Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.
The author discloses that he has no significant financial interests in any product or class of products discussed directly or indirectly in this activity, including research support.
Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.
The endocrine system refers to a system of glands, each of which secretes a particular hormone that serves to regulate certain functions throughout the body. There is a reciprocal and interactive relationship between the central nervous system (CNS) and various endocrine glands, such that the secretion of endocrine hormones is regulated in part by the CNS and endocrine hormones influence the function of the CNS. Disturbances in some endocrine hormones have been implicated in the pathophysiology of mental disorders, especially depression. For this reason, some hormones (and drugs that affect hormone function) have been used as therapeutic agents for the treatment of depression. Adrenal, thyroid, and gonadal hormones have been investigated most extensively, and these will be briefly reviewed in this article.
Adrenal Axis Hormones
The perception of stress is linked to adrenal gland activity by pathways extending from the cerebral cortex and hypothalamus to the pituitary gland, referred to as the hypothalamic-pituitary-adrenal (HPA) axis. The stress-responsive glucocorticoid hormone cortisol is released by the adrenal gland in response to a wide variety of physical and psychological stresses. In the hypothalamus, the neuropeptide corticotrophin-releasing hormone (CRH) is released, typically in response to the perception of stress or threat. CRH then triggers release of adrenocorticotrophic hormone, which travels from the pituitary gland to the adrenal gland, where glucocorticoid hormones are synthesized and released.
Abnormal regulation of the HPA axis, leading to persistently elevated cortisol levels, has been implicated in the pathophysiology of depression. Evidence of hypercortisolism and dysregulation of HPA axis activity is typically found in 40% to 60% of depressed individuals but is more commonly associated with older age, psychotic symptoms, severe depression and anxiety, psychomotor agitation, weight loss, insomnia, and suicidality. Hypercortisolism is also associated with memory and other cognitive impairments (commonly reported in severe depression); this may reflect neuronal atrophy and cell death in the prefrontal cortex and hippocampus.
Antidepressant medications, lithium, second-generation (atypical) antipsychotic (SGA) drugs, and other psychotropic medications have been shown to normalize dysregulated activity of the HPA axis, and this effect may contribute to their antidepressant properties. A number of open-label and controlled studies of drugs that directly suppress or inhibit HPA axis function, such as dexamethasone (Decadron®), aminoglutethimide (Cytadren®), metyrapone (Metopirone®), ketoconazole (Nizoral®), and mifepristone (Mifeprex®), have shown some benefit for the treatment of major depression, including treatment-resistant depression (Reus & Wolkowitz, 2001; Rogóz et al., 2004).
Because of the typical delayed onset of effect and less-than-optimal remission rates associated with antidepressant agent monotherapy, adding a second medication at the beginning of antidepressant treatment is one approach to induce a more rapid, efficacious, and sustained response. On the basis of this rationale, a randomized, double-blind, placebo-controlled study demonstrated that the steroid-synthesis inhibitor drug metyrapone was effective in accelerating response to the antidepressant agents nefazodone (Serzone®) and fluoxetine (Prozac®) and improved the response to these drugs (Jahn et al., 2004).
Thyroid Axis Hormones
The hypothalamic-pituitary-thyroid (HPT) axis is composed of the neuropeptide thyrotropin-releasing hormone (TRH), which is secreted from the hypothalamus and stimulates the secretion of thyroid-stimulating hormone (TSH) from the pituitary. TSH stimulates the thyroid to secrete its primary hormones triiodothyronine (T3) and thyroxine (T4). The HPT axis is regulated primarily by negative feedback inhibition of pituitary TSH secretion by circulating levels of T3 and T4.
The importance of the HPT axis in depressive disorders is supported by evidence that receptors for TRH and T3 are found in the brain, such that these hormones function like neurotransmitters, modulate norepinephrine and serotonin receptors, and have antidepressant-like effects. There also is a significant degree of homology (similarity) in the genes that code for T3 receptors and cortisol receptors. Hence, thyroid dysfunction (i.e., hyperthyroidism, hypothyroidism) leads to significant changes in thyroid hormone levels that may affect CNS function and cause or contribute to the development of depression.
Although clinical hypothyroidism is often associated with depression, most studies of depressed patients have found low rates of hypothyroidism. However, subtle degrees of hypothyroidism may be relatively more common in chronic or treatment-resistant depression, requiring combined treatment using antidepressant drugs together with thyroid hormone augmentation (Howland, 1993). Thyroid augmentation has been studied almost exclusively in patients who have not responded to tricyclic antidepressant agents (TCAs), although more recent studies have included those who have not responded to selective serotonin reuptake inhibitors (SSRIs) (Abraham, Milev, & Lawson, 2006; Joffe, Singer, Levitt, & MacDonald, 1993; Nierenberg et al., 2006). Thyroid augmentation may be more effective in women, perhaps because of their higher risk for thyroid disease.
Thyroid hormone augmentation has not been studied as extensively as lithium augmentation or augmentation with SGA drugs (e.g., olanzapine [Zyprexa®], aripiprazole [Abilify®], quetiapine [Seroquel®]), but it has been better studied than other combination and augmentation strategies. The T3 form is easier to use and has been better studied than T4. In a placebo-controlled comparison, T3 augmentation and lithium augmentation were similarly effective for patients who have not responded to TCAs (Joffe et al., 1993). However, in the augmentation arm of the third level of the STAR*D study, patients whose depression had not remitted after two treatment steps were randomly assigned to augmentation with lithium or T3 (Nierenberg et al., 2006). Remission rates were lower for lithium compared with T3, but the difference was not statistically significant. Lithium was more frequently associated with side effects, and more patients taking lithium left treatment because of these effects.
Despite the rationale for combining or augmenting antidepressant drugs from the beginning of antidepressant treatment, an analysis of four randomized, double-blind, placebo-controlled trials showed that T3 augmentation of SSRIs at the start of treatment was not effective (Papakostas et al., 2009).
Gonadal Axis Hormones
The gonads (ovaries and testes) produce sex-specific hormones in men and women. Several lines of evidence have suggested an important role for gonadal steroid hormones in mood regulation. Women are especially vulnerable to mood disturbances during premenstrual, postpartum, and perimenopausal periods. Evidence also shows that mood disturbances may be associated with decreased steroid hormone levels in men (Shores, Kivlahan, Sadak, Li, & Matsumoto, 2009). In addition, steroid hormones act on specific receptors in the brain and affect neuronal function and neurotransmission.
Estrogen may improve mild mood symptoms in perimenopausal women (Epperson, Wisner, & Yamamoto, 1999), but there is less consistent evidence that estrogen or estradiol is effective alone for major depression (Morgan, Cook, Rapkin, & Leuchter, 2005; Morrison et al., 2004; Soares, Almeida, Joffe, & Cohen, 2001). Some but not all studies have found that estrogen may augment the effects of antidepressant drugs in major depression (Amsterdam et al., 1999; Morgan et al., 2005; Schneider et al., 1997; Shapira et al., 1985). A small placebo-controlled study found that estrogen augmentation was effective for perimenopausal women with treatment-resistant depression (Morgan et al., 2005).
Evidence of the antidepressant effects of testosterone in men is inconsistent (Kanayama, Amiaz, Seidman, & Pope, 2007). Several placebo-controlled studies of testosterone augmentation in men with treatment-resistant depression had mixed results, although the sample of each study was small (Kanayama et al., 2007). A recent placebo-controlled study found that testosterone replacement was effective in older hypogonadal men with dysthymia or minor depression (Shores et al., 2009).
The adrenal steroid hormone dehydroepiandrosterone (DHEA), which is a precursor to testosterone and estrogen, has an important role in mood regulation and may have significant antidepressant effects (Schmidt et al., 2005; Wolkowitz et al., 1999). A small placebo-controlled study suggested benefit with DHEA augmentation for treatment-resistant depression (Wolkowitz et al., 1999).
Adrenal, thyroid, and gonadal hormones have important effects on the CNS. Many of these hormones (or drugs that affect their function) have been used clinically to treat depression, typically in combination with conventional antidepressant agents. Because many patients have questions about “hormones” and depression, nurses should be broadly familiar with these three endocrine hormone systems and how they have been studied for the treatment of depression.
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