The HPA Axis and Circadian Rhythm in Bipolar

The relationship between bipolar and the circadian rhythm, although not well understood, is thoroughly discussed.  Many popular books on bipolar recommend regimented schedules in the hopes that having such a schedule might help control the sleep disturbances that sometimes come with bipolar.  In this post, we first continue the discussion of bipolar and the circadian rhythm.  Second, we discuss the hypothesis that HPA axis disregulation may mediate sleep disregulation in bipolar.  This last is a hypothesis, because it is speculative.

On the topic of mood disorders and the circadian rhythm, there is a review article:

C.A. McClung, Circadian Genes, Rhythms and the Biology of Mood Disorders. Pharmacol Ther. 114(2): 222–232, 2007.

Disruptions in biological rhythms are known to be strongly associated with mood disorders. .... Thus, it has long been hypothesized that abnormalities in the molecular clock underlie he development of these disorders.  In addition, nearly all of the successful treatments for mood disorders seem to affect circadian rhythms, and it appears that the shifts, resetting and stabilization of these rhythms produced by these treatments are important for therapeutic efficacy.  Though these associations have been known for many years, we are only now starting to understand the biology that underlies this connection.

That article is not specific to bipolar, and covers all the mood disorders.  There are plenty of articles that are more specific to bipolar, including studies of the genetics such as

McCarthy MJ, Nievergelt CM, Kelsoe JR, Welsh DK.  A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response.  PLoS One. 2012;7(2):e32091. doi: 10.1371/journal.pone.0032091. Epub 2012.

This study, using a meta-analysis approach, concluded that the core circadian clock genes that regulate the circadian rhythm are associated both with bipolar and with lithium drug response.  This is an important discovery because it provides a molecular basis for the association between sleep disturbances and bipolar.

An interpersonal therapy technique also deserves a nod.

E Frank, H A Swartz, D J Kupfer.  Interpersonal and social rhythm therapy: managing the chaos of bipolar disorder. Biological Psychiatry. 48(6):593–604, 2000.

Interpersonal and social rhythm therapy is an individual psychotherapy designed specifically for the treatment for bipolar disorder. Interpersonal and social rhythm therapy grew from a chronobiological model of bipolar disorder postulating that individuals with bipolar disorder have a genetic predisposition to circadian rhythm and sleep–wake cycle abnormalities that may be responsible, in part, for the symptomatic manifestations of the illness.

All of the above is well discussed, if not completely understood.  What is less discussed is the possibility that the HPA axis may mediate disturbances in the sleep cycle.  In support of forming that hypothesis, there is plenty of evidence that the circadian clock interacts with the HPA axis:

N. Nader, G. P. Chrousos, T. Kino.  Interactions of the circadian CLOCK system and the HPA axis.  Trends in Endocrinology and Metabolism, 21(5):277–286, 2010.

Organisms have developed concurrent behavioral and physiological adaptations to the strong influence of day/night cycles, as well as to unforeseen, random stress stimuli. These circadian and stress-related responses are achieved by two highly conserved and interrelated regulatory networks, the circadian CLOCK and stress systems, which respectively consist of oscillating molecular pacemakers, the Clock/Bmal1 transcription factors, and the hypothalamic–pituitary–adrenal (HPA) axis and its end-effector, the glucocorticoid receptor. These systems communicate with one another at different signaling levels and dysregulation of either system can lead to development of pathologic conditions.

When discussing other sleep conditions, it has been discovered that the HPA axis can play a role:

T. M. Buckley and A. F. Schatzberg. On the Interactions of the Hypothalamic-Pituitary-Adrenal (HPA) Axis and Sleep: Normal HPA Axis Activity and Circadian Rhythm, Exemplary Sleep Disorders.  The Journal of Clinical Endocrinology & Metabolism. 90(5):3106-3114. 2005. 

The hypothalamic-pituitary-adrenal (HPA) axis plays important roles in maintaining alertness and modulating sleep. Dysfunction of this axis at any level (CRH receptor, glucocorticoid receptor, or mineralocorticoid receptor) can disrupt sleep.

Following this discussion, I would put forward the following hypothesis: disruption in the HPA axis may mediate the development of sleep disturbances in bipolar.  Since we know that bipolar is associated with circadian rhythm disruptions and with HPA axis disregulation, it is reasonable to speculate that the two may have something to do with each other.