Sunday, November 22, 2015

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


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.

Saturday, November 21, 2015


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

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

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

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

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

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

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

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

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

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

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

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

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

George Dawson, MD, DFAPA


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

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

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

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

Sunday, November 15, 2015

APA Misses On The Opioid Crisis - Several Times

The above infographic is courtesy of the CDC (see attribution for the direct link).  To those of us involved in treating addictions talking with many people who are addicted to opioids, getting them to see the problem, and helping them prevent accidental overdoses and death is an everyday occurrence.  The prescription opioid problem is widespread and has been a reality for the last 15 years even though it seems to have hit the news in about the last 5.  That probably coincides with heroin use starting to escalate.  The driving force for that has been economics.  Heroin is generally available in most areas for about a quarter the cost of diverted prescription painkillers.  In the past 5 years I have probably given about 50 lectures on the topic to physicians and graduate students and been actively involved in the clinical care of individuals with heroin addiction only or heroin addiction in addition to a number of other addictions.

When I got a post from the American Psychiatric Association (APA) on my Facebook feed last week it piqued my interest.  Part of what I teach is how failed policy is the root cause of the opioid epidemic and what physicians can do on an individual basis to correct the problem.  I was very interested to see what the APA had to say at a policy level.  Reading through the document that is really a blog post from the Medical Director the answer is "not much".  It appears that the APA has joined a Task Force of other professional organizations that includes that other great laggard the AMA.  They will be working to identify "best practices" and implementing them as soon as possible. Using Prescription Drug Monitoring Programs (PDMPs) is encouraged.  There will also be the focus on stigma.  Dr Levin states: "The APA maintains that substance use disorder is a medical condition that can be successfully treated, and we are actively advocating on behalf of the patients who are too often stigmatized by their community and disenfranchised by insurance carriers who fail to comply with mental health parity laws."

While there is no doubt that most people are biased against people with mental illness and addictions as well as their psychiatrists - I don't think that stigma has any traction in terms of increasing access to care or more importantly access to quality care.  I could argue that the APA support for the collaborative care initiative colludes with stigma-like biases.  That takes the form of "you don't have to see a psychiatrist - take this checklist instead."  I won't get into that today, only to say that I wonder how many people with heroin or opioid addiction are being seen in primary care clinics and being treated for anxiety, insomnia, or depression?  From what I see the numbers are significant.  But it is hard to fault primary care doctors because unless they are the prescribers of opioids, they may not realize that their patient has a problem with them.  There is also the issue of institutional stigma versus public stigma.  Public stigma or the type of stigma that everyday people have is more elastic and it usually depends on their experience with the problem.  If you live in a family where a member has a severe mental illness or addiction - you know that these problems are real, life-threatening, and you are ready to let people know that.  Institutional stigma is the type of stigma that governments and businesses can have, especially health care businesses.  They might grudgingly admit that there is some kind of problem largely because there is such a large secondary impact on medical and surgical services.  In some trauma centers over half of all admissions are primarily due to drug and alcohol problems.  At the same time,  institutional stigma is impervious to change.  It is codified in some texts on healthcare management and as noted in the APA blog post - not even amenable to change when new federal parity laws are implemented.  In terms of managing health care systems there is nothing like having a certain groups of disorders to shift resources away from in a pinch.  Mental illnesses and substance use disorders are that group.  The other considerations would include:

1.  Irrational policy initiatives:  There is no doubt that several policy initiatives to liberalize opioid prescribing were responsible for the start of this epidemic in or around the year 2000.  Making pain the "fifth vital sign", encouraging the use of opioids for chronic non-cancer pain, treating minor conditions with opioids, and a widespread policy initiative that encourage more aggressive treatment of pain even though specific measures were not know are among these initiatives.  I use the word irrational here to mean speculative initiatives that were not based on science.

2.  A serious misunderstanding of the current problem:  When all else fails blame physicians.  That is a highly effective political strategy that worked to consolidate control of the health care system under business and government.  To many of the politicians involved it flowed directly from their negative campaigning experiences.  In this case, the opioid problem is being framed at some level as a problem of inappropriate prescribing by physicians.  Some physicians are being subjected to criminal prosecution for deaths and complications that have resulted from opioid prescribing.  There are no references to the policy changes that occurred in the late 1990's that led to this change in physician prescribing behavior - the loss of gate keep functions in particular.

3.  A misunderstanding of the epidemiology of the problem: The upper decile of opioid prescribers (total number of prescriptions) account for 50-60% of all opioid prescriptions.  These prescribers are almost all family physicians, internal medicine specialists, and mid-level prescribers.  Available databases allow for rapid identification and intervention with these prescribers and that is where resources should be focused and not on all physicians across the board.  A mechanism for feedback on an individual physician's or physician extender's ranking in terms of their prescription of controlled substances is needed as well as individual access to that information.

4.  A serious misunderstanding for the overprescribing problem in general exists: As I have previously pointed out, opioids are one small group of medications that are overprescribed in the US.  Practically everyone who wants this problem to go away sees it as a cognitive problem or knowledge deficit.  If the physician involved just knew more they would not prescribe pain medications this way.  In fact, it is a much more complicated interpersonal, social and intrapsychic problem for physicians.  Until there is a widespread acknowledgement of this - all of the CME courses in the world on appropriate opioid prescribing will not change a thing.

5.  There is a widespread cultural problem:  Opioid hoarding in medicine cabinets across the country, neighbors sharing opioids and neighbors and family members discussing what is the best (translation best = most euphorigenic) is a major problem in the US.  Many politicians have agreed that America's "insatiable appetite for illegal drugs" fuels the international drug trafficking problem.  It also fuels the opioid epidemic.  There are very few initiatives focusing on cultural change.

6.  Misunderstanding the problems inherent in prescribing addictive drugs:  Most physicians are not aware of the unconscious and conscious elements that are activated in susceptible individuals when they take addictive drugs.  There are widespread misconceptions in this area that lead to the prescription of addictive drugs during active addiction,  not assessing the risk of prescribing addictive drugs to a person in recovery, and failing to assess some of the indirect signs of addiction in patients who deny that they have a problem with addiction.  There is also a belief among many physicians that if their goal is to help people that well intended prescribing will not lead to problems in the future.  

These are 6 areas that the APA could be focused on.  I don't think that you will see that analysis anywhere else.  I expect that "best practices" will fall disproportionately on the average physician and be a waste of time on their time and energy.  But it does fall back on the time honored political strategy of taking the heat off of the people who really failed and pretending it is a physician based problem.

George Dawson, MD, DFAPA


The infographic is from the CDC at this URL:

The CDC has done great work in this area and their site should be closely monitored for new data relevant to the problem.

Saturday, November 14, 2015

Reductionism Is Not A Dirty Word...

A recent opinion piece in the New York Times, by George Makari, MD has me shaking my head.  The thesis was that a recent headline grabbing story (what's wrong with that criteria?) on the effects of comprehensive treatment of psychosis as opposed to treatment as usual surprised many and highlighted the problem with reductionism.  He bemoans the fact that the reaction to the story was one of surprise.  He doesn't specify who was surprised.  I certainly was not surprised.  I attended recent meeting and somebody in the audience asked Daniel Weinberger if he was surprised.  His response: "They spent $15 million dollars showing that good treatment is better than bad treatment."    He certainly was not surprised.  I have not heard about Eric Kandel's response, but based on his 1979 paper on plasticity and what happens in psychotherapy - I doubt that he would be surprised.  The exact population of who might be surprised by these findings seems poorly defined at this point in time but I doubt that it included any psychiatrists.

Speaking for myself, I will elaborate on why I was not be surprised.  At one point, I was the Medical Director of a community support program of a group of about 100 outpatients in the State of Wisconsin.  According to the state statutes, access to the program depended on diagnosis and degree of psychiatric disability.  You could only apply if you had a diagnosis of Bipolar Disorder, Major Depression, Schizophrenia,  or Borderline Personality Disorder had significant associated disability or were at high risk for hospitalization.  The clinical goal of the program was to reduce hospitalizations, maintain independent living, and facilitate employment.  The program was staffed by a psychologist, 2 social workers, three nurses and me.  When I arrived, one of the early dynamics was to frame problems in terms of medication needs.  That translated to increasing the dose of a medication (typically an antidepressant or antipsychotic) in crisis situations or other emotional crises.  The patients in the program had chronic problems and symptoms that did not necessarily respond to medication.  One of my first steps was to start to discuss problems and solutions with the patients.  I met with all of the patients and did supportive psychotherapy when possible.  We had team meetings every morning and problem solved around the needs of the patients in the community, how to solve any crises, and how to approach people in ways other than medications.  I tracked the total dose of antipsychotic medication and days of hospitalization as outcome measures.  At the end of three years, the days in hospital had gone down from about 14 days per person to less than 1, and the total dose of antipsychotic medication had gone down a total of 600 mg chlorpromazine equivalents.

My point is obviously that comprehensive care of patients with severe problems results in improved outcomes.  In this case lower doses of medications were used and the patients spent less time in the hospital and more time at home.  My orientation and ability to implement such a program was not an accident.  I was trained by Len Stein, MD at the University of Wisconsin.  Dr. Stein was a pioneer in the area defined as community psychiatry.  He was motivated by realizing that once people were in large state hospitals - it was very easy to warehouse them in overcrowded conditions.  Nobody seems to recognize it but overcrowding and suboptimal conditions were the state hospital equivalent of managed care rationing.  Once your state hospital is on the spreadsheet of a state bean counter with no accountability to patients or their families rationing and fewer and fewer resources are the order of the day.   In a community psychiatry seminar, Dr. Stein projected a slide of a gymnasium-sized room populated by male patients with hundreds of cots aligned edge to edge.  There was no room to walk between the cots.  That was his motivation for moving people out of these state facilities and into their own housing.  When I trained, there were three programs with independent living and quality of life as the primary goals and the staff involved in the programs was very good at it.  My effort just extended that skill set.  Contrary to the "surprising" results of the quoted study - I did the same thing back in 1986!

If it is true that we have known for 30 years that comprehensive care for psychiatric disorders trumps "treatment as usual" what is all of the rhetoric about?  Dr. Makari seems to want to make this into a mind-brain argument.  In other words, the biopsychosocial approach and the uncertain effect it has on the mind as opposed to a brain based approach that looks at specific mechanisms of action and seems to be focused on psychopharmacology.  He points out for example that the highlighted study would possible not qualify for current NIMH funding unless it looked at specific brain mechanisms.  He throws around the word "reductionism".  Anytime reductionistic or reductionism is used rhetorically in the same sentence with psychiatry it is pejorative.  My old psychoanalytic teacher would refer to anyone who talked about brain biology as a "dial twister".  The implication is that the reductionists are somewhat simple minded largely because they cannot accept the uncertainty of dealing with an organ that has poorly defined inputs and outputs.  Kind of a double whammy of rhetoric - you are a unsophisticated reductionist and you really can't see the big picture.  Are things really that simple?  Are these arguments accurate?  Are there problems with equating reductionism with "bad".

Of course there are major problems.  The first is the statement that inherent to the proposition that mental illness is a brain disease is "the implication that psychological and social events somehow are not also brain events."  This is a serious misreading of the definition of plasticity or experience dependent changes in the brain.  When I give my neurobiology of the brain lectures. I use Kandel's original New England Journal of Medicine article that discusses brain changes in a patient and a therapist conducting psychotherapy and how those changes are associated with brain plasticity.  I give further examples - weightlifting,  playing the violin, and how the typical stream of consciousness is profoundly altered by drug addiction.  There is no neuroscientist or biological psychiatrist I know who would suggest that psychological and social events are not brain events and there are numerous experimental paradigms that look specifically at how these events occur in the brains of animals.

The second aspect of Dr. Makari's argument has to do with reductionism.  His specific comment is:

"With luck, studies like Dr. Kane’s, which undermine these suppositions, will help move us away from such narrow thinking and embolden the substantial community within psychiatry that has never accepted such reductionism."

The suppositions in this case are that mental illness is a brain disease and that social or psychological events have no brain representation.  The argument is based on that false premise.  But further the use of the term "reductionism" is instructive here as previously noted.  By definition reductionism applies to many proposed etiologies of psychiatric disorders.  Those etiologies can be studied at a molecular level or at a higher level.  Schaffer (2) says that a model is reductive if it "employs standard biochemical and molecular entities to account for psychiatric symptoms and disorders".  Non-reductive models discuss "causal connections at higher levels of aggregation."  He illustrates these definitions by looking at Kendler's non-reductive account of major depression.  Kendler has used path analysis to look at clinical variables relevant to psychiatric disorders and although I do not have access to the one used in the book, here is a typical example.  The model looks at life stages, familial factors and psychological factors and all are higher levels of aggregation than molecular mechanisms.  At the reductive side of things he examines Harrison and Weinberger's proposed genetic susceptibility genes for schizophrenia.  At the time the book was written the author limited the discussion to 5 genes.  He also looked at the continuum of psychiatric genetic models ranging from basic and advanced genetic epidemiology being non-reductive, gene finding partially reductive, and molecular genetics fully reductive.  It seems perfectly logical to me that the study of brain biology proceeds in the same way that the biology of all living organisms proceeds.  The difference is that we are studying an infinitely more plastic organ with significant computational power.  There is clearly a lot of phenotypic heterogeneity that is unexplained in psychiatric diagnostic categories.  It is highly unlikely that refining diagnostic descriptors or applying clinical methods will lead to any significant change in the diagnostic or treatment process.  I don't understand the reluctance to go after more specific mechanisms or treatments.

The idea that a molecular or clinical focus in psychiatry is the problem with psychiatric services is also misleading.  As I hoped to point out by my mental health center example, psychiatrists know all about comprehensive care but they are rarely able to provide it.  They have known about how to provide it for decades.  State asylums became overcrowded and not therapeutic due to the financial management of the system by state governments.  The bean counters have moved out of the asylum and they are now integrated at every level in the health care system.  They all have a very strong bias against the comprehensive treatment of mental illness.  They insist that patients with severe psychiatric problems do not get comprehensive evaluations, that they are discharged before they have been adequately treated, and that any associated addictions are poorly treated.  They do not have the same biases against people hospitalized for medical or surgical illnesses.  They have in effect, moved the poorly run, overcrowded asylum model into the general health care system.  Any comprehensive care for severe mental disorders in such a system is an advertising phenomenon rather than reality.

The reductionism argument is good for New York Times opinion pieces.  It may sell a few more papers or get a few more clicks online.  Unfortunately it perpetuates an old pattern of blaming people and psychiatrists in particular for the shortcomings of a non-system of mental health care in this country that is set up to favor large health care businesses.  You can blame psychiatrists all you want for that - but until people realize that the real problems are the product of business and politics - and not the scientific interests of psychiatrists - nothing will change.

George Dawson, MD, DFAPA


1.   George Makari.  Psychiatry’s Mind-Brain Problem.  New York Times.  November 11, 2015.

2.  Scaffner KF.  Etiological Models in Psychiatry - Reductive and Nonreductive Approaches in  Philosophical Issues in Psychiatry.  Kenneth Kendler, Josef Parnas (Eds), The Johns Hopkins University Press, Baltimore, 2008:  pp 48-98.


Image is Microscope 1 by Bill3t Hughes on Flickr.  Reposted as noncommercial via Creative Commons License on 11/14/2015.  The original work is not modified.

Saturday, November 7, 2015

The Myth of "Rescue" Medications

First off a clarification.  I am talking about the specific case where a short acting medication is added to a long acting form of the same medication and not "as needed" medication in order to determine the correct daily dosage.   In my line of work it occurs in two situations, long acting stimulants and their immediate release versions and long acting opioids and their immediate release versions.  I will illustrate that these practices are driven by myths about the medication rather than pharmacokinetics.  There is always the additional consideration about addiction lurking in the background, but the conscious and unconscious determinants of addiction frequently depend on the myths that I will be discussing about medication effects.

The example that I will use here is Concerta (long acting methylphenidate) compared with immediate release methylphenidate.  The graph from the package insert above shows the plasma concentration from a single 18 mg dose of Concerta and three successive 5 mg doses of immediate release methylphenidate.  As noted in the comparison of the curves and additional pharmacokinetic parameters the curve associated with three successive doses of immediate release methylphenidate is nearly identically replicated by a single dose of Concerta.

What is happening when additional doses of a immediate release methylphenidate are prescribed to a person who is already taking Concerta?  I  have seen this happen with sustained release stimulants and sustained release opioids.  I have seen it happen as a single dose of the immediate release preparation or multiple doses over the course of the day.  The patient is usually advised that this is a "rescue" medication that they should take if needed.  The first possibility is that the dose of sustained release medication has not been optimized and a higher dose of the sustained release medication needs to be given.  That is usually not the case.  The most frequent reason for taking the rescue medication is that the patient believes they are experiencing breakthrough symptoms and for a moment they need a higher dose of a medication.  There are serious problems with that concept.  As can be seen from the curves comparing Concerta and methylphenidate it does not make pharmacokinetic sense.  Any additional dose of immediate release methylphenidate on top of Concerta would greatly increase the expected plasma concentration at that point.

The main problem is that both ADHD and non-cancer pain are chronic conditions.  By definition they do not respond well to medications and they will not resolve typically with any amount of the medication.  Many people who take stimulants for ADHD assume that the human brain can be fine tuned with a medication.  There is also a widespread myth that they are cognitive performance enhancing drugs.  The real effects of stimulants are modest at best and there is no good research evidence to support a cognitive enhancing effect.  A similar bias exists for the use of opioids for chronic non-cancer pain.  The person believes that "If I take enough of this medication - my pain will be gone."  Study after study of opioids for chronic non-cancer pain shows that pain relief with opioids is modest at best, with results very similar to what would be expected with non-opioid medications like gabapentin and antidepressants.

There are secondary problems with believing a medication will produce perfect cognition or perfect pain relief.  The first is a tendency to see any medication with such powerful abilities as being able to solve a number of problems that are not the primary indication for the medication.  As an example, with a stimulant - if this medication has such a profound effect on my cognition maybe it can help with with other difficult problems like excessive appetite and weight problems or feeling like I don't have enough energy at certain times during the day.  With the opioid the  thought typically is that it can be used for mental pain as well as physical pain and it is used to treat anxiety, depression, and insomnia.  Whenever a medication is not used strictly for the prescribed indication there is a risk that it will be used for "what ails you."  The danger is dose escalation and addiction.  There is also the risk of attributing too much of an effect to the medication when it does not appear to be doing much.  A person may start to believe that they can't function without the medication but a detailed review of their target symptoms and ability to function shows that there has been a negligible effect.  And finally there is the danger of taking a medication that may produce euphoria, increased energy, and create a sense of well being and not realizing that at some point that is the only reason the medication is being taken.  I have had many people tell me that the medicine did nothing for their pain or cognition but that they kept getting refills because they "liked taking it."

The is also the Talisman effect, but probably to a lesser extent than with benzodiazepines.  Many people develop the idea that they are taking a medication that is much more effective than it really is and therefore they have to take it with them wherever they go.  They are conferring what are essentially magical properties to the medication and at some level thinking that they are unable to function in life without it.  They get anxious if they think about not having it or running out.  This not only causes a lot of unnecessary anxiety, but it also prevents the person from using other psychological or conditioning techniques that may work as well or much better than the medication.

These are some of the problems with the idea of taking a rescue medication if you are already on a long-acting form of the medicine.  Physicians in general do not do a good job of explaining these potential problems or even the basic problem of taking a medication that causes euphoria or that for some other reason a person really likes taking for a reason other than the one it was prescribed for.  A more widespread recognition of these problems would go a long way toward curbing overprescription, overuse, and addiction to these medications.    

George Dawson, MD, DFAPA


1.  Graph of plasma concentrations of Concerta and methylphenidate is from the package insert on FDA web site at:

Monday, November 2, 2015

Minnesota's Mental Health Crisis - The Logical Conclusion of 30 years of Rationing

It is clear to me that Minnesota doesn't want to hear from any psychiatrists.  Psychiatrists in this state have been complaining about managed care, prior authorization of medications and hospital treatment, managed care medical necessity criteria and mismanagement of the state mental health systems by the State of Minnesota for as long as I have worked here and that is now 27 years.  All of that work at various levels has basically been ignored by the politicians and responsible bureaucrats in this state who are quite happy to address the problems of severe mental illness by progressive rationing at all levels.  That is their only response.  This march toward the managed care approach to mental health has been inexorable and has resulted in major problems with access and quality of care.

I have been writing in various formats about the problem of mismanaging acute care beds in Minnesota for at least 15 years.  What do I mean about mismanagement?  The problem started in the late 1980s when the state of Minnesota gave carte blanche to one of the local insurance companies to start denying alcohol and drug related admissions to inpatient psychiatric units.  Anyone with a sparse knowledge of addiction knows that about 70% of people with addictions have significant psychiatric morbidity and many are at much higher risk of aggression or suicide if intoxicated.  That was not enough of a deterrent to prevent this insurance company (with full collusion of the State) to start denying psychiatric admissions to anyone with an addiction or eventually to anyone with acute alcohol or drug intoxication.  The effects of those denials filtered through the entire acute care system and eventually intoxicated people were held in emergency departments until they were less intoxicated, sent to county detox units where they got no medical or psychiatric care, sent to jail, or discharged to the street.  In some cases people were discharged to the street with a bottle of benzodiazepines and expected to manage their own detoxification.  Many of those patients take the entire bottle the first day.  None of those pathways leads to sobriety or treatment of associated medical and psychiatric conditions and it is not an acceptable level of medical care.

Treatment of mental health conditions has fared no better.  At some point the vague concept of "dangerousness" became the only reason that a person with a severe mental illness could be hospitalized.  In some cases it was a "dangerous enough" standard.  In other words if you happened to have chronic suicidal ideation or self injurious behavior, the gatekeeper (who is usually an emergency department (ED) social worker) has to decide if you are dangerous enough to admit.  That combined with bed availability, other persons needing admission, the availability of psychiatrists to cover the beds, any associated intoxication states, and even the likelihood that a probate court would hold or commit the person led to a gauntlet that even outpatient psychiatrists could not negotiate.  Outpatient psychiatrists from the same clinic could not admit their outpatients to hospitals run by their colleagues.  That led to more and more psychiatrists advising patients and their families to just go the the ED and "let them sort it out."  The ED provides no psychiatric care - only a triage decision on admissions.  This quasi-system of care results in a large circulating pool of people who are never stable, at risk for incarceration or victimization, and who never receive standard care for their problems.

The unstated toll that this chaotic system takes is on the psychiatrists and nursing staff who work in it.  They are frequently the first ones to be blamed for a lack of beds and timely discharges.  A completely unrealistic bed situation becomes a psychiatrist not discharging people soon enough.  Psychiatrists and nursing staff end up treating the consequences of patients being held too long in hospitals that are not equipped to be long term care hospitals.  Patients and family members can become frustrated or irate as a result of this situation and the only people to blame are not the people who caused the problem in the first place.

The quasi-system of mental health care was well described by Karl Olsen, a Hennepin County Crisis Intervention nurse in the Star Tribune about three weeks ago.  He describes the backlog of patients in the ED and crisis centers due to a lack of psychiatric beds.  He describes the risk to both the patients and staff in this setting as well as the impossibility of trying to provide care that can only occur in a hospital setting in an emergency department or crisis unit.  But most of all, he describes the ongoing active discrimination against people with severe mental illnesses by insurance companies and the state.  A more recent article is written by a reporter interviewing a state bureaucrat who reports that the situation is "the worst I have seen it in 20 years."  How can representatives of the State get away with these remarks when the State of Minnesota is largely responsible for the problem?  The article describes the lack of beds in State hospital facilities as being the problem and the State has made no secret of the fact that they are closing down State Hospital facilities and until very recently planned to close the last facility.  This article goes on to conclude:

"Hennepin County Sheriff Rich Stanek was in Washington, D.C., Thursday, helping brief members of Congress about mental health issues and seeking additional funding for treatment beds in a state that has the 50th lowest rate of mental health beds for its population..."

It is truly a sad state of affairs when a county sheriff is advocating for treatment of the mentally ill in Congress.  On the other hand it is also a direct result of the opinions of psychiatrists being actively ignored in this state for decades.

We have seen the bottom of the managed care rabbit hole - and it is called Minnesota.  We take the prize with the lowest rate of psychiatric beds in the US.  There are only two groups of people in this State with any credibility when it comes to critiquing this failed system of care - psychiatrists and psychiatric nurses.  There is no politician or bureaucrat interested in proposed solutions - they are directly responsible for the 30 years of rationing that led to this problem.   One of the retorts by state officials has been: "What's your solution?".  It is time to acknowledge that this is little more than political rhetoric.  They have ignored the solutions including many that have been proposed right here on this blog.

Until the psychiatrists and psychiatric nurses are heard - expect continued deterioration in the treatment of mental disorders that we have witnessed here over the past 30 years.

George Dawson, MD, DFAPA


Jeremy Olsen.  Shortage of state psychiatric beds leaves local hospitals jammed.  Star Tribune. November 2, 2015.

Karl Olsen.  Minnesota's mental health system is in crisis.  Star Tribune.  October 16, 2015.


Supplementary 1:  The image used for this post is of Dexter Asylum attributed to Lawrence E. Tilley [Public domain], via Wikimedia Commons.  The original image was Photoshopped with a graphic pen filter.

Supplementary 2:  For a detailed post on some of what happened try this.

Saturday, October 31, 2015

UW 3rd Annual Update - Treatment Resistant Depression

There were two presentations relevant to depression that were given at the UW conference this year.  The first was from Karen Dineen Wagner, MD, PhD from the University of Texas Medical Branch in Galveston, Texas.  Her message was a mix of the old and the new.  The old is the state of pharmacology of depressed children seems to have changed very little over the past 20 years.  This seem largely due to the fact that there have been few successful antidepressant trials in children.  This has led to the state where there are only two FDA approved medications fluoxetine and escitalopram based on a total of 4 clinical trials.  She  showed an additional 14 clinical trials of typical antidepressants including 3 that were positive for citalopram and sertraline but an additional negative study for the FDA approved medication escitalopram.  The difficulty in many of these trials is a high placebo response rate in the trials (40% greater than in adult clinical trials).  She recommended an informed consent approach explaining to the parents any time an off label approach was being used and the rationale for using any medication based approach.  She also recommended starting with the FDA approved medications for pediatric depression.

Her suggested approach to depression in children and adolescents is to start out with an FDA approved SSRI plus cognitive behavior therapy (CBT).  This is the most evidence based approach with the evidence rapidly disappearing at subsequent levels where the usual augmentation and substitution steps that are typically used in adults were suggested.  The Treatment for Adolescents with Depression (TADS) study was presented with the recovery rates for fluoxetine, fluoxetine + CBT, and CBT alone at 12, 18, and 36 weeks were presented.  The fluoxetine + CBT arm had superior results at 12 and 18 weeks but at 36 weeks the recovery rates were similar at 86% versus 81%.  Those are good results for any antidepressant trial and the placebo response rate in this study was more similar to the adult placebo response rate.  The results of this study were presented as a rationale for using antidepressants in adolescents with severe depression and/or suicidal ideation since the response rate for fluoxetine + CBT were faster than fluoxetine or CBT alone at 12 and 18 weeks and essentially the same at 18 and 36 weeks.

The issue of strategies for addressing SSRI resistant depression were presented in the form of a previous trial where 334 adolescents with SSRI treatment failures were randomized to a different SSRI or venlafaxine or SSRI + CBT or venlafaxine + CBT.  The trial done by Brent, et al showed that there was no difference in response rates switching to another SSRI or venlafaxine but switching antidepressants and adding CBT produced superior results.  Sides effects were greater for the venlafaxine arm with a slight increase in diastolic blood pressure and heart rate and a four fold increase in skin rashes - a complication that I have rarely seen in adults.  The overall impression was that CBT was the most effective intervention for adolescent depression but I am sure that most psychiatrists in the crowd were left wondering: "If I can't find CBT therapists for my adult patients with depression - what are the odds I can find them for my adolescent patients?  To me that has always been the critical shortage in psychiatry - not the number of people who can prescribe medications.

Others trials of medical interventions (omega-3 fatty acids, ECT, TMS, bright light therapy), psychotherapies (Interpersonal Therapy(IPT), family based IPT), and exercise were sparse.  Computer-based CBT has always been an underutilized modality and it showed that there were similar response rates between treatment-as-usual and an interactive fantasy based CBT called SPARX (Smart, Positive, Active, Realistic, X-factor thoughts).  In the game the child chooses an avatar and the goal is to restore balance in a fantasy world dominated by GNATS (Gloomy Negative Automatic Thoughts).  The SPARX game is available free online to residents of New Zealand.  New Zealand and Australia have been pioneers in the area of online CBT.  To find resources just Google "SPARX virtual therapy for depression".

Paul Holtzheimer, MD provided the adult perspective in the topic Management of Treatment Resistant Depression in Adults.  He made the epidemiological point that treatment resistant depression (TRD) is present in 10-33% of patients with major depressive disorder and in the U.S. that is about 1-3% of the population.  He had a fairly comprehensive agenda covering pharmacotherapy and augmentation strategies, electroconvulsive therapy, more recent non-invasive electromagnetic therapies and deep brain stimulation.  There was nothing new on the medication front.  After reviewing the basic medication groups, he suggested that the newest antidepressants offered no advantage over earlier medication.  He suggested that monoamine oxidase inhibitors (MAOIs) were being underutilized as a treatment for depression unresponsive to standard agents.  In the moderated discussion Ned Kalin, MD - the head of the department of psychiatry at the University of Wisconsin agreed.  The speaker said that he typically used phenelzine and tranylcypromine.  I personally have not prescribed either of these agents in some time.  I recall using them in situations where the person has treatment resistant depression and did not have any responders.  In those situations, response rates tend to be low anyway.  The other problem is that you have to think that your chronically depressed patient is going to be motivated and cognitively intact enough to adhere to the necessary diet, report what could be significant side effects and not try to kill themselves with the medication.  During the discussion there was a report of one patient who decided to eat high tyramine content food (prohibited on this diet due to a the risk of a hypertensive reaction) - have a stroke and die.  The patient in this case did have a stroke but did not die.  I personally know of situations where strokes have occurred, so this strategy is not without risk.

The augmentation strategies discussed were right out of STAR*D with the exception of using atypical antipsychotics with antidepressants.  Dr. Holtzheimer said that this was probably the most common augmentation strategy and the risks were discussed.  He and Dr. Kalin were advocates of augmentation with lithium and triiodothyronine (T3).  There were three slides on STAR*D showing cumulative remission and remission rates across all levels of care.  Those rates were 33% with initial monotherapy and 66% after 4 treatments and as expected less remission rates at each level of treatment change.  Dr. Holtzheimer made the point that the current rates of remission with medication and psychotherapy have really not changed since the 1950s and that makes electroconvulsive therapy (ECT) the most effective antidepressant treatment with a 50-75% remission rates and a >50% relapse rate in the first 6 months.  He touched on novel pharmacological agents categorized by neurotransmitter, neuroendocrine, or immunological systems.  He did not say much about ketamine (there is an intranasal preparation in clinical trials right now) but did mention that there is a IL-6 (cytokine) antibody trial going on right now.

He moved on to talk about more invasive therapies.  He presented a graphic that was a drawing by Papez.  To anyone trained in neuroanatomy around the time I was in medical school, many anatomy professors would present a saggital section of the brain and refer to the limbic structures as the Papez circuit.  At first I thought the drawing had a surprising amount of detail for a 1937 publication but then I went to the original article online (AMA web site) and found that the original drawing was not used.  The 1937 drawing had the surface anatomy correct but no tracts.  Papez mentions the amygdala three times in the last few paragraphs of his article but does not label it in the drawing.  Dr. Holtzheimer used this slide as a prelude to an article by Mayberg (3) providing a rational for deep brain stimulation as treatment for depression.  I plan to come up with a separate post in this technology based on several sources but right now there are a number of centers looking a deep brain stimulation for depression and addiction.  Dr. Holtzheimer briefly commented on transmagnetic stimulation (TMS).  There are apparently 4 FDA approved devices, use is expanding and insurance reimbursement is expanding.  He said it was 50% effective for treatment resistant depression.  I am highly skeptical of that number based on the people I see, but I also realize that I am seeing a highly treatment resistant with multiple comorbidities.  Seizure risk was listed as the most significant side effect.

Vagus nerve stimulation (VNS) has been around for about a decade.  I have seen a few of these patients and never referred anyone for placement of this device.  There is limited third part reimbursement and in my opinion waning enthusiasm for this technology.  The last time I interviewed a person with VNS, their speech quality changed every time the stimulator was active.  That is a significant side effect and I don't know if that has been addressed with current technology.   Transcranial direct current stimulation (tDCS), transcutaneous vagus nerve stimulation, and cranial electrical stimulation were all listed as having limited data.

Deep brain stimulation (DBS) was clearly the main focus of Dr. Holtzheimer's presentation.  The first article suggesting that it may be effective for obsessive compulsive disorder (OCD) was in the Lancet in 1999.  Based on that research DBS of the anterior internal capsule is an FDA approved indication for DBS.  An open label study suggested that it may also be effective for TRD and there were no adverse effects or neuropsychological effects.  Three additional pilot studies of DBS to the nucleus accumbens suggested that it may be useful for TRD and features of TRD like anxiety and anhedonia.  Since then there have been two randomized controlled trials of DBS to the ventral striatum subcallosal cingulate gyrus (SCC).  The first study (ventral striatum) was negative and the second (SCC) was stopped after a futility analysis.

The overall conclusion had to be that TRD was still a common and disabling condition.  The mainstays of treatment at this point are still the medications and ECT that we have had throughout my career.  My experience is that I can help most people get well, but there are significant obstacles even to standard care.  Every lecturer here emphasized the utility of cognitive behavioral therapy.  Like most psychiatrists, I can do cognitive behavioral therapy but by myself I can't meet the demand.  The people responsible for mental health policy and insurance standards certainly do not want to fund the recommended research courses of CBT for chronic depression.  There is no distinction for TRD versus non-TRD depression and no differential resource allocation.  That leaves most patients with TRD and non-TRD depression looking for "prescribers" who can see them for 10-30 minute appointments to get advice on how to recover and try various prescriptions.  None of the available care matches what top researchers recommend in these CME seminars, in articles, or in books.

We could do a lot better trying to live up to that standard while additional diagnostic and treatment strategies are developed.          

George Dawson, MD, DFAPA


1:  David Brent Adolescent depression references  

2:  Papez JW. A proposed mechanism of emotion. 1937. J Neuropsychiatry ClinNeurosci. 1995          Winter;7(1):103-12. PubMed PMID: 7711480.

3: Mayberg HS. Targeted electrode-based modulation of neural circuits for depression. J Clin Invest. 2009 Apr;119(4):717-25. doi: 10.1172/JCI38454. Review. PubMed PMID: 19339763