Future studies in depression will further explore these findings, and promise to add an important group of medications to the treatment repertoire for depression. Beyond this, research is currently under way to delineate the epidemiological,

biochemical, and genetic factors that mediate the effects of psychosocial stress on depressive syndromes. An important aspect of this research will be to better define the interaction between the HPA axis and the monoamine neurotransmitter systems, especially given the apparent role of serotonin Inhibitors,research,lifescience,medical neurotransmission in modulating the effects of stress on the development of depression (see above). For example, we recently reported that 5-HT depletion in humans is associated with dramatic increases Inhibitors,research,lifescience,medical in CSF CRF concentrations, demonstrating an important 5-HT-CRF link.87 HPT axis Hypothyroidism is classically associated with a depressive syndrome that is ameliorated by correcting the underlying thyroid hormone deficit. This suggests a relation between the hypothalamic-pituitary-thyroid (HPT) axis and the neurobiology of depression. In the HPT axis, thyrotropin-releasing hormone (TRH) is secreted by the hypothalamus

and stimulates thyroid-stimulating hormone (TSH) release from the pituitary. Inhibitors,research,lifescience,medical TSH acts on the thyroid to stimulate iodine uptake, follicle cell metabolism, and release of the two thyroid hormones (triiodothyronine [T3] and thyroxine [T4). Thyroid hormones are responsible for a number of homeostatic and metabolic Inhibitors,research,lifescience,medical functions and also provide feedback to the hypothalamus and pituitary to decrease further TRH and TSH release, respectively.

A mixed database supports some role for the HPT axis in the pathophysiology of depression. In depressed patients, CSF TRH has been shown to be elevated (suggesting decreased feedback from thyroid hormones) Inhibitors,research,lifescience,medical compared with controls,88,89 though discordant findings have been reported.90 Several studies have revealed a blunted TSH response to TRH stimulation in depressed patients despite normal thyroid hormone levels,91 consistent with downregulation of TRH receptors in the pituitary, Ixazomib in vitro perhaps secondary to elevated TRH levels. Alternatively, thyroid hormone in the periphery may not be efficiently transported into the CNS in depressed patients; CSF levels of transthyretin – the protein responsible Digestive enzyme for transporting thyroid hormones across the bloodbrain barrier at the choroid plexus – have been shown to be decreased in depressed patients.92,93 Thyroid hormone augmentation (primarily with T3) has been reported to exert antidepressant effects, even in the absence of clinical hypothyroidism,94-95 though several negative studies are available (P. Ninan and C. B. Nemeroff, unpublished observations).96 Future studies will help clarify the role of the HPT axis in the pathophysiology and treatment of depression. As with the HPA axis, areas of interest include the interaction of the HPT system with other neuromodulatory systems.