Search

ABSTRACTThe thermosensory system is relevant to both the conceptualization and treatment of depression. There is evidence that depression is associated with changes in thermoregulatory functioning, and that thermosensory pathways can be recruited to influence affect and reduce depressive symptoms. In this study, we investigated the relationship between severity of depressive symptoms and changes to measures of subjective experiences associated with thermoregulatory processes as well as the relationship between severity of depressive symptoms and affective responses to warm stimuli, specifically frequency of warmth-seeking behavior. Participants (N = 529) completed measures of depressive symptoms, subjective experiences associated with thermoregulatory processes (i.e., perceived sweating and preferred ambient temperature) and frequency of warmth-seeking behavior (e.g., long hot baths, saunas, etc.). We demonstrate that, controlling for age and gender, greater severity of depressive symptoms is associated with greater perceived sweating and lower preferred ambient temperature. Furthermore, we demonstrate that greater severity of depressive symptoms is associated with more frequent warmth-seeking behavior, and that something other than thermal preference (i.e., stated preference for warmer temperature) is driving this behavior. These data highlight the importance of incorporating the thermoregulatory system in our conceptualization of the pathophysiology of depression and support the potential to recruit thermosensory pathways to target depressive symptoms.

A single dose of psilocybin, a psychedelic that acutely causes distortions of space–time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trials1–4. In animal models, psilocybin induces neuroplasticity in cortex and hippocampus5–8. It remains unclear how human brain network changes relate to subjective and lasting effects of psychedelics. Here we tracked individual-specific brain changes with longitudinal precision functional mapping (roughly 18 magnetic resonance imaging visits per participant). Healthy adults were tracked before, during and for 3 weeks after high-dose psilocybin (25 mg) and methylphenidate (40 mg), and brought back for an additional psilocybin dose 6–12 months later. Psilocybin massively disrupted functional connectivity (FC) in cortex and subcortex, acutely causing more than threefold greater change than methylphenidate. These FC changes were driven by brain desynchronization across spatial scales (areal, global), which dissolved network distinctions by reducing correlations within and anticorrelations between networks. Psilocybin-driven FC changes were strongest in the default mode network, which is connected to the anterior hippocampus and is thought to create our sense of space, time and self. Individual differences in FC changes were strongly linked to the subjective psychedelic experience. Performing a perceptual task reduced psilocybin-driven FC changes. Psilocybin caused persistent decrease in FC between the anterior hippocampus and default mode network, lasting for weeks. Persistent reduction of hippocampal-default mode network connectivity may represent a neuroanatomical and mechanistic correlate of the proplasticity and therapeutic effects of psychedelics.

Objective: Previous theories have emphasized the role of excessive glucocorticold 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). Method: The literature on neuroendocrine function and glucocorticoid-relevant pathologies in stress-related neuropsychiatric disorders, including posttraumatic stress disorder and major depression, was reviewed. Results: 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. Conclusions: 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.

Objective: 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. Method: 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. Results: 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. Conclusions: 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.

Despite advances in neuroscience, limited progress has been made in developing new and better medications for psychiatric disorders. Available treatments in psychiatry rely on a few classes of drugs that have a broad spectrum of activity across disorders with limited understanding of mechanism of action. While the added value of more targeted therapies is apparent, a dearth of pathophysiologic mechanisms exists to support targeted treatments, and where mechanisms have been identified and drugs developed, results have been disappointing. Based on serendipity and early successes that led to the current drug armamentarium, a haunting legacy endures that new drugs should align with outdated and overinclusive diagnostic categories, consistent with the idea that “one size fits all”. This legacy has fostered clinical trial designs focused on heterogenous populations of patients with a single diagnosis and non-specific outcome variables. Disturbingly, this approach likely contributed to missed opportunities for drugs targeting the hypothalamic-pituitary-adrenal axis and now inflammation. Indeed, cause-and-effect data support the role of inflammatory processes in neurotransmitter alterations that disrupt specific neurocircuits and related behaviors. This pathway to pathology occurs across disorders and warrants clinical trial designs that enrich for patients with increased inflammation and use primary outcome variables associated with specific effects of inflammation on brain and behavior. Nevertheless, such trial designs have not been routinely employed, and results of anti-inflammatory treatments have been underwhelming. Thus, to accelerate development of targeted therapeutics including in the area of inflammation, regulatory agencies and the pharmaceutical industry must embrace treatments and trials focused on pathophysiologic pathways that impact specific symptom domains in subsets of patients, agnostic to diagnosis. Moreover, closer collaboration among basic and clinical investigators is needed to apply neuroscience knowledge to reveal disease mechanisms that drive psychiatric symptoms. Together, these efforts will support targeted treatments, ultimately leading to new and better therapeutics in psychiatry.

Major depressive disorder (MDD) is a critical health issue that is inadequately addressed with currently available treatments, indicating a need for novel treatment approaches. This case report describes a patient’s outcomes after completing an integrated mind-body depression intervention that combined cognitive-behavioral therapy (CBT) administered by a clinician with whole-body hyperthermia (WBH) administered using an infrared sauna device.

Chaos--definition [from wordnet.princeton.edu]: a state of extreme disorder or confusion Consilience--definition [from Wikipedia]: literally a jumping together of knowledge by the linking of facts and fact-based theory across disciplines to [...]

Significant attention has been paid to the potential adaptive value of depression as it relates to interactions with people in the social world. However, in this review, we outline the rationale of why certain features of depression including its environmental and genetic risk factors, its association with the acute phase response and its age of onset and female preponderance appear to have evolved from human interactions with pathogens in the microbial world. Approaching the relationship between inflammation and depression from this evolutionary perspective yields a number of insights that may reveal important clues regarding the origin and epidemiology of the disorder as well as the persistence of its risk alleles in the modern human genome.

Crosstalk between inflammatory pathways and neurocircuits in the brain can lead to behavioural responses, such as avoidance and alarm, that are likely to have provided early humans with an evolutionary advantage in their interactions with pathogens and predators. However, in modern times, such interactions between inflammation and the brain appear to drive the development of depression and may contribute to non-responsiveness to current antidepressant therapies. Recent data have elucidated the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression. Here, we detail our current understanding of these pathways and discuss the therapeutic potential of targeting the immune system to treat depression.

Mounting data suggest that there is a reliable association between inflammatory markers and depression. This association has led to the speculation that anti-inflammatory drugs may have antidepressant activities. Although an increasing number of studies have addressed this issue, there are several considerations that have confounded attempts to interpret the extant literature in this area. These include: (1) the use of anti-inflammatory drugs with potential antidepressant effects unrelated to inflammation, (2) the evaluation of antidepressant effects of anti-inflammatory drugs in patient populations whose underlying inflammatory disorder may directly benefit from anti-inflammatory treatment (unrelated to mood), (3) potential cultural biases of available studies, and (4) a nonlinear relationship between inflammation and depression that may contribute to a differential response in anti-inflammatory-treated versus placebo-treated patients depending on inflammatory status. Taken together, these data indicate that anti-inflammatory agents do not likely exhibit generalized antidepressant effects and may only be effective in subgroups of patients with increased inflammation. Moreover, the data raise the larger question of whether any antidepressant agent is truly an antidepressant, or whether all medications are only antidepressants for select populations of patients with more biologically discreet disease states we have yet to identify or name. Mounting data suggest that there is a reliable association between inflammatory markers and depression. This association has led to the speculation that anti-inflammatory drugs may have antidepressant activities. Although an increasing number of studies have addressed this issue, there are several considerations that have confounded attempts to interpret the extant literature in this area. These include: (1) the use of anti-inflammatory drugs with potential antidepressant effects unrelated to inflammation, (2) the evaluation of antidepressant effects of anti-inflammatory drugs in patient populations whose underlying inflammatory disorder may directly benefit from anti-inflammatory treatment (unrelated to mood), (3) potential cultural biases of available studies, and (4) a nonlinear relationship between inflammation and depression that may contribute to a differential response in anti-inflammatory-treated versus placebo-treated patients depending on inflammatory status. Taken together, these data indicate that anti-inflammatory agents do not likely exhibit generalized antidepressant effects and may only be effective in subgroups of patients with increased inflammation. Moreover, the data raise the larger question of whether any antidepressant agent is truly an antidepressant, or whether all medications are only antidepressants for select populations of patients with more biologically discreet disease states we have yet to identify or name. [[Psychiatr Ann. 2015;45(5):255–261.]

Inflammatory physiology has been linked to behavioral and emotional symptoms in a variety of contexts and experimental paradigms. Hematopoietic cell transplantation (HCT) represents an intersection of significant immune dysregulation and psychosocial stress, and this biobehavioral relationship can influence important clinical outcomes. For those undergoing HCT with inflammation-related neuropsychiatric symptoms, using targeted agents such as the IL-6 receptor antagonist tocilizumab may be an effective therapeutic approach. We conducted an observational cohort study to explore patient reported outcomes (PROs) and inflammatory biomarkers among allogeneic HCT recipients who received tocilizumab compared to those who did not. Individuals on a larger trial of tocilizumab for prevention of graft-versus-host disease received a single dose of tocilizumab 24 h prior to stem cell infusion. Measures of anxiety, depression, pain, fatigue, and sleep quality and parallel blood samples for inflammatory cytokines were collected from participants and an analogous comparison cohort at baseline and Day 28 after stem cell infusion. Demographic and medical characteristics were reported; an analysis of covariance regression model was fitted to evaluate differences in PROs and distance correlation t-tests assessed for associations between biomarkers and PRO measures. For n = 18 tocilizumab-treated and n = 22 comparison patients, there were no significant differences between patient demographics, but the tocilizumab cohort had a different distribution of primary diagnoses (p = 0.009) with more patients with leukemias and a higher proportion of patients in their first remission (64% vs 28%, p = 0.024). Depression was higher at Day 28 compared to baseline in both groups (comparison group: +5.1 [95% CI 0.14–10, p = 0.045], tocilizumab: +8.6 [95% CI 2.3–15, p = 0.011]), though the difference between groups did not reach statistical significance. The tocilizumab group had significantly increased circulating IL-6 and decreased CRP at Day 28 (all p < 0.05). There was an association between collective baseline biomarkers and PROs (distance correlation dCor = 0.110, p = 0.005), but this same association was not present at Day 28 (dCor = −0.001, p = 0.5). In univariate analyses, a 10-fold increase in plasma IL-6 was associated with a 3.6-point higher depression score (95% CI 1.0–6.2, p = 0.008). In this exploratory analysis of PROs and inflammatory biomarkers in patients undergoing HCT, tocilizumab was not associated with favorable patient-reported symptom profiles. This finding is aligned with our prior work in the HCT population but diverges from hypothesized therapeutic effects of tocilizumab on depressive symptoms, thus highlighting the need for larger prospective translational studies in biobehavioral HCT research.

To compare the prevalence of psychiatric disorders in persons with chronic fatigue syndrome (CFS) identified from the general population and a chronically ill group of people presenting with subsyndromic CFS-like illness (“insufficient symptoms or fatigue” (ISF)). Previous studies in CFS patients from primary and tertiary care clinics have found high rates of psychiatric disturbance, but this may reflect referral bias rather than true patterns of comorbidity with CFS.

Significant evidence suggests that the immune system is capable of profoundly affecting central nervous system (CNS) functioning in ways that may contribute to the development and expression of neuropsychiatric disorders, including disorders of mood. This paper reviews evidence that the production of proinflammatory cytokines, whether in the context of therapeutic administration (e.g. interferon-a-2b for hepatitis C infection) or medical illness, induces a state of sickness behavior that closely resembles major depression. Antidepressants have been shown to abolish or attenuate cytokine-induced sickness behavior in laboratory animals and to protect against the development of major depression in the context of therapeutic cytokine administration in humans. Potential mechanisms by which antidepressants ameliorate depressive and/or sickness symptoms in the context of immune activation include direct effects on immune cell functioning, as well as modulatory effects on monoamine neurotransmitters, intracellular second messenger pathways and the neuroendocrine system, in particular the hypothalamic–pituitary–adrenal axis.

Major depressive disorder (MDD) is associated with chronic inflammation. Exercise training can treat depression in adults with MDD, potentially through reducing inflammatory activity. This improvement may occur through adaptations to repeated acute inflammatory responses. Cytokine responses to acute steady-state exercise of varying intensities were determined in women with different levels of depression.