Does Identifying Bipolar I Disorder Come Down To 6 Proteins?

The Mayo Clinic puts on very good conferences in Psychiatry.  Two of the last three that I have attended had a strong biological and genetic emphasis.  I was interested when I saw a reference in my Facebook feed to a study of potential biological markers of Bipolar I Disorder.  It was even better that the article was published in the open access journal Translational Psychiatry.  In the current article the authors looks at the results from the analysis of serum protein levels in controls and adults seeking treatment for depression and bipolar disorder.  The sera of their subjects and controls was analyzed by Myriad RBM in a quantitative immunoassay designed to search for biomarkers through large numbers of proteins.  The actual product and the proteins analyzed are described on the company's web page.  All of the six proteins identified as possibly being discriminating as listed in the above graphic including growth differentiation factor 15 (GDF-15),  hemopexin (HPX), hepsin (HPN), matrix metalloproteinase-7 (MMP-7), retinol-binding protein 4 (RBP-4), and transthyretin (TTR) can be located on this page and additional information is provided about the specific proteins

The authors emphasize in several places that this is a pilot or exploratory study but also point out that sufficient power to detect odds ratios for pairwise comparisons between mood disorders versus controls, bipolar disorder versus controls, and bipolar I versus controls.  They looked at 272 proteins from 288 samples (141 controls, 52 Unipolar depression, 49 Bipolar II, and 46 Bipolar I).  It was a one time cross sectional sample and no longitudinal sampling was done.  Rigorous patient selection was used to reduce the risk of substance abuse disorders and inflammatory conditions. In a table describing patient characteristics, the cases had significantly greater BMI, greater lifetime illicit drug use,  greater BMI, greater percentage of smokers, and fewer years of education.  Existing symptoms were rated with the following scales IDS-C (depression), PHQ-9 (depression), GAD-7 (anxiety), YMRS (mania), and AUDIT (alcohol use).  The cases were also being actively treated with antipsychotics, AED mood stabilizers, lithium, antidepressants, sedative/hypnotics, and thyroxine supplement.

The graphic from the article labelled figure 2 above shows the differences in protein concentrations for the six proteins that were significantly different after Bonferroni correction by diagnosis.  As can be seen from the figure all six proteins were at the highest levels in Bipolar I disorder.  ROC curves and the ROC-AUC was used to determine which proteins were better predictors of Bipolar I Disorder.  The text contains theoretical and speculative discussions of these particular proteins, what they have been associated with so far, and what importance that has for the issue of why their concentrations may vary in bipolar disorder.

There are a number of relevant considerations when looking at this type of proteomic analysis.  The most obvious is the assumption that the underlying dynamics of the biological substrate can be measured in meaningful ways by knowing the protein signature of those systems.  Although most of us are used to looking at cartoon depictions of neuron and synapses but the reality is much more complex.  Recent work in Science shows that there are 62 proteins associated with synaptic bouton (2) and vesicle trafficking and that the copy number of these proteins varies greatly.  The authors of that paper speculate that the production and number of those proteins may vary because some physical locations within the neuron may allow for an enrichment effect.  One of the implicit assumptions in the Frye, et al paper is that psychiatric disorders may have a unique configuration in terms of synaptic architecture and that it will be reflected in the proteins responsible for that architecture.  A further assumption is these CNS protein changes are all going to be reflected in the periphery and detectable in blood samples.  

Although it is premature to draw many conclusions about the data in this study, the implications may be far reaching.  It will be an interesting day in psychiatry if and when proteins will be used as biomarkers.  It will be an interesting day even if variants can be found and reliably detected.  Until then students of neuroscience and psychiatry will be able to appreciate that information flow in these systems is significant and we are just on the cusp of being able to understand it.  We are just at the stage of moving from cartoon versions of neurons - to the real thing.


George Dawson, MD, DFAPA

References:

1: Frye MA, Nassan M, Jenkins GD, Kung S, Veldic M, Palmer BA, Feeder SE, Tye SJ, Choi DS, Biernacka JM. Feasibility of investigating differential proteomic expression in depression: implications for biomarker development in mood disorders. Transl Psychiatry. 2015 Dec 8;5:e689. doi: 10.1038/tp.2015.185. PubMed PMID: 26645624.

2: Wilhelm BG, Mandad S, Truckenbrodt S, Kröhnert K, Schäfer C, Rammner B, Koo SJ, Claßen GA, Krauss M, Haucke V, Urlaub H, Rizzoli SO. Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins. Science. 2014 May 30;344(6187):1023-8. doi: 10.1126/science.1252884. PubMed PMID: 24876496.

Attribution:

The figure at the top of this post is from the above reference 1 and is used per the conditions of a Creative Commons Attribution 4.0 International License.

Better Living Through Pharmacology

One of the great unspoken biases in psychopharmacology is the belief system about the medication.  What is the medication supposed to do after all?  Is it supposed to be life-changing in terms of positive improvements?  Is it supposed to eradicate all types of depression and anxiety?  Is it supposed to create the perfect cognitive and emotional state?  Is it supposed to turn an average student into an MIT professor?  Is it just supposed to treat a symptom and if so - how many symptoms?  Does it need to address some underlying physiological disturbance or can anyone take it and get the same benefits?  These are all unspoken biases about psychiatric medications that need to be explored with people who are taking the medications.  I don't think that a psychiatrist should even take for granted that a patient knows the difference between depression or anxiety or why thinking that Attention Deficit Hyperactivity Disorder (ADHD)  with essentially no impairment in professional, academic, or social life is not the same as having that diagnosis.

One of the best examples is the myth of the perfect mind.  If ADHD is finally diagnosed and treated, that means the person's mental functioning will either be normalized or be much better than it was in the past.  It should be possible to read entire book chapters and even books for the first time.  That is true isn't it?  It turns out that the effects of most medications for ADHD are modest and rarely life changing.  I have talked with many people who had clear diagnoses of ADHD as children who did not like the side effects of the medication and stopped taking it or even faked taking it in school.  They developed strategies for coping in the world and were able to achieve academic and vocational success.   Even some of the strongest proponents of medical treatment of ADHD will agree that proper care also involves lifestyle and management strategies and in some cases formal therapies in addition to medication.  That does not mean that some people will not do better with medications and worse with lifestyle modification, but it does mean that there is much more latitude in the treatment of this disorder than is commonly assumed.  It is fair to say that in many clinics these days, there are clinicians actively looking fro any treatable psychiatric disorder.  The theory seems to be: "If I treat the social anxiety disorder, bipolar disorder, ADHD, panic attacks, and insomnia this person will be a lot better off."  There is really no evidence that this is true or that there is even a good way to select what disorders should be treated first.

The patient side of this problem seems to be the myth of the perfect mind extended to many conditions.  It is evident in a number of ways.  Some people present with some very basic knowledge of psychopharmacology.  They may suggest that their "serotonin" or "dopamine" is out of whack and that they heard that there are specific medications to correct that.  In some cases they will suggest a medication.  In other cases, a person will not be very stress tolerant and suggest that they need something that will either reduce day to day stress or significant stress from predictable major life stressors like the disruption of a job or relationship.  They seem to think that there is a medication that will both reduce the emotional reaction to this pain but also remove the cognitive elements from their mental life.  Depending on the person's baseline cognitive state, they can become quite demanding if they think that they are not getting adequate relief or it is not happening fast enough.  The risk in these situations is starting to take a number of medications with substantial side effects that frequently precludes them getting back to their baseline conscious state.  There is often a focus on a person's baseline in psychiatry or medicine, but that baseline is almost never adequately characterized.  That is true in the case of blood pressure but more true in the case of mental illnesses.  In the case of severe mental illnesses like bipolar disorder baseline is almost always defined in terms of the presence or absence of a few symptoms.  Wide areas of a person's life like their baseline intellectual functioning, social behavior, and typical stream of consciousness are rarely considered - even in research studies.

Addiction makes everything worse and therefore it also provides the best illustration.  The graphs at the top of the page show two drug response curves with the blue lines showing a good response.  A person who is using an addictive drug and the high risk response to that drug is conditioned to expect the drug response curve on the right - a continued therapeutic response for increasing doses of the medication.  In that case there is no element of safety or toxicity.  True drug responses are represented by the curve on the left - an interval of response followed by toxicity and limited response at the higher levels.  Addictions have a second effect by creating a bias that mental states can be fine tuned within the space of hours by drugs.  Any feeling state can be immediately modified by the addition of benzodiazepines, stimulants, opioids or alcohol.  This is often erroneously referred to as "self-medication" and it is a strong conditioned response that generalizes to the treatment of disorders with non-addicting drugs.

The psychological effects of these patterns are significant.  They can lead to continued addiction and disrupted care.  A person may have the belief: "If this doctor can't give me something that will get rid of the negative way I feel right now - I will take something to get rid of it."  It may lead to disruption of the therapeutic alliance, through anger and open criticism about the lack of immediate effects or minimization of physician concern about side effects and a general lack of concern about toxicity on the part of the patient.  There is often an associated belief: "I have a very high tolerance for drugs and you can give me higher starting doses and higher maintenance doses of drugs than you give most people."  Many people in this situation experience very high levels of anxiety if they are not getting high doses or the physician does not seem to be increasing the medication fast enough.

The thoughts and feelings about medications is one of the most difficult areas in psychiatry.  Contrary to what is written by critics - nobody is complaining about being overmedicated.  Most of the complaints I hear about are about not getting enough medication and not getting to those high doses fast enough.  The solution is rarely to provide the medication and amount requested.  The solution is to spend enough time talking with the patient about these issues.  I generally start with the limitations of the defined treatment and a medication strategy that is risk avoidant.  In that initial conversation I usually tell the person whether or not they have a diagnosis or if I agree with a pre-existing diagnosis.  If I detect signs that unrealistic expectations about the medication are present I move into that area, point out that the medication will not lead to a perfect mind, and what they have to do in addition to taking medication.  If I find that they are really focused on medication issues to the point that they are experiencing anxiety from it - I usually encourage them to think about something else and provide some examples of what else can be done.

There is some literature on psychodynamic issues and medication in the transference that I have not found very useful. I suppose you could say that from what I have written the medication has meaning far beyond its pharmacology.  There is an interpersonal and intrapsychic context.  I think it is addressable in what is usually considered straightforward supportive psychotherapy, but it definitely needs to be addressed.  It is a frequent cause of medication or treatment "failures".


George Dawson, MD, DFAPA        

Never Miss An Opportunity To Harass A Physician

Despite some PR releases to the contrary, pharmacy benefit managers (PBM) continue to harass physicians and waste their time.  My latest inane conversation occurred after a pharmacy left their usual message about prior authorization and an 800 number about a prescription that I had written.  Unless I call the PBM and jump through all of the necessary hoops they will not cover my patient's prescription and it will likely go unfilled.  It was a newer medication and more importantly one that I had not started in the first place.  In other words, the patient had been maintained on this medication before seeing me.  That means the specific prescription had been approved from another physician a few months earlier.  I was writing this prescription because the patient did not have access to the previous pharmacy and I was the physician of record in another treatment facility.  The conversation with the PBM went like this:

PBM:  "Is this a doctor's office or a pharmacy?"
Me:  "Doctor".
PBM:  "Who is the doctor?"
Me:  "George Dawson"
PBM:  "Who are you?"
Me:  "George Dawson"
PBM: "OK - I was just checking.  What is your fax number?  I can fax you the form in 20 minutes"
Me: (fax number given)
PBM: "OK - you will need to complete the form and then fax it back to us and we will have 15 days to make a determination?"
Me:  "Do you understand that the patient needed this medication two days ago and I just got a notification about this today?"
PBM:  "That is the patient's policy.  We can do an expedited review and give you a determination in 3 days if you like?  But that is in the patient's policy.  We have either 15 days or 3 days to make a determination.  Do you have any questions about that?"
Me:  "Well no I do not.  I am only concerned about appropriate medical care and this delay is not appropriate medical care.  I don't care about your policies.  Your policies have nothing to do with appropriate medical care."
PBM:  "Is there anything else that I can do for you today?"
Me:  "No there is not."

I expected to receive the fax in 20 minutes but did not get it until the next day.  The form is designed to waste additional physician time.  It could have been pre-populated with all of my information and the patients information - but it was not and I had to complete the form by hand.  There were two sections on the form that had to do with failed medication trials.  One wanted specific dates.  Since I am a consultant I do not have specific dates and my experience with most patients is that they have a difficult enough time with the names of medications.  I do know that the patient had tried 8 different medications from the same class and stopped them due to lack of efficacy or intolerable side effects.  I added them to the section and wrote "refer to the previous section" on the redundant form.  Total time to complete the form and try to figure out what they wanted was 20 minutes.   I was seeing other patients it took me an additional 2 1/2 hours to complete the form and fax it.  The 72 hour clock started at that point but there was no place on the form to request an "expedited review".  

I have several posts about PBMs on this blog.  They all have the same modus operandi.  PBMs are at the very minimum a significant delaying action.  They are hoping that the physician, the patient, or both just give up and either withdraw the prescription or opt for a much cheaper generic prescription.  There are a couple of significant problems with that theory.  The first is that all generics in the same so-called drug class are not equivalent.  Any physician with a modicum of experience knows that individual patients have highly individualized responses to medications that are broadly similar and that there are generally sound pharmacological reasons for those responses.  Secondly, physicians have been prescribing less expensive generics medications for decades now and if a new unique medication is being prescribed the odds are very high that the person has not responded to that medication.  In the example given here,  I had a list of 8 medications in my record that failed due to intolerable side effects or a lack of efficacy.  They were all inexpensive generics.  I listed them on the form and faxed it back to them.

This behavior does highlight an important difference in ethics between physicians and medical businesses.  In every case where I prescribe a medication for a patient, the medication is carefully selected and monitored for how well it is tolerated and the effectiveness.  The ethical concept here for physicians is to provide continuity of care for the patient.  That is the reason that I am obligated to provide follow up prescriptions to patients who leave one care setting and go to another.  The PBM obviously has no similar constraint.  I would argue that their 15 or even 3 day policy ignores the fact that the patient needs the medication right now.  The telephone conversation makes it explicit - the company cares more about the policy than the patient who needs the medication.

The political process in all of this is frequently ignored.  How is it possible for a private company to waste so much physician time and interfere with patient care?  A long time ago the healthcare industry and its friends in government sold the American public on the idea that businesses should ration health care.  They sold that idea with rhetoric about how physicians were greedy and tended to squander health care dollars on unnecessary tests, surgical procedures and medicines.  They sold that idea in spite of the fact that the largest independent review organization of physicians documented a trivial amount of excessive resource use.  Businesses are now firmly entrenched as middle men whose only job is to ration health care and that includes prescription medications.  They do that in part by having physicians make tens of thousands of calls like the one outlined here every day and essentially leaving that physician and their patient in the lurch.

Health care businesses currently have the best of all possible worlds.  They are funded by mandatory health care insurance that is essentially the second largest tax on all Americans.  The annual health care premiums easily exceed property taxes, state income taxes, and state sales taxes for almost all Americans.  The does not include the amount of physician and patient time that is wasted by these rationing tactics.  In return Americans get a system of corporate management that consistently places the interests of the corporation and corporate profits ahead of them.  They talk like they are competitive businesses - but they are in fact some of the most heavily subsidized businesses in the US and nobody seems to make the connection between the most expensive health care system in the world and this corporate welfare.

It is well past the time for change and the first step should be to return medical decision making to physicians and stop pretending that a for-profit company cares more about patients than the monied interests of the corporation.


George Dawson, MD, DFAPA

Minnesota Psychiatrist Workforce Shortage

It should be well known by now that Minnesota has a shortage of psychiatrists.  Government officials and administrators everywhere think that the solutions are simple - hire more psychiatrists or (even better from the administrators perspective) - hire more non-physicians to prescribe increasing amounts of medications for psychiatric disorders.  Various posts on this blog elaborate what the real problems are and why it is not a straightforward hiring problem.  There are various markers that point to the real problem as rationing and business approaches to psychiatric care.  At the latest Minnesota Psychiatric Society meeting, there was an invitation to participate in an interview project that is being conducted by the Minnesota Department of Health.  I am posting the following description of that project here as a public service announcement.  I think it offers a rare opportunity to provide direct information on the practice environment to government officials.  Please contact Ms. Morgenstern for the interview if you are interested.  She will provide you with a document of the standard interview questions.  I encourage everyone to be very frank about the practice environment here in Minnesota and what is wrong with it.

The Minnesota Department of Health Office of Rural and Primary Care is doing an interview project on the psychiatric workforce shortage. We wish to conduct ethnographic-style interviews of 30 minutes to a half hour in length with practicing and retired psychiatrists to get their perspectives on job satisfaction, location desirability, and difficulties in entering the workforce. This information will be used in conjunction with other workforce data in a report to the Mental Health Workforce Commission, which is charged with making recommendations to the legislature. If you would like to be a part of this project, please email Gabrielle.Morgenstern@state.mn.us



George Dawson, MD, DFAPA




Attribution:

By Alexrk2 (Own work) [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC BY 3.0 (http://creativecommons.org/licenses/by/3.0)], via Wikimedia Commons

Dreaming of the EHR

The Dream:

I am at the APA convention.

It is in a crummy hotel attached to a mall. I am going down to the street level in an elevator and it stops at a level where there is a big cinema complex. An 8 year old boy runs excitedly into the elevator and jams in to my left. The elevator is crowded. He looks at my name badge and says: "What would George Dawson say if the Watson computer said he wasn't doing a good job?"

I glance down at him and say: "George Dawson would not care."

The kid says: "That's not good" and laughs intensely.......


It is all a dream. I had that dream early Saturday morning. It doesn't require detailed analysis. That last thing I did on Friday was try to review a 22-page paper record that was generated by a modern electronic health record (EHR) system. With the exception of a few paragraphs it was largely unintelligible. It contained bits and pieces of information. I was looking for imaging (CT, MRI, ultrasound reports) and ECG data, but instead could find only a few lines that summarized fewer results. There were no dates - no hospital admission or discharge date.  Although the hospitalization was longer than a week - there was no medication administration record or MAR - showing the specific dates when medications were changed.  There were no comprehensive reports that I am used to seeing for the past 30 years from Radiologists. There was no discharge summary. The documentation was basically unacceptable as a source of clinical information and yet it was created by a very high end, enterprise wide EHR system. It brought back a memory of a mandatory meeting I had with a "coding specialist" about 10 years ago. That person let me know that I had "passed" the documentation review in that I had ticked off the necessary "bullet points" so that documentation specialists would approve my EHR note for the day and the associated billing document that had to be submitted with each note.  She showed me how I could do things faster by ticking off a series of check boxes and electronically signing the note.  She was shocked when I told her that I really could not sign my name to that document because there was no sign that an intelligent human being had seen the patient.  For all of these reasons, very poor documentation in the EHR is always on my mind.

My attempt to read the last report may have been enough of a reason for the dream, but I also spent time on Thursday with a colleague who really dislikes the EHR for additional reasons. We regaled our spouses with tales of incomprehensible reports.  In addition, his reports require a synthesis of many imaging, lab, and clinical reports.  He previously used a system where all of the reports showed up in a queue and he could go down that list in chronological order to dictate the report.  In the new system, he has to go to tabs to find all of the reports he is looking for.  Some of these tabs are hyperlinked and the reports don't load very well.  In the end, he and his colleagues end up printing out all of the reports on paper so they can dictate then more efficiently without having to search for what they need in real time in the EHR.  That reminded me of an experiment I did about 8 years ago with the same EHR.  I went in and read all of the clinical notes looking for chronic diagnoses that were not addressed.  I came up with an additional 8 diagnoses from 340 clinical notes buried in the EHR. There is generally no good way for physicians to mine data on their own patients to make sure that they have done the most thorough assessment of their problems.  On the other hand administrators can get detailed numbers of mouse clicks by nurses in primary care clinics and rate their productivity in terms of mouse clicks, screen views, or tasks completed.  My colleague's theory was that the current EHR is selected for the administrative capabilities like monitoring doctors or nurses rather than any inherent advantage for medical staff.  The major evidence for that is that many EHR vendors have permanent staff in the hospital and they are making constant modifications to the EHR.  In many cases there are meetings of all the physicians in a particular department about these modifications.  The hospitals and clinics purchasing these systems are purchasing incomplete products that require what seems like constant revisions.

It has been about 15 years since the blight of the EHR hit physicians.  It was originally called the electronic medical record (EMR) but I suppose some business type decided that they could really solidify the corporate stranglehold on medicine by eliminating the word "medical" from another phrase.  Corporate psychology also dictates that they give the impression that they are maintaining health rather than treating medical problems.  That is another good reason for eliminating the word medical from the corporate lexicon.

The marketing of the EHR has been masterful.  The political hype promised untold savings.  National candidates seemed to suggest that we could actually "save" enough with the EHR that it would cover a substantial part of American health care inflation.  Any physician involved in the implementation phase of enterprise EHRs knew that was a bold faced lie.  There is no way that annual multimillion dollar a year licensing fees as far as the eye can see are going to save anybody any money.  In fact, I am certain that many clinics and hospitals have had to cut staff and services just to bankroll the EHR. Nobody has ever followed the money on the EHR debacle as far as I know.  Congress is well known to invent businesses and turn people into billionaires overnight.  All it takes is a few Congressional mandates about the need to use an EHR and electronic prescribing.  There is no mandate to keep things cost effective of make sure that independent practitioners can afford it.  There are mandates to implement EHRs and electronic prescribing and the White House brags about it.  The following graphic and text are from a White House document on the EHR entitled: More than Half of Doctors Now Use Electronic Health Records Thanks to Administration Policies.

The problem with the White House statement is that despite spending about $3 billion dollars a year and in some cases $44,000 per physician,  the value of the EHR for the reasons already stated remains in question.  It is very handy to be able to pull up lab results and x-rays on a computer screen.  It is also very handy to be able to send electronic prescriptions to any pharmacy in the country.  On the other hand, it is reasonable to expect that a multimillion dollar piece of software will write a report that any hundred dollar database software from the 1990s could write.  That same software should be capable of allowing physicians to search their own patient results for quality and report writing purposes.  In the end we are left with very expensive, high maintenance systems, and massive amounts of information that is either buried in storage because it is not easily accessible or because it is worthless and generated primarily for justifying a billing document.

That is one of the many real costs of having a health care system run by bureaucrats and politicians.  


George Dawson, MD, DFAPA


Attribution:

Photo at the top of this blog is by Paco Burrola on Flickr and is used courtesy of this Creative Commons license.

NEJM Review of Generalized Anxiety Disorder

There was a review of Generalized Anxiety Disorder (GAD) in this week's New England Journal of Medicine by Stein and Sareen (1).  I just did a bit of a critical review of the concept here and thought I would look at what these authors had to say.  

They start the review with a clinical vignette of a 46 year old married woman with insomnia, headaches, back pain, and excessive worry about a number of daily stressors.  She is also drinking alcohol on a daily basis to "self-medicate".  She is described as a person who comes in frequently for appointments.  After reviewing the phenomenology,  comorbidity, and differential diagnosis - the authors come back to this case and apply what is in the review.

Their review of the diagnosis does highlight a few things that are problematic about the diagnosis.  The key diagnostic feature is chronic excessive worry.  The worry has to be there for at least 6 months.  In their review of other psychiatric causes of anxiety they omit diagnoses that can cause short term worry or anxiety - the adjustment disorders.  They point out that GAD is more common in primary care clinics where it usually presents with a chief compliant of somatic problems rather than excessive worry.  They discuss major depression as a common co-occuring condition and suggest that anhedonia may be a distinguishing symptom for depression.  They also describe anxious depression as episodic depression superimposed on chronic anxiety.  There is no mention of the low diagnostic reliability of the disorder and why that might occur.  I think that any psychiatrist who sees GAD over time experiences the same problem that occurred in the DSM-5 field trials, the diagnosis can seem to change between visits from GAD to major depression, even in the absence of any new stressful life events.  Critics of psychiatry frequently cite this as a problem with DSM-5.  I think that DSM-5 does a good job with the symptom descriptors, but we don't know why this change occurs and I have not heard anyone talk about it like it is a real phenomenon.

Alcohol use is described as a common co-morbidity with 35% of people with GAD "self-medicating."  I put that term in quotes because it suggests that alcohol can actually be used for the purpose of medication.  What really occurs is that over time the person becomes more anxious and sleep deprived because of the negative effects of alcohol on sleep, baseline anxiety, and baseline mood.  Practically everyone I talk with who has an alcohol use disorder can recognize this pattern and modify any remarks about self-medication to "feel better for a few hours" or "knock myself out and forget about my problems".  There is also the issue of alcohol use being the cause of an anxiety disorder rather than temporary relief.  While I am on the topic of substance use and GAD, at one point the authors make the statement: "Data are also lacking on the use, usefulness, and safety of medicinal marijuana for generalized anxiety disorder" (p. 2066).  Many if not most anxious people are averse to the use of marijuana for anxiety.  Initial use of marijuana typically causes a drop in blood pressure with a compensatory tachycardia.  Tachycardia especially if there is a noticeable accentuation of heart beats is not tolerated well by patients with anxiety.  Many have had panic attacks.  Others have cardiac awareness and are sensitive to any changes in heart rate or intensity.  Many people tell me they thought that marijuana was effective for anxiety, but over time it seemed to make them more and more anxious, they developed panic attacks, and they had to stop using it.  These features combined with a tendency of patients to stop talking to their primary care physicians about substance use are good reasons to heavily educate them about these problems at the earliest possible time.

The authors take a risk factor analysis approach to looking at historical features that can also be associated with the diagnosis.  They point out that they are nonspecific and amy be associated with other psychiatric diagnoses.  I would encourage a more developmental approach, looking back at the first recollection of anxiety - usually at some point in childhood and how that developed in the childhood environment.  It is fairly common for the patient to describe one or both parents being anxious and how that was transmitted to them  eg. ) "I started to worry about the same things my  mother worried about" or "I started to worry about my mother because she was worried all of the time - I worried that something was going to happen to her."  Those learning patterns associated with adult anxiety are fairly common and may explain the low heritability (15-20%) of the disorder.  The authors do discuss one feature that is important in this context and that is intolerance of uncertainty.  Clinically that translates to excessive and at times catastrophic worry about uncertain situations.  They are unsure about the biological or experiential origins of the symptom.  I think the important part is that with a careful enough history and sometimes collateral information the learning aspects of this bias can be examined and it can be unlearned in therapy.

The authors advocate for a stepped approach to treatment and I certainly agree.  This approach would include an initial medical assessment to look for common medical conditions that can cause anxiety followed by education about anxiety and lifestyle changes to address sleep, exercise, caffeine intake and alcohol use with monitoring response to those interventions.  Those first two phases could be accomplished at the initial visit.  If those initial interventions don't help moving on to "low intensity psychological interventions" like self-help books, computer-assisted psychotherapy, and support groups.  The next step up is more intensive psychological interventions like individualized cognitive behavioral therapy (CBT) or pharmacological management based on the patient's preference.  The highest level of care would include pharmacotherapy and more intensive CBT alone or in combination with other therapies (psychodynamic or acceptance and commitment therapy (ACT)).  The practical issue with this 4 step algorithmic approach to care is that it is generally not available in primary care settings.  In many of those settings, the patient is screened with the Generalized Anxiety Disorder 7-item questionnaire (GAD-7) and the patient is treated with a medication.  This is viewed as "cost-effective" care by managed care systems because an inexpensive prescription and a 20 minute appointment with a physician is apparently much more "cost effective" to the organization than maintaining computerized psychotherapy or educational and monitoring systems.  There is also the largely undetermined effect of the patient taking a completely passive role in their care.  There is a significant difference between a patient who is actively engaged in lifestyle changes and self education and one who expects a complete cure from a pill.  The actively participating patient has better outcomes.   

The authors include a table of 16 medications used to treat GAD.  They point out that the effects of medication are modest at best and no single medication has better efficacy.  They discuss vilazodone as a promising medication in clinical trials and do not include it in the list.  My current prescribing information says that it is FDA approved only for major depression, but only 4 of the 16 drugs on the list are approved for GAD: paroxetine, venlafaxine XR, duloxetine, and buspirone.   The authors comment on the practice of using hydroxyzine for GAD and suggest not to use it.  I am in complete agreement with that recommendation and think that any anti-anxiety effect comes from the non-specific sedating effect of antihistamines.  The side effect profile is also not very favorable.  They point out the benzodiazepine paradox with GAD - they are recommended for short term (3-6 month) use but the condition is chronic.  There is even more subtlety there.  Some early studies of GAD treated with antidepressants suggests that patients needed to take the medication only 30% of the time over ten years of treatment.  I don't think you will see a similar study with benzodiazepines and I think it has to do with the behavioral pharmacology of the drug.  The single-most important issue when it comes to benzodiazepines is the informed consent and letting the patient know that they are taking a potentially addictive drug.  

The  authors are silent about the fact that GAD may be the most heterogenous of all of the DSM-5 categories.  In October and November of this year, I went to three excellent conferences.  One of the central themes was phenotypic diversity in DSM-5 categories and what it implies for biology and genetics.  GAD seems to offer some of the best clinical features for distinguishing intermediate phenotypes and I outline a few in my previous post.  There are problems with a diagnostic category that says "excessive worry" is a discriminating feature and ignores real physiological markers like persistent tachycardia, hypertension, body mass index, and hyperarousal at the time of sleep.   This also points out how basic science can drive clinical diagnoses in psychiatry and hopefully at some point in the near future we will see this kind of research.

    

I think that we have gotten as much as we can out of the GAD diagnosis at this point and it is time to break it down into what can be more reliably observed. 

George Dawson, MD, DFAPA

References:

1: Stein MB, Sareen J. Generalized Anxiety Disorder. N Engl J Med. 2015 Nov 19;373(21):2059-68. doi: 10.1056/NEJMcp1502514. PubMed PMID: 26580998.

Sprituality.....

I was born and raised a Methodist.  My father was a Catholic and had some problem with that church despite the fact that many of his siblings were devout.  To this day, I have a vague notion of what being a Methodist means.  I remember going to a church that looked like a large house from the outside.   It was a very modest building.  There were a hundred or so people on the inside.  They became familiar faces over time.  I was always interested in what the clergy had to say and the message varied considerably.  I did not know it at the time, but being a protestant clergy is a very political position.  People have to like you or they start to talk and that talk can eventually undermine your ministry.  Even as a kid I thought I could figure out how serious the minister was by what he said.  Was it a rote presentation or did he brings things alive.  I don't mean in the entertaining sense.  Could he (we only had male ministers in those days) get a serious lesson across in an inspirational way?  I was always impressed with how little commentary there was about this central feature of the church service.  It seemed routine to go there, listen to the sermon, sing a few songs and leave.  No enduring message or feeling.

It wasn't until I was a teenager that I saw the inside of a Catholic church.  I was there for my father's funeral.  Several of his devout siblings arranged for the funeral service to occur in the Catholic church despite the fact that (to my knowledge) in my 15 years on earth at that time - he never set foot in church.  In assessing what the church looked like, I recall thinking that "this is the big time."  The structure was huge compared to the Methodist church and the architecture was inspiring.  No wood framing.  There were concrete arches, stained glass, symbols, and actual sculptures of Christ on the cross everywhere.  In a Methodist church there is usually one large plain wooden cross.  The stained glass is always basic with the words: "Faith, Hope, Charity".  The acoustics were definitely different.  Words spoken in a Methodist church tend to project out about 15 rows and rapidly drop off in volume.  In the Catholic church the sound carried and echoed all the way back to the last row.  That last row was at least 4 times the distance of the last row in the Methodist church.  Since then I have been in many churches Catholic and Protestant - typically for weddings and funerals.  Even though the church architecture can be an impressive instrument for the speaker - it all really comes down to the clergy.  Are they doing more than dialing it in?  Are they inspirational?  Is there intellect behind the spoken words?  Can they convey the idea that there is something much larger than our individual conscious states out there?  Those were my first lessons in spirituality.

When I was in the Peace Corps in the 1970s, a fellow volunteer introduced me to a book called Zen and the Art of Motorcycle Maintenance by Robert Pirsig.  On the surface, it was a book about a cross country motorcycle trip by the author and his son.  Below the surface there were lessons about philosophical approaches to life - both eastern and western philosophies.  There was also a flashback to a crisis in the author's life when he was in graduate school and developed a psychotic depression while in the midst of an academic interpersonal conflict with one of his professors.  The lessons for me from Pirsig's book was that spirituality is really independent of other contexts.  He summarizes it in this statement:

“The Buddha, the Godhead, resides quite as comfortably in the circuits of a digital computer or the gears of a cycle transmission as he does at the top of the mountain, or in the petals of a flower. To think otherwise is to demean the Buddha - which is to demean oneself.” ― Robert M. Pirsig, Zen and the Art of Motorcycle Maintenance: An Inquiry Into Values.

After reading Pirsig's book five times, I concluded that he had an unprecedented intellectual look at what he described overall as values.  He also had a look at spirituality in a very unique way and could see it it places where it is not commonly seen - like welding or motorcycle mechanics.  Moreover, it was also a view that made immediate sense to me.  I had been doing the same thing for years.

That brings me up to my work as a psychiatrist.  In that work, spirituality ranges all of the way from religious delusions to the higher power concept in Alcoholics Anonymous and all points in between.  I don't know how many people I have talked with who believed they were God or Jesus or Satan or The Antichrist - but I have had hundreds of conversations about those topics.  On the quieter end of the spectrum, I have had even more conversations with people who were anhedonic, hopeless, spiritually bereft and who felt abandoned by God.  Many of these folks felt as though any spirituality they had was gone.  They lost interest in it like everything else and they had doubts about whether they wanted to get it back.  Did it really mean anything when they had it?  Getting it back turned out to be a critical part of their recovery.  I try to figure out a way to describe it in my clinical assessments and it is difficult.  Some have suggested using the term to capture the Gestalt of the person, but I think it is more complex than that.  In many ways it is like describing people who are charismatic and trying to use the appropriate descriptors.

There is an experiential aspect to spirituality that requires concrete examples rather than me just writing about it.  For that I will turn to a couple of examples from the best interview program anywhere - MPR's Fresh Air with Terry Gross.  I consider it a laboratory for the spectrum of human consciousness and it contains a lot about spirituality.  The first example comes from a story about Iris Dement.  She is a folk singer who began singing in the Pentecostal Church.  Until you hear an explanation of someone who is in that church or experience what they are doing - it is very unlikely that you know what is happening.  After carefully developing the context during the interview she summarizes it at this intellectual level (1) :

   "I saw my parents use music to survive.  They had to have that music.  My mom had to sing and my dad had to go to church and he had to hear that music washing over him and through him.  It wasn't a, "Oh, this is nice"; it was a, "I'm not going to make it if I don't have that."  So I've felt that that's my job.  That's how I think of what I do.  I have to give people that lifeline, you know, that I saw my parents reach out for, and that I was taught to reach out for, and so that's what I aim to do.  And I guess I don't feel like I can do that without that connection to the spirit."

When I listened to that interview and heard that quote, I realized that had just experienced one of the best examples of spirituality.  I encourage anyone with an interest to listen to the audio and have that same experience.  I think that you have to look past your taste in music to what motivates this artist.  Too many people get stopped in their tracks by thinking: "I don't like folk music" or "I don't like country music" or some appalling lack of knowledge of the Pentecostal faith.  Listen to the audio from the perspective of what motivates Iris Dement and keeps her going.

The second MPR experience on spirituality just occurred and it was the final push for this post.  I heard Terry Gross interviewing the Iranian born photographer Abbas on his series of photographs about what people do in the name of God.  The process of the interview is again very important.  Gross sees a spiritual element in one of the photographs but Abbas does not.  He comments that his relationship with God is purely professional - he has no stake in religion.  At the same time he describes some experiences that were moving while he was engaged in photography(2) :  

"Of course.  You know, I mean, you can't touch such a subject without being touched and moved.  I remember very vividly, for instance, a mass in France among the Benedictines, you know, it's monks. They're different from priests, you know, monks - very moved by a mass.  Normally when there's a mass, I don't listen, I just take photographs because it's always the same.  But this time, you know, the father who was saying mass was very spiritual.  He was talking about Jesus, not as a distant prophet, but as a personal friend.  So suddenly I start listening, and I became very moved.  In most religions, at least one event made me - well, I wouldn't say a believer but a participant....."

Like the Iris Dement story, I encourage listening to the actual audio and Abbas description of his technique before and after this excerpt.

What is spirituality?  It is not the same thing as religion, but for some people it is very close.  I also think that it is not easily acquired.  I don't think it is as easy as declaring a higher power.  Spirituality might be haunting rather than reassuring - it may not be a good feeling but it probably leads to a sense of calm.  I like Abbas's idea that it can make you a participant.  I can see it as an unconscious emotional force that probably has some obvious and many not so obvious origins that leads to consistency and may be noticeable by observers.  Some very spiritual people are described as serene and others as inscrutable.  It is not listed in the DSM-5 and that is a good thing.  It is another aspect of conscious experience that psychiatry neglects for the most part.   As far as I can tell, it is like an experiment in consciousness.  Like the examples I gave - you know it when you experience it.


George Dawson, MD, DFAPA


References:

1.  Terry Gross.  Fresh Air on National Public Radio.   For Iris DeMent, Music Is The Calling That Forces Her Into The Spotlight.  October 21, 2015.

2.  Terry Gross.  Fresh Air on National Public Radio.  Photographer Abbas Chronicles 'What People Do In The Name Of God'.  November 19, 2015.

3.  Melissa Block.  All Things Considered on National Public Radio.  A Nephew's Quest: Who Was Brother Claude Ely?  July 14, 2011.

Story of the importance of Pentecostals in rock and roll, especially Brother Claude Ely - with parallel comments about the spirituality involved in that music.  If you doubt it - read the last two paragraphs of the written story first.