Significantly Lower Mortality With Antipsychotic Use

It is always an interesting phenomenon to see the headline grabbing news about how toxic psychiatric medications are killing people.  At first it was just  cult news, but these days it seems that some people can make a fairly good living at it.  A knowledge of psychiatry or clinical experience is never a prerequisite.  It always requires the reader to suspend their sense of reality and what they know happens in real life.  That reality is that a family member, neighbor, or friend was having some very serious problems - saw a psychiatrist and got better.  It also requires a suspension of belief in the tremendous history of what happens with untreated psychotic disorders both in terms of morbidity and mortality.  Finally it requires suspension of a belief in the usual regulatory mechanisms.  If so many people were dying from treatment - it would be obvious and somebody would be held accountable.  Every state has medical boards that basically solicit complaints against physicians.  Surely any group of physicians prescribing an inordinately toxic medication would come to light.  You have to suspend all of these realities of course because none of it has occurred.  Despite those reality factors there are any number of antipsychiatrists or people claiming to be critics who are basically using the same rhetoric warning people about the toxicities and how many people are killed by these medications each year.  Some of their estimates are astronomical and suggest a clear and biased agenda.  Actual community surveillance reveals an accurate picture and the medications with the highest complication rates are easily recognized by any psychiatrist or primary care physician.

That is not to say that the medications prescribed by psychiatrists are perfectly safe.  As I just posted - no medical decision including one that involves taking a common medication is risk free.  I spend a good deal - if not over half of my time warning people about side effects that will never happen, warning people about severe but rare side effects, managing side effects that do happen, and screening for potential side effects that might go unnoticed by the patient like electrocardiogram abnormalities or blood tests for a specific bodily systems.  In 30 years of practice, I have diagnosed the most severe problems including serotonin syndrome, neuroleptic malignant syndrome, prolonged QTc interval, various degrees of heart block, arrhythmias, myocardial infarctions, strokes, drug-induced liver disease, agranulocytosis, diabetes mellitus, diabetes insipidus, hypo/hyperthyroidism and many other that were either caused by a medication or picked up as a result of my screening for a medical complication or pre-screening for safe use.  But relative to primary care, the number of diagnoses in psychiatric practice for this reason is smaller.  The most significant cause of mortality in psychiatric populations is cigarette smoke.  The most significant number of medical conditions are pre-existing and if the psychiatric disorder is caused by an underlying medical condition - it is not common.

All of the factors in the first two paragraphs led me to read an article on the epidemiology of antipsychotics, antidepressants, and benzodiazepines in a well determined population and the effects on mortality in the June American Journal of Psychiatry.  The authors have a number of studies that appear to use a similar epidemiological approach.  For this study they identified cohort participants from national health care registers of all people 17-65 living in Sweden in 2005.  They identified anyone receiving health care for schizophrenia or psychosis (by ICD-10 codes) and anyone on disability for schizophrenia.  They also  determined all of the antipsychotics, antidepressants and benzodiazepines dispensed from 2006-2010.  They were classified by Anatomical Therapeutic Chemical Codes (ATC codes).  They calculated cumulative exposures using the WHO defined daily dose (DDD) methodology.  The WHO web site has a search engine that will let you search for the defined daily dose of medications.  Examples for antipsychotic medications would include 10 mg for olanzapine and 5 mg for risperidone.  The researchers summed the follow up days minus any hospitalization days and divided this into the sum of the dispensed medication.  That allowed the subjects with schizophrenia to be broken into four DDD groups: 1) no antipsychotics, antidepressants or benzodiazepines during the follow-up, 2) low dose -  small or occasional medications (0-0.5 DDD/day), 3) moderate doses (0.5-1.5 DDD/day, inclusive), and 4) high doses (>1.5 DDD/day).  Using the olanzapine example that would mean a dose range from 0 - >15 mg/day cross all 4 groups.  

A total of 1,591/21,492 or 7.4% of the cohort died in follow-up.  That was 4.8 times higher than a control group of age and gender matched patients.  The commonest causes of death were cardiovascular disease, neoplasms, respiratory diseases, and suicide in that order.  No interactions were noted at the level of demographic variables.  Mortality rates and hazard ratios for antipsychotic, antidepressant, and benzodiazepine use were calculated and the following observations were noted:

1.  Any exposure to antipsychotics or antidepressants was associated with a lower rate of mortality (15-40% lower) compared to no use.          

2.  High exposure to benzodiazepines was associated with a 74% higher risk of death than no exposure.  Benzodiazepine users had the highest mortality, highest risk of suicide, and more frequent visits to health care services.  

3.  In terms of cardiovascular mortality, only high dose antipsychotic use showed an equal mortality to no exposure to antipsychotics with low and moderate dose showing decreased mortality.

4.  A sensitivity analysis of first episode patients showed that there was a decreased risk of mortality with exposure to low and moderate exposure to antipsychotics and increased mortality with exposure to moderate to high dose benzodiazepines.  More striking is the fact that during the follow up period this was a cohort of 1,230 patients and 45 (4%) of them died.  Most of the patients with first episode psychosis who I treated were otherwise healthy 20 year olds, illustrating the significance of this problem.

This is an excellent study from a number of perspectives.  It looks at well defined data across a population that is generally possible only in Scandinavian populations.  By contrast studies done in the US typically look at either incomplete retail pharmacy data designed originally for pharmaceutical sales or detailed health interview data that is based entirely on self report using long and detailed questionnaires.  The study uses WHO methodology suggested for pharmacoepidemiological research.  The follow-up period is during a times when most atypical antipsychotic medications are widely available.  These are the drugs that are suggested as a source of higher cardiovascular mortality in psychiatric patients.  The authors findings are discussed in light of several other studies that show similar effects.

 The finding of this study will come as no surprise to acute care psychiatrists across the US.  It is the reason why psychiatrists cover these settings despite the hardships involved.  They know they are treating very difficult problems with very little assistance and that even in the absence of a continuum of care they can be successful.  These psychiatrists are also aware of the medication toxicity and more importantly as this article points out - they can identify high risk patients and safely treat them.  Despite the concerns about the metabolic effects of atypical antipsychotic medication there is an implication that other factors (like smoking) may be more significant in the development of cardiovascular disease (3).  The risk of antidepressant and antipsychotic medication can be seen in an appropriate context in this study and that is lowering mortality rather than causing it.

The study also provides very useful guidance on benzodiazepine use.  In my opinion, benzodiazepines should be used only briefly for the treatment of catatonia and acute agitation in patients with psychotic disorders.  They should not be used on a long terms basis.  I agree with the authors' idea that tolerance is a problem.  When dose escalation fails or results in withdrawal and panic attacks or protracted insomnia, the risk for impulsive behavior and increasing depression is much greater.  More frequent primary care visits can also occur due to tolerance and the need for dose escalation and more discussions of appropriate use.  Treating this population in the United States is problematic because at a certain point, people can be safely detoxified from benzodiazepines only in an inpatient unit, and those services are widely unavailable.   This study is a blueprint for quality assurance projects using the same methodology on electronic health records (EHR) across the country.   Every clinical population should be examined using the authors' techniques and followed for outcomes and active interventions.

The reference provides an opportunity to see the realistic risk and benefits of treatment in people with high risk psychiatric illness.  It also presents an opportunity to use this methodology to provide better treatment to people with the same illness and prescription profiles everywhere.  Instead of using the EHR to catalogue useless full text information and track physicians, the authors methods can be used with much finer tracking of details like BMI, blood pressure, smoking status and other relevant lifestyle factors.  Apart from the aspects of polypharmacy, the overall difference in mortality due to a diagnosis of a psychotic disorder needs to be addressed, and it needs the level of detail available in an EHR.  Psychiatrists in major health plans using large databases could get active feedback in a very similar manner.  The EHR could finally be used the way they advertised it a decade ago.         

George Dawson, MD, DFAPA

1: Tiihonen J, Mittendorfer-Rutz E, Torniainen M, Alexanderson K, Tanskanen A. Mortality and Cumulative Exposure to Antipsychotics, Antidepressants, and Benzodiazepines in Patients With Schizophrenia: An Observational Follow-Up Study. Am J Psychiatry. 2016 Jun 1;173(6):600-6. doi: 10.1176/appi.ajp.2015.15050618. Epub 2015 Dec 7. PubMed PMID: 26651392.

2: Robinson DG. Early Mortality Among People With Schizophrenia. Am J Psychiatry.2016 Jun 1;173(6):554-5. doi: 10.1176/appi.ajp.2016.16030334. PubMed PMID: 27245185.

3:  Newcomer JW, Hennekens CH. Severe mental illness and risk of cardiovascular disease. JAMA. 2007 Oct 17;298(15):1794-6. PubMed PMID: 17940236.

Pharmacosurveillance, Suicide and Antidepressants

I was board certified in geriatric psychiatry initially in 1991 and have been a member of the American Association of Geriatric Psychiatry since then.  Members receive the American Journal of Geriatric Psychiatry.  Treating depression in geriatric patients is a a very rewarding experience for psychiatrists because depression often masquerades as a severe medical problem like dementia, chronic pain, or Parkinson's disease.  Treating the underlying depression clears the manifestations that appear to be these other illnesses.  Even pure depression in an elderly patient can lead to significant medical compromise because of diminished physiological reserve and rapid compromise of nutrition or mobility as the result of sleep deprivation and inadequate intake.  That can occur as the result of discontinuing long standing antidepressant maintenance therapy.  The elderly also have some of the highest rates of completed suicide and that also factors in decisions about maintenance antidepressant treatment as well as effective psychosocial interventions to address that problem. 

In the January edition of the AJGP, Erlangsen and Conwell look at the relationship of completed suicide and antidepressant redemption in a nationwide cohort in Denmark.  The methodology of this study is not available in the United States.  Denmark has several registers based on a unique personal identifier for all of its citizens.  The authors looked at the Register of Medicinal Product Statistics and suicide as a cause of death in the Registry of Causes of Death for a cohort of people who were 50 years of age or older on January 1, 1996 through December 31, 2006.  Data on antidepressant use was identified and classified into tricyclic antidepressants, selective serotonin reuptake inhibitors and other types of antidepressants.  A treatment episode was considered to have occurred if a second prescription of antidepressants was filled and the patient appeared to be taking 0.75 tablets per day.

In terms of sheer number the study included 1,222,941 men and 1,346,973 women.  In the follow up period deaths by suicide numbered 3,061 men and 1,456 women.  As illustrated by Figure 1. below there is a decreasing number of those dying by suicide who redeemed antidepressant prescriptions.  In the 80+ year olds it was less than one in four women and less than one in eight men.  Trends were noted that percentage of men and women dying of suicide who took antidepressants decreased with increasing age.  This data is consistent with previous data that show that most elderly patient die by suicide are not in treatment at the time and they have clinically significant symptoms of depression.         

 (graphic removed by copyright manager - please see the original article)

This study is a good example of what kind of data is available with large databases across entire populations.  The limitations of the data are discussed by the authors including the fact that the pharmaceutical registry does not have any diagnoses and antidepressants have numerous indications.  They discuss why antidepressant redemption may not be the optimal proxy for antidepressant use.  In this case their study design considering only people who have redeemed the second antidepressant prescription to be in treatment.  That contrasts with some data suggesting the highest risk for suicide may occur in the initial days or weeks of antidepressant treatment.  They point out the usual qualification about association versus causality, but also conclude that "it is possible that antidepressants protect the oldest old from death by suicide" and point out the important public policy question of how to identify these patents.

There is a similar interesting study available that looks at a database that includes 3/4 of the population of the Netherlands (see reference 2).  It looks at the correlation between antidepressant use and both suicide and violence and concludes that there are significant negative correlations with both.  In other words increased antidepressant use led to decreased rates of suicide and violent behavior over the years 1994-2008.

When I read this study, I was also interested in what medical specialty is prescribing the bulk of the antidepressants.  I e-mailed one of the authors and asked that question.  The response was that the specific specialty of the prescriber was unknown but that bulk of antidepressants in Denmark were prescribed by primary care physicians and the likelihood of antidepressant prescription by primary care increases with patient age.  Psychiatric consultation was more likely to occur at a younger patient age.

In the United States we need pharmaceutical registries similar to the Danish registry.  We need a more factual basis to evaluate issues of pharmaceutical use over time, complications of prescription drugs, over prescription of drugs, and adequate drug utilization.  For example, with the recent concerns about stroke risk factor reduction in the elderly and stroke risk reduction from atrial fibrillation graphs similar to Figure 1. looking at all of the relevant medications may prove very useful.  Practically all pharmacy data in this country is proprietary and the largest database was developed to see if pharmaceutical representatives were having an impact on prescriptions written by individual physicians.  The  current development by individual states focused on the prescription of controlled substances is an opportunity to expand that data to identify important public health trends and reduce speculation.
  

George Dawson, MD, DFAPA

Figure 1. is reprinted from Am J Geriatr Psychiatry 2014 Jan; 22(1) Erlangsen A, Conwell Y. Age-related response to redeemed antidepressants measured by completed suicide in older adults: a nationwide cohort study, with permission from Elsevier. 

1:  Erlangsen A, Conwell Y. Age-related response to redeemed antidepressants measured by completed suicide in older adults: a nationwide cohort study. Am J Geriatr Psychiatry. 2014 Jan;22(1):25-33. doi: 10.1016/j.jagp.2012.08.008. PubMed Central PMCID: PMC3844115

2:  Bouvy PF, Liem M. Antidepressants and lethal violence in the Netherlands 1994-2008. Psychopharmacology (Berl). 2012 Aug;222(3):499-506. doi: 10.1007/s00213-012-2668-2. Epub 2012 Mar 7. PubMed PMID: 22395429; PubMed Central PMCID: PMC3395354

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).

Hyperbole and a Half blogger on NPR

It's Tuesday night and I just finished a lecture at about 7:40 and headed home.  That involves about a 45 minute drive down Minnesota Highway 8.  The last two days in Minnesota have been bitterly cold.  That first bitter cold that feels like it is 35 below, but it is really only there to steel you against 35 below.  It was actually 19 above.  The only consolation to driving down one of the most dangerous roads in Minnesota in the dark and bitter cold is that I get to listen to Terry Gross on NPR.  To make things even more interesting she was interviewing a depressed blogger with huge appeal on the internet.  She writes the popular blog Hyperbole and A Half.  

Terry Gross started out with a lot of questions about the quirky cartoon character that blogger Allie Brosh uses to represent herself on the blog.  The interview proceeds through some introductory excerpts but comes to the author's depression at about the 13:38 mark and goes for about 20 minutes.  As I am listening to her talk about depression, I am thinking of the hundreds of people I have talked with about their depressions.  I am always trying to find out if I missed anything or if there is a different way to view all of these unique presentations of depression.

Ms. Brosh's description of depression and its personal and interpersonal toll is unique among descriptions of depression I have seen in the media.  She talks about the transition from an emotional depression with excessive emotion and self loathing to a state that is totally devoid of emotion.  The "emotional deadening" in some ways is a relief and she later says that it has lead to reduced anxiety.   She has thought of herself as too emotional and thought it was interesting that she no longer had that weakness.  She blogs about it as Adventures in Depression and Depression Part Two and we have already learned that these were very popular posts on her blog.

In one example, she describes an interaction with a friend telling her that her cat has died and she states she is not able to generate enough "organic emotion" that she needs to be concerned about showing an appropriate facial expression to her friend.  Her concern is that she is doomed to live an emotionless state and that rapidly equates to meaninglessness and eventual suicidal thinking.  She talks about needing to manage this information to protect people and also protect herself from their emotional reaction.  She is eventually able to tell her husband and mother, but even during this interview she discloses that her husband may have heard details of her plan that he had never heard before.  This disclosure is clearly painful and she pauses - overcome with emotion.

The emotion in the interview is familiar to me.  It is how people really describe severe depressions.  They don't recite symptoms in a diagnostic manual, they talk about what the depression means to them and how it affects them and their relationships.  They talk about how it affects their inner life.  They talk about what seems to help and what strategies are useful and not useful.  In the moment, it can be painful to be around a person with depression.  Any empathic person resonates with the emotion in this interview.  At one point Terry Gross apologizes for putting her through it.  Things are tense.

Ms. Brosh talks about the type of interpersonal interaction that was most useful.  She cautions against advice giving like "try yoga" or be thankful for everything that you have and you will come out of your depression.  What was helpful was somebody taking her seriously and listening to her experience especially her thoughts about suicide.  As you listen to the interview she is clearly changed by the depression and has adapted to it.  Her main deterrent to suicide was the impact it would have on the people she loved, but we also hear how tenuous that connection can be during severe depression.  We learn that one of the thoughts that would keep her going if she got depressed again would be the idea that she knows she will come out the other side.  Terry Gross asks her about treatment and whether "any kind of therapy or medication that alleviates some of it?"  She clarifies that she is about 60% recovered.  Despite some initial concerns about medication she found that it (bupropion) was "very helpful".

I found this to be a powerful piece  about depression.  It describes the feeling and thinking state of the depressed person and the associated problems with relatedness.  At one point Terry Gross comments on the artistic aspects of creativity that flows from the depression and Ms. Brosh appreciates than comment.  With all of the abstract discussion of depression in the popular press and the assembly line treatment approach in health care systems, this interview is a more genuine discussion and rich source of information about what it is really like for the person and the struggle to recover.  I highly recommend listening to the audio file and reading the blog.

George Dawson, MD, DFAPA

Homicide Debate Goes Further Off the Rails

Apparently broadcast news is about as reliable as the Internet these days.  I was watching an "expert" on the weekend discuss the connection between homicide and antidepressant medications.  He apparently believed that there was one.  I understand that Sanjay Gupta made a similar comment today on CNN.  The misinformation is flying out there.  There are several political interests that would like that statement to be true and they appear to be out in full force. What is the short answer to the association between antidepressants and homicide?  Who can you believe?

Well there is always the scientific approach and a review of the medical literature.  Admittedly the literature is a lot drier and less entertaining than Dr. Gupta.

There is also simple arithmetic   The American media like to give the impression that violent crime and homicide are at epidemic levels.  It is always a shock when people discover that in fact we are at a 30 year low:

The homicide rate has actually declined from 10.2 per 100,000 in 1980 to 5.0 per 100,000 in 2009.  What are the odds of that happening if a major new cause of homicide is being added at the same time (namely antidepressants).  How does that compare with antidepressant use?  A recent study estimated that from 1996 to 2005, the number of Americans older than 6 years of age in surveyed households who received at least one antidepressant in the year studies increased from 5.84% in 1996 to 10.12% in 2005.  From the table there was a 24% reduction in the homicide rate during a time that antidepressant use nearly doubled.  One in ten Americans received an antidepressant prescription   The authors of this study noted this trend was broad based and correlated with a lower percentage of people receiving psychotherapy.

But what does that tell us about the observation that antidepressants cause homicide?  Technically there is no current way to demonstrate causality from a negative correlation between homicide rates and the rate of people taking antidepressants.  A large scale significant negative correlation between antidepressant use and lethal violence over a 15 year period has already been reported in the Netherlands.

What about the commentator suggesting that the toxicology of homicide perpetrators shows that they can have psychiatric drugs present that explain their homicidal behavior.  In fact, a study looking at that issue showed that 2.4% of 127 murder-suicide perpetrators had toxicology that was positive for antidepressants.  That is a lower than expected rate of antidepressant use than in the general population.   In a study of elderly spousal homicide-suicide perpetrators, depression was seen as an antecedent to this act but none of the perpetrators tested positive for antidepressants.

Given these observations any claim that antidepressant or any psychiatric drug causes homicidal behavior needs to be backed up with some hard data.  I don't mean a series of cases reported by somebody to make a point and I don't mean a legal decision where lawyers and judges can pretend that scientific data do not exist and make a decision about what they hear in a court room.  I also do not mean listening to somebody claim that we will never know the real relationship until we conduct "prospective double blind placebo controlled studies" of homicidality as a medication side effect.  If it isn't obvious, that study would by definition be unethical and would not pass the scrutiny of any human subjects committee.

Anyone with potential homicidal thinking needs close supervision and treatment.  They may need inpatient treatment in a unit that specialized in treating homicidal thinking and behavior.  Any clinician working in these settings will tell you that the people being treated generally come in with aggressive and violent thoughts and behavior before they take any medication.  If they have positive toxicology associated with homicidal thinking it is generally alcohol or an illicit drug like cocaine or methamphetamine.  Anyone with this problem also needs close monitoring and management of medication side effects.  Antidepressants can cause agitation and restlessness.  There are some people who do not benefit from antidepressants.  In the case of persons with the potential for aggression and suicide the medication response may need to be determined in a controlled environment before they can be safely treated.  Like all medications antidepressants are not perfect medications and they need to be administered by an expert who can provide effective treatment while managing and eliminating any potential drug side effects.

George Dawson, MD, DFAPA

Why antidepressants are not addictive

I recently noticed that a blogger posted his theory on the addictive properties of antidepressants. He pointed out that people get "psychologically addicted" and that using the term "addiction" for physical addiction seemed too restrictive. His supporting evidence is a newspaper article about how Glaxo Smith Kline dropped its claim on a patient information pamphlet for paroxetine saying that the drug was "not addictive".  David Healy is quoted as saying "If there is withdrawal, then there is physical dependence. There will be some people who will never be able to halt this drug, there will be some for whom halting will not be awfully difficult and some for whom it is a real issue". The article goes on to say that although SSRIs are not like opiates they are "more comparable to the benzodiazepines such as diazepam, which is now prescribed only with great caution because of withdrawal problems".

Working in the addiction field this entire line of thinking is rhetorical. There is significant psychiatric comorbidity in people with addictions with anywhere from 40-75% having co-occurring disorders. Most of those co-occurring disorders are anxiety disorders and depression and they are well known triggers for relapse as well as initiating drug and alcohol use in the first place. Contrary to public denial,  addictive disorders have huge liabilities in terms of morbidity and they are often lethal illnesses.  My goal is to reduce the risk of relapse by treating the co-occurring disorder while the person is being treated for addiction. SSRI medications are one of the mainstays of treating anxiety and depression these days. They are effective medications. I would not be prescribing them if they caused "psychological addiction". Furthermore, many treatment programs for addiction teach the concept of cross addiction and nobody studying that concept would want to take an SSRI if it caused any kind of addiction.

A better starting point would be to look at more comprehensive definition of what an addiction is. That starting point would be the October 2011 definition issued by the American Society of Addiction Medicine.  Paragraph 2 of the short definition will suffice and reading those four lines should make it very clear that the use of antidepressant medications does not lead to addiction. The real hallmark of addictions is uncontrolled use and there is no evidence that modern antidepressants are used in an uncontrolled manner.  Additional evidence is that antidepressants have absolutely no street value and therefore are in the majority of 34 million chemical compounds listed in Chem Abstracts of which only about 322 are addicting.

If your doctor has recommended that you take an antidepressant medication certainly be aware of the fact that there may be discontinuation symptoms. Discontinuation symptoms are not an addiction.  Needing to take an antidepressant for a chronic mood or anxiety disorder is not an addiction.  Contrary to Dr. Healy's opinion there are a number of nonpsychiatric medications can be discontinued and cause severe discontinuation symptoms.  The term "physical dependence" suggests an addiction or the inappropriate use of a potentially addicting drug where in fact that is not the case with antidepressants.  Comparing antidepressants to other clearly addictive compounds like benzodiazepines or opioids is not an accurate comparison across any dimension.  I agree that any person considering an antidepressant drug needs to be aware of the fact that mild to moderate symptoms can respond to psychotherapy as well as medication.  ANY medication can lead to rare but very serious complications.  Any person considering treatment with medications needs to be working with a physician who is skilled in the use of these medications and who can address any potential side effects.  My personal experience in treating people who have severe anxiety and depression is that they reach a point that anyone with a severe chronic illness reaches in making a decision about medication. That point generally involves asking themselves: "What else am I going to do?".

As physicians we can never minimize the importance of that question.

Does the FDA discriminate against antidepressants?

The FDA came out with a new warning on citalopram on 3/28/2012.  The main point of the warning is that citalopram may lead to electrocardiogram changes that can be associated with an abnormal heart rhythm or arrhythmia that is potentially fatal.  The specific change is prolongation of the QTc interval or the interval that correlates with the total duration of ventricular activation and recovery.

Citalopram is a widely used antidepressant medication and it widely used for three reasons.  It is not likely to have a lot of interactions with other drugs.  Citalopram figured prominently in the STAR*D algorithm from the largest study done on enhancing antidepressant effectiveness.  A third reason is that it is a generic medication and it is very inexpensive.  Psychiatrists have broad experience with the drug and the general experience is that it is well tolerated with little toxicity.

Flecainide is a Type IC antiarrhythmic agent indicated for the prevention of paroxysmal atrial fibrillation (AF), paroxysmal supraventricular tachycardia (PSVT), and the prevention of life-threatening ventricular  arrhythmias like sustained ventricular tachycardia. The FDA warnings on the drug include proarrhytmic effects and excess mortality.  The excess mortality was directly observed in a clinical trial done to suppress ventricular arrhythmias.

The black box warnings for each drug listed below are directly from Medline:

Looking at the safety concerns for both medications - important differences emerge.  First, the FDA recommends maximum doses for the citalopram not just for the a maximum dose for adults but in specific conditions including aging.  Searching the FDA web site shows exactly 25 references for safety concerns of flecainide and none of them contain that level of information.  Second, the citalopram warning shows a table of QTc interval changes by dose for both citalopram and escitalopram.  There is no information in FDA documents (that I could find) for flecainide even though it is widely accepted that flecainide causes dose related changes in not just the QTc interval but also the QRS and PR intervals  along with a host of additional effects on cardiac pacemakers and conduction.  The  overall tone of the release is  that citalopram is a potentially cardiotoxic drug.  Third, the ECG monitoring recommendations are not internally consistent.  The absolute cut off of a QTc interval of 500 ms is highly unlikely - even in cases where the patient is taking 60 mg per day or more of citalopram.  It is also unlikely that the QTc intervals in the citalopram warning will lead to a QTc interval of greater than 500 ms.  This will result in tens of thousands of ECGs done because that is the only way that the QTc interval can be determined.

The black box warnings and the recently issued warning all considered, serious questions are raised relative to drugs with known cardiotoxicity and the whole issue of QTc warnings in all psychiatric drugs.  Certainly nobody wants a rare severe complication as a result of a prescription medication but can it really be avoided?  What good would ECG screening do?  There have not been any trials to address that issue of whether all patients taking citalopram need baseline ECGs.  All the patients taking flecainide have probably had multiple ECGs done that indicate a possible need for treatment but there is little guidance on the ECG issue.  In many patients taking flecainide, patients get serial ECGs and they do exercise stress tests to rule out proarrhythmic effects.  Are the same precautions needed for patients on citalopram?

Are the thresholds for treatment different given the fact that flecainide caused increased mortality during clinical trials and citalopram did not?  There would be an argument that flecainide is used to treat life-threatening arrhythmias, but the other indication is for prevention of atrial fibrillation and atrial fibrillation is not a life threatening arrhythmia.  With regard to the seriousness of the diagnosis, major depression carries a lifetime mortality of 10%.  Finally, where is the table on the relationship between flecainide dose and QTc prolongation like we see for both citalopram and escitalopram?  Is it possible that flecainide has more of an effect throughout the dosage range than citalopram?

These are serious questions given that I have already established that there is a significant bias in the media against psychiatry, psychiatrists and psychiatric medications.  The most recent FDA warning has created a lot of anxiety for psychiatrists and any patient taking citalopram.  The majority of those patients are being seen by primary care physicians.

  

If citalopram is that cardiotoxic, let's see the evidence and let's see how it compares to a medication with known cardiotoxicity.  Let's have the same level of warning for both medications and some concrete ideas about what needs to be done to manage that risk.

George Dawson, MD, DFAPA

The Day the Quality Died

I don't know when it happened exactly but if I had to guess it was somewhere in the mid-1990's.  That was the time when quality changed from a medically driven dimension to a business and public relations venture. The prototypical example was this depression guideline promulgated by AHCPR or the  Agency for Health Care Policy and Research.  The guideline was written by experts in the field and there was consensus that it was a high quality approach to treating depression in primary care settings. One of my colleagues used this guideline in its original form to teach family practice residents for years about how to treat depression in their outpatient clinics. The actual treatment algorithm is listed below:

Managed care companies had a different idea about treating depression not only in primary care settings but also in psychiatric clinics. In less than a decade the standard of care had devolved to the point where antidepressants were started on the initial visit and the standard outpatient follow-up was at one month. In addition, even though cognitive behavioral therapy was proven to be effective for the treatment of depression the standard course recommended in those research studies was never used. It was common then and even more common now for depressed patients to see a therapist and be told that they seem to be doing well after two or three sessions and there is probably no need for further psychotherapy. They typically did not receive the research proven approach.

The latest innovation is to assess and treat depression in outpatient clinics on the basis of a PHQ-9 score, and have psychiatrists follow those scores and additional information from a case manager in recommending alterations in therapy for patients with depression.  Although it was never designed to be a diagnostic or outcome measure the PHQ-9 is used for both.

The current model of maximizing medical treatment of depression in managed care clinics is an interesting counterpoint to psychiatrists bearing the brunt of criticism for over treating depression with ineffective antidepressants. The recent FDA warning about prolonged QTc syndrome from citalopram is another variable that suggests there are potential problems in maximizing antidepressant exposure across a primary care population where the number of people responding to psychotherapy alone is not known but probably significant.

There is another aspect of treating depression in primary care clinics that illustrates what happens when you think you are treating a population of people with depression. The new emphasis by politicians and managed care companies is screening for early identification of problems. The political spin on that is early intervention will reduce problem severity and of course save money.  Various strategies have been proposed for screening primary care populations for depression. It reminds me of the initiative to ask everyone about whether or not they have pain when their chief complaint has nothing to do with pain.

In the Canadian Medical Journal earlier this year, Thombs, et al, concluded that the evidence screening is beneficial and the benefit outweighs the potential harm is currently lacking and that study should be done before depression screening in primary care clinics is recommended. A recent op-ed by H. Gilbert Welch, M.D. in the New York Times is more accessible in the discussion of the risks of screening.

The irony of these approaches to depression in primary care clinics can only be ignored if the constant drumbeat of managed care companies about how they are going to save money and improve the quality of care is ignored. Despite the frequently used buzzword of "evidence-based medicine" this has nothing to do with evidence at all. It is all smoke, mirrors and public relations.  It makes it seem like managed care companies can keep you healthy when in fact they have all they can do to treat the sick and make a profit.

That is the true end result when medical quality dies and politicians and public relations takes over.

George Dawson, MD, DFAPA

Thombs BD, Coyne JC, Cuijpers P, de Jonge P, Gilbody S, Ioannidis JP, Johnson BT, Patten SB, Turner EH, Ziegelstein RC. Rethinking recommendations for screening for depression in primary care. CMAJ. 2012 Mar 6;184(4):413-8.

H. Gilbert Welch.  If You Feel O.K., Maybe You Are O.K.  NY Times February 27,2012.

Managed Care 101 – The Prior Authorization Hoax

As managed care organizations worked on how they could prioritize pricing over medical decisions they came up with various plans to “manage” how physicians prescribed medications.  I was a member of two Pharmacy and Therapeutics Committees (P & T) that  both had this as a goal.  One of those committees had a much stricter mandate in terms of saving money.  The basic strategy used by that committee was to place a drug “on formulary” or “off formulary”.  If it was “off formulary” it was not available to any doctors within the HMO to prescribe.

The idea that all drugs within a class that had the same purported mechanism of action ruled the day.  As an example, all of the selective serotonin reuptake inhibitors (fluoxetine, paroxetine, sertraline, citalopram, escitalopram, fluvoxamine) would be considered equivalent medications and the committee would decide to place the least expensive ones on the formulary.  At the time, the major controversy was fluoxetine because there was no generic brand available and the company that produced it was notorious for not negotiating prices with hospitals and health care systems.  There was an eventual appeal by psychiatrists who presented to the committee on the unique qualities of fluoxetine.  At the time it was the only medication studied in adolescent depression for example.  Eventually a rule was passed that it was nonformulary for any physician who was not a psychiatrist.

The total cost of the drug was more of a consideration than the absolute price.  Very expensive drugs were approved that had questionable endpoints based on the fact that utilization would be low and that advocates for a particular untreatable illness would want it.  So the decision of the committee and their mandate was to reduce the use of relatively more expensive drugs that would be used fairly frequently.  In some cases, the off formulary drugs were available by “prior authorization” meaning that the prescribing physician needed to usually write up an appeal and fax it to the pharmacy or health plan and in some cases make additional calls.

The health care business has a long history of introducing layers and layers of management driven largely by the amount of money involved.  If you can successfully insert more management for even a small percentage of the available health care dollars you will potentially have a multi billion dollar business.   The management of pharmaceuticals is no exception and the Pharmacy Benefit Manager or PBM was born.  The task of the PBM like the task of a P & T Committee is to control the prescribing physician and force them to choose a medication based on the lowest cost.  Individual variation between patients and all of the other variables that physicians have to take into account do not matter.  If the physician or the patient thinks that they do – it will take a prior authorization for the alternate medication.  

The PBM model was designed from the outset to take a central role in the management of prescription drugs by replacing the relationship that the patient has with their health plan, their pharmacist, and even their physician.  How do I know this?  Take a look at their game plan from an internal memo in the diagram below.  This diagram was taken from an internal memo from over 15 years ago.  The structure depicted in the diagram is the system of care that exists today and the one that 95% of patient have their benefits managed through 

The prior authorization fallacy is essentially the same as the utilization review fallacy.  The most charitable interpretation is that it assumes that a person who is not necessarily a physician and who has no personal responsibility for your care can substitute their judgment based on a cost consideration.    

The diagram is also instructive in the way that the prescribing decision (and the dispensing decision) is trivialized as a "habit" rather than a decision that takes into account the evaluation and personal knowledge of the individual patient.

Today all physicians are routinely subjected to prior authorization procedures that waste significant amounts of their time and the time of their staff in order to make seem like the PBM decision has some degree of medical legitimacy.  The cost to medical practices is huge and completely unnecessary.  If PBMs are really businesses there is really no legitimate reason that they need to include physicians in their decisions of what medication should be covered.  They just need to plainly state that to their patients and deal with the public relations problems instead of wasting about one million hours of physician time per week.  In the weeks that follow I will demonstrate just how far this business plan has infiltrated medicine and psychiatry and what the response has been to date.

George Dawson, MD

Antidepressants - the limited analysis of a polarized argument

The current President John Oldham and President-elect Jeffrey Lieberman of the American Psychiatric Association came out with this press release today on a 60 Minutes episode characterizing antidepressants as no better than placebo.  They describe this characterization as “irresponsible and dangerous reporting” and “a message that could potentially cause suffering and harm to patients with mood disorders.”

It is good to see the APA finally taking a stand on this issue.  Antidepressants and the psychiatrists who prescribe them have been taking a pounding in the popular press for years.  The main proponent here was also featured in a Newsweek headline story two years ago.  This is a prototypical example of how the media and special interest groups can distort science and facts and politicize the discussion that must be nuanced.  The problem is that you have to know something and be fairly free of bias to participate in a nuanced discussion.  Like most issues pertaining to psychiatry, the issue is always polarized and poorly discussed in the media.

I got involved in this issue as a managing editor of an Internet journal and I solicited a paper from a world renowned epidemiologist to get his current view on antidepressant meta-analyses. In order to present the entire argument I also solicited response from a world renowned psychopharmacologist with broad expertise in this field. Both articles are available online for free and I think if they are both read in total they represent the most accurate picture of antidepressant response.  Both references are listed at the bottom of this page.

Rather than get into the specific details at this point I will say that it was extremely difficult to find a anyone willing to provide a rebuttal to the to the original article by Ioannidis, but anyone who reads that paper by Davis, et al and who follows the antidepressant literature will have a greater appreciation of the effectiveness of these medications.  I hope to post some information on the statistical analysis as well.  At some level people tend to view statistics as a hard mathematical science and there is plenty of room for interpretation.  The use of meta-analysis is a common approach to these problems and a detailed look at the shortcomings of meta-analysis are seldom discussed.  That might explain why one meta-analysis shows minimal effects and another shows that there might be some antidepressants with unique effectiveness (see Cipriani, et al)

A final dimension that is critical in the analysis of any source is potential conflicts of interest.  The only conflict of interest that is typically discussed is the financial interests of authors and pharmaceutical companies in producing positive trials.  That ignores the fact that many of these trials have been very public failures and that post trial surveillance limits the use of some of these compounds.  There are other conflicts of interest to consider when an author is selling a viewpoint and can potentially profit from it – either financially or politically.

The APA could provide a valuable service here in making the documents from the FDA and the EMA widely available for public discussion and analysis.

George Dawson, MD

 “60 Minutes” Segment on Antidepressants "Irresponsible and Dangerous" – APA New release Febrary 22, 2012.

Ioannidis JP. Effectiveness of antidepressants: an evidence myth constructed

from a thousand randomized trials? Philos Ethics Humanit Med. 2008 May 27;3:14.

Davis JM, Giakas WJ, Qu J, Prasad P, Leucht S. Should we treat depression with drugs or psychological interventions? A reply to Ioannidis. Philos Ethics Humanit Med. 2011 May 10;6:8.

Cipriani A, Furukawa TA, Salanti G, Geddes JR, et al.  Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis.  The Lancet - 28 February 2009 ( Vol. 373, Issue 9665, Pages 746-758 )