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.

Thyroid hormones have been considered as viable treatments for patients with mood disorders, particularly those with treatment-resistant illness. Hypothalamic thyrotropin releasing hormone (TRH) has a regulatory effect on the thyroid axis by stimulating thyrotropin (TSH) which, in turn, regulates thyroid hormone synthesis and release. Triiodothyronine (T3) is the most widely and extensively studied thyroid hormone for the treatment of depression. It has been employed as monotherapy, to accelerate antidepressant effect and to augment therapeutic effects in antidepressant non-responders. The majority of the earlier studies employed T3 as it was felt that with its short half-life it would be less likely to cause symptoms of toxicity. It was assumed that thyroxine (T4) would be comparable to T3 in augmentation of antidepressant response as both would enhance thyroid hormone levels. Two of the most commonly employed antidepressant augmentation strategies are the addition of lithium and T3.