to be associated with worse quality of life, functioning, disability, cognitive function or medical comorbidity.
doi:10.1016/j.jpsychires.2013.01.017
PMCID: PMC3594429  PMID: 23414701
comorbidity; subsyndromal depression; anxiety; prevention; cognition; functioning
18.  Altered fatty acid concentrations in prefrontal cortex of schizophrenic patients 
Journal of psychiatric research  2013;47(5):636-643.
Background
Disturbances in prefrontal cortex phospholipid and fatty acid composition have been reported in schizophrenic (SCZ) patients, often as percent of total lipid concentration or incomplete lipid profile. In this study, we quantified absolute concentrations (nmol/g wet weight) of several lipid classes and their constituent fatty acids in postmortem prefrontal cortex of SCZ patients (n = 10) and age-matched controls (n = 10).
Methods
Lipids were extracted, fractionated with thin layer chromatography and assayed.
Results
Mean total lipid, phospholipid, individual phospholipids, plasmalogen, triglyceride and cholesteryl ester concentrations did not differ significantly between the groups. Compared to controls, SCZ brains showed significant increases in several monounsaturated and polyunsaturated fatty acids in cholesteryl ester. Significant increases or decreases occurred in palmitoleic, linoleic, γ-linolenic and n-3 docosapentaenoic acid in total lipids, triglycerides or phospholipids.
Conclusion
These changes suggest disturbed prefrontal cortex fatty acid concentrations, particularly within cholesteryl esters, as a pathological aspect of schizophrenia.
doi:10.1016/j.jpsychires.2013.01.016
PMCID: PMC3620602  PMID: 23428160
fatty acids; lipids; phospholipids; brain; prefrontal cortex; postmortem; schizophrenia; composition; concentrations
19.  GABAergic Neuroactive Steroids and Resting-State Functional Connectivity in Postpartum Depression: A Preliminary Study 
Journal of psychiatric research  2013;47(6):816-828.
Postpartum depression (PPD) affects up to 1 in 8 women. The early postpartum period is characterized by a downward physiological shift from relatively elevated levels of sex steroids during pregnancy to diminished levels after parturition. Sex steroids influence functional brain connectivity in healthy non-puerperal subjects. This study tests the hypothesis that PPD is associated with attenuation of resting-state functional connectivity (rs-fc) within corticolimbic regions implicated in depression and alterations in neuroactive steroid concentrations as compared to healthy postpartum women. Subjects (n=32) were prospectively evaluated during pregnancy and in the postpartum with repeated plasma neuroactive steroid measurements and mood and psychosocial assessments. Healthy comparison subjects (HCS) and medication-free subjects with unipolar PPD (PPD) were examined using functional magnetic resonance imaging (fMRI) within 9 weeks of delivery. We performed rs-fc analysis with seeds placed in the anterior cingulate cortex (ACC), and bilateral amygdalae (AMYG), hippocampi (HIPP) and dorsolateral prefrontal cortices (DLPFC). Postpartum rs-fc and perinatal neuroactive steroid plasma concentrations, quantified by liquid chromatography/mass spectrometry, were compared between groups. PPD subjects showed attenuation of connectivity for each of the tested regions (i.e. ACC, AMYG, HIPP and DLPFC) and between corticocortical and corticolimbic regions vs. HCS. Perinatal concentrations of pregnanolone, allopregnanolone and pregnenolone were not different between groups. This is the first report of a disruption in the rs-fc patterns in medication-free subjects with PPD. This disruption may contribute to the development of PPD, at a time of falling neuroactive steroid concentrations.
doi:10.1016/j.jpsychires.2013.02.010
PMCID: PMC3983790  PMID: 23499388
Postpartum depression; functional magnetic resonance imaging; resting-state functional connectivity; neuroactive steroids
20.  Cerebrospinal fluid glutamate concentration correlates with impulsive aggression in human subjects 
Journal of psychiatric research  2013;47(9):1247-1253.
Neurochemical studies have pointed to a modulatory role in human aggression for various central neurotransmitters. Some (e.g., serotonin) appear to play an inhibitory role, while others appear to play a facilitator role. While recent animal studies of glutaminergic activity suggest a facilitator role for central glutamate in the modulation of aggression, no human studies of central glutaminergic indices have yet been reported regarding aggression. Basal lumbar cerebrospinal fluid (CSF) was obtained from 38 physically healthy subjects with DSM-IV Personality Disorder (PD: n = 28) and from Healthy Volunteers (HV: n = 10) and assayed for glutamate, and other neurotransmitters, in CSF and correlated with measures of aggression and impulsivity. CSF Glutamate levels did not differ between the PD and HC subjects but did directly correlate with composite measures of both aggression and impulsivity and a composite measure of impulsive aggression in both groups. These data suggest a positive relationship between CSF Glutamate levels and measures of impulsive aggression in human subjects. Thus, glutamate function may contribute to the complex central neuromodulation of impulsive aggression in human subjects.
doi:10.1016/j.jpsychires.2013.05.001
PMCID: PMC3980459  PMID: 23791397
CSF; Glutamate; Aggression
21.  The impact of killing and injuring others on mental health symptoms among police officers 
Journal of psychiatric research  2011;45(10):1332-1336.
This study examined the relationship between killing or seriously injuring someone in the line of duty and mental health symptoms in a sample of police officers (N = 400) who were first assessed during academy training and at five additional time points over three years. We found that nearly 10% of police officers reported having to kill or seriously injure someone in the line of duty in the first three years of police service. After controlling for demographics and exposure to life threat, killing or seriously injuring someone in the line of duty was significantly associated with PTSD symptoms (p< .01) and marginally associated with depression symptoms (p < .06). These results highlight the potential mental health impact of killing or seriously injuring someone in the line of duty. Greater attention to mental health services following these types of exposures can serve as a preventative measure for police officers who have been negatively impacted.
doi:10.1016/j.jpsychires.2011.05.004
PMCID: PMC3974970  PMID: 21658717
Killing; Injuring; Use of force; Police; PTSD
22.  Using electronic health records data to assess comorbidities of substance use and psychiatric diagnoses and treatment settings among adults 
Journal of psychiatric research  2013;47(4):555-563.
Objective
To examine prevalences of substance use disorders (SUD) and comprehensive patterns of comorbidities among psychiatric patients ages 18–64 years (N=40,099) in an electronic health records (EHR) database.
Method
DSM-IV diagnoses among psychiatric patients in a large university system were systematically captured: SUD, anxiety (AD), mood (MD), personality (PD), adjustment, childhood-onset, cognitive/dementia, dissociative, eating, factitious, impulse-control, psychotic (schizophrenic), sexual/gender identity, sleep, and somatoform diagnoses. Comorbidities and treatment types among patients with a SUD were examined.
Results
Among all patients, 24.9% (n=9,984) had a SUD, with blacks (35.2%) and Hispanics (32.9%) showing the highest prevalence. Among patients with a SUD, MD was prevalent across all age groups (50.2–56.6%). Patients aged 18–24 years had elevated odds of comorbid PD, adjustment, childhood-onset, impulse-control, psychotic, and eating diagnoses. Females had more PD, AD, MD, eating, and somatoform diagnoses, while males had more childhood-onset, impulse-control, and psychotic diagnoses. Blacks had greater odds than whites of psychotic and cognitive/dementia diagnoses, while whites exhibited elevated odds of PA, AD, MD, childhood-onset, eating, somatoform, and sleep diagnoses. Women, blacks, and Native American/multiple-race adults had elevated odds of using inpatient treatment; men, blacks, and Hispanics had increased odds of using psychiatric emergency care. Comorbid MD, PD, adjustment, somatoform, psychotic, or cognitive/dementia diagnoses increased inpatient treatment.
Conclusion
Patients with a SUD, especially minority members, use more inpatient or psychiatric emergency care than those without. Findings provide evidence for research on understudied diagnoses and underserved populations in the real-world clinical settings.
doi:10.1016/j.jpsychires.2012.12.009
PMCID: PMC3581730  PMID: 23337131
anxiety disorders; comorbidity; comparative effectiveness research; electronic health records; mood disorders; personality disorders; substance-related disorders
23.  The CC genotype in the T102C HTR2A polymorphism predicts relapse in individuals after alcohol treatment 
Journal of psychiatric research  2013;47(4):527-533.
The serotonin system is hypothesized to contribute to predisposition and course of alcohol dependence. However, the potential association between the T102C polymorphism (rs6313) in the type 2A serotonin receptor (HTR2A) gene and treatment outcomes in alcohol dependence has not been investigated. The aim of the study was to assess the contribution of this genetic polymorphism as a predictor of relapse in relation to other previously identified predictors. A sample of 254 alcohol dependent subjects, were recruited in alcohol treatment centers in Warsaw, Poland and prospectively assessed at baseline and follow-up after 12 months. At baseline, information about demographics, psychopathological symptoms and alcohol problems was obtained. The stop-signal task was performed and blood samples for genetic analysis of HTR2A T102C (rs6313) were collected. Relapse was defined as any drinking during the follow-up period. The statistical analysis showed that the CC genotype was significantly associated with increased relapse. Other significant factors were baseline depressive symptoms, number of drinking days during the 3 months prior to the baseline assessment, severity of alcohol-related problems, and a lifetime history of impulsive suicide attempts. Logistic regression analysis with and without the genetic factor revealed that adding the genetic factor increased the R square value by about 4%, with the CC genotype in the T102C polymorphism being the strongest predictor of relapse (OR=2.32). The significant influence on relapse of the CC genotype, which is associated with fewer 5-HT2A receptors in the central nervous system, suggests the possibility that this genetic polymorphism could influence response to serotonergic medications.
doi:10.1016/j.jpsychires.2012.12.004
PMCID: PMC3581721  PMID: 23321485
Alcohol dependence; Serotonin; HTR2A; Genetic polymorphism; Relapse
24.  Trajectories of posttraumatic stress symptomatology in older persons affected by a large-magnitude disaster 
Journal of psychiatric research  2013;47(4):520-526.
This study examined the nature and determinants of longitudinal trajectories of disaster-related posttraumatic stress disorder (PTSD) symptoms in older persons affected by a large-magnitude disaster. Two hundred six adults age 60 or older (mean=69, range=60–92) who resided in the Galveston Bay area when Hurricane Ike struck in September 2008 completed telephone interviews an average of 3-, 6-, and 15-months after this disaster. Latent growth mixture modeling was employed to identify predominant trajectories of disaster-related PTSD symptoms over time; and pre-, peri-, and post-disaster determinants of these trajectories were then examined. A 3-class solution optimally characterized PTSD symptom trajectories, with the majority (78.7%) of the sample having low/no PTSD symptoms over all assessments (i.e., resistant); 16.0% having chronically elevated symptoms (i.e., chronic); and 5.3% having a delayed onset course of symptoms (i.e., delayed-onset). Lower education, greater severity of Hurricane Ike exposure (i.e., Ike-related physical illness or injury and high level of community destruction), and greater number of traumatic and stressful life events after Hurricane Ike, particularly financial problems, were associated with a chronic PTSD trajectory. Greater number of traumatic and stressful life events, particularly financial problems after Hurricane Ike, was also associated with a delayed-onset trajectory. These findings suggest that there are heterogeneous trajectories of disaster-related PTSD symptoms in older adults and that these trajectories have common and unique determinants. They also underscore the importance of prevention efforts designed to mitigate the effects of post-disaster stressors, most notably financial distress, in older persons affected by disasters.
doi:10.1016/j.jpsychires.2012.12.005
PMCID: PMC3581738  PMID: 23290559
disaster; posttraumatic stress disorder; longitudinal data; older adults; latent modeling; risk factors

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