Shannon K. Crowley

Neurosteroid, GABAergic and hypothalamic pituitary adrenal (HPA) axis regulation: what is the current state of knowledge in humans?

RationaleA robust epidemiological literature suggests an association between chronic stress and the development of affective disorders. However, the precise biological underpinnings of this relationship remain elusive. Central to the human response and adaptation to stress, activation and inhibition of the hypothalamic pituitary adrenal (HPA) axis involves a multi-level, multi-system, neurobiological stress response which is as comprehensive in its complexity as it is precarious. Dysregulation in this complex system has implications for human stress related illness.ObjectivesThe pioneering research of Robert Purdy and colleagues has laid the groundwork for advancing our understanding of HPA axis regulation by stress-derived steroid hormones and their neuroactive metabolites (termed neurosteroids), which are potent allosteric modulators of GABAA receptor function in the central nervous system. This review will describe what is known about neurosteroid modulation of the HPA axis in response to both acute and chronic stress, particularly with respect to the current state of our knowledge of this process in humans.ResultsImplications of this research to the development of human stress-related illness are discussed in the context of two human stress-related psychiatric disorders — major depressive disorder and premenstrual dysphoric disorder.ConclusionsNeurosteroid-mediated HPA axis dysregulation is a potential pathophysiologic mechanism which may cross traditional psychiatric diagnostic classifications. Future research directions are identified.

Blunted neuroactive steroid and HPA axis responses to stress are associated with reduced sleep quality and negative affect in pregnancy: a pilot study

RationaleAnxiety during pregnancy has been linked to adverse maternal health outcomes, including postpartum depression (PPD). However, there has been limited study of biological mechanisms underlying behavioral predictors of PPD during pregnancy.ObjectivesConsidering the shared etiology of chronic stress amongst antenatal behavioral predictors, the primary goal of this pilot study was to examine associations among stress-related physiological factors (including GABA-ergic neurosteroids) and stress-related behavioral indices of anxiety during pregnancy.MethodsFourteen nulliparous women in their second trimester of a singleton pregnancy underwent speech and mental arithmetic stress, following a 2-week subjective and objective recording of sleep-wake behavior.ResultsLower cortisol, progesterone, and a combined measure of ALLO + pregnanolone throughout the entire stressor protocol (area under the curve, AUC) were associated with greater negative emotional responses to stress, and lower cortisol AUC was associated with worse sleep quality. Lower adrenocorticotropic hormone was associated with greater anxious and depressive symptoms. Stress produced paradoxical reductions in cortisol, progesterone, and a combined measure of allopregnanolone + pregnanolone, while tetrahydrodeoxycorticosterone levels were elevated.ConclusionsThese data suggest that cortisol, progesterone, and ALLO + pregnanolone levels in the second trimester of pregnancy are inversely related to negative emotional symptoms, and the negative impact of acute stress challenge appears to exert its effects by reducing these steroids to further promote negative emotional responses.

Nonpharmacologic Treatments for Depression Related to Reproductive Events

There is a growing body of evidence suggesting that nonpharmacological interventions have an appropriate place in the treatment of major depressive disorders (MDDs) as both stand-alone and supplemental treatments. Because women may be reluctant to use psychotropic medications due to strong values or treatment preferences during specific reproductive events, clinicians need to be able to offer empirically based alternatives to medication. In this review, we present recent findings from studies of acupuncture, bright light therapy, electroconvulsive therapy, omega fatty acid supplementation, physical activity, and psychosocial intervention for women experiencing depressive symptoms in the contexts of menstruation, pregnancy, postpartum, and menopause.

The influence of early life sexual abuse on oxytocin concentrations and premenstrual symptomatology in women with a menstrually related mood disorder

Oxytocin (OT), associated with affiliation and social bonding, social salience, and stress/pain regulation, may play a role in the pathophysiology of stress-related disorders, including menstrually-related mood disorders (MRMDs). Adverse impacts of early life sexual abuse (ESA) on adult attachment, affective regulation, and pain sensitivity suggest ESA-related OT dysregulation in MRMD pathophysiology. We investigated the influence of ESA on plasma OT, and the relationship of OT to the clinical phenomenology of MRMDs. Compared to MRMD women without ESA (n=40), those with ESA (n=20) displayed significantly greater OT [5.39pg/mL (SD, 2.4) vs. 4.36pg/mL (SD, 1.1); t (58)=-2.26, p=0.03]. In women with ESA, OT was significantly, inversely correlated with premenstrual psychological and somatic symptoms (rs=-0.45 to -0.64, ps<0.05). The relationship between OT and premenstrual symptomatology was uniformly low and non-significant in women without ESA. In women with ESA, OT may positively modulate MRMD symptomatology.

Exercise is medicine: The role of exercise in the prevention and treatment of mood and anxiety disorders in children and adults.

Stress-related psychiatric disorders, including depression and anxiety, are commonly associated with low levels of physical activity. Data derived from epidemiological studies consistently suggest a relationship exists between physical inactivity and increased risk for depression and/or anxiety disorders. Additionally, recent literature reviews maintain that exercise compares favorably to antidepressant medications as a first-line and/or adjuvant treatment for mild to moderate depression in adults. While the mechanisms underlying the antidepressant and anxiolytic effects of exercise training are still under investigation, research has indicated that the antidepressant effects of regular exercise training might be mediated through neurobiological adaptations, (e.g., increased availability of neurotransmitters including serotonin and dopamine, positive effects on HPA axis reactivity to stressors) which may be protective against the deleterious psychological effects of stress. The potential for exercise to prevent or treat psychiatric disorders might, therefore, involve adaptations resulting from regular physical exercise training which also positively impact physiological adaptations to psychological stressors. Moreover, research suggests that the protective and treatment effects of physical exercise for depression and anxiety might be mediated through the positive impact of exercise on fundamental psychological processes of affective dysregulation (e.g., emotion regulation, mood) and/or comorbid conditions (e.g., sleep problems). Importantly, research on the effects of early life adversity in precipitating and maintaining physiological and psychological processes underlying depression and anxiety disorders highlights not only the importance of early identification of vulnerability factors in the development of psychiatric disease, but also a potential role for exercise in mitigating these factors in children and adults.

Biopsychosocial vulnerability to postpartum depression: A laboratory-based feasibility study of sleep dysregulation, daytime stress reactivity, and anxiety symptomology during pregnancy

Clear evidence has linked dysregulated hypothalamus– pituitary–adrenocortical (HPA) axis function to the aetiology and pathophysiology of major depression (MD), as observed in the majority of patients. Increased stress reactivity and hyperactivity of the HPA axis seem characteristic for psychotic/melancholic depression, while the atypical subtype of depression has been connected with the opposing phenotypes. However, the underlying molecular-genetic mechanisms are poorly understood. In the present study, mouse lines selectively bred for extremes in stress reactivity (SR), i.e. presenting high (HR) or low (LR) corticosterone secretion in response to stressors, were used to characterise the molecular alterations on all levels of the HPA axis. Results were contrasted with clinical phenotypes of MD patients from the Munich Antidepressant Response Signature project, stratified according to their cortisol response in the Dex/CRH test. Distinct differences between HR and LR mice were found in the expression of HPA axis-related genes in the adrenals, pituitary and selected brain areas. Moreover, HR animals presented an enhanced adrenal sensitivity, increased stress-induced neuronal activation in the PVN and an overshooting Dex/CRH test response, whereas LR animals showed a blunted response in these paradigms. Interestingly, analogous neuroendocrine, morphometric, psychopathological and behavioural differences were observed between the respective high and low HPA axis responder groups of MD patients. Our findings suggests that (i) the SR mouse model can serve as a valuable tool to elucidate HPA axis-related mechanisms underlying affective disorders and (ii) a stratification of MD patients according to their HPA axis-related neuroendocrine function should be considered for clinical research and treatment.