University of Wisconsin 2nd Annual Update - Day 2

The second day of the conference was actually a half day that was as interesting as day 1.  The first speaker was Kenneth E. Towbin on Chronic Irritability and Pediatric Bipolar Disorder.  Dr. Towbin pointed out that all of the research discussed by him at the meeting was funded by the NIMH Intramural Research Program or the American taxpayers.  He briefly mentioned the advantages and disadvantages of working under those conditions including no usual conflicts of interest and working in an ivory tower with possible ascertainment bias.  The main focus of his discussion was to make a few points about the concept of bipolar disorder and how the overdiagnosis of this disorder came about.  The first point was that bipolar disorder is an episodic illness.  The word I like to use is phasic.  The second point sounds obvious to psychiatrists and that is that in order to make a diagnosis of bipolar disorder the patient has to have had an episode of mania or hypomania.

I am going to digress here a bit on my own before continuing the review of Dr. Towbin's work.  Much of what I do these days is correcting incorrect diagnoses of bipolar disorder.  When I try to reconstruct what happened patients will invariably tell me that they were given an "assessment" and told that they tested positive for bipolar disorder.  The assessment typically consists of a brief interview and then a battery of checklists and psychological tests.  Many are surprised when I tell them that the diagnosis really doesn't depend on any of those things.  It depends on whether or not they have had an episode of mania or hypomania and then I define those syndromes for them.  We try to reconstruct their history of mood disorders and whether or not they have ever had such an episode.   I also emphasize that these episodes have to occur when they are not using excessive amounts of alcohol or other intoxicants.  I ask them about the time before they developed a substance use problem and during their longest periods of sobriety.  In this day of overdiagnosis of Attention Deficit-Hyperactivity Disorder (ADHD) it is not uncommon to hear that a person who has developed a substance use problem using all of their Adderall in the first week or two.   When that is gone  they switch to alcohol for the second half of the month.  That combination can result in what appears to be a manic episode during the first week or two of the month followed by a 2-3 week depression.  That sequence of stimulant intoxication followed by stimulant withdrawal/alcohol intoxication followed by sustained alcohol intoxication is not bipolar disorder.

Dr. Towbin went on to give his very interesting take on how some mistakes can be made from reading diagnostic criteria.  He focused initially on how there could be ambiguity in the DSM-IV-TR.  For example under the "A-Criteria" - how is the requirement of a one week episode of elevated mood determined?  Does it have to be every day or every hour?  Could it last for a short a period of time as an hour?  Under the "B-Criteria" - could some symptoms antedate mood symptoms and what does "present to a significant degree" mean?  I was familiar with Angst's work on following patients with various durations of mania and what the outcomes could be and had since incorporated a shorter period of time into my evaluations of mania.  The DSM-5 criteria sought to clear up these areas by stating that the mood symptoms had to be present most of the day and nearly every day and the symptoms had to represent a noticeable change from usual behavior.   After these discussions of the nature and importance of manic episodes he went on to look at some epidemiological data on the increasing rates of bipolar disorder in children (1, 2).  In the study by Moreno, et al the authors demonstrated a significant increase in office visits by adults and children.  Between the years of 1994 and 2002 the rates of visits increased 60% for adults and 4,000% for children, but the rates from that graphic increased from 0.01-0.4% in children and 0.3 to 0.5% in adults.  Between 1996 and 2004, the number of inpatient discharges with a principle diagnosis of bipolar disorder increased 296.4% in adolescents and 438.6% in children.

Towbin's explanation for the increase in bipolar disorder diagnoses in children was that a cultural change was advanced by two research groups.  That cultural change was operationalized by saying that episodes of illness were not required and the diagnosis could be applied to children with chronic illness.   That led to the idea that bipolar disorder in children is not the same as bipolar disorder in adults and that chronic irritability was synonymous with bipolar disorder.  Or as he put it another way: "If you were really angry you must have bipolar disorder."  The importance of bipolar disorder as an episodic illness was also emphasized in the area of "double counting symptoms."  As an example, could the psychomotor agitation and flight of ideas of bipolar disorder be the same thing as severe hyperactivity or distractibility of ADHD?  Only if bipolar disorder was not an episodic illness.

Dr. Towbin proceeded to discuss how the concept of Severe Mood Dysregualtion (SMD) was developed at the NIMH as an additional clinical phenotype that could be compared to bipolar disorder.  SMD was defined as chronic irritability, ADHD-like symptoms and significant impairment.  At about the same time he went on the one of my favorite topics - irritability.  I like it because it is used as a descriptor in many DSM diagnoses but never well defined.  Many people are surprised that it is listed as a symptoms in Generalized Anxiety Disorder (and in the criteria for 6 other DSM diagnoses and in the text for an additional 3 DSM disorders.)  He defined a two component model for irritability including a background of a grumpy, annoyed and irritable mood and a phasic component of briefer flashes of anger or explosive episodes.  That allowed for a clearer definition of SMD and the subsequents development of Disruptive Mood Dysregulation Disorder DMDD) diagnostic criteria.  He reviewed the evidence from longitudinal studies, family history studies and pathophysiology that SMD/DMDD is not the same as bipolar disorder.  Followed for a long enough period of time this population tends to develop depressions rather than bipolar disorder and have families with histories of bipolar disorder.  From a recent study by Sparks that he referenced: "Parental bipolar disorder increase the risk for multiple categories of childhood psychopathology and DMDD is no more on the bipolar spectrum than anxiety disorders, MDD, or ADHD." He went on to discuss treatment approaches to this population emphasizing the significant degree of disability the is usually not discussed in non-technical publications about this problem.

The final speaker of the day was Zachary N. Stowe, MD.  His presentation was: Treatment of Mood Disorders in Pregnancy and Lactation: Where Are We Now?  He made two observations at the outset that probably captured the imagination of at least some of the crowd.  The first was that any psychiatrist who specialized in the neuropsychiatric disorders of pregnancy would be unchallenged in any community they decided to practice. The second was that every psychiatrist treating women should treat all women of child-bearing age as though were pregnant and therefore needed clear conversations about whether they are using contraception and what the permutations might be with respect to prescribed psychiatric medications.  The method of birth control should be documented.  In terms of safe use of medications in pregnancy he made the point that is is all based on post marketing surveillance and there is no safety data for using 2 medications at a time.

He reviewed the frequent scenario that clinicians face when a patient who is being treated becomes pregnant.  He used an excellent graphic showing how pharmacokinetics and the timing of human development combine to virtually assure that the fetus will probably be exposed at some critical stage of organogenesis and how that factors into the decision to continue, discontinue, or change pharmacotherapy.  He showed survival curve data from both treated and untreated major depression and bipolar disorder on the proportion of women remaining euthymic at and several weeks following delivery.  As expected the rates of recurrence of the mood disorders was high and significantly higher for bipolar disorder.

When discussing the risks of medication he mentioned the current FDA Pregnancy Categories and the fact that there will be a new system that looks at more of the clinical aspects of making these decisions.   The old system will remain in place for existing ratings meaning that for the forseeable future there will be two FDA systems looking at medication safety in pregnancy.  He looked at a number of maternal and neonatal outcome variables for pregnancies associated with maternal depression and maternal antidepressant use.  There was a significant overlap and he suggested that a psychiatric illness diathesis and all that encompasses in terms of cormorbid medical illnesses and activation of the maternal and fetal HPA axis was a possible explanation.  In other words there  would be non-optimal outcomes whether the depression is treated or not.  He went on to discuss detailed basic science research in this area as well as fairly detailed treatment recommendations.  From a clinical standpoint, he pointed out that psychiatrists are more likely to discontinue antidepressants in pregnant women than OB-GYN physicians and attributed that to the American College of Obstetricians and Gynecologists treatment guidelines for depression in pregnancy.

Dr. Stowe's presentation covered all modalities of treatment including electroconvulsive therapy, medications, psychotherapy and exercise.  He was a participant in a workshop I attended on treating depression with exercise.  I think the single most important fact that he discussed in terms of medication was the need to avoid valproate and consider it to be the last drug used in women of child bearing age because of its effects on the fetus and subsequent development of the child.  I recommend that any psychiatrist who has the opportunity to see Dr. Stowe and who treats women of childbearing age take advantage of that opportunity.

That ends my brief review of the UW conference this year in Madison.  I felt fortunate to have been actively involved in all of the clinical work that these clinicians and researchers discussed over a day and a half.  I thought of all of the patients I had seen who could have benefitted from seeing this basic and clinical science applied.  As I listened to the translational aspects of Dr. Stowe's work, I tried to think of all the women I had treated who developed a severe post-partum affective psychosis at some point in their lives and never recovered from that.  I appreciated the quality of a conference that puts all of that information out there and tries to bring everyone up to the same speed as the top researcher-clinicians out there.

If you think this approach might interest you - mark your calendar for next October 23 and 24 and I hope to see you there.  In the two years that I have attended, Art Walaszek, MD and Ned Kalin, MD have an excellent method of picking presenters who can cover both the clinical and basic science of important disorders and treatment modalities that psychiatrists need to be aware of.  That information is presented well and there is ample time for discussion.

George Dawson, MD, DFAPA

1: Moreno C, Laje G, Blanco C, Jiang H, Schmidt AB, Olfson M. National trends in the outpatient diagnosis and treatment of bipolar disorder in youth. Arch Gen Psychiatry. 2007 Sep;64(9):1032-9. PubMed PMID: 17768268.

2: Blader JC, Carlson GA. Increased rates of bipolar disorder diagnoses among U.S. child, adolescent, and adult inpatients, 1996-2004. Biol Psychiatry. 2007 Jul 15;62(2):107-14. Epub 2007 Feb 16. PubMed PMID: 17306773.

University of Wisconsin 2nd Annual Update

I was in Madison Wisconsin for the Second Annual University of Wisconsin Clinical Update.  I reviewed the first conference last year.  For anyone unfamiliar with the conference it started last year as a replacement for the long running conference run by John Greist, MD and James “Jeff” Jefferson, MD.  They were acknowledged again this year for their contributions to psychiatric education.   This is a very good conference because it builds on that tradition.  The actual venue is the Monona Terrace Convention Center on the shore of Lake Monona.  It is an excellent modern facility with only one drawback - they charge for high speed wireless access.  I talked with many psychiatrists there who had attended the previous conferences for a long time.  They bring in speakers who are some of the top experts in their fields for in depth presentations and there is also a strong department at Wisconsin headed by Ned Kalin, MD.  The conference wraps up in in a day and a half and that seems like a very good length for working psychiatrists.  Combine that with very accessible speakers and an excellent course syllabus and it has what I consider to be the elements of a good educational experience.  The other bonus is that I have never really seen an unbalanced presentation at this conference.  The overarching message is that there are a number of interventions, that treatment is successful, and that there is a scientific basis for what psychiatrists do.

I thought I would make a few comments on day 1 and then move on to day 2.

The first lecture was given by Maria A. Oquendo, MD on the Neurobiology, Assessment, and Treatment of Suicidal Behavior.  Aleman and Denys have called for the investigation of suicide as a special problem apart from any particular diagnosis.  She began with a review of the epidemiology of suicide, including the fact that 90-95% of suicides have an psychiatric disorder.  She also discussed the converse of that statement - the vast majority of patients with psychiatric disorders never attempt suicide.  That statement is usually not discussed.  It is a parallel argument to violence and aggression in psychiatric disorders.  It has implications for any care based on dangerousness (threat of aggression or suicide).  She presented an interesting stress diathesis model of suicidal behavior that takes into account clinical features (impulsivity, cognitive inflexibility,  substance use,  family history, poor social support) and neurobiological features (low serotonin, decreased noradrenergic (NA) neurotransmission, inflammatory markers).  Her model links norepinephrine neurotransmission with pessimism.   She cited evidence that included a slide of CRH innervation of NA neurons and behavioral models that lead to NA depletion in animals.   She reviewed some of the evidence of inflammatory signaling related to childhood adversity, the mechanism of interferon-alpha induced depression and markers of inflammation in suicide attempters versus controls (increased interleukin- 6 (IL-6), tumor necrosis factor - alpha (TNF-alpha), elevated microglial cells, increased IL-4 in women, and increased IL-13 in men.  The tentative conclusion is that suicide occurs in the context of a stress response or at least it appears to have the same neurobiology of a stress response.   She concluded with a discussion of public health approaches to preventing suicide.  She had no specific recommendations for how psychiatry fits into that response apart from presenting data that increased antidepressant prescriptions led to decreased suicide rates in Sweden, Hungary, Japan, and Slovenia.   She also discussed specific psychotherapeutic interventions for suicide by name and presented a study of cognitive behavioral therapy that led to a 50% reduction in suicide attempts.   Dr. Oquendo also provided an excellent contrast in how the results of observational studies, meta-analyses, and double blind placebo controlled studies can differ and what biases may be in effect.  In the case of lithium preventing suicidal behavior, most clinicians are aware of the fact that only lithium and clozapine are consider medications that prevent suicide.  In the case of lithium, it turns out that data is from observational studies and meta-analyses but not double blind placebo controlled trials.  The two double blind studies do not suggest that lithium is more effective in preventing suicides than other agents.  She suggested one bias may be a tendency of clinicians to use lithium in people who can use it more safely and that led to fewer suicide attempts.          

I found the presentation on suicide and suicide assessment very interesting.  It is such a broad topic that a single lecture has to pick a focus.  The presentations on suicide that I have seen tend to focus on trying to figure out which people attempt suicide and interventions in those populations.    People with psychosis and suicidal ideation – a common clinical scenario for psychiatrists are generally left out.  It would definitely complicate the presentation at a couple of levels.  There is the issue of what happens to the usual risk factor analysis, especially in the case of subtle forms of psychosis.  Factors that are typically seen as reliable (deterrents to suicide, prevention plans) can be thrown out in that situation since the patient has had a marked change in their conscious state.  That is true whether or not the patient is clinically interviewed or given a structured interview like the CCRS.   In the case of psychotic individuals paranoia is also a risk factor for suicidal behavior.  The paranoia is focused on a particular situation where the individual believes that he or she will be tortured or killed by someone.  They develop a plan to kill themselves rapidly using a highly lethal method before that can happen.   A common scenario is to have a knife or handgun on the nightstand just in case it becomes necessary.  In both of these treatment situations, the preferred course of treatment is to address both the depression and psychosis at the same time.   Past studies of these populations also suggest very high levels of hypothlamic-pituitary-adrenal (HPA) axis activation, consistent with Dr. Quendo's model.

Roger McIntyre, MD followed with Practical Considerations in the Successful Treatment of Bipolar Depression.  There seems to be fairly widespread confusion about the diagnosis of bipolar disorder.  I think it is common for consulting and subspecialty psychiatrists to reverse the diagnosis of bipolar disorder more often than they make new diagnosis.  Dr. McIntyre made that point but said that misdiagnosis is still a problem even in an era of overdiagnosis.   He took the assessment up a notch to discuss the utility and limitations of the diagnostic issues of bipolar qualifiers in DSM-5 ( mixed features, anxious distress) and what they imply for diagnosis and treatment.  He also emphasized the need for time to do an assessment.  He appreciates the fact that primary care physicians may have as little as 6 minutes to make a mood disorder diagnosis but said that even in his specialty clinic he may not know the diagnosis of 25% of the patient after doing a lengthy assessment.  He made this point to illustrate that in many patients a single cross sectional view of symptoms in a clinic appointment is insufficient to make the correct diagnosis.

He presented an excellent graphic showing the DSM-5 continuum from manic to manic with mixed features to depressed with mixed features to depressed.  He also spent a fair amount of time discussing the treatment of comorbid anxiety as a significant morbidity in bipolar disorder.  He presented interesting data on how comorbid medical and psychiatric conditions in bipolar disorder were the rule rather than the exceptions.   His main focus was on metabolic syndrome, obesity, and migraine headaches.  He presented very good graphics on mechanisms associated with these comorbidities.  He made the point that the metabolic abnormalities (much like studies done in patient with schizophrenia who had never been treated with medications) were associated with a number of social, metabolic, and environmental factors.  He suggested that the obesity/major depression and obesity/bipolar disorder phenotypes carried specific risks including poor cognitive performance, anxiety symptoms, and in the case of depression a possible higher suicide risk.   He cited estimates of metabolic syndrome ranging form 20-66% in populations with bipolar disorder compared to a general population estimate of 23.7% from the NHANES III study.  He presented interesting data on the correlation between cognitive impairment in obese and overweight bipolar patients that can be demonstrated in first episode manic patients (obese versus non-obese).  At the molecular level it has been demonstrated that there is a gradient of inflammatory markers between obese and non obese bipolar patients.   He has a published paper that looks at the relationship between treatment response in depression and body weight.  Although he did not speculate on an exact mechanism he suggested there were altered brain systems involved in cognition in many of these patients.

The section of Dr. MacIntyre's lecture included an interesting graphic that had all FDA and EMA (European Medicines Agency) approved medications for bipolar-manic, bipolar depressed, and maintenance therapy.  Both agencies have approved quetiapine for bipolar and only the FDA has approved lurasidone and olanzapine-fluoxetine combination (OFC).  The number of medications not approved in all columns is about the same (4 for EMA and 3 for FDA).  He presented number needed to treat (NNT) and number needed to harm (NNH) analyses for OFC, quetiapine, and lurasidone and in that analysis lurasidone looked like the superior medication but that analysis is for specific side effects.  The NNT was nearly identical for all medications.  In terms of overall treatment he was in general agreement with the Florida Medicaid Drug Therapy management Algorithm.   One of the very interesting points he made during his presentation was that treating and preventing recurrent manic  episodes may reduce risk for Alzheimer's dementia but that is potentially confounded by the effect of lithium on GSK-3-induced tau phosphorylation.         

Lithium Pearls (From several lectures)

1.  The claim that lithium is one of two medications that can prevent suicide is based on observational studies and meta-analyses.  There have been two double blind studies looking at this issue and they have both been negative.

2.  Experts continue to use lithium and consider it to be one of the major treatments for bipolar disorder.  Lithium may provide more benefit to manic prone patients with long periods of stability and a positive family history.

3.  Once a day dosing was recommended.

4.  Lithium can be used in pregnancy given several specific precautions and informed consent issues; including precautions are the time of delivery to prevent elevated lithium levels in the newborn.

5.  Lithium may decrease the risk of Alzheimer’s Disease and minimal cognitive impairment.

   
After afternoon breakout sessions on various topics, the final presentation was by Ned Kalin, MD on the Neurobiology of Depression.  As a point of disclosure I know Dr. Kalin and was his first fellow at the University of Wisconsin back in 1984 and I completed my residency there.  He is a model of the clinical researcher who has seen patients his entire career and also been involved in basic science research.  There were several other department members at Wisconsin engaged in the same balance of clinical and scientific activities.   I learned that he was also President Elect of the Society of Biological Psychiatry.  The UW has always been active in primate research and Dr. Kalin discussed some important ethical and scientific issues about basic science research in non-human primates including the reason for primate research and the changes in standards and research settings over the years.  He has broadened his research over the years to include how depression and anxiety start in childhood and adolescence.   He posted an interesting graphic on deaths worldwide due to violence that suggested suicide was the top cause, followed by homicide and then warfare.  It was based on World Health Organization (WHO) data.  He showed experimental data on conscious regulation of the amygdala.  These interesting studies show that activity in the amygdala can be modulated by cognitive activity that either enhances of decreases the response to the feared stimulus.  The ventromedial prefrontal cortex (vmPFC) and orbitofrontal cortex (OFC) are critical associated areas with activity correlating inversely with activity in the amygdala (high vmPFC and OFC activity correlate with low activity in the amygdala).   Preliminary data suggests that depressed patients fail to suppress activity in the amygdala with vmPFC and OFC activity.  A similar change occurs in the ventral striatum when depressed individuals attempt to enhance their positive affect over the course of an imaging session.  Controls show a significant increase in left nucleus accumbens activity (LNAcc).

Dr. Kalin reviewed the genetics and environmental factors in depression using a graphic that cited 3 of Kendler's papers.  He reviewed the progression of hypotheses ranging from monoamine depletion to altered serotonin neurotransmission to serotonin alteration hypothesis to  stress diathesis to neurotoxins to inflammatory/cytokine theories.  One of the possibilities he discussed was a theory that at least some developmentally based depressions are based on frontal cortical-amygdala substrates that result in increased activity in the amygdala and associated neuroplasticity mechanisms that also lead to increased vulnerability.   Cognitive therapy for depression may strengthen the ability of the frontal cortex to regulate the amygdala.  One of his areas of intensive investigation has bee the HPA axis and its effect in depression.  He reviewed the important roles of CRF both as an endocrine modulator and a neurotransmitter.   He used a Vonnegut quote from Breakfast of Champions as a quick review of HPA axis physiology.  For anyone who had read the book (and forgotten some physiology) it was an interesting reference.   In the last quarter of the lecture he reviewed the issue of stress in separated infants, maternal stress, and adults in human and non-human primates.  The focus was primarily on neuroanatomy, neuropathology, neuroendocrinology and possible treatments that target these systems.  Earlier in his discussion he also posted a graphic on translational neuroscience and how neuroscience findings need to be able to correlate at the clinical level.  A detailed discussion of that approach is available in this article that is available online at no cost.              

The first day in Madison went as well as expected.  Lectures with very high quality content by researcher-clinicians who actually see patients and investigate clinically relevant topics.  Psychiatry taught, researched, thought about, and practiced the way it should be.


George Dawson, MD, DFAPA



1: Oquendo MA, Galfalvy HC, Currier D, Grunebaum MF, Sher L, Sullivan GM, Burke AK, Harkavy-Friedman J, Sublette ME, Parsey RV, Mann JJ. Treatment of suicide attempters with bipolar disorder: a randomized clinical trial comparing lithium and valproate in the prevention of suicidal behavior. Am J Psychiatry. 2011 Oct;168(10):1050-6. doi: 10.1176/appi.ajp.2011.11010163. Epub 2011 Jul 18. Erratum in: Am J Psychiatry. 2012 Feb;169(2):223. PubMed PMID: 21768611

2: Lauterbach E, Felber W, Müller-Oerlinghausen B, Ahrens B, Bronisch T, Meyer T, Kilb B, Lewitzka U, Hawellek B, Quante A, Richter K, Broocks A, Hohagen F. Adjunctive lithium treatment in the prevention of suicidal behaviour in depressive disorders: a randomised, placebo-controlled, 1-year trial. Acta Psychiatr Scand. 2008 Dec;118(6):469-79. doi: 10.1111/j.1600-0447.2008.01266.x.

3: Fox AS, Kalin NH. A Translational Neuroscience Approach to Understanding the Development of Social Anxiety Disorder and Its Pathophysiology. Am J Psychiatry. 2014 Aug 26. doi: 10.1176/appi.ajp.2014.14040449. [Epub ahead of print] PubMed PMID: 25157566.

4: McIntyre RS, Rosenbluth M, Ramasubbu R, Bond DJ, Taylor VH, Beaulieu S, Schaffer A; Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force. Managing medical and psychiatric comorbidity in individuals with major depressive disorder and bipolar disorder. Ann Clin Psychiatry. 2012 May;24(2):163-9. Review. PubMed PMID: 22563572.


Supplementary 1: I thought it was very interesting that we are still talking about lithium as a very effective medication for psychiatric disorders int he same city that hosted the Lithium Information Center cofounded by Greist and Jefferson and the same location where the Lithium Encyclopedia for Clinical Practice was published.