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.