Ioannidis - Why His Landmark Paper Will Stand The Test of Time

John P. A. Ioannidis came out with an essay in 2005 that is a landmark of sorts.  In it he discussed the concern that most published research is false and the reasons behind that observation (1).  That led to some responses in the same publication about how false research findings could be minimized or in some cases accepted (2-4).  Anyone trained in medicine should not find these observations to be surprising.  In the nearly 30 years since I have been in medical school - findings come and findings go.  Interestingly that was a theory I first heard from a biochemistry professor who was charged with organizing all of the medical students into discussion seminars where we would critique research at the time from a broad spectrum of journals.  His final advice to every class was to make sure that you kept reading the New England Journal of Medicine for that reason.  Many people have an inaccurate view of science, especially as it applies to medicine.  They think that science is supposed to be true and that it is a belief system.  In fact science is a process, and initial theories are supposed to be the subject of debate and replication.  If you look closely in the discussion of any paper that looks at correlative research, you will invariably find the researchers saying that their research is suggestive and that it needs further replication.  In the short time I have been writing this blog asthma treatments, the Swan Ganz catheter, and the diagnosis and treatment of acute bronchitis and acute chronic obstructive pulmonary disease are all clear examples of how theories and research about the old standard of care necessarily change over time.  It is becoming increasingly obvious that reproducible research is in short supply.

Ioannidis provided six corollaries with his original paper.  The first 4 regarding power, effect size, the greater the number of relationships tested, and the greater the design flexibility are all relatively straightforward.  The last two corollaries are more focused on subjectivity and are less accessible.  I think it is common when reading research to look at the technical aspects of the paper and all of the statistics involved and forget about the human side of the equation.  From the paper, his 5th Corollary follows:

"Corollary 5: The greater the financial and other interests and prejudices in a scientific field, the less likely the research findings are to be true. Conflicts of interest and prejudice may increase bias, u.  Conflicts of interest are very common in biomedical research [26], and typically they are inadequately and sparsely reported [26,27].  Prejudice may not necessarily have financial roots.  Scientists in a given field may be prejudiced purely because of their belief in a scientific theory or commitment to their own findings.  Many otherwise seemingly independent, university-based studies may be conducted for no other reason than to give physicians and researchers qualifications for promotion or tenure.  Such non-financial conflicts may also lead to distorted reported results and interpretations.  Prestigious investigators may suppress via the peer review process the appearance and dissemination of findings that refute their findings, thus condemning their field to perpetuate false dogma. Empirical evidence on expert opinion shows that it is extremely unreliable [28]"  all from Reference 1.

The typical conflict of interest arguments that are seen in medicine have to do with financial conflict of interest.  If the current reporting database is to be believed they may be considerable.  A commentary from Nature earlier this month (5) speaks to the non-financial side of conflicts of interest.  The primary focus is on reproducibility as a marker of quality research.  They cite the facts that 2/3 of members of the American Society for Cell Biology were unable to reproduce published results and that pharmaceutical researchers were able to reproduce the results from 1/4 or fewer high profile papers.  They cite this as the burden of irreproducible research.  They touch on what scientific journals have done to counter some of these biases, basically checklists of good design and more statisticians on staff.  That may be the case for Science and Nature but what about the raft of online open access journals who not only have a less rigorous review process but in some cases require the authors to suggest their own reviewers?  A central piece of the Nature article was a survey of 140 trainees at the MD Anderson Cancer Center in Houston, Texas.  Nearly 50% of the trainees endorsed mentors requiring trainees to have a high impact paper before moving on.  Another 30% felt pressured to support their mentors hypothesis even when the data did not support it and about 18% felt pressured to publish uncertain findings.  The authors suggest that the home institutions are where the problem lies since that is where the incentive for this behavior originates.  They say that the institutions themselves benefit from the perverse incentives that lead to researchers to accumulate markers of scientific achievement rather than high quality reproducible work.  They want the institutions to take corrective steps toward research that is more highly reproducible.

One area of bias that Ioannidis and the Nature commentators are light on is the political biases that seem to preferentially affect psychiatry.  If reputable scientists are affected by the many factors previously described how might a pre-existing bias against psychiatry, various personal vendettas, a clear lack of expertise and scholarship, and a strong financial incentive in marshaling and selling to the antipsychiatry throng work out?  Even if there is a legitimate critic in that group - how would you tell?  And even more significantly why is it that no matter what the underlying factors - it seems that conspiracy theories are the inevitable explanations rather than any real scientific dispute?  Apart from journalists, I can think of no group of people who are more committed to their own findings or the theory that monolithic psychiatry is the common evil creating all of these problems than the morally indignant critics who like to tell us what is wrong with our discipline.  Knowing their positions and in many cases - over the top public statements why would we expect  them sifting through thousands of documents to produce a result other than the one they would like to see?  

I hope that there are medical scientists out there who can move past the checklists suggested to control bias and the institutional controls.  I know that this is an oversimplification and that many can.  Part of the problem in medicine and psychiatry is that there are very few people who can play in the big leagues.  I freely admit that I am not one of them.  I am a lower tier teacher of what the big leaguers do at best.  But I do know the problem with clinical trials is a lack of precision.  Part of that is due to some of Ioannidis' explanation, but in medicine and psychiatry a lot has to do with measurement error.  Measuring syndromes by very approximate means or collapsing some of the measurements into gross categories that may more easily demonstrate an effect may be a way to get regulatory approval from the FDA, but it is not a way to do good science or produce reproducible results. 


George Dawson, MD, DFAPA




References:  

1:  Ioannidis JPA (2005) Why Most Published Research Findings Are False. PLoS Med 2(8): e124. doi:10.1371/journal.pmed.0020124

2:  Moonesinghe R, Khoury MJ, Janssens ACJW (2007)  Most Published Research Findings Are False—But a Little Replication Goes a Long Way. PLoS Med 4(2): e28. doi:10.1371/journal.pmed.0040028

3:  Djulbegovic B, Hozo I (2007)  When Should Potentially False Research Findings Be Considered Acceptable? PLoS Med 4(2): e26. doi:10.1371/journal.pmed.0040026

4:  The PLoS Medicine Editors (2005) Minimizing Mistakes and Embracing Uncertainty. PLoS Med 2(8): e272. doi:10.1371/journal.pmed.0020272

5:  Begley CG, Buchan AM, Dirnagl U. Robust research: Institutions must do theirpart for reproducibility. Nature. 2015 Sep 3;525(7567):25-7. doi: 10.1038/525025a. PubMed PMID: 26333454.

Subtext of "The Autism Spectrum"

I was free associating to public radio a while ago as I listened to Terry Gross interviewing actor Timothy Spall on playing J.M.W. Turner (1775-1851).  Turner was an English artist in the 1800s, renowned for his use of color and light.  His painting above from 1839 was voted Britain's favorite painting in a 2005 BBC Radio poll.  I placed it here to illustrate these techniques that are visible looking toward the sun as it illuminates the cloud cover and some outlines at the horizon as it sets.  Some of the technical aspects of his painting that distinguish him from his contemporaries include the use of a white primer, limited use of underdrawing (sketching before the paint is applied), painting fast with a hard brush and palette knife, and parsimonious use of pigments (see reference 1 for details).  Spall studied art for two years in preparation for this role and was eventually able to recreate a Turner painter.  He describes Turner as possibly one of the greatest landscape painters of all time.  He also teaches how words change in meaning over time when describing how the sublime art movement grew out of the romantic and had as its goal "to capture the beauty of nature, as well as its terror and its horror."

The actual film Mr. Turner as described in the Fresh Air episode seemed somewhat different than the one described.  It did cover the last two decades of Turner's life.  In it we meet Turner, his ex-wife and two adult daughters, his housekeeper, several of his colleagues, and a woman who he meets when she is married and marries when her husband dies.  We see enough of these relationships to develop an impression of what may be going on.  The relationships are set against a visually stunning backdrop of the cinematographer shooting Turner as he travels to sketch seascapes and eventually convert them to paintings.  In many cases, such as the painting at the top of the post we see the scene blend into the painting.  The cinematography of these scenes is some of the best that I have seen anywhere.

I think the key about whether you might enjoy the film or not depends a lot on whether you can appreciate Turner's eccentricities and the attempt at portraying the depth of his character.  He certainly does things that many would find repugnant.  The impression that I had about his relationship to his family was that he had abandoned them.  His ex-wife was somewhat intrusive in attempting to get him to show some interest.  She did not seem to impress him in the least and he would typically walk away.  He did not attend the funeral of his daughter and when asked told people that he had no children, while his father had a facial expression of disapproval in the background. On the other hand he did marry a widow and stayed with her until his death.  Along the way he had a sexual relationship with his housekeeper.  There was one scene of perfunctory sexual intercourse between Turner and his housekeeper.  No words were spoken between them during that scene or at any point to suggest that they had any emotional intimacy but the actress in this case projects a strong sense of caring for him and eventually travels to see him when he is dying in his new home.  She appears saddened when learning he has a new wife and walks away without seeing him.

Throughout the film Turner communicates at times with a series of grunts, even though he has communication skills as good as anyone else in the film.  He has a characteristically gruff and unkempt appearance and only seems to smile when he is in the midst of a deathbed delirium.  I think that presentation is what led Terry Gross to ask the question about whether he might be on the autism spectrum and Spall's excellent response on subtext.  Spall speaks to the fact that he portrayed Turner's inner anguish after hearing that one of his children had died despite his overtly dismissive relationship with them.  He expands on the relationship with his housekeeper and what that means.  He describes his intellect as implosive as a reason for the communication in grunts at times, even though he could be quite articulate at others.

That response was a great one in so many ways.  It explodes the idea that observable behaviors mean much of anything out of context.  If I am gruff appearing or eccentric does that mean much of anything by itself?  Probably not.  Being gruff or eccentric appearing is not really a risk factor for seeing a psychiatrist and it is unlikely that those features mean much of anything.  And what about the communication style and the frequent grunting?  The first time I heard it I had the impression that it was the equivalent of the modern day English expression "oi"  or the American expression "hey".    I did not see it as the typical communication problems in autism.  It also speaks to the larger headlines of famous people who either think they are "on the spectrum" or somebody else thinks there are.  That comes from a number of sources - not the least of which is the popular notion that reading the DSM without being trained in psychopathology means much of anything.  Should a person get evaluated for congestive heart failure by a doctor who has just pulled up an internet site that lists the diagnostic criteria for congestive heart failure or is it better to see a doctor who has made the diagnosis many times, and by learning those patters of illness can successfully parse cases that are in the grey zone (eg. is this congestive heart failure or asthma?).

That is the ultimate value of Spall's comment on subtext.  There is not a lot that is explicitly known about this character in the film.  Certainly nowhere near as much explicit content as Spall discusses in his interview.  And yet he is pointing out that there is something implicitly there to suggest that Turner is not autistic (whatever that might be).  One of the many misconceptions about psychiatrists is that we want to diagnose everyone with some kind of disorder.  A substantial number of the people I have seen over the years want to know that they don't have a problem.  They either ask me up front or at the end:  "So do you think I have (bipolar disorder, Alzheimer's Disease, alcoholism, OCD, borderline personality disorder, etc.)?"  They are relieved that I know the subtext and can say no.  Some people will just ask the generic question: "Do you think I am crazy?" and I explain why that is not a relevant question.  In many cases I just have to tell people:  "I know that you are being treated for this disorder (usually bipolar disorder or ADHD), but there is no real evidence that you have it.  I have treated hundreds of people with this problem and there are a number of reasons why you don't have it.  And by the way, if you don't have the disorder - I would not recommend that you take medications for the disorder."  In rare cases I will see a person who asks a very specific question: "I have been in psychotherapy for 5 years now.  That is a long time.  Do I need to keep going?" and I am obliged to give them my opinion.

Often the observations have to do with non-verbal behavior like Sprall's comment on Turner.  What does silence mean from one meeting to the next?  In one meeting it means tacit unanimous agreement.  In the other it means just the opposite.  What happens if I see a young man thrashing about on the floor and the people around him are panicked and implore me to "Do something doctor?"  Instead of calling a code I reach out and pull him up off the floor and he stands there looking mildly anxious.  And what about that anxious patient who has a piece of pipe in his hands and says: "Do you want a piece of this?"  Instead of confronting him and telling him what to do, I explain what is really happening here - he is scaring the hell out of people (including me) and it is unlikely that an old man with glasses is going to fight him or anybody else.  He apologizes and drops the pipe.  I can recall walking into a gas station in Northern Wisconsin on brisk winter morning at about 7 AM.  A large man crashed into me and my wife right in the front doorway.  I grabbed him by the jacket, he went limp and I lowered him to the ground.  "What are you doing?  What's wrong with him?" my wife asked excitedly.  He was drunk at 7AM and in a stupor on the ground.  In all of these situations things are not what they seem to be.  We all act quickly based on limited information and the chances for error are great.

One of the more critical subtexts is what happens when a person you know very well appears to be different in some subtle way but there is no clear way to describe it.  The standard mental status exam including their cognitive screening turns out to be a very blunt instrument in this situation.  I have talked with people and done complete cognitive screening and when I see them again, they have no recollection of ever seeing me again despite a perfect score on the cognitive exam.  The only differentiating points were the smell of whiskey in the air and a coarsening of affect.  In other cases, a person may deny all problems including the ones that are the focus of treatment and exhibit a slight clouding of consciousness as a prelude to serotonin syndrome or neuroleptic malignant syndrome.

All of that commentary, representing a significant part of psychiatric practice has to do with subtext and not reading a diagnostic manual.  I thank Timothy Spall for his response on the issue of the Autism Spectrum, because it is really about a lot more than that.  I have always been impressed with the observations of artists and my English professors in looking at theories of human behavior and the applied metaphors.  It is also an indication of how difficult it is to be an actor.



George Dawson, MD, DFAPA                



References:

1:  Antonino Cosentino.  Cultural Heritage Science Open Source.  J. M. W. Turner (1775–1851).  Technical Art Examination.  March 24, 2014.

2:  Terry Gross.  Fresh Air.  Timothy Spall Takes On Painter J.M.W. Turner A "Master of the Sublime."  December 14, 2014.  Be sure to listen to the audio to appreciate Spall's voice and accent in this role.




Supplementary 1:

The painting here is: "The Fighting Temeraire tugged to her last berth to be broken up" by J.M.W. Turner.  It was downloaded from the WikiArt web site that advises that the copyright expired because the painter died more than 70 years ago.

Supplementary 2:

Don't try any of the interventions described in this post at home.  They are likely to backfire.

Supplementary 3:

Definition of Subtext from Theatrecrafts.com:

"Subtext or undertone is content of a book, play, musical work, film, video game, or television series which is not announced explicitly by the characters (or author) but is implicit or becomes something understood by the observer of the work as the production unfolds.  Subtext can also refer to the thoughts and motives of the characters which are only covered in an aside. ...."

Is Mental Health Legislation Really The Joke That I Think It Is?

The above graphic is a headline search of mental health parity going back to 2004.  I was in the thick of things from 2009-2012 as the transitioning President of a District Branch of the American Psychiatric Association - the Minnesota Psychiatric Society.  Not that it gave me the inside track on anything.  I think officers in district branches spend most of their time trying to get members motivated to do something.  My strategy was basically to approach things in the way I do on this blog.  I don't think that is was any more or less successful than the dialogue promoters, but at one point some people became uncomfortable when I suggested that one of the hospitals could have been managed better.  It was apparent to me at that time that professional organizations do not tolerate disagreement very well.  As far as I can tell, there can be no real changes in organizations without disagreement and disagreement should be expected anytime there are people who want to talk endlessly and people who want action.  On the other hand nobody has to take it personally.  That may not be possible in Minnesota or in professional organizations.  I have previously referred to it here as the "big tent" approach where multiple goals are tolerated even some that conflict with the overall goals and ethics  of the organization.  An example would be prior authorization of medications.  The vast majority of members find it extremely intrusive and a waste of their time, but the members who are executives in managed care organizations do not.  Accepting both of those positions is a tacit acceptance of prior authorization while working with the members to change it.  How do you think that will work out?

Parity or equal coverage for mental illness and physical illness was a legislative initiative of two U.S. Senators Paul Wellstone and Peter Domenici.  Both had personal experience with the problem having family members with severe mental illness.    That personal experience remains critical in the political and cultural landscape.  There are still plenty of people pushing the "myth of mental illness" fallacies.  Some have moved on to just blame psychiatrists.  People with experience recognize those arguments for what they really are and can try to proceed with real solutions.  I never met Paul Wellstone, but I liked him a lot.  He was one of a handful of US Senators who voted against authorizing the invasion of Iraq based on the flawed weapons of mass destruction argument.  He was vilified by some for the vote and referred to as an ultra-liberal.  That is a glib characterization during an era where there are no liberals.  In Minnesota he was widely known as a populist.  People perceived him as a common man who cared about the common people.  He was tragically killed in a in a plane crash in northern Minnesota in 2002 while campaigning for his fourth term in the Senate.  Senator Domenici retired from the Senate in 2009, after the longest tenure at that position by anyone from the state of New Mexico.  My guess is that the final form of this bill and the way it is implemented was not the intent of either of these Senators.

I read through several iterations of their bill until it became The Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity Act of 2008 (MHPAEA).  All of those versions are available on the Congressional web sites, but the factsheet is available from CMS.  It should be fairly obvious by any casual read of the factsheet that there are so many exceptions and vagaries associated with this law that it would not take the insurance industry and their government affiliates long to shred it.  I pointed this out at the APA 2011 Annual Meeting in Hawaii.  There was a meeting about how the MHPAEA was going to revolutionize the care of people with addictions.  A prominent psychiatrist and government official was scheduled to be there to explain how this was going to happen.  At the time, the impact of the law was not apparent on any of the acute care services where I was working.  At the meeting after listening to an overenthusiastic presenter explain how funding all of these programs were going to greatly increase bed capacity and services for all, I asked the simple question: "What would prevent any managed care company from providing a screening test and calling that assessment and treatment?"  The answer was "Nothing would prevent that."  No elaboration.  No discussion of how employers can just opt out of mental health and substance use treatment.

That introduction allows me to flash forward to the current time.  I was recently interested in referral for an acute psychiatric hospitalization in the Twin Cities - a metropolitan area of 3.8 million people.  According to a 2007 state report there were a total of 563 acute care beds for that area or 14.8 beds per 100,000 population.  According to the Organisation for Economic Co-operation and Development (OECD), the US ranks about 30th of 35 ranked industrial countries in terms of psychiatric beds per 100,000 population and the Minnesota metro is significantly below the US average of 25/100,000.   Based on those factors it should not be surprising that I was advised that there were no available beds and that the emergency department we could refer to had a 30 hour wait for assessments.

Compare that to Cardiology services in the same area.  Any middle-aged person (or younger) with chest pain would be immediately admitted to a coronary care unit or telemetry and have a standard evaluation completed even if they were discharged or undergo emergency catheterization and angioplasty/stenting.   I have never heard of a wait for acute Cardiology services.  I have never heard of a 30 hour wait in the emergency department for Cardiology services.   My point here is that the MHPAEA or parity legislation has done exactly nothing for the availability of acute psychiatric services.  These same numbers and waiting times in the ED have been there for the past 15 years.  There is no parity as long as there is no equal funding, and mental health services are funded at a fraction of what Cardiology services are.  Walk through any modern Cardiology Department or Heart Hospital and ask yourself: "Where are the equivalent psychiatric or mental health services?"  There are a few exceptions but generally not many and even then, a new facility is still managed by rationing strategies that result in people being discharged with inadequate plans and before their problems are completely addressed.  Inpatient psychiatric services are in effect behind a firewall and accessible only through the bottleneck in the ED.

The grim picture of acute care mental health services is only exceeded by the state of acute care addiction services.  As early as 1988, I was being advised by managed care companies that I could not detoxify patients with alcohol dependence on inpatient psychiatric units,  even if they had significant psychiatric comorbidity like suicidal ideation and depression.  The picture has gotten progressively worse since then.  It is common practice these days to send alcohol dependent people home with benzodiazepines and expect them to manage their own detox.  The lack of functional detoxification services keeps many people in the cycle of addiction to benzodiazepines, opioids and alcohol.

Confirmation of my skepticism about parity came in the form of the Mental Health Reform Act of 2015.  It is also a bipartisan bill introduced by Senators Bill Cassidy (R-Louisiana) and Chris Murphy (D-Connecticut).   There are House and Senate versions.  Both establish a new assistant secretary position for mental health and substance use disorders under the Department of Health and Human Services (HHS).   The fate of the Substance Abuse and Mental Health Services Administration (SAMHSA) hangs in the balance and getting rid of this highly flawed agency should be a priority.  SAMHSA has been the lead agency for mental health during this time of no parity and has not said anything about it.  The remaining description of the bill has to do with education people about HIPAA (do we really need that?) and insurance company accountability for a lack of parity.  The fanfare for this bill including praise from the APA is the exact same way the parity legislation started.  It should be evidence to every American by now that Congress is really interested in appearing to do something and appearing to want reform rather than getting the job done.

I don't think that there is anyone in Washington who knows the meaning of the word reform.  Until politicians everywhere realize that mental health services and substance use services have been an easy way for health care companies to make money by denying reasonable services nothing will happen.   It would help legislators to realize that they also have the highly flawed idea that managed care actually saves money and it is a conflict of interest for them to continue to promote this middle man on that basis.  I am not holding my breath, but it should be obvious that when a reform bill happens every 7 years, and there are still 30 hour emergency department waits and no acute care beds for admissions - there is no parity and there has been no reform.

George Dawson, MD, DFAPA





         

Billboard - Stigma or Not?

I don't know how I missed the controversy but the APA has vigorously criticized a billboard that sends a message about inadequate access to mental health services and inadequate gun control.  I found out about it only through the APA listserv yesterday.  The Psychiatric News alert can be viewed here.  The billboard can be seen on major news services like NBC here.   If anyone can spare a photo of this billboard please e-mail to me and I will post it in the body of this essay.  The message basically states "Over 40 million Americans with mental illness - some can access care - all can access guns."  It is signed by Kenneth Cole.  He has a history of activist billboards and Twitter posts and is no stranger to controversy.  He has also discussed raising his brand's profile through the social responsibility messages.  In this case some APA members were outraged at what they perceived to be a stigmatizing message.

My perspective is that the message on the billboard is accurate. There is nothing to be gained by suggesting that Mr. Cole is trying to state that most people with mental illness are dangerous.  But there is the issue of whether a professional organization should be commenting on what they perceive as a controversial billboard in the first place, especially when it may be used to promote a brand name.  In this era of social media and the current trend for public shaming, I would suggest that scoring points in that landscape is the last thing any professional organization should be doing.

The fact is that most acute care psychiatrists are making these kinds of assessments every day in the United States and multiple times a day.  The vast majority of people designated to have a mental illness on this billboard do not need to see psychiatrists.  Acknowledging the fact that psychiatrists are actively engaged in violence prevention and that a small but significant number of people with mental illness are violent and aggressive and that it is a treatable problem is a very important message.  The potential benefits include:

1. Less stigma for people who are violent and aggressive as a result of severe mental illness.  The current bias is to see this behavior was willful and punish them based on a moralistic approach to mental illness.  That is until the violent and aggressive person is a family member trying to harm other family members.  At that point, there is no myth of mental illness and all of the talk about how the mentally ill are not aggressive is meaningless.

2. Clearly define the problem and develop centers of excellence for treating this problem.  In every metro area in the U.S. there are a handful of acute care psychiatric units and even fewer who accept violent and aggressive patients.  All of the violent and aggressive patients are typically brought to one or two hospitals that are set up to address the problem.  Those hospitals have protocols in place to treat the problem and many of them do a lot of civil commitments.  There is no funding source that is adequate to provide the level of treatment for these patients who must be hospitalized until they are no longer dangerous.  They also require more intensive staffing patterns by staff who must have a much higher level of training than in less intensive situations.

3. A denial of the potential for violence and aggression is inconsistent with the recently released Practice Guidelines for the Psychiatric Evaluation of Adults, Third Edition.  That document has explicit commentary about the psychiatrist’s role in addressing aggression.  There are 41 references to aggression in the body of the paper including 13 bullet points on the Assessment of Risk For Aggressive Behavior (p 23).  There are thirteen references to firearms.

In my opinion, the assessment of violence and aggression that is typically done in crisis situations by psychiatrists is more extensive than what is captured in the guideline. As an example there is no discussion of transference or countertransference issues and how they affect the treatment team and their approach to the safe treatment of violent and aggressive patients.

4. A more clearly defined role among advocacy organizations is a better role for professionals. The political use of the term “stigma” is at times all encompassing and it obscures the real source of the problem. For example, stigma is not the reason why there are no services available for psychiatric care.  Managed care companies and the governments that subsidize them and sanctify their business tactics are the reason there are no services.  The APA has been talking about stigma for years and it has done absolutely nothing to increase services or stop the rationing.  The highly acclaimed parity legislation initiated by Senators Paul Wellstone and Pete Domenici has done nothing to break the chokehold on mental health by businesses and governments.  There is new legislation in the works to “enhance” the original parity legislation because it has no teeth and has not made a difference. Businesses do what they want with the blessing of state and federal governments.

5. In some cases advocacy organizations are at odds with clinical psychiatrists who are treating patients with severe mental illness and aggression.  One of the positions taken by at least one of these organizations is that psychiatrists could be easily replaced by “prescribers” in state hospitals where aggressive patients are sent.  The government in that case took the position that an administrator with no clinical experience could come into a state hospital setting and develop a program to treat patients with mental illness and violence and aggression.  That plan failed.

These are a few of the problems associated with denying the correlation between severe mental illness and violence and aggression in a subset of patients with severe mental illness. The reality is that there are thousands of psychiatrists that face these problems every day. Their goal is to keep people safe and prevent violence. Acknowledging what they do on a daily basis, supporting that work and the importance of that work to patients, families and the community is a step in the right direction.

Suggesting that it is too stigmatizing to discuss that issue is not a step in the right direction.




George Dawson, MD, DFAPA



Supplementary 1:    I contacted Kenneth Cole (the company) through the web site and asked them to send me an image of their billboard for use in this post.  I included a link to the post so the specifics could be read as well as the entire blog.  I was advised that although they appreciate my interest, the image was proprietary and therefore they could not send it to me.  I don't know if they are claiming that about every image or just the one I wanted them to send me.  It made me wonder if they are aware of how widespread the image is used on the Internet.

Supplementary 2:   I was graciously sent a photo of this billboard by a resident New Yorker.  I contacted Kenneth Cole again and was told again that I could not even use an independent photograph of their billboard for this post.  I really doubt that any place else displaying these billboard photos has gotten permission from them, but I am just a guy writing a blog and can't afford to get into it with them.  So there you have it.  Go to any one of the other hundreds of places on the Internet that have posted this picture to view it.

    

Happy Labor Day IV

This is my fourtth Labor Day writing this blog and it is my custom to summarize the work environment for physicians like I did in Happy Labor Day I, II, and III.  Things have not improved very much and there was a timely piece by an anonymous physician filed on another blog entitled Confessions of a Burnt Out Physician.  That post is full of anecdotes about physicians being managed like production workers and to the point of not even having an adequate work space to conduct work that requires focus and confidentiality.  Another key element of managing physicians is to make sure that their days and nights are filled with the modern equivalent of paperwork - e-mails and charting that is read by nobody except the occasional coding and billing staff.  If that is not demoralizing enough, there are always the suggestions that physicians are not doing enough, even though they are easily in the hospital for 4 or 5 hours after all of the business people are long gone.  This can all be handled masterfully.  As an example, the RVU productivity system was in many cases introduced to physicians as a system of "fairness".  That is - the idea that everyone has to pull their own weight.  That works very well in any environment of competitive physicians.  It was dovetailed in nicely with multimillion dollar lawsuits by the Department of Justice that were based on charting.  Now physicians could be fined or imprisoned if their documentation was not up to snuff.  And of course the Department of Justice wanted every physician in this country to know that any discussion of fees was a potential antitrust offense.  When all of that business rhetoric had settled out, the only things that really changed was how easily physicians could be manipulated and overworked while their professionalism was completely ignored.  Apparently none of us knew how to work or act before managed care came along.

There have been some additional business innovations in the last year to make physician's lives even more difficult.  I read another blog recently where the topic of physician managers affiliated with Big Pharma were desired to bring money into departments and how that and key opinion leaders (KOLs) from that field was a key corrupting influence in medicine and psychiatry.  That influence is trivial compared with the business influences on medicine and their adverse effects.  Excellent clinicians, teachers and researchers now need to get an MBA before they are considered as a department head.  A managerial class that is progressively less competent to manage may be an acceptable business standard but it seems like an extravagance in medicine and one that has cost us hundreds billions of dollars and untold unnecessary work for physicians.

Furthermore, we know what works in terms of physician management.  I worked in tens of departments where the department head was a physician who was in that position because of skills pertaining to clinical care, teaching and research.  That doesn't mean that they were necessarily easy to get along with, but in teaching institutions their skill set was on display every day.  That model transitioned to one where a physician and an administrator of some type both co-lead the department.  The physician leader was still affiliated with physicians in the field at that point and could feel their pain.  The next step was removing any physician with those alliances from an administrative position.  In many cases, this meant people who had no hesitation to manipulate physicians either by a "It's my way of the highway" attitude,  making the environment so hostile that they forced selected dissenting physicians to quit, or after pretending that the physicians had some input (usually through endless mind-numbing meetings about the business) simply telling them that no matter what their opinion was - this was what would be happening.  Throughout the process there was an endless stream of "Change is good", "Cost effectiveness", and "Managed care friendly" propaganda.  But it didn't stop there.  Managed care run institutions have an entire cadre of case managers whose primary job is to "manage" physicians and make sure they are discharging people according to the companies proprietary standards.  If there are any disagreements that low level administrator can easily go up the change of command to get decisions in their favor or identify physicians who are not in lock step with the company.  Everywhere within these organizations there are rules about identifying "disruptive physicians" and penalizing them.  I am not talking about doctors throwing scalpels across the operating room.  The threshold can be so low these days that a "disruptive physician" is anyone who gets into it with an administrator for any reason, including legitimate disagreements.

The effect on the psychological environment of physicians has been corrosive.  Within a generation we have gone from a training environment where medical students and residents could identify with senior physicians who embodied professionalism and an intellectual approach to medicine to managed care employees who use a business approach.  Instead of rounding on patients and learning the importance of medicine as a life-long intellectual pursuit, trainees are focused on the business manager's pursuit of getting patients out of the hospital so that corporate America can keep making money by easily beating the fixed reimbursement scheme set up by the government.   The business rationalization has always been "of course we need to make money to keep the doors open", but that never addresses the trade-offs.  In this case the trade-off is no relationship or plan to assist the patient.  In the case of patients with psychiatric disorders, there are inadequate inpatient and outpatient services, both due to business rationing to maintain profits in a rationed and cost-shifted world.  In many cases health care systems have carried these plans to their absurd conclusion - just close any inpatient beds, close the outpatient clinics, and hope that some taxpayer funded clinic or jail can pick up the slack.  The typical health care manager has an endless stream of bad ideas.

Are there any bright lights on the horizon?  I think that there are.  I would count the movements against the medical specialty boards and the proposed maintenance of certification (MOC) programs.  It is very positive that physicians are standing up and saying that they are unnecessary, not evidence based, and a tremendous waste of time, money, and resources.  More importantly all of that stress falls squarely on overworked physicians.  There is now at least one parallel certification organization that depends primarily on initial board certification and then continuing medical education courses - the historical standard.  It will take a significant commitment, especially from younger physicians to keep this movement alive because it is just a matter of time before credentialing committees for clinics and hospitals will be putting the squeeze on their physicians to use the labor intensive MOC programs.  There is also the question of medical boards.  Will they require MOC for maintenance of licensure (MOL)?  Only time will tell, but like all things American - the bet is on the oligarchs and that currently is everyone making a lot of money out of managing physicians.  At some level that includes professional organizations populated by members who are very friendly to the business world.  If anyone doubts the benefits to professional organizations, just visit the American Psychiatric Associations Learning Center and the MOC offerings.  If the monopoly can be broken, it suggests that physicians may have the ability to counter the business and government strategies that keep what is basically an anti-physician system afloat.  Business strategies have nothing to do with the practice of medicine.

Another bright light that I neglected to comment on initially is the young psychiatrists going into private practice.  At first I was reluctant to endorse this idea, primarily because it contrasts so starkly with my experience in community psychiatry, acute care psychiatry, and general hospital psychiatry.  I was concerned that there would not be enough psychiatric expertise to care for very ill people.  But in conversations with many young colleagues they are some of the brightest, happiest, and enthusiastic physicians that I have seen.  The reason I am given by these docs is that they decide who they are going to see and what their schedule is and not some administrator.  They decide what their clinic policies are and not some administrator.  Some of them have worked in managed care settings and had the courage to walk away after the standard "performance evaluation", especially when it had become an exercise in a loyalty oath to the company and trying to dredge up anonymous critical remarks from coworkers.  My opinion on this private practice trend is that it is a good one.  Any person consulting these folks is going to get recommendations based on quality psychiatric care and not proprietary managed care guidelines.  They will also be talking with a psychiatrist who has not seen ten other people before them and one who has the energy to focus on their problems and possible solutions.  Some of these private physicians also spend days in community mental health centers and on community support teams - treating patients with severe problems.      

So my fourth Labor Day message is slightly brighter than the last three, but not much.   I have to say that there are a few of us around yet who know exactly what happened and what is possible -  and I feel your pain.  If you feel up to it post your anonymous story here.


George Dawson, MD, DFAPA

Patentable Biomarkers of Suicide

From: Understanding and predicting suicidality using a combined genomic and clinical risk assessment approach (reference 1 with permission).

One of the most interesting aspects of biological psychiatry is the attempt to characterize complex biological systems.  It may not have been apparent but complex biological systems factored in a recent post about bronchitis.  Lungs are certainly complex with two different blood supplies and complicated immunology, but the lungs are not thinking organs.  They don't come up with any secondary concepts that need to be analyzed as possible derivatives of the biological substrate.  And even then, basic syndromes that we all learned about in medical school and in clinical rotations, defy more useful classifications.  I have previously posted on endophenotypes and their usefulness in the treatment of asthma and only recently noted that they have proliferated to include an obese endophenotype and how that affects response to therapy.  Diagnostic and treatment approaches to asthma and bronchitis are necessarily crude, largely because the biological complexity in these processes is not fully appreciated and addressed.

The brain is certainly the most complex organ in the body.  Cellular arrays in the brain produce a stream of consciousness, robust unconscious processing, unique conscious states, and all forms of emotional, social and intellectual constructs that can be observed, monitored, and changed.  That brings me to a paper from Molecular Psychiatry on possible biomarkers for suicide.  Not just any paper - at this point it is the most downloaded paper from the top-ranked psychiatry journal (1/140) in the world.  Molecular Psychiatry has an impact factor of 14.496 and that is the highest impact factor of all psychiatry journals.  In part that is probably driven by how absurdly expensive that similar journals like Biological Psychiatry are or other barriers to purchase like needing to be a member of the sponsoring society.  This is a public access journal that uses Creative Commons Licenses for their content.  The authors in this case have provided a 20 pages article and 124 pages in Supplemental Information.

The idea of a biomarker for suicide is very attractive to psychiatrists, because assessing suicide risk is a big part of what we do.  Current clinical guidelines suggest that we need to make that assessment at every patient visit.  The actual prediction of suicide is difficult due to the fact that mental states change over time and people may not be able to communicate their true level of risk.  I have had people tell me in retrospect that they lied about their degree of suicidal thinking and level of control when I asked them about it.  I have had acute care colleagues tell me that they were weary of having to guess about whether a person was going to try to kill themselves or not - many times a day.  The assessment is further complicated by a lack of acceptable acute care options that may further hinder complete self disclosure.  A biomarker would potentially be beneficial.  I qualify that by the fact that the dexamethasone suppression test was once considered a biomarker of suicide (1), but these days it is rarely done and certainly not as part of a suicide assessment.  A study by Coryell, et al (9) notes that the DST was not able to differentiate patients who died from suicide or cardiovascular disease when long term mortality was determined by the National Death Index.  Those authors suggest it may be useful as a predictor of suicide only in patients with depression.

In this article the authors take a look at possible biomarkers in blood that could predict both suicide and some associated markers like risk of hospitalization.  There is a lot going on in this paper.  All the research participants were men.  They studied four different patient cohorts including 217 patients followed longitudinally.  This group was called the Discovery Cohort because markers were discovered based on 37 patients who had a switch from a no suicide state to a high suicide state defined as a score of 2 - 4 on the HAMD question about suicide.  26 deceased patients who committed suicide were used to validate the initial markers.  Two psychiatric cohorts of 108 and 157 to look at prediction of suicidal ideation and hospitalization with the chosen tests.  The flow of these experiments in depicted in the graphic at the top of this post from the original paper.  In the diagram, the designations AP (absent-present) and DE (differential expression) are techniques to capturing genes that are turning of and turning on and off and gradual  changes in gene expression.  The respective genes in this analysis are color-coded based on those properties.  The Convergent Functional Genomic (CFG) Approach is depicted in the box.  Candidate genes are ranked in the triangles according to CFG score.  The CFG score was the sum of various weighted factors including evidence of human brain expression, evidence of human peripheral presence, human genetic evidence and linkage with weighted scores in the CFG box.  Using their discovery and validation sequence the authors were able to pare down the total number of genes down from 412 to 208 to 143 and ultimately to 76 genes.  The supplementary information provides the validation of biomarkers and a table that looks at each gene and prior human genetic evidence, prior evidence of brain expression and prior human evidence of peripheral expression.

The authors discussion of the biological relevance of their findings was interesting.  They did pathway analysis looking at Ingenuity, KEGG, and GeneGO databases.  Of these only the Kyoto Encyclopedia of Genes and Genomes (KEGG) is publicly available without a subscription fee.  It is very useful to know about KEGG because of the relevance of pathway analysis in the psychiatric literature.  As an example, I have been teaching about the mTOR pathway discussed in this article in my neurobiology of addiction lectures for the past 4 years.    

This article is very interesting and can be read at  several levels.  It is premature to consider it definitive at this point and based on this paper and the work of the associated lab these authors are working on additional validation strategies.  If they are  correct,  suicidality may be captured in time as a polygenic event based on a combination of genes that are turned off and on and others that gradually change.  I titled this post as "patentable genes" because the only conflict of interest cited is the lead author is listed as an inventor on a patent application being filed by Indiana University.  For trainees and early career psychiatrists a familiarity with this technology and its potential uses and limitations would be one of the reading goals and including Molecular Psychiatry and its sister journal from the same group Translational Psychiatry (8) is probably a good idea.  Both are potentially good sources of neuroscientific information in psychiatry and if popularity is any indication - fill a niche in the field.  Some of the tools that they developed along the way are useful to think about from a clinical perspective (4, 5).  The thought that the CFI-S Scale was particularly interesting because it is a 22 point binary scale that looks at factors (excluding suicidal ideation) that they determined to be important.  The factors are also classified as to whether they represent increased reasons (IR) or decreased barriers (DB) to suicide.  The emphasis on suicide as a discrete syndrome independent of diagnosis is a research strategy that has been called for recently based on the need to come up with better ways to diagnose and treat the problem.  In a clinical setting I think that clinicians are still frequently surprised by suicide attempts and suicides being able to determine if a patient is in a high risk state based on a blood test independent of their clinical presentation and statements would be useful both in terms of the test but also the associated dialogue.

What I really like about this paper is that it is an attempt to deal with a common psychiatric problem at the appropriate level of complexity.  Clinical trials do exactly the opposite.  As an example, clinical trials in psychiatry will look at heterogeneous groups of patients pulled together under a vague diagnostic category.  There may be rating scales or global ratings just because the rating scales don't seem to have much discriminatory power.  In the end, the entire study is generally collapsed for a very simple statistical analysis.  Getting to those final variables and what has been ignored in the process is always the critical question.  I think it is trendy these days to commiserate about the fact that there are inconclusive, weak and non-reproducible results from the standard clinical trials technology.  I don't know why anyone would expect a different result.  If anything this paper illustrates that a lot of biological information can be considered and analyzed.  The popularity of this paper leaves me hopeful that this is a positive trend for the future.            


George Dawson, MD, DFAPA


References:

1:  Niculescu AB, Levey DF, Phalen PL, Le-Niculescu H, Dainton HD, Jain N,Belanger E, James A, George S, Weber H, Graham DL, Schweitzer R, Ladd TB, Learman R, Niculescu EM, Vanipenta NP, Khan FN, Mullen J, Shankar G, Cook S, Humbert C, Ballew A, Yard M, Gelbart T, Shekhar A, Schork NJ, Kurian SM, Sandusky GE, Salomon DR. Understanding and predicting suicidality using a combined genomic and clinical risk assessment approach. Mol Psychiatry. 2015 Aug 18. doi: 10.1038/mp.2015.112. [Epub ahead of print] PubMed PMID: 26283638.

2:   Lee BH, Kim YK. Potential peripheral biological predictors of suicidal behavior in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Jun 1;35(4):842-7. doi: 10.1016/j.pnpbp.2010.08.001. Epub 2010 Aug 11. Review. PubMed PMID: 20708058.

3:   Collection of references for biomarkers in suicide.

4:  Simplified Affective State Scale (SASS).

5:  Convergent Functional Information for Suicide (CFI-S) Scale.

6:  Laboratory of Neurophenomics Web Site.

7.  Niculescu AB Medline Collection on additional convergent functional genomics references.

8.  Translational Psychiatry Web Site.

9.  Coryell W, Young E, Carroll B.  Hyperactivity of thehypothalamic-pituitary-adrenal axis and mortality in major depressive disorder.  Psychiatry Res. 2006 May 30;142(1):99-104. Epub 2006 Apr 21. PubMed PMID: 16631257.

Attribution:

The figure at the top of the post is from the original article listed completely in reference 1 under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License.  To view the condition of that license view it here.

Supplementary:

1.  There is a Mayo Clinic Conference coming up this fall for anyone interested in translational approaches to psychiatric disorders and addictions.  Further information is available at this web site.

2.  There is also the 3rd Annual Update and Advances in Psychiatry conference at the US Madison and one of presentations is by Daniel Weinberger, MD on the neuroscience of schizophrenia and psychotic disorders.   Information on that conference and the conference brochure is available at this web site.

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.