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Major depressive disorder (MDD) is associated with increased allostatic load (AL; a measure of physiological costs of repeated/chronic stress-responding) and metabolic dysregulation (MetD; a measure of metabolic health and precursor to many medical illnesses). Though AL and MetD are associated with poor somatic health outcomes, little is known regarding their relationship with antidepressant-treatment outcomes.
Methods
We determined pre-treatment AL and MetD in 67 healthy controls and 34 unmedicated, medically healthy MDD subjects. Following this, MDD subjects completed 8-weeks of open-label selective serotonin reuptake inhibitor (SSRI) antidepressant treatment and were categorized as ‘Responders’ (⩾50% improvement in depression severity ratings) or ‘Non-responders’ (<50% improvement). Logistic and linear regressions were performed to determine if pre-treatment AL or MetD scores predicted SSRI-response. Secondary analyses examined cross-sectional differences between MDD and control groups.
Results
Pre-treatment AL and MetD scores significantly predicted continuous antidepressant response (i.e. absolute decreases in depression severity ratings) (p = 0.012 and 0.014, respectively), as well as post-treatment status as a Responder or Non-responder (p = 0.022 and 0.040, respectively), such that higher pre-treatment AL and MetD were associated with poorer SSRI-treatment outcomes. Pre-treatment AL and MetD of Responders were similar to Controls, while those of Non-responders were significantly higher than both Responders (p = 0.025 and 0.033, respectively) and Controls (p = 0.039 and 0.001, respectively).
Conclusions
These preliminary findings suggest that indices of metabolic and hypothalamic-pituitary-adrenal-axis dysregulation are associated with poorer SSRI-treatment response. To our knowledge, this is the first study to demonstrate that these markers of medical disease risk also predict poorer antidepressant outcomes.
Anxiety disorders increase the risk of onset of several ageing-related somatic conditions, which might be the consequence of accelerated cellular ageing.
Aims
To examine the association between anxiety status and leukocyte telomere length (LTL) as an indicator of cellular ageing.
Method
Data are from individuals with current (n = 1283) and remitted (n = 459) anxiety disorder, and controls (n = 582) with no psychiatric disorder from the Netherlands Study of Depression and Anxiety. We determined DSM-IV anxiety diagnoses and clinical characteristics by structured psychiatric interviews and self-report questionnaires; LTL was assessed using quantitative polymerase chain reaction and converted into base pairs (bp).
Results
Patients in the current anxiety group (bp = 5431) had significantly shorter LTL compared with the control group (bp = 5506, P = 0.01) and the remitted anxiety group (bp = 5499, P = 0.03) in analyses adjusted for sociodemographics, health and lifestyle. The remitted anxiety group did not differ from the control group (P = 0.84), however, time since remission was positively related with LTL. Furthermore, anxiety severity scores were associated with LTL in the whole sample, in line with a dose–response association.
Conclusions
Patients with current – but not remitted – anxiety disorder had shorter telomere length, suggesting a process of accelerated cellular ageing, which in part may be reversible after remission.
Clinical applications of psychoneuroendocrinology are largely in their infancy, but certain strategies have already entered clinical practice and others appear promising. This chapter deals with the more well-established hormonal therapies for treatment-resistant depression. Thyroid augmentation in treatment-resistant depression and in rapid cycling bipolar affective disorder has received the greatest empirical support, followed by estrogen replacement therapy or estrogen augmentation in postmenopausal women. Strategies directly targeting the hypothalamic-pituitary-adrenal (HPA) axis (for example, antiglucocorticoids, dexamethasone, DHEA) are being actively investigated but, to date, have not received sufficient empirical support to enter into routine clinical practice. The prediction that drugs that directly lower HPA axis activity should have antidepressant effects has been widely studied in patients with Cushing's syndrome but only recently in psychiatric patients with major depression. For individual treatment-resistant patients who have exhausted other options, however, empirical trials with informed consent and with attention to possible side-effects, seem reasonable.
Dehydroepiandrosterone (DHEA) and its sulfated metabolite, DHEA-S (together abbreviated DHEA(S)), are quantitatively the most important adrenal corticosteroids in man, although their physiological roles are unknown. These steroids have captured widespread scientific and public attention in recent years due to three key observations. First, circulating levels of these steroids progressively decline from young adulthood through the end of the lifespan; they also decrease in response to chronic stress or illness. Second, preclinical studies suggest that DHEA(S) protects against certain pathological processes seen in illness and with aging. Third, some epidemiological studies in man suggest that relatively higher DHEA(S) levels are associated with enhanced physical and mental well-being. Such findings have raised hope that replacement dosing with pharmaceutical DHEA may enhance and prolong life, although very limited clinical data exist to support this. This chapter will review preclinical and clinical data regarding the effects of DHEA(S) in the central nervous system, its biological role in aging and mental health and its possible efficacy in treating neuropsychiatric illness in the middle-aged and elderly.
DHEA(S) as a neurosteroid
DHEA(S) is synthesized in situ in brain, with glial cells playing a major role in its formation and metabolism; it has therefore, been termed a neurosteroid (Baulieu, 1997). Accumulation of DHEA(S) in rat brain is largely independent of adrenal and gonadal synthesis, remaining constant after orchiectomy, adrenalectomy and dexamethasone administration (Robel & Baulieu, 1995; Corpechot et al., 1981).
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