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.

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.