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.

Credit

Credit is an issue that concerns everyone connected to academia from students to professors.  We have names for situations where due credit is not given: plagiarism.  The act of plagiarism can be committed by students, professors, and academic researchers.  While it is a serious offence, it is extremely common, in part due to there being a fuzzy boundary between what is plagiarism and what is not.

Why am I discussing this issue on a blog about mental health and academia?  I am writing about this, because I see my students struggle with it, and I myself struggle with it.  Indeed my struggles over this issue go so deep that they have been the subject of deep worries.  The reason behind these worries is that it is not sufficient to do good work, rather that work must be credited to the one doing the work.

Careers are made by proper credit and destroyed by improper credit.  Credit is the currency of academia, the currency of success, and some people advance their careers by taking credit for the work done by others.  There are professors who believe, correctly or incorrectly, that they are responsible for the work done by their subordinates.  There are labs where the culture is such that the supervisor takes credit for all the work published by people in that laboratory.  Some people do not believe that those actions are plagiarism.  I disagree.  I feel that such a policy is tantamount to the lower power individuals buying the support of the more senior people by essentially ghost writing papers for them.  I think these sorts of policies have no place in academia, because it is essentially plagiarism.

Coming back the students, I have heard my students express concern over the credit on their group projects.  Invariably, it is the students who are succeeding in class that find themselves in a group with weaker contributors and that find themselves carrying their weaker classmates along.  Not only can the extra burden of work be onerous, but also the assignment of credit in the form of a project grade can seem unfair.  Is it not plagiarism if the weaker student takes equal credit for the project?

So, how should we deal with these issues?  In the case of researchers, we need more strict rules defining what is plagiarism in research and more frequent use of ethical sanctions on individuals who violate the ethical rules.  Individuals in low power situations, such as graduate students and post-doctoral fellows, should have ways of speaking up about mis-credited work without fearing for their jobs or degrees.

As for students, they, too, should have ways of speaking up.  For example as part of grading projects, the professor can ask for the students' input on how much each person of the group contributed, including themselves.  While most of the responses will have an inflated self-assessment, the average over the responses of several group members should be more reliable.  (Because of the inflation, there is some difficulty when considering groups of one or two people.) However, grading mechanisms such as this can help give credit where credit is due.

Because of the amount of extreme worry that can result from mis-attributed credit.  I call on all of us to try our hardest to be fair.  We shouldn't just be more than fair to ourselves.  In the wording of Orson Welles our current situation is the following:

All animals are equal, but some are more equal than others.

Let us try to be at least as fair to our subordinate and our students, as we are to ourselves.  Let us have strict definitions of what a research contribution is.  Let us not accept having our name on a paper that we did not contribute to.  Let us be open about who contributed what to each paper, and let us give credit where it is due.   Let us not have our judgement about credit be clouded by (potential) acclaim.  And, let us remember that some of us, perhaps those with the greatest ability to contribute to scientific progress, are even more sensitive to unfairness and mis-attribution of credit than other people are.  While many people brush these issues off and play the credit game as it is, there are others, like myself, who are greatly pained by the status quo.

Accepting a Job Offer

Commensurate with the post on academic interviewing, I am pleased to report that I have secured my first faculty position!  This is a tenure track job at a major research university in North America.

Why is this exciting?  I survived both the interviewing procedure and the negotiations for the terms on my contract.

I have previously described the interviewing process, which I survived to the best of my ability.  I had some 13 interviews that left my head spinning and my internal clock totally confused due to the multiple trips across time zones in North America.  You might be thinking to yourself that 3 time zones is not much, and indeed for one trip it is not much.  But if you factor in the 11 trips back and forth across 3 time zones in three months, this gets to be a bit excessive.  At any rate, my head was spinning. At the time I thought I had 3 more interviews which were subsequently cancelled.

Arriving home after the 13th interview, I found myself in a situation where I had one verbal job offer (in academia job offers are usually verbal first and written in paper second), and I was anxiously waiting news from 4 other places.  Over the space of the next 3 weeks, I received 3 additional job offers and 1 rejection.  Why does this matter?  Well the waiting is hard, and the timing even harder.  Unfortunately each paper offer comes with a deadline by which one must either reply or ask for an extension.  In my case the original deadline was not long enough to hear from the 4 other places, so I wasted some political capital on asking for an extension.  In addition to this, I was negotiation slightly better contract terms for myself with the employer of my choosing.  All the while I was waiting for the 4 other places to get back to me.  The hope was that someone else would give me a better offer than the original offer.  (All this is very stressful.)  In the end, I accepted the offer from the original place while having 3 back-up offers that I ended up rejecting.

I must say that these negotiations are not easy on someone who has low grade psychotic symptoms that include paranoia.  How exactly is it hard?  Well if you are prone to paranoid thinking, you may not believe that people are playing it straight during sensitive job negotiations.  This is precisely what happened to me.  I noticed the paranoia early and upped the dose of a medication in an attempt to handle these symptoms.  I am happy to report the success of these actions, as I quickly restored my normal thought patterns and successfully negotiated a contract with the university of my choosing.

Three cheers for getting a job!  Three cheers for negotiating the terms of the job! And, three cheers for surviving the interviews!

I will very soon be a professor in a science field!

Personal Electronic Medical Record

Due to my many relocations, frequent travelling  and the risks of accidents and episodes, I have decide to compile a personal electronic medical record.  Imagine the situation where a medical professional needs to treat me without my being able to provide adequate information verbally.  This could happen if I am unconscious due to an accident, or if I am in a deep state of confusion due to psychosis.  Furthermore, even when totally conscious with my full mental faculties, I usually find it difficult to communicate my situation to a new doctor.  In all these situations, it would be useful to have a personal electronic medical record to give to the medical professional.

Many people suggest to have their insurance information and a credit-card-sized list of emergency contact information in their wallet.  I find this to be insufficient for the amount of information, and I feel more would need to be told to medical professionals who know nothing about my situation.  A potential solution is presented here.

I now carry a USB drive that contains the information that is necessary.  I currently wear the USB drive on a chain around my neck, but I have seen drives that are credit-card-sized and fit in wallet.  There are even companies marketing these credit-card-sized USBs for personal electronic medical records.  At any rate there are sufficient USB options, that they need not look too tacky or be too bulky.  (An option besides USB is a SD card, which would nicely fit in a wallet.  However not all computers have SD card Readers.)

What sort of information do I find necessary for this personal electronic medical record?  Cancer.net suggests information to put in a personal electronic medical record.  Most of this information is straight forward to compile, and needs updating only once in a while.  My list of suggestions are

1. Photo of myself
2. Description of myself and my chronic illness
3. Basic info: contact info, insurance plans, etc.
4. Current doctors: general practitioner and psychiatrist
5. Family contact info
6. Current medications, dosages, reasons for taking them, and side-effects
7. Past medications, dosages, reasons for taking and not taking them, and side-effects
8. Medical history, in brief, with dates of surgeries, and other major events
9. Emergency plan for episodes

Items not included in my list that might be important:

• Family medical history
• Results from lab tests such as lithium levels, thyroid functioning, etc.

The hardest item might be (9). This is a plan, potentially worked out with family member and/or supportive friends, to deal with episodes that can hit when least expected.  My plan involves me being the front-line person for recognizing when things are starting to go south.  Some people prefer to have a friend recognize the beginning of an episode.  In either case, once an the beginning of an (potential) episode is noted, it is necessary to put the plan into motion.  Steps in the plan can include increasing the dose of some medication(s), consolidating your support system by asking family and friends to spend time together with you, having an emergency clause for when you will seek help at a psychiatric hospital, etc.  The most important aspect of a plan is to actually follow it when things begin to go wrong.  An important reason for having your plan written down is that this makes it easier to communicate your plan to new medical professionals.

So, I have said what information should be compiled and have suggested that the information be stored on a USB drive.  I have not suggested how the data should be stored.  If you go with a company such as ER Card you have to use their proprietary way of storing your data.  On the other hand, if you choose a do-it-yourself approach, you can store your information in the file format of your choosing.  I choose to use an HTML file, the format of files on the world wide web.  Since every computer sold in the last decade has a web browser for reading the file, this format is a logical choice.  Another equally good choice is a flat text file.  Yet another choice is a PDF file.

In the electronic age, it makes sense to have an electronic medical record that is kept up to date.  It also makes tremendous sense for patients to keep their own records, because this is currently the only way for multiple doctors to have access to the same record.  While keeping such a record might seem tedious, it is a way to communicate vital medical information when it is needed most.

If anyone else tries this out, please post about your experiences.  I will try to post updates on how this scheme is working for me.

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.