INDIAN JOURNAL OF PSYCHIATRY, 2003, 45(11), 5-14 R E V I E W A R T I C L E G l u c o c o r t i c o i d r e c e p t o r d y s f u n c t i o n : consequences f o r t h e pathophysiology and . t r e a t m e n t of mood disorders AJU ABRAHAM, STUART W A T S O N , A L L A N H Y O U N G A B S T R A C T Background: Hypothalamic-pituitary-adrenal (HPA) axis dysfunction in mood disorders is one of the most robust findings in biological psychiatry. However, considerable debate surrounds the nature of the core abnormality, its cause, consequences and treatment implications. Aims: To review the evidence for the role of HPA axis dysfunction in the pathophysiology of mood disorders with particular reference t o corticosteroid receptor pathology. Methods: A selective review of the published literature in this field, focusing on human studies. Results: The nature of basal HPA axis dysregulation described in both manic and depressed bipolars appears t o be similar to those described in M D D . But studies using the dexamethasone/ corticotropin releasing hormone (dex/CRH) test and dexamethasone suppression test (DST) have shown that HPA axis dysfunction is more prevalent in bipolar than in unipolar disorder. There is robust evidence for corticotropin releasing hormone (CRH) hyperdrive and glucocorticoid receptor (GR) dysfunction in mood disorders, with increasing evidence for disorders within ^ the AVP system. Conclusion: HPA axis dysfunction is prevalent in patients with mood disorder, particularly those with psychotic disorders and bipolar affective disorder. This may be secondary t o genetic factors, early life adversities or both. Dysfunction of GR may be the underlying abnormality and preliminary findings suggest that it is a potential target for novel therapies. Declaration of interest: None Key words: Mood disorders, pathophysiology, Glncocorticoid Receptor Mood disorders are common, often severe, life long; associated with significant handicap and disability and are associated with a high risk of death by both suicide (6-15%-(Goodwin, et al, 1990; Inskip, et al, 1998) and physical disorders. It is still uncertain whether modern treatments have i substantially changed either the length of episodes or the number of relapses. Contemporary studies have found a life­ time prevalence of major depressive disor­ der of 4-19%. Traditionally episodes of unipolar-depression were pictured as acute illnesses, self-limiting and lasting approxi­ mately 6-9 months from the time of onset to full recovery. A number of studies , however, show potential for great variation from this. Recovery may take much longer, or not occur at all. Moreover the risk of relapse and recurrence must be considered (Angst, 2000). At 5 years, 12% of unipolar depressed patients have still not recovered (Keller, et al, 1992) and by 10 years 7% have not recovered (Solomon, et al, 1997). For Bipolar I Disorder, the majority of epidemiological studies indicate lifetime (S) prevalence rates of approximately 0.5-1% (Kessler, et al, 1994; Weissman, et al, 1996). Classically, bipolar disorder manifests as repeated periods of illness with complete recovery (Kraepelin, 1899). However, many patients have a poor outcome, a third suffer chronic symptoms and up to a quarter may develop rapid cycling disorder, where four or more episodes occur within a year. This poor clinical outcome is associated with significant disability in terms of social, marital and occupational dysfunction (Zarate, et al, 2000). Co-morbid illnesses include anxiety disorders, substance abuse and personality disorders (Kay, et al, 1999; McElroy, et al, 2001). A much wider, less well characterised bipolar spectrum also exists. This includes not only bipolar II disorder, characterised by episodes of de­ pression and hypomania but also less well recognised sub-syndromes combining hypo- mania and minor depression or manic/ hypomanic symptoms alone. Hypothalamic-pituitary-adrenal (HPA) axis The hypothalamic-pituitary-adrenal (HPA) axis is a multifaceted regulatory system which integrates neuronal and endocrine function and consists of the hypothalamus, pituitary, adrenal cortex, and the associated regulatory inputs, releasing factors and hormones (see Fig. 1). The neurosecretory cells in the paraventricular nucleus (PVN) of the hypothalamus secrete corticotropin- releasing hormone (CRH) and arginine vasopressin (AVP) into the microportal circulatory system of the pituitary stalk. They induce the release of adrenocortico­ tropic hormone (ACTH) from the anterior lobe of the pituitary into the systemic circulation. ACTH in turn promotes the release of the glucocorticoid - Cortisol from the zona fasciculate and zona reticularis of the adrenal cortex, and mineralocorticoid - aldosterone from the zona glomerulosa of the adrenal cortex. The HPA axis has an extrinsic and intrinsic regulatory mechanism. The extrin­ sic regulatory inputs are received by the secretory cells in the PVN of the hypothalamus, from many brain regions, including amygdala, hippocampus and nu­ clei of the midbrain. In addition to these