Neuroendocrine Stress System in Bipolar Disorder Mario F. Juruena, Anthony J. Cleare, and Allan H. Young Contents 1 Introduction .................................................................................. 150 2 Endocrine Axis .............................................................................. 151 2.1 Regulation of the Hypothalamic-Pituitary-Adrenal Axis ............................ 151 2.2 The Glucocorticoid Receptor (GR) ................................................... 153 2.3 Mineralocorticoid Receptors (MRs) .................................................. 154 2.4 Molecular Mechanisms for Resistance of Glucocorticoid Receptors ................ 156 3 Abnormalities of the HPA Axis in Depression ............................................. 157 3.1 Impact of Stress on Bipolar Disorders ................................................ 159 3.2 Impact of Mediating Factors on the HPA Axis ...................................... 161 4 Factors Associated with an Endophenotype Increasing Vulnerability ..................... 163 5 Conclusion ................................................................................... 164 References ....................................................................................... 165 Abstract Hormones have a crucial part in the progress and manifestation of a wide variety of different behaviors. The main influence of the neuroendocrine system on behavior is its action on the neurobiology of neuropsychiatric disorders and its relationship with the pharmacodynamics of medicines. Of all the neuroendocrine axes, the hypothalamic-pituitary-adrenal (HPA) axis has been the most extensively studied. There is evidence that disturbance in the HPA axis, the primary stress hormone system, could increase treatment resistance and relapse, worsen illness outcome, and cause cognitive deficits. Glucocorticoids mediate their actions in negative feedback binding in two different cytoplasmatic receptors described as mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs). Different psychopathologies underlying bipolar disorders are supposed to involve persistent dysfunctions in the expression and role of both MR and GR in the hippocampus. We review and analyze the evidence related to the correlation between bipolar disorders and the consequences and impact of stressful life events on the HPA axis, exploring M. F. Juruena (*), A. J. Cleare, and A. H. Young Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK e-mail: mario.juruena@kcl.ac.uk © Springer Nature Switzerland AG 2020 Curr Topics Behav Neurosci (2021) 48: 149–172 https://doi.org/10.1007/7854_2020_184 Published Online: 13 February 2021 149