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Major depressive disorder is the leading cause of disability worldwide. Currently available pharmacological approaches to the treatment of depression (which are the mainstay of treatment in the United States) suffer from important shortcomings, including limited efficacy, delayed onset of action, increased relapse risk upon withdrawal, and significant side effects that impair quality of life and promote treatment nonadherence and/or discontinuation. There is an emerging interest in the potential use of evolutionarily conserved interoceptive pathways (i.e., pathways that relay sensory information, related to the internal, physiologic state of the body, from the periphery to the central nervous system) as “gateways” to neural systems controlling affective and cognitive function relevant to the pathophysiology of depression. In support of the potential utility of this approach, we have shown in open and randomized, double-blind, sham-controlled trials that infrared whole-body heating has significant and long-lasting antidepressant effects relative to a sham condition. In this review, we explore the potential role of thermosensory pathways in the etiology, pathophysiology, and symptomatology of major depressive disorder, as well as its potential as a novel therapeutic approach to the treatment of major depressive disorder.

Previous theories have emphasized the role of excessive glucocorticoid activity in the pathology of chronic stress. Nevertheless, insufficient glucocorticoid signaling (resulting from decreased hormone bioavailability or reduced hormone sensitivity) may have equally devastating effects on bodily function. Such effects may be related in part to the role of glucocorticoids in restraining activation of the immune system and other components of the stress response, including the sympathetic nervous system (SNS) and corticotropin-releasing hormone (CRH).The literature on neuroendocrine function and glucocorticoid-relevant pathologies in stress-related neuropsychiatric disorders, including posttraumatic stress disorder and major depression, was reviewed.Although not occurring together, both hypocortisolism and reduced responsiveness to glucocorticoids (as determined by dexamethasone challenge tests) were reliably found. Stress-related neuropsychiatric disorders were also associated with immune system activation/inflammation, high SNS tone, and CRH hypersecretion, which are all consistent with insufficient glucocorticoid-mediated regulation of stress hyperresponsiveness. Finally, antidepressants, a mainstay in the treatment of stress-related disorders, were regularly associated with evidence of enhanced glucocorticoid signaling.Neuroendocrine data provide evidence of insufficient glucocorticoid signaling in stress-related neuropsychiatric disorders. Impaired feedback regulation of relevant stress responses, especially immune activation/inflammation, may, in turn, contribute to stress-related pathology, including alterations in behavior, insulin sensitivity, bone metabolism, and acquired immune responses. From an evolutionary perspective, reduced glucocorticoid signaling, whether achieved at the level of the hormone or its receptor, may foster immune readiness and increase arousal. Emphasis on insufficient glucocorticoid signaling in stress-related pathology encourages development of therapeutic strategies to enhance glucocorticoid signaling pathways.

Major depression is a devastating disorder that represents a major public health concern. Of special relevance is the high percentage of patients whose depression does not respond to or who are unable to tolerate conventional antidepressant medications, which primarily target monoamine neurotransmission. Recent data indicate that the immune system may play a role in the pathophysiology of depression, representing a novel pathway for therapeutic development. Patients with major depression have been found to exhibit evidence of an activated innate immune response as reflected by increased biomarkers of inflammation, including innate immune cytokines, acute-phase proteins, chemokines, and adhesion molecules. In addition, administration of innate immune cytokines to laboratory animals and humans has been shown to induce behavioral changes that significantly overlap with the symptom criteria of major depression. Treatment of patients with inflammatory disorders using anticytokine therapies has also been found ...

The authors assessed the relationship between the hypothalamic-pituitary-adrenal (HPA) axis response to interferon-alpha (IFN-alpha) and the development of major depression during IFN-alpha treatment.Adrenocorticotropic hormone (ACTH), cortisol, and interleukin-6 (IL-6) plasma concentrations were measured in 14 patients with malignant melanoma at regular intervals during the first 12 weeks of IFN-alpha therapy, both immediately before and 1, 2, and 3 hours after IFN-alpha administration. Symptom criteria for major depression were also evaluated at each visit.ACTH and cortisol responses but not IL-6 responses to the initial administration of IFN-alpha were significantly higher in the seven patients who subsequently developed symptom criteria for major depression than in those who did not. No differences in hormonal or cytokine responses were found between these two groups during chronic IFN-alpha administration.The HPA axis response to the acute administration of IFN-alpha reveals a vulnerability to IFN-alpha-induced depression, possibly due to sensitization of corticotropin-releasing factor pathways.