Mood Disorders and Pathophysiology of the HPT Axis

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Several lines of inquiry are indicative of dysregulation of the HPT axis in depression (Table 45–3). Elevated CSF TRH concentrations have been reported in depressed patients (Banki et al. 1988; Kirkegaard et al. 1979), although there is one discordant report (Roy et al. 1994). In addition, reduction of the mean and peak amplitudes of the 24-hour TSH secretion cycle in depressed patients suggests the presence of chronobiological dysfunction within the HPT axis (Duval et al. 1990, 1996). Furthermore, a multitude of studies using a standardized TRH stimulation test in depressed patients with normal thyroid function have consistently revealed a blunted TSH response (Esposito et al. 1997; Nemeroff and Evans 1989), suggesting downregulation of pituitary TRH receptors perhaps in response to hypersecretion of hypothalamic TRH. Alternatively, thyroid hormones may not be effectively transported to the CNS in patients with depression. Reduced CSF concentrations of transthyretin, which is essential for the transport of thyroid hormone across the blood–brain barrier, have been reported in patients with depression (Hatterer et al. 1993; G. M. Sullivan et al. 1999). Clinically, there have been reports that thyroid hormone supplementation, primarily with T3, is an effective augmentation strategy in the treatment of depression (Aronson et al. 1996; Iosifescu et al. 2005), although again discordant reports have appeared (Appelhof et al. 2004). Recently, a double-blind, placebo-controlled multisite trial of T3 augmentation of sertraline treatment of depression demonstrated clear efficacy of this augmentation strategy (Cooper-Kazaz et al. 2007). Our group failed to demonstrate any advantage of T3 coadministration with sertraline compared with placebo in depressed patients in terms of speed of onset or magnitude of antidepressant response (Garlow et al. 2007). One major difference between these two studies is the dose of sertraline; in the former, the mean dose was considerably lower than in the latter.

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Table Reference Number
TABLE 45–3. Alterations in hypothalamic-pituitary-thyroid (HPT) axis activity in unipolar depression
Table Reference Number
TABLE 45–4. Grades of hypothyroidism
Table Reference Number
TABLE 45–5. Alterations in hypothalamic-pituitary-thyroid (HPT) axis activity in bipolar disorder


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