The June 2005 issue (Volume 28 Number 2) of Psychiatric Clinics of North America edited by E. Sherwood Brown is devoted to Bipolar Disorder. It contains articles on psychopharmacology, neuroimaging, and psychosocial interventions. I would like to summarize some of the new research on neuroendocrinological functioning in bipolar disorder. My doctoral research in the 1970’s involved neuroendocrinology of stress/anxiety/fear and I have been studying this research as it relates to severe mental illness since then. I have always felt that anxiety is central in mental disorders. Mania seemed to me partly an expression of anxiety and partly a defense against the anxiety/mental pain derived from loss, fear of one’s destructiveness, etc. I believe there now exists significant research indicating the significant role of anxiety in the initiation of manic episodes (neuroendocrinological evidence of increased stress/anxiety prior to symptomatology). Previously, I posted a summary of the psychosocial research demonstrating the role of social and psychological risk factors not only influencing the course of bipolar disorder, but in its initiation as well (similar to the psychosocial research emerging in schizophrenia). Bipolar disorder, as in schizophrenia, may be initiated in some individuals by multiple genes of low-moderate effect in a dose-response relationship to the environment, particularly the interpersonal and social environment. The putative genetic diathesis could be dynamic and intimately related to transgenerational transmission of trauma (epigenetic processes) as well as early childhood adversity (e.g., separations, abuse, neglect, etc.). Psychogenic stress has been demonstrated to be genotoxic, at the level of chromosome and DNA, in various somatic cells.
I would like to refer to the research summarized in “Hypothalamic-pituitary-adrenal axis and bipolar disorder” by C. Daban, E. Vieta and A. H. Young (2005)-a chapter in the above volume dedicated to new research in bipolar disorder.
For many decades, dysfunctional neuroendocrinological systems in the pathogenesis in mood disorders have been a focus of research. More recently, research has centered on the role of the hypothalamic-pituitary-adrenal axis (HPA-or what I prefer, LHPA, i.e., limbic-hypothalamic-pituitary-adrenal axis) in bipolar disorder.
I will briefly review this neuroendocrine system in relation to stress. Glucocorticoids (e.g., cortisol) are hormones that are the final product of the LHPA axis and are central in the stress response (I planned my doctoral research in the library at Rockefeller University in New York and I was delighted to learn of the significant research of a neuroendocrinologist at Rockefeller, Bruce McEwen-his book “The End of Stress As We Know It” published in 2002 by Joseph Henry Press, is an excellent resource on the psychobiological effects of stress-McEwen’s concept of allostatic load is invaluable). During acute stress, glucocorticoids induce adaptive changes such as mobilizing energy reserves (e.g., to confront a threatening situation). Long-term changes include the regulation of immune responsiveness and activation of the sympathetic nervous system. Excessive secretion of cortisol leads to disruptions in cellular functioning and widespread physiologic dysfunction. The LHPA axis includes regulatory neural inputs (e.g., from the amygdala), a variety of releasing factors/hormones as well as a feedback loop which includes the hypothalamus, pituitary and adrenal glands. During stress, the hypothalamus secretes two hormones: corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). CRH acts on the pituitary to secrete adrenocorticotropic hormone (ACTH), which in turn reaches the adrenal cortex through systemic circulation and causes it to secrete cortisol.
The widespread effects of cortisol are mediated by two intracellular receptor subtypes: the high-affinity type I receptor or mineralocorticoid receptor (MR), and the low-affinity type II receptor or glucocorticoid receptor (GR). The LHPA axis has an autoregulatory mechanism mediated by cortisol When levels of cortisol rise, the MR’s are saturated. The GR’s become the main transducer of glucocorticoid activity and, therefore, the primary mediator of LHPA feedback. These autoregulatory mechanisms are crucial; in the maintenance of the homeostatic functioning of the LHPA axis. The loop allows for negative feedback of cortisol to reach the hypothalamus, pituitary and higher neural centers.
The functioning of the LHPA axis is measured by levels of cortisol, CRH and ACTH release. In addition, the dexamethasone (DEX) suppression test (DST) is a sensitive measure of the functional integrity of the GR-mediated negative feedback mechanism: the cortisol suppressing activity of the synthetic glucocorticoid, DEX, is an indicator of GR status. A newer test, a combined DEX/CRH challenge, in which the LHPA axis is both stimulated by CRH and inhibited by DEX, is said to be more sensitive for detecting LHPA axis dysfunction in depression.
Cortisol and Bipolar Disorder
Dysregulation of ACTH and cortisol response after CRH stimulation have been reported in bipolar patients. Changes in CRH secretion appear prior to manic or hypomanic symptoms are clinically evident. This is also reported in schizophrenia research and counters the more reductionistic arguments that the anxiety is a response to the symptoms (no doubt there is increasing anxiety as a result of non-adaptive defenses). Abnormal DST results are found more often during depressive episodes in the course of bipolar disorder than in unipolar disorder. Reduced pituitary volume secondary to LHPA stimulation, resulting in pituitary hypoactivity, has been observed in bipolar patients. The severity of the manic episode is highly correlated with the degree of neuroendocrine alteration. Anxiety, insomnia, and the intensity of depression are all highly correlated with cortisol response. Higher degrees of LHPA dysfunction, even during periods of remission, are observed in bipolar patients as compared with unipolar depressed patients. Daban et al (2005) concluded: “The HPA axis dysfunction could be a potential trait marker in bipolar disorder and thus possibly indicative of the core pathophysiologic process in this illness” (p. 473).
Consequences of Hypercortisolemia
Hypersecretion of CRH causing hypercortisolemia may be caused by impaired feedback processes resulting from GR abnormalities, e.g., decreased number or dysfunction. Chronic administration of glucocorticoids impairs learning and memory (causal factor in the working memory deficits sometimes seen in schizophrenia research?). This may underlie some of the cognitive deficits observed in severe mood disorder. High levels of cortisol in the hippocampus could produce atrophy which would compound the problem because the hippocampus provides negative feedback to the HPA. Cognitive deficits in bipolar disorder are associated with poorer outcomes. The number of previous manic episodes predicted cognitive dysfunction. Reports of higher ACTH and cortisol levels prior to the emergence of manic episodes further supports the view that hypercortisolemia leads to cognitive problems. For an excellent discussion of the research on the neurotoxic effects of cortisol see Bruce McEwen’s “The End of Stress As We Know It” published in 2002 by Joseph Henry Press.
Daban et al (2005) concluded:
“There is robust evidence demonstrating abnormalities of the HPA axis in bipolar disorder. Hypercortisolemia may be central to the pathogenesis of depressive symptoms and cognitive deficits, which may in turn result from neurocytotoxic effects of raised cortisol levels. Manic episodes may be preceded by increased ACTH and cortisol levels, leading to cognitive problems and functional impairments...Manipulation of the HPA axis has been shown to have therapeutic effects in preclinical and clinical studies, and recent data suggest that direct antagonism of GR’s may be a future therapeutic strategy in the treatment of mood disorders” (pp. 477-478).
For an excellent discussion of the research literature demonstrating that depression can be caused by chronic stress see Herman van Praag, Ron de Kloet and Jim van Os (2004) “Stress, the Brain and Depression” published by Cambridge University Press.
Brian Koehler PhD
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New York NY 10003