Hormonal Treatments for Major Depressive Disorder: State of the Art

Abstract

Major depressive disorder is a common psychiatric disorder associated with marked suffering, morbidity, mortality, and cost. The World Health Organization projects that by 2030, major depression will be the leading cause of disease burden worldwide. While numerous treatments for major depression exist, many patients do not respond adequately to traditional antidepressants. Thus, more effective treatments for major depression are needed, and targeting certain hormonal systems is a conceptually based approach that has shown promise in the treatment of this disorder. A number of hormones and hormone-manipulating compounds have been evaluated as monotherapies or adjunctive treatments for major depression, with therapeutic actions attributable not only to the modulation of endocrine systems in the periphery but also to the CNS effects of hormones on non-endocrine brain circuitry. The authors describe the physiology of the hypothalamic-pituitary-adrenal (HPA), hypothalamic-pituitary thyroid (HPT), and hypothalamic-pituitary-gonadal (HPG) axes and review the evidence for selected hormone-based interventions for the treatment of depression in order to provide an update on the state of this field for clinicians and researchers. The review focuses on the HPA axis-based interventions of corticotropin-releasing factor antagonists and the glucocorticoid receptor antagonist mifepristone, the HPT axis-based treatments of thyroid hormones (T₃ and T₄), and the HPG axis-based treatments of estrogen replacement therapy, the progesterone derivative allopregnanolone, and testosterone. While some treatments have largely failed to translate from preclinical studies, others have shown promising initial results and represent active fields of study in the search for novel effective treatments for major depression.

Keywords: Antidepressants; Neuroendocrinology.

Figure 1-. Hypothalamic-pituitary- adrenal (HPA) axis:

The paraventricular nucleus of the hypothalamus (PVN) releases corticotropin releasing factor (CRF) and, to a lesser extent, arginine-vasposressin (AVP). These factors stimulate the anterior pituitary to release adrenocorticotropic hormone (ACTH) into the peripheral circulation, which stimulates the adrenal gland to release glucocorticoids (e.g. cortisol). Glucocorticoids act on both glucocorticoid receptors and mineralocorticoid receptors. Negative feedback occurs at the level of the pituitary, the hypothalamus, and higher brain structures (e.g. cortex, hippocampus, and periventricular thalamus)

Figure 2-. Hypothalamic-pituitary- thyroid (HPT) axis:

The paraventricular nucleus of the hypothalamus (PVN) releases thyroid releasing hormone (TRH), which stimulates the anterior pituitary to release thyroid stimulating hormone (TSH) into the peripheral circulation. The Thyroid gland then releases T4 and T3 into the circulation. Circulating T4 can also be converted to T3 via deiodinases. These hormones act on thyroid receptors in target organs, and as a means of regulating negative feedback at the level of the hypothalamus and pituitary.

Figure 3

(A) Hypothalamic-pituitary- gonadal (HPG) axis: The medial preoptic area of the hypothalamus (mPOA) releases gonadotropin releasing hormone (GnRH), which stimulates the anterior pituitary to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH) into the peripheral circulation. These factors stimulate the gonads to produce sex hormones, with the ovaries producing estradiol and progesterone, and the testes producing testosterone. (B) Steroid hormone synthesis: Cholesterol is the precursor molecule to sex hormones, which can undergo a variety of enzymatic transformations. (C) The menstrual cycle: The cycle begins at day 0 with the occurrence of of menses. Estradiol gradually climbs during the follicular phase (days 0 through 14 of a 28-day cycle). Ovulation is triggered by the spike in anterior pituitary production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). During the luteal phase (days 14 through 28), progesterone, and to a lesser extent, estradiol, rises. The production of both hormones then begins to fall toward the end of the luteal phase, a time of vulnerability for PMDD symptoms. In the absence of pregnancy, falling ovarian hormones levels lead to the the shedding of the uterine lining with menses, beginning the cycle again.

Figure 3

(A) Hypothalamic-pituitary- gonadal (HPG) axis: The medial preoptic area of the hypothalamus (mPOA) releases gonadotropin releasing hormone (GnRH), which stimulates the anterior pituitary to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH) into the peripheral circulation. These factors stimulate the gonads to produce sex hormones, with the ovaries producing estradiol and progesterone, and the testes producing testosterone. (B) Steroid hormone synthesis: Cholesterol is the precursor molecule to sex hormones, which can undergo a variety of enzymatic transformations. (C) The menstrual cycle: The cycle begins at day 0 with the occurrence of of menses. Estradiol gradually climbs during the follicular phase (days 0 through 14 of a 28-day cycle). Ovulation is triggered by the spike in anterior pituitary production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). During the luteal phase (days 14 through 28), progesterone, and to a lesser extent, estradiol, rises. The production of both hormones then begins to fall toward the end of the luteal phase, a time of vulnerability for PMDD symptoms. In the absence of pregnancy, falling ovarian hormones levels lead to the the shedding of the uterine lining with menses, beginning the cycle again.