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To characterize neuronal mitochondrial abnormalities in major depressive disorder (MDD), functional mitochondrial proteins (MPs) extracted from enriched plasma neuron-derived extracellular vesicles (NDEVs) of MDD participants (n = 20) were quantified before and after eight weeks of treatment with a selective serotonin reuptake inhibitor (SSRI). Pretreatment baseline NDEV levels of the transcriptional type 2 nuclear respiratory factor (NRF2) which controls mitochondrial biogenesis and many anti-oxidant gene responses, regulators of diverse neuronal mitochondrial functions cyclophilin D (CYPD) and mitofusin-2 (MFN2), leucine zipper EF-hand containing transmembrane 1 protein (LETM1) component of a calcium channel/calcium channel enhancer, mitochondrial tethering proteins syntaphilin (SNPH) and myosin VI (MY06), inner membrane electron transport complexes I (subunit 6) and III (subunit 10), the penultimate enzyme of nicotinamide adenine dinucleotide (NAD) generation nicotinamide mononucleotide adenylytransferase 2 (NMNAT2), and neuronal mitochondrial metabolic regulatory and protective factors humanin and mitochondrial open-reading frame of the 12S rRNA-c (MOTS-c) all were significantly lower than those of NDEVs from matched controls (n = 10), whereas those of pro-neurodegenerative NADase Sterile Alpha and TIR motif-containing protein 1 (SARM1) were higher. The baseline NDEV levels of transcription factor A mitochondrial (TFAM) and the transcriptional master-regulator of mitochondrial biogenesis PPAR γ coactivator-1α (PGC-1α) showed no differences between MDD participants and controls. Several of these potential biomarker proteins showed substantially different changes in untreated MDD than those we reported in untreated first-episode psychosis. NDEV levels of MPs of all functional classes, except complex I-6, NRF2 and PGC-1α were normalized in MDD participants who responded to SSRI therapy (n = 10) but not in those who failed to respond (n = 10) by psychiatric evaluation. If larger studies validate NDEV MP abnormalities, they may become useful biomarkers and identify new drug targets.

Effective regulation of harmful environmental chemicals found in wide variety of consumer products and consumables has been thwarted by the lack of agreement between government scientists and university/academic laboratories regarding the quantification of significant human harms. This is particularly relevant regarding plastic-derived chemicals (PDCs), such as Bisphenol A, now that the federal CLARITY-BPA program has failed to achieve any credible, human-significant scientific consensus. Because of this disagreement, direct, clinical human experimental data is vital to resolving this situation. In an effort to develop direct human-relevant data, some academic investigators have employed dietary intervention studies in an attempt to shed light on the controversy. Unfortunately, dietary intervention efforts thus far have not demonstrated causality or replicability.Investigators of this study propose a novel human dietary intervention protocol that can be both replicable and causal. This first-of-a-kind dietary intervention study explores a potential causal relationship between human serum levels of BPA and High-Sensitivity C-Reactive Protein (hsCRP), a proven clinical indicator of inflammation. Investigators used the equivalent of a USDA-defined typical diet followed by a PDC-reduced diet to compare blood levels of hsCRP. This proof-of-concept investigation is the first to use an easily accessible, medically-accepted clinical laboratory test to directly measure human health effects of PDC reduction.Unexpected phenomena discovered during the investigation offer study protocol modifications to enhance widespread replicability, and economically practical expansion to a substantial proportion of the approximately 84,000 mostly unregulated chemicals found in the human environment. In addition, our LC/MS-MS results offer the first direct quantitative human clinical evidence (of which we are aware) confirming the existence of regrettable substitutions in which product manufacturers have reduced BPA usage while substituting Bisphenol analogues that appear to equal or exceed BPA human toxicity. Bolstered by the unexpected results in this proof-of-concept investigation, novel lessons and techniques described herein may further specific and improved methods and best practices that can enable future dietary interventions to produce replicable, causal human results.

BackgroundThe identification of geographic variation in incidence can be an important step in the delineation of disease risk factors, but has mostly been undertaken in upper-income countries. Here, we use Electronic Health Records (EHR) from a middle-income country, Colombia, to characterize geographic variation in major mental disorders.MethodWe leveraged geolocated EHRs of 16,295 patients at a psychiatric hospital serving the entire state of Caldas, all of whom received a primary diagnosis of bipolar disorder, schizophrenia, or major depressive disorder at their first visit. To identify the relationship between travel time and incidence of mental illness we used a zero-inflated negative binomial regression model. We used spatial scan statistics to identify clusters of patients, stratified by diagnosis and severity: mild (outpatients) or severe (inpatients).ResultsWe observed a significant association between incidence and travel time for outpatients (N = 11,077, relative risk (RR) = 0.80, 95% confidence interval (0.71, 0.89)), but not inpatients (N = 5,218). We found seven clusters of severe mental illness: the cluster with the most extreme overrepresentation of bipolar disorder (RR = 5.83, p < 0.001) has an average annual incidence of 8.7 inpatients per 10,000 residents, among the highest frequencies worldwide.ConclusionsThe hospital database reflects the geographic distribution of severe, but not mild, mental illness within Caldas. Each hotspot is a candidate location for further research to identify genetic or environmental risk factors for severe mental illness. Our analyses highlight how existing infrastructure from middle-income countries can be extraordinary resources for population studies.

BackgroundFor DSM – 5, the American Psychiatric Association Board of Trustees established a robust vetting and review process that included two review committees that did not exist in the development of prior DSMs, the Scientific Review Committee (SRC) and the Clinical and Public Health Committee (CPHC). The CPHC was created as a body that could independently review the clinical and public health merits of various proposals that would fall outside of the strictly defined scientific process.MethodsThis article describes the principles and issues which led to the creation of the CPHC, the composition and vetting of the committee, and the processes developed by the committee – including the use of external reviewers.ResultsOutcomes of some of the more involved CPHC deliberations, specifically, decisions concerning elements of diagnoses for major depressive disorder, autism spectrum disorder, catatonia, and substance use disorders, are described. The Committee's extensive reviews and its recommendations regarding Personality Disorders are also discussed.ConclusionsOn the basis of our experiences, the CPHC membership unanimously believes that external review processes to evaluate and respond to Work Group proposals is essential for future DSM efforts. The Committee also recommends that separate SRC and CPHC committees be appointed to assess proposals for scientific merit and for clinical and public health utility and impact.

BackgroundMajor depressive disorder (MDD) is associated with increased allostatic load (AL; a measure of physiological costs of repeated/chronic stress-responding) and metabolic dysregulation (MetD; a measure of metabolic health and precursor to many medical illnesses). Though AL and MetD are associated with poor somatic health outcomes, little is known regarding their relationship with antidepressant-treatment outcomes.MethodsWe determined pre-treatment AL and MetD in 67 healthy controls and 34 unmedicated, medically healthy MDD subjects. Following this, MDD subjects completed 8-weeks of open-label selective serotonin reuptake inhibitor (SSRI) antidepressant treatment and were categorized as ‘Responders’ (⩾50% improvement in depression severity ratings) or ‘Non-responders’ (ResultsPre-treatment AL and MetD scores significantly predicted continuous antidepressant response (i.e. absolute decreases in depression severity ratings) (p= 0.012 and 0.014, respectively), as well as post-treatment status as a Responder or Non-responder (p= 0.022 and 0.040, respectively), such that higher pre-treatment AL and MetD were associated with poorer SSRI-treatment outcomes. Pre-treatment AL and MetD of Responders were similar to Controls, while those of Non-responders were significantly higher than both Responders (p= 0.025 and 0.033, respectively) and Controls (p= 0.039 and 0.001, respectively).ConclusionsThese preliminary findings suggest that indices of metabolic and hypothalamic-pituitary-adrenal-axis dysregulation are associated with poorer SSRI-treatment response. To our knowledge, this is the first study to demonstrate that these markers of medical disease risk also predict poorer antidepressant outcomes.

DNA methylation patterns at specific cytosine-phosphate-guanine (CpG) sites predictably change with age and can be used to derive “epigenetic age”, an indicator of biological age, as opposed to merely chronological age. A relatively new estimator, called “DNAm GrimAge”, is notable for its superior predictive ability in older populations regarding numerous age-related metrics like time-to-death, time-to-coronary heart disease, and time-to-cancer. PTSD is associated with premature mortality and frequently has comorbid physical illnesses suggestive of accelerated biological aging. This is the first study to assess DNAm GrimAge in PTSD patients. We investigated the acceleration of GrimAge relative to chronological age, denoted “AgeAccelGrim” in combat trauma-exposed male veterans with and without PTSD using cross-sectional and longitudinal data from two independent well-characterized veteran cohorts. In both cohorts, AgeAccelGrim was significantly higher in the PTSD group compared to the control group (N = 162, 1.26 vs −0.57, p = 0.001 and N = 53, 0.93 vs −1.60 Years, p = 0.008), suggesting accelerated biological aging in both cohorts with PTSD. In 3-year follow-up study of individuals initially diagnosed with PTSD (N = 26), changes in PTSD symptom severity were correlated with AgeAccelGrim changes (r = 0.39, p = 0.049). In addition, the loss of CD28 cell surface markers on CD8 + T cells, an indicator of T-cell senescence/exhaustion that is associated with biological aging, was positively correlated with AgeAccelGrim, suggesting an immunological contribution to the accelerated biological aging. Overall, our findings delineate cellular correlates of biological aging in combat-related PTSD, which may help explain the increased medical morbidity and mortality seen in this disease.

Increased inflammation is reported in Major Depressive Disorder (MDD), which may be more pronounced in suicidal subjects. Vitamin D deficiency may drive this pro-inflammatory state due to vitamin D's anti-inflammatory effects.We quantified plasma 25-hydroxyvitamin D (25(OH)D) and inflammatory markers interleukin (IL)-6 and tumor necrosis factor (TNF)-α, and other inflammatory indices, neutrophil-to-lymphocyte ratio (NLR) and white blood cell count (WBC) in 48 un-medicated MDD subjects (n = 17 with mild-to-moderate suicidal ideation [SI]) and 54 controls. IL-6 and TNF-α were combined into a composite inflammation score.There were no significant differences in 25(OH)D levels between MDD and controls (p = 0.24) or between MDD with and without SI (p = 0.61). However, 25(OH)D was negatively correlated with all measured inflammatory markers; these correlations were stronger in MDD subjects, and particularly in those with SI. MDD status significantly moderated the relationships between 25(OH)D and NLR (p = 0.03), and 25(OH)D and WBC (p 0.05), and SI significantly moderated the relationship between 25(OH)D and NLR (p = 0.03).The study was cross-sectional, thereby limiting causal inference, and had a small sample size. Only seventeen of the MDD subjects had SI.While 25(OH)D levels did not significantly differ in MDD vs. controls, or in MDD with or without SI, lower 25(OH)D was associated with indices of immune activation in MDD, especially in cases with SI. Although our findings do not address causality, they are consistent with findings that relatively low 25(OH)D levels in MDD are associated with a pro-inflammatory state.

Alison R Hwong,1 Stefana Morgan,1 Chelsea Anne Young,2 Aaron D Besterman,3 Michael Jacob,1 Jody Williams,1 Victor I Reus,1 Carol A Mathews,4 Erick Hung,1 Susan Voglmaier1 1Department of Psychiatry and Behavioral Sciences, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA; 2Department of Psychiatry, Stanford University, Palo Alto, CA, USA; 3Department of Psychiatry, University of California, San Diego, CA, USA; 4Department of Psychiatry, College of Medicine at the University of Florida, Gainesville, FL, USACorrespondence: Alison R HwongUniversity of California, San Francisco, Department of Psychiatry and Behavioral Sciences, Weill Institute for Neurosciences, 401 Parnassus Avenue, Box 0984, San Francisco, CA, 94143-0983, USATel +1 406 414 7185Email alison.hwong@ucsf.eduAbstract: Psychiatry residency programs with robust research training can prepare physician-scientists to make contributions that advance the mental health field. Our psychiatry residency developed a chief resident for research position to help provide mentorship, community building, and advising around scholarly activities for residents. We present the process of implementing this new position in our residency to offer a model for engaging psychiatry residents in research.Keywords: academic psychiatry, residency training, research career

(Reprinted with permission from Am J Psychiatry 2018; 175:86–90)

The “neurotrophic hypothesis of depression” posits that low levels of brain-derived neurotrophic factor (BDNF) are associated with Major Depressive Disorder (MDD). Low levels of BDNF have also been found in individuals with suicide attempts, in MDD or other disorders, suggesting that low BDNF may also be associated with suicidality. We assessed serum BDNF in 68 physically healthy and unmedicated (for at least 6 weeks) MDD subjects, who expressed no suicidal ideation (NSI; N = 40) or endorsed suicidal ideation (SI; N = 28), but were not actively suicidal, and in healthy controls (HC; N = 76). Serum BDNF levels were significantly lower in MDD with SI compared to NSI MDD but were not significantly correlated with total Hamilton Depression Rating Scale (HDRS-17) severity or severity on any HDRS subscale. Covarying for age, sex, body mass index, platelets, perceived stress, smoking and physical activity did not alter the significant association between BDNF and SI. SI status was not significantly different between HC and MDD. Our findings show an association between low serum BDNF and SI in individuals with less than severe and non-active suicidal intent, suggesting that the individual symptom of suicidality may extend the neurotrophic hypothesis of depression to include suicidal ideation within MDD.

Attempts to correlate blood levels of brain-derived neurotrophic factor (BDNF) with post-traumatic stress disorder (PTSD) have provided conflicting results. Some studies found a positive association between BDNF and PTSD diagnosis and symptom severity, while others found the association to be negative. The present study investigated whether serum levels of BDNF are different cross-sectionally between combat trauma-exposed veterans with and without PTSD, as well as whether longitudinal changes in serum BDNF differ as a function of PTSD diagnosis over time. We analyzed data of 270 combat trauma-exposed veterans (230 males, 40 females, average age: 33.29 ± 8.28 years) and found that, at the initial cross-sectional assessment (T0), which averaged 6 years after the initial exposure to combat trauma (SD=2.83 years), the PTSD positive group had significantly higher serum BDNF levels than the PTSD negative controls [31.03 vs. 26.95 ng/mL, t(268) = 3.921, p

We sought to find clinical subtypes of posttraumatic stress disorder (PTSD) in veterans 6–10 years post-trauma exposure based on current symptom assessments and to examine whether blood biomarkers could differentiate them. Samples were males deployed to Iraq and Afghanistan studied by the PTSD Systems Biology Consortium: a discovery sample of 74 PTSD cases and 71 healthy controls (HC), and a validation sample of 26 PTSD cases and 36 HC. A machine learning method, random forests (RF), in conjunction with a clustering method, partitioning around medoids, were used to identify subtypes derived from 16 self-report and clinician assessment scales, including the clinician-administered PTSD scale for DSM-IV (CAPS). Two subtypes were identified, designated S1 and S2, differing on mean current CAPS total scores: S2 = 75.6 (sd 14.6) and S1 = 54.3 (sd 6.6). S2 had greater symptom severity scores than both S1 and HC on all scale items. The mean first principal component score derived from clinical summary scales was three times higher in S2 than in S1. Distinct RFs were grown to classify S1 and S2 vs. HCs and vs. each other on multi-omic blood markers feature classes of current medical comorbidities, neurocognitive functioning, demographics, pre-military trauma, and psychiatric history. Among these classes, in each RF intergroup comparison of S1, S2, and HC, multi-omic biomarkers yielded the highest AUC-ROCs (0.819–0.922); other classes added little to further discrimination of the subtypes. Among the top five biomarkers in each of these RFs were methylation, micro RNA, and lactate markers, suggesting their biological role in symptom severity.

Current evidence from case/control studies indicates that genetic risk for psychiatric disorders derives primarily from numerous common variants, each with a small phenotypic impact. The literature describing apparent segregation of bipolar disorder (BP) in numerous multigenerational pedigrees suggests that, in such families, large-effect inherited variants might play a greater role. To identify roles of rare and common variants on BP, we conducted genetic analyses in 26 Colombia and Costa Rica pedigrees ascertained for bipolar disorder 1 (BP1), the most severe and heritable form of BP. In these pedigrees, we performed microarray SNP genotyping of 838 individuals and high-coverage whole-genome sequencing of 449 individuals. We compared polygenic risk scores (PRS), estimated using the latest BP1 genome-wide association study (GWAS) summary statistics, between BP1 individuals and related controls. We also evaluated whether BP1 individuals had a higher burden of rare deleterious single-nucleotide variants (SNVs) and rare copy number variants (CNVs) in a set of genes related to BP1. We found that compared with unaffected relatives, BP1 individuals had higher PRS estimated from BP1 GWAS statistics (P = 0.001 ~ 0.007) and displayed modest increase in burdens of rare deleterious SNVs (P = 0.047) and rare CNVs (P = 0.002 ~ 0.033) in genes related to BP1. We did not observe rare variants segregating in the pedigrees. These results suggest that small-to-moderate effect rare and common variants are more likely to contribute to BP1 risk in these extended pedigrees than a few large-effect rare variants.

Dietary intervention studies thus far have failed to be replicable or causal. The results, therefore, have failed to provide clinicians and the general public with consistent and useful information on which to base reliable food-related health decisions. This is particularly relevant regarding plastic-derived chemicals (PDCs), such as Bisphenol A, now that the federal CLARITY-BPA program has failed to achieve scientific consensus. Investigators propose a novel human dietary protocol that is both replicable and causal, based upon BPA’s demonstrated inflammatory effects in humans. This first-of-a-kind dietary intervention study explores a potential causal relationship between human serum levels of BPA and High-Sensitivity C-Reactive Protein (hsCRP), a proven clinical indicator of inflammation. Investigators used the equivalent of a USDA-defined “typical diet” followed by a PDC-reduced diet to compare blood levels of hsCRP. This proof-of-concept investigation is the first to use an easily accessible, medically-accepted clinical laboratory test to directly measure human health effects of PDC reduction. Unexpected new complications discovered during the investigation indicate that these results may yet be inconclusive for direct causal relationship. However, the novel lessons and techniques developed as a result of those discoveries offer further specific and improved methods and best practices that can enable future dietary interventions to produce replicable, causal results.

Major depressive disorder (MDD) is associated with premature mortality and is an independent risk factor for a broad range of diseases, especially those associated with aging, such as cardiovascular disease, diabetes, and Alzheimer’s disease. However, the pathophysiology underlying increased rates of somatic disease in MDD remains unknown. It has been proposed that MDD represents a state of accelerated cellular aging, and several measures of cellular aging have been developed in recent years. Among such metrics, estimators of biological age based on predictable age-related patterns of DNA methylation (DNAm), so-called ‘epigenetic clocks’, have shown particular promise for their ability to capture accelerated aging in psychiatric disease. The recently developed DNAm metric known as ‘GrimAge’ is unique in that it was trained on time-to-death data and has outperformed its predecessors in predicting both morbidity and mortality. Yet, GrimAge has not been investigated in MDD. Here we measured GrimAge in 49 somatically healthy unmedicated individuals with MDD and 60 age-matched healthy controls. We found that individuals with MDD exhibited significantly greater GrimAge relative to their chronological age (‘AgeAccelGrim’) compared to healthy controls (p = 0.001), with a median of 2 years of excess cellular aging. This difference remained significant after controlling for sex, current smoking status, and body-mass index (p = 0.015). These findings are consistent with prior suggestions of accelerated cellular aging in MDD, but are the first to demonstrate this with an epigenetic metric predictive of premature mortality.

Bipolar disorder is a highly heritable illness, associated with alterations of brain structure. As such, identification of genes influencing inter-individual differences in brain morphology may help elucidate the underlying pathophysiology of bipolar disorder (BP). To identify quantitative trait loci (QTL) that contribute to phenotypic variance of brain structure, structural neuroimages were acquired from family members (n = 527) of extended pedigrees heavily loaded for bipolar disorder ascertained from genetically isolated populations in Latin America. Genome-wide linkage and association analysis were conducted on the subset of heritable brain traits that showed significant evidence of association with bipolar disorder (n = 24) to map QTL influencing regional measures of brain volume and cortical thickness. Two chromosomal regions showed significant evidence of linkage; a QTL on chromosome 1p influencing corpus callosum volume and a region on chromosome 7p linked to cortical volume. Association analysis within the two QTLs identified three SNPs correlated with the brain measures.

DNA methylation patterns at specific cytosine-phosphate-guanine (CpG) sites predictably change with age and can be used to derive "epigenetic age", an indicator of biological age, as opposed to merely chronological age. A relatively new estimator, called "DNAm GrimAge", is notable for its superior predictive ability in older populations regarding numerous age-related metrics like time-to-death, time-to-coronary heart disease, and time-to-cancer. PTSD is associated with premature mortality and frequently has comorbid physical illnesses suggestive of accelerated biological aging. This is the first study to assess DNAm GrimAge in PTSD patients. We investigated the acceleration of GrimAge relative to chronological age, denoted "AgeAccelGrim" in combat trauma-exposed male veterans with and without PTSD using cross-sectional and longitudinal data from two independent well-characterized veteran cohorts. In both cohorts, AgeAccelGrim was significantly higher in the PTSD group compared to the control group (N = 162, 1.26 vs -0.57, p = 0.001 and N = 53, 0.93 vs -1.60 Years, p = 0.008), suggesting accelerated biological aging in both cohorts with PTSD. In 3-year follow-up study of individuals initially diagnosed with PTSD (N = 26), changes in PTSD symptom severity were correlated with AgeAccelGrim changes (r = 0.39, p = 0.049). In addition, the loss of CD28 cell surface markers on CD8 + T cells, an indicator of T-cell senescence/exhaustion that is associated with biological aging, was positively correlated with AgeAccelGrim, suggesting an immunological contribution to the accelerated biological aging. Overall, our findings delineate cellular correlates of biological aging in combat-related PTSD, which may help explain the increased medical morbidity and mortality seen in this disease.

Background Traumatic stress can adversely affect physical and mental health through neurobiological stress response systems. We examined the effects of trauma exposure and posttraumatic stress disorder (PTSD) on telomere length, a biomarker of cellular aging, and volume of the amygdala, a key structure of stress regulation, in combat-exposed veterans. In addition, the relationships of psychopathological symptoms and autonomic function with telomere length and amygdala volume were examined. Methods Male combat veterans were categorized as having PTSD diagnosis (n = 102) or no lifetime PTSD diagnosis (n = 111) based on the Clinician-Administered PTSD Scale. Subjects were assessed for stress-related psychopathology, trauma severity, autonomic function, and amygdala volumes by magnetic resonance imaging. Results A significant interaction was found between trauma severity and PTSD status for telomere length and amygdala volume after adjusting for multiple confounders. Subjects with PTSD showed shorter telomere length and larger amygdala volume than those without PTSD among veterans exposed to high trauma, while there was no significant group difference in these parameters among those exposed to low trauma. Among veterans exposed to high trauma, greater telomere shortening was significantly correlated with greater norepinephrine, and larger amygdala volume was correlated with more severe psychological symptoms and higher heart rates. Conclusions These data suggest that the intensity of the index trauma event plays an important role in interacting with PTSD symptomatology and autonomic activity in predicting telomere length and amygdala volume. These results highlight the importance of trauma severity and PTSD status in predicting certain biological outcomes.

Objective Leukocyte telomere length (LTL) is a biomarker of cellular aging affected by chronic stress. The relationship of LTL to the stress hormones, cortisol and catecholamines, is unclear, as are possible differences between healthy controls (HC) and individuals with Major Depressive Disorder (MDD). This small pilot study is the first to examine the relationship between cortisol, catecholamines and LTL specifically in un-medicated MDD in comparison with HC. Methods Participants included 16 un-medicated MDD subjects and 15 HC for assay of LTL, 12-hour overnight urinary free cortisol and catecholamine levels. Results LTL, cortisol and catecholamine levels did not significantly differ between groups. In HC, a hierarchical regression analysis indicated that higher levels of cortisol were correlated with shorter LTL ( p = 0.003) above and beyond age and sex. Higher catecholamine levels were nearly-significant with shorter LTL ( p = 0.055). Neither hormone was correlated with shorter LTL in MDD ( p's > 0.28). To assess a possible cumulative effect of stress hormone activation, a summary score was calculated for each subject based on the number of stress hormone levels above the median for that group (HC or MDD). A significant inverse graded relationship was observed between LTL and the number of activated systems in HC ( p = 0.001), but not in MDD ( p = 0.96). Conclusion This pilot study provides preliminary evidence that stress hormone levels, especially cortisol, are inversely related to LTL in HC, but not in un-medicated MDD. Clarification of these relationships in larger samples could aid in understanding differential mechanisms underlying stress-related cellular aging in healthy and depressed populations.

Objective Increased inflammation and oxidative stress have been shown in Major Depressive Disorder (MDD), although there is significant heterogeneity across studies. Whether markers of inflammation and oxidative stress are associated with antidepressant treatment response in MDD is currently unclear. The goals of the present study are to investigate markers of inflammation and oxidative stress in unmedicated MDD subjects and controls and test the relationship between these markers and antidepressant response in MDD subjects. Methods Interleukin (IL)-6, tumor necrosis factor (TNF)-α, C-reactive protein, F2-isoprostanes, 8-OH 2-deoxyguanosine (8-OHdG), glutathione peroxidase, glutathione, and vitamin C were quantified in blood samples from 50 unmedicated MDD subjects and 55 healthy controls. Depression symptom severity was rated with the 17-item Hamilton Depression Rating Scale (HDRS). All subjects were somatically healthy and free from medications that could interfere with inflammation and oxidative stress markers. A subgroup of 22 MDD subjects underwent open-label selective serotonin reuptake inhibitor (SSRI) antidepressant treatment for eight weeks, after which blood sampling and the HDRS were repeated. Antidepressant treatment “response” was defined as ≥50% decrease in HDRS ratings over 8 weeks of treatment. Results After controlling for the effects of age, sex, body mass index and smoking, MDD subjects had significantly higher levels of IL-6 (p < 0.001), TNF-α (p < 0.001), 8-OHdG (p = 0.018), and F2-isoprostanes (p = 0.012). Compared to Responders, Non-responders to SSRI antidepressant treatment had higher levels of F2-isoprostanes at baseline (p = 0.006), and after eight weeks of treatment (p = 0.031). Non-responders showed a significant increase in 8-OHdG over the course of treatment (p = 0.021), whereas Responders showed a significant decrease in IL-6 over the course of treatment (p = 0.019). Conclusion Our results are in line with previous reports of increased levels of markers of inflammation and oxidative stress in MDD. Moreover, poorer antidepressant treatment response was related to higher baseline levels of the major oxidative stress marker, F2-isoprostanes, in vivo. Further, antidepressant response was associated with changes in oxidative (8-OHdG) and inflammatory (IL-6) markers.

Introduction Several lines of evidence indicate that increased inflammation is associated with Post-Traumatic Stress Disorder (PTSD). We have previously reported that peripheral inflammatory markers are significantly higher in combat-exposed veterans with than without PTSD. This study was designed to replicate these findings in a new study cohort using the same population and recruitment strategies. Methods Sixty-one male war veterans (31 PTSD and 30 control subjects) were included in this replication study. Levels of Interleukin-6, Tumor Necrosis Factor-alpha, Gamma interferon, and high-sensitivity C-reactive protein were quantified in blood samples. A standardized “total pro-inflammatory score” was calculated to limit the number of statistical comparisons. The Clinician Administered PTSD Scale (CAPS) rating scale was used to assess PTSD symptom severity. Results PTSD subjects had significantly higher total pro-inflammatory scores compared to non-PTSD subjects in unadjusted analysis (Cohen’s d = 0.75, p = 0.005) as well as after adjusting for potentially confounding effects of age, BMI, smoking, and potentially interfering medications and somatic co-morbidities (p = 0.023). There were no significant correlations between inflammatory markers and severity of symptoms within the PTSD group. Conclusions We replicated, in a new sample, our previous finding of increased inflammatory markers in combat-exposed PTSD subjects compared to combat-exposed non-PTSD controls. These findings strongly add to the growing literature suggesting that immune activation may be an important aspect of PTSD pathophysiology, although not directly correlated with current PTSD symptom levels in the PTSD group.

BackgroundSevere mental illness (SMI) diagnoses display overlapping symptomatology and shared genetic risk, motivating trans-diagnostic investigations of disease-relevant quantitative measures. We analyzed relationships between neurocognitive performance, symptom domains, and diagnoses, in a large sample of SMI cases (ascertained agnostic to diagnosis) and healthy controls from a single, homogeneous population.Methods2,406 participants (1,689 cases, 717 controls; mean age 39 years, 64% female) were assessed for speed and accuracy using the Penn Computerized Neurocognitive Battery (CNB). Cases carried structured-interview based diagnoses of schizophrenia (SCZ, n=160), bipolar-I (BP-I, n=519), bipolar-II (BP-II, n=204) and major depressive disorder (MDD, n=806). Linear mixed models, using CNB tests as repeated measures, modeled neurocognition as a function of diagnosis, sex, and all interactions. Follow-up analyses, in cases, included symptom factor scores obtained from exploratory factor analysis of symptom data, as main effects.FindingsBP-I and SCZ displayed nearly identical impairments in accuracy and speed, across cognitive domains. BP-II and MDD performed similarly to controls, with subtle deficits in executive and social cognition. A three-factor model (psychosis, mania, and depression) best represented symptom data. Controlling for diagnosis, premorbid IQ, and disease severity, high lifetime psychosis scores were associated with reduced accuracy and speed across cognitive domains, while high depression scores were associated with increased social cognition accuracy.InterpretationTrans-diagnostic investigations demonstrated that neurocognitive function in SMI is characterized by two distinct profiles (BP-I/SCZ and BP-II/MDD), and is associated with specific symptom domains. These results suggest the utility of this design for elucidating SMI causes and trajectories.

Background Less than half of patients with major depressive disorder (MDD) respond to their first antidepressant trial. Our understanding of the underlying mechanisms of selective serotonin reuptake inhibitors (SSRIs) remains poor, and there is no reliable method of predicting treatment response. Methods Thirty-seven MDD subjects and 41 healthy controls, somatically healthy and medication-free for at least six weeks, were recruited, and plasma serotonin (5-HT) levels were assessed at baseline. Twenty-six of the MDD subjects were then treated in an open-label manner with clinically appropriate doses of sertraline for 8 weeks, after which plasma 5-HT levels were again assessed. Response to treatment was defined as an improvement of 50% or more on the Hamilton Depression Rating Scale. Results Non-responders to sertraline treatment had significantly lower pre-treatment 5-HT levels compared to both healthy controls and responders (F = 4.4, p = 0.004 and p = 0.036, respectively). There was a significant decrease in 5-HT levels over treatment in all MDD subjects (t = 6.2, p = 0.000003). The decrease was significantly more prominent in responders compared to non-responders (t = 2.1, p = 0.047). There was no significant difference in post-treatment 5-HT levels between responders and non-responders. Limitations The study had a modest sample size. 5-HT levels in plasma may not reflect 5-HT levels in the brain. Conclusions The results indicate that SSRI response may be facilitated by adequate baseline plasma 5-HT content and that successful SSRI treatment is associated with greater decreases in circulating 5-HT. Plasma 5-HT content may be a predictor of SSRI treatment outcome. Potential underlying mechanisms are discussed.

Posttraumatic stress disorder (PTSD) is associated with impaired major domains of psychology and behavior. Individuals with PTSD also have increased co-morbidity with several serious medical conditions, including autoimmune diseases, cardiovascular disease, and diabetes, raising the possibility that systemic pathology associated with PTSD might be identified by metabolomic analysis of blood. We sought to identify metabolites that are altered in male combat veterans with PTSD. In this case-control study, we compared metabolomic profiles from age-matched male combat trauma-exposed veterans from the Iraq and Afghanistan conflicts with PTSD (n = 52) and without PTSD (n = 51) ('Discovery group'). An additional group of 31 PTSD-positive and 31 PTSD-negative male combat-exposed veterans was used for validation of these findings ('Test group'). Plasma metabolite profiles were measured in all subjects using ultrahigh performance liquid chromatography/tandem mass spectrometry and gas chromatography/mass spectrometry. We identified key differences between PTSD subjects and controls in pathways related to glycolysis and fatty acid uptake and metabolism in the initial 'Discovery group', consistent with mitochondrial alterations or dysfunction, which were also confirmed in the 'Test group'. Other pathways related to urea cycle and amino acid metabolism were different between PTSD subjects and controls in the 'Discovery' but not in the smaller 'Test' group. These metabolic differences were not explained by comorbid major depression, body mass index, blood glucose, hemoglobin A1c, smoking, or use of analgesics, antidepressants, statins, or anti-inflammatories. These data show replicable, wide-ranging changes in the metabolic profile of combat-exposed males with PTSD, with a suggestion of mitochondrial alterations or dysfunction, that may contribute to the behavioral and somatic phenotypes associated with this disease.

Understanding the etiology and meaning of behavioral symptomatology in the context of neurologic disease, and choosing the most effective intervention is a vexing task. This introduction summarizes the history of our understanding of the relationship between behavioral symptoms and primary neurologic conditions, and considers the ways in which both psychiatric and neurologic disorders occurring simultaneously may inform both knowledge of etiology and treatment decisions.

Psychiatric, physical and biological aspects of posttraumatic stress disorder (PTSD) may be associated with dysfunctions in several cellular processes including nitric oxide (NO) production. NO is synthesized from arginine in a reaction carried out by NO synthase (NOS) enzymes. The recently introduced "global arginine bioavailability ratio" (GABR; ratio of arginine to [ornithine+citrulline]) has been proposed as a reliable approximation of NO synthetic capacity in vivo. The objectives of the present study were to test the hypotheses that (i) subjects with combat-related PTSD have lower GABR scores than combat controls, (ii) GABR score is inversely associated with the severity of psychopathological measures, (iii) GABR score is inversely associated with markers of inflammation.Metabolic profiling for plasma samples (i.e. arginine, citrulline and ornithine) and inflammation markers (interleukin [IL]-6, IL-1β, tumor necrosis factor [TNF]-α, interferon [IFN]-γ and C-reactive protein [CRP]) were assessed in 56 combat-exposed males with PTSD and 65 combat-exposed males without PTSD. We assessed severity of PTSD (Clinician Administered PTSD Scale [CAPS]) and depression (Beck Depression Inventory-II [BDI-II]) as well as history of early life trauma (Early Trauma Inventory [ETI]) and affectivity (Positive and Negative Affect Schedule [PANAS]).The GABR value was (i) significantly lower in PTSD subjects compared to controls (p=0.001), (ii) significantly inversely correlated with markers of inflammation including IL6 (p=0.04) and TNFα (p=0.02), and (iii) significantly inversely correlated with CAPS current (p=0.001) and lifetime (p0.001) subscales, ETI (p=0.045) and PANAS negative (p=0.006). Adding antidepressant use or MDD diagnosis as covariates led to similar results. Adding age and BMI as covariates also led to similar results, with the exception of IL6 and ETI losing their significant association with GABR.This study provides the first evidence that global arginine bioavailability, a marker of NO synthetic capacity in vivo, is lower in veterans with PTSD and is negatively associated with some markers of inflammation as well as with measures of PTSD symptom severity, negative affectivity and childhood adverse experiences. These findings add to the accumulating evidence that specific cellular dysfunction may be associated with the symptomatology of PTSD and may help to explain the higher burden of cardio-metabolic disturbances seen in this disorder.

Short leukocyte telomere length (LTL) may be associated with several psychiatric disorders, including major depressive disorder (MDD). Short LTL has previously been associated with poor response to psychiatric medications in bipolar disorder and schizophrenia, but no studies have prospectively assessed the relationship of LTL to selective serotonin reuptake inhibitor (SSRI) response in MDD. We assessed pre-treatment LTL, depression severity [using the Hamilton Depression Rating Scale (HDRS)], and self-reported positive and negative affect in 27 healthy, unmedicated adults with MDD. The subjects then underwent open-label treatment with an SSRI antidepressant for 8 weeks, after which clinical ratings were repeated. The analyses were corrected for age, sex, and body mass index. ‘Non-responders' to treatment (HDRS improvement

BackgroundStudies testing the relationship between cortisol levels, depression, and antidepressant treatment response have yielded divergent results suggesting the possibility of moderators of a cortisol effect. Several studies indicate that age may moderate the relationship between cortisol and psychopathology. In patients with Major Depressive Disorder (MDD), we studied the interactive effects of age and cortisol on predicting diagnostic status, improvement in mood and memory function with antidepressant treatment, and brain response to negative emotional stimuli.Methods66 unmedicated patients with MDD and 75 matched healthy controls had serum assayed at pre-treatment baseline for cortisol. Logistic regression was used to determine an association of age, cortisol and their interaction with MDD diagnosis. Thirty-four of the MDD participants (age range: 19-65 years; median: 36) underwent treatment with a selective serotonin reuptake inhibitor (SSRl) for 8 weeks. Clinician and self-ratings of depression symptoms, as well as tests of verbal and visual delayed recall were obtained at baseline and post treatment. Moderation analyses determined the effect of age on the relationship between baseline cortisol and treatment outcome. A separate sample of 8 MDD participants prospectively underwent fMRI neuroimaging and cortisol collection while viewing negative emotional faces.ResultsAge moderated the effects of cortisol on predicting MDD diagnosis (pConclusionsOur results indicate that age moderates the relationship between peripheral cortisol levels and (1) MDD diagnosis, (2) brain reactivity to emotional stimuli, and (3) antidepressant-associated improvement in depression and memory symptoms. These results indicate that previous disparities in the literature linking peripheral cortisol levels with depression characteristics and treatment response may critically relate, at least in part, to the age of the patients studied.

Major depressive disorder (MDD) has been linked to mitochondrial defects, which could manifest in mitochondrial DNA (mtDNA) polymorphisms or mutations. Additionally, copy number of mtDNA (mtDNA-cn) can be quantified in peripheral blood mononuclear cells (PBMC)s, indirectly reflecting cellular energetics, or in the circulating cell-free mtDNA (ccf-mtDNA) levels, which may reflect a fraction of the mitochondrial genome released during cellular stress. Few studies have examined ccf-mtDNA in MDD, and no studies have tested its relationship with intracellular mtDNA-cn or with antidepressant treatment response. Here, mtDNA levels were quantified in parallel from: (i) PBMCs and (ii) cell-free plasma of 50 unmedicated MDD subjects and 55 controls, in parallel with PBMC telomere length (TL) and antioxidant enzyme glutathione peroxidase (GpX) activity. MtDNA measures were repeated in 19 MDD subjects after 8 weeks of open-label SSRI treatment. In analyses adjusted for age, sex, BMI, and smoking, MDD subjects had significantly elevated levels of ccf-mtDNA (F = 20.6, p = 0.00002). PBMC mtDNA-cn did not differ between groups (p > 0.4). In preliminary analyses, we found that changes in ccf-mtDNA with SSRI treatment differed between SSRI responders and non-responders (F = 6.47, p = 0.02), with the non-responders showing an increase in ccf-mtDNA and responders not changing. Baseline ccf-mtDNA was positively correlated with GpX (r = 0.32, p = 0.001), and PBMC mtDNA correlated positively with PBMC TL (r = 0.38, p = 0.0001). These data suggest that plasma ccf-mtDNA and PBMC mtDNA-cn reflect different cellular processes and that the former may be more reflective of certain aspects of MDD pathophysiology and of the response to SSRI antidepressants.