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.

A Basic Question About Anxiety

For the past 5 years I have seen more anxiety than in the first 24 years of my career.  I just realized last night that is one of the consequences of being an acute care psychiatrist.  In that setting, I am sure that I have seen more people with schizophrenia, bipolar disorder, severe depression, catatonia, dementia, and delirium than most psychiatrists.  If the anxiety was present it was associated with a severe disruption caused by the major psychiatric diagnosis.  When that syndrome was treated, the associated anxiety and insomnia also resolved.  I think that inpatient docs also get a fairly skewed perspective of what kinds of problems the average person is looking for help with.  Now that I am no longer seeing an acute care population it seems pretty clear that most people present with a mixture of anxiety and depression.  They present with varying levels of sophistication to give the history of the problem.  It is common for me to hear: "I am not sure that I know the difference between anxiety and depression.  Can you explain it to me?"  It is also common to hear combinations of symptoms or descriptions that cross over from one category to another.  A good example would be getting a referral for the assessment of "hopelessness" and learning that happens only during a panic attack and in the complete absence of depression.

Symptom severity and the perception of that severity turns out to be another problem.  Some people are fairly intolerant of the slightest bit of worry, especially if it leads to insomnia.  Others have a pattern of hyperarousal at night.  When their head hits the pillow, it is not a time to fall asleep.  It is a time to worry about what happened that day, the kids, the spouse, finances, and work.  Many of those folks are chronically sleep deprived but they are used to it and don't really complain about it.  A few will go to an even higher level of worry.  At that point their thoughts "race" (another cross-over symptom), but they seem more concerned about insomnia than anxiety.  In the people with severe early onset anxiety it is very common for that to morph into depression - a phenomenon written about by several researchers.  It is also common to see that happen on a week to week basis - with reports of anxiety dominating one week and depression the next.  After I define the symptoms for people I always try to ask a question about which syndrome is dominant this week and get the expected scatter of symptoms.  It is not surprising to me that these diagnoses have some of the lowest reliabilities of DSM-5 diagnoses in field  trials.  Critics of course point to problems with psychiatric diagnosis or the diagnostic manual.  Nobody seem to make the obvious point that this may reflect how people actually experience their problems.

I consider the developmental approach to psychiatric diagnosis the best one, especially when you have enough time to do that kind of work.  It requires constructing a timeline of symptoms across the lifetime of the patient.  It is necessarily biased by the imperfections of human memory including the reports of events that may not have really happened.  With anxiety and depressive disorders there are major landmarks that need to be discussed including sleep problems (insomnia and nightmares), school refusal or phobias, relationships with major attachments figures, losses of attachment figures, psychological trauma, and other forms of childhood adversity.  When I do that I notice that two patterns seem to emerge.  In one case, there are a number of people with what I would call an unremarkable developmental history in terms of events that might be associated with anxiety or depression.  At the other extreme are people with multiple events who have developed what I would call an anxious temperament.  Worry and some associated physiological symptoms are part of their personality.  They worry about everything.  They may know that they come from a long line of "worriers" and recognize these traits.  They have insight into the fact that they "overthink" everything and they are seen as being far too cautious about life.  They appear anxious, jittery and jumpy at times.  I am usually not the first physician seeing them and they have been treated with all manner of psychiatric medications with very few positive results.  They may be at risk for addiction, because some of them are looking for a medication that just "turns my mind off".   If they are prescribed a potentially addictive drug for that purpose, the dose required to turn off the mind is often very close to the euphorigenic dose and addiction results.  The people with anxious temperament do not have an episodic problem with anxiety, like some research articles describe.  It is with them all of the time.  I think it is also associated with other personality traits and disorders that makes treatment even more difficult.

In an effort to resolve this problem of episodic generalized anxiety versus anxious temperament I sent an e-mail to one of the top anxiety experts in the world.  He has hundreds of publications and is a co-author of what is considered on the the most authoritative texts on this subject.  I had that text sitting on my library shelf.  He agreed with my assessment of the problem but referred me back to a chapter in his text written by Kathleen Brady and colleagues on substance induced anxiety.  I read that but ended up on a section on the phenomenology of generalized anxiety disorder (GAD).  That section suggested a different phenomenology based on age.  The chapter by Taylor, et al had more detail on trait, temperaments and endophenotype models and I was able to take a closer look at endophenotypes in reference 5.  The Venn diagram below is based on the high points in this chapter.  It also confirmed by longstanding conviction that temperament are traits discussed about children and general and specific personality traits are discussed with adults.

Looking at the state of the art here it is apparent that a diagnosis of GAD does not provide anywhere near the level of information that is needed to treat it.   That is important because people are walking in to see psychiatrists with the expectation that there is a quick cure for the problem.  They will generally not get that if a checklist diagnosis is made based on GAD symptoms and they are given a prescription.  It is easy to see how some people will believe that blunting their levels of arousal with a non-specific sedating effect from a benzodiazepine is treating their anxiety.  Those same traits put people with high levels of trait anxiety at risk for alcohol and substance use problems.  More comprehensive formulations of anxiety need to be done that incorporate these factors in order to break the pattern of chronic anxiety and in some cases associated substance use.   Telling a person that they have generalized anxiety and treating them with medications alone, will probably not be enough to address the problem.  That is also the message that trainees might get when they consider research articles or read any modern text of psychopharmacology.  One text (6) provides stratified algorithms of decision-making for acute and chronic generalized anxiety, phobic disorders, PTSD, OCD, and panic disorder.  The authors do name specific psychotherapies in the algorithms and in some cases show that a trial of psychotherapy may be prudent before medications but all of the treatment is predicated on diagnoses rather than specific subtypes of the main conditions.  For example, there are a number of people with chronic anxiety who also have elevated heart rates (greater than 100 beats per minutes), marginal blood pressure and cardiac awareness in that they can sense their heart pounding in their chest when they are trying to sleep or they are in a quiet room.  These sensations are often a source of excessive worry and increased anxiety.  In the primary care setting there are many physicians who do not treat sinus tachycardia in the absence of a clear medical cause for it.  Is this a type of anxiety (endophenotype?) that should be treated with beta blockers? Does it require more than that for the cerebral component of anxiety or just the beta blocker?  Will physical exercise or psychotherapy treat the chronic tachycardia?  Are otherwise healthy patient with tachycardia excluded from clinical trials for anxiety on that basis?  And what constitutes an adequate medical evaluation for these patients?  Even today, I don't think that anyone has the answers to these questions and the same can be said for many other variants of generalized anxiety.

I have never seen a clinical trial of patients with anxiety and persistent tachycardia and doubt that I will.  If I had to guess, I would say that very few people are asked if they have cardiac awareness and whether that perception increases their anxiety.  I would also guess that (like hypertension) many of these patients do not have their vital signs followed very closely.  These are just a few of the ways to break down this very heterogenous syndrome and why further analysis is necessary.



George Dawson, MD, DFAPA


References:


1:  Dan J. Stein, MD, PhD; Eric Hollander, MD, and Barbara O. Rothbaum, PhD.  Textbook of Anxiety Disorders. Second Edition.  American Psychiatric Publishing, Inc.  Washington DC,  2010.

2:  Sudie E. Bach, Angela E. Waldrop, and Kathleen T. Brady.  Anxiety in the Context of Substance Abuse.   In Stein, et al, pp 665-679.

3:  Steven Taylor, Jonathan S. Abramowitz, Dean KcKay and Gordon JG Asmundson.  Anxious Traits and Temperaments.  In Stein, et al pp. 73-86.

4:  Lazlo A. Papp.  Phenomenology of Generalized Anxiety Disorder.  In Stein, et al pp.159-171.

5:  NLM Collection on Anxiety Endophenotypes

6:  Phillip G. Janicak, Stephen R. Marder, Mani Pavluri.  Principles and Practice of Psychopharmacotherapy, Fifth Edition.  Wolters Kluwer Lippincott Williams and Wilkins.  Philadelphia, 2011.

Attribution:

Attribution for the painting at the top of this post is is Edvard Munch [Public domain], via Wikimedia Commons.  This is a reproduction of an original work that is in the public domain based on US Copyright Law.


Supplementary 1:

I was sent a question about my comment in the above post about anxiety and morphing into depression and where that is referenced in the literature.  The earliest reference I have is in ES Paykel's text Handbook of Affective Disorders from 1982.  In the chapter by Roth and Mountjoy "The distinction between anxiety states and depressive disorders." the authors state:

"Clancey, et al (1978) reported that 49 of 112 (43.8%) anxiety neurotics developed secondary depression during a 4 - 9 year follow up period."

1: Clancy J, Tsuang MT, Norton B, Winokur G. The Iowa 500: a comprehensive study of mania, depression and schizophrenia. J Iowa Med Soc. 1974 Sep;64(9):394-6, 398. PubMed PMID: 4425518.

There are more of these articles and it may take me a while to find them due to the usual discussions about comorbidity and similar biological substrates:

2:   Martin C. [What is the outcome of childhood anxiety in adulthood?]. Encephale. 1998  May-Jun;24(3):242-6. Review. French. PubMed PMID: 9696917.

3:   Kessler RC, Keller MB, Wittchen HU. The epidemiology of generalized anxietydisorder. Psychiatr Clin North Am. 2001 Mar;24(1):19-39. Review. PubMed PMID: 11225507.

"The strong comorbidity between GAD and major depression, the fact that most people with this type of comorbidity report that the onset of GAD occurred before the onset of depression, and the fact that temporally primary GAD significantly predicts the subsequent onset of depression and other secondary disorders raise the question of whether early intervention and treatment of primary GAD would effectively prevent the subsequent first onset of secondary anxiety and depression."

4:   Kessler RC. The epidemiology of pure and comorbid generalized anxiety disorder: a review and evaluation of recent research. Acta Psychiatr Scand Suppl. 2000;(406):7-13. Review. PubMed PMID: 11131470.

"Results arguing that GAD is an independent disorder include the finding that GAD is usually temporally primary in cases of comorbidity with major depression, that primary GAD is a significant predictor of subsequent depression and that the course of GAD is independent of comorbidity."

5: Angst J, Vollrath M. The natural history of anxiety disorders. Acta Psychiatr Scand. 1991 Nov;84(5):446-52. Review. PubMed PMID: 1776498.

"The course is often characterized by a certain chronicity that manifests itself in residual symptoms and mild impairment in social roles even after many years and is frequently complicated with depression."

6:   Beesdo K, Knappe S, Pine DS. Anxiety and anxiety disorders in children andadolescents: developmental issues and implications for DSM-V. Psychiatr Clin North Am. 2009 Sep;32(3):483-524. doi: 10.1016/j.psc.2009.06.002. Review. PubMed PMID: 19716988; PubMed Central PMCID: PMC3018839.

"The development of secondary depression seems to be a particularly frequent and concerning heterotypic outcome of anxiety disorders. Is this a characteristic of anxiety in general rather than an issue of specific anxiety disorders or anxiety features (such as panic, avoidance, accumulation of risk factors)? Or is this related to an overarching anxiety or anxiety-depression liability, possibly through shared etiopathogenetic mechanisms (eg, neurobiology)?"

The authors of this study have a table summarizing the outcomes of childhood anxiety showing that in studies where is was mentioned 10/17 studies found depression as an outcome of anxiety.  This reference is available for free online.

DSM5 Dead on Arrival!

That's right.  The latest sensational blast on the fate of that darling of the media the DSM5 is that it is dead on arrival.  That recent proclamation is from the Neuroskeptic and it is based on the analysis of  criticism of DSM5 criteria for Generalized Anxiety Disorder (GAD).  OK - the original proclamation was "increasingly likely DOA".  I confess that at this point I have not read the original article by Starcevic, Portman, and Beck but the Neuroskeptic provides significant excerpts and analysis.

The broad criticism is that the category has been expanded and is therefore less specific.  The authors are concerned that this will lead to more inclusion and that will have "negative consequences."  The main concern is the "overmedicalization" of the worried and the dilution of clinical trails.  All this gnashing of the teeth leads me to wonder if anyone has actually read the Generalized Anxiety Disorder DSM5 criteria that is available on line.  The proposed new criteria, the old DSM-IV criteria and the rationale for the changes are readily observed.  The basic changes include a reduction on the time criteria for excessive worry from 6 months to three months, the elimination of criteria about not being able to control worry, and the elimination of 4/6 symptoms under criteria C (easy fatigue, difficulty concentrating, irritability and sleep disturbance).  A new section on associated behaviors including avoidance behavior a well known feature of anxiety disorders is included.  The remaining sections on impairment and differential diagnosis are about the same.  The GAD-7 is included as a severity measure although I note that the Pfizer copyright is not included.

So what about all of the criticism?  The "Rationale" tab is a good read on the DSM5 web site.  I can say that clinically non-experts are generally clueless about the DSM-IV features of anxiety especially irritability.  Most psychiatrists have a natural interest in irritability because we tend to see a lot of irritable people.  There has been some isolated work on irritability but it really has not produced much probably because it is another nonspecific symptoms that cuts across multiple categories like the authors apply to cognitive problems and pain.  So I will miss irritability but not much.  Psychiatrists have to deal with it whether we have a category for it or not and hence the need for a diagnostic formulation in addition to a DSM diagnosis (managed care time constraints permitting).

But like most things psychiatric - the worried masses rarely present to psychiatrists for treatment these days.   How likely is it that a busy primary care physician is going to review ANY DSM criteria for GAD?  How likely is it that a person with a substance abuse disorder is going to disclose those details to a primary care physician as a probable cause of their anxiety disorder?  How likely is it that benzodiazepines will be avoided as a first line treatment for any anxiety disorder?  In my experience as an addiction psychiatrist I would place the probability in all three questions to be very low.  It doesn't really matter if you use DSM-IV criteria or DSM5 criteria - the results are the same.

As far as "medicalization" goes, I am sure that somebody (probably on the Huffington Blog) will whip this into another rant about how the DSM5 enables psychiatrists to overdiagnose and overprescribe in our role as stooges for Big Pharma.  But who really has an interest in treating all anxiety like a medical problem?  I have previously posted John Greist's  single handed efforts in promoting psychotherapy and computerized psychotherapy for anxiety disorders even to the point of saying that the results are superior to pharmacotherapy.  In the meantime, what has the managed care cartel been doing?  Although their published guidelines appear to be nonexistent it would be difficult to not see the parallels between approaches that use the PHQ-9 to assess and treat depression and using the parallel instrument GAD-7 in a similar manner.  The problem with both approaches is that they are acontextual and the severity component cannot be adequately assessed.  The goal of managed care approaches to treat depression is clearly to get as many people on medications as possible and call that adequate treatment.  Why would the treatment of GAD be any different?

It should be obvious at this point that I am not too concerned about the DSM5, DSM-IV, or whatever diagnostic system somebody wants to use.  The DSM5 is clearly about rearranging criteria based on recent studies with the sole exception of including valid biological markers for the sleep disorders section.  Like many my speculation is that the ultimate information based approach to psychiatric disorders rests in genomics and refined epigenetic analysis and I look forward to that information being incorporated at some point along the way.

But let's get realistic about why the results of DSM technology are limited.  As it is with DSM-IV and as it will be with DSM5, clinicians are free to interpret and diagnose basically whatever they want.  Even with the vagaries of a DSM diagnosis, I doubt that the majority of primary care treatment hinges on a DSM diagnosis of any sort.  I also doubt that the dominant managed care approach to diagnosis and treatment of GAD depends on a psychiatric diagnosis or research based treatment.  It certainly excludes psychotherapy.  Trying to pin those serious deficiencies as well as overexposure to medication on the DSM and psychiatrists is folly.

George Dawson, MD, DFAPA


1: Gorman JM. Generalized anxiety disorders. Mod Probl Pharmacopsychiatry. 1987; 22: 127-40. PubMed PMID: 3299062.