This study explores whether inflammatory biomarkers act as moderators of clinical response to omega-3 (n-3) fatty acids in subjects with Major Depressive Disorder (MDD). 155 subjects with DSM-IV MDD, a baseline 17-item Hamilton Depression Rating Scale (HAM-D-17) score ≥ 15 and baseline biomarker data (IL-1ra, IL-6, hs-CRP, leptin, adiponectin), were randomized between 05/18/06 and 06/30/11, to 8 weeks of double-blind treatment with eicosapentaenoic acid (EPA)-enriched n-3 1060 mg/day, docosahexaenoic acid (DHA)-enriched n-3 900 mg/day, or placebo. Outcomes were determined using mixed model repeated measures (MMRM) analysis for “high” and “low” inflammation groups based on individual and combined biomarkers. Results are presented in terms of standardized treatment effect size (ES) for change in HAM-D-17 from baseline to treatment week 8. While overall treatment group differences were negligible (ES=−0.13 to +0.04), subjects with any “high” inflammation improved more on EPA than placebo (ES=−0.39) or DHA (ES=−0.60) and less on DHA than placebo (ES=+0.21); furthermore, EPA-placebo separation increased with increasing numbers of markers of high inflammation. Subjects randomized to EPA with “high” IL-1ra or hs-CRP or low adiponectin (“high” inflammation) had medium ES decreases in HAM-D-17 scores versus subjects “low” on these biomarkers. Subjects with “high” hs-CRP, IL-6 or leptin were less placebo-responsive than subjects with low levels of these biomarkers (medium to large ES differences). Employing multiple markers of inflammation facilitated identification of a more homogeneous cohort of subjects with MDD responding to EPA versus placebo in our cohort. Studies are needed to replicate and extend this proof of concept work.

Objective To inform the first-line treatment choice between cognitive behavior therapy (CBT) or an antidepressant medication for treatment-naïve adults with major depressive disorder by defining a neuroimaging biomarker that differentially identifies the outcomes of remission and treatment failure to these interventions. Method Functional magnetic resonance imaging resting state functional connectivity analyses using a bilateral subcallosal cingulate cortex (SCC) seed was applied to 122 patients from the Prediction of Remission to Individual and Combined Treatments (PReDICT) study who completed 12 weeks of randomized treatment with CBT or antidepressant medication. Of the 122, 58 achieved remission (Hamilton Depression Rating Scale, HDRS) ≤7 at weeks 10 and 12); 24 were treatment failures (HDRS <30% decrease from baseline). A 2×2 ANOVA using voxel-wise subsampling permutation tests compared the interaction of treatment and outcome. ROC curves constructed using brain connectivity measures were used to determine possible classification rates for differential treatment outcomes. Results The resting state functional connectivity of three regions with the SCC was differentially associated with outcomes of remission and treatment failure to CBT and antidepressant medication, and survived application of the subsample permutation tests: left anterior ventrolateral/insula prefrontal cortex, dorsal midbrain, and left ventromedial prefrontal cortex. Using the summed SCC functional connectivity scores for these three regions, we demonstrated overall classification rates of 72–78% for remission and 75–89% for treatment failure. Positive summed functional connectivity was associated with remission with CBT and treatment failure with medication, whereas negative summed functional connectivity scores were associated with remission to medication and treatment failure with CBT. Conclusions Imaging-based depression subtypes defined using resting state functional connectivity differentially identified an individual’s probability of remission or treatment failure with first-line treatment options for major depression. This biomarker should be explored in future research through prospective testing and as a component of multivariate treatment prediction models.

Individuals vary substantially in their vulnerability to physical and psychosocial stressors. The causes of such variation in susceptibility to stress are poorly understood, but are thought to relate in part to genetic factors. The present study evaluated the extent to which polymorphisms in the gene encoding the serotonin reuptake transporter (5HTTLPR or SERT) modulated physiologic responses to the imposition of psychosocial stress (social reorganization and subordinate social status) in female rhesus monkeys. Forty females, drawn from the middle ranking genealogies of several large social groups, were reorganized into eight groups containing 5 monkeys each; four groups were comprised entirely of animals homogeneous for the long promoter variant in the SERT gene (l/l), while the other four groups had monkeys with at least one allele of the short promoter variant (l/s or s/s). Females were sequentially introduced into these new groups in random order and dominance ranks were established within several days. During the ensuing 6 weeks, dominant monkeys exhibited elevated rates of aggression while subordinates displayed high rates of submission. Notably, females with the s-variant SERT genotype, collapsed across social status positions, exhibited the highest overall rates of both aggression and submission. Although neither social status nor SERT genotype influenced morning cortisol concentrations, glucocorticoid negative feedback was reduced significantly in subordinate compared to dominant females irrespective of genotype. All animals lost weight and abdominal fat across the experiment. However, decreases were greatest in subordinates, regardless of genotype, and least in dominant females with the l/l genotype. Serum concentrations of insulin, glucose, and ghrelin decreased significantly during the group formation process, effects that were independent of genotype or social status. In contrast, social status and genotype interacted to influence changes in serum concentrations of leptin and triiodothyronine (T3), as dominant, l/l females had the highest levels while subordinate s-variant females had the lowest levels. The order in which a female was introduced to her group generally predicted her eventual social rank. However, rank was additionally predicted by pre-experimental T3 and abdominal fat values, but only in the l/l animals. While these findings must be replicated with a larger sample size, the data suggest that the s-variant SERT genotype confers increased vulnerability to the adverse effects of psychosocial stress associated with subordinate status while the l/l genotype benefits the most from the absence of stress conferred by dominant social status. These findings suggest that genetic factors modify the responses of monkeys to social subordination and perhaps other psychosocial stressors.

The Alzheimer's disease (AD) epidemic is a looming crisis, with an urgent need for new therapies to delay or prevent symptom onset and progression. There is growing awareness that clinical trials must target stage-appropriate pathophysiological mechanisms to effectively develop disease-modifying treatments. Advances in AD biomarker research have demonstrated changes in amyloid-beta (Aβ), brain metabolism and other pathophysiologies prior to the onset of memory loss, with some markers possibly changing one or two decades earlier. These findings suggest that amyloid-based therapies would optimally be targeted at the earliest clinically detectable stage (such as mild cognitive impairment (MCI)) or before. Postmortem data indicate that tau lesions in the locus coeruleus (LC), the primary source of subcortical norepinephrine (NE), may be the first identifiable pathology of AD, and recent data from basic research in animal models of AD indicate that loss of NE incites a neurotoxic proinflammatory condition, reduces Aβ clearance and negatively impacts cognition - recapitulating key aspects of AD. In addition, evidence linking NE deficiency to neuroinflammation in AD also exists. By promoting proinflammatory responses, suppressing anti-inflammatory responses and impairing Aβ degradation and clearance, LC degeneration and NE loss can be considered a triple threat to AD pathogenesis. Remarkably, restoration of NE reverses these effects and slows neurodegeneration in animal models, raising the possibility that treatments which increase NE transmission may have the potential to delay or reverse AD-related pathology. This review describes the evidence supporting a key role for noradrenergic-based therapies to slow or prevent progressive neurodegeneration in AD. Specifically, since MCI coincides with the onset of clinical symptoms and brain atrophy, and LC pathology is already present at this early stage of AD pathogenesis, MCI may offer a critical window of time to initiate novel noradrenergic-based therapies aimed at the secondary wave of events that lead to progressive neurodegeneration. Because of the widespread clinical use of drugs with a NE-based mechanism of action, there are immediate opportunities to repurpose existing medications. For example, NE transport inhibitors and NE-precursor therapies that are used for treatment of neurologic and psychiatric disorders have shown promise in animal models of AD, and are now prime candidates for early-phase clinical trials in humans.

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Treatment guidelines that recommend either an evidence-based psychotherapy or antidepressant medication for nonpsychotic major depression can be extended to treatment-naive patients. Treatment preferences among patients without prior treatment exposure do not significantly moderate symptomatic outcomes.

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Background Medication and psychotherapy treatments for posttraumatic stress disorder (PTSD) provide insufficient benefit for many patients. Substantial preclinical and clinical data indicate abnormalities in the hypothalamic-pituitary-adrenal axis, including signaling by corticotropin-releasing factor, in the pathophysiology of PTSD. Methods We conducted a double-blind, placebo-controlled, randomized, fixed-dose clinical trial evaluating the efficacy of GSK561679, a corticotropin-releasing factor receptor type 1 (CRF1) antagonist in adult women with PTSD. The trial randomized 128 participants, of whom 96 completed the six-week treatment period. Results In both the intent-to-treat and completer samples, GSK561679 failed to show superiority over placebo on the primary outcome of change in Clinician Administered PTSD Scale total score. Adverse event frequencies did not significantly differ between GSK561679- and placebo-treated subjects. Exploration of the CRF1 SNP rs110402 found response to GSK561679 and placebo did not significantly differ by genotype alone. However, subjects who had experienced a moderate or severe history of childhood abuse and who were also GG homozygotes for rs110402 showed significant improvement after treatment with GSK561679 (n=6) but not with placebo (n=7) on the PTSD Symptom Scale, Self-Report. Conclusions The results of this trial, the first evaluating a CRF1 antagonist for the treatment of PTSD, combined with other negative trials of CRF1 antagonists for major depressive disorder, generalized anxiety disorder, and Dunlop social anxiety disorder, suggest that CRF1 antagonists lack efficacy as monotherapy agents for these conditions. ClinicialTrials.gov Evaluation of GSK561679 in Women With Post-Traumatic Stress Disorder; https://clinicaltrials.gov/ct2/show/NCT01018992?term=NCT01018992&rank=1; NCT01018992