Omega-3 fatty acids for inflamed depression - A match/mismatch study.

Despite decades of research on the pathophysiology of depression, the development of new therapeutic interventions has been slow, and no biomarkers of treatment response have been clinically implemented. Several lines of evidence suggest that the clinical and biological heterogeneity among patients with major depressive disorder (MDD) has hampered progress in this field. MDD with low-grade inflammation - "inflamed depression" - is a subtype of depression that may be associated with a superior antidepressant treatment response to anti-inflammatory compounds. Omega-3 fatty acid eicosapentaenoic acid (EPA) has anti-inflammatory properties, and preliminary data suggest that it may be particularly efficacious in inflamed depression. In this study we tested the hypothesis that add-on EPA has greater antidepressant efficacy in MDD patients with high baseline high-sensitivity C-reactive protein (hs-CRP) compared to MDD patients with low hs-CRP. All subjects received 2.2 g EPA, 400 mg docosahexaenoic acid and 800 mg of other fatty acids daily for 8 weeks, added to stable ongoing antidepressant treatment. The primary outcome was change in the 17-item Hamilton Depression Rating Scale (HAMD-17). Patients and raters were blind to baseline hs-CRP status. In an intention-to-treat analysis including all subjects with at least one post baseline visit (n = 101), ahs-CRPcut-off of ≥1 mg/L, but not ≥3 mg/L, was associated with a greater improvement in HAMD-17 total score. In addition to a general antidepressant effect among patients with hs-CRP ≥ 1 mg/L, adjuvant EPA treatment improved symptoms putatively related to inflamed depression such as fatigue and sleep difficulties. This adds to the mounting evidence that delineation of MDD subgroups based on inflammation may be clinically relevant to predict treatment response to anti-inflammatory interventions.

Chemically modified recombinant human sulfamidase (SOBI003) in mucopolysaccharidosis IIIA patients: Results from an open, non-controlled, multicenter study.

PURPOSE: Mucopolysaccharidosis IIIA (MPS IIIA) is an inherited lysosomal storage disorder caused by mutations in the N-sulfoglucosamine sulfohydrolase gene that result in deficient enzymatic degradation of heparan sulfate (HS), resulting in progressive neurodegeneration in early childhood and premature death. A chemically modified variant of recombinant human sulfamidase, SOBI003, has shown to cross the blood-brain barrier (BBB) in mice and achieve pharmacologically relevant levels in cerebrospinal fluid (CSF). We report on a phase 1/2, open-label, first-in-human (FIH) study (NCT03423186) and its extension study (NCT03811028) to evaluate the long-term safety, tolerability, pharmacokinetics/pharmacodynamics (PK/PD) and clinical efficacy of SOBI003 in patients with MPS IIIA for up to 104 weeks. METHODS: Six patients aged 1-6 years with confirmed MPS IIIA with developmental age ≥ 12 months received weekly intravenous injections of SOBI003 at 3 mg/kg (Cohort 1, n = 3) or 10 mg/kg (Cohort 2, n = 3). During the extension study, the individual dose of SOBI003 could be adjusted up to 20 mg/kg at the discretion of the investigator. RESULTS: SOBI003 was generally well tolerated. Serum concentrations of SOBI003 increased in proportion to dose, and presence in CSF confirmed that SOBI003 crosses the BBB. Anti-drug antibodies (ADA) were detected in serum and CSF in all patients, with subsequent reductions in serum SOBI003 exposure at high ADA titers. SOBI003 exerted a clear PD effect: a mean reduction in HS levels in CSF of 79% was recorded at the last assessment, together with reductions in HS levels in serum and urine. Neurocognitive development age-equivalent scores showed a stabilization of cognition for all patients, whereas no clear overall clinical effect was observed on adaptive behavior, sleep pattern or quality of life. CONCLUSION: SOBI003 was well tolerated when administered as weekly intravenous infusions at doses of up to 20 mg/kg for up to 104 weeks. ADA development was common and likely affected both PK and PD parameters. SOBI003 crossed the BBB and showed pharmacological activity on HS in CSF.

Efficacy of eicosapentaenoic acid in inflammatory depression: study protocol for a match-mismatch trial.

BACKGROUND: Most antidepressant treatment studies have included patients strictly based on the Diagnostic and Statistical Manual of Mental Disorders definition of Major Depressive Disorder (MDD). Given the heterogeneity of MDD, this approach may have obscured inter-patient differences and hampered the development of novel and targeted treatment strategies. An alternative strategy is ​​to use biomarkers to delineate endophenotypes of depression and test if these can be targeted via mechanism-based interventions. Several lines of evidence suggest that "inflammatory depression" is a clinically meaningful subtype of depression. Preliminary data indicate that omega-3 fatty acids, with their anti-inflammatory and neuroprotective properties, may be efficacious in this subtype of depression, and this study aims to test this hypothesis. METHOD: We conduct a match-mismatch-trial to test if add-on omega-3 fatty acid eicosapentaenoic acid (EPA) reduces depressive symptoms in patients with MDD and systemic low-grade inflammation. MDD patients on a stable antidepressant treatment are stratified at baseline on high sensitivity-C-reactive protein (hs-CRP) levels to a high-inflammation group (hs-CRP ≥ 3 mg/L) or a low-inflammation group (hs-CRP < 3 mg/L). Both groups receive add-on EPA (2 g per day) for 8 weeks with three study visits, all including blood draws. Patients and raters are blind to inflammation status. Primary outcome measure is change in Hamilton Depression Rating Scale score between baseline and week 8. We hypothesize that the inflammation group has a superior antidepressant response to EPA compared to the non-inflammation group. Secondary outcomes include a composite score of "inflammatory depressive symptoms", quality of life, anxiety, anhedonia, sleep disturbances, fatigue, cognitive performance and change in biomarkers relating to inflammation, oxidative stress, metabolomics and cellular aging. DISCUSSION: In this study we will, for the first time using a match-mismatch trial design, test if omega-3 is an efficacious treatment for inflammatory depression. If our study is successful, it could add to the field of precision psychiatry. TRIAL REGISTRATION: This trial was registered May 8, 2017 on clinicaltrials.gov under the reference number NCT03143075.

Pre-treatment allostatic load and metabolic dysregulation predict SSRI response in major depressive disorder: a preliminary report.

BACKGROUND: Major 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. METHODS: We 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' (<50% improvement). Logistic and linear regressions were performed to determine if pre-treatment AL or MetD scores predicted SSRI-response. Secondary analyses examined cross-sectional differences between MDD and control groups. RESULTS: Pre-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). CONCLUSIONS: These 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.

Multi-omic biomarker identification and validation for diagnosing warzone-related post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) impacts many veterans and active duty soldiers, but diagnosis can be problematic due to biases in self-disclosure of symptoms, stigma within military populations, and limitations identifying those at risk. Prior studies suggest that PTSD may be a systemic illness, affecting not just the brain, but the entire body. Therefore, disease signals likely span multiple biological domains, including genes, proteins, cells, tissues, and organism-level physiological changes. Identification of these signals could aid in diagnostics, treatment decision-making, and risk evaluation. In the search for PTSD diagnostic biomarkers, we ascertained over one million molecular, cellular, physiological, and clinical features from three cohorts of male veterans. In a discovery cohort of 83 warzone-related PTSD cases and 82 warzone-exposed controls, we identified a set of 343 candidate biomarkers. These candidate biomarkers were selected from an integrated approach using (1) data-driven methods, including Support Vector Machine with Recursive Feature Elimination and other standard or published methodologies, and (2) hypothesis-driven approaches, using previous genetic studies for polygenic risk, or other PTSD-related literature. After reassessment of ~30% of these participants, we refined this set of markers from 343 to 28, based on their performance and ability to track changes in phenotype over time. The final diagnostic panel of 28 features was validated in an independent cohort (26 cases, 26 controls) with good performance (AUC = 0.80, 81% accuracy, 85% sensitivity, and 77% specificity). The identification and validation of this diverse diagnostic panel represents a powerful and novel approach to improve accuracy and reduce bias in diagnosing combat-related PTSD.

Differences in antipsychotic treatment between depressive patients with and without a suicide attempt.

BACKGROUND: Depressed suicide attempters are, according to some earlier studies, treated more often with antipsychotics than depressive non-suicide attempters. Cluster B personality disorders, especially borderline personality disorder, are associated with a high suicide risk, and antipsychotics are commonly used for the reduction of symptoms. However, no previous study has taken comorbid personality disorders into account when assessing the use of antipsychotics in patients with unipolar depression. Therefore, the aim of this study was to investigate the clinical selection of pharmacotherapy in unipolar depression with and without a previous suicide attempt, taking into account potential confounders such as cluster B personality disorders. METHODS: The study sample consisted of 247 patients with unipolar depression. The study was approved by the Regional Ethical Review Board in Lund, Sweden. Study participants were recruited from 4 different secondary psychiatric care clinics in Sweden and were diagnosed according to the DSM-IV-TR with the MINI and SCID II. Previous and ongoing psychiatric treatments were investigated in detail and medical records were assessed. RESULTS: Thirty percent of the patients had made previous suicide attempts. Depressed suicide attempters underwent both lifetime treatment with antipsychotics and an ongoing antipsychotic treatment significantly more often than non-attempters. Significances remained after a regression analysis, adjusting for cluster B personality disorders, symptom severity, age at the onset of depression, and lifetime psychotic symptoms. CONCLUSIONS: This is the first study to consider the effect of comorbidity with cluster B personality disorders when comparing treatment of depressive suicide and non-suicide attempters. Our findings suggest that suicide attempters are more frequently treated with antipsychotics compared to non-suicide attempters, regardless of cluster B personality disorder comorbidity. These findings are important for clinicians to consider and would also be relevant to future studies evaluating reduction of suicide risk with antipsychotics in patients with psychiatric comorbidity and a history of attempted suicide.

Inflammatory Depression-Mechanisms and Non-Pharmacological Interventions.

Treatment of depression is hampered by the failure to identify distinct symptom profiles with distinct pathophysiologies that differentially respond to distinct treatments. We posit that inflammatory depression is a meaningful depression subtype associated with specific symptoms and biological abnormalities. We review several upstream, potentially causative, mechanisms driving low-grade inflammation in this subtype of depression. We also discuss downstream mechanisms mediating the link between inflammation and symptoms of depression, including alterations in dopaminergic neurotransmission and tryptophan metabolism. Finally, we review evidence for several non-pharmacological interventions for inflammatory depression, including probiotics, omega-3 fatty acids, and physical exercise interventions. While some evidence suggests that these interventions may be efficacious in inflammatory depression, future clinical trials should consider enriching patient populations for inflammatory markers, or stratify patients by inflammatory status, to confirm or refute this hypothesis.

Non randomized study on the potential of nitisinone to inhibit cytochrome P450 2C9, 2D6, 2E1 and the organic anion transporters OAT1 and OAT3 in healthy volunteers.

PURPOSE: Nitisinone inhibits the cytochrome P450 (CYP) subfamilies CYP2C9, CYP2D6, and CYP2E1 and the organic anion transporter (OAT) isoforms OAT1 and OAT3 in vitro. Since the effect of nitisinone on these enzymes and transporters in humans is still unknown, the purpose of this study was to evaluate the effect of nitisinone on these CYP subfamilies and OAT isoforms. METHODS: This was an open-label, nonrandomized, two-arm, phase 1 study (EudraCT: 2016-004297-17) in healthy volunteers. The substrates (tolbutamide, metoprolol, and chlorzoxazone for the respective CYPs and furosemide for the OATs) were administered as single doses, before and after 15 days of once daily dosing of 80 mg nitisinone, to determine the AUC∞ ratios ([substrate+nitisinone]/[substrate]). Nitisinone pharmacokinetics, safety, and tolerability were also assessed, and blood and urine were collected to determine substrate and nitisinone concentrations by LC-MS/MS. RESULTS: Thirty-six subjects were enrolled with 18 subjects included in each arm. The least square mean ratio (90% confidence interval) for AUC∞ was 2.31 (2.11-2.53) for tolbutamide, 0.95 (0.88-1.03) for metoprolol, 0.73 (0.67-0.80) for chlorzoxazone, and 1.72 (1.63-1.81) for furosemide. Clinically relevant nitisinone steady-state concentrations were reached after 12 days: mean Cav,ss of 94.08 µM. All treatments were well tolerated, and no safety concerns were identified. CONCLUSIONS: Nitisinone did not affect CYP2D6 activity, was a weak inducer of CYP2E1, and was a weak inhibitor of OAT1 and OAT3. Nitisinone was a moderate inhibitor of CYP2C9, and treatment may therefore result in increased plasma concentrations of comedications metabolized primarily via this enzyme. CLINICAL TRIAL REGISTRY IDENTIFICATION: EudraCT 2016-004297-17.

Depression severity is associated with increased inflammation in veterans with peripheral artery disease.

The present study examines the association between depressive symptoms and inflammatory markers in peripheral artery disease (PAD) to better understand the mechanistic relationship between depression and PAD. A cross-sectional sample of 117 patients with PAD (97% male, 76% Caucasian) was recruited from the San Francisco Veterans Affairs Medical Center. Patients were categorized into three subgroups based upon current depressive symptom severity, as defined by Patient Health Questionnaire-8 scores: no symptoms (score of 0-4, n = 62), mild symptoms (score of 5-9, n = 33), and moderate/severe symptoms (score ≥ 10, n = 22). Serum levels of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (ICAM-1), and tumor necrosis factor-alpha (TNF-α) were assayed and log-transformed for multivariable analysis. To decrease the possibility of Type 1 errors, inflammatory markers were standardized and summed to create a total inflammatory score. In a multivariable analysis controlling for demographics, PAD severity, and atherosclerotic risk factors, mild and moderate/severe depressive symptoms were predictive of a higher total inflammatory score when compared to the group with no symptoms (mild symptoms p = 0.04, moderate/severe symptoms p = 0.007). Exploratory multivariable analyses of individual inflammatory markers found IL-6 levels were significantly higher in the moderate/severe symptoms group ( p = 0.006) than in the no symptoms group. Moreover, hs-CRP and ICAM-1 trended upwards with increasing depression severity. TNF-α was not associated with depression severity. We conclude that depressive symptom severity was independently associated with greater inflammation in PAD. Future research should examine the strength and directionality of this association through larger prospective cohort studies, as well as investigate the pathophysiological mechanisms responsible.

Increased pro-inflammatory milieu in combat related PTSD - A new cohort replication study.

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.

The Association Between Psychiatric Disorders and Telomere Length: A Meta-Analysis Involving 14,827 Persons.

OBJECTIVE: This study examined the relationship between leukocyte telomere length (LTL), a marker of cell aging, and psychiatric disorders in adults compared with controls using meta-analytic methods. METHODS: Data were abstracted from studies examining the relationship between LTL and adult psychiatric disorders. In addition to an overall estimate of effect size, subgroup analyses and meta-regression were performed to examine whether covariates (including psychiatric diagnoses) moderated the estimate. RESULTS: A significant overall effect size showing LTL shortening was found across all psychiatric disorders (Hedge g = -0.50, p < .001). Subgroup analyses did not demonstrate significant differences in effect size based on individual covariates (psychiatric disorder, sex, age, or assay method). The meta-regression indicated that although type of disorder and, likely, age moderate the overall effect size, the heterogeneity between studies could not be explained by a model that included these variables as well as sex and assay method. Although not significantly different, posttraumatic stress disorder, anxiety disorders, and depressive disorders had comparatively larger effect sizes (-1.27, -0.53, and -0.55), and psychotic and bipolar disorders had comparatively smaller ones (-0.23 and -0.26). CONCLUSIONS: We observed a robust effect size of LTL shortening for psychiatric disorders as a whole compared with controls. The results were less straightforward regarding relative differences in the strength of this association by specific disorder. Future studies should focus on mechanisms explaining accelerated cell aging with psychiatric illness, defining directions (if any) of causality and elucidating possible differences in this association between disorders.

Global arginine bioavailability, a marker of nitric oxide synthetic capacity, is decreased in PTSD and correlated with symptom severity and markers of inflammation.

INTRODUCTION: 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. METHODS: Metabolic profiling for plasma samples (i.e. arginine, citrulline and ornithine) and inflammation markers (interleukin [IL]-6, IL-1ß, 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]). RESULTS: 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 (p<0.001) 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. DISCUSSION: 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.

A population of atypical CD56(-)CD16(+) natural killer cells is expanded in PTSD and is associated with symptom severity.

INTRODUCTION: Post-traumatic stress disorder (PTSD) has been associated with immune disturbances, including a higher incidence of infections and autoimmune diseases as well as a net pro-inflammatory state. Natural killer (NK) cells, a key component of the innate immune system, have been less well-studied in PTSD despite their importance in immunity. METHODS: We studied two independent samples of combat-exposed male war veterans with or without PTSD, the first ("Discovery Sample") to generate hypotheses, and the second ("Validation Sample") to replicate the findings. The Discovery Sample was comprised of 42 PTSD subjects and 42 controls. The Validation Sample was comprised of 25 PTSD subjects and 30 controls. Participants had fasting, morning blood samples collected for examination of the frequency of NK cell subsets, determined by flow cytometry. The current and lifetime Clinician Administered PTSD Scale (CAPS) was used to assess symptom severity. Statistical analyses were adjusted for age and BMI. RESULTS: PTSD subjects compared to controls had (i) a significantly higher relative frequency of atypical CD56(-)CD16(+) NK cells in the Discovery Sample (p=0.027), which was replicated in the Validation Sample (p=0.004) and the combined sample (p<0.001), and (ii) a non-significantly lower relative frequency of CD56(bright)CD16(-) NK cells in the two samples (p=0.082; p=0.118), which became statistically significant in the combined sample (p=0.020). Further, within subjects with PTSD of both samples, the relative frequency of atypical CD56(-)CD16(+) NK cells was near significantly positively correlated with lifetime PTSD severity (p=0.074). DISCUSSION: This study is the first to characterize NK cell subsets in individuals with PTSD. The results suggest that combat-exposed men with PTSD exhibit an aberrant profile of NK cells with significantly higher frequencies of an atypical population of CD56(-)CD16(+) cells and possibly lower frequencies of the functional CD56(bright)CD16(-) NK cell subsets. Higher proportions of dysfunctional CD56(-)CD16(+) cells have been reported in certain chronic viral infections and in senescent individuals. It is possible that this could contribute to immune dysfunctions and prematurely senescent phenotypes seen in PTSD.

Hypothalamic-pituitary-adrenal axis hyperactivity is associated with decreased brain-derived neurotrophic factor in female suicide attempters.

INTRODUCTION: Both decreased levels of brain-derived neurotrophic factor (BDNF) and hypothalamic-pituitary-adrenal (HPA) axis dysregulation may be involved in the pathophysiology of suicidal behaviour, as well as cognitive symptoms of depression. Pre-clinical and clinical studies have shown interactions between HPA-axis activity and BDNF, but this has not been studied in a clinical cohort of suicidal subjects. The purpose of this study was, therefore, to investigate associations between HPA-axis activity and BDNF in suicide attempters. Furthermore, this study examined the relationship between the HPA-axis, BDNF, and cognitive symptoms in suicidal patients. Since previous data indicate gender-related differences in BDNF and the HPA axis, males and females were examined separately. METHOD: Seventy-five recent suicide attempters (n = 41 females; n = 34 males) were enrolled in the study. The Dexamethasone Suppression Test (DST) was performed and BDNF in plasma were analysed. Patients were evaluated with the Comprehensive Psychopathological Rating Scale (CPRS) from which items 'Concentration difficulties' and 'Failing memory' were extracted. RESULTS: Only among females, DST non-suppressors had significantly lower BDNF compared to DST suppressors (p = 0.022), and there was a significant correlation between post-DST serum cortisol at 8 a.m. and BDNF (rs = -0.437, p = 0.003). Concentration difficulties correlated significantly with post-DST cortisol in all patients (rs = 0.256, p = 0.035), in females (rs = 0.396, p = 0.015), and with BDNF in females (rs = -0.372, p = 0.020). CONCLUSION: The findings suggest an inverse relationship between the HPA-axis and BDNF in female suicide attempters. Moreover, concentration difficulties may be associated with low BDNF and DST non-suppression in female suicide attempters.

Parkinson's Disease Case Ascertainment in the EPIC Cohort: The NeuroEPIC4PD Study.

BACKGROUND/AIMS: Large epidemiological prospective studies represent an important opportunity for investigating risk factors for rare diseases such as Parkinson's disease (PD). Here we describe the procedures we used for ascertaining PD cases in the EPIC (European Prospective Investigation into Cancer and Nutrition) study. METHODS: The following three-phase procedure was used: (1) elaboration of a NeuroEPIC4PD template for clinical data collection, (2) identification of all potential PD cases via record linkage and (3) validation of the diagnosis through clinical record revision, in a population of 220,494 subjects recruited in 7 European countries. All cases were labelled with the NeuroEPIC4PD diagnoses of 'definite', 'very likely', 'probable', or 'possible' PD. RESULTS: A total of 881 PD cases were identified, with over 2,741,780 person-years of follow-up (199 definite, 275 very likely, 146 probable, and 261 possible). Of these, 734 were incident cases. The mean age at diagnosis was 67.9 years (SD 9.2) and 458 patients (52.0%) were men. Bradykinesia was the most frequent presenting motor sign (76.5%). Tremor-dominant and akinetic rigid forms of PD were the most common types of PD. A total of 289 patients (32.8%) were dead at the time of the last follow-up. CONCLUSIONS: This exercise proved that it is feasible to ascertain PD in large population-based cohort studies and offers a potential framework to be replicated in similar studies.

Proinflammatory milieu in combat-related PTSD is independent of depression and early life stress.

BACKGROUND: Chronic inflammation may be involved in combat-related post-traumatic stress disorder (PTSD) and may help explain comorbid physical diseases. However, the extent to which combat exposure per se, depression, or early life trauma, all of which are associated with combat PTSD, may confound the relationship between PTSD and inflammation is unclear. METHODS: We quantified interleukin (IL)-6, IL-1ß, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and C-reactive protein (CRP) in 51 combat-exposed males with PTSD and 51 combat-exposed males without PTSD, and assessed PTSD and depression severity as well as history of early life trauma. To decrease the possibility of Type I errors, we summed standardized scores of IL-1ß, IL-6, TNFα, IFNγ and CRP into a total "pro-inflammatory score". PTSD symptom severity was assessed with the Clinician Administered PTSD Scale (CAPS) rating scale. RESULTS: Subjects with PTSD had significantly higher pro-inflammatory scores compared to combat-exposed subjects without PTSD (p=0.006), and even after controlling for early life trauma, depression diagnosis and severity, body mass index, ethnicity, education, asthma/allergies, time since combat and the use of possibly confounding medications (p=0.002). Within the PTSD group, the pro-inflammatory score was not significantly correlated with depressive symptom severity, CAPS total score, or with the number of early life traumas. CONCLUSIONS: Combat-related PTSD in males is associated with higher levels of pro-inflammatory cytokines, even after accounting for depression and early life trauma. These results, from one of the largest studies of inflammatory cytokines in PTSD to date, suggest that immune activation may be a core element of PTSD pathophysiology more so than a signature of combat exposure alone.

Peripheral serotonin levels as a predictor of antidepressant treatment response: A systematic review.

There are currently no reliable biomarkers to predict clinical response to pharmacological treatments of depressive disorders. Peripheral blood 5-hydroxytryptamine (5-HT; serotonin) has been suggested as a biomarker of antidepressant treatment response, but there has not been an attempt to systematically summarize and evaluate the scientific evidence of this hypothesis. In this systematic review we searched MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials. Twenty-six relevant studies investigating peripheral 5-HT as an antidepressant biomarker were identified. In all, we did not find robust support for an association between baseline 5-HT and treatment response. Several larger studies with lower risk of bias, however, showed that higher baseline 5-HT was associated with a greater antidepressant response to SSRIs, prompting future studies to investigate this hypothesis. Our results also confirm previous reports that SSRI treatment is associated with a decrease in peripheral 5-HT levels; however, we were not able to confirm that larger decreases of 5-HT are associated with better treatment outcome as results were inconclusive.

Inflammatory depression is associated with selective glomerular hypofiltration.

BACKGROUND: Systemic low-grade inflammation may be a pathophysiological mechanism in a subtype of depression. In this study we investigate a novel candidate mechanism of inflammatory depression - Selective Glomerular Hypofiltration Syndromes (SGHS) - which are characterized by a reduced estimated glomerular filtration rate (eGFR) based on cystatin C (cysC) relative to eGFR based on creatinine (crea). SGHS have been associated with increased blood levels of pro-inflammatory markers, but have never been investigated in a sample of depressed individuals. METHOD: The prevalence of SGHS was compared between 313 patients with difficult-to-treat depression and 73 controls. Since there is no single established eGFRcysC/eGFRcrea-ratio cut-off to define SGHS, several cut-offs were investigated in relation to a depression diagnosis, inflammation, and symptom severity. Plasma inflammatory markers tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interleukin (IL)-6, IL-8, and IL-10 were available from 276 depressed patients. We examined mediation effects of IL-6 on the relationship between SGHS and depression. RESULTS: Depressed patients were more likely to have SGHS compared to controls defining SGHS as either eGFRcysC/eGFRcrea-ratio < 0.9 (33.2 % vs 20.5 %, p = 0.035) or < 0.8 (15.7 % vs 5.5 %, p = 0.023). Lower eGFRcysC/eGFRcrea-ratio was associated with higher levels of inflammatory markers in depressed patients. IL-6 partly mediated the relationship between SGHS and depression. CONCLUSION: This is the first study to demonstrate a link between SGHS and inflammatory depression. If replicated in independent and longitudinal cohorts, this may prove to be a relevant pathophysiological mechanism in some cases of depression that could be targeted in future intervention and prevention studies.

Circulating cell-free mitochondrial DNA levels and glucocorticoid sensitivity in a cohort of male veterans with and without combat-related PTSD.

Circulating cell-free mitochondrial DNA (ccf-mtDNA) is a biomarker of cellular injury or cellular stress and is a potential novel biomarker of psychological stress and of various brain, somatic, and psychiatric disorders. No studies have yet analyzed ccf-mtDNA levels in post-traumatic stress disorder (PTSD), despite evidence of mitochondrial dysfunction in this condition. In the current study, we compared plasma ccf-mtDNA levels in combat trauma-exposed male veterans with PTSD (n = 111) with those who did not develop PTSD (n = 121) and also investigated the relationship between ccf mt-DNA levels and glucocorticoid sensitivity. In unadjusted analyses, ccf-mtDNA levels did not differ significantly between the PTSD and non-PTSD groups (t = 1.312, p = 0.191, Cohen's d = 0.172). In a sensitivity analysis excluding participants with diabetes and those using antidepressant medication and controlling for age, the PTSD group had lower ccf-mtDNA levels than did the non-PTSD group (F(1, 179) = 5.971, p = 0.016, partial η2 = 0.033). Across the entire sample, ccf-mtDNA levels were negatively correlated with post-dexamethasone adrenocorticotropic hormone (ACTH) decline (r = -0.171, p = 0.020) and cortisol decline (r = -0.149, p = 0.034) (viz., greater ACTH and cortisol suppression was associated with lower ccf-mtDNA levels) both with and without controlling for age, antidepressant status and diabetes status. Ccf-mtDNA levels were also significantly positively associated with IC50-DEX (the concentration of dexamethasone at which 50% of lysozyme activity is inhibited), a measure of lymphocyte glucocorticoid sensitivity, after controlling for age, antidepressant status, and diabetes status (ß = 0.142, p = 0.038), suggesting that increased lymphocyte glucocorticoid sensitivity is associated with lower ccf-mtDNA levels. Although no overall group differences were found in unadjusted analyses, excluding subjects with diabetes and those taking antidepressants, which may affect ccf-mtDNA levels, as well as controlling for age, revealed decreased ccf-mtDNA levels in PTSD. In both adjusted and unadjusted analyses, low ccf-mtDNA levels were associated with relatively increased glucocorticoid sensitivity, often reported in PTSD, suggesting a link between mitochondrial and glucocorticoid-related abnormalities in PTSD.