Major depressive disorder is a common psychiatric disorder associated with marked suffering, morbidity, mortality, and cost. TheWorld HealthOrganization 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-pituitaryadrenal (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 (T3and 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.
Bibliographical noteFunding Information:
Child Study Center and Department of Radiology and Biomedical Imaging, Yale University, New Haven, Conn. (Dwyer); Department of Psychiatry, Case Western Reserve University, Cleveland, and Northcoast Behavioral Healthcare Hospital, Northfield, Ohio (Aftab); Department of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis (Widge); Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif., and VA Palo Alto Health Care System, Palo Alto, Calif. (Rodriguez); Department of Psychiatry and Human Behavior, Butler Hospital, Brown University, Providence, R.I. (Carpenter); Department of Psychiatry, University of Texas at Austin (Nemeroff); Department of Psychiatry and Human Behavior, Emory University School of Medicine, Atlanta (McDonald); and Department of Psychiatry, University of Wisconsin–Madison (Kalin). Send correspondence to Dr. Dwyer (email@example.com). Drs. Dwyer and Aftab share first authorship. Dr. Dwyer was supported by NIMH training grant T32 MH018268 during the preparation of this manuscript. Dr. Widge’s work on this project was supported in part by NIH grants R21 MH113101, UH3 NS100548, and R01 MH119384, the OneMind Institute, the MnDRIVE Brain Conditions initiative, and the University of Minnesota Medical Discovery Team on Additions. Dr. Dwyer has received research support from the Klingenstein Third Generation Foundation and has served as a consultant for Axsome Therapeutics. Dr. Widge has served as a consultant for Medtronic and Circuit Therapeutics, has received speaking fees from Medtronic and Livanova, and has received research device donations from Medtronic; he has multiple patent applications in the areas of brain stimulation and biomarkers of cognitive dysfunction. Dr. Carpenter has served as a consultant for Affect Neuro, Janssen, Neurolief, Neuronetics, Nexstim, and Sage Therapeutics and has received research support from Affect Neuro, Janssen, NeoSync, Neuronetics, and Nexstim. Dr. Nemeroff has received grants or research support from NIH; he has served as a consultant for Acadia Pharmaceuticals, EMA Wellness, Gerson Lehrman Group, Intra-Cellular Therapies, Janssen Research and Development, Magstim, Navitor Pharmaceuticals, Signant Health, Sunovion Pharmaceuticals, Taisho Pharmaceutical, Takeda, TC MSO, and Xhale; he has served on scientific advisory boards of the American Foundation for Suicide Prevention, the Anxiety Disorders Association of America (ADAA), the Brain and Behavior Research Foundation, the Laureate Institute for Brain Research, Signant Health, Skyland Trail, and Xhale and on boards of directors for ADAA, Gratitude America, Smart, Inc., and Xhale; he is a stockholder in AbbVie, Antares, BI Gen Holdings, Celgene, Corcept Therapeutics, EMA Wellness, OPKO Health, Seattle Genetics, TC MSO, Trends in Pharma Development, and Xhale; he has income sources or equity of $10,000 or more from American Psychiatric Publishing, CME Outfitters, EMA Wellness, Intra-Cellular Therapies, Magstim, Signant Health, and Xhale; he holds patents on a method and devices for transdermal delivery of lithium (US 6,375,990B1), a method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2), and compounds, compositions, methods of synthesis, and methods of treatment (CRF Receptor Binding Ligand) (US 8,551,996B2). Dr. McDonald has received research support from Cervel Neurotherapeutics, the National Institute of Neurological Disease and Stroke, the National Institute on Aging, NeoSync, Neuronetics, NIMH, Soterix, and the Stanley Foundation; he has served as a consultant for Signant Health; he receives royalties from Oxford University Press; and he receives funding from the J.B. Fuqua Foundation. Dr. Kalin is Editor-in-Chief and Dr. Rodriguez is Deputy Editor for the American Journal of Psychiatry; the editors’ disclosures appear in the April issue of the Journal. Dr. Aftab reports no financial relationships with commercial interests.
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