The Heuristic is Dead - Long Live The Heuristic

One of the latest non-scandals to rock monolithic psychiatry and psychiatrists everywhere is David Healy's commentary on serotonin and depression (1).  Certainly nothing new there from the Healian perspective - SSRIs don't work, SSRIs don't work for melancholic depression, no evidence that SSRIs raise or lower serotonin levels, SSRIs pushed tricyclic antidepressants out of the market, and SSRIs forced the abandonment of research on biological disturbances in depression like hypercortisolemia.  The only thing I did not see was the idea that SSRIs are somehow addicting because they cause discontinuation symptoms in a subgroup of people who take them.  Feel free to call that a withdrawal syndrome, but withdrawal does not constitute an addiction.  All of these premises allow him to reject serotonin and it's role in depression on the vaguest possible grounds while stating that it is not irrelevant:

"Serotonin is not irrelevant.  Just as with noradrenaline, dopamine, and other neurotransmitters, we can expect some correlation with personality and temperament."

Indeed - but I expect those to be a very weak correlations probably not on par with the mood disorder work.  I was glad to see his reference to the late Marrku Linnoila (2) or more specifically Linnoila and Virkkunen.  Linnoila had done some of the outstanding work in this area and work on serotonin metabolites (CSF HIAA) in alcohol use disorders remains a classic.  He talks about the serotonin based research running into the sand.  I did a Medline search of serotonin and major depression and plotted the papers per year and there does not seem to be any precipitous fall off (the 2015 references are through March).  If anything I would expect the research to increase with the availability of ligands for additional receptors and the further characterization of serotonin transporter (SERT) variants.

But the main problem with Healy's argument is that he is talking about serotonin as if there is a chemical floating around in the brain and that is it.  He is basically describing his own brand of chemical imbalance theory.  So if he is saying there is no serotonin chemical imbalance theory I would of course have to wholeheartedly agree with him.  And in fact, I would tell him the same thing I told the Prozac rep back in the 1980's:  "The brain is far more than a bag of chemicals.  Unless you can say something about brain structure and physiology naming a neurotransmitter is meaningless."  There is no such thing as a chemical imbalance theory and reading through the index of any psychopharmacology text printed in the past 30 years will confirm that.

Healy can't stop himself at that level.  He goes on to describe the impact of his chemical imbalance theory on clinicians:

"This history raises a questions about the weight doctors and others put on biological and epidemiological plausibility.  Does a plausible (but mythical) account of biology and treatment let everyone put aside clinical trial data that show no evidence of lives saved or restored function?"

Things get very tenuous at that point.  As a clinician who has made a career out of treating patients with the most severe problems  I don't care at all about the "biological and epidemiological plausibility" of a theory of a medication.  I got past that in the 1990s when the elegant Nobel laureate mechanism of action of aminophylline was debunked and the former first line drug for asthma and COPD exacerbations was suddenly relegated to tertiary status.  And even then, with the people I was running up on gurneys from the emergency department while calculating the parameters of their aminophylline drip - not a patient of mine was lost.  I suppose you could say it was all an elaborate placebo response, treating all of those people with acute shortness of breath bad enough to be brought in by paramedics.  I was after all using a tertiary treatment with a disproven molecular mechanism.  But really?  And my living, breathing pulmonary patients did not seem to mind.

The only thing that matters to me is if the medication works in my hands, has few side effects, and I am using it exclusively to save lives and restore functioning.  And without keeping anyone in suspense, I do prescribe SSRIs and they do work, and I do fully acknowledge to anyone willing to listen that the mechanism of action is unknown. Not surprisingly many patients want more than that and I can discuss speculative mechanisms as well as the next psychiatrist.  I don't think that makes me a drug company stooge or an idiot, because I am the only person with any accountability in the entire scheme of things.  It really doesn't matter to me what David Healy or anybody else thinks.  I am seeing very ill people and it is my job to get them better and not cause them side effects with the medication and not have the drug interact with one of their underlying medical conditions.  When you get right down to it, I don't need a mechanism of action to use a medication - only the approval of a regulatory body like the FDA.  At some point somebody may say that  SSRIs are no better for depression than aminophylline was for asthma, but so far (apart from Healy and various sympathizers) that has not happened.  I just attended a CME conference last weekend and they were still recommended.  As far as I know the FDA has not sent out any letter to doctors telling them not to prescribe them any more.

Healy also asks the irrelevant question:  "Do clinical trial data marketed as evidence of effectiveness make it easier to adopt a mythical account of biology ?"  Or I guess the real question is do these data make it easier to accept this strawman?  I strongly encourage any psychiatrist to read and reread the FDA approved package insert on any drug they prescribe and any drug their patient happens to be taking.  I encourage reading and rereading those package inserts especially if they are updated and sent out in a mass mailing by the FDA.  These package inserts need to be studied because they are not the final word in safe prescribing.  If you are an experienced psychiatrist you will routinely be called on to decide if a medication (based on all of the available evidence) is safe to prescribe to a patient with cardiac, liver and renal disease.  You will have minimal data to go by in most cases, because people with significant medical illness are typically eliminated from clinical trials.   Any psychiatrist reading those package inserts will recognize that for some time now, the package inserts have contained clinical trials data and that data is very useful.  It's utility has nothing to do with putative biological mechanisms, it has to do with safely monitoring and prescribing the medication.  The other consideration implicit in this question is that clinical psychiatrists are unaware that clinical trials are really a primitive technology.  Given that awareness exists, why would anyone accept clinical trials data as proof of much of anything.  How in the world does a double-blind placebo controlled study with an intent to treat analysis have anything at all to do with my practice of psychiatry?  It is totally irrelevant clinically and even less relevant theoretically.  Its only use is to get a new drug in my hands that my patients and I will accept as useful or reject as too toxic or worthless.

Why are reasonable people interested in serotonin despite Healy's commentary?

The complexity of serotonin or more appropriately serotonergic signaling for one.  Absolute levels of neurotransmitters are rarely the issue in complex disorders.  In the case of serotonin any bare bones discussion needs to consider the fact that there are 14 serotonin (5-HT) receptor subtypes coded by 18 genes.  Those receptors are organized into 7 families, 6 of which are G-protein receptor linked superfamily.  The remaining family is part of the ligand-gated ion channel superfamily.  The combinatorics of these receptor types, their specific locations, and their genetic variants can lead to a dizzying number of signaling variations that can easily be found in psychiatric research (4).  As an example, this is from a 2013 review of serotonin signaling in depression and suicide by Mann (3):

".......Part of the neurobiology observed in recurrent major depression, that is present between episodes as well as during episodes, is a series of abnormalities in the serotonergic system [19]. Cerebrospinal fluid (CSF) levels of the main serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), are low in more lethal suicide attempters, and predict the risk for future suicide with an odds ratio of 4.6 [20].  Convergent evidence comes from some reports of low CSF 5-HIAA in suicide attempters with other diagnoses such as schizophrenia [21,22], bipolar disorder [23] and personality disorders, although there are fewer studies and less consensus in these other disorders [24,25]. Nevertheless, if correct, such findings suggest that less serotonin transmission, as implied by less 5-HIAA, appears to be associated with suicidal behaviour across psychiatric diagnostic boundaries, as would be expected if it were associated with the diathesis for suicidal behaviour instead a specific psychiatric disorder. A review of post-mortem brain studies of suicides has found much the same thing: most studies find suicides have lower levels of serotonin and/or 5-HIAA in the brainstem serotonin neurons compared with psychiatric-matched groups [26–28]."
   
Apart from all of the disputed technical details, what is the importance of the Healy commentary?  It follows the political tradition of other commentaries mentioned on this blog by prominent psychiatrists.  People have sent me e-mails and asked me: "What do you mean by political?"  In the simplest analysis it is taking one end of a polarized position and running with it and bringing everything that you can to support that position.  That is the classic way that politicians work.  They are fueled by ideology.  On the surface, it seems that science operates like that as well, but ongoing scientific arguments don't include comments about marketing or words like "neurobabble".  They don't make assumptions about how clinicians think or whether they are confusing science and hypothesis testing with clinical work.  The best science encompasses complexity and contradictory data and we are past the point where neuroscience can be watered down for the masses in a 2 minute sound bite.

Neurobabble happens when a neuroscience discussion is reduced to a sound bite and debated the way that Democrats and Republicans discuss just about anything.  That is what happens when we are all polled "Serotonin - yes or no?"

If you really want to get your opinion out in the press that way that is one thing.  Let's not pretend that psychiatrists really think this way or that psychiatrists are just flunkies for Big Pharma talking about some crazy chemical imbalance theory or that we based our clinical practice on heuristics or for that matter marketing.

Psychiatrists are really bright people, time to stop pretending that we are not.


 George Dawson, MD, DFAPA



References:

1: Healy D. Serotonin and depression. BMJ. 2015 Apr 21;350:h1771. doi: 10.1136/bmj.h1771. PubMed PMID: 25900074.

2:  View my collection, "Marku Linnoila" from NCBI

3: Mann JJ. The serotonergic system in mood disorders and suicidal behaviour. Philos Trans R Soc Lond B Biol Sci. 2013 Feb 25;368(1615):20120537. doi: 10.1098/rstb.2012.0537. Print 2013. Review. PubMed PMID: 23440471

4:  KEGG.  The Serotonergic synapse.

5: Albert PR, Benkelfat C. The neurobiology of depression--revisiting the serotonin hypothesis. II. Genetic, epigenetic and clinical studies. Philos Trans R Soc Lond B Biol Sci. 2013 Feb 25;368(1615):20120535. doi: 10.1098/rstb.2012.0535. Print 2013. PubMed PMID: 23440469

6: Albert PR, Benkelfat C, Descarries L. The neurobiology of depression--revisiting the serotonin hypothesis. I. Cellular and molecular mechanisms. Philos Trans R Soc Lond B Biol Sci. 2012 Sep 5;367(1601):2378-81. doi: 10.1098/rstb.2012.0190. PubMed PMID: 22826338

An Obvious Response to "Psychiatry Gone Astray"

David Healy has what I consider to be inconsistent viewpoints.  I have previously critiqued his viewpoint on the "addictive" qualities of antidepressants (they clearly are not) and whole heartedly endorsed his position that pills don't treat depression - psychiatrists do.   He recently posted what I would refer to as a screed written by a Danish internist on (what else?) all of the problems with psychiatry.  The obvious lack of symmetry here is striking.  You won't find a psychiatrist anywhere posting a similar piece about internal medicine, even though it could be easily done and would probably be more evidence based.  In that regard this physician has slightly more credibility that the typical layperson screed against psychiatry - but not much more.  What follows is my point by point refutation of the "myths".  They are mythical in that they are from the mind of the author - I know of no psychiatrist who thinks this way.

Myth 1: Your disease is caused by a chemical imbalance in the brain -

This is a red herring that is frequently marched out in the media and often connected with a conspiracy theory that psychiatrists are tools of pharmaceutical companies who probably originated this idea.  What are the facts?  Psychiatry has at least a century old tradition of researching all possible etiologies for mental health problems.  Psychiatrists were among the first people to look at the effects of social deprivation in orphanages, the effects of acute grief and loss, the effects of psychological trauma, the effects of a full gamut of psychotherapies, and the effects of family and environment.  The biopsychosocial formulation of Engel in 1977 was an advance detailed in Science magazine.  Any comprehensive psychiatric formulation covers all possible etiologies (as an obvious example see Systematic Psychiatric Evaluation by Chisolm and Lyketsos).  In addition there are many clinical methods where the diagnostic formulation is essential for the treatment plan for psychotherapy based treatment.  By definition that formulation would have few biological references.  So the alleged myth fails at the clinical level.

It fails even worse at the neurobiological level.  Chemical imbalance rhetoric always seems to ignore one huge fact and that is Eric Kandel's classic article on plasticity in 1979 in the New England Journal of Medicine.  Certainly any psychiatrist who saw that article has never bought into a "chemical imbalance" idea and I can recall mocking the idea when pharmaceutical companies presented it to my colleagues and I in medical school.  So why don't we hear: "Your disease is caused by plasticity?"  Probably because they gave Eric Kandel the Nobel Prize for it.

Myth 2: It’s no problem to stop treatment with antidepressants - 

Another red herring.  I have trained psychiatrists, internists, family physicians and medical students and taught them psychopharmacology.  A general principle of psychopharmacology is no abrupt changes in therapy and most drug prescribing information suggests that.  I routinely address this issue as part of informed consent and advise people that there may be difficulty discontinuing antidepressants and describe the potential symptoms.  This criticism from an internist has a certain degree of asymmetry to it.  Certainly there are medications prescribed by internists that cause both acute withdrawal and discontinuation symptoms.  My impression is that many adults who see internists are basically going along with life long therapy in many cases for conditions that could be treated by psychosocial measures.  It is quite easy to criticize if you are never faced with the prospect of discontinuing therapy.

Myth 3: Psychotropic Drugs for Mental Illness are like Insulin for Diabetes -

The author here conflates the certainty of insulin deficiency with pathophysiological certainty in medicine and how that correlates with prescribed treatment.  Certainly that is not the case in diabetes mellitus Type II or the recent example I provided with an asthma exacerbation.  In fact the pathophysiology in those heterogenous groups are about as accurate as endophenotypes in psychiatry.  Am I getting prednisone for my asthma because I am deficient in prednisone?  Am I getting it because of some specific pathophysiological mechanism rather than a shotgun approach to shut down all of my inflammatory signalling?  Was predisone prescribed only based on the purported pathophysiological mechanisms?  The answer to all three questions is - of course not.  If the author is really concerned about medication side effects, I can't think of any psychiatric medication that is the equal of prednisone but I am certainly not going to suggest that it should not be prescribed.

Myth 4: Psychotropic drugs reduce the number of chronically ill patients - 

I don't know of anyone who has actually suggested this and from an internal medicine perspective does it make sense?  Here are a few additional comparison statistics on asthma and hypertension for example.  There is a 10% prevalence of asthma in the developed world.  Only 1 in 7 has their symptoms in good control.  People continue to die of asthma possible as many as 1/250 deaths world wide.  In the case of hypertension, 31% of Americans have it and another 30% have prehypertension.  Only 47% have adequate blood pressure control.  There is really not much evidence that medications prescribed by internists are much more effective than what he refers to as "psychotropic drugs" and that is borne out in a previous analysis and my own recent experience with the health care system.

I find this argument also demeaning to anyone with a severe psychiatric disorder who is interested in staying out of hospitals and being able to function or trying to avoid a suicide attempt.  Being able to adhere to that kind of plan depends on multiple variables including taking medications.  It is reckless to suggest otherwise and any psychiatrist knows about severe adverse outcomes that have occurred as a result of stopping a medication.  The author conveniently plugs his book at this point.

Myth 5: Happy pills do not cause suicide in children and adolescents -

The author reveals his antipathy to medication used by psychiatrists here by referring to antidepressants as "happy pills."  I know of no psychiatrist who I have ever met who calls antidepressants "happy pills" and in fact most of us are engaged in trying to find an effective medication with minimal side effects.  David Healy himself describes this as one of the primary functions of psychiatrists.  On the actual suicide issue, psychiatrists goal is preventing suicide.  Suicide is a possible outcome of all clinical encounters and psychiatrists follow this symptom closely.

Saying that happy pills are a cause of suicide is the equivalent of saying that "sugar medicine" (insulin) is a cause of hypoglycemia that harms children and therefore it should not be prescribed.

Myth 6: Happy pills have no side effects -

The author has one legitimate point in that depression screening is not a good idea but in his zeal to criticize everything psychiatric he has to whip that into "happy pills have no side effects".  Of course they do and I have elaborated my clinical method on how to approach that in detail.  He goes on to make an anecdotal argument about single study results versus "what the company says."  In fact, companies have to rigorously record side effects in clinical trials and all of that is recorded in the FDA prescribing information.  Looking at standard FDA reported data for sexual side effects (his example) the number for all SSRI antidepressants is   9-37% and not the 5% figure suggested by the author.  (see page 1684 of Drugs Facts and Comparisons 2013).

Myth 7: Happy pills are not addictive -

This is interesting because of David Healy's confusion on this subject.  It indicates a serious lack of knowledge about addiction because there are no behavioral features of antidepressant medications or animal models that describe these drugs as addictive.  They have no street value and they will not make you high.  The authors comparison to amphetamine is completely off the mark and consistent with his general lack of knowledge of addiction.

Myth 8: The prevalence of depression has increased a lot -

He has to attach epidemiological data on depression in order to attack the argument that increasing antidepressant use is not a problem because of the increasing prevalence.  He offers a sarcastic comment as evidence and misses both the issue of why antidepressant prescriptions are increasing and the real data on the prevalence of depression.  Even if his argument is correct, since 80% of antidepressants are prescribed by primary care physicians wouldn't this be "Primary care gone astray?"

On the epidemiology issue I would encourage a quick look at an actual text on the issue like Textbook of Psychiatric Epidemiology, 3rd Edition.(p 292)  The authors look at 30 national and international studies and do not conclude that there is an increasing prevalence of depression, but that variation is likely due to methodological differences and sociocultural factors. 

Myth 9: The main problem is not overtreatment, but undertreatment -

More sarcasm as evidence here.  I debunked the arithmetic used in this argument in an earlier Washington Post piece.  This is also a huge disservice to people with severe mental illness and addictions in this country who have been thrown out of treatment, received useless hospital treatments, and restricted from medications by managed care.  The primary prescribers of antidepressants (by far) are primary care physicians and it is certainly possible that they are prescribing too many antidepressants.  But don't blame psychiatrists for that.

Myth 10: Antipsychotics prevent brain damage -

More rhetoric.  In this case he is using a research hypothesis and suggesting that this has something to do with clinical psychiatry.  Despite significant obstacles, psychiatric research at the neurobiological level continues and studies on imaging are a large part of that process.  One of the major areas has to do with brain volumes and their implications.  The author presumes he knows what the outcome of that research will be.  He also talks about antipsychotic medication with the arrogance of a person who does not have to treat acutely psychotic people and incredibly talks about these drugs killing people.  In fact, the number one killer of people with severe mental illnesses is tobacco smoke and there is ample evidence that they get suboptimal primary care.

At the end of this refutation what have we learned?  I am more skeptical than ever of David Healy and his web site.  I thought he did good work with his investigation of SSRIs and his analysis of the role of psychiatrists as opposed to medications was accurate.  But I can't ignore the fact that he places this screed on his web site.  He also lists  himself as a "scientist" and this screed contains surprisingly little science.  It is essentially all rhetoric and politics.

It is one thing to ridicule psychiatrists but the obvious concern here is that it stigmatizes people who need treatment especially treatment with medication who are actively denied treatment in the U.S. on an ongoing basis.  The author here uses a familiar dynamic that I have described in the past. He suggests that internists (like the author here) have clearly superior methods or pathophysiological mechanisms than psychiatrists but they don't.  In terms of the accusation of overprescribing, it is well know in the US that the 20 year CDC initiative to control antibiotic overprescribing is a failure.  Some authors believe that this heralds a new "post antibiotic era" where untreatable infections will become the rule.

It seems to me that internists have enough to focus on in their own specialty before criticizing an area that they obviously know so little about.  It also seems that if you claim your web site is scientific, you should probably put a little science on it.  The author here also states that he is affiliated with the Nordic Cochrane Center and I think that anyone who considers the output of that Institute should consider what he has written here and the relevant conflict of interest issues.

George Dawson, MD, DFAPA

Supplementary 1: About a month after this post was completed Ronald Pies, MD came out with an article in the Psychiatric Times entitled Nuances, Narratives, and the “Chemical Imbalance” Debate.  He presents very similar arguments to the ones presented here and concludes that it is time for the critics using this false argument to give it up.  I also like his characterization of "a recent online polemic posing as investigative journalism" and how the "chemical imbalance hypothesis" is used to mischaracterize psychiatry.  He also provides a link to a 2011 article that he wrote that contain the following quote:

"I am not one who easily loses his temper, but I confess to experiencing markedly increased limbic activity whenever I hear someone proclaim, “Psychiatrists think all mental disorders are due to a chemical imbalance!” In the past 30 years, I don’t believe I have ever heard a knowledgeable, well-trained psychiatrist make such a preposterous claim, except perhaps to mock it. "

Readers of this blog have heard seen me say this many times before.  It is good to see these opinions being offered in the more mainstream media.  It is also good to see Dr. Pies taking calling a critic on what is rhetoric rather than reality.  Well done.

Supplementary 2:  I have an updated post on the issue of how medical syndromes and psychiatric syndromes are far more similar than different and how there is a complete lack of criticism relative to psychiatry. (added on September 3, 2015).

Pills Don't Save Lives - Psychiatrists Do

I am paraphrasing David Healy from a previous post and I am doing it here to emphasize - it's all about the side effects.  Healy's comment serves as a counterpoint to a highly successful multi-decade advertising campaign by pharmaceutical companies.  It began with the first National Depression Screening Day in 1991.  The emphasis  was on identifying and treating depression with antidepressants.  There was no real discussion of antidepressant side effects or the general problem of side effects with most medications.  Since then antidepressant treatment has been conceptualized as comprehensive treatment wrapped up in a pill or capsule.  That bias continues today as various political forces have shifted depression screening from an annual event to primary care clinics.  Some health care organizations and states consider depression screening and serial ratings of depression to be quality markers of health care services despite the fact that there are definite problems with that idea.  Unless there is a highly specific screening test any screening procedure has the potential to expose more people to the side effects of treatment.  There is no highly specific screening test for depression.

A second factor in considering side effects is the physician's role.  Doctors are trained to identify and treat conditions with surgery or medications.  Psychiatrists have additional training in psychotherapy. When you are in your training, the emphasis in on making the correct diagnosis and selecting the medication that will be the most useful.  Even though medical training is long, the longest you might follow any patient might be for a couple of years.  In medical practice you have the ability to see people for decades rather than months or years and how their medical treatment changes over those years.  You also observe first hand the long term toxicity of many medications when you might have only been exposed to that on a theoretical basis during training.  As a practicing physician you are expected to help people deal with the fact that they have side effects and the medications they are using may not be that useful.  In fact, in many cases they may not be beneficial or may be causing more harm than good.

All of that experience with side effects leads clinicians to develop new practices that they were never trained to do.  Very early in my career, I had the experience of treating a person who had been on an antidepressant for about 6 years.  She had headaches and depression and like many people with chronic depression she was in a stressful situation that she could not remove herself from.  She had chronic depression in the context of a chronic stressor that was not going away.  At some point her headaches resolved and her depression improved.  We decided to taper her off the antidepressant.  She came in 2 weeks later and said: "I feel much better.  All of the years that I was taking that medication I didn't realize it, but I felt like I had the flu.  That has now cleared up."  That early experience led me to modify the ways that I discuss medications with people.

I generally tell people that I don't expect anyone to "get used to" a medication.  I often tell them that people may get used to feeling ill rather than develop a tolerance to medication side effects.  I tell them that if they are experiencing any side effects at all to let me know about it and we will decide what to do about it at that time.  I let them know the range of experiences with medications and what they might expect.  As an example, I might say that "60-80% of people might take this medication and not notice that they are taking anything, but 5-10% of people might not tolerate it at all."  I let them know about all of the FDA contraindications, in some cases I review it with them many times.  I discuss the common side effects and usually provide them with the MedlinePlus handout on the medication.  I think it is more comprehensive than most handouts and it gives the FDA black box warnings (in a red box) on the front of every handout.  I talk with them about rare but potentially serious side effects like drug induced liver disease and arrhythmias and what to look for.  In the case of atypical antipsychotics, I discuss movement disorders and metabolic effects.  I demonstrate what the movements of tardive dyskinesia may look like.  I let people know if the medications they are taking are potentially addictive.  I the case of lithium, I let people know about the unique toxicities and the safest possible way they can take it.  In the case of antidepressants, I let people know that they may be difficult to stop due to discontinuation symptoms.

My side effect discussions with people have taught me valuable lessons.  There are people who are placebo responders and nocebo responders.  The nocebo responders develop problems taking any medication, even medications that are generally well tolerated at low doses.  Some of them are aware of the problem and decline any discussion of side effects.  They might say they don't want the MedlinePlus handout because: "If I read about any side effects I will probably get them."  They would rather be surprised.  Whenever I encounter that attitude, I respect their wishes but advise them to contact me if they have any side effects.  I also recall my Forensic Psychiatry lectures during residency.  The instructor advised us that we "could be sued" if our side effect discussions prevented a patient from taking a useful medication and there was an adverse outcome as a result.  I have realized over the years that basing your decisions on whether you could be sued is generally a bad idea because you can be sued for just about anything.  I think that people need to hear about what really happens with psychiatric medications and consider myself to be a good source of information.

I have also found that there is a hearty group of people who decide on their own that they will try to tolerate side effects and not let me know about it despite our discussion.  When I see them in the follow up appointment they will say: "Well you know doc, I had a pretty good headache the first three days on the medications, but I decided to keep taking it to see if it would go away and sure enough on day 4 the headache was gone."  They tell me that even though I advised them to not tolerate side effects and to call me if they had any side effects.  These patients are almost always men with a history of avoiding doctors and not taking care of themselves.  I guess their experience confirms that some people develop a tolerance to side effects but why would you want to?  I was at a large conference on the treatment of anxiety disorders and listened to a renowned psychopharmacologist talk about his technique for treating anxiety disorders with SSRI and SNRI type antidepressants.  His approach was to keep titrating the medication "to the point of toxicity" and then back off to the lower dose.  My experience has taught me that the best approach in non acute situations is to use the lowest possible dose.  That is usually the dose recommended for anxiety disorders and titrate it to the exact point where the symptoms are in remission.  I am never  compelled to increase a medication by a multiple based on the pill size or a drug level based on the aggregate experience of a cohort of people in a drug trial.

I obsess about the hypothetical.  Physicians in practice are aware of trends in the medications that are prescribed and psychiatry is no exception.  Drug interactions have been an area of focus in psychiatry since it was first learned that fluoxetine could inhibit the hepatic metabolism of tricyclic antidepressants and that could lead to antidepressant toxicity.  I treat people who are often on a mind boggling combination of medications for their chronic illnesses and psychiatric disorders.  I routinely run those lists through one or more computerized drug interaction software packages.  The software is inconsistent and I often have to look up the case report or study that suggest a specific interaction or problem.  I have to make the decision to accept or reject what the software is telling me.  The QTc interval or the interval on the electrocardiogram that corresponds with the total time of ventricular contraction and relaxation has been a major concern since the approval of ziprasidone.  It has been complicated lately by the FDA concern that citalopram may prolong the QTc interval in some people to a significant extent.  I screen people with electrocardiograms if it appears that their clinical status or total medication burden may lead to prolongation of the QTc interval.          

In some cases a concern for the hypothetical requires some inductive reasoning.  Current textbooks, literature, and standard prescribing references create the illusion at times that everything is known about a medication, it is just a matter of finding it.  There are plenty of examples where that is not true or where there is a lot of uncertainty about when a medication can be safely and effectively prescribed.  To illustrate, consider a hypothetical situation of patient with bipolar disorder who may benefit from taking lithium.  For a time during my residency training the renal toxicity of lithium was openly debated.  Nephrologists at the time certainly believed it was nephrotoxic but there were large series of patients who were described with minimal signs of renal toxicity.  Clinical practice treating patients with severe bipolar disorder has lead me into situations where I have treated patients on, during and after dialysis and kidney transplantation.  The estimation of glomerular filtration rate (GFR) by 24 hour urine collections was also problematic.  That has been greatly improved by the practice of using calculated GFRs.   I have no doubt at all that taking lithium for a period of time can lead to renal failure in a portion of patients taking it.  Anyone prescribing lithium needs to be aware of this fact and take all measures necessary to minimize episodes of lithium toxicity and exposure to other nephrotoxins.  In some cases like NSAIDs, the toxins are well known.  In other cases like tenofovir, the interactions are not known and in fact you can scan an entire FDA approved package insert and might find no references to lithium.   Making that decision may take hours or a weekend of study to figure out the best course of action.

I hope that I have made the case for psychiatric medications needing a careful analysis of side effects before they can be initiated and continued.  The decision to take medications is a serious one.  In 29 years of practice I have not met a single person who told me that they liked to take medications.  The decision to take medications often comes down to having tried everything else and realizing that a major change is necessary to get back to where you want to be.  A recent reply to my previous blog post described medications as "tools" rather than a panacea and I think that until perfectly safe and effective medications are invented that is true.  Healy's point is that the advertising notion of "Take an antidepressant and get better" is false.  Psychiatrists are trained to help you navigate the complicated process of recovery from depression and side effects and the potential for side effects is generally the most complicated aspect.

George Dawson, MD, DFAPA


Additional Clinical Note 1:  Another blogger sent me an e-mail earlier this week asking me to send a list of psychiatrists who I thought were competent to taper people off of SSRI/SNRI type antidepressants.  The intention of the e-mail was to have a ready list of people who could help people with that particular problem.  I think that all psychiatric residents should be taught about medication discontinuation effects and how to resolve them, but apparently that is not the experience of some people who end up taking these medications.  As an instructor in a psychopharmacology course, I can verify that the residents I taught were all aware of this problem and how to deal with it.  They also had the very good back up reference of the ASCP psychopharmacology course PowerPoints and lecture materials on this problem.  I realize that this blog is not widely read, but I would appreciate any posts from instructors or professors about the issue of side effect recognition and treatment in general and SSRI discontinuation symptoms in particular and the approach to teaching these topics in your program.  I would also appreciate hearing your thoughts on this problem about SSRI/SNRI discontinuation symptoms and the variable experiences of people trying to get the problem diagnosed and treated.

Additional Clinical Note 2:  The processes that I am describing in the above post take time.  In many cases the equivalent amount of time required to do psychotherapy and longer.  I do have people telling me that their physicians (all types) seem to be poised over a prescription pad.  They tell me nobody has ever informed them of the risks or potential side effects of a medication.  I don't think the problem has been investigated and it would be difficult to do.  The idea that "medication management" in psychiatry, internal medicine or any other field is a brief uncomplicated encounter that takes little thinking on the part of a physician is largely an invention of business interests seeking to reimburse physicians at the lowest possible rate.  If you are a consumer of medical services, consider my approach in the above post and ask yourself if you have had the discussions that I describe.

Why Psychiatrists Should Agree with David Healy

One of the big media stories today is about David Healy's address to the American Psychiatric Association's Psychiatric Services meeting.  Like many of the psychiatrists turned critic his celebrity and notoriety status depend a lot of the amount of controversy that he is associated with and he comments on that in the opening remark.  If you carefully read through this article, you will find that the financial conflicts of interest alluded to in the article are largely historical at this point.  The elephant in the room for these critics is that practically all antidepressants are generics these days and they are no longer marketed by pharmaceutical companies.

I was an early adopter of maintaining  clear boundaries with pharmaceutical companies and for the past 20 years or so - did not see detail salespeople, did not accept food and did not accept any gifts.  On the other hand, I have always found pharmaceutical companies to be a rich source of data in addition to the usual FDA approved package insert.  As an example, I am looking at a disc sitting on my desk right now entitled "Iloperidone unsolicited slides - for education use only."  I gave a lecture on newer atypical anti psychotics several years ago and contacted the scientific divisions of three pharmaceutical companies looking for basic science data on the new drugs and they all supplied me with complete clinical trials data and basic science information on the receptor profiles that I wanted.  I will also call them up with possible adverse events and get detailed information about that frequently via fax the same day.

Healy appeared to have made a controversial remark about psychiatrists committing "professional suicide" by their affiliation with pharmaceutical companies.  In his previous remarks he make the comment about professional suicide as a preface to the second paragraph below:


"Healy noted further that when data surfaced showing a link between antidepressant use and risk of suicide in children, the APA issued a statement proclaiming that “we believe that antidepressants save lives.”

“What I believe they should have said is that the APA believes that psychiatrists can save lives because it takes expertise to manage the risks of risky pills,” he said; if psychiatrists’ only role were to dole out drugs, then less-trained physician’s assistants could easily replace them, he noted."

I have seen the comment on his blog at least 6 months ago and there should be complete agreement with this statement.  Just in the past month I have had to diagnose and address drug induced liver disease, serotonin syndrome, eosinophilia, antidepressant associated hypertension, and spent a considerable larger amount of time making sure that antidepressants could be safely prescribed and that they were not making pre-existing medical problems worse.   Recognizing those problems goes beyond the diagnostic process to coming up with a plan to monitor and treat it.  A considerable amount of my time is, if not most of my time is spent managing side effects and protecting the health of my patients.

Although Healy takes positions that I would consider to be inaccurate, in this case he is dead on.  It is professional suicide to collude with the idea that the treatment of any mental illness resides in a pill.  Marketing genius maybe, but certainly not reality.  Drugs don't treat and cure depression, psychiatrists do and it goes far beyond selecting a medication.  Monitoring the patient for these complications and recognizing rare complications takes time and that time needs to be available - even in visits that are supposed to be focused on "medication management".

George Dawson, MD, DFAPA