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.

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

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

While perusing posters at a recent international psychiatry conference, a prominent subject garnering intensive interest was the understanding and treatment of treatment-resistant depression (TRD). The definition of TRD, however, was notably vague: ranging from 1 to as many as 8 failed antidepressant treatment trials. This lack of a consensual TRD definition creates enormous problems: it limits the ability to do comparative treatment research, to understand the biological underpinnings of TRD, and produces ambiguous medical insurance coverage issues. This disparity in defining TRD begs the question: When does major depressive disorder (MDD) become resistant? Approximately 30% of patients with MDD have a failed response to antidepressant medications or psychotherapy1 and are referred to as having “treatmentresistant depression.”1,2 Compared with other patients with MDD, those with TRD have lower productivity, higher medical comorbidity, and more suicide attempts.3 Naturalisticantidepressanttreatmentstudiesdemonstratethat TRD response rates are poor: Dunner and colleagues,4 studying community-based patients with TRD, observed a low (approximately 10%) 1-year response rate to standard MDD treatments. However, there is reason for hope: recently, multiple novel TRD treatments have emerged, includingrepetitivetranscranialmagneticstimulation (rTMS), intravenous/intranasal ketamine, inhaled nitrous oxide, vagus nerve stimulation, deep brain stimulation, and buprenorphine, among others. Though still under study, the new nonpharmacological MDD treatments appear to have better response durability in TRD compared with medication alternatives (vagus nerve stimulation5 or rTMS6). rTMS and vagus nerve stimulation are US Food and Drug Administration (FDA)– approved for TRD; however, variability in insurance reimbursement has limited patient access. One significant factor limiting use of these treatments is the lack of a standardized operational TRD definition. We propose consideration of an evidence-based, operational definition as a starting point for identifying TRD. On April 27, 2016, the Centers for Medicare & Medicaid Services (CMS) sponsored a Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) for TRD. This public meeting was intended to provide independent guidance and expert advice to CMS and obtain the MEDCAC panel’s recommendations regarding a definition of TRD in clinical research; the committee was to advise CMS on the feasibility of defining TRD for coverage with evidence development trials and treatment outcomes. The MEDCAC panel did not officially define TRD; however, it strongly supported that an evidence-based, operational TRD definition is achievable. This conclusion is critical: it will potentially influence research and reimbursement for all future FDAapproved TRD treatment modalities. The field of psychiatry now needs to move toward an acceptable operational TRD definition applicable in research, clinical care, and insurance reimbursement.

https://jamanetwork.com/journals/PSYCH/articlepdf/2569455/yvp160009.pdf

Toward an Evidence-Based, Operational Definition of Treatment-Resistant Depression: When Enough Is Enough.

Treatment-resistant depression and suicidality

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

The economic impact of depression: Resistance or severity?

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

The economic impact of depression: Resistance or severity?