Withdrawal

There are many reasons that one might chose to withdraw from a psychiatric medication, ranging from health concerns to drug ineffectiveness.  Such a decision is complicated, can occur with or without the introduction of another treatment, and is highly personal.  The goal of this post is not to discuss the reasons for choosing to withdrawal but rather to discuss the process of successful withdrawal.

The process of withdrawing from a psych drug is not to be taken lightly.  Some people who have been through it say that it is more difficult by far than withdrawal from many legal and illegal drugs, including alcohol, cannabis, and tobacco.  Some people compare withdrawing from psych drugs to withdrawal from cocaine or meth which are both psychoactive drugs.  The difficulty in the process is further complicated by the lack of social support for, resources for, and understanding of psych drug withdrawal.  Most of the support and information that exists is anecdotal and found in the experiences of consumers who have experienced withdrawal.

Withdrawal can include anxiety, depersonalization, brain flashes, seizures, psychosis, pain, fatigue, mania, depression, and drug sensitivities, some of which can be worse that anything previously experienced.  Sometimes withdrawal is precipitated by health problems which only makes the experience more difficult.  For example, people who abruptly withdraw from Lithium due to kidney failure are at greatly increased risk of mania.  Furthermore, the negative withdrawal experiences can go on literally for years if a person experiences protracted withdrawal.  Some people think they have recovered, only to experience withdrawal-like issues ten years after they chose to abstain.

The previous paragraphs are meant to scare and (ironically) to comfort.  If you are thinking of withdrawing, please take care and beware of what you might confront.  If you are having an agonizing withdrawal, please know that you are not alone.  There are people who have lived through it and who can support you.  On the other hand, some people are able to easily withdraw, and they are to be envied.

Knowing all this, let us proceed with our eyes wide open to discuss a single drug: Zyprexa.  I choose this one due to my personal experience with it.  Again, I will not discuss my reasons for choosing to withdraw, nor will I say that other people must make the same choice.  It is often said that the higher the starting dose and the longer one took the drug, the harder the withdrawal may be.

A reasonable approach to withdrawal from Zyprexa is as follows:

1. Reduce the dosage slowly over many months.
2. Hold each dose for a week to a month before further reductions in dose (rule of thumb: reduce dose by about 10% of starting dose, for 30mg starting dose, reduce by 2.5-3mg per step).
3. The last few reductions are often the hardest, e.g. 5 mg to 2.5mg to 0mg.
4. If necessary, use a compound pharmacist to make specialized doses.
5. Zyprexa has a 1-2 day half-life depending on ones metabolism, making a difficult proposition out of dose averaging by alternating doses.  For a four day example, one might take 2.5mg, 0mg, 2.5mg, 0mg, to obtain an average dose of 1.75mg.  However, the drug has to remain in the body long enough for the doses to average, and for some people the Zyprexa half-life might be too short.

It should be noted that some people may need a long slow tail to the reductions before getting completely off.  Some people advise to only make reductions after a time period in which all the withdrawal symptoms have been absent for 2 weeks.  This can make for long hold times between reductions, and is easier to do if the withdrawal symptoms are physical or otherwise very obvious.

Things to know about Zyprexa withdrawal:

1. Target is 6-10 months abstinence.
2. Withdrawal can include: nausea, insomnia, anxiety, lack of self-confidence, paranoia, psychosis, weight loss, appetite changes, neuroleptic malignant syndrome, tardive dyskinesia (TD), tardive akathisia (TA), etc.
3. Reinstating, or increasing the dose to a previous level, can provide relief from withdrawal symptoms (indeed, the definition of a withdrawal symptom is one that almost always disappears upon reinstatement and that usually slowly disappears without reinstatement).
4. If one is switching to a new medication, drug interactions might also cause temporary side-effects.
5. Although some people find that they cannot withdrawal completely, there are options such as specialized dosing from a compound pharmacist that can ease withdrawal symptoms at the tail of the withdrawal

(The caveat, for antipsychotics, is that TD and TA can be permanent--existing after successful withdrawal--or transitory, but we have no way of predicting this.  The mechanisms involved in making TD and TA permanent are not known.)

While some of the withdrawal symptoms can feel like illness, it is important to recognize them as drug-related.  This recognition usually provides quick path to relief (reinstatement) and hope for decreased symptoms over time.  It may be tempting to try treating the withdrawal symptoms with yet another antipsychotic.  This may or may not work, while true withdrawal symptoms can usually be fixed by reinstating the original drug.  (The caveat is that it is possible for a withdrawal symptom to be resistant to reinstatement, but this seems to be rare.)  In my experience, an attempt to treat a Zyprexa withdrawal psychosis with Abilify failed, and the symptoms only responded to the reinstatement of Zyprexa.  On the other hand, some people have a much easier withdrawal if they are switching medications.  Indeed, switching medications can be a successful way to withdrawal, for example some people progressively switch from short-half-life benzodiazepine (benzo) to longer-half-life benzos before withdrawing completely.

There should be absolutely no shame in reinstating.  It is not failure.  It also does not preclude a later successful withdrawal.  Sometimes people have their hearts so set on being free of a drug that they forget to consider all their options.  Since reinstatement can reduce withdrawal symptoms, it can mitigate agony.  If one is withdrawing due to health reasons, the decision to reinstate must be carefully considered and the potential harms weighed.

There is also no shame in using another drug as a crutch to get through the hard parts.  For example, a person might take Benadryl or even a benzodiazepine to help ease insomnia.  While one should consider the risks of becoming dependent on yet another drug, short-term usage of even a highly-addictive benzo can be less risky than courting sleep-deprivation psychosis.

Of course, if you are one of those unlucky people who have multiple drug sensitivity, an extremely sensitive to all drugs, adding even a safe-seeming additional drug at low dose may not be wise.  Such a sensitivity could be transitory and limited to the withdrawal process or could be permanent.  Indeed, some people find that their withdrawal symptoms are better if they do not even use supplements (vitamins, minerals, etc.).  So, if you find your withdrawal experience worsening or becoming increasingly chaotic, you might look into multiple drug sensitivity and even supplement sensitivity as an explanation.

If only I had known all this before I first tried to withdraw from Zyprexa.
After many failed withdrawals (always followed by reinstatement), the keys to my successful withdrawal from Zyprexa were:

1. the insight of my psychiatrist who insisted that I taper slowly
2. the recognition that my reinstatement threshold was psychosis and that I could tough out the insomnia, the anxiety, the crashes in self-esteem, and the arbitrary suspicious thoughts that came and went for the first few months of abstinence.

I can happily say that I have passed the 6-month mark and believe that I have passed the dangerous portion of withdrawal.


It should be clear that while withdrawal from psychiatric drugs can be quite difficult for some people, there are also people who come through the process with little trouble.  There is little science to guide the process, and a person cannot know their likely situation before experiencing it.  Due to the degree of problems that can arise, many people who have experience with this process suggest proceeding slowly.  Slow can mean different things to different people, so it is important for each person to stay within their comfort level.  It is also important to research the particular drug from which you are withdrawing, in order to discover how slow other people take it, what the likely problems, and what other people's experiences are.  The resource, below, Coming Off Psychiatric Drugs is a basic reference that discusses many different drugs.


Resources:

Coming Off Psychiatric Drugs 

Beyond Meds

Long Silence

Please forgive the long silence on my part.  I have been busy this summer with moving around North America, taking a long vacation, and preparing myself to begin my new job.

I hope to resume my discussion of the HPA axis soon.  Until then, take care.

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.

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.

The Puzzle of Lithium

Why does lithium work for some people with bipolar?

This one question has puzzled and continues to puzzle the scientific community.  It is known that in the brains of people with bipolar, schizophrenia, and other mood disorders, the volume of gray matter is decreased relative to healthy controls.  Lithium works very well for a large portion these people ergo the hypothesis that lithium works by increasing gray matter in the brain.

G.J. Moore, J.M. Bebchuk, K. Hasanat, G. Chen, N. Seraji-Bozorgzad, I.B. Wilds et al. Lithium increases N-acetyl-aspartate in the human brain: In vivo evidence in support of bcl-2’s neurotrophic effects? Biol Psychiatry, 48:1-8, 2000.

Indeed this seemed to be true from imaging studies that appeared to show an increase of gray matter in people who take lithium (for both people with and without bipolar).  However a recent study

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

shows that the when the lithium ions are mixed with water, they show increased volume on the images. This finding contradicts the hypothesis that lithium works by increasing the volume of the brain.

We are still left with the puzzle of why and how lithium works.  Without a definitive scientific explanation, we are left to rely on phenomenology to determine whether lithium works for a given person.  It is up to the patient based on their first-person experience to determine whether lithium works for them.  This is why a respectful therapeutic relationship is needed, and the role of the patient's experience of the world must largely influence treatment.  Despite the wishful thinking of some doctors or psych hospital staff, doctors cannot determine on their own whether a particular course of treatment is going to work.

Mixed Episodes Redux

Earlier in a post titled Mixed Episodes we discussed the DSM definition of a mixed episode and we discussed some other ways of viewing mixed episodes.  Adding to that discussion is a recent article:

Swann et al. Bipolar Mixed States: An International Society for Bipolar Disorders Task Force Report of Symptom Structure, Course of Illness, and Diagnosis. Am J Psychiatry. 170:31-42, 2013.

This article is the result of discussions and several conferences involving a long list of people who appear on the author list of the paper.  The point of the article is best summarized by its conclusion:

Components of what are considered manic and depressive states can combine in bipolar disorder. Mixed features may be associated with illness course and treatment response characteristics distinct from more exclusively depressive or manic states. Clinical characteristics, including co-occurring conditions, suicidal behavior, anxiety, poor treatment outcome, and severely recurrent and complicated course, appear stable across definitions and criteria for mixed states. The importance of recognizing and monitoring mixed features during a hypomanic, manic, or depressed episode is highlighted by their relationship to recurrent course, treatment resistance, co-occurring substance use, and potential for suicidality.

The article does give a specific clinical algorithm for identifying mixed states, similar to the algorithms that the DSM gives.  The primary type of episode is identified (manic or depressive) with concomitant identification of an episode as mixed if it has sufficiently many non-overlapping symptoms from the 'opposite' type of episode.  Symptoms are said to be non-overlapping if they are unlikely to occur in both non-mixed depression and non-mixed mania.

There were several interesting sets of symptoms brought up by the article.  The authors segregate symptoms as to whether they are manic or depressive.  Then they segregate mixed episodes as to whether they are primarily manic or primarily depressive.

The authors say that manic symptoms of maniac mixed episodes are "greater mood lability and irritability and decreased grandiosity, euphoria, pressured speech, and need for sleep ," and depressive symptoms of manic mixed episodes are "dysphoric mood, anxiety, excessive guilt, and suicidality" are symptoms of mixed episodes.    In depressive episodes, manic symptoms include "irritable mood, distractibility, racing thoughts, and increased talking."

There is a collection of symptoms that the authors say characterize mixed episodes regardless of the primary categorization (into mania or depression) of the mixed episode.  These include "anxiety, agitation, or psychosis."  About anxiety the authors say

Anxiety has been shown to correlate with depressive symptoms in manic episodes, with manic symptoms in depressive episodes, and with the degree to which symptoms were mixed regardless of polarity. This pervasive role of anxiety is consistent with mixed states being driven by hyperarousal. 

Agitation is a combination of hand-ringing and uninhibited impulsive action.  Psychosis, as we know, is typified by thought disorder, including paranoia, delusions, and hallucination.  Psychosis is thought by the authors to be present primarily in either manic or mixed episodes.

While this article represents a step forward in terms of diagnostic tools for bipolar, I have reservations about it.  This article makes heavy use of the binary description of bipolar while simultaneously breaking the binary thinking and expanding it to be trinary.  The authors want to have their cake (the dichotomy) and eat it (make it trinary), too.  Also, they assume that one can always identify a primary episode type.  I suspect this last assumption is based on circular logic.  I think there are examples of episodes not having a clearly distinguishable primary type, and yet these episodes should still be classified as being bipolar episodes.

I am an example of a person having episodes that fall between the diagnostic cracks.  This has previously been discussed in the post titled My Diagnosis or Lack of One.  One comforting thing about the article mentioned above is that I finally find a description that matches my experiences.  This is comforting, because I know that I am not the only one who experiences the combination of symptoms that I experience.  In particular, my episodes have been marked by anxiety, agitation, and psychosis.  According to the authors it would seem that I have been having mixed bipolar episodes.  However, I find this categorization of my episodes to be unsatisfactory.  The popular conception of bipolar is wedded to the idea of a dichotomy between mania and depression.  My experience has nothing to do with such a dichotomy.  I experience no highs, no extreme lows.  On the other hand, the drugs that help me also help people with the traditional bipolar.  So, it seems to me that we are missing some important biological connection between patients exhibiting these disparate sets of symptoms.

The analysis performed by the authors is on individuals who are incontrovertibly diagnosed as bipolar, according to the binary definition of bipolar.  Then the authors take these people and group their symptoms into the binary categories of mania and depression. The authors then use that grouping of categories to decide whether an episode is primarily manic or primarily depressive.  Does this sound like circular logic?  They first assumed there were categories for mania and depression, then used patients diagnosed according to this dichotomy to establish whether symptoms and subsequently episodes were primarily manic or depressive. The correct statement of their argument goes something like this: if there exist two poles for the bipolar disease, then there is a grouping of symptoms into the two poles and a subsequent categorization of episodes into primary types of mania and depression.  But the classification of episodes cannot provide evidence for episodes having a primary manic or depressive categorization, unless we first assume that there is a dichotomy matching the labels mania and depression, making the logic circular.

Another problem with the article is that most reasonable experiments involving phenotype data would yield the result that there is a mixed trait.  This is because such a study would be based on the false binary assumption that there are two clusters of phenotypes.  I can take any cases (individuals with a disease) having any binary disease along with a set of multiple symptoms that have some noise (meaning that the symptoms do not exactly predict the presence of the disease).  The binary analysis described above can be performed whereby the cases are grouped into two poles based on some of the symptoms.  Most certainly, since there is noise, there will be symptoms that do not segregate exactly with the two poles as they are defined by a few of the symptoms. As a result it will seem as if there are cases with 'mixed' symptoms.  And the 'mixed' symptoms would be an artifact of the incorrect assumption that there is a dichotomy describing the disease.

It would seem that the simplest explanation for the presence of mixed episodes is that we have a collection of noisy symptoms that do not describe a disease having binary poles.  This would be an application of Occam's razor where we reject the introduction of a more complicated mixed bipolar model involving manic, depressive, mixed manic, and mixed depressive episodes, and we instead entertain simpler models which not based on a binary description of the disease symptoms.  For example, if we are committed to having phenomenological diagnostic tools, we could diagnose bipolar and schizophrenia from a single bucket of symptoms.  The diagnostic algorithm would be something like the following: if a person has at least 6 of the symptoms displayed in an episodic fashion then they might benefit from lifestyle changes, therapy, and anti-pychotic and mood-stabilizing drugs.  This approach would better reflect what we know about these diseases than current approaches based on false dichotomies.

Such approaches could facilitate investigations into the biology of these diseases, perhaps recognizing that there are changes in the brains of people with bipolar and schizophrenia.  Maybe our current biological studies are inhibited by the ascertainment bias that comes from our insistence on a separation between mania and depression.  Perhaps we would discover biological diagnostic tools faster if we were to discard the notion that there is a polar distinction between mania and depression.  In a similar vain, perhaps the distinction between schizophrenia and bipolar is something that needs to be reconsidered as well.  Perhaps there is a common biological basis for both schizophrenic episodes and mixed episodes.

I see that the biggest weakness of this article is that it clings to the idea that there are two poles of bipolar.  While the article seems at first glance to break the binary by introducing a definition of mixed episodes, a closer look reveals that the authors diagnosis of mixed episodes only reinforce a possibly false dichotomy between mania and depression.  It is certainly not the case that there are two main types of episodes; this thinking seems to me to be an artifact of our attempt to understand this disease by categorization.  It is time to move beyond the binary or trinary thinking and look for a biological basis from which to diagnose this disease.

Antidepressants and Pharmacogenomics

Tansey et al. Contribution of Common Genetic Variants to Antidepressant Response. Biological Psychiatry. 73(7):679-682, 2013.

PsychCentral posted a news article about this study.

The above mentioned study is a pharmacogenomic study that performed a genome-wide association study of to detect genetic variants that are associated with antidepressent drug response.  Since the previous sentence uses a lot of jargon, I will try to break it down.

Pharmacogenomics is the study of how the genetics of individuals influences their biochemical response to drugs.  Namely, we are interested in how well a particular drug treats the disease that it is designed to treat.  So, these studies are usually an investigation of the main-effects of a drug, rather than an investigation of the side-effects.  (Although the pharmacogenomic approach can also be used to study side-effects, it is hard to get sample sizes that are large enough to find anything with such a study.)  The reason we are interested in pharmacogenomic studies is because drug response is partially genetic.  For many diseases we know that whether or not a drug works for your parent(s) can well predict whether the drug works for you.  So, not only are diseases genetic, but the effective treatments can also be genetic.

To explain how traits can be genetic, first we need to understand what genetic variation is.  Humans have two copies of every chromosome, and we have a distinct sequence of nucleotides (the molecular units that make up DNA) on each chromosome.  There are sites or positions in the genomic sequence where if we look across many individuals, we find that there are multiple nucleotides that appear at that site.  These sites of variation are called single nucleotide polymorphisms (SNPs).  If a SNP is responsible for a disease trait then there would be a single mathematical function that relates for each person the nucleotides that they have at the SNP site to disease trait.  The simplest examples involve single SNP sites that are Mendelian diseases (either recessive or dominant) and have binary disease traits, or traits that either exist or do not exist.  We call diseases complex (or polygenic, meaning that it involves many sites) when the trait is a function of the nucleotides at several SNPs.  Now we have described the generative model, i.e. given the genetic data and a mathematical function, decide what the trait value is for each person.  The aspect that makes this novel research is that the mathematical function linking the genetics to the trait is unknown.  This is why governments and foundations are spending millions of dollars on studies that try to discover these mathematical functions that link genetics to the trait.

The most common type of study that attempts to do this is called the genome-wide association study (GWAS).  These studies are used not only for in pharmacogenomics, but also for studying the genetics of heritable disease.  A GWAS study that looks for an association between some trait, in this case drug response by depressed individuals when given anti-depressant drugs, and the nucleotides at a particular SNP site.  An association (usually meaning a significant correlation) is a specific mathematical function, like the ones that we discussed above, that relates, with few errors, the nucleotides of the individuals at a SNP site to the value of the trait.  (The functions we described above were completely general whereas most GWAS methods rely on correlations which are a restricted class of functions.)

The study that was sited at the top of this post, had two main results.  The first result is a negative result in terms of being able to use the genome of a patient to identify which drugs will most help them.  The second result is a positive result saying that if a patient's close relative responds well to a particular drug then the patient likely will as well.

First, they found many SNPs that are associated with antidepressant drug response.  This means that drug response is polygenic and therefore is a complex trait involving multiple SNP sites.  Knowing that antidepressant drug response is polygenic helps us know what to look for in the genome.  We should be looking for interacting sites that work together to produce the trait.  This is a negative result, because it means that there is not just one genetic site that we can use to test for what drug each person will respond to.

Second, the paper gives results about the heritability of drug response.  Heritability is the fraction of trait variability that is due to genetics.  When we say that the heritability is 42%, we do not mean that there is a 42% chance that a child of a person with the trait will also have the trait.  Rather, we mean that heritability is the ratio of the variance of the trait that is due to genetics and the total variance of a trait.  Heritability is not about the risk of having a trait but rather it is about whether the trait is genetic or not.  A trait having a heritability of 42% means that 42% of the variance of the trait value is due to genetic causes.  This main result of the study is best expressed in this sentence

We find that common genetic variants explain 42% (SE = .180, p = .009) of individual differences in antidepressant response.

What can we as potential users of antidepressants take away from all this?  First, it will be a while until the science advances to the point that it can predict which drug will work best for us.  Second, the best predication about which antidepressants would work well for us is the list of antidepressants that work well for our relatives.

In the wider discussion of which psychotropic drugs may be helpful to a person, it might be quite reasonable to assume that there is heritability of drug response.  For example imagine two siblings, one who has anxiety and one who has schizophrenia.  (This example is quite plausible because we know that families having bipolar or schizophrenia also have a lot of anxiety and depression.)  At any rate, in our imagining, the sibling with the anxiety was diagnosed first and found Zyprexa to be a very useful drug for pro re nata treatment of anxiety.  The second sibling, when diagnosed with schizophrenia, recognizes that Zyprexa has worked for their sibling and tries that drug to good effect.  As another example, suppose antidepressants cause a family member with bipolar to become manic.  Then it might be good for other family members to avoid that class of drugs regardless of which diagnoses they may have.

Although there is not much research yet that elucidates the heritability of psychotropic drug response, the experience of patients indicates that this is a critical aspect of successful treatment.  I fervently hope that the research will move in the direction of attempting to elucidate the heritability of drug response, because it would lead to successful treatment.

Academic Interviews

Interviewing is difficult for everyone.  Imagine interviewing while managing a mental illness and dealing with low grade psychotic symptoms.  Indeed, some people would hypothesize that the stress of interviewing would make the symptoms worse.

For those of you who are not familiar with academic interviews, the process requires some explaining.  (This description is specific to North America.)  Early in the fall each school wishing to hire someone will convene a search committee.  The search committees job is to

• locate candidates for hiring by advertizing the open position, 
• invite the best ones for interviewing, 
• interview the selected candidates in one- or two-day interview, and 
• recommend the best candidate to the hiring authority (usually the dean or the department chair/head).

From the applicant's perspective, they put in their applications to as many schools as they feel will consider them and wait to hear if they have an interview.  The application usually consists of a cover letter, a research statement that describes the applicants research aspirations, a teaching statement that describes the applicants teaching aspirations, some samples of the applicants academic writing such as journal articles, a CV, and letters of recommendation.  Getting all of this material collected together can take time, and submitting an application is considered the easiest part of the whole process.  Once an applicant is selected for interviewing, they need to prepare a 45-minute job talk (sometimes a short teaching lecture or chalk-talk is also required).  Again, preparing these talks is considered to be part of the due diligence of accepting an interview invitation.

The difficult part for the candidate and for the search committee is actually having the interview.  The search committee spends a significant amount of time preparing a one- or two-day schedule for the candidate.  This usually involves arranging numerous 30- to 45-minute meetings with various busy faculty members who each have their own tight schedule.  Typically all these faculty members are from the department that is considering hiring the candidate, but in interdisciplinary situations, meetings might be scheduled with faculty from diverse departments.  To fully understand the level of planning involved in this scheduling, it is necessary to explain that that everything is choreographed from the time the candidate arrives at the local airport to the time that they leave.  It is not uncommon for the candidates every meal to be scheduled and for faculty members to shuttle the candidate from appointment to appointment.  It is considered polite and hospitable for the interviewers to manage the candidate's schedule like this.

After interviewing several candidates like this, the search committee makes a recommendation of the best fitting candidate to the hiring authority.  The candidate, knowing little of the machinations of the search committee, is simply left to wait and wonder unless they are the lucky candidate that receives the telephone call letting them know that the school will make them an offer.  For the interviewed candidates that do not receive the telephone call, there typically is no indication that they have not been selected except silence.

For the candidate receiving the lucky telephone call, the process is not over.  They have received what is called the verbal offer.  Next they are required to negotiate with the hiring authority over salary, start-up, and other terms of the contract.  It is not uncommon for the negotiations to be completed before the paper offer is printed and sent to the candidate.  Until receiving the paper offer, the candidate must be careful, because the verbal offer could be rescinded at any time.  For example, offers can be rescinded,  because funding for the position is not granted.  Therefore, the candidate must be careful not to count their chickens before they hatch and continue to make a good impression.  Once the paper offer has been given, the candidate typically has a deadline for accepting the offer and for negotiating any remaining items that have not been agreed upon prior to the paper offer being extended.

Now, having described the process of getting an academic job, I will discuss interviewing from the perspective of the candidate.  The academic interviewing process is almost ideally designed to foster extreme emotions.  The amount of ambiguity, the lack of clear communication (i.e. deafening silence), and tricky negotiations can easily inspire feelings of uncertainty, insignificance, and nervousness.  On the flip side, being invited for interviews, perhaps many of them, can inspire feelings of grandeur.  In short, academic interviewing is not for the faint of heart, because nobody feels normal during the interview process.

For myself, I felt anxious over double scheduling and missed flights.  I worried about whether my taxi drivers were driving me directly to my destinations.  I felt indicted by the people who fell asleep during my seminars.  I worried over every little mistake that I made.  I double scheduled interviews by mistake.  I hated all the travel and the many time-zone changes.  And, I felt the rush of exhilaration over being invited to interview at good places.

There are many challenges one might face during such an interview process.  I will list each along with potential strategies for overcoming the challenges.

1. The anticipation before an interview can cause insomnia.  I find it most useful just to take something that encourages sleep.  Benadryl can be perfect for this.
2. Worries about travelling, getting stuck in snowstorms, missing flights, double scheduling and other hiccups in the schedule.  I find it most useful to pad the travel schedule with a bit of extra time, so as to avoid anxiety over being late.  Beyond that a Zen approach to uncontrollable events works well.  In the worst case, medication can be adjusted slightly and anti-anxiety medication can help ease the obsessive worries.
3. The demanding schedules can cause stress due to the constant demand of trying to impress people.  I found it useful to insist on bathroom breaks frequently.  This gave me a chance to catch my breath.  Some interviews scheduled some free time to prepare for the talk.  I did my best to be alone during that time.  The most demanding schedule that I had was a 3 day interview at one university, and I got a break by asking for the dinner on the second day to not be scheduled.
4. Good news like interview invitations and offers can be stressful.  I made sure to stay immersed in work when I wasn't interviewing, so that I had something besides the job hunt to focus on.
5. Flying around a lot can be very stressful due to noisy plane, busy airports, late or cancelled flights and time-zone changes.  I dealt with this by making myself as comfortable as possible on flights.  I got a small blanket, eye cover, and ear plugs.  I made sure that my carry-on contained all the essentials, such as medications, emergency food, my computer, and power cables.  I travelled light, so that most of the time I had everything I needed in my two carry-on bags.
6. Decision making can be hard.  The offers are when you begin to see your hard work paying off, but there is still decisions to be made.  I tried to deal with this by making them as quickly as I could.  Certainly, one might be stuck waiting for more information before making a decision, but it is best to let the hiring authority know as soon as you can what your decision is.  No's are important because they might allow the search committees to pursue other candidates.

Despite difficulties of the academic job search it is likely worth the effort.  The stresses can be managed with a little care, foresight, and fortitude.

Pills on the Go

Taking pills on the go can be challenging.  If you are like me, you are more likely to miss a dose when you are away from home than when you are at home.  Of course the main challenge is that the medication is so important that doses should not be missed.  The other challenge is to prevent questions from other people about your medical condition.

How do I deal with these challenges?  Travel is required for my job, and some times a lot of travel is required.  Pills are required as well.  My strategy for dealing with this situation is:

1. I take the pills around the same time every day.  This is particularly important for people with bipolar (or perhaps bipolar-schizophrenia) which seems to be influenced by the circadian rhythm.  I use an electronic device that has an alarm set to ring every day at pill time which for me is 6pm.  
2. I do not take my pills in front of people that I do not want to have asking questions.  If I am with other people when the alarm goes off, I simply excuse myself and take my pills.  My alarm unfortunately sounds like a phone call, so I try to be polite.  Sometimes I have to pretend not to be taking a call, and later I will pretend to use the restroom as an opportunity to take my pills. 
3. I always carry my pills on me.  In order to take the pills, I must have them.  If I fly, they are always in my carry-on.  That way, if my luggage is lost or delayed, then I can still take my pills.
4. I always have extra pills.  This is in case a flight is delayed or cancelled.  The last thing you want to do when you are stuck in Chicago in a snowstorm is to worry about whether or not you have enough pills.
5. When travelling internationally, I always check the immigration and airport security rules to see if I must have with me my prescription or perhaps the original pill bottle.

These strategies will help anyone who has to consistently take pills.  In particular, people who have medical issues they do not want to discuss or have a particular timing regimen to their pill taking.

If anyone has any other strategies to share, please post them.

Bipolar-Schizophrenia as One Disease

Are bipolar and schizophrenia actually separate illnesses?  For technical accuracy, I should also include schizo-affective disorder which is the DSM's way of acknowledging that there is not a clear distinction between bipolar and schizophrenia.

Before I get into this, I should frame my participation in this discussion by explaining my controversial belief that bipolar and schizophrenia are not different diseases.  I believe that they are two faces to the same genetically-caused illness.  I think that there are clusters of symptoms whereby the people typically labelled with having schizophrenia may appear to have a different presentation than people typically labelled with having bipolar.  I do not deny that there may be some biological difference between the two presentations of symptoms, but I believe these differences are few enough as to consider bipolar and schizophrenia to be two subtypes of the same disease.

A primary driver of my belief is the growing evidence that bipolar and schizophrenia probably share common causes.  This is born out with both genetic and neurological evidence.  I will briefly describe the type of evidence along with providing references to the literature.

The evidence says that bipolar and schizophrenia have associations with some of the same regions of the genome.  What does it mean for a disease to be correlated with a region of the genome?  This means there is a statistical correlation between the presence/absence of the disease(s) and the nucleotides at a polymorphic position in the genome.  Typically researchers are testing Single Nucleotide Polymorphisms (SNPs), but some studies have examined Copy Number Variations (CNVs).  One can think of the association between a SNP and the disease as trying to place the disease in the genome at some position that explains the inheritance of the disease.

[Lichtenstein et al., The Lancet, 2009] This study looked at approximately 75,000 individuals with either schizophrenia or bipolar.  They examined relative risk, that is the risk of disease for a relative of a diseased person as compared with the risk for a relative of a diseased person.  They showed that relatives of people with bipolar had elevated risk of schizophrenia and vice verse.  They measured heritability of schizophrenia as 64% and of bipolar as 59%.  Heritability is the percentage of the disease variance that is accounted for by genetic factors.  (It does not mean that the child of a schizophrenic has that percentage as risk of getting the disease.)  The authors concluded that:

Similar to molecular genetic studies, we showed evidence that schizophrenia and bipolar disorder partly share a common genetic cause. These results challenge the current nosological dichotomy between schizophrenia and bipolar disorder, and are consistent with a reappraisal of these disorders as distinct diagnostic entities.

[The International Schizophrenia Consortium, Nature, 2009] This study did a genome-wide association study (GWAS) of roughly 3,000 individuals with schizophrenia.  They demonstrated the contribution of thousands of SNPs to the risk of schizophrenia.  And, they showed that many of those SNPs also appeared in a GWAS study of bipolar.

[Cross-Disorder Group of the Psychiatric Genomics Consortium, The Lancet, 2013] This study is actually of five psychiatric disorders: autism spectrum disorder, attention deficit hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia.  They found four SNPs that were significantly associated with all these diseases.  They also separated the people with the disease into two categories  child and adult onset of disease, which further refined the SNPs that they found.  The authors say

 Doubt remains about the boundaries between the syndromes and the degree to which they signify entirely distinct entities  disorders that have overlapping foundations or different variants of one underlying disease.

The pathogenic mechanisms of psychiatric disorders are largely unknown, so diagnostic boundaries are difficult to define.  Genetic risk factors are important in the causation of all major psychiatric disorders and genetic strategies are widely used to asses potential overlaps.

These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause.

On the neurology front, brain imaging provides evidence both of the similarities and differences between schizophrenia and bipolar.  Generally speaking, brain imaging can involve functional magnetic resonance imaging (fMRI) which images the blood flow in the brain and voxel-based morphometry studies which examine the gray matter.

[Ongur et al., Psychiatry Research: Neuroimaging, 2010] In this study the researchers selected 17 patients with bipolar and 14 patients with schizophrenia and did fMRI scans.  They used independent component analysis to analyze the data and identify synchronous activity patterns.  The data suggest abnormal functional organizations of the brain in both disorders when compared with controls.  The people with schizophrenia have abnormalities in the frontopolar cortex/basal ganglia while the people with bipolar showed abnormalities in the parietal cortex.  It is not clear how the abnormalities are related to the symptoms of the disorders. Indeed it is possible that eye movement during the fMRI explains some of the differences in the scans of bipolar and schizophrenic people.  This paper leads us to think that there may be a reliable way to differentially diagnose bipolar and schizophrenia, however the sample sizes are small and eye movement may have confounded the results.

[Ellison-Wright et al., Schizophrenia Research, 2010] This paper did a meta-analysis of around 2000 patents with schizophrenia and around 350 patients with bipolar.  The goal was to find whether there was similar brain imaging for the people with bipolar and people with schizophrenia.  This was done in light of the genetic studies suggesting a common cause for bipolar and schizophrenia.  The studies looked at gray matter using voxel-based morphometry studies. They found that the areas of gray matter reduction in bipolar overlapped the gray matter reductions found in schizophrenia with the exception of a region of anterior cingulate where the gray matter reduction was only found in bipolar.  They also found that gray matter reductions in schizophrenia were more extensive.

[Chai et al. Neuropsychopharmacology, 2011] This paper looked at 14 patients with bipolar and 16 patients with schizophrenia.  They remark that "a significant body of genetic, imaging, and neurophysiology research has established that schizophrenia and bipolar share substantial overlap in clinical features, as well as in contributing genetic factors."  Their goal was to find if there are common neural substrates for bipolar and schizophrenia.  This work also used fMRIs and independent component analysis (similar to the Ongur paper).  To paraphrase the authors, they found that there is a decoupling of the dorsal lateral prefontal cortex from the medial prefrontal cortex in both bipolar and schizophrenia, and that this decoupling is consistent with the impaired executive functioning seen in these disorders.  In addition to this commonality between bipolar and schizophrenia, they found a distinguishing feature.  The authors say:

Functional connectivity between [medial prefrontal cortex] and insula/[ventral lateral prefrontal cortex] distinguished bipolar disorder from schizophrenia, and may reflect differences in the affective disturbances typical of each illness.

Due to the weight of genetic and neurological evidence that is establishing commonalities between bipolar and schizophrenia, it is reasonable to hypothesize that they share common causes.  In light of this it might be better to revise the diagnostic categories so that bipolar, schizoaffective, and schizophrenia are subtypes under the same disorder.  As The Lancet, 2013 paper suggests, we may also need to significantly revise our categorizations of other diseases, as well.  We may be better able to diagnose and treat these diseases if we classify them according to common causes.

Response to 'A Loded Gun'

In the New Yorker, there is an article titled
A Loaded Gun
by Patrick Radden Keefe


I want to respond to this article.  First, a thank you to the author of the article.  This is precisely the type of topic which is open for discussion on this blog about academia and mental health.

The article is a story about a woman professor who shot six of her colleagues not long after her tenure case was denied at the University of Alabama.  Her name is Amy Bishop.  The smoking gun, according to the article, is that Bishop shot her brother in what their mother claimed was an accident.  The article makes a character sketch and attempts to detail the events leading up to Bishop's academic career.

There are several threads to the article.  I will talk about several, but the one that concerns me the most is the incidence of undiagnosed mental illness among high-achieving individuals.  Page 12 of the article implies that high-functioning people cannot have a mental health problems.  This is as if nobody with a mental health issue can be high-functioning, earn a Ph.D., and be a professor.  I spent the last blog post addressing this.  Suffice it to say, that people with mental disorders can be very successful and still struggle with a mental disorder.  To me it seems a gross miscarriage of justice that Bishop did not receive a diagnosis or have a successful insanity plea.  I believe Bishop to be a paranoid schizophrenic just as she claimed in the article.  To me it seems to be a crime that the justice system did not recognize this.  Due to this, she is currently serving life without parole at the Tutwiler Prison for Women.  It is not clear whether she is receiving treatment.

Another thread in the article is the academic career path and the stresses of it.  The career path is typically graduate school to post-doctoral position to faculty interview to faculty position to tenure.  The article mentioned a first impression formed by a colleague of Bishop as crazy, presumably formed during the interview process.  The article also mentioned that this perspective was shared after the fact, and could have been a reinterpretation of past events in light of present information (the shooting at U. of Alabama).  I, for one, believe that it is almost never the right of someone to make judgements about another's mental health, particularly if that someone is not a health professional.

Throughout the article I was disturbed by the tendency of people to judge Bishop's mental health despite not being mental health professionals.  I am continually disturbed by this in society.  Perhaps we should better venerate the mental health profession so that we are less likely to inadvertently undermine their attempts to help people.

Continuing the thread about the academic career path, the article also mentioned women in academia as having a difficult time.  It can be true that some women have a hard time balancing the competing demands of family and career.  This is an expectation that is thrust upon them by both themselves and society.  The idea that you have to be a helicopter parent combined with the 60+ hour a week career demands of an assistant professor can be crippling.  On the other hand, plenty of people handle these pressures just fine, perhaps by not being helicopter parents.

As for tenure pressures, although I do not have first-hand experience of them, it should be remarked that job turnover in industry is much higher than academia.  Most young professionals do not even keep the same job for the first 6 years (the number of years to tenure) of their career.  The idea that the threat of not getting tenure and loosing ones job can possibly explain a massacre is absurd.

The article also mentioned one 'symptom' which appears in the DSM-4 but is suggested to be removed from the DSM-5, that is narcissism.  The article said that some people claimed that Bishop was narcissistic.  My problem with the whole discussion of narcissism is that nobody can adequately define the term.  Even mania is better defined than narcissism, which seems to depend on high subjective judgements of what is normal.  Even if Bishop was concerned about academic credit and acclaim, this should not be taken out of the context of tenure pressures.

Now, I want to return to the question of guilt.  There is no doubt that Bishop was responsible for the massacre on Feb. 12, 2010 at the University of Alabama.  There were too many witnesses to conclude anything else.  What is most striking is that Bishop does not remember the incident.  She said that she has no memory of the event.  This makes one wonder both about the memory of someone having a schizophrenic episode and about the memory of someone experiencing extreme trauma, even trauma that they inflicted.  I do not believe that Bishop is lying about this, because she would have nothing to gain.  It is really interesting to think that her disease may have progressed to the point that she was unaware of her own actions.

High-Functioning with Schizophrenia and/or Bipolar

NY Times Article:
  Successful and Schizophrenic
  by Elyn R. Saks

This is a really excellent article by a person with schizophrenia who holds a professorship at the University of Southern California.  She is enormously successful as witnessed by many awards, not the least of which is the MacArthur "genius" grant.  She relates how she was given a grave prognosis for her disease which included a lack of happiness, fulfilment, and family.  She has disproved each of these by managing her illness successfully.  She shares the coping skills that have helped her and discusses those that have helped other people like her.

I am going to answer what she said by discussing the analogous setting for people with bipolar.  The setting is that of high-functioning people with bipolar.  Our first task when discussing this is to define what we mean by high-functioning.  Does it just mean success?  Does it mean disease remission?  Does it mean creativity or intelligence?  I would argue that an individual is high-functioning if their disease is in remission and their life is fulfilling and productive.  This is analogous to the archetype of a 'productive member of society.'  Notice my definition says nothing about intelligence or creativity.  While there is much written about the supposed creativity and intelligence of people with bipolar, I question whether manic creativity or intelligence equates to a high-functioning status, because it may not be a state that can be maintained in remission.

Returning to the article, the author lamented a lack of acknowledgement of high-functioning schizophrenics by medical community.  With bipolar, there seems to be a longer history of the medical community recognizing occasionally functional people.  However, this occasionally functional person is stereotyped: while they may be creative and high-functioning at times, they will crash into an episode at other times.   I would argue that this occasionally functional person is not high functioning as we have defined it.  Our definition requires remission.  This highlights the strong tendency by medical professionals to warn that a person having one episode will almost certainly experience another.  This attitude denies the existence of high-function people and flies in the face of evidence that people can become stable.

Just as the author of the article was discouraged by the medical community not acknowledging high-functioning schizophrenics, I am disappointed by my experiences of being denied treatment due to 'not needing it'.  That comment, made by a doctor, took acknowledgement of high-functioning bipolar to the extreme of assuming that such people do not need treatment. I wish there were more medical support for maintaining remission of psychotic illnesses and for maintaining a high-functioning status.  Furthermore, there should be an effort to discover how people are able to be high-functioning.  Perhaps the mental health community can learn much from those of us who successfully manage our illnesses.

The author warned against romanticizing illness by idolizing people like John Nash in "A Beautiful Mind" who was brilliantly productive while his symptoms slowly worsened.  The challenge when identifying high-function people is to not romanticize their experience.  Indeed we need to be careful about what we mean by high-functioning; is success in life enough to be considered high-functioning or is disease remission required?  With bipolar, there is a strong tendency to romanticize the supposed creativity and intelligence which is advertized to accompany the disease.  While people with mental illness may indeed have unique and productive ways of thinking, to romanticize a disease as a route to such uniqueness is dangerous.  It denies the crippling power of disease to destroy rather than create, as we see in the way that John Nash's illness overtook him.

The author also mentioned wanting to do a study on high-functioning schizophrenics in stable relationships.  This is a fantastic idea, and while we are at it, why not study high-functioning people with bipolar who are in stable relationships?  There is a stereotype that people with bipolar always have unstable relationships.  Since I know of several counterexamples to this, it would be nice to understand the coping strategies these people use, and to understand them well enough to teach the coping skills to other patients.

So, how do people attain and maintain their high-functioning status?  For schizophrenia, the author of the article points to a trifecta of disease management: drugs, psychotherapy, and family/friend support.  My experience is that while maintenance drugs can bring about remission, a plethora of coping skills are required to deal with break-through symptoms which are not controlled by maintenance drugs.  These coping skills involve managing sensory input (limit interactions with other people if social settings cause stress, limit light, noise, and movement if those are stressful), dealing with delusions, paranoia, and hallucinations (confronting them in a brutally honest and logical way), and dealing with voices (sometimes by ignoring them).  For those of us with bipolar, we share those coping skills, along with additional coping skills that involve managing: anger, mania, depression, and suicidal thoughts.  For both people with bipolar and those with schizophrenia, it always pays to avoid witnessing or participating in bullying situations.  Those situations can drive anyone to anxiety or paranoia.

Work is another critical coping skill that the author mentioned.  She mentioned that doing something that is valued and having time commitments can help manage the schizophrenia.  I second this, as I find that having responsibilities helps me keep from succumbing to paranoia, anger, or depression.  Doing something productive helps me manage mixed mood states.  Because of these things, the author reminds us that it can be devastating when doctors tell patients not to work or predict that they will not be able to work.

A final critical coping skill is learning to adjust medications in response to symptoms.  I believe that the ability to recognize worsening symptoms is key to being able to respond to them with medication.  This can be said of both schizophrenia and bipolar.  One needs to learn to recognize 'triggers' or events that tend to contribute to a developing problems.  One way to identify triggers is to examine past problems honestly and try to identify the turning points that lead to the worsening of symptoms.

I believe that bipolar and schizophrenia are not so different from each other, certainly in regards to how high-functioning patients are treated.  We must be careful not to stereotype people out of access to care or stereotype them out of remission into a worsening disease state by depriving them of needed coping skills like work.  Additionally, the coping skills that lead to the successful management of schizophrenia can help with the successful management of bipolar and vice verse.  In all cases the goal is to use a combination of therapy, medication and family/friend support, to develop and implement coping skills for the successful management of disease.

Anger

Anger is one of those words that discomfort most people.  Even though we all get angry, we often want to pretend as if we do not.  Rage, on the other hand, is a word that evokes vivid images of spousal abuse, drunken rages, or wild combat.  It is a word that most civilized people dare not breath.  So, we have euphemisms:  "very angry", "riotously drunk", and "seeing red."  We almost never label rage for what it is; the extreme anger that is accompanied by an unbridled energy that demands action.  Rage is either uncontrollable or almost uncontrollable.  Normal anger is white when rage is red; it is controllable even as it simmers.  Rage is a fire-brand; it demands uncontrolled action.  This is why people in the boxing profession say that rage looses fights; it burns out the fighter with its fury leaving behind a shell of a boxer who cannot box any longer.  In the fighting sports rage is the antithesis of control and success.  And, young fighters are warned never to get angry in the ring.

I write about anger and rage because they have touch my life.  Rage has threatened to consume me over and over.  Anger, on the other hand, is a healthy, not so consuming, experience.  I write about rage and anger, because they are apart of my experience of bipolar.  I wish that all of my experiences with rage could be retroactively converted to experiences of anger.  I wish all my future experiences with rage would be converted to anger.  Through hard work, I have learned to moderate the rage, to convert it to anger, and to prevent it from getting out of control.  I am not always successful, but I will share the tools that I use.

It should be noted that one needs to recognize the difference between anger and rage when it is happening.  This is more sophisticated than your run-of-the-mill recognize-your-anger-feelings that is used in therapy.  One has to distinguish the minor feelings of frustration from the major rage feelings that threaten self-control.  Indeed, the very threat to self-control can be the tip-off that rage is under way.

What goes on physiologically when rage is starting up?  Something activates the stress-response cycle.  The heart rate increases, paling or flushing occurs, constriction of blood vessels every where except the muscles occur, the tear duct constricts, blood vessels for the muscles dilate, pupils dilate, and there is tunnel vision and auditory exclusions.  In the intended circumstance, this all helps one focus on the threat to survival.  However, rage, at some ordinary event, is not the intended circumstance for the stress-response cycle.  Instead, with rage, this all helps one focus on the source of the trigger.  This means that most people with rage can easily recognize their trigger(s), although they may have less success dealing with the stress-response itself.

When I feel myself getting hot-under-the-collar in a rage kind of way, I find intense exercise to be the most useful.  I have literally interrupted conversations to sprint as hard as I can around the block.  Intense exercise has the effect of directly relieving the stress-response through action--through placing a demand on the dilated blood vessels for the muscles.  A sprint, done properly, both is harmless and effective, as sprinting is one of the most strenuous sports in the world.  One should exercise care and warm up properly, as in jog for 5 minutes to prepare the hamstrings for the strenuous effort of sprinting at full speed.  Another type of intense exercise that I like to use is hitting a punching bag.  This is demanding both in terms of accuracy and in terms of the weight of the bag, i.e. a heavy bag.  I cannot count the times that I have mentally pasted the picture of a adversary on the bag and walloped it.  Aside from sprinting and punching bags, I have done other exercises that come in handy: jumping, push-ups, grip work, and kicking.  It is easy to see that my tastes run in the martial direction and having a punching bag handy is useful for me.

The other tool that I have used is deep breathing.  Here the task is to slow down when the rage threatens to strike.  One must have the presence of mind to breath.  One breath, hold it for a 2-count, second breath, hold it for a 2-count, and so on up to a ten breaths.  There is abundant evidence that a deliberate breathing pattern slows down the stress-response cycle.  Slowly the blood vessels to the muscles stop dilating and the tunnel vision and auditory exclusions cease.  Usually this strategy requires stepping outside the triggering circumstance, in order to fully implement the deep breathing.

Since I regularly deal with rage, I cultivate an understanding among my closest relatives that I might take off to sprint at any moment.  I encourage them to be understanding of my exercise and deep breathing, and I ask them just to wait for me if I take off suddenly.  Through experience, they have all come to understand that I will come back better collected and able to handle whatever circumstance triggered the rage.