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.

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.

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.

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.

Mixed States

Mixed states are thought to look different in everyone, and a single person might experience multiple different mixed states.  If you think you are experiencing mixed states, the best thing to do is to consult a psychiatrist.

My opinion is slightly non-standard, but I like to think of it this way: mania is an episode centered around feeling good and depression is an episode centered around feeling bad.  I believe there are other feelings that can anchor an episode such as anger, or fear.  In each case, the trademark of bipolar is that these episodes take an emotion and make an extreme experience.  So that anger becomes a rage episode and fear becomes a paranoia episode. These emotional episodes are called mixed, because they are said to have symptoms of both classical mania and depression.  For instance a rage episode might be considered energetic and may also involve suicidal thoughts.  Or a paranoid episode might be sleepless and may also involve difficulty with concentration.

Recognizing Mixed States
The definition of a mixed state is still being developed.  Here is what the DSM IV-TR says:

A. The criteria are met both for a manic episode and for a major depressive episode (except for duration) nearly every day during at least a 1-week period.
B. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.
C. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment), or a general medical condition (e.g., hyperthyroidism)

There seems to be considerable discussion about how the definition of mixed episodes should be written.  Some doctors require a few symptoms from both mania and depression, other doctors require more than a few symptoms.  Some doctors will disagree on the classification of a particular symptom, for example, extreme fear and it's cognitive dysfunction, into mania or depression.

I believe that mixed states are particularly difficult to diagnose because the subjective experience of the person who experiences them is so much different than the objective experience of an observer.  I also believe that this is an instance where language fails to capture the experience and discussion of these things is extremely difficult.

I believe that I experience mixed episodes, both anger-based episodes and fear-based episodes.  Detecting the onset of these episodes is critical.  Since I have been experience anger episodes, I have long since learned to spot the change in thinking that accompanies it.  Fear-based episodes are more challenging, and I have a two-pronged strategy to detect thought changes and cognitive decline.  To detect changes in my thinking process, I compare my current thoughts to past thoughts about similar situations.  To detect the fear-induced cognitive decline, I use my activity log (discussed in depression). When there is a sudden gap in my productive activities, I try to determine whether the cause is a depressive episode or a fear-based episode, and my overall emotional tenor usually answers this.

Preventing and Treating Mixed States
Similar to mania and depression, drugs are commonly thought to be the best treatment.  The appropriate drugs include mood stabilizers and anti-psychotics.  There have been a number of studies claiming that mood stabilizers are less effective for people who experience mixed episodes than those who do not.  It is not clear why this might be or what to do about it.

Drugs are not the only treatment, it is necessary to employ other coping skills.  In this it is best if the person with bipolar takes charge of their illness, as attempts to force the person to comply will likely destroy the very trust needed for success.  This can involve contingency planning for future episodes.  Discussions with family can cover when family might be requested to aid in decision making.  A high level of trust is required to make such discussions useful.  (Note, trust will be broken if family involve themselves in decision making without permission.)  If family is not available, one can turn to close friends, often termed chosen family.  As part of contingency planning, one can decide at which stage of an episode voluntary hospitalization will be sought.  Having a plan ahead of time makes implementation easier.

Whereas for depression I mentioned that keeping an activity log could be helpful, I am not sure that is helpful during these episodes.  In my experience these episodes get entrenched much faster and much deeper than some depressions.  I do, however, find the activity log useful for charting recovery, and it is encouraging to use the log to watch improvements in activity levels and cognitive function.

Depression

Many people have an image of depression as the monster that keeps a person in bed all day, saps their energy, and colors their emotions blue.  This post is about another kind of depression that creeps up on a person, saps their energy, but does not put them in bed.  In this kind of depression a person is functional but has little motivation and little ability to accomplish things.  Neither of these depression types is more sever than the other, they are just different.  I choose to focus on this last type of depression, because it is the kind that I can speak about from personal experience.

Recognizing Depression

Here is a list of symptoms of depression as taken from the Major Depression category of the DSM IV-TR.

1. Depressed mood most of the day.
2. Diminished interest or pleasure in all or most activities.
3. Significant unintentional weight loss or gain.
4. Insomnia or sleeping too much.
5. Agitation or psychomotor retardation noticed by others.
6. Fatigue or loss of energy.
7. Feelings of worthlessness or excessive guilt.
8. Diminished ability to think or concentrate, or indecisiveness.
9. Recurrent thoughts of death (thoughts of suicide)

Symptom (4) sleep disturbances is stereotypically taken as the most indicative of depression.  It is understandable that changes in sleep patterns are easy to notice and certain to draw attention.  On the other hand, for people that do not experience disruptions in sleep, detecting the presence of depression can be more difficult due to the subjective nature of most of the other symptoms.  Particularly if one does not feel very 'blue' as in symptom (1) depressed mood, recognizing depression is challenging.

I am in the category of people who do not experience symptom (4) sleep disturbances.  In addition, I do not seem to experience (1) depressed mood or (3) weight gain/loss.  This leaves me with the following symptoms diminished interest, fatigue or loss of energy, feelings of guilt, diminished ability to think or concentrate.  Now, people that know the DSM and that are counting may have noticed that I did not list 5 symptoms of depression which is the threshold for a Depression diagnosis.  They would be correct.  Recall also that I have had diagnostic issues, perhaps partly for this reason.  Despite this issue, I feel that I have indeed experienced depression.

This leaves me with a problem, how do I detect the onset of depression?  All the easy indicators like thoughts of suicide and sleep disturbances are not appropriate.  While my strategy may evolve further, I am currently using an activity log to track my engagement in work.  This is similar to a time-sheet, but it involves extreme honesty about when I am actually working productively.  (This is for my eyes only, so I do not have to worry about a negative opinion from my supervisor.)  I track the time that I work productively each day and each week.  Then I can watch the trend over time.  If I start to become fatigued, uninterested in work, or lack the ability to concentrate, my weekly productive time drops.

You might ask if keeping an activity log is difficult.  I find that it is not (of course I sometimes lapse), but I have integrated the activity log with my lab notebook which records my research/work activities.  So, the log has a dual purpose.  Also, I use a computer to compute statistics like average productivity.

This tool is very important to me, because at the beginning of a depression it is easy to rationalize the symptoms.  I will end up thinking that I just need a break to recharge when in reality a break might only make the depression worse.  This tool allows an objective view of the time I spend being active and helps cut through the subjectivity of the situation.

Preventing and Treating Depression

For me, the primary prevention and treatment of depression is medications.  It has been critical to have the right combination of psychotropic medications and to treat physical illnesses that could cause depression.  Additionally, I use a motivational tool which turns out to be the activity log described above.

On the topic of medications, being a person with a bipolar family history of sensitivity to SSRIs, I avoid antidepressants.  I rely mostly on the antidepressant properties of Lithium.  I have experienced an instance where a failure to treat a thyroid problem appeared to result in depression.  So, I also keep on top of my general health.

The motivational tool that I use is the activity log mentioned above.  In a bad depression, I try to do at least one activity a day.  Once each activity is complete, I log it in the activity log making the log into a sort of achievement wall.  I get to feel good about each thing that I accomplish.  By continuing to track my active hours each day, I can also see whether the depression is improving which also makes me feel more positive.

The activity log could also be viewed negatively, if one were to focus on how little they accomplished each day.  To avoid this, I strongly subscribe to a view of life that everyone can improve from where they are at.  This view is typically accepting of whatever activity level I find myself at during a depression, and it helps to keep me focused on improvements, no matter how small.

Does anyone else have depression strategies to share?  If you do, please post them in the comments.

Mania

Mania seems to be one aspect of bipolar that is both the best understood and the most misunderstood generally.  It is generally understood that mania is a strong indicator of bipolar, however it is misunderstood that all people with bipolar experience mania.  For example, to the best of my knowledge, I have not experienced mania.  This makes me less qualified to write a post on this topic.  However, since it would be remiss of me to discuss depression and bipolar without mania, here is a post drawn mostly from the literature.

Recognizing Mania
This description from the DSM IV is an objective description of mania which might be different from the subjective experience of it.

A) A distinct period of abnormally and persistently elevated, expansive or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary)
B) During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree:

1. inflated self-esteem or grandiosity
2. decreased need for sleep (e.g., feels rested after only 3 hours of sleep)
3. more talkative than usual or pressure to keep talking
4. flight of ideas or subjective experience that thoughts are racing
5. distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli)
6. increase in goal-directed activity (at work, at school, or sexually) or psychomotor agitation
7. excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)

C) The symptoms do not meet criteria for a Mixed Episode

D) The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.

E) The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication or other treatment) or a general medical condition (e.g., hyperthyroidism)

It seems to me that mania is difficult to recognize without having repeated experiences with it.  Even when I saw mania in a close friend I had difficulty discerning their lack of judgement and impulsiveness.

Preventing and Treating Mania
Mania should be treated together with whatever other bipolar symptoms that one has.  This is typically done using drugs such as Lithium that act as a mood stabilizer.

It is not sufficient to treat mania only with drugs, as therapy and support from family and friends also plays a large role.  In this it is best if the person with bipolar takes charge, as attempts to force the person to comply will likely destroy the very trust needed for success.  One should try to identify triggers as much as possible and make contingency plans for future episodes. Involving family in contingency plans can help with determining when the family can make decisions on the behalf of the person with bipolar and when support is wanted or needed.  Or perhaps the person with bipolar might request for a family member to have control over their finances with a mutually agreed upon allowance, and with mutually agreed upon ability to revise the agreement.

These sorts of plans and frank conversations help prevent misunderstandings such as relatives refusing to make a monetary loan to a stable person because they mistakenly believe the request is a symptom of mania.  Or an even more harmful misunderstanding, relatives may unilaterally decide when a person with bipolar should be involuntarily hospitalized.  Planning helps with decide the conditions under which a person will voluntarily be hospitalized or when they might wish to request decision making help from certain trusted relatives.

Bipolar Episodes

The establishment subscribes to 2-3 types of bipolar episodes:

1. mania - high of euphoria, activity, grandiosity, impulsiveness, etc.
2. depression - low of activity, energy, negative thoughts, suicidal thoughts, etc.
3. mixed states - properties of both mania and depression, perhaps including psychosis

Believe it or not, there is still debate on whether the third type actually exists.  I have encountered prominent doctors at a university who subscribed only to the traditional bipolar I and II distinction in which bipolar I is thought to involve both mania and depression and bipolar II is thought to involve hypomania (baby mania) and depression.  These doctors would not discuss mixed states, but instead discuss schizoaffective disorder as the third disorder that can explain bipolar-like symptoms.

The first two types of episodes are what give bipolar its a name where the 'bi' refers to mania and depression, and the 'polar' refers to the presumed spectrum on which mania and depression sit at opposite ends.  It is fairly easy to see that the name bipolar comes from the traditional description of bipolar I and II.  The addition of mixed states is an acknowledgement that there is actually not a depression-mania spectrum for some people, and opens a diagnostic category for the people having episodic bi-polar-like symptoms that are not clearly related to schizoaffective disorder.

What are mixed states?
It is thought that they look different in everyone that experiences them.  And, one person might experience more than one type of mixed episode.  (Keep in mind that this discussion is not very scientific, as the definition of a mixed episode is still being developed.)  I like to think of it this way, and notice that my view is different from the traditional definition: mania is an episode centered around feeling good and depression is an episode centered around feeling bad.  I believe there are other feelings that can anchor an episode such as anger, or fear.  In each case, the trademark of bipolar is that these episodes take an emotion and make an extreme experience.  So that anger becomes a rage episode and fear becomes a paranoia episode.

These emotional episodes are called mixed, because they are said to have symptoms of both classical mania or depression.  For instance a rage episode might be considered energetic and may also involve suicidal thoughts.  Or a paranoid episode might be sleepless and may also involve difficulty with concentration.

Personally, I find the task of identifying both mania and depression symptoms in an episode to be difficult.  I would prefer to see descriptions of multiple types of emotion centered episodes.  But we will see where scientific discovery takes mixed episodes.  Hopefully we will see progress in the near future.

Does anyone else have thoughts about the distinction between mania, depression, and mixed episodes?

Workplace Bullying in the Academy

Following on the last post about student-on-student bullying, this post discusses workplace bullying situations of the faculty and graduate student variety.  I will say up-front that this is a topic about which I try to be objective, but my experience as student with low power inherently influences my viewpoint.  I will tell the story of a friend who experienced psychological harm as result, and this undoubtedly influences my subjectivity.  Also, there may be some missing details and some awkward phrasing designed to hide peoples identities.

This bullying situation involves faculty and graduate students, so why do I call it workplace bullying?  I call it this, because graduate students in the sciences are typically paid by their faculty advisors to do research.  This is an employment situation where the faculty advisor is the boss and the student is the employee.  Some faculty advisors are extremely collegial with their students and treat them as almost equal proto-researchers.  But other faculty advisors perform the boss role.  Like any employment situation this usually works out quite well.  However, there are times that bullying situations arise.  While it is possible for a faculty advisor to feel harassed and bullied by their students, we tend to hear of situations where the student gets harmed.  However please keep in mind that there are infamous examples of students trying to kill their advisors, so the potential for bullying is certainly not unidirectional.

As before in Student Bullying in the Academy, I will try to avoid discussions of bullies and targets.  I think it is most productive to discuss the harm that results from bullying situations and to talk constructively about what could have been done differently.  This way of discussing bullying opens the conversation to include aggression by individuals who are not always aggressors or who may not have the intent to harm.  Since the target can only perceive intent through the actions of another, this means that the target and bully experiences might not agree.  This perspective also opens possibility that the target might as an aggressor either in retaliation or ignorance.  And the aggressor might be responding to a perceived harm done to them by the target either through action or inaction.

Many, sometimes contradictory, descriptions of bullying exist.  I prefer the description given in Prevalence, antecedents, and effects of workplace bullying: A review which says that bullying can be

"described in terms of: the intentionality of the behavior; the frequency (for example, weekly) and the duration (for example, about six months) of such behaviors; the targets’ reaction(s) to that situation; a perceived imbalance and misuse of power between perpetrator and target; inadequate support; and inability of the target to defend him or herself in that situation, where they have to
face constant negative social interactions, badgering, insulting remarks, and intense pressure. This
strengthens the aspect of power imbalance between the perpetrator and the targets as the perpetrator is believed to be in a position of strength as compared to the victim."  

There are two aspects of this description on which I will provide my opinion, the first is intent which was covered above and the second is frequency which need not be frequent if the person suffering harm has been severely harmed. Because the threshold for harm is lowered, and an aggressor can provoke harm easily with relatively benign or infrequent stimulus.

An Example
In presenting this scenario, I am inherently influenced by having only heard one side.  Because of this I will be presenting what happened to the best of my knowledge.

My friend was approaching their final years in graduate school and had two faculty advisors.  One of these had just moved to a different school.  My friend had gotten along well with both their advisors and had only received one performance-related request of something to change--one advisor had mentioned that my friend did not communicate well enough what was being working on.  Another aspect of this situation is that advisor had a collegial style of working while the other advisor had an boss-employee model of working.

The event that triggered the bullying situation was when the collegial advisor told my friend that they were not working hard enough and that they were lazy.  My friend asked when the problem started and got no answer.  There was no attempt to assess where my friend might be at or what they were doing.  They were also told that the advisor might not write a recommendation letter in support of applications for post-doctoral positions.

This was a situation of intense pressure from which my friend did not think they could escape.  Not only were career aspirations on the line, but as always my friend had a thesis to write which required their advisor's support. As typical in academia my friend was not told what was expected of them or how to retrieve the situation, but they decided the solution was to sacrifice their holidays to finishing a project that was half finished.

This gambit paid off.  My friend finished the project, submitted the paper, and had a successful meeting with their committee.  At this point my friend's advisor seemed very happy with their work and was told that it was good.  This should be the end of the story, however, it was not since a second bullying situation arose that may or may not have been related to the first situation.

My friend had decided that visiting their other advisor would be a good idea, so they arranged a 2 month visit to that advisor's lab.  No sooner had my friend arrived than that advisor took my friend into  confidence and started saying how the advisor was doing as little as possible to organize an event.  This way, the advisor could get credit for organizing the event without it taking up much time.  My friend was horrified, because they knew who would pick up the pieces: the staff.  My friend was also encouraged to manage collaborations with other colleagues so that my friend could minimize their contribution.  Again, my friend was horrified, because this was the antithesis of what they believe in.  Despite my friend's opinion of professed attempts to manipulate other people, they did their best to perform their role in the research project while continuing to work on their thesis projects.

My friend was also told that two of the students had been goofing off.  The students were threatened with the advisor taking away their project and giving it to my friend.  My friend did not find this amusing neither as a threat nor as a potential work-load increase.  My friend was quite disturbed that this comment transformed their social position from being a friendly outsider to being a threatening outsider.

From there things continued to deteriorate.  My friend received a threat that if they weren't productive enough, one of their projects would get taken away and given to someone who could do it.  They experienced sexual harassment perpetrated by the advisor--a reference on the part of the advisor to the potential for a sexual relationship between my friend and the advisor.  They had a rocky relationship with another member of the group  who added to the stress by arbitrarily mirroring the gestures of my friend and by seeming to enact a now-I-like-you now-I-do-not relationship.  This person repeatedly presented a catch-22 to my friend on the point of whether the advisor was a good person.  The stress of not knowing whether this student was a friend coupled with either an ambiguous threat or an ambiguous opportunity to support compounded the stress of the other interactions.

The advisor decided that since the project was not progressing rapidly enough, the students should stay up nights until it was finished.  The advisor did seem to have the philosophy that he should be there with them and that if he could handle being awake so could they.  Unfortunately, the power difference in the situation played a key role.  Over the course of two weeks, my friend watched their two colleagues get warn down and increasingly discouraged.  It got the point where my friend begged the advisor to stop making the students work so hard but was told that the students deserved it.

This last was too much for my friend.  They had been in this situation a short time, but it followed on the stress that had previously occurred.  My friend experience intense sleep-disrupting anxiety for the first time in their life.  They were extremely scared, and they had very negative opinions about their colleagues.  Indeed, my friend ended up interpreting the second bullying situation as being the result of the first.  This made these two incidences, one with each advisor, into one continuous bullying situation for my friend, regardless of the intent of the people involved.

My friend believes that the stress of this situation caused the onset of a sever psychological disorder.  While some people might be tempted to claim that such a disorder might be the source of an invented story about bullying, I would remind them that to jump to conclusions when they were not there is discrimination.  While hasty conclusions are dangerous, questions are always welcome.  My friend's perspective, no matter how it came about, is a valid experience of the world.  I would urge people to remember that it is more productive to entertain everyone's perspective and to constructively find ways to change situations.  It is also very important that people in positions of power consider carefully how their actions might influence those with less power, particularly since bullying situations and harm can occur without the intent to harm by anyone involved.

For this reason, I will not jump to conclusions about the motives of the people involved.  They had their own performance pressures to deal with, and they had other people to keep happy.  However, I do think many people could have acted in more constructive ways even to achieve the same performance outcomes.  Indeed, if there had been fewer threats, less harassment, and fewer negative social interactions, in the second situation my friend believed they would have been more productive.  As things happened, my friend wasted many weeks being too distracted and scared to work productively.  Similarly, the students with the second situation who stayed up nights might have also been more productive if they were not hounded into sleepless nights spent working.

My Diagnosis or Lack of One

I have mentioned that my psychiatric disorder seems to most closely resemble bipolar.  I am being as precise as possible when I say 'seems' and 'resembles'.

The one thing that all my doctors and I can agree on is that I do have an episodic psychiatric disorder characterized by depression, anxiety, and paranoia.  However, I have received a range of opinions about what I might have and have gotten 3-4 different diagnoses depending on whether a vaguely stated opinion from a doctor that I had a 2 hour conversation with can be considered a diagnosis.  At this point I have seen a total of 7 doctors.  Some of these doctors I saw for an hour and others I saw for over a year.  I am grateful that I do not have 7 different diagnoses, because some of these doctors were wise enough to refrain from offering an opinion.  The closest to a common denominator for the diagnoses is 'bipolar NOS'.  However, I do not mean to say that all the doctors necessarily agreed with this.

Reliability
For this reason, I say that my bipolar diagnosis is not reliable.  I would define a reliable diagnosis for a person as one which is repeatable in that a new doctor would be likely to make the same diagnosis for that person.  As my experience indicates, this is certainly not the case with my diagnosis.  I hope that science can one day produce tests that will conclusively determine just what I have.  Until then I will say that I may have bipolar.

Accepting a Diagnosis
A charge that is often leveled against people like me is that we are 'refusing to accept our diagnosis' or that we are 'in denial'.  Indeed, I do not feel compelled to argue against these people as their tendency to jump to conclusions is devoid of reason.  But all the same, I will say a few words on this topics.

I argue that I am not in denial, because I accept that I have a psychiatric disorder, and have since the very beginning.  I was the one who first noticed problems, because I was closest to the problems.  And, I continue to be the person to first notice recurrences of the problems.  My current focus is on treatment, the success of which I define as a short-term mental stability.  I argue that I would neither notice my symptoms, nor be interested in treatment if I were 'in denial'.

I do, however, believe strongly in the accepting ambiguities that are caused by the limits of human knowledge.  I have accepted that my diagnosis is unknown and unreliable.  This helps make it possible for me to keep an open mind and to consider treatment methods that are typically applied to a variety of disorders.

Alcohol and Bipolar

The Literature

Alcohol and bipolar is a topic about which there seems to be much confusion.  There is a little-understood known correlation between alcohol abuse and bipolar disorder [Regier et al. 1990, Kessler et al. 1996].  "These studies show that about 50% of individuals with bipolar disorder also manifest alcohol abuse or dependence and altogether about 75% have a substance use disorder. [Lydall et al. 2011]"

There are several things to note here.  First, this statement is about alcohol abuse and dependency which is the consumption of alcohol to the extent that it harms ones health and social obligations, the craving of alcohol, and the inability to limit its use.  This statement says nothing about moderate drinkers.  Second, this should not be taken to mean that alcohol abuse is causative of bipolar, since a correlation does not imply causation [correlation and causation].  For example asthma and socioeconomic status are correlated, but it is commonly thought that there are environmental factors which explain the trend [Almqvist et al. 2005].

The correlation between alcohol abuse and bipolar could have many explanations [Sonne and Brady 2002].  Alcohol abuse could cause bipolar, bipolar could cause alcohol abuse, or there could be a third factor such as genetics which is causing both.

The case for alcohol abuse causing bipolar is circumstantial and somewhat misleading.  The argument rests on studies done of substance abuse which includes cocaine abuse as well as alcohol abuse.  It should be clear that the mind-altering substances could produce results that are not generally applicable to alcohol abuse.  In other words, if the same study was done while considering only alcohol abuse, the correlation might disappear or be less strong. Additionally, the study authors themselves admit that "the effects of drugs of abuse, particularly with chronic use, can mimic nearly any psychiatric disorder."  At any rate, the results of these studies should be carefully considered since they show a correlation between a worse disease course and substance abuse [Sonne et al. 1994, Sonne and Brady 1999].    Again, all the caveats about drawing conclusions from correlations also apply to these studies. Additionally, it is known that treatment resistant forms of bipolar are more correlated with alcohol abuse, potentially providing a third explanation for disease-course correlation.  This suggests that the type of bipolar is predictive of both disease course and alcohol abuse, in turn suggesting that effective treatment of bipolar might alleviate both disease course and alcohol abuse.

The case for bipolar causing alcohol abuse is also circumstantial, but at least the studies are done for alcohol abuse and not substance abuse.  There are several studies indicating that alcohol abusers with bipolar recover better from alcoholism than other alcoholics [for discussion see Sonne and Brady 2002].  This leads to the additional explanation that "bipolar patients may use alcohol primarily as a means to medicate their affective symptoms, and if their bipolar symptoms are adequately treated, they are able to stop abusing alcohol."

The case for bipolar and alcohol abuse being influenced by a third factor is strong.  There was a recent study showing that there are underlying genetic factors that strongly correlates with alcoholism in people with bipolar [Lydall et al. 2011].  The wording may be awkward, but it is precise.  The study was performed on a group of individuals (n=1016), some with bipolar alcoholism (143) and some bipolar non-alcoholics (363), and some control nonbipolar non-alcoholics (510).  Then the genes known to be correlated with alcoholism were tested for correlation in the bipolar alcoholics vs. the controls and the bipolar non-alcoholics vs the controls.  They then looked for genes with a higher correlation in the bipolar alcoholics than in the bipolar non-alcoholics.  These are the genes that would predict risk for alcoholism for people with bipolar.  It turns out that they also found some of the alcoholism genes were also associated with bipolar in the bipolar non-alcoholics.  This indicates that those alcoholism genes are also risk factors for bipolar (independent of alcoholism).  The study authors reached the conclusion that "the relationship between bipolar and unipolar affective disorder and alcohol dependence is bidirectional (Sonne and Brady, 2002) and there is little room for doubt that the two disorders have reciprocal effects on each other."

The final topic that we know little about is the interaction between alcohol and medications for bipolar. Most psychotropic medications include a warning about alcohol consumption.  However, I have been unable to find a study which points to what bad effects or interactions might actually occur.  There is not a citation for this, but one doctor explained to me that the main concern is that the liver might be overworked since both alcohol and psychotropic medications both cause the liver to work hard.  The potential for harm to the liver seem to be a good reason to not drink large quantities of alcohol while on psychotropic medications.  While little is known about drug interactions of alcohol and psychotropic medications, there is something known about the effectiveness of treatment for different groups of substance abusers [Sonne and Brady. 2002].  It would seem that choice of medication should be tailored if one is a substance abuser.

In summary, we have many hypotheses about the known correlation between alcohol abuse and bipolar.  We have very few solid conclusions, at this point, and more research needs to be done.  Finally, all the existing conclusions are about alcohol abuse or alcoholism and are not about moderate drinking.  We know very little about how moderate drinking might interact with bipolar disorder, because studies on those topics have not been done.  We also do not know if there are drug interactions between alcohol and psychotropic medications.


My Choices

My statement of what I do should not be taken as a judgement of what other people should do.  There are many ways to deal with alcohol from alcoholism to abstinence.  I am not advocating for any particular choice for anyone else.  I am not advocating for illicit drug use, as this discussion is restricted to alcohol.  I am not advocating binge drinking, as there is a lot of strong evidence that binge drinking is dangerous.  My comments about what I do are limited to myself, and not a judgement of what other people should or should not do.

I choose to drink occasionally at home and in social settings.  By occasionally, I mean that most of my drinking falls in the moderate category and occasionally I abstain.  (Moderate drinking is defined as at most one drink per day for women and at most two drinks per day for men.)  I never drink and drive.  I do not appear to experience any alcohol cravings, and nobody has had reason to tell me that my drinking habits are harmful.  I understand that other people interact with alcohol differently than I do, and my choices regarding alcohol are not a judgement on what they should do.

I would like to see more studies done on the effect of moderate drinking for people with bipolar.  We know that in general populations, wine and beer have been shown to have benefits to the heart when consumed in moderation [Klatsky et al, 1997].  It seems to be unknown how frequently alcohol can be consumed before the risks of alcohol consumption out-weigh the health benefits.  On the subject of bipolar and alcohol, it is unknown at what consumption levels the health benefits out-weigh the elevated risk of developing alcoholism.