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.

Science as a Social Process

I recently posted about a study that corrects our (scientists') understanding of the effects of lithium treatment.  

 Cousins et al. Lithium, Gray Matter, and Magnetic Resonance Imaging Signal. Biological Psychiatry. 73(7):652-657, 2013.

One of the interesting things about this study is that it invalidates a number of previous findings that appeared to show increased gray matter in the brains of people with bipolar who take lithium.  This new study invalidates those findings by giving an alternative explanation for the apparent increase in gray matter size---that lithium ions an water together appear to have more volume when imaged---that is more parsimonious.  This alternative explanation not only explains the increased imaged volumes for people with bipolar who are taking lithium while also explaining why lithium takers without bipolar also showed an increase in volume.

While I have already discussed how this study influences our understanding of lithium, what I have not discussed is the scientific process that led to both the original erroneous hypotheses about lithium and also the recent correction to out understanding.  For lay people this may appear to be a scientific scandal when in fact this simply a part of the scientific method. 

Science is a social process.  What this means is that science is conducted by fallible people in a social environment.  We as scientists subscribe to some version of the scientific method which is a loose collection of techniques that help us design studies, collect data, analyze the data, and draw conclusions.  Every step of this process has the potential to introduce error, so the broader scientific community engages in publishing whereby the authors of a scientific study have their work vetted by reviewers, published, and then discussed both at conferences and sometimes with a series of follow-up articles if the community is interested enough in the original paper.

In this particular case, the original hypothesis that lithium acts to increase the gray matter of people with bipolar was sufficiently interesting to the community that many papers were generated on the subject.  This is the scientific method at work.

For example, one of the original volume studies discussed their findings with precise scientific language that hedges in precisely the ways that are needed for accuracy

Bearden et al. Greater Cortical Gray Matter Density in Lithium-Treated Patients with Bipolar Disorder. 62(1):7-16. 2007.

These brain maps are consistent with previous voxel-based morphometry reports of greater GMD in portions of the anterior limbic network in bipolar patients and suggest neurotrophic effects of lithium as a possible etiology of these neuroanatomic differences.

The emphasis is mine.  The reason that these authors use the emphasized words is because they do not actually know a mechanism that might link lithium use to changes in brain volume.  Their studies simply showed correlation, not causation.  Because of the precise language used by studies such as this one, their findings are not actually invalidated by the new Cousins et al. study---mearly reinterpreted in light of a more parsimonious hypothesis.

The lay public also learned about this thread of scientific inquiry, because there were news articles on the topic.  Unfortunately news articles tend to sensationalize by relating extreme conclusions even in the titles of the articles:

Lithium Builds Gray Matter in Bipolar Brains, UCLA Study Shows

This illustrates the danger of taking a scientific exchange out of context.  The hedging of Bearden et al. means their work is not invalidated but reinterpreted by Cousins et al.  However, the news article referenced above is entirely invalidated by the result of Cousins et al.  If any part of this story is scandalous, it the sensationalized reporting.

I hope everyone reading my account of this scientific exchange will understand that the hedging used by scientists is a necessary both for correctness and for future scientific inquiry.  I hope more people will respect the scientific method, will understand that there is no scientific scandal in this case.  And I fervently hope that people will refrain from sensationalizing the results of studies.