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.

The HPA Axis in Bipolar

In the last post, I threw around the term HPA axis without describing what it is.  I will try to rectify that here.  The HPA axis, more correctly called by its full name the hypothalamic-pituitary-adrenal axis, is a part of the  neuroendocrine system.  The HPA Axis is largely involved in responses to stress---sometimes termed the 'flight or flight' response.  Stress is the input to the system and can come in the form of either physiological or psychological demands.  In either event, these stresses are input to the HPA axis through the neurons that connect to it, including those involved in mood regulation.

There is a nice review of the HPA axis for bipolar

Duffy A et al. Biological indicators of illness risk in offspring of bipolar parents: targeting the hypothalamic-pituitary-adrenal axis and immune system. Early Interv Psychiatry. 6(2):128-37.  2012.

How does the HPA axis work?  There is a nice picture of this process at Wikipedia.  What we know at the moment says that there are three major organs (in italics) involved in signalling cascade and feedback loop whereby the system self-regulates.  The signal cascade originates in the neurons connected to the paraventricular nucleus in the  hypothalamus which in turn produces vasopressin and corticotropin-releasing hormone (CRH).  The vasopressin and CRH work together to cause the pituitary gland to produce adrenocorticotropic hormone (ACTH).  In response to ACTH, the adrenal cortex produces glucocorticoid hormones (mainly cortisol in humans).  These glucocorticoid hormones in sufficient quantity suppress the activity of the hypothalamus and the pituitary gland which generate less CRH and ACTH.  The glucocorticoid hormones by suppression work to extinguish the stress-response.  It is important to note that cortisol has many functions throughout the body (including functions for the immune system), and most tissues have glucocorticoid receptors.

The previous paragraph is fairly detailed.  Why should we go through all this?  There are various times at which the HPA axis can be disregulated.  Specifically, we are interested in the form of disregulation called hyperactivity which is characterized by inhibited response to CRH and increased levels of cortisol in the saliva and blood.  We know that Cushing's syndrome is a disease where hyperactivity of the HPA axis can result in euphoria or even psychosis.  Additionally, many studies show strong evidence of a link between HPA axis disregulation and bipolar.  For example

Watson S et al. Hypothalamic-pituitary-adrenal axis function in patients with bipolar disorder. Br J Psychiatry.  184:496-502. 2004.

which shows a p-value of 0.001 for the presence of increased cortisol in the saliva of individuals with bipolar.  Just to remind everyone, the lower the p-value the likely that the result is real, and values below 0.05 are typically considered strong.  The p-value is the probability of the ranked cortisol levels in the saliva of the two groups (non-bipolar, and bipolar) under a random model of ranked cortisol levels.  The main point is that there are many papers such as the one cited here, and the result of statistically elevated cortisol levels in people with bipolar is a robust finding regardless of whether the people have active or remitted bipolar.

There are similar findings of increase cortisol levels in people with depression.

Daban et al. Hypothalamic-pituitary-adrenal axis and bipolar disorder.  Psychiatr Clin North Am. Jun;28(2):469-80. 2005.

Similarly depression can remit, but the HPA axis function might not return to normal.  Indeed, for people in remission, if the HPA axis function improves, and then a return to hyperactivity can predict the return of depression.  This relationship causes one to wonder if HPA axis hyperactivity should be taken into account when diagnosing mental illnesses.

Duffy et al. suggest that the HPA hyperactivity is due to the over production of CRH which results in a failure of the suppressing effect of cortisol.  They say that successful treatment with fluoxetine, amitriptyline, desipramine or electroconvulsive treatment returns CRH levels to normal.  They also speculate that Lithium is effecting one of these pathways.  Notice in this paragraph all the tentative words such as 'suggest' and 'speculate'.  These words indicate that much of this is hypothetical and has not been tested.  However, this is the opinion of experts formed from the most recent available data.

Is the relationship between bipolar and the HPA axis overstated?  The relationship between the HPA axis and bipolar are not fully explained, yet.  We do not know if there is a causality to the link, or in what direction it might go.  We have some strong links between cortisol and bipolar, but we have yet to have solid data on the potential links between bipolar and the other hormones in the HPA axis.  We do not know whether it is the input to the HPA axis that is faulty or some part of the signal cascade in the HPA axis.  We do not know the temporal associations between HPA axis disregulation and bipolar mood states.  While it would be nice to predict that perturbations in cortisol levels correlates to extreme mood states, we simply do not have the data to draw any conclusions of this nature.

A Theory of Bipolar

The title of this post may be a bit more grand than the contents.  For instance there is not one theory and certainly not one coherent theory that tries to explain the whole phenomenon referred to as bipolar.  In this instance, I mean to describe the most coherent theory of bipolar that I see emerging from recent research.  Please bear in mind that the theory is not totally coherent and is missing some pieces of the puzzle.

Along the way of describing this emerging theory, I will try to use examples from my own experience and will suggest possible explanations for how things might fit together.  Please to not take any of these stories or suggestions as fact.  There is much research left to do on these topics, and my presentation could end up being a bit wrong.

What is the theory?  It suggests a mechanism for bipolar by joining two research threads:

1. HPA axis disregulation
2. circadian rhythm disturbances

The first one is the potential mechanism, and the second is correlated with the first.  Another feature of bipolar that is correlated with HPA axis disregulation alcoholism. There is strong evidence that the HPA axis is disregulated in alcoholism, and this provides a mechanism to explain the correlation between alcoholism and worsening bipolar symptoms.  In line with my previous posts about alcohol, I will emphasize that these correlations have only been found for alcohol abuse, not short-term light alcohol use.

I intend to follow this post with a series of posts that explore this hypothesized mechanism, the connection to the circadian rhythm, potential drug treatments, and practical steps to be taken.  More specifically:

1. I will attempt to explain the potential mechanism that results in HPA axis disregulation.  There is evidence, in the form of another disease, Cushing's Syndrome, that has the potential for mood symptoms, including depression, irritability, and sleeplessness, and is strongly correlated with HPA axis disregulation.  
2. I will explain as well as possible the connection between circadian rhythm disturbances and the HPA axis. 
3. I will try to explain the scant evidence for how the HPA axis disregulation due to alcoholism might interact with the HPA axis disregulation that is observed for bipolar.
4. I will mention a drug trial that was just finished for the drug Mifepristone that acts on the HPA axis and has been used for Cushing's Syndrome.  
5. I will do a post on what this research means from a practical perspective to a person living with bipolar and on what lessons I take from this research.