Serum brain-derived neurotrophic factor, Val66Met polymorphism and open-label SSRI treatment response in Major Depressive Disorder.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) has been implicated in the therapeutic action of antidepressants and possibly in the pathophysiology of Major Depressive Disorder (MDD). Clinical studies of peripheral blood levels of BDNF in MDD have provided conflicting results, and there are also conflicting reports regarding the predictive value of peripheral BDNF levels for antidepressant treatment response. The present study investigated the association between serum BDNF levels, the BDNF Val66Met polymorphism (rs6265), clinical characteristics and SSRI treatment response. METHODS: This open-label clinical trial included 99 physically healthy, unmedicated MDD participants and 70 healthy controls. Following a baseline assessment, 53 of the MDD participants completed an eight-week, open-label course of SSRI antidepressant treatment. Serum BDNF levels and Hamilton Rating Scale for Depression (HDRS) ratings were examined at baseline and after eight weeks of treatment. Antidepressant response was defined as a decrease in HDRS ratings of > 50% from baseline to the end-of-treatment. Finally, serum BDNF levels and SSRI treatment response were compared between MDD participants who were heterozygous or homozygous for the Met allele ("Met-carriers") and individuals homozygous for the Val allele. RESULTS: Serum BDNF levels at baseline were significantly higher in the unmedicated MDD participants compared to healthy controls (15.90 ng/ml vs 13.75 ng/ml, t (167) = -2.041, p = 0.043). In a post-hoc analysis, this difference was seen in the female but not male participants (16.85 ng/ml vs 14.06 ng/ml, t (91) = -2.067, p = 0.042; 14.86 ng/ml vs 13.31 ng/ml, t (74) = -0.923, p = 0.359). Baseline serum BDNF levels were not associated with treatment responder status or with absolute change in depression ratings over the course of 8-week SSRI treatment (p = 0.599). In both Responders and Non-responders, no significant changes in serum BDNF levels were found over the 8-week period of SSRI-treatment (16.32 ng/ml vs 16.23 ng/ml, t (18) = 0.060, p = 0.953; 16.04 ng/ml vs 15.61 ng/ml, t (29) = 0.438, p = 0.665, respectively). Further, no differences were found in serum BDNF levels prior to treatment between MDD Met-carriers and MDD Val/Val homozygotes (15.32 ng/ml vs 16.36 ng/ml, t (85) = 0.747, p = 0.457), and no differences were found in post-treatment serum BDNF (F1,42= 0.031, p = 0.862). However, MDD Val/Val homozygotes showed significantly greater antidepressant responses at week 8 than did MDD Met-carriers (F1,46 = 4.366, p = 0.043). CONCLUSION: Our results do not support sufficient reliability of using peripheral BDNF to characterize depression or to predict antidepressant response in clinical use. The role of sex in moderating BDNF differences in depression, and the role of BDNF gene polymorphisms in predicting antidepressant response, remain to be further investigated. We conclude that, while central nervous system BDNF is likely involved in antidepressant efficacy and in aspects of MDD pathophysiology, its reflection in serum BDNF levels is of limited diagnostic or prognostic utility.

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.

Shorter telomere length predicts poor antidepressant response and poorer cardiometabolic indices in major depression.

Telomere length (TL) is a marker of biological aging, and shorter telomeres have been associated with several medical and psychiatric disorders, including cardiometabolic dysregulation and Major Depressive Disorder (MDD). In addition, studies have shown shorter TL to be associated with poorer response to certain psychotropic medications, and our previous work suggested shorter TL and higher telomerase activity (TA) predicts poorer response to Selective Serotonin Reuptake Inhibitor (SSRI) treatment. Using a new group of unmedicated medically healthy individuals with MDD (n = 48), we sought to replicate our prior findings demonstrating that peripheral blood mononuclear cell (PBMC) TL and TA predict response to SSRI treatment and to identify associations between TL and TA with biological stress mediators and cardiometabolic risk indices. Our results demonstrate that longer pre-treatment TL was associated with better response to SSRI treatment (ß = .407 p = .007). Additionally, we observed that TL had a negative relationship with allostatic load (ß = - .320 p = .017) and a cardiometabolic risk score (ß = - .300 p = .025). Our results suggest that PBMC TL reflects, in part, the cumulative effects of physiological stress and cardiovascular risk in MDD and may be a biomarker for predicting SSRI response.

Dimensions of childhood adversity differentially affect biological aging in major depression.

Adverse childhood experiences have been consistently linked with physical and mental health disorders in adulthood that may be mediated, in part, via the effects of such exposures on biological aging. Using recently developed "epigenetic clocks", which provide an estimate of biological age, several studies have demonstrated a link between the cumulative exposure to childhood adversities and accelerated epigenetic aging. However, not all childhood adversities are equivalent and less is known about how distinct dimensions of childhood adversity relate to epigenetic aging metrics. Using two measures of childhood adversity exposure, we assess how the dimensions of Maltreatment and Household Dysfunction relate to epigenetic aging using two "second-generation" clocks, GrimAge and PhenoAge, in a cohort of unmedicated somatically healthy adults with moderate to severe major depression (n = 82). Our results demonstrate that the dimension of Maltreatment is associated with epigenetic age acceleration (EAA) using the PhenoAge but not the GrimAge clock. This association was observed using both the Childhood Trauma questionnaire (CTQ; ß = 0.272, p = 0.013) and the Adverse Childhood Experiences (ACEs) questionnaire (ß = 0.307, p = 0.005) and remained significant when adjusting for exposure to the dimension of Household Dysfunction (ß = 0.322, p = 0.009). In contrast, the dimension of Household Dysfunction is associated with epigenetic age deceleration (ß = -0.194, p = 0.083) which achieved significance after adjusting for exposure to the dimension of Maltreatment (ß = -0.304, p = 0.022). This study is the first to investigate these effects among individuals with Major Depressive Disorder and suggests that these dimensions of adversity may be associated with disease via distinct biological mechanisms.

Serum brain-derived neurotrophic factor remains elevated after long term follow-up of combat veterans with chronic post-traumatic stress disorder.

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 < 0.001]. This difference remained significant after excluding individuals with comorbid major depressive disorder, antidepressant users and controlling for age, gender, race, BMI, and time since trauma. Fifty-nine of the male veterans who participated at the first timepoint (T0) were re-assessed at follow-up evaluation (T1), approximately 3 years (SD=0.88 years) after T0. A one-way ANOVA comparing PTSD positive, "subthreshold PTSD" and control groups revealed that serum BDNF remained significantly higher in the PTSD positive group than the control group at T1 [30.05 vs 24.66 ng/mL, F(2, 56)= 3.420, p = 0.040]. Serum BDNF levels did not correlate with PTSD symptom severity at either time point within the PTSD group [r(128) = 0.062, p = 0.481 and r(28) = 0.157, p = 0.407]. Serum BDNF did not significantly change over time within subjects [t(56) = 1.269, p = 0.210] nor did the change of serum BDNF from T0 to T1 correlate with change in PTSD symptom severity within those who were diagnosed with PTSD at T0 [r(27) = -0.250, p = 0.192]. Our longitudinal data are the first to be reported in combat PTSD and suggest that higher serum BDNF levels may be a stable biological characteristic of chronic combat PTSD independent of symptom severity.

"GrimAge," an epigenetic predictor of mortality, is accelerated in major depressive disorder.

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.

Posttraumatic stress or posttraumatic growth? Using network analysis to explore the relationships between coping styles and trauma outcomes.

Trauma can produce posttraumatic stress disorder (PTSD), but may also foster positive outcomes, such as posttraumatic growth. Individual differences in coping styles may contribute to both positive and negative sequelae of trauma. Using network analytic methods, we investigated the structure of PTSD symptoms, elements of growth, and coping styles in bereaved survivors of a major earthquake in China. Hypervigilance and difficulty concentrating were identified as the most central symptoms in the PTSD network, whereas establishing a new path in life, feeling closer to others, and doing better things with life ranked highest on centrality in the posttraumatic growth network. Direct connections between PTSD symptoms and elements of growth were low in magnitude in our sample. Our final network, which included PTSD symptoms, growth elements, and coping styles, suggests that adaptive and active coping styles, such as positive reframing, are positively related to elements of growth, but not appreciably negatively related to PTSD symptoms. Conversely, maladaptive coping styles are positively related to PTSD symptoms, but are not negatively associated with growth. Future longitudinal studies could shed light on the direction of causality in these relationships and their clinical utility.

A DNA methylation clock associated with age-related illnesses and mortality is accelerated in men with combat PTSD.

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.

Effect of Combat Exposure and Posttraumatic Stress Disorder on Telomere Length and Amygdala Volume.

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.

Low serum brain-derived neurotrophic factor is associated with suicidal ideation in major depressive disorder.

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.

Exercise and emotion dynamics: An experience sampling study.

Though it has been widely demonstrated that regular exercise is associated with better emotional wellbeing, the nature of this association remains unclear. The present study explored the relationship between voluntary exercise and the temporal dynamics of daily emotions, and thus how voluntary exercise could be impacting emotional reactivity and recovery in naturalistic contexts. Seventy-six young adults participated simultaneously in this ecological momentary assessment study, and received 75 prompts over the course of 15 days. Emotional inertia (persistence of emotional states), emotional variability (intensity of emotional fluctuations), and emotional instability (tendency for emotional fluctuations) were considered. Past research has shown that low wellbeing tends to be associated with high inertia, variability, and instability. Each prompt included ratings of present emotions (anxiety, sadness, cheerfulness, contentment) and any recent physical activity. Greater average exercise time was significantly associated with less inertia (reduced autocorrelation) of anxiety. Exercise was not significantly associated with inertia of the other emotions, although results were in the same direction. Exercise habits were unrelated to emotional variability and instability. Results suggest that exercise may buffer against prolonged or persistent negative affective states and consequently could benefit a person's ability to self-regulate or recover from changes in the environment and internal emotional experiences, rather than simply reducing the frequency or intensity of anxious emotions. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Cognitive and emotional processing of pleasant and unpleasant experiences in major depression: A matter of vantage point?

BACKGROUND AND OBJECTIVES: In nonclinical populations, adopting a third-person perspective as opposed to a first-person perspective while analyzing negative emotional experiences fosters understanding of these experiences and reduces negative emotional reactivity. We assessed whether this generalizes to people with major depression (MD). Additionally, we assessed whether the emotion-reducing effects of adopting a third-person perspective also occur when subjects with MD and HC subjects analyze positive experiences. METHODS: Seventy-two MD subjects and 82 HC subjects analyzed a happy and a negative experience from either a first-person or a third-person perspective. RESULTS: Unexpectedly, we found no emotion-reducing effects of third-person perspective in either group thinking about negative events. However, across groups, third-person perspective was associated with less recounting of negative experiences and with a clearer, more coherent understanding of them. Negative affect decreased and positive affect increased in both groups analyzing happy experiences. In MD subjects, decreases in depressive affect were stronger for the third-person perspective. In both groups, positive affect increased and negative affect decreased more strongly for the third-person perspective. LIMITATIONS: While reflecting on their positive memory, MD subjects adopted their assigned perspective for a shorter amount of time (70%) than HC subjects (78%). However, percentage of time participants adopted their assigned perspective was unrelated to the significant effects we found. CONCLUSIONS: Both people suffering from MD and healthy individuals may benefit from processing pleasant experiences, especially when adopting a self-distant perspective.

How Smart are Smartphone Apps for Smoking Cessation? A Content Analysis.

INTRODUCTION: Smartphone technology is ideally suited to provide tailored smoking cessation support, yet it is unclear to what extent currently existing smartphone "apps" use tailoring, and if tailoring is related to app popularity and user-rated quality. METHODS: We conducted a content analysis of Android smoking cessation apps (n = 225), downloaded between October 1, 2013 to May 31, 2014. We recorded app popularity (>10,000 downloads) and user-rated quality (number of stars) from Google Play, and coded the existence of tailoring features in the apps within the context of using the 5As ("ask," "advise," "assess," "assist," and "arrange follow-up"), as recommended by national clinical practice guidelines. RESULTS: Apps largely provided simplistic tools (eg, calculators, trackers), and used tailoring sparingly: on average, apps addressed 2.1 ± 0.9 of the 5As and used tailoring for 0.7 ± 0.9 of the 5As. Tailoring was positively related to app popularity and user-rated quality: apps that used two-way interactions (odds ratio [OR] = 5.56 [2.45-12.62]), proactive alerts (OR = 3.80 [1.54-9.38]), responsiveness to quit status (OR = 5.28 [2.18-12.79]), addressed more of the 5As (OR = 1.53 [1.10-2.14]), used tailoring for more As (OR = 1.67 [1.21-2.30]), and/or used more ways of tailoring 5As content (OR = 1.35 [1.13-1.62]) were more likely to be frequently downloaded. Higher star ratings were associated with a higher number of 5As addressed (b = 0.16 [0.03-0.30]), a higher number of 5As with any level of tailoring (b = 0.14 [0.01-0.27]), and a higher number of ways of tailoring 5As content (b = 0.08 [0.002-0.15]). CONCLUSIONS: Publically available smartphone smoking cessation apps are not particularly "smart": they commonly fall short of providing tailored feedback, despite users' preference for these features.