Journal of Psychiatric Research - Articles in Press

Negative expectancies in posttraumatic stress disorder: Neurophysiological (N400) and behavioral evidence - Corrected Proof

Matthew Kimble, Laura Batterink, Elizabeth Marks, Cordelia Ross, Kevin Fleming — 2012-05-18

Abstract: Background: Posttraumatic stress disorder (PTSD) is a disorder that theoretically and clinically is thought to be associated with persistent and exaggerated negative expectancies. This study used the N400 event-related potential (ERP) to investigate expectancies for threatening endings to ambiguous sentence stems. The N400 ERP is thought to reflect the amount of effort required to integrate a stimulus into a given context. In sentence reading tasks, the N400 is reliably larger when a word is unexpected.Method: In this study, fifty-seven trauma survivors of various types (22 with PTSD and 35 without) read ambiguous sentence stems on a computer screen. These sentence stems were completed with either an expected (“The unfortunate man lost his…wallet”), unexpected (“The unfortunate man lost his…artist”), or threatening word endings (“The unfortunate man lost his…leg”).Results: Participants with PTSD, as compared to those without, showed significantly smaller N400s to threatening sentence endings suggesting enhanced expectancies for threat. Behavioral responses supported this conclusion.Conclusions: These findings are consistent with the clinical presentation of hypervigilance and proposed revisions to the DSM-V that emphasize persistent and exaggerated negative expectations about one's self, others, or the world. Relative to earlier behavioral studies, this work further suggests that this expectancy bias occurs automatically and at the early stages of information processing. The discussion focuses on the potential impact of a negative expectancy bias in PTSD and the value of the ambiguous sentence paradigm for studying PTSD as well as other disorders.

Alcohol and cannabis use and mortality in people with schizophrenia and related psychotic disorders - Corrected Proof

2012-05-18

Abstract: The impact of co-morbid substance use on mortality is not well studied in psychotic disorders. The objective of this study was to examine the impact of substance use on mortality in people with psychotic disorders and alcohol and/or drug use. We examined the rate of substance use and the risk of substance use on mortality risk over a 4–10 year period in 762 people with psychotic disorders. Deceased patients were identified from the Social Security Death Index and the Maryland Division of Vital Records. Substance use was defined as regular and heavy use or abuse or dependence. Seventy seven percent had co-morbid lifetime substance use, with co-morbid cannabis and alcohol use occurring most commonly. Out of 762 subjects, 62 died during follow up. In a Cox model, predicted mortality risk was higher in age group 35–55 compared to <35 years and in males, but reduced in cannabis users. Overall five- (3.1% vs 7.5%) and ten-year mortality risk (5.5% vs. 13.6%) was lower in cannabis users than in non-users with psychotic disorders (p = 0.005) in a survival model. Alcohol use was not predictive of mortality. We observed a lower mortality risk in cannabis-using psychotic disorder patients compared to cannabis non-users despite subjects having similar symptoms and treatments. Future research is warranted to replicate these findings and to shed light on the anti-inflammatory properties of the endocannabinoid system and its role in decreased mortality in people with psychotic disorders.

Smaller volumes of caudate nuclei in prepubertal children with ADHD: Impact of age - Corrected Proof

2012-05-18

Abstract: Objective: Age-related abnormalities in caudate volumes have been reported to differ across the periods of childhood and puberty in children with ADHD. This study assessed caudate volumetric abnormalities across two narrow age clusters within the childhood period.Method: Three-dimensional manual tracings of the head and body of the caudate nucleus and of the cerebrum were acquired from 26 medication-naïve boys with a diagnosis of ADHD (ages 5.9–10.8 years), and 24 age-matched normal controls.Results: Boys with ADHD had smaller total caudate volumes relative to controls, F(1,48)=4.29, p=0.04. Adjustment of caudate volumes with respect to age demonstrated that this group difference was driven solely by participants in the 5.9–7.3 year range, F(1, 46)=5.64, p=0.022, with an effect size of d=0.69. No Group effect was found in older participants, F(1, 46)=0.82, p=0.37.Conclusions: These novel findings suggest a different pattern of caudate volume abnormalities across narrow age clusters prior to puberty in boys with ADHD. Anatomical differences in brain structures related to ADHD in prepubertal children should be evaluated with respect to the changing developmental trajectory of brain regions within this period of rapid brain growth.

Suicidality and sexual orientation among men in Switzerland: Findings from 3 probability surveys - Corrected Proof

Jen Wang, Michael Häusermann, Hans Wydler, Meichun Mohler-Kuo, Mitchell G. Weiss — 2012-05-17

Abstract: Few population-based surveys in Europe have examined the link between suicidality and sexual orientation. The objective of this study was to assess the prevalences of and risk for suicidality by sexual orientation, especially among adolescent and young adult men. Data came from three probability-based surveys in Switzerland from 2002: 1) Geneva Gay Men's Health Survey (GGMHS) with 571 gay/bisexual men, 2) Swiss Multicenter Adolescent Survey on Health (SMASH) with 7,428 16–20 year olds, and 3) Swiss Recruit Survey (ch-x) with 22,415 new recruits. In GGMHS, suicidal ideation (12 months/lifetime) was reported by 22%/55%, suicide plans 12%/38%, and suicide attempts 4%/19%. While lifetime prevalences and ratios are similar across age groups, men under 25 years reported the highest 12-month prevalences for suicidal ideation (35.4%) and suicide attempts (11.5%) and the lowest attempt ratios (1:1.5 for attempt to plan and 1:3.1 for attempt to ideation). The lifetime prevalence of suicide attempts among homo/bisexual men aged 16–20 years varies from 5.1% in ch-x to 14.1% in SMASH to 22.0% in GGMHS. Compared to their heterosexual counterparts, significantly more homo/bisexual men reported 12-month suicidal ideation, plans, and attempts (OR = 2.09–2.26) and lifetime suicidal ideation (OR = 2.15) and suicide attempts (OR = 4.68–5.36). Prevalences and ratios vary among gay men by age and among young men by both sexual orientation and study population. Lifetime prevalences and ratios of non-fatal suicidal behaviors appear constant across age groups as is the increased risk of suicidality among young homo/bisexual men.

Region-specific glutamate changes in patients with unipolar depression - Corrected Proof

2012-05-17

Abstract: The present study aimed to investigate glutamate concentrations in patients with unipolar depression in the midcingulate cortex (MCC) as compared to the left dorsolateral prefrontal cortex (DLPFC). We hypothesized a dissociation of glutamate levels with unchanged levels in DLPFC and abnormally changed levels in MCC as well as differential effects of antidepressant pharmacotherapy. Glutamate was determined using magnetic resonance spectroscopy at 3 T in DLPFC and MCC in fourteen depressed patients and matched healthy volunteers. A follow-up measurement was performed after 4 weeks of antidepressant treatment. The main finding is a region-specific pattern of glutamate concentrations with increased MCC glutamate concentrations and no significant differences in DLPFC glutamate concentrations in unipolar depressive patients compared to healthy controls. Response and non-response to antidepressant pharmacotherapy were predicted by high glutamate at baseline in DLPFC and MCC, respectively. In addition, treatment responders showed a further increase in DLPFC glutamate levels after successful antidepressant treatment. Findings indicate altered region-specific glutamate concentrations in DLPFC and MCC that are predictive of response and non-response, respectively, to antidepressant pharmacotherapy. These findings might serve as a starting point for future studies in which the value of this metabolite pattern for treatment response prediction should be investigated.

Pilot study of the efficacy of double-blind, placebo-controlled one-week olanzapine stabilization therapy in heterogeneous symptomatic bipolar disorder patients - Corrected Proof

2012-05-14

Abstract: Background: Olanzapine has demonstrated efficacy in acute mania and bipolar I disorder (BDI) maintenance, but efficacy in brief therapy in more diverse populations, including patients with bipolar II disorder (BDII)/bipolar disorder not otherwise specified (BDNOS) with syndromal/subsyndromal depressive/mood elevation symptoms and taking/not taking concurrent medications remains to be established.Methods: Fifty adult outpatients (24 BD1, 22 BDII, 4 BDNOS, mean ± SD age 40.8 ± 11.5 years, 28.1% female, already taking 1.1 ± 1.2 [median 1] prescription psychotropics) with 17-item Hamilton Depression Rating Scale (HDRS) ≥10 and/or Young Mania Rating Scale (YMRS) ≥10 and ≤24, were randomized to double-blind olanzapine (2.5–20 mg/day) versus placebo for one week.Results: Among 45 patients with post-baseline ratings, olanzapine (9.0 ± 5.8 mg/day, n = 23) compared to placebo (n = 22) tended to yield greater Clinical Global Impressions-Bipolar Version-Overall Severity of Illness (−1.4 ± 0.9 versus −0.8 ± 1.1, p = 0.08) and Hamilton Anxiety Scale (−7.9 ± 6.3 versus −3.8 ± 6.1, p = 0.07) improvements, and YMRS/HDRS remission rate (47.8% versus 22.7%, p = 0.08), but significantly increased median weight (+2 versus −1 lbs, p = 0.001), and rates of excessive appetite (54.2% versus 22.7%, p = 0.04) and tremor (50.0% versus 9.1% p = 0.004). Number Needed to Treat and 95% Confidence Interval for YMRS/HDRS remission were 4 (1–∞). Numbers Needed to Harm for excessive appetite and tremor were 4 (1–21) and 3 (1–6), respectively.Conclusions: Olanzapine tended to yield affective improvement and significantly increased weight, appetite, and tremor. Larger controlled studies appear feasible and warranted to assess brief olanzapine therapy in heterogeneous symptomatic bipolar disorder patients.

Sleep promotes consolidation and generalization of extinction learning in simulated exposure therapy for spider fear - Corrected Proof

Edward F. Pace-Schott, Patrick W. Verga, Tobias S. Bennett, Rebecca M.C. Spencer — 2012-05-14

Abstract: Simulated exposure therapy for spider phobia served as a clinically naturalistic model to study effects of sleep on extinction. Spider-fearing, young adult women (N = 66), instrumented for skin conductance response (SCR), heart rate acceleration (HRA) and corrugator electromyography (EMG), viewed 14 identical 1-min videos of a behaving spider before a 12-hr delay containing a normal night's Sleep (N = 20) or continuous daytime Wake (N = 23), or a 2-hr delay of continuous wake in the Morning (N = 11) or Evening (N = 12). Following the delay, all groups viewed this same video 6 times followed by six 1-min videos of a novel spider. After each video, participants rated disgust, fearfulness and unpleasantness. In all 4 groups, all measures except corrugator EMG diminished across Session 1 (extinction learning) and, excepting SCR to a sudden noise, increased from the old to novel spider in Session 2. In Wake only, summed subjective ratings and SCR to the old spider significantly increased across the delay (extinction loss) and were greater for the novel vs. the old spider when it was equally novel at the beginning of Session 1 (sensitization). In Sleep only, SCR to a sudden noise decreased across the inter-session delay (extinction augmentation) and, along with HRA, was lower to the novel spider than initially to the old spider in Session 1 (extinction generalization). None of the above differentiated Morning and Evening groups suggesting that intervening sleep, rather than time-of-testing, produced differences between Sleep and Wake. Thus, sleep following exposure therapy may promote retention and generalization of extinction learning.

Regional differences in treatment response and three year course of schizophrenia across the world - Corrected Proof

2012-05-11

Abstract: Data from the Worldwide-Schizophrenia Outpatient Health Outcomes (W-SOHO) study was used to determine the frequency of response and describe the course of disease in outpatients with schizophrenia in different regions of the world. The W-SOHO study was a 3-year, prospective, observational study that included over 17,000 outpatients with schizophrenia from 37 countries classified into six regions (Northern Europe, Southern Europe, Latin America, East Asia, Central & Eastern Europe, North Africa & Middle East). Cox proportional-hazards regression was employed to assess the factors associated with response. Multinomial logistic regression was used to assess the correlates of disease course. We found that approximately two-thirds of the patients (66.4%) achieved response during the 3-year follow up. Response rates varied across regions, and were highest in North Africa & Middle East (84.6%) and Latin America (78.6%) and lowest in Southern Europe (62.1%) and East Asia (60.9%). There were significant differences between the regions in the proportion of patients experiencing continuous remission, remission plus relapse and a persistent symptomatic course, and between the regions in the duration of remission. Overall, Latin America, East Asia, and North Africa & Middle East had more favorable outcomes because they had the largest proportion of people who achieved continuous remission, the longest time in remission and lowest percentage with a persistent symptomatic course. Having good social functioning at baseline was consistently associated with better clinical outcome. These results seem to indicate that patients from Latin America, East Asia, North Africa & Middle East may have a more favorable disease course than patients from European nations.

Predicting future suicide attempts among depressed suicide ideators: A 10-year longitudinal study - Corrected Proof

Alexis M. May, E. David Klonsky, Daniel N. Klein — 2012-05-11

Abstract: Suicidal ideation and attempts are a major public health problem. Research has identified many risk factors for suicidality; however, most fail to identify which suicide ideators are at greatest risk of progressing to a suicide attempt. Thus, the present study identified predictors of future suicide attempts in a sample of psychiatric patients reporting suicidal ideation. The sample comprised 49 individuals who met full DSM-IV criteria for major depressive disorder and/or dysthymic disorder and reported suicidal ideation at baseline. Participants were followed for 10 years. Demographic, psychological, personality, and psychosocial risk factors were assessed using validated questionnaires and structured interviews. Phi coefficients and point-biserial correlations were used to identify prospective predictors of attempts, and logistic regressions were used to identify which variables predicted future attempts over and above past suicide attempts. Six significant predictors of future suicide attempts were identified – cluster A personality disorder, cluster B personality disorder, lifetime substance abuse, baseline anxiety disorder, poor maternal relationship, and poor social adjustment. Finally, exploratory logistic regressions were used to examine the unique contribution of each significant predictor controlling for the others. Comorbid cluster B personality disorder emerged as the only robust, unique predictor of future suicide attempts among depressed suicide ideators. Future research should continue to identify variables that predict transition from suicidal thoughts to suicide attempts, as such work will enhance clinical assessment of suicide risk as well as theoretical models of suicide.

Identifying comorbid depression and disruptive behavior disorders: Comparison of two approaches used in adolescent studies - Corrected Proof

2012-05-10

Abstract: Interest in commonly co-occurring depression and disruptive behavior disorders in children has yielded a small body of research that estimates the prevalence of this comorbid condition and compares children with the comorbid condition and children with depression or disruptive behavior disorders alone with respect to antecedents and outcomes. Prior studies have used one of two different approaches to measure comorbid disorders: 1) meeting criteria for two DSM or ICD diagnoses or 2) scoring .5 SD above the mean or higher on two dimensional scales. This study compares two snapshots of comorbidity taken simultaneously in the same sample with each of the measurement approaches. The Developmental Pathways Project administered structured diagnostic interviews as well as dimensional scales to a community-based sample of 521 11–12 year olds to assess depression and disruptive behavior disorders. Clinical caseness indicators of children identified as “comorbid” by each method were examined concurrently and 3-years later. Cross-classification of adolescents via the two approaches revealed low agreement. When other indicators of caseness, including functional impairment, need for services, and clinical elevations on other symptom scales were examined, adolescents identified as comorbid via dimensional scales only were similar to those who were identified as comorbid via DSM-IV diagnostic criteria. Findings suggest that when relying solely on DSM diagnostic criteria for comorbid depression and disruptive behavior disorders, many adolescents with significant impairment will be overlooked. Findings also suggest that lower dimensional scale thresholds can be set when comorbid conditions, rather than single forms of psychopathology, are being identified.

Frontal and right temporal activations correlate negatively with depression severity during verbal fluency task: A multi-channel near-infrared spectroscopy study - Corrected Proof

2012-05-10

Abstract: Multi-channel near-infrared spectroscopy (NIRS) is a noninvasive, on-the-spot, functional neuroimaging technique allowing detection of the spatiotemporal characteristics of brain activity. Previous NIRS studies indicated the oxy-hemoglobin (oxy-Hb) increase during a verbal fluency task (VFT) is attenuated in patients with major depressive disorder (MDD) as compared with healthy controls. However, the possible relationship between depression symptom severity and oxy-Hb change on NIRS has not yet been elucidated. To examine this relationship, we recruited 30 patients with MDD and 30 age-, gender- and intelligence quotient-matched controls. All underwent NIRS during VFT. As expected, the oxy-Hb increase during the task was significantly smaller in patients than in controls. After false discovery rate correction using 31 channels, the mean increase in oxy-Hb during the task showed a significant negative correlation with the total score of the Hamilton Rating Scale for Depression 21-item version (ch25: rho = −.56; FDR-corrected p: .001). When each item of the HAM-D21 was examined individually, insomnia early in 9 channels (rho = −.63 to −.46; FDR corrected p: .000–.014), work and activity in 2 channels (rho = −.61 to −.57; FDR corrected p: .001 to .003) and psychomotor retardation in 12 channels (rho = −.70 to −.44; FDR corrected p: .000–.018) showed significant negative correlations with the mean oxy-Hb increase in the right frontal temporal region. Although it is possible that our results were affected by medication, these data suggest reduced right frontal temporal activation on NIRS during VFT is related to the symptom severity of MDD.

Pre-trauma verbal ability at five years of age and the risk of post-traumatic stress disorder in adult males and females - Corrected Proof

Kim Steven Betts, Gail M. Williams, Jacob M. Najman, William Bor, Rosa Alati — 2012-05-10

Abstract: Previous studies have shown that high cognitive ability, measured in childhood and prior to the experience of traumatic events, is protective of PTSD development. Our aim was to test if the association between pre-trauma verbal ability ascertained at 5 years with DSM-IV lifetime post-traumatic stress disorder (PTSD) at 21 years was subject to effect modification by gender, trauma type or prior behaviour problems. Using a prospective birth cohort of young Australians, we found that both trauma type and behaviour problems did not change the association between cognitive ability and PTSD. During multivariate analysis, testing for the interactive effect of gender revealed that verbal ability was linearly and inversely associated with PTSD in females only, with those in the lowest verbal ability quintile having strongly increased odds of PTSD (OR=3.89: 95% CI; 1.50, 10.10) compared with those in the highest quintile. A graph of the interaction revealed lower verbal ability placed females, but not males, at an increased risk of PTSD. Our results indicate that lower verbal ability in early childhood is a vulnerability factor for PTSD in females but not in males, and may constitute a gender-specific risk factor responsible for part of the increased risk of PTSD found in females compared with males.

The relationship between risk-taking propensity and the COMT Val158Met polymorphism among early adolescents as a function of sex - Corrected Proof

2012-05-10

Abstract: Although adolescents frequently engage in a variety of risky behaviors, much remains unknown about the specific etiologies of such tendencies. Candidate genetic variants, such as the COMT Val158Met polymorphism, may be related to risk-taking propensity, particularly as this variant is linked to functional enzymatic differences influencing dopamine function in regions including the prefrontal cortex. The present study aimed to examine the COMT Val158Met variant in relation to risk-taking propensity in a community sample of youth. As part of a larger longitudinal study on adolescent risk behaviors, 223 youths (average age 11.3 years) from the metropolitan Washington D.C. area completed a measure of risk-taking propensity, the Balloon Analog Risk Task-Youth Version (BART-Y), and provided saliva samples for DNA extraction and genotyping. Results indicate that females, but not males, who are carriers of the COMT 158Met allele had higher risk-taking propensity scores on the BART-Y compared to Val homozygotes. Analyses were also conducted in the 111 European American participants, and results were consistent with those of the full sample analyses. This study represents the first investigation of a genetic substrate of risk-taking propensity, measured by a behavioral task, in youth. Results should be taken as quite preliminary, given the small sample. Implications are discussed.

Fatty acid composition in the postmortem amygdala of patients with schizophrenia, bipolar disorder, and major depressive disorder - Corrected Proof

Kei Hamazaki, Tomohito Hamazaki, Hidekuni Inadera — 2012-05-10

Abstract: Previous studies with postmortem brain tissues showed abnormalities in n-3 polyunsaturated fatty acids (PUFAs) in the orbitofrontal cortex of individuals with schizophrenia and mood disorders. However, in the hippocampus, we were not able to find any significant differences in PUFAs except for small differences in n-6 PUFAs. In the present study we investigated levels of PUFAs in the amygdala of postmortem brains from patients with schizophrenia, bipolar disorder, and major depressive disorder (MDD) compared with those of unaffected controls. Amygdala samples from patients with schizophrenia (n = 15), bipolar disorder (n = 15), or MDD (n = 15), and controls matched for age, sex, and five other confounding factors (n = 15) were analyzed for fatty acid composition by gas chromatography. In contrast to previous studies of the orbitofrontal cortex and hippocampus, we were unable to find any significant differences in major PUFAs. The relative compositions of docosahexaenoic acid (DHA), the major n-3 PUFA, were 10.0 ± 1.1%, 10.0 ± 1.3%, 9.3 ± 1.3%, and 9.7 ± 1.1%, respectively, in patients with schizophrenia, bipolar disorder, and MDD and unaffected controls (not significantly different). The corresponding relative compositions of arachidonic acid (AA), the major n-6 PUFA, were 9.0 ± 0.8%, 9.2 ± 0.5%, 9.4 ± 0.7%, and 9.4 ± 0.7%, respectively (not significantly different). Significant differences were found in some of the other fatty acids. In particular, we found a 6.5% increase in palmitic acid and 6.2% decrease in oleic acid in patients with MDD compared to controls. With regard to schizophrenia, there was an 8.0% decrease in docosatetraenoic acid compared to controls. In conclusion, the changes in DHA and/or AA seen in orbitofrontal cortex and hippocampus were not observed in amygdala. These changes may be specific to particular brain regions.

Functional MRI of the amygdala and bed nucleus of the stria terminalis during conditions of uncertainty in generalized anxiety disorder - Corrected Proof

Michael A. Yassa, Richard L. Hazlett, Craig E.L. Stark, Rudolf Hoehn-Saric — 2012-05-10

Abstract: Generalized anxiety disorder (GAD) is a common psychiatric disorder characterized by constant worry or anxiety over every day life activities and events. The neurobiology of the disorder is thought to involve a wide cortical and subcortical network that includes but is not limited to the amygdala and the bed nucleus of the stria terminalis (BNST). These two regions have been hypothesized to play different roles in stress and anxiety; the amygdala is thought to regulate responses to brief emotional stimuli while the BNST is thought to be involved in more chronic regulation of sustained anxiety. In this study, we exposed medication-free GAD patients as well as non-anxious controls to a gambling game where one of the conditions involved non-contingent monetary loss. This condition of high uncertainty was intended to elicit a stressful response and sustained anxiety. Functional MRI scans were collected simultaneously to investigate BOLD activity in the amygdala and BNST during performance of this task. Compared to controls, we found that GAD patients demonstrated decreased activity in the amygdala and increased activity in the BNST. Skin conductance measures showed a consistent early versus late effect within block where GAD patients demonstrated higher arousal than controls late in the task blocks. Based on these results, we hypothesize that GAD patients disengage the amygdala and its response to acute stress earlier than non-anxious controls making way for the BNST to maintain a more sustained response. Future studies are needed to investigate the temporal dynamics of activation and deactivation in these regions.

The administration of olanzapine and fluoxetine has synergistic effects on intracellular survival pathways in the rat brain - Corrected Proof

2012-05-10

Abstract: Recently, several studies have emerged suggesting a role of the intracellular survival pathways in the treatment of mood disorders. In addition, the beneficial effects of using a combination of antipsychotics and antidepressants have been shown. With this in mind, we evaluated the effects of the acute administration of fluoxetine (FLX), olanzapine (OLZ) and the combination of fluoxetine/olanzapine on the brain-derived-neurotrophic factor (BDNF), cAMP response element-binding (CREB), Protein Kinase B (PKB, Akt), B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated death promoter (BAD) in the rat brain. Adult Wistar rats received an acute injection of OLZ (3 or 6 mg/kg) and/or FLX (12.5 or 25 mg/kg), and were evaluated for Akt, BDNF, CREB, Bcl-2 and BAD protein levels in the prefrontal cortex, hippocampus and striatum. Our results showed that treatment with FLX and OLZ alone or in combination increased the Akt, CREB, BDNF, Bcl-2 and BAD levels in the prefrontal cortex, hippocampus and striatum. However, the combination of FLX and OLZ at high doses was associated with a greater increase in the levels of Akt in the prefrontal cortex, and did not have an effect on the levels of BAD in any of the brain areas that we evaluated. Finally, these findings further support the hypothesis that treatment with FLX and OLZ alone or in combination exert neuroprotective effects, and that intracellular survival pathways could be involved in the therapeutic effects of combining antipsychotic and antidepressant drugs in mood disorders.

Childhood trauma and platelet brain-derived neurotrophic factor (BDNF) after a three month follow-up in patients with major depressive disorder - Corrected Proof

2012-05-03

Abstract: A large amount of brain-derived neurotrophic factor (BDNF) is stored in the human platelets and only small amounts of it circulate in the plasma. However, a few studies have focused on platelet BDNF in patients with major depressive disorder (MDD) and childhood trauma. Our study population consisted of 105 MDD patients and 50 healthy controls. We used the Mini-International Neuropsychiatric Interview (M.I.N.I.), the Early Trauma Inventory Self Report-Short Form (ETISR-SF), as well as measured serum, plasma, and platelet BDNF at baseline, 1 month, and 3 month periods. There was a significant association between childhood trauma and platelet BDNF at baseline, 1 month, and 3 months, after adjusting for age, gender, education, body mass index, severity of depression, anxiety, alcohol consumption, and current stress. Conversely, plasma and serum BDNF did not have a significant association with childhood trauma. MDD patients revealed significantly higher levels of platelet BDNF in those with childhood trauma than in those without (t = 2.4, p = 0.018), and platelet BDNF was significantly higher in cases with sexual abuse on post-hoc analysis (p = 0.042). However, no significant differences were found in healthy controls, according to whether or not they had experienced childhood trauma. Platelet BDNF showed a significant correlation with severity of childhood trauma at baseline (r = 0.25, p = 0.012) and at 3 months (r = 0.38, p = 0.003) in MDD. In conclusion, platelet BDNF was significantly higher in MDD patients with childhood trauma than in those without, and it was correlated with severity of trauma.

Higher prefrontal cortical thickness in high schizotypal personality trait - Corrected Proof

Simone Kühn, Florian Schubert, Jürgen Gallinat — 2012-05-03

Abstract: A model of schizophrenia-spectrum disorders hypothesized that schizotypy shares biomarkers with schizophrenia but due to protective factors such as a greater prefrontal cortex those individuals have a reduced vulnerability to schizophrenia. In contrast to previous studies exploring volumetric brain correlates of schizotypy focussing on clinical samples or relying on between-group comparisons we measured cortical thickness and correlated it with the expression of schizotypal personality traits in a mentally healthy sample.We acquired high-resolution MRI scans from 34 subjects and used FreeSurfer to model the grey–white and pial surfaces for each individual cortex in order to compute the distance between these surfaces to obtain a measure of cortical thickness. Differences in cortical thickness were correlated with positive and negative factors of schizotypy as assessed by means of the Schizotypal Personality Questionnaire.We found a significant positive correlation between right dorso-lateral prefrontal cortex (DLPFC) and right dorsal premotor cortex/frontal eye fields (dPMC/FEF) and the total schizotypy score, between right DLPFC and the positive factor, and between right temporo-parietal junction and the negative factor of schizotypy. The volume of thalamus was negatively correlated with schizotypy. A significant negative correlation between thalamus volume and dPMC/FEF cortical thickness was observed.One may speculate that this finding is in line with the hypothesis of a compensatory role of greater prefrontal cortex in schizotypy in healthy populations.

The prospective relationship between sleep problems and suicidal behavior in the National Longitudinal Study of Adolescent Health - Corrected Proof

Maria M. Wong, Kirk J. Brower — 2012-05-03

Abstract: Objective: Previous research has found a longitudinal relationship between sleep problems and suicidal behavior while controlling for depression and other important covariates in a high risk sample of adolescents and controls. In this paper, we replicated this longitudinal relationship in a national sample and examined whether the relationship was partially mediated by depression, alcohol-related problems and other drug use.Methods: Study participants were 6504 adolescents from the National Longitudinal Study of Adolescent Health (ADD HEALTH).Results: In bivariate analyses, sleep problems (i.e., having trouble falling asleep or staying asleep) at Wave 1 were associated with suicidal thoughts and suicide attempts at Waves 1, 2, and 3 (W1, 2 and 3). In multivariate analyses, controlling for depression, alcohol problems, illicit drug use, and important covariates such as gender, age, and chronic health problems, sleep problems at a previous wave predicted suicidal thoughts and suicide attempts at a subsequent wave. In mediation analyses, W2 depression significantly mediated the effect of W1 sleep problems on W3 suicide thoughts. Moreover, W2 suicidal thoughts also significantly mediated the effect of W1 sleep problems on W3 suicidal attempts.Conclusions: Sleep problems appear to be a robust predictor of subsequent suicidal thoughts and attempts in adolescence and young adulthood. Having trouble falling sleeping or staying asleep had both direct and indirect effects (via depression and suicidal thoughts) on suicidal behavior. Future research could determine if early intervention with sleep disturbances reduces the risk for suicidality in adolescents and young adults.

Exploration of the associations between neurocognitive function and neuroleptics side effects - Corrected Proof

Samuel Suk-Hyun Hwang, Yeni Kim, Da Young Yun, Yong Sik Kim, Hee Yeon Jung — 2012-05-01

Abstract: The etiology of side effects of antipsychotic medications can be conceptualized as involving both specific pharmacological actions of a drug and any mental and physical states attributed by the patient. Both factors are likely to be linked with neurocognitive functioning which may largely affect the subjective experience of side effects in patients with schizophrenia. In this study, we examined whether baseline neurocognitive functions, such as IQ, attention, executive functioning, and short-term memory, are associated with baseline and 6-month follow-up measures of self-reported Liverpool University Neuroleptics Side Effects Scale (LUNSERS) and clinician-rated Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). At the baseline, anxiety and depression were significantly associated with LUNSERS red herring (RH) and total side effects (SE) but not with DIEPSS. There was no association between LUNSERS and DIEPSS. Controlling for anxiety and depression, IQ was significantly correlated with DIEPSS, while choice reaction time (CRT) and stop signal task (SST) direction errors correlated with RH, and intra–extradimensional set-shifting (IED) total errors and pre-extradimensional set-shifting (pre-EDs) errors correlated with SE. The baseline SST direction errors further correlated significantly with RH and SE and DIEPSS total score of 6-month follow-up, and CRT mean and SD correct latency also correlated with DIEPSS. The correlations between the 6-month changes (Δ) in the same side effects measures and baseline neurocognitive measures were also significant, except that between RH and SST direction errors. Such evidences supported association between both self-rated and clinician-rated side effects and selective impairments in attention and executive functioning.

Expression pattern of the cannabinoid receptor genes in the frontal cortex of mood disorder patients and mice selectively bred for high and low fear - Corrected Proof

2012-04-25

Abstract: Although the endocannabinoid system (ECS) has been implicated in brain development and various psychiatric disorders, precise mechanisms of the ECS on mood and anxiety disorders remain unclear. Here, we have investigated developmental and disease-related expression pattern of the cannabinoid receptor 1 (CB1) and the cannabinoid receptor 2 (CB2) genes in the dorsolateral prefrontal cortex (PFC) of humans. Using mice selectively bred for high and low fear, we further investigated potential association between fear memory and the cannabinoid receptor expression in the brain. The CB1, not the CB2, mRNA levels in the PFC gradually decrease during postnatal development ranging in age from birth to 50 years (r2 > 0.6 & adj. p < 0.05). The CB1 levels in the PFC of major depression patients were higher when compared to the age-matched controls (adj. p < 0.05). In mice, the CB1, not the CB2, levels in the PFC were positively correlated with freezing behavior in classical fear conditioning (p < 0.05). These results suggest that the CB1 in the PFC may play a significant role in regulating mood and anxiety symptoms. Our study demonstrates the advantage of utilizing data from postmortem brain tissue and a mouse model of fear to enhance our understanding of the role of the cannabinoid receptors in mood and anxiety disorders.

Course of comorbid anxiety disorders among adults with bipolar disorder in the U.S. population - Corrected Proof

2012-04-25

Abstract: Objective: To examine the prevalence and correlates of comorbid anxiety disorders among individuals with bipolar disorders (BP) and their association with prospectively ascertained comorbidities, treatment, and psychosocial functioning.Method: As part of the National Epidemiologic Survey on Alcohol and Related Conditions, 1600 adults who met lifetime DSM-IV criteria for BP-I (n = 1172) and BP-II (n = 428) were included. Individuals were evaluated using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DMS-IV Version and data was analyzed from Waves 1 and 2, approximately 3 years apart.Results: Sixty percent of individuals with BP had at least one lifetime comorbid anxiety disorder. Individuals with BP and anxiety disorders shared lifetime risk factors for major depressive disorder and had prospectively more depressive and manic/hypomanic episodes, suicidal ideation, suicide attempts, and more treatment seeking than those without anxiety. During the follow-up, higher incidence of panic disorder, drug use disorders, and lower psychosocial functioning were found in individuals with BP with versus without anxiety disorders.Conclusions: Anxiety disorders are prospectively associated with elevated BP severity and BP-related mental health service use. Early identification and treatment of anxiety disorders are warranted to improve the course and outcome of individuals with BP.

Brain-derived neurotrophic factor Val66Met polymorphism and obsessive-compulsive symptoms in Egyptian schizophrenia patients - Corrected Proof

Haytham M. Hashim, Nagy Fawzy, Mohab M. Fawzi, Rehab A. Karam — 2012-04-23

Abstract: Background: Brain-derived neurotrophic factor (BDNF) has been advanced as a candidate gene for schizophrenia. BDNF promote the function and growth of 5-HT neurons in the brain and modulate the synaptic plasticity of DRD3-secreting neurons in the striatum, suggesting involvement of BDNF in the mediation of obsessive-compulsive disorder.Objectives: To test the hypothesis that the BDNF Val66Met polymorphism influence obsessive-compulsive symptoms (OCS) in schizophrenia, we examined the association between the BDNF Val66Met genotypes and OCS in a group of patients with schizophrenia.Methods: 320 schizophrenia patients were assessed using the Yale–Brown Obsessive-Compulsive Scale (YBOCS). BDNF Val66Met polymorphism was genotyped using PCR-RFLP method, and severity of OCS were compared between the genotype groups.Results: Out of the 320 schizophrenia patients, 120 patients (37.5%) had significant OCS. There was a significant excess of valine allele in the schizophrenia with-OCS group compared to the without-OCS group. The mean YBOCS scores were significantly different among the three genotype groups. Val/Val homozygote patients had higher mean YBOCS scores compared to Val/Met genotype (p = 0.0001) as well as to the Met/Met homozygote group (p = 0.003).Conclusion: Our data suggested an association between BDNF Val66Met polymorphism and OCS in Egyptian schizophrenia patients.

Similarities in serum oxidative stress markers and inflammatory cytokines in patients with overt schizophrenia at early and late stages of chronicity - Corrected Proof

2012-04-23

Abstract: Schizophrenia (SZ) is a debilitating neurodevelopmental disorder that strikes at a critical period of a young person’s life. Its pathophysiology could be the result of deregulation of synaptic plasticity, with downstream alterations of inflammatory immune processes regulate by cytokines, impaired antioxidant defense and increased lipid peroxidation. The aim of this study was to examine serum oxidative stress markers and inflammatory cytokines in early and late phases of chronic SZ. Twenty-two patients at early stage (within first 10 years of a psychotic episode), 39 at late stage (minimum 10 years after diagnosis of SZ) and their respective matched controls were included. Each subject had 5ml blood samples collected by venipuncture to examined thiobarbituric acid-reactive substances (TBARS), total reactive antioxidant potential (TRAP), protein carbonyl content (PCC), Interleukins 6 and 10 (IL-6, IL-10) and tumor necrosis factor alpha (TNF-alpha). TBARS, IL-6 and PCC levels were significantly higher in patients with SZ at early and late stages than in controls. There were no differences for TRAP and TNF-alpha levels in patients with SZ at early and late stages than in controls. IL-10 levels were decreased in patients at late stage and a decrease trend in early stage was found. Results provided evidence consistent with comparable biological markers across chronic SZ. The concept of biochemical staging proposed by others for bipolar disorder is not seen in this cohort of patients with SZ, at least for cytokines and oxidative stress markers. Our findings reinforce the need of assessment of individuals in ultra high risk to develop psychosis and first-episode population.

Suicide ideators and attempters with schizophrenia – The role of 5-HTTLPR, rs25531, and 5-HTT VNTR Intron 2 variants - Corrected Proof

2012-04-20

Abstract: Aim: To examine the role of 5-HTTLPR, rs25531 and 5-HTT VNTR Intron 2 variants in subjects with psychotic disorders manifesting suicide ideation and behaviour.Methods: The study included 519 subsequently hospitalized subjects who were genotyped for 5-HTTLPR, rs25531 and 5-HTT VNTR In2 variants. Clinical assessments included structured psychiatric interview, sociodemographic characteristics, suicide ideation and behaviour (SIBQ), severity of psychopathology (PANSS) and depression (CDSS).Results: Three subgroups were identified: suicide attempters (N = 161), suicide ideators (N = 174) and subjects who never reported suicide ideation or behaviour (comparative group, N = 184). Major findings: 1) Suicide attempters scored highest on the CDSS, while no differences between the three clinical subgroups were detected in the PANSS scores; 2) Suicide attempters were more frequently the carriers of LA allele, while subjects in the comparative group were more frequently the carriers of low expression 5-HTTLPR/5-HTT rs25531 haplotype SLG; 3) No difference was found between the three clinical groups in the 5-HTT VNTR In2 variants; 4) Subjects with 5-HTTLPR/5-HTT rs25531 intermediate expression haplotype (LALG, SLA) scored higher on the PANSS general psychopathology subscale; 5) There was no association between suicide attempt or ideation and 5-HTTLPR/In2 or 5-HTTLPR/rs25531/In2 haplotype distribution.Conclusion: The suicide ideators, attempters and controls did not differ significantly in 5-HTTLPR or 5-HTT VNTR In 2 variants, but 5-HTTLPR/5-HTT rs25531 haplotype might be a useful genetic marker in distinguishing these three clinical groups.

Different serine and glycine metabolism in patients with schizophrenia receiving clozapine - Corrected Proof

Jaromir Hons, Martina Vasatova, Eva Cermakova, Pavel Doubek, Jan Libiger — 2012-04-16

Abstract: Dysfunction of the N-methyl-d-aspartate receptor, which is modulated by excitatory amino acids (EAA), is involved in the pathophysiology of schizophrenia. The effects of antipsychotics on EAA metabolism are uncertain. Positive clinical effects of treatment with antipsychotics were not always associated with changes in EAA serum levels in patients with schizophrenia in clinical trials. To examine EAA serum levels in relation to the intensity of psychotic symptoms and the type of medication received we compared these variables among patients with schizophrenia (n = 49) treated with first (FGA) or second (SGA) generation antipsychotics or clozapine. Glutamate, aspartate, glycine, total serine and d-serine serum levels were measured by High Performance Liquid Chromatography. The Positive and Negative Syndrome Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS) were used to assess symptoms of schizophrenia. Lower average levels of glycine and total serine were found in the serum of patients receiving clozapine when compared to the groups of patients treated with FGA or SGA. There were no differences in serum glutamate, aspartate or d-serine levels or in the intensity of schizophrenic symptoms assessed by PANSS or SANS among the groups of patients treated with FGA or SGA or clozapine. Lower glycine and total serine serum levels could be caused by the particular characteristics of the population of patients receiving clozapine rather than as an effect of the clozapine. The results suggest selective deficiency of l-serine synthesis in the patients with resistance to non-clozapine treatment. It might be an unique biochemical and pathophysiological characteristic of the treatment-resistance in schizophrenia.

Neuropsychological functioning and social anhedonia: Three-year follow-up data from a longitudinal community high risk study - Corrected Proof

Alex S. Cohen, Shannon M. Couture, Jack J. Blanchard — 2012-04-16

Abstract: Social anhedonia is a promising vulnerability marker for schizophrenia-spectrum pathology. Prior research has demonstrated that individuals with psychometrically-defined social anhedonia show a range of “schizophrenia-like” neurocognitive abnormalities. However, this research is limited in that it is based largely on the study of college students. The present article reports findings from a longitudinal study of social anhedonia recruited from a community sample. As part of this study, a neurocognitive battery was administered at baseline and at three-year follow-up sessions to participants with (n = 78) versus without (n = 77) social anhedonia. Additional measures of global functioning and schizotypal, schizoid and paranoid schizophrenia-spectrum symptoms were also administered. Across groups, subjects showed significant improvement in neurocognitive functioning over time. Compared to controls, at follow-up, individuals with social anhedonia showed significantly poorer attentional vigilance and simple processing speed, but failed to evidence impairments in immediate or delayed verbal memory, immediate or delayed visual memory, visual or verbal working memory, olfaction or executive abilities. At follow-up, within the social anhedonia group, schizoid (and to a lesser extent, schizotypal) symptom severity was associated with a range of neurocognitive impairments. Neurocognitive impairments were generally not associated with paranoid symptoms or global functioning. Baseline neurocognitive performance was not significantly predictive of follow-up symptom severity or functioning. Collectively, these findings suggest that neurocognitive dysfunctions only characterize a subset of individuals with social anhedonia.

Increase in dopaminergic, but not serotoninergic, receptors in T-cells as a marker for schizophrenia severity - Corrected Proof

2012-04-13

Abstract: Schizophrenia is characterized by a slow deteriorating mental illness. Although the pathophysiology mechanisms are not fully understood, different studies have suggested a role for the immune system in the pathogenesis of schizophrenia. To date, an altered expression or signaling of neurotransmitters receptors is observed in immune cells during psychiatric disorders. In the present study, we investigated the expression of different serotonin and dopamine receptors in T-cells of schizophrenic and control patients. We used flow cytometry to determine the pattern of expression of dopamine (D2 and D4) and serotonine receptors (SR1A, SR1C, SR2A, SR2B), as well as serotonin transporter (ST), in T-cell subsets (CD4 and CD8). Expression of serotonin receptors and ST in T-cells of schizophrenic patients were not different from controls. However, the percentages of CD4+D4+ and CD8+D4+ were increased in schizophrenic patients as compared to controls. In addition, increased percentages of CD8+D2+ cells were also observed in schizophrenic patients, albeit this population revealed lower CD4+D2+ cells in comparison to controls. Interestingly, a relationship between clinical symptoms and immunological parameters was also observed. We showed that the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS) and the Abnormal Involuntary Movement Scale (AIMS) were positively related to CD8+D2+ cells, though AIMS was inversely related to CD4+D4+ cells. In conclusion, the alteration in the pattern of cell population and molecules expressed by them might serve as a promising biomarker for diagnosis of schizophrenia.

Do the same factors predict outcome in schizophrenia and non-schizophrenia syndromes after first-episode psychosis? A two-year follow-up study - Corrected Proof

2012-04-09

Abstract: Objective: The aim of this two-year longitudinal study was to identify the best baseline predictors of functional outcome in first-episode psychosis (FEP). We tested whether the same factors predict functional outcomes in two different subsamples of FEP patients: schizophrenia and non-schizophrenia syndrome groups.Methods: Ninety-five patients with FEP underwent a full clinical evaluation (i.e., PANSS, Mania, Depression and Insight). Functional outcome measurements included the WHO Disability Assessment Schedule (DAS-WHO), Global Assessment of Functioning (GAF) and Clinical Global Impression (CGI). Estimation of cognition was obtained by a neuropsychological battery which included attention, processing speed, language, memory and executive functioning.Results: Greater severity of visuospatial functioning at baseline predicted poorer functional outcome as measured by the three functional scales (GAF, CGI and DAS-WHO) in the pooled FEP sample (explaining ut to the 12%, 9% and 10% of the variance, respectively). Negative symptoms also effectively contributed to predict GAF scores (8%). However, we obtained different predictive values after differentiating sample diagnoses. Processing speed significantly predicted most functional outcome measures in patients with schizophrenia, whereas visuospatial functioning was the only significant predictor of functional outcomes in the non-schizophrenia subgroup. Conclusions: Our results suggest that processing speed, visuospatial functioning and negative symptoms significantly (but differentially) predict outcomes in patients with FEP, depending on their clinical progression. For patients without a schizophrenia diagnosis, visuospatial functioning was the best predictor of functional outcome. The performance on processing speed seemed to be a key factor in more severe syndromes. However, only a small proportion of the variance could be explained by the model, so there must be many other factors that have to be considered.

The cognitive profile of aripiprazole differs from that of other atypical antipsychotics in schizophrenia patients - Corrected Proof

2012-04-05

Abstract: We investigated the effects of the atypical antipsychotics risperidone, olanzapine, and aripiprazole on the cognitive functions of Japanese patients with schizophrenia with respect to dosage amounts and dosing schedules. We performed a cross-sectional survey using the Brief Assessment of Cognition in Schizophrenia – Japanese Language Version (BACS-J) to evaluate the neurocognitive functions of 101 schizophrenic patients who took the same dose of one of the three aforementioned antipsychotics for at least 3 months. The BACS-J composite score correlated negatively with the prescribed dosages of risperidone and olanzapine. In contrast, we did not find a correlation between the BACS-J composite score and the prescribed dosage of aripiprazole. Moreover, the primary scores for verbal learning, motor function, and attention and processing speed were significantly lower among the patients who were taking the prescribed dosage of risperidone. The scores for verbal learning and motor function were also significantly lower when correlated with the prescribed dosage of olanzapine. We did not find a correlation between any of the primary scores on the BACS-J and the prescribed dosage of aripiprazole. In fact, the results suggest there is no linear relationship between the dose of aripiprazole and cognitive impairment, which may be due to its unique pharmacological profile.

Striatal activity in borderline personality disorder with comorbid intermittent explosive disorder: Sex differences - Corrected Proof

2012-04-05

Abstract: Borderline Personality Disorder (BPD) is associated with behavioral and emotional dysregulation, particularly in social contexts; however, the underlying pathophysiology at the level of brain function is not well understood. Previous studies found abnormalities in frontal cortical and limbic areas suggestive of poor frontal regulation of downstream brain regions. However, the striatum, which is closely connected with the medial frontal cortices and plays an important role in motivated behaviors and processing of rewarding stimuli, has been understudied in BPD. Here we hypothesized that, in addition to frontal dysfunction, BPD patients may show abnormal striatal function. In this study, 38 BPD patients with intermittent explosive disorder (BPD-IED) and 36 healthy controls (HC) participated in the Point Subtraction Aggression Paradigm (PSAP), a computer game played with a fictitious other player. 18Fluoro-deoxyglucose positron emission tomography (FDG-PET) measured relative glucose metabolism (rGMR) within caudate and putamen in response to aggression-provoking and non-provoking versions of the PSAP. Male BPD-IED patients had significantly lower striatal rGMR than all other groups during both conditions, although male and female BPD-IED patients did not differ in clinical or behavioral measures. These sex differences suggest differential involvement of frontal-striatal circuits in BPD-IED, and are discussed in relation to striatal involvement in affective learning and social decision-making.

Behaviorally-indexed distress tolerance and suicidality - Corrected Proof

Michael D. Anestis, Thomas E. Joiner — 2012-04-05

Abstract: Research indicates that distress tolerance exhibits a complicated relationship with risk factors for suicidal behavior. Specifically, low self-reported distress tolerance has been linked to perceived burdensomeness and thwarted belongingness. Contrastingly, high self-reported distress tolerance has been linked to the acquired capability for suicide. Given the frequently discrepant findings between self-report and behavioral indices of distress tolerance, we sought to expand upon prior findings by testing these relationships utilizing a behavioral measure of distress tolerance. Additionally, in an effort to further clarify the role of distress tolerance relative to painful and/or provocative experiences in the acquired capability, we examined whether distress tolerance serves as a moderator. Results revealed no significant associations between distress tolerance and burdensomeness or belongingness; however, distress tolerance was positively associated with the acquired capability. Furthermore, the interaction of distress tolerance and painful and/or provocative experiences significantly predicted the acquired capability, with the strength of the association increasing at higher levels of distress tolerance. Results highlight the potential importance of perceived versus actual ability to tolerate distress with respect to suicidal desire. In contrast, the results reflect the importance of actual persistence in the acquired capability.

Differential relationships of impulsivity or antisocial symptoms on P50, N100, or P200 auditory sensory gating in controls and antisocial personality disorder - Corrected Proof

2012-04-05

Abstract: Limited information is available on the relationship between antisocial personality disorder (ASPD) and early filtering, or gating, of information, even though this could contribute to the repeatedly reported impairment in ASPD of higher-order information processing. In order to investigate early filtering in ASPD, we compared electrophysiological measures of auditory sensory gating assessed by the paired-click paradigm in males with ASPD (n = 37) to healthy controls (n = 28). Stimulus encoding was measured by P50, N100, and P200 auditory evoked potentials; auditory sensory gating (ASG) was measured by a reduction in amplitude of evoked potentials following click repetition. Effects were studied of co-existing past alcohol or drug use disorders, ASPD symptom counts, and trait impulsivity. Controls and ASPD did not differ in P50, N100, or P200 amplitude or ASG. Past alcohol or drug use disorders had no effect. In controls, impulsivity related to improved P50 and P200 gating. In ASPD, P50 or N100 gating was impaired with more symptoms or increased impulsivity, respectively, suggesting impaired early filtering of irrelevant information. In controls the relationship between P50 and P200 gating and impulsivity was reversed, suggesting better gating with higher impulsivity scores. This could reflect different roles of ASG in behavioral regulation in controls versus ASPD.

Clinical features of obsessive-compulsive disorder with hoarding symptoms: A multicenter study - Corrected Proof

2012-04-05

Abstract: Background: Factor analyses indicate that hoarding symptoms constitute a distinctive dimension of obsessive-compulsive disorder (OCD), usually associated with higher severity and limited insight. The aim was to compare demographic and clinical features of OCD patients with and without hoarding symptoms.Method: A cross sectional study was conducted with 1001 DSM-IV OCD patients from the Brazilian Research Consortium of Obsessive-Compulsive Spectrum Disorders (CTOC), using several instruments. The presence and severity of hoarding symptoms were determined using the Dimensional Yale-Brown Obsessive-Compulsive Scale. Statistical univariate analyses comparing factors possibly associated with hoarding symptoms were conducted, followed by logistic regression to adjust the results for possible confounders.Results: Approximately half of the sample (52.7%, n = 528) presented hoarding symptoms, but only four patients presented solely the hoarding dimension. Hoarding was the least severe dimension in the total sample (mean score: 3.89). The most common lifetime hoarding symptom was the obsessive thought of needing to collect and keep things for the future (44.0%, n = 440). After logistic regression, the following variables remained independently associated with hoarding symptoms: being older, living alone, earlier age of symptoms onset, insidious onset of obsessions, higher anxiety scores, poorer insight and higher frequency of the symmetry-ordering symptom dimension. Concerning comorbidities, major depressive, posttraumatic stress and attention deficit/hyperactivity disorders, compulsive buying and tic disorders remained associated with the hoarding dimension.Conclusion: OCD hoarding patients are more likely to present certain clinical features, but further studies are needed to determine whether OCD patients with hoarding symptoms constitute an etiologically discrete subgroup.

Dopamine response to psychosocial stress in humans and its relationship to individual differences in personality traits - Corrected Proof

2012-04-05

Abstract: Background: Previous studies have reported inter-individual variability in the dopamine (DA) response to stress. This variability might be related to individual differences in the vulnerability to experience the negative effect of stress.Objective: To investigate whether personality traits as measured by the Revised NEO Personality Inventory explain variability in DA response to a psychosocial stress task.Methods: Eleven healthy adults, mean age of 26 ± 3.87 underwent two Positron Emission Tomography (PET) scans using the dopamine D2/3 agonist, [11C]-(+)-PHNO under a control and stress condition. The Simplified Reference Tissue Model (SRTM) was used to obtain [11C]-(+)-PHNO Binding Potential (BPND). Stress-induced DA response was indexed as a percent change in [11C]-(+)-PHNO BPND between control and stress conditions. The regions of interest were defined into D2-rich regions, which included the Associative and Sensorimotor Striatum (AST and SMST); D2/3 mixed regions, which included the Limbic Striatum (LST) and Globus Pallidus (GP); and D3-rich region, which included the Substantia Nigra (SN).Results: Several personality traits within the Neuroticism and Openness to Experience domain were significantly correlated with blunted DA response to stress. Specifically, the Angry-Hostility, Vulnerability, and Depression trait were associated with blunted DA stress response in the AST (r = −0.645, p = 0.032), LST (r = −0.677, p = 0.022) and GP (r = −0.736, p = 0.010), respectively. The Openness to Values was correlated with a decreased DA release in the SN (r = −0.706, p = 0.015).Conclusion: Variability in DA stress response might be related to individual differences in personality.

The latent structure of attention deficit/hyperactivity disorder in an adult sample - Corrected Proof

David K. Marcus, Alyssa L. Norris, Emil F. Coccaro — 2012-04-05

Abstract: The vast majority of studies that have examined the latent structure of attention deficit/hyperactivity disorder (ADHD) in children and adolescents have concluded that ADHD has a dimensional latent structure. In other words, ADHD symptomatology exists along a continuum and there is no natural boundary or qualitative distinction (i.e., taxon) separating youth with ADHD from those with subclinical inattention or hyperactivity/impulsivity problems. Although adult ADHD appears to be less prevalent than ADHD in youth (which could suggest a more severe adult ADHD taxon), researchers have yet to examine the latent structure of ADHD in adults. The present study used a sample (N = 600) of adults who completed a self-report measure of ADHD symptoms. The taxometric analyses revealed a dimensional latent structure for inattention, hyperactivity/impulsivity, and ADHD. These findings are consistent with previous taxometric studies that examined ADHD in children and adolescents, and with contemporary polygenic and multifactorial models of ADHD.

The burden of full and subsyndromal posttraumatic stress disorder among police involved in the World Trade Center rescue and recovery effort - Corrected Proof

2012-04-05

Abstract: Background: This study examined the prevalence, correlates, and perceived mental healthcare needs associated with subsyndromal PTSD in police involved in the World Trade Center (WTC) rescue and recovery effort.Methods: A total of 8466 police completed an interview/survey as part of the WTC Medical monitoring and Treatment Program an average of four years after 9/11/2001.Results: The past month prevalence of full and subsyndromal WTC-related PTSD was 5.4% and 15.4%, respectively. Loss of someone or knowing someone injured on 9/11 (odds ratios [ORs]=1.56–1.86), pre-9/11 stressors (ORs=1.30–1.50), family support (ORs=0.83–0.94), and union membership (ORs=0.50–0.52) were associated with both full and subsyndromal PTSD. Exposure to the dust cloud (OR=1.36), performing search and rescue work (OR=1.29), and work support (OR=0.89) were additionally associated with subsyndromal PTSD. Rates of comorbid depression, panic disorder, and alcohol use problems (ORs=3.82–41.74), and somatic symptoms and functional difficulties (ORs=1.30–1.95) were highest among police with full PTSD, with intermediate rates among police with subsyndromal PTSD (ORs=2.93–7.02; and ORs=1.18–1.60, respectively). Police with full and subsyndromal PTSD were significantly more likely than controls to report needing mental healthcare (41.1% and 19.8%, respectively, versus 6.8% in trauma controls).Conclusions: These results underscore the importance of a more inclusive and dimensional conceptualization of PTSD, particularly in professions such as police, as operational definitions and conventional screening cut-points may underestimate the psychological burden for this population. Accordingly, psychiatric clinicians should assess for disaster-related subsyndromal PTSD symptoms in disaster response personnel.

Recovery and subsequent recurrence in patients with recurrent major depressive disorder - Corrected Proof

Boadie W. Dunlop, Peter Holland, Weihang Bao, Philip T. Ninan, Martin B. Keller — 2012-04-04

Abstract: In contrast to “remission” from an episode of major depressive disorder (MDD), for which there is general agreement in the literature, the optimal definition of “recovery” from MDD is uncertain. Previous definitions of recovery have used inconsistent thresholds for symptom severity and duration of wellness. To address the effects of duration and degree of recovery from an episode of MDD on recurrence risk, and the impact of maintenance antidepressant treatment on recurrence, we analyzed 258 patients from a randomized, double-blind study of outpatients with recurrent MDD. All patients had responded to 8½ months of venlafaxine extended release and were subsequently randomized to receive venlafaxine ER or placebo during 2 consecutive 12-month maintenance phases. Four definitions of recovery were used to evaluate recovery rates and time to recurrence: (1) 17-item Hamilton Depression Rating Scale (HAM-D17) total score ≤3 with duration ≥120 days; (2) HAM-D17 ≤3 with duration ≥56 days; (3) HAM-D17 ≤7 with duration ≥120 days; and (4) HAM-D17 ≤7 with duration ≥56 days. Recovery definitions using lower symptom severity and longer duration thresholds produced lower rates of recurrence. Patients on placebo were more likely to have a recurrence than patients on venlafaxine ER, with hazard ratio (HR) ranging from 2.5 among patients who recovered by the most relaxed criteria (definition 4), to 5.3 among patients who recovered by the most stringent criteria (definition 1). We conclude that protection against recurrence derives from the degree and duration of recovery, particularly for patients maintained on antidepressant medication.

Downregulation of TOMM40 expression in the blood of Alzheimer disease subjects compared with matched controls - Corrected Proof

2012-04-03

Abstract: Translocase of outer mitochondrial membrane 40 homolog (TOMM40) gene has been reported in several GWAS to be associated with Alzheimer disease (AD). Gene expression studies thus far only showed TOMM40 differential expression in one study on brain cortex and not in peripheral blood. We studied the gene expression profiles of AD blood versus controls in an Asian population in Singapore. In this first analysis we focused on genes that have been previously reported on GWAS. We found TOMM40 to be significantly down-regulated in blood samples of AD in one discovery and two validation sets, totalling 45 subjects (mean age 76.90, SD 6.46) and 45 controls (mean age 76.23, SD 5.09), matched for ethnicity and gender. The function of TOMM40 is not yet fully characterized but is believed to be involved in import and trafficking of protein into mitochondria. Therefore TOMM40 downregulation, found in the brain in severe AD and in our blood profile, may be a potential marker for AD, disease severity or progression and merit further investigation.

Is puberty a trigger for 5HTTLPR polymorphism association with depressive symptoms? - Corrected Proof

2012-04-03

Adolescence is not only a critical period for depression onset, but also the period that gender became a risk factor for depression susceptibility (). Puberty is one of the most important landmarks of adolescence with clear consequences in emotion regulation, thinking and behavior. During puberty, steroid hormones trigger various brain circuits remodeling responses for functional and structural changes (). The serotonin transporter gene promoter polymorphism (5HTTLPR) has been implicated as a moderator of the effects of psychosocial stressors in depression in several studies (). Furthermore, there is clinical () and animal () evidence for age-related developmental moderation of serotonergic pathways. The aim of this study was to test whether the 5HTTLPR polymorphism would be associated with depressive symptoms in adolescents in different stages of development. We hypothesized that low functional variants would be associated with higher depressive symptoms only in post-pubertal adolescents.

Life stressors, emotional distress, and trauma-related thoughts occurring in the 24 h preceding active duty U.S. Soldiers' suicide attempts - Corrected Proof

Craig J. Bryan, M. David Rudd — 2012-04-02

Abstract: External life events and internal experiences (i.e., emotional distress and trauma-related thoughts) occurring in the 24 h preceding suicide attempts were examined in a sample of active duty U.S. Soldiers. Seventy-two Soldiers (66 male, 6 female; 65.3% Caucasian, 9.7% African-American, 2.8% Asian, 2.8% Pacific Islander, 4.2% Native American, and 9.7% “other”; age M = 27.34, SD = 6.50) were interviewed using the Suicide Attempt Self Injury Interview to assess the occurrence of external events and internal experiences on the day of their suicide attempts, and to determine their associations with several dimensions of suicide risk: suicidal intent, lethality, and deliberation about attempting. Multiple external stressors and internal states were experienced by Soldiers in the 24 h preceding their suicide attempts, with emotional distress being the most common. Trauma-related thoughts were much less frequently reported in the 24 h preceding suicide attempts. Emotional experiences were directly associated with suicidal intent, and explained the relationship between external events and suicidal intent. Lethality was unrelated to any external events, emotional experiences, or trauma-related thoughts. Greater emotional distress and trauma-related thoughts were associated with shorter deliberation about whether or not to attempt suicide. Soldiers experience multiple sources of distress in the period immediately preceding their suicide attempts. Soldiers who experience more negative emotional experiences have a stronger desire for suicide and spend less time deliberating before an attempt.

Ginkgo biloba extract EGb 761® in dementia with neuropsychiatric features: A randomised, placebo-controlled trial to confirm the efficacy and safety of a daily dose of 240 mg - Corrected Proof

2012-03-29

Abstract: A multi-centre, double-blind, randomised, placebo-controlled, 24-week trial with 410 outpatients was conducted to demonstrate efficacy and safety of a 240 mg once-daily formulation of Ginkgo biloba extract EGb 761® in patients with mild to moderate dementia (Alzheimer's disease or vascular dementia) associated with neuropsychiatric symptoms. Patients scored 9 to 23 on the SKT cognitive battery, at least 6 on the Neuropsychiatric Inventory (NPI), with at least one of four key items rated at least 4. Primary outcomes were the changes from baseline to week 24 in the SKT and NPI total scores. The ADCS Clinical Global Impression of Change (ADCS-CGIC), Verbal Fluency Test, Activities of Daily Living International Scale (ADL-IS), DEMQOL-Proxy quality-of-life scale and 11-point box scales for tinnitus and dizziness were secondary outcome measures. Patients treated with EGb 761® (n = 200) improved by 2.2 ± 3.5 points (mean ± sd) on the SKT total score, whereas those receiving placebo (n = 202) changed only slightly by 0.3 ± 3.7 points. The NPI composite score improved by 4.6 ± 7.1 in the EGb 761®-treated group and by 2.1 ± 6.5 in the placebo group. Both drug-placebo comparisons were significant at p < 0.001. Patients treated with EGb 761® also showed a more favourable course in most of the secondary efficacy variables. In conclusion, treatment with EGb 761® at a once-daily dose of 240 mg was safe and resulted in a significant and clinically relevant improvement in cognition, psychopathology, functional measures and quality of life of patients and caregivers.

The dopamine b-hydroxylase 19 bp insertion/deletion polymorphism was associated with first-episode but not medicated chronic schizophrenia - Corrected Proof

2012-03-26

Abstract: Background: Numerous studies report dysfunctional dopaminergic and noradrenergic neurotransmission in the pathogenesis of schizophrenia. Dopamine beta-hydroxylase (DBH) is an intracellular enzyme catalyzing the conversion of dopamine to noradrenaline. Functional polymorphisms have been reported in the promoter region of DBH gene, including a 19 bp insertion/deletion polymorphism. The purpose of this study was to investigate whether there was an association between the functional polymorphism (DBH5′-Ins/Del) and schizophrenia in a Han Chinese population.Methods: This polymorphism was genotyped in 221 first-episode schizophrenics, 360 chronic schizophrenics and 318 healthy controls using a case-control design. We assessed their psychopathology using the Positive and Negative Syndrome Scale (PANSS).Results: We showed that the DBH5′-Ins/Del deletion (Del) allelic and genotypic frequencies were significantly lower in controls than first-episode of schizophrenics (FES) (both p < 0.001), but controls were not different from chronic schizophrenics. Furthermore, the PANSS positive symptom and total scores were significantly higher in FES with the Del/Del genotype than those with Ins/Del and Ins/Ins genotypes (all p < 0.05).Conclusions: The DBH5′-Ins/Del polymorphism may play a role in susceptibility to the positive symptoms of FES and to these FES not progressing on to chronic schizophrenia.

A cost-consequence analysis of long-acting injectable risperidone in schizophrenia: A one-year mirror-image study with national claim-based database in Taiwan - Corrected Proof

Hui-Chih Chang, Chao-Hsiun Tang, Sheng-Tzu Huang, Paul McCrone, Kuan-Pin Su — 2012-03-23

Abstract: Objective: The development of long-acting atypical antipsychotics has provided a new paradigm for schizophrenia treatment. The economic effectiveness of risperidone long-acting injection (RLAI) on service costs has, however, never been studied in the real world with national claim-based database.Method: To assess the change of service utilization and costs for schizophrenia before and after RLAI treatment, we conducted this 1-year mirror-image study with Taiwanese national claimed-data. Comparison was made for service sectors (the number of visits, acute admissions and relapse events) and cost components (outpatient, inpatient, emergency, medication and non-medication costs).Results: Service uses reduced in the post-RLAI period, along with a reduction of 34% and 32% on total inpatient services costs and inpatient non-medication costs, respectively (p < 0.005). However, overall psychiatric service costs went up by 26%, with an increase of 190% on total outpatient service costs and 177% on overall medication costs (p < 0.0001).Conclusions: This 1-year mirror-image analysis showed that RLAI treatment was associated with reductions of service uses; however, overall psychiatric service costs were compromised by costs incurred from increased utilization of outpatient service and RLAI medication costs under the context of healthcare in Taiwan.

Temporal analysis of heart rate variability as a predictor of post traumatic stress disorder in road traffic accidents survivors - Corrected Proof

2012-03-19

Abstract: Background: Road Traffic Accidents (RTA) are most probably the leading cause of post traumatic stress disorder (PTSD) in developed countries. The autonomic nervous system (ANS) disturbances, due to psychological trauma, are part of the pathophysiology of PTSD. The aim of the present study was to determine whether early heart rate variability (HRV) measurement, a biomarker of the ANS function, could act as a predictor of PTSD development after a RTA.Methods: We prospectively investigated 35 survivors of RTA with both physical injury and psychological trauma. HRV data were obtained from 24-h Holter ECG monitoring, which was performed on the second day after the accident. Time domain analysis was applied to the inter-beat (RR) interval time series to calculate the various parameters of HRV. PTSD status was assessed 2 and 6 months after RTA.Results: There was a global diminution of HRV measurements in the PTSD group at both 2 and 6 months. The variability index was the best predictor of PTSD with the area under the receiveroperating curve for discriminating PTSD at 6 months at 0.92 (95% CI: 0.785; 1.046). A cut-off at 2.19% yielded a sensitivity of 85.7% and a specificity of 81.8% for PTSD. Positive and negative predictive values were respectively 75% and 90%. However, initial heart rate (HR) data were relevant at 2 months but not at 6 months.Conclusion: RTA survivors exhibiting lower parasympathetic modulation of HR, indexed by temporal analysis of HRV, are more susceptible to developing PTSD as a short and long-term outcome.

Changes in facial electromyographic activity in spider-phobic girls after psychotherapy - Corrected Proof

Verena Leutgeb, Anne Schienle — 2012-03-19

Abstract: Recent studies of spider phobia have indicated that disgust is a crucial disorder-relevant emotion and that the facial electromyogram (EMG) of the levator labii region is a reliable disgust indicator. The present investigation focused on EMG effects of psychotherapy in thirty girls (aged between 8 and 14 years) suffering from spider phobia. They were presented with phobia-relevant, generally fear-inducing, disgust-inducing and affectively neutral pictures in a first EMG session. Subsequently, patients were randomly assigned to either a therapy group or a waiting-list group. Therapy-group participants received a single session of exposure therapy in vivo. One week later a second EMG session was conducted. Patients of the waiting-list group received exposure therapy after the second EMG session. After therapy, the girls were able to hold a living spider in their hands and rated spiders more positive, and less arousing, fear- and disgust-inducing. Moreover, they showed a reduction of average levator labii activity in response to pictures of spiders, reflecting the reduction of feelings of disgust. A positive side effect of the therapy was a significant drop in overall disgust proneness and a decreased average activity of the levator labii muscle in response to generally disgust-inducing pictures. Results emphasize the role of disgust feelings in spider-phobic children and suggest that overall disgust proneness should also be targeted in therapy.

Increased expression of the spliced DDR1c isoform in brain tissues from schizophrenia patients - Corrected Proof

Bàrbara Roig, Nerea Abasolo, Sílvia Moyano, Lourdes Martorell, Elisabet Vilella — 2012-03-15

An allelic association between the Discoidin domain receptor 1 (DDR1) variant rs1049623 and schizophrenia suggests that DDR1 is a schizophrenia susceptibility gene. This genetic association is confirmed in the DDR1 haplotype composed of the DDR1 variants rs1049623, rs2267641 and rs2239518 (). DDR1 is present in the human myelin fibers of the central nervous system (CNS), specifically in oligodendrocyte cells, where the expression of myelin genes such as myelin-associated glycoprotein (MAG) and oligodendrocyte transcription factor 2 (OLIG2) positively correlates with that of DDR1 (). Alternative splicing of the human DDR1 gene generates five isoforms (DDR1a-e) () and previous studies suggest that the function of DDR1 may be isoform dependent (; ). However, studies examining the expression levels of the various DDR1 isoforms in human brain tissue remain scarce. Recently, we identified an A2 response element (A2RE), which is involved in RNA transport, in the sequence of the DDR1 gene. Furthermore, we found that the polymorphism that gives rise to DDR1 variant rs2267641 is located in the A2RE and that the expression of the DDR1b and DDR1c isoforms is differentially modulated in human brain tissues that have this variant (). Multiple lines of evidence have demonstrated that oligodendrocyte function and myelination are altered in the brain tissues of schizophrenic patients, mainly in the dorsolateral prefrontal cortex (DLPFC), and also in other brain regions (; ).

Contribution of spontaneous improvement to placebo response in depression: A meta-analytic review - Corrected Proof

2012-03-14

Abstract: Objectives: It is unknown to what degree spontaneous improvement accounts for the large placebo response observed in antidepressant trials for Major Depressive Disorder (MDD). The purpose of this study was to estimate the spontaneous improvement observed in treatment-seeking individuals with acute MDD by determining the symptom change in depressed patients assigned to wait-list controls in psychotherapy studies.Method: The databases PubMed and PsycINFO were searched to identify randomized, prospective studies randomizing outpatients to psychotherapy or a wait-list control condition for the treatment of acute MDD. Standardized effect sizes calculated from each identified study were aggregated in a meta-analysis to obtain a summary statistic for the change in depression scores during participation in a wait-list control.Results: Ten trials enrolling 340 participants in wait-list control conditions were identified. The estimated effect size for the change in depression scores during wait-list control was 0.505 (95% CI 0.271–0.739, p < 0.001), representing an average improvement of 4 points on the Hamilton Rating Scale for Depression.Discussion: Depressed patients acutely experience improvement even without treatment, but spontaneous improvement is unlikely to account for the magnitude of placebo response typically observed in antidepressant trials. These findings must be interpreted in light of the small number wait-list control participants available for analysis as well as certain methodological heterogeneity in the psychotherapy studies analyzed.