Non-depressed Controls Research Articles

Reward-Processing Behavior in Depressed Participants Relative to Healthy Volunteers

Dysfunctional reward processing is a leading candidate mechanism for the development of certain depressive symptoms, such as anhedonia. However, to our knowledge, there has not yet been a systematic assessment of whether and to what extent depression is associated with impairments on behavioral reward-processing tasks. To determine whether depression is associated with impairments in reward-processing behavior. The MEDLINE/PubMed, Embase, and PsycInfo databases were searched for studies that investigated reward processing using performance on behavioral tasks by individuals with depression and nondepressed control groups, published between January 1, 1946, and August 16, 2019. Studies that contained data regarding performance by depressed and healthy control groups on reward-processing tasks were included in the systematic review and meta-analysis. Summary statistics comparing performance between depressed and healthy groups on reward-processing tasks were converted to standardized mean difference (SMD) scores, from which summary effect sizes for overall impairment in reward processing and 4 subcomponent categories were calculated. Study quality, heterogeneity, replicability-index, and publication bias were also assessed. Performance on reward-processing tasks. The final data set comprised 48 case-control studies (1387 healthy control individuals and 1767 individuals with major depressive disorder). The mean age was 37.85 years and 58% of the participants were women. These studies used tasks assessing option valuation (n = 9), reward bias (n = 6), reward response vigor (n = 12), reinforcement learning (n = 20), and grip force (n = 1). Across all tasks, depression was associated with small to medium impairments in reward-processing behavior (SMD = 0.345; 95% CI, 0.209-0.480). When examining reward-processing subcomponent categories, impairment was associated with tasks assessing option valuation (SMD = 0.309; 95% CI, 0.147-0.471), reward bias (SMD = 0.644; 95% CI, 0.270-1.017), and reinforcement learning (SMD = 0.352; 95% CI, 0.115-0.588) but not reward response vigor (SMD = 0.083; 95% CI, -0.144 to 0.309). The medication status of the major depressive disorder sample did not explain any of the variance in the overall effect size. There was significant between-study heterogeneity overall and in all subcomponent categories other than option valuation. Significant publication bias was identified overall and in the reinforcement learning category. Relative to healthy control individuals, individuals with depression exhibit reward-processing impairments, particularly for tests of reward bias, option valuation, and reinforcement learning. Understanding the neural mechanisms driving these associations may assist in designing novel interventions.

The roles of comorbidity and trauma exposure and its timing in shaping HPA axis patterns in depression

BackgroundMuch work has documented hypothalamic pituitary adrenal (HPA) axis abnormalities in major depressive disorder (MDD), but inconsistencies leave this system’s role in the illness unclear. Comparisons across studies are complicated by variation in co-morbidity (Posttraumatic Stress Disorder-PTSD, anxiety disorders), exposure to trauma, and timing of trauma (child vs. adult). Here, we examined the impact of these factors on HPA axis profiles in depression. MethodsWe recruited 5 groups of participants: MDD (n = 14), comorbid MDD + PTSD following adulthood trauma (MDD + PTSD-Adult; n = 12), comorbid MDD + PTSD following childhood trauma (MDD + PTSD-Child; n = 18), comorbid MDD + social anxiety disorder (MDD + SAD; n = 12), and non-depressed control participants who were sex and age matched to patients (combined total n = 36). HPA axis function was assessed using three challenges: stress reactivity via the Trier Social Stress Test (TSST), feedback sensitivity via a dexamethasone suppression test (DST), and central drive via a metyrapone challenge (MET). We compared hormonal responses between patient groups and their respective non-depressed controls. ResultsMDD + PTSD-Child showed low cortisol levels at baseline, and reduced adrenocorticotropic hormone (ACTH) levels at baseline and throughout the TSST. MDD-only, MDD + PTSD-Adult, and MDD + SAD did not differ from non-depressed controls in HPA axis responses to the TSST. Controlling for childhood trauma severity, the reduced baseline levels in MDD + PTSD-Child were no longer significant and significantly reduced baseline cortisol levels emerged for MDD + PTSD-Adult. No diagnostic group effects were detected with DST and MET. Childhood maltreatment subtypes were associated with unique HPA axis responses to TSST and MET. ConclusionComorbidity and trauma exposure, as well as their timing and type, contribute to inconsistencies in the depression literature and must be included in efforts to clarify the role of the HPA axis in MDD.

Pro-inflammatory markers and fatigue in patients with depression: A case-control study

The aim of this work was to investigate differences between depressed subjects (PG) and non-depressed healthy control participants (HCG) with regard to fatigue dimensions and inflammation. For this purpose, 43 participants in the PG and 51 participants in the HCG were included in the study. IL-6, IL-1β, TNF-α, IFN-γ, and CRP were assessed in venous blood samples. Fatigue and depression were assessed using the FIS-D and BDI-FS questionnaires. Main results showed higher BDI-FS values in PG. Moreover, PG showed mean differences for fatigue dimensions when compared to the HCG. For the pro-inflammatory markers, a moderate group effect was found between PG and HCG which was mainly caused by IL-6. Correlations between TNF-α and BDI-FS, TNF-α and cognitive fatigue, TNF-α and psychosocial fatigue were found within the PG. In the HCG, correlations were found between IL-6, TNF-α and somatic fatigue, as well as IL-6 and cognitive fatigue. Significant correlations were found between the psychological variables in both groups. All results were controlled for the confounding variables gender, age, BMI and multiple comparisons. These results suggest the presence of inflammation in both depression and fatigue. However, each correlates with different pro-inflammatory parameters, suggesting a biological heterogeneity.

Major Depressive Disorder is Associated with Impaired Mitochondrial Function in Skin Fibroblasts.

Mitochondrial malfunction is supposed to be involved in the etiology and pathology of major depressive disorder (MDD). Here, we aimed to identify and characterize the molecular pathomechanisms related to mitochondrial dysfunction in adult human skin fibroblasts, which were derived from MDD patients or non-depressive control subjects. We found that MDD fibroblasts showed significantly impaired mitochondrial functioning: basal and maximal respiration, spare respiratory capacity, non-mitochondrial respiration and adenosine triphosphate (ATP)-related oxygen consumption was lower. Moreover, MDD fibroblasts harbor lower ATP levels and showed hyperpolarized mitochondrial membrane potential. To investigate cellular resilience, we challenged both groups of fibroblasts with hormonal (dexamethasone) or metabolic (galactose) stress for one week, and found that both stressors increased oxygen consumption but lowered ATP content in MDD as well as in non-depressive control fibroblasts. Interestingly, the bioenergetic differences between fibroblasts from MDD or non-depressed subjects, which were observed under non-treated conditions, could not be detected after stress. Our findings support the hypothesis that altered mitochondrial function causes a bioenergetic imbalance, which is associated with the molecular pathophysiology of MDD. The observed alterations in the oxidative phosphorylation system (OXPHOS) and other mitochondria-related properties represent a basis for further investigations of pathophysiological mechanisms and might open new ways to gain insight into antidepressant signaling pathways.

COGNITION AND LATE-LIFE SUICIDE: COGNITIVE PROFILES AMONG DEPRESSED SUICIDAL SUBGROUPS AS A FUNCTION OF MEDICAL SERIOUSNESS AND ONSET OF SUICIDAL BEHAVIOR

Introduction Depressed older adults are at high-risk for suicidal behavior (Pfeiffer et al., 2013, Vannoy et al., 2007) and for developing dementia (Kaup et al, 2016; Mizra et al., 2016). Executive dysfunction has been described across the life-span in suicide attempters (Keilp et al., 2013, Clark et al., 2011, Richards-Devantoy et al., 2012). However, few studies have explored the links between several domains of cognition and suicide risk in those with late-life depression and the extant evidence is equivocal at best (Conejero et al., 2018, Tu et al., 2018, Erlangsen et al., 2008). Suicidal behavior is heterogeneous, and it is unclear whether the medical seriousness (Beck et al., 1975) of the suicide attempt or whether the onset of first suicidal behavior (initiated earlier in life relative to late-life (60+ years)) relates differently to cognitive deficits. Methods This project uses a case-control design and includes 278 adults aged 50?years and older: 56 non-depressed controls (no life-time history of psychiatric disorder), 67 non-suicidal depressed older adults(no life-time history of suicide ideation or suicide attempt), 63 depressed suicide ideators, and 92 depressed adults with a history of suicide attempt. Analysis 1 examined cognitive profiles of low (n=52) vs. high-lethality (i.e., potentially fatal without medical intervention) (n=40) suicide attempters relative to non-suicidal depressed older adults and non-depressed controls. Analysis 2 examined cognitive profiles of those making their first suicide attempt prior to age 60 (early onset: n=66) and those making their first suicide attempt at or after age 60 (late-onset: n=26) relative to non-suicidal depressed older adults and non-depressed controls. Lethality of attempt was similarly distributed across early- and late-onset attempters. Depression severity was assessed using the Hamilton Depression Rating Scale (HAM-D-17 minus the suicide item). Cognitive functioning was assessed using the Repeatable Battery of Neuropsychological Status (RBANS) and the Trail Making Test from the Delis Kaplan Executive Functioning System (D-KEFS). Linear mixed effects models were used for assessing group differences cognitive domains assessed using multiple subtests or trials (i.e., learning and memory) and linear regression was used for cognitive domains assessed using a single test (i.e., processing speed, executive functioning). Demographic covariates were used for all data analyses (i.e., age, sex, education). Analyses comparing suicidal subgroups with non-suicidal depressed older adults additionally adjusted for depression severity and lifetime history of anxiety and substance use disorders. Results High-lethality attempters performed worse than low-lethality attempters and non-depressed controls on measures of verbal memory (Linear mixed effects model; group x test interaction: F=1.997, p=0.03). On a measure of executive functioning, low- but not high-lethality attempters performed worse than non-suicidal depressed older adults (LL: Beta= -0.18, p=0.01; HL: Beta=-0.12, p=0.08) and non-depressed controls (LL: Beta=0.31, p Conclusions Cognitive profiles of older suicidal attempters varied based on the lethality of most lethal suicide attempt and age of first suicide attempt. Those with low-lethality and early-onset suicide attempts exhibited executive dysfunction relative to non-suicidal depressed older adults, in-line with previous findings indicating executive dysfunction as part of life-long suicide vulnerability factors. In contrast, late-onset attempters exhibited slower processing speed relative to non-suicidal depressed older adults, and high-lethality attempters performed worse on memory measures relative to low-lethality attempters, possibly indicating a dementia prodrome. This research was funded by: NIMH: R01 MH085651; VA VISN 4 MIRECC Advanced Research Fellowship, VA Office of Academic Affiliations

Sad as a Matter of Evidence: The Desire for Self-Verification Motivates the Pursuit of Sadness in Clinical Depression.

BackgroundResearch on desired emotions revealed that individuals want to feel negative emotions if they expect these emotions to yield certain benefits. In previous studies, the pursuit of sadness (e.g., via pursuing art that evokes sadness) has been attributed to hedonic motives, i.e., to feel pleasure. We propose that in individuals with major depressive disorder (MDD) the pursuit of sadness may be more strongly related to self-verification motives, i.e., to sustain their sense of self through feeling sad.MethodsParticipants with MDD (n = 50) were compared to non-depressed controls (n = 50) in their desired emotional states, as indicated by selected music (sad, happy and neutral), and in their motives (hedonic vs. self-verification) for choosing sad music. Groups were also compared in their self-reported general preference for sadness and the perceived functionality of sadness.ResultsMDD participants showed a significant higher desire for sadness; more than half of them deliberately chose sad music. Whereas MDD participants had a marked preference for self-verification over hedonic motives, the reverse was true for non-depressed controls. MDD participants also agreed more strongly with self-verifying functions of sadness and expressed a stronger general preference for sadness.ConclusionFindings indicate that emotion regulation in MDD might be driven by self-verification motives. They point to the relevance of exploring patients’ desired emotional states and associated motives. The systematic integration of positive affect into the self-image of depressed patients might help to deemphasize the self-verifying function of sadness, thereby overcoming the depression.

Exploratory study on the role of emotion regulation in perceived valence, humour, and beneficial use of depressive internet memes in depression

This study examined whether individuals experiencing significant depressive symptoms would differ from non-depressed controls in their interpretation of internet memes related to depression, whilst incorporating the mediating role of emotion regulation difficulty. Forty-three individuals presenting clinically significant depressive symptoms (indicating ≥15 on the PHQ-9) and 56 non-depressed controls (indicating ≤4) rated the emotional valance, humour, relatability, shareability, and mood improving potential of 32 depressive and control (depicting general neutral or positive social commentaries) internet memes. Measures of depression and emotion dysregulation were also completed. The perception of humour, relatability, shareability and mood improving potential of depressive, but not control, memes were all greater amongst individuals with symptoms of depression relative to controls. However, these differences were mediated by deficits in the ability to deploy adaptive emotion regulation strategies. Despite their negative orientation, internet memes related to depression may be beneficial for individuals experiencing consistent symptoms. Specifically, by potentially facilitating: a humorous take on a negative experience and situation; the perception of peer-support through affiliation with others experiencing similar symptoms; and adaptive emotion regulation strategies amongst those with deficits in the ability to deploy such strategies.

Disruption of the structural and functional connectivity of the frontoparietal network underlies symptomatic anxiety in late-life depression

The present study investigated functional connectivity and white matter integrity of the fronto-parietal network (FPN) to reveal the neural mechanisms that underlie late-life depression (LLD). Fifty patients with LLD and 40 non-depressed controls were included in the study. A multi-parametric approach was used by applying independent component analysis (ICA) to estimate functional connectivity of the FPN and by applying tract­based spatial statistics to examine white-matter integrity in tracts to the FPN. Patients with LLD exhibited functional abnormalities in the right inferior frontal gyrus, middle frontal gyrus, and inferior parietal gyrus and lower white matter fractional anisotropy in the right inferior fronto-occipital fasciculus, anterior thalamic radiation, and uncinate fasciculus. Alterations of functional connectivity and white matter fractional anisotropy in these regions were negatively correlated with the severity of symptomatic anxiety in LLD patients. The right inferior frontal gyrus might be a crucial hub in transferring information between these abnormal regions. Significant correlations were found between anxiety symptoms and brain alterations, suggesting that impairments in the FPN network might be involved in symptomatic anxiety in elderly individuals with depression.

Effects of acute transcutaneous vagus nerve stimulation on emotion recognition in adolescent depression.

Transcutaneous vagus nerve stimulation (tVNS) is a promising therapeutic option for major depressive disorder (MDD) in adults. Alternative third-line treatments for MDD in adolescents are scarce. Here we aimed to assess the effects of acute tVNS on emotion recognition in adolescents with MDD. Adolescents (14-17 years) with MDD (n = 33) and non-depressed controls (n = 30) received tVNS or sham-stimulation in a cross-sectional, case-control, within-subject cross-randomized controlled trial, while performing different tasks assessing emotion recognition. Correct responses, response times, and errors of omission and commission on three different computerized emotion recognition tasks were assessed as main outcomes. Simultaneous recordings of electrocardiography and electro dermal activity, as well as sampling of saliva for the determination of α-amylase, were used to quantify the effects on autonomic nervous system function. tVNS had no effect on the recognition of gradually or static expressed emotions but altered response inhibition on the emotional Go/NoGo-task. Specifically, tVNS increased the likelihood of omitting a response toward sad target-stimuli in adolescents with MDD, while decreasing errors (independent of the target emotion) in controls. Effects of acute tVNS on autonomic nervous system function were found in non-depressed controls only. Acute tVNS alters the recognition of briefly presented facial expressions of negative valence in adolescents with MDD while generally increasing emotion recognition in controls. tVNS seems to specifically alter early visual processing of stimuli of negative emotional valence in MDD. These findings suggest a potential therapeutic benefit of tVNS in adolescent MDD that requires further evaluation within clinical trials.

Association of platelet function with depression and its treatment with sertraline in patients with chronic kidney disease: analysis of a randomized trial

BackgroundMajor Depressive Disorder (MDD) can lead to adverse cardiovascular outcomes in patients with chronic kidney disease (CKD). Although one of the proposed mechanisms is heightened platelet activation, effects of MDD and its treatment with a selective serotonin reuptake inhibitor (SSRI) on platelet function in patients with CKD remain unclear.MethodsIn a pre-specified analysis, changes from baseline to 12 weeks in whole blood platelet aggregation (WBPA) and plasma levels of E-selectin and P-selectin on treatment with sertraline vs. placebo were investigated in 175 patients with CKD (estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73m2) and MDD (MDD+/CKD+) in a randomized, double-blind trial. Correlations between severity of depressive symptoms and platelet function were also analyzed. In order to investigate whether differences in platelet function were due to presence of CKD or MDD, we compared a subgroup of 49 MDD+/CKD+ patients with eGFR < 30 ml/min/1.73m2 to 43 non-depressed CKD controls (28 CKD with eGFR < 30 ml/min/1.73m2 [MDD−/CKD+] and 15 individuals with eGFR ≥90 ml/min/1.73m2 [MDD−/CKD-].ResultsIn MDD+/CKD+ individuals, there were no significant correlations between severity of depressive symptoms and platelet function, and no significant changes in platelet function after 12 weeks of treatment with sertraline vs. placebo. There were no significant differences in platelet function among MDD+/CKD+ patients and controls without MDD except in WBPA to 10 μM ADP (P = 0.03). WBPA to ADP was lower in the MDD−/CKD- group (8.0 Ω [5.0 Ω, 11.0 Ω]) as compared to the MDD−/CKD+ group (12.5 Ω [8.0 Ω, 14.5 Ω]), P = 0.01, and the MDD+/CKD+ group (11.0 Ω [8.0 Ω, 15.0 Ω]), P < 0.01.ConclusionsHeightened ADP-induced platelet aggregability was observed in CKD patients compared to controls with normal kidney function, regardless of presence of comorbid MDD, and treatment with sertraline did not affect platelet function. These findings suggest that increased platelet activation may not be a major contributory underlying mechanism by which depression may lead to worse cardiovascular outcomes in patients with CKD. Future studies should include positive MDD controls without CKD to confirm our findings.Trial registrationClinicalTrials.gov identifier numbers: CAST Study: NCT00946998 (Recruitment Status: Completed. First Posted: July 27, 2009. Results First Posted: January 30, 2018). WiCKDonASA Study: NCT01768637 (Recruitment Status: Completed. First Posted: January 15, 2013. Results First Posted: April 19, 2019).

Five Personality Traits in Late-onset Depression in Hong Kong.

This study aimed to examine the association between five personality traits and late-onset depression in Hong Kong older people. This cross-sectional study included a convenience sample of 40 older people with late-onset depression (LOD) and 54 non-depressed elderly controls. The patients were assessed using the NEO Five Factor Inventory (for personality), the Hamilton Depression Rating Scale (for depression severity), the Mini-Mental State Examination (for cognitive function), the Lawton Instrumental Activities of Daily Living (for functioning), and the Cumulative Illness Rating Scale (for number of physical illnesses). The LOD group had a higher Hamilton Depression Rating Scale score (18.9 vs 3.7, p < 0.001), lower Mini Mental State Examination score (24.9 vs 26.4, p = 0.004), and lower Instrumental Activities of Daily Living scale score (21.9 vs 23.7, p = 0.013). On the NEO Five Factor Inventory, the LOD group had a higher neuroticism score (30.7 vs 17.5, p < 0.001) and lower scores on extraversion (19.0 vs 26.4, p < 0.001), openness (18.9 vs 21.5, p = 0.026), and conscientiousness (29.1 vs 33.8, p < 0.001). Neuroticism was the only significant predictor of LOD (odds ratio = 2.325, p = 0.001) and the only significant factor associated with depression severity (β = 0.581, p = 0.003). The personality trait of neuroticism is associated with LOD and its severity. Assessment of personality traits should be included in the assessment of people with depression.

Brain Changes Induced by Electroconvulsive Therapy Are Broadly Distributed

BackgroundElectroconvulsive therapy (ECT) is associated with volumetric enlargements of corticolimbic brain regions. However, the pattern of whole-brain structural alterations following ECT remains unresolved. Here, we examined the longitudinal effects of ECT on global and local variations in gray matter, white matter, and ventricle volumes in patients with major depressive disorder as well as predictors of ECT-related clinical response. MethodsLongitudinal magnetic resonance imaging and clinical data from the Global ECT-MRI Research Collaboration (GEMRIC) were used to investigate changes in white matter, gray matter, and ventricle volumes before and after ECT in 328 patients experiencing a major depressive episode. In addition, 95 nondepressed control subjects were scanned twice. We performed a mega-analysis of single subject data from 14 independent GEMRIC sites. ResultsVolumetric increases occurred in 79 of 84 gray matter regions of interest. In total, the cortical volume increased by mean ± SD of 1.04 ± 1.03% (Cohen’s d = 1.01, p < .001) and the subcortical gray matter volume increased by 1.47 ± 1.05% (d = 1.40, p < .001) in patients. The subcortical gray matter increase was negatively associated with total ventricle volume (Spearman’s rank correlation ρ = −.44, p < .001), while total white matter volume remained unchanged (d = −0.05, p = .41). The changes were modulated by number of ECTs and mode of electrode placements. However, the gray matter volumetric enlargements were not associated with clinical outcome. ConclusionsThe findings suggest that ECT induces gray matter volumetric increases that are broadly distributed. However, gross volumetric increases of specific anatomically defined regions may not serve as feasible biomarkers of clinical response.

Parent\u2013youth conflict as a predictor of depression in adulthood: a 15-year follow-up of a community-based cohort

Experiencing conflictual relations with one’s parents while growing up has been linked to onset, recurrence, and worse treatment outcome of adolescent depression. While this suggests that significant problems in the parent–youth relationship make depressive disorders more relentless, it is not clear whether this effect lasts into adulthood. Our aim was to examine if major and minor conflict with parents while growing up predicts depression in adulthood in youth with and without a history of depression. We utilized data from the Uppsala Longitudinal Adolescent Depression Study. This community-based cohort was assessed with structured diagnostic interviews both at age 16–17 and at follow-up 15 years later. The analyses included 382 individuals (227 with a history of child or adolescent depression; 155 peers without such a history). Binary logistic regression was used, adjusting for sex, disruptive behavior disorders, and additional family-related adversities. Among individuals with adolescent depression, major conflict with parents was strongly associated with adult depression (adjusted OR 2.28, 95% CI 1.07–4.87). While major conflict with parents was rare among non-depressed controls, a non-significant association of similar magnitude was still observed. Minor conflict, on the other hand, was not significantly associated with adult depression. Overall, conflict with parents did not predict adult anxiety disorders, substance use, suicidal behavior, somatoform disorders, or psychotic disorders. In conclusion, major parent–youth conflict during upbringing seems to be linked with an increased risk of depression in adulthood. These findings underscore the need to consider contextual/familial factors in the prevention and clinical management of early-life depression.

Circadian skin temperature rhythms, circadian activity rhythms and sleep in individuals with self-reported depressive symptoms

BackgroundDisturbed circadian rhythms have been associated with depression. New body-worn devices allow the objective recording of circadian parameters such as physical activity, skin temperature and sleep. The objective of this study was to investigate whether circadian skin temperature and circadian activity rhythms are altered in depressed individuals. MethodsData on skin temperature, physical activity and sleep were available for 1610 subjects from a population-based cohort study. In a matching process two groups were formed for analysis: 121 participants with pronounced depression symptoms (CES-D Score > 21) and n = 121 matched non-depressed controls (CES-D Score < 15). Circadian rhythms were investigated by analyzing non-parametric rhythm indicators of 24-h skin temperature and physical activity data. Sleep timing, continuity and quantity were calculated from actigraphy. ResultsNo differences between the groups were found when all participants were considered. After excluding antidepressant medicated participants, the depression group was found to have a lower skin temperature amplitude t(208) = 2.45, p = .015 and a less stable skin temperature rhythm t(208) = 2.40, p = .017. The amplitude predicted the group status (beta = −5.529, p = .016). No effects were found for activity or sleep. ConclusionThe results indicate that skin-temperature rhythms are blunted in unmedicated depressed individuals. This could be a promising non-invasive marker for further analysis.

MON-449 Serum Neuroactive Steroid Levels in Postmenopausal Women with Treatment-Resistant Major Depressive Disorder

Background: Neuroactive steroids such as 3α-5α-tetrahydroprogesterone (allopregnanolone) and 5α-androstane-3α,17β-diol (3α-androstanediol) are modulators of traditional neurotransmitter receptors and have been implicated in the etiopathology of psychiatric disorders, including depression, but levels have not been assessed in women with treatment-resistant major depressive disorder (MDD). We hypothesized that allopregnanolone, 3α-androstanediol, and the ratio of these steroid levels to their precursors (progesterone and testosterone, respectively) would be lower in postmenopausal women with treatment-resistant MDD than non-depressed controls. Methods: Fasting serum neuroactive steroid levels measured by gas chromatography/mass spectrometry were compared in women with treatment-resistant MDD (MDD, n=12) [Montgomery-Asberg Depression Rating Scale (MADRS) >12 despite an adequately dosed antidepressant] and in healthy controls without depression (HC, n=28). All subjects were postmenopausal nonsmokers; none were receiving systemic estrogen. Results: Mean age and BMI did not differ between groups. In MDD, mean number of antidepressants per subject was 1.5±0.5 (SD), with 58% receiving selective serotonin reuptake inhibitors and 50% bupropion. Mean MADRS was 24.4±5.8 (moderate depression severity). In MDD vs HC, the mean allopregnanolone/progesterone ratio was lower (0.20±0.19 vs 0.47±0.46, p=0.03) and progesterone levels were higher (153±177 vs 57±50 pg/mL, p=0.04). There was no difference in mean allopregnanolone levels between groups. Compared with HC, MDD subjects had lower serum free testosterone (0.21±0.16 vs 0.38±0.18 ng/dL, p=0.006) and a trend toward lower total testosterone (13.3±5.9 vs 18.6±9.9 ng/dL, p=0.06). There was no difference in 3α-androstanediol levels or 3α-androstanediol/total testosterone ratio between groups. There was a trend toward a positive association between progesterone levels and depression severity (r=0.34, p=0.06) and an inverse association between the allopregnanolone/progesterone ratio and depression severity (r=-0.36, p=0.07). Lower free testosterone levels were associated with greater depression severity (r=-0.45, p=0.03). Conclusion: In postmenopausal women with treatment-resistant MDD, the allopregnanolone/progesterone ratio was lower and progesterone levels higher than in non-depressed controls. Allopregnanolone levels did not differ between groups. This may be due to reduced metabolism of progesterone to allopregnanolone and could have treatment implications. Additionally, testosterone levels were lower in depressed women, but there was no difference in 3α-androstanediol levels or the 3α-androstanediol/total testosterone ratio between depressed and non-depressed women, suggesting that testosterone may play a greater role in depression symptomatology than its metabolite.

Review of Abnormal Self-Knowledge in Major Depressive Disorder.

Background: Major depressive disorder (MDD) is an affective disorder that is harmful to both physical and mental health. Abnormal self-knowledge, which refers to abnormal judgments about oneself, is a core symptom of depression. However, little research has summarized how and why patients with MDD differ from healthy individuals in terms of self-knowledge.Objective: To gain a better understanding of MDD, we reviewed previous studies that focused on the behavioral and neurological changes of self-knowledge in this illness.Main Findings: On the behavioral level, depressed individuals exhibited negative self-knowledge in an explicit way, while more heterogeneous patterns were reported in implicit results. On the neurological level, depressed individuals, as compared with non-depressed controls, showed abnormal self-referential processing in both early perception and higher cognitive processing phases during the Self-Referential Encoding Task. Furthermore, fMRI studies have reported aberrant activity in the medial prefrontal cortex area for negative self-related items in depression. These results revealed several behavioral features and brain mechanisms underlying abnormal self-knowledge in depression.Future Studies: The neural mechanism of implicit self-knowledge in MDD remains unclear. Future research should examine the importance of others' attitudes on the self-concept of individuals with MDD, and whether abnormal self-views may be modified through cognitive or pharmacological approaches. In addition, differences in abnormal self-knowledge due to genetic variation between depressed and non-depressed populations remain unconfirmed. Importantly, it remains unknown whether abnormal self-knowledge could be used as a specific marker to distinguish healthy individuals from those with MDD.Conclusion: This review extends our understanding of the relationship between self-knowledge and depression by indicating several abnormalities among individuals with MDD and those who are at risk for this illness.

ASSOCIATION BETWEEN WHITE MATTER HYPERINTENSITIES, FRONTAL BRAIN VOLUMES AND NEUROTICISM IN LATE LIFE DEPRESSION

Introduction The neurobiology of neuroticism in late life depression (LLD) is understudied. Previous structural imaging research has linked both smaller hippocampal volumes and greater volume of vascular white matter changes to LLD. We hypothesized older depressed subjects scoring high in measures of neuroticism would have smaller hippocampal volumes compared with non-neurotic older depressed subjects and with non-depressed controls. Methods Non-demented subjects were recruited and were either depressed with high neuroticism, depressed with low neuroticism or not depressed (control). Neuroticism was assessed using the NEO PI. A study psychiatrist confirmed or ruled out diagnosis of depression for depressed and control subjects. Brain MRIs were performed. Results The study sample consisted of 128 older depressed subjects and 36 never depressed controls. Subjects had a mean age of 72 and were 70% female. 50% of depressed subjects scored high on the NEO-PI neuroticism measure. For outcomes focusing on white matter changes, we found that non-neurotic depressed subjects had a higher volume of white matter vascular change than did neurotic depressed subjects and non-depressed controls. For imaging outcomes focused on volumetric analyses, we several frontal lobe regions for which depressed subjects with high neuroticism scores had smaller volumes compared with non-neurotic older depressed subjects and with non-depressed controls, controlling for age and gender. These regions included frontal pole, medial orbitofrontal cortex and left pars orbitalis. We did not find significant between-group differences in hippocampal volume. Conclusions In late-life depression hippocampal volume was not associated with depression or neuroticism. Our finding that those depressed subjects low in neuroticism had higher white matter vascular change volumes is consistent with prior literature on “vascular depression.” However, our finding that those high in neuroticism had similar white matter vascular change to controls implies that there may be a different neurobiological mechanism in older neurotic depressed group. This notion is supported by our finding that several frontal lobe structures were smaller in patients who scored high in measures of neuroticism than in non-neurodepressed subjects and in non-depressed controls. Our results suggest that multiple biological pathologies that can lead to different clinical expressions of LLD. This research was funded by The Leo and Anne Albert Charitable Trust National Institute of Mental Health Grant R01 MH108578

Reduced Serum and Cerebrospinal Fluid Levels of Autotaxin in Major Depressive Disorder.

BackgroundThe autotaxin/lysophosphatidic acid axis is involved in diverse biological processes including neurodevelopment, inflammation, and immunological functioning. The lysophosphatidic acid 1 receptor has been implicated in the pathophysiology of major depressive disorder and in the mechanism of action of antidepressants. However, it is unclear whether central or peripheral autotaxin levels are altered in patients with major depressive disorder.MethodsSerum autotaxin levels were measured by an enzyme-linked immunosorbent assay in 37 patients with major depressive disorder diagnosed using DSM-IV-TR who underwent electroconvulsive therapy and were compared with those of 47 nondepressed controls matched for age and sex between January 2011 and December 2015. Patient serum levels of autotaxin before and after electroconvulsive therapy were also compared. In a separate sample set, cerebrospinal fluid autotaxin levels were compared between 26 patients with major depressive disorder and 27 nondepressed controls between December 2010 and December 2015. A potential association was examined between autotaxin levels and clinical symptoms assessed with the Hamilton Depression Rating Scale.ResultsBefore electroconvulsive therapy, both serum and cerebrospinal fluidautotaxin levels were significantly lower in major depressive disorder patients than in controls (serum: P = .001, cerebrospinal fluid: P = .038). A significantly negative correlation between serum, but not cerebrospinal fluid, autotaxin levels and depressive symptoms was observed (P = .032). After electroconvulsive therapy, a parallel increase in serum autotaxin levels and depressive symptoms improvement was observed (P = .005).ConclusionThe current results suggest that serum autotaxin levels are reduced in a state-dependent manner. The reduction of cerebrospinal fluid autotaxin levels suggests a dysfunction in the autotaxin/lysophosphatidic acid axis in the brains of patients with major depressive disorder.

Nonlinear effect of depression symptoms on the time course of emotional reactivity

The literature on emotion reactivity among people with major depressive disorder (MDD) indicates that people with MDD show diminished reactivity to negative events as compared to non-depressed controls. This diminished reactivity may only be at the highest levels of depression symptoms, suggesting a nonlinear association between depression symptoms and emotion reactivity. Unfortunately, depression has not been examined as a continuum in this line of research; moreover, the time course of reactivity during an emotional event has not been adequately examined. Participants (N = 100) completed a measure of depression symptoms and then viewed a sadness-inducing 11-min film clip while their facial expressions were video recorded and coded separately for each minute of the film clip. Growth-curve analyses indicated a quadratic effect of depression symptoms on curves for facial expressions of sadness and happiness, such that the change in growth/decay first increased and then decreased from low to high levels of depression symptoms. This result supports the idea that the negative mood inherent in depression potentiates reactivity at lower ends of the depression continuum but that reactivity is dampened at higher levels of depression. This suggests that researchers specify the specific range of depression symptoms under investigation (e.g., mild, moderate, dysphoric, severely depressed) when studying the role of depression on emotional reactivity.

Inflammatory profiles of severe treatment-resistant depression.

Treatment-resistant depression (TRD) contributes substantially to the burden of mood disorders and is undoubtedly an important subpopulation in whom there are clear unmet treatment needs. Despite a paucity of research focusing specifically on TRD, recent studies indicate that inflammatory activity may be particularly elevated in these patients. 36 patients with TRD were investigated longitudinally before and after undertaking a specialist inpatient treatment program. 27 inflammatory proteins were compared between patients and a matched sample of non-depressed controls, as well as between treatment responders and non-responders. Treatment outcomes were calculated from depression severity scores before and after admission, and at a long-term follow-up 3-12 months after discharge. TRD patients had higher levels of numerous inflammatory proteins than controls, and elevated interleukins 6 and 8, tumour necrosis factor, c-reactive protein and macrophage inflammatory protein-1 were associated with poorer treatment outcomes. A separate set of proteins (either anti-inflammatory in nature or attenuated at baseline) showed increases during treatment, regardless of clinical response. Participants with the greatest elevations in inflammation tended to be older, more cognitively impaired and more treatment-resistant at baseline. The small sample and large number of comparisons examined in this study must be taken into account when interpreting these results. However, this study provides empirical support for theories that more severe, chronic or treatment-resistant depressive disorders are associated with dysregulated inflammatory activity. If a predictor or predictors of response in TRD are established, improved and targeted care might be more reliably provided to this vulnerable population.