Depression is a significant public health problem, but its etiology and pathophysiology remain poorly understood. Such incomplete understanding likely arises from the fact that depression encompasses a heterogeneous set of disorders. To overcome these limitations, renewed interest in intermediate phenotypes (endophenotypes) has resurfaced, and anhedonia has emerged as one of the most promising endophenotypes of depression. Here, a heuristic model is presented postulating that anhedonia arises from dysfunctional interactions between stress and brain reward systems. To this end, we review and integrate three bodies of independent literature investigating the role of (a) anhedonia, (b) dopamine, and (c) stress in depression. In a fourth section, we summarize animal data indicating that stress negatively affects mesocorticolimbic dopaminergic pathways critically implicated in incentive motivation and reinforcement learning. In the last section, we provide a synthesis of these four literatures, present initial evidence consistent with our model, and discuss directions for future research.

Depression, stress, and anhedonia: toward a synthesis and integrated model.

Treatment outcomes for major depressive disorder (MDD) need to be improved. Presently, no clinically relevant tools have been established for stratifying subgroups or predicting outcomes. This literature review sought to investigate factors closely linked to outcome and summarize existing and novel strategies for improvement. The results show that early recognition and treatment are crucial, as duration of untreated depression correlates with worse outcomes. Early improvement is associated with response and remission, while comorbidities prolong course of illness. Potential biomarkers have been explored, including hippocampal volumes, neuronal activity of the anterior cingulate cortex, and levels of brain-derived neurotrophic factor (BDNF) and central and peripheral inflammatory markers (e.g., translocator protein (TSPO), interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor alpha (TNFα)). However, their integration into routine clinical care has not yet been fully elucidated, and more research is needed in this regard. Genetic findings suggest that testing for CYP450 isoenzyme activity may improve treatment outcomes. Strategies such as managing risk factors, improving clinical trial methodology, and designing structured step-by-step treatments are also beneficial. Finally, drawing on existing guidelines, we outline a sequential treatment optimization paradigm for selecting first-, second-, and third-line treatments for acute and chronically ill patients. Well-established treatments such as electroconvulsive therapy (ECT) are clinically relevant for treatment-resistant populations, and novel transcranial stimulation methods such as theta-burst stimulation (TBS) and magnetic seizure therapy (MST) have shown promising results. Novel rapid-acting antidepressants, such as ketamine, may also constitute a paradigm shift in treatment optimization for MDD.

/pdf/prognosis-and-improved-outcomes-in-major-depression-a-review-4rxj8jyshb.pdf

Prognosis and improved outcomes in major depression: a review

Importance Patients with treatment-resistant depression (TRD) do not respond sufficiently to several consecutive treatments for major depressive disorder. Deep brain stimulation (DBS) is a promising treatment for these patients, but presently placebo effects cannot be ruled out. Objective To assess the efficacy of DBS of the ventral anterior limb of the internal capsule (vALIC), controlling for placebo effects with active and sham stimulation phases. Design, Setting, and Participants Twenty-five patients with TRD from 2 hospitals in the Netherlands were enrolled between March 22, 2010, and May 8, 2014. Patients first entered a 52-week open-label trial during which they received bilateral implants of 4 contact electrodes followed by optimization of DBS until a stable response was achieved. A randomized, double-blind, 12-week crossover phase was then conducted with patients receiving active treatment followed by sham or vice versa. Response and nonresponse to treatment were determined using intention-to-treat analyses. Interventions Deep brain stimulation targeted to the vALIC. Main Outcomes and Measures The change in the investigator-rated score of the 17-item Hamilton Depression Rating Scale (HAM-D-17) was the main outcome used in analysis of the optimization phase. The primary outcome of the crossover phase was the difference in the HAM-D-17 scores between active and sham DBS. The score range of this tool is 0 to 52, with higher scores representing more severe symptoms. Patients were classified as responders to treatment (≥50% decrease of the HAM-D-17 score compared with baseline) and partial responders (≥25 but Results Of 25 patients included in the study, 8 (32%) were men; the mean (SD) age at inclusion was 53.2 (8.4) years. Mean HAM-D-17 scores decreased from 22.2 (95% CI, 20.3-24.1) at baseline to 15.9 (95% CI, 12.3-19.5) ( P  = .001), Montgomery-Asberg Depression Rating Scale scores from 34.0 (95% CI, 31.8-36.3) to 23.8 (95% CI, 18.4-29.1) ( P P  = .005) in the optimization phase. Following the optimization phase, which lasted 51.6 (22.0) weeks, 10 patients (40%) were classified as responders and 15 individuals (60%) as nonresponders. Sixteen patients entered the randomized crossover phase (9 responders [56%], 7 nonresponders [44%]). During active DBS, patients scored significantly lower on the HAM-D-17 scale (13.6 [95% CI, 9.8-17.4]) than during sham DBS (23.1 [95% CI, 20.6-25.6]) ( P Conclusions and Relevance Deep brain stimulation of the vALIC resulted in a significant decrease of depressive symptoms in 10 of 25 patients and was tolerated well. The randomized crossover design corroborates that vALIC DBS causes symptom reduction rather than sham. Trial Registration trialregister.nl Identifier:NTR2118

/pdf/deep-brain-stimulation-of-the-ventral-anterior-limb-of-the-2l65omy5za.pdf

Deep Brain Stimulation of the Ventral Anterior Limb of the Internal Capsule for Treatment-Resistant Depression A Randomized Clinical Trial

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jabr.12137

The neurobiology of central sensitization

The serotonin (5-HT) hypothesis of depression has played an important role in the history of psychiatry, yet it has also been criticized for the delayed onset and inadequate efficacy of selective serotonin reuptake inhibitors (SSRIs) With evolvement of neuroscience, the neuroplasticity hypothesis of major depressive disorder (MDD) has been proposed and may provide a better framework for clarification the pathogenesis of MDD and antidepressant efficacy In this article, we first summarized the evidence challenging the monoamine hypothesis and proposed that the antidepressant efficacy of SSRIs is not derived from elevated monoamine (5-HT, noradrenaline (NE), or dopamine (DA)) concentration or monoamine neurotransmission Second, we reviewed the role of stress in the pathogenesis of MDD and gave a brief introduction to the neuroplasticity hypothesis of MDD Third, we explored the possible mechanisms underlying the antidepressant efficacy of typical antidepressants in the context of neuroplasticity theory Fourth, we tried to provide an explanatory framework for the significant difference in onset of efficacy between typical antidepressants and ketamine Finally, we provided a brief summarization about this review article and some perspectives for future studies

/pdf/from-serotonin-to-neuroplasticity-evolvement-of-theories-for-25s6ifpreo.pdf

From Serotonin to Neuroplasticity: Evolvement of Theories for Major Depressive Disorder

Objectives Fibromyalgia syndrome (FMS) has been associated with various psychiatric and other, ill-defined disorders. We recently showed that fibromyalgia is more prevalent in men suffering from combat-related Post Traumatic Stress Disorder (PTSD). In this paper we analyze the relationship between engagement in physical activity, the psycho-metric traits of PTSD and the future development of FMS. Methods Fifty-five male patients, all known to have combat-related PTSD, were investigated for the presence of fibro-myalgia according to the American College of Rheumatology (ACR) criteria. Each patient completed questionnaires characterizing his quality of sleep, and the Sheehan Disability Scale measuring performance in the familial, social and vocational spheres. Additionally, each of the enrollees was interviewed by an experienced psychiatrist, who then completed a Clinician Administered PTSD Scale, a Clinical Global Impression Scale, and calculated an SF-36 score. Each patient was asked whether he exercised often, occasionally or not at all. The data was analyzed by the chi2 test and by ANOVA. Results PTSD patients who also suffered from FMS had a more severe form of disease as measured by the Clinician Administered PTSD Scale (CAPS) score, 88.2 +/- 14.0 (n = 28) compared to 97.6 +/- 13.2 of patients with PTSD and FMS (n = 27) (p = 0.013, F(d.f 2)-6.61, ANOVA test). Interestingly, engaging in physical exercise was also associated with less severe disease. When the patients were analyzed based on their tender point count (0-5, 6-10, or > 11), the number of tender points decreased with increasing physical activity (p = 0.02, chi2(d.f.-4) = 11.3). Conclusion Physical exercise in male patients with combat-related PTSD provides protection from the future development of fibromyalgia. Furthermore, physical activity is related in this group of patients to a better perception of their quality of life.

Physical activity protects male patients with post-traumatic stress disorder from developing severe fibromyalgia.

Physical co-morbidity among treatment resistant vs. treatment responsive patients with major depressive disorder

Serious life events among resistant and non-resistant MDD patients.

The economic impact of depression: Resistance or severity?

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Physical activity protects male patients with post-traumatic stress disorder from developing severe fibromyalgia.

Physical co-morbidity among treatment resistant vs. treatment responsive patients with major depressive disorder

Serious life events among resistant and non-resistant MDD patients.

The economic impact of depression: Resistance or severity?