Unmedicated Depressed Subjects Research Articles

PET radioligand binding to translocator protein (TSPO) is increased in unmedicated depressed subjects

BackgroundInflammation is associated with major depressive disorder (MDD). Translocator protein 18 kDa (TSPO), a putative biomarker of neuroinflammation, is quantified using positron emission tomography (PET) and 11C-PBR28, a TSPO tracer. We sought to (1) investigate TSPO binding in MDD subjects currently experiencing a major depressive episode, (2) investigate the effects of antidepressants on TSPO binding, and (3) determine the relationship of peripheral and central inflammatory markers to cerebral TSPO binding. Twenty-eight depressed MDD subjects (unmedicated (n = 12) or medicated (n = 16)) and 20 healthy controls (HC) underwent PET imaging using 11C-PBR28. Total distribution volume (VT, proportional to Bmax/Kd) was measured and corrected with the free fraction in plasma (fp). The subgenual prefrontal cortex (sgPFC) and anterior cingulate cortex (ACC) were the primary regions of interest. Peripheral blood samples and cerebrospinal fluid were analyzed to investigate the relationship between TSPO binding and peripheral and central inflammatory markers, including interleukins and neurotrophic factors previously linked to depression.ResultsTSPO binding was higher in MDD versus HC in the sgPFC (Cohen’s d = 0.64, p = .038, 95% CI 0.04–1.24) and ACC (d = 0.60, p = .049, 95% CI 0.001–1.21), though these comparisons missed the corrected threshold for statistical significance (α = .025). Exploratory analyses demonstrated that unmedicated MDD subjects had the highest level of TSPO binding, followed by medicated MDD subjects, who did not differ from HC. TSPO binding correlated with interleukin-5 in cerebrospinal fluid but with no other central inflammatory markers.ConclusionsThis study found a trend towards increased TSPO binding in the brains of MDD subjects, and post hoc analysis extended these findings by demonstrating that this abnormality is significant in unmedicated (but not medicated) MDD subjects.

Resting-state functional connectivity in women with Major Depressive Disorder

ObjectiveLimited research has focused on whole-brain functional connectivity in a well-characterized sample of subjects with current Major Depressive Disorder (MDD). We aimed to investigate resting-state functional connectivity and the extent to which this is correlated with depression severity in unmedicated depressed subjects without comorbidities. MethodsWe utilized Independent Component Analysis (ICA) to investigate whole-brain functional connectivity in a sample of healthy controls (n = 26) and unmedicated subjects diagnosed only with current MDD (n = 20). Correlations were calculated between network connectivity strength and depression severity. ResultsDepressed subjects demonstrated significantly decreased connectivity in the right frontoparietal (p = 0.03), left frontoparietal (p = 0.01), and language (p = 0.02) networks compared to healthy control subjects. ConclusionWe found abnormal resting-state functional connectivity not previously reported in MDD. Decreased connectivity in the frontoparietal and language networks may represent depression-related difficulties in attention, cognitive control, goal-directed cognition, and language. Findings from this study may further elucidate functional connectivity as a diagnostic marker of depression severity.

Serum BDNF levels before treatment predict SSRI response in depression

The "neurotrophin hypothesis" of depression posits a role of brain-derived neurotrophic factor (BDNF) in depression, although it is unknown whether BDNF is more involved in the etiology of depression or in the mechanism of action of antidepressants. It is also unknown whether pre-treatment serum BDNF levels predict antidepressant response. Thirty un-medicated depressed subjects were treated with escitalopram (N=16) or sertraline (N=14) for 8 weeks. Twenty-five of the depressed subjects completed 8 weeks of antidepressant treatment and had analyzable data. Twenty-eight healthy controls were also studied. Serum for BDNF assay was obtained at baseline in all subjects and after 8 weeks of treatment in the depressed subjects. Depression ratings were obtained at baseline and after 8 weeks of treatment in the depressed subjects. Pre-treatment BDNF levels were lower in the depressed subjects than the controls (p=0.001) but were not significantly correlated with pre-treatment depression severity. Depression ratings improved with SSRI treatment (p<0.001), and BDNF levels increased with treatment (p=0.005). Changes in BDNF levels were not significantly correlated with changes in depression ratings. However, pre-treatment BDNF levels were directly correlated with antidepressant responses (p<0.01), and "Responders" to treatment (≥ 50% improvement in depression ratings) had higher pre-treatment BDNF levels than did "Non-responders" (p<0.05). These results confirm low serum BDNF levels in un-medicated depressed subjects and confirm antidepressant-induced increases in BDNF levels, but they suggest that antidepressants do not work simply by correcting BDNF insufficiency. Rather, these findings are consistent with a permissive or facilitatory role of BDNF in the mechanism of action of antidepressants.

Low serum IL-10 concentrations and loss of regulatory association between IL-6 and IL-10 in adults with major depression

Elevated circulating pro-inflammatory cytokines are associated with symptoms of depression, and disorders involving chronic inflammation are often co-morbid with major depression. Since healthy immune regulation is accomplished through counter-balancing effects of pro- and anti-inflammatory cytokines, we hypothesized that depressed subjects (compared to controls) would express lower concentrations of the anti-inflammatory/immunoregulatory cytokine interleukin (IL)-10, and a higher IL-6/IL-10 ratio. We also examined the possibility that depressed subjects may exhibit a deficiency in the regulatory loop involving IL-6 induced secretion of IL-10. Therefore, we hypothesized that circulating IL-6 and IL-10 would be positively correlated in controls, while the correlation would be weaker in depressed subjects. Resting state serum cytokine concentrations were quantified in 12 unmedicated depressed subjects, and 11 age, gender, and ethnicity-matched controls. Depressed subjects showed significantly lower IL-10 ( p = 0.03, Cohen’s d = −0.96), non-significantly higher IL-6, and significantly higher IL-6/IL-10 ratios ( p = 0.05, Cohen’s d = 0.50). Across all participants, higher scores on the self-rated Inventory of Depressive Symptoms were associated with lower IL-10 ( r(21) = −0.57, p = 0.005) and non-significantly higher IL-6/IL-10 ratios ( r(21) = 0.38, p = 0.07), but not related to IL-6 concentrations. As hypothesized, IL-6 and IL-10 concentrations were strongly and positively correlated in controls ( r(9) = 0.81, p = 0.003), but were completely dissociated in depressed subjects ( r(10) = 0.01, p = 0.98). These results suggest that lower IL-10 levels, a higher IL-6/IL-10 ratio, and the apparent absence of a counter-balancing, immunoregulatory increase in IL-10 in response to elevated IL-6 concentrations contribute to the pro-inflammatory physiological milieu that is known to be associated with major depression. Therefore, reduced induction/availability of IL-10, that would normally inhibit pro-inflammatory cytokine actions and resolve inflammation, may contribute to the depressogenic as well as the inflammatory disease-promoting effects of chronic, low-level elevations in pro-inflammatory cytokines.

Hot and cold cognition in unmedicated depressed subjects with bipolar disorder

Neuropsychological studies in subjects with bipolar disorder (BD) have reported deficits on a variety of cognitive measures. However, because the majority of subjects were medicated at the time of testing in previous studies, it is currently unclear whether the pattern of deficits reported is related to BD itself or to psychotropic medication. We addressed this issue by examining cognitive performance in a group of unmedicated, currently depressed subjects with BD. Forty-nine unmedicated subjects who met DSM-IV criteria for BD, depressed phase, and 55 control subjects participated in this study. Most patients were diagnosed with bipolar II disorder. Performance on emotion-dependent, or 'hot', and emotion-independent, or 'cold', cognitive tasks was assessed using tests from the Cambridge Neuropsychological Test Automated Battery. The groups were well matched with respect to general intelligence and demographic variables. Deficits in the unmedicated depressed BD group were apparent on tests tapping 'hot' cognitive processing, for example the Cambridge Gamble task and the Probabilistic Reversal Learning task. However, other than a deficit on the Spatial Span test in the depressed BD subjects, the groups performed equivalently on most measures of 'cold' cognitive processing, for example visual memory, attention, and working memory. These data suggest that deficits on tests involving reward processing, short-term spatial memory storage, and sensitivity to negative feedback in depressed BD subjects represent an effect of the illness itself and not mood-stabilizing medication.

Monoamine depletion in unmedicated depressed subjects

Background: Although significant evidence suggests that diminished monoamine function is associated with clinical depression, catecholamine or indoleamine depletion alone has not been associated with significant mood changes in unmedicated depressed subjects or never-depressed control subjects. This study assesses the integrated role of these monoamine systems in depressed patients.Methods: Unmedicated depressed subjects underwent a 2-week, double-blind, random-ordered crossover study consisting of the following active and control conditions respectively: indoleamine (via tryptophan depletion) plus catecholamine (via alpha-methyl-paratyrosine administration) depletion and, separately, indoleamine plus sham (via diphenhydramine administration) catecholamine depletion. Ten subjects completed both conditions; two subjects were withdrawn after active testing and one after control testing.Results: Mean Hamilton Depression Rating Scale (HDRS) scores decreased progressively throughout the study days (baseline 26.7 points ± 1.7 SEM and termination 20.0 ± 2.4, active depletion; baseline 26.1 points ± 2.3 SEM and termination 23.2 ± 2.6, control testing) but did not differ between groups. Only three patients demonstrated 20% or greater increases from baseline HDRS at any point during the observation days.Conclusions: Overall, results show that simultaneous disruptions of indoleamine and catecholamine function do not exacerbate symptoms in unmedicated depressed subjects, thus lending further support to the notion that monoamines regulate mood in actively depressed patients via indirect mechanisms.

268. Simultaneous catecholamine and indoleamine depletion in unmedicated depressed subjects

Although significant evidence suggests that alterations in monoamine systems are associated with clinical depression, catecholamine or indoleamine depletion alone has not been associated with significant mood changes in unmedicated depressed subjects, a finding that complicates the classic monoamine hypotheses on the neurobiology of depression. As one possible explanation, dysfunction in one monamine system may be balanced by intact function in another. To test this hypothesis, unmedicated depressed subjects underwent a 2-week, double-blind, random-ordered crossover study consisting of the following active and control conditions respectively: indoleamine (via tryptophan depletion) plus catecholamine (via alpha-methyl-paratyrosine administration) depletion and, separately, indoleamine plus sham (via diphenhydramine administration) depletion and, separately, indoleamine plus sham (via diphenhydramine administration) catecholamine depletion. Ten subjects completed both conditions; 2 subjects were withdrawn after active testing and one after control testing. Time (F 7.1, df 4, 36, p = 0.0003) but not time-by-condition or condition effects were statistically significant. Mean HDRS scores decreased progressively throughout the study days (baseline 26.7 points ± 1.4 SEM; termination 21.3 ± 1.7). Response (i.e., >50% HDRS decrease and maximum score <15 points) rates were 3 [25%] of 12 subjects undergoing active testing and 4 [36%] of 11 undergoing control testing, inclusive of follow-up day ratings. Overall, results suggest that simultaneous disruptions of indoleamine and catecholamine function do not exacerbate symptoms in unmedicated depressed subjects, thus lending further support to the notion that monoamines regulate mood in actively depressed patients via indirect mechanisms.