Saturday, May 25, 2019

Chemical Imbalance As Advertising Meme




After a protracted discussion on the previous post, I thought I would go down to the University of Minnesota Biomed library today and look at the drug ads in psychiatric journals at about the time Prozac came out in 1987. I was interested in the trends before and after so I picked the years 1985 to 1995. I also picked the journals the American Journal of Psychiatry, Archives of General Psychiatry (currently JAMA Psychiatry), and the Journal of Clinical Psychiatry.  I was going to include JAMA and the New England Journal of Medicine.  They had about the same number of ads but none of them in that year contained ads for psychiatric medications.

This kind of search is labor intensive these days. There was a time on the early days of the Internet when entire journals with all of the ads were scanned in. As a subscriber I could have run that search from home.  These days, all of the ads are gone and the references are saved as text files only. In order to see historical ads - the hard copy of the original journal needs to be examined. Even then there are some problems.  I encountered some bound volumes where the ads were physically removed. There were two to three bound volumes per year and additional copies of the NEJM and JAMA - I may have looked at 75 bound volumes over 4 hours.

In many ways it was a walk down memory lane.  Clozaril and Haldol Decanoate ads were especially heavy in the early 1990s.  There were ads for medications that I prescribed all of the time like Navane and Pamelor and ads for drugs that I seldom prescribed like Stelazine, Serzone and Luvox. There were ads for new drugs that I would prescribe once like Paxil.  It was a reminder that despite all of the advertising - a  lot of drugs end up never being prescribed by physicians.  My reason for being there was to look for the origins of the term "chemical imbalance" in this advertising.

I decided to embark on this project because of all of the inaccuracy about the term, especially the tendency to blame psychiatrists for it. In my previous post, I attempted to point out that it is a fairly straightforward process to conclude that the human brain does not run on chemical imbalances - just based on the average scientific knowledge of physicians. On the advertising side, I was there for the first National Depression Screening Day in 1990 and that was the first time I heard the term. The event has been criticized as a venue for allowing a pharmaceutical company to showcase their product.  I participated in the event for 3 years and the advertising involved was much more subtle than is found today at NAMI walks for example. But the question is whether the advertising meme "chemical imbalance" was introduced at that time. Any event that happened 30 years ago is very hard to track. As the Public Affairs Rep for my District Branch of the APA, I had a lot of files about it that I subsequently trashed. I am guessing there were also some files on disk drives that would have been helpful.  This is a reconstruction without that data.

I successfully located the first Prozac ad in AJP from 1988.  The graphics are all iPhone photos so there is some distortion.  Chemistry is emphasized on page one as in the chemical structure, chemically unrelated to other antidepressants, distinctive chemistry, and the first highly specific and highly potent blocker of serotonin reuptake.



Why is this important? At the time most of the antidepressants being used were tricyclic antidepressants.  They could not claim any specificity and in subsequent ads manufacturers start to compare possible side effects based on transporter monoamine protein and receptor affinities. The Prozac molecule was being hyped as being chemically unique and with a better side effect profile. As Prozac started to sell more it became a blockbuster drug for Eli Lilly and at that point the manufacturers of other new antidepressants noted and the competition heated up.  There were some direct references to Prozac in the ads from competitors.

The best example is this Wellbutrin ad from AJP in 1991. Prozac is directly mentioned in the ad and reasons are given for choosing Wellbutrin over Prozac.  Being non-serotonergic is one of them and this is more of a counter to Prozac advertising as being a unique first highly selective serotonergic drug.  It gives little or no weight gain as a reason, but at the time I was seeing obese patients who were taking 80 mg of Prozac because their primary care physicians told them they could lose weight taking it. Of the other bullet points it seems that lack of sexual dysfunction would be  the most relevant. The marketing decision in this case was a conscious decision to go after the purported serotonergic effects of Prozac rather discuss the hypothetical mechanism of Wellbutrin.  The side effect of Wellbutrin that most physicians are concerned about - seizures - is in the smaller print below the bullet points.


Effexor came up with similar ads.  In the late 1980s and early 1990s, synaptosome technology was invented to look at binding affinities of central nervous system medications to specific receptor sites.  The quantitative aspects of these studies were generally globalized in the psychiatric literature to qualitative ballpark effects.  For example a plus or minus grading system could be used ranging from no effect at a receptor (-) to a robust effect (++++).  Effexor advertising used this to compare side effect profiles among the competitive antidepressants at the time.


This ad emphasizes that Effexor is "a structurally novel antidepressant and is chemically unrelated to any other available antidepressant."  It shows the table with comparisons to tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) and what might be predicted based on the in vitro synaptosome data with the qualifier that the clinical significance of that data is unknown.  Clinically most people are able to tolerate all three classes of medication but some will not.  The differences can't be predicted on the basis of the receptor binding studies because of receptor heterogeneity and differences in drug metabolism.  For example, I still prescribe TCAs. It is nortriptyline and it is the only one I have ever prescribed. At the doses I prescribe and per the table in the ad - it is as well tolerated as SSRIs and SNRIs (Effexor).  The ad appeared in the AJP in April of 1994.  On that basis the argument could be made that it is an appeal to the technical expertise of psychiatrists and it should contain this information.  That also points to a weakness in my informal advertising study and that is a lack of ads from the non-technical consumer literature from the same period. (see supplementary on a proposal).

I have 30 additional ads from the journals but the themes are roughly the same. An emphasis on medicinal chemistry and the suggestions that some chemistry is better than others. Interestingly, in my previous post the whole point was that this is the kind of argument that would not fly based on what the average physician knows about chemistry and molecular biology. Psychiatrists should know a lot more because the evidence for and against these theories had been reviewed in the psychiatric literature 20 years before these ads came out (1974-2002) (1).  And they are engaged in clinical practice and need to be skeptical of newly introduced products and claims.

What I did find so far is unequivocal evidence that the chemical imbalance meme was used to directly market antidepressants to the public.  The Zoloft ad embedded at the top of this page from 2001 is the first example.  The second example is this Paxil ad from the same year.

That is what I have so far.  See the Supplementary below to find out what you can do to complete the story. I don't have a problem with people telling me that their doctor told them that they have a chemical imbalance and their antidepressant is supposed to treat that. I don't have a problem with people saying that their psychiatrist told them that.  I do have a problem with people saying that all or even most psychiatrists say this and that psychiatrists are behind this meme.

There is an exaggerated focus on the mechanism of action of medications used for psychiatric indications. I have never heard anyone say their doctor told them about the mechanism of action of antibiotics or even their blood pressure medications. In the case of antibiotics it is clear that people demand them and they don't care what the risks or mechanisms are.  This advertising campaign may have something to do with the conversion of folk psychologists to folk psychopharmacologists.  A friend of mine also brought up an important aspect of this campaign that is also addressed by these manufacturers and that is legitimacy. For decades people with depression and anxiety were viewed as weak people with a questionable problem.  My friend told me that these ads confirmed that she had a serious problem that needed a serious solution and that it was finally acceptable to talk about it.  Say whatever you want about Big Pharma advertising but it apparently carried the message that current "Let's Talk About Mental Health" programs do - but over 15 years ago.

The attribution of an advertising meme to psychiatry and psychiatrists despite the fact it has never appeared in 30 years of psychopharmacology texts is not a trivial fact.  The advertising videos posted here  were viewed by tens of millions of people.  I hope to get more information and still have some people to contact. With any luck I will be able to fill in the additional data between the release date of Prozac in 1987 and the ads posted here from 2001.

Please send me anything you might have from those dates.



George Dawson, MD, DFAPA


References:

1.  Nathan KI, Schatzberg AF. Mood disorders. in Review of Psychiatry, vol 13. American Psychiatric Press, Washington DC(1994): p.171-184


Supplementary 1:

From the  information I posted above it is clear that chemical imbalance was an advertising meme introduced during the height of competition of blockbuster  antidepressant drugs.  The  common Wall Street definition of a blockbuster pharmaceutical is a product that generates sales of a billion dollars a year.  There are two important pieces of data that would be useful to complete the story.

The first is earlier ads with the term chemical imbalance. So far, I have two from 2001, but I am certain it appeared before that. I don't have time to search all of the popular literature.  If you subscribe to a magazine that has pharmaceutical advertising and keep all of the old volumes - take a look at the editions from about 1987 to 1995. If you see the term chemical imbalance please send me the image with the name and date of the periodical.  Let me know if you want credit for finding the image and I will give you full credit.

If you are a current or former pharmaceutical rep or marketing person and have access to any documents or videos with the chemical imbalance phrase please send it to me with the date it was being used. If you have recollections of how it was implemented and when I can also use that information but I am most interested in clear documentation like the videos I have posted. I have no interest in vilifying the pharmaceutical industry and understand the need for marketing and advertising.  I am just interested in the origins of this term and how it was implemented.

If you are an APA member and you were involved in the original National Depression Screening Day in 1990 - you may also have some information about this.  Please send it to me.

Thanks!


Supplementary 2:

All of the name brand drugs/medications mentioned in this post are currently generics or are no longer manufactured.  I have no affiliation with the original manufacturers or the generic drug industry.


Supplementary 3:

There are various Internet sites that attribute the term chemical imbalance to Pfizer or Lilly but they do not appear to be reliable - many appear to be antipsychiatry sites.  I would like to hear from people who were there at the time and can provide the necessary proof.  In those days (1986-1996) it would have been an internal memo or presentation.  Send me a copy if you have it.


Supplementary 4:

I had the opportunity to discuss this issue with a corporate attorney - especially the issue of available emails and memoranda dating back to 1987.  He told me that corporations hold this data only as long as the law states they needs to.  For example, if the law states the data must be held for 4 years it will be held exactly that long and then everything will be shredded.  If this information exists it will probably be in private hands.

Supplementary 5:

I got the expected low level feedback from a Twitter poster who thought he was making some point about this link on the Royal College of Psychiatrists web site suggesting that at least one of the causes of schizoaffective disorder was "a chemical imbalance".  I guess he really thought he had made me looking foolish especially with the proclamation "You aren't psychiatry - they are."

https://www.rcpsych.ac.uk/mental-health/problems-disorders/schizoaffective-disorder

In fact, I can't tell who wrote this and whether or not it is a psychiatrist. I don't know what the RCP official position is.  I was happy to see that they are much more flexible than the anti-psychiatry Twitter posters I encounter.  There was a feedback form that I completed and advised them to lose the "chemical imbalance" and that replacing it with "unknown etiology" was preferable. What I would like to see is an exposition of the latest theories and a suggestion that the critics actually read psychiatric literature.  They would be less likely to perseverate the same criticism they have used for year after year. This poster also seemed to ignore the fact that the RCP public information was posted in 2015 - that's 14 years after the television ad posted at the top of this page.  Royal College of Psychiatrists - the ball is in your court.



Monday, May 20, 2019

The Non-Existent Chemical Imbalance Theory





I keep looking for it and can never find it.  The above picture is my stack of psychopharmacology texts dating back to about 1980 and none of them mentions "chemical imbalance".  I could add another foot or two that stack and there still would be no mention of this theory.

Why is that important? The main reason is that one of the favorite arguments by anti-psychiatrists is that real psychiatrists believe that psychiatric disorders are caused by a “chemical imbalance” in the brain. This criticism showed up on this blog several years ago in a post that I critiqued that was largely a screed against psychiatrists. Accusing psychiatrists of promoting a chemical imbalance theory is an almost perfect rhetorical strategy. It uses what essentially was a marketing device for antidepressants in the late 1980s to portray psychiatrists as excessively reductionist at the minimum and at the worst biologically naïve and dishonest.

My colleague Ron Pies, MD has written a recent piece on the historical, philosophical, and rhetorical aspects of this argument. What I hope to accomplish in this post is taking a look at the science behind why no psychiatrist would consider the brain to be a substrate run by “chemical imbalances”. Some might find this argument to be quite boring but I can attest to the fact that the premises used allowed me to state unequivocally to the first pharmaceutical rep to use the term that no such state exists in the brain.

The main factor has to do with how physicians are trained. There’s still a lot of confusion about whether a psychiatrist is a physician or not. I can assure anyone reading this that we all are. That means in order to get into medical school certain prerequisites at the undergraduate level have to be completed. That includes a year of general chemistry, a year of organic chemistry, and a year of general physics. A significant number of psychiatrists that I have encountered were chemistry majors. That training means that physicians in general have had exposure to physical science and how chemistry works in solutions and gases.  In these basic two or three component systems there are limited possibilities in terms of reaction outcomes. Even electrochemical reactions produce electron flow that decays predictably over time but that is not able to transmit any nuanced signal.  In other words the information content in these systems is low – too low to run biological organisms.

In the basic science years of medical school biochemistry, neuroanatomy, neurophysiology, pharmacology, and all of the associated molecular biology provided medical framework that all of the physical science can be mapped onto. The study of enzyme and receptor systems highlight the basic concept that the chemistry involved can only occur because it is in a specific microenvironment. That microenvironment includes the protein structure of the enzyme or receptor molecules as well as associated membrane components and cell signaling components. The intracellular and extracellular environments are exquisitely controlled as is the synaptic cleft. Many of the reactions involve additional acid-base and ionic gradients. The degrees of freedom in this many component and many phase systems are large. They are so large in fact that I have been unable to find an estimate of degrees of freedom for neurobiological systems.

A good example of the kind of microenvironments and complex interactions that I am taking about is the GABAA receptor depicted diagrammatically below. The GABAreceptor is a transmembrane cylindrical receptor that is a member of the pentameric ligand-gated ion channel superfamily.   The diagram is a top down view of the receptor complex cylinder highlighting that it is composed of 5 glycoprotein subunits.   Each subunit is composed of 4 domains with one domain that lines the chloride ion channel through the center of the receptor complex. Binding sites on these protein allow for allosteric modification of the cylindrical receptor to facilitate chloride ion influx and fast inhibition of neuronal signals.  Allosteric modulation of enzymes and receptors occurs when a molecule reversibly binds to the protein molecule resulting in inhibition or stimulation of the overall process.  For example, benzodiazepines bind to a specific site at the α-γ interface leading to increased affinity for GABA at the receptor sites and increased chloride ion influx. Benzodiazepines are the classic allosteric modulators of the  GABAreceptor but there are others.  Barbiturates,anesthetic agents, neurosteroids and ethanol are also allosteric modulators at the GABAA receptor.  The detailed structure of both the benzodiazepine and flumazenil binding sites on the human synaptic GABAA receptor have only recently been detailed (1). 



The above paragraph is a glance into the types of systems that modern psychiatry is focused on.  In the case of the GABAreceptor global inhibitory effects can be expected at some point, but there are not the product of chemicals floating about inside the body or brain. They are the effects of complex interactions between proteins, positive and negative modulators, neurotransmitter effects, ion fluxes, and additional signalling.  The effects result from where these receptors are located in the brain and central nervous system. The education of physicians assures that this level of complexity in the brain is appreciated as both the basis for normal physiology and also the basis for pharmacology and toxicology. It may be tempting to try to simplify things - but real brain function defies simplification.  The basic working of the GABA receptor was discovered when I was in medical school back in the 1980s. The lectures in those days showed a simple structure with an arrow showing increased chloride ion permeability but nowhere near the structure that we currently have. 

This is one set of receptors and modulators very simplified. To get more of the story read the 22 pages of reference 1.  To understand the brain and modern pharmacology much more needs to be understood. Forgetting about the term "chemical imbalance" is a good first step.

George Dawson, MD, DFAPA


References:

1: Zhu S, Noviello CM, Teng J, Walsh RM Jr, Kim JJ, Hibbs RE. Structure of a human synaptic GABA(A) receptor. Nature. 2018 Jul;559(7712):67-72. doi: 10.1038/s41586-018-0255-3. Epub 2018 Jun 27. PubMed PMID: 29950725; PubMed Central PMCID: PMC6220708.

2:  Human GABA-A receptor alpha1-beta2-gamma2 subtype in complex with GABA and flumazenil, conformation A.  Detailed structure from the above paper.





Tuesday, May 7, 2019

Suicide Risk After Hospital Discharge





Inpatient psychiatrists in the United States deal with three problems: suicide risk, aggression risk, and the inability care for oneself or impaired functional capacity. Those have always been the primary reasons why people are admitted to psychiatric hospitals. Over the past 30 years there has been a problem with business intruding on these medical indications. Businesses and or more specifically managed care companies eventually adopted a single codeword “dangerousness”. Dangerousness was supposed to encompass all three of the dimensions but eventually it developed a life of its own. As an example, I have been asked by insurance company reviewers “Where’s the dangerousness?” whenever they tried to throw one of my patients out of the hospital and onto the street. Science or medical principles were not involved, just the economics of being able to use a word to make money.

The reality of inpatient work is that the people there are very high-risk for suicide, aggression, and premature death from multiple causes. There was a study done in Germany about 20 years ago where they looked at all-cause mortality of people discharged from psychiatric units five years later and the number was very high. Post discharge suicide rates are much higher than suicide rates in the general population. These high numbers are expected because patients and inpatient units are selected for these traits that predispose to higher mortality and morbidity. The trends have been complicated by much shorter lengths of stay and bed limitations that means patients with severe mental illness may be refused admission even if they clearly need it. As example, since leaving the inpatient setting about 10 years ago, I have attempted to refer severely ill patients to psychiatric hospitals and they were turned away at the emergency department. In some cases they were turned away without being seen by a physician. There are probably a handful of psychiatrists in the United States who know the type of problem that needs to be treated that inpatient units and I am one of them.

That situation makes a recent study on risk of suicide after discharge from inpatient psychiatric care and interesting one. The study was done in Sweden. It encompassed the years 1973 to 2009. During that time there were 2,883,088 admissions and presumed discharges. 690,937 patients were discharged more than once. Most the discharges were men (57.6%). There were no explicit indications for admission. Patients were followed up and it was determined that there were 3695 suicides within 30 days of discharge. The authors calculated a suicide rate of 181/10,000.  The discharge diagnosis most associated with suicide with depression. They gave some rough estimates of the prevalence of disorders in this population: 34% alcohol use disorder, 15.5% had mood disorders and (bipolar disorder or depression) and 9.9% had schizophrenia. 

Looking at the results according to diagnosis depression was followed by reaction to crisis or what is probably called an adjustment disorder in the US, but any specific psychiatric disorder and elevated hazard ratio for suicide within the first 30 days of discharge relative to the diagnosis of alcohol use disorder. 

Suicide risk was also examined relative to recent suicidal behavior. The suicidal behavior was considered to be any deliberate self-harm less than 30 days prior to admission. That was noted to have a hazard ratio of 4.75. The diagnoses were re-examined in the context of deliberate self-harm prior to admission and the risks were significantly higher in schizophrenia (HR = 8.94) and other nonorganic psychosis (HR =6.82).  Interested readers are referred to the full text which is available free online for the specific details including hazard ratios and confidence intervals for those hazard ratios.

The main findings of this study include the association of relatively high risk at discharge for most diagnoses and much higher risk if a specific diagnostic category was associated with a self-harm event 30 days prior  to admission.  This confirms clinical risk assessments that are typically done and also the fact that this is a high-risk population.

The authors do state that they regarded principal diagnosis at discharge to be the best available information on the reason for admission. I contacted the corresponding author about this and he did confirm that the reasons for admission in Sweden are very similar to what they are in the United States and that is suicide risk, aggression risk, and ability to care for oneself - but those specific metrics were not listed in the paper. 

The authors speculate on why the suicide risk is high. They describe the slow recovery from depression and the clearing of psychomotor retardation prior to the resolution of depressogenic thinking.  In the US, psychiatrists are generally taught that psychomotor retardation may reduce the risk of acting on suicidal thoughts so that during treatment there may be a point where activation may put the person at risk for acting on unresolved suicidal thoughts. Given the characteristics of suicide particularly the impulsivity associated with it this progression of events has never been proven and remains highly speculative. The authors also had the interesting observation that crisis events or negative life events are expected to offer good prognosis but this study showed men with the diagnosis of reaction to a crisis were at high risk after discharge irrespective of whether there was any recent suicidal behavior.

The authors review the strengths and limitations of the study. The main strength is that it is a large-scale study with a significant number of suicides. They also point out how their study has similarities with other studies of suicide in hospitalized patients. On the limitation side most of the limitations had to do with a lack of granularity in the data. I pointed out the lack of specific admission indication in addition to diagnosis. In current databases there may be metrics having to do with the level of suicide or aggression risk. There are some large-scale studies being done on an outpatient basis looking at those metrics as well as supportive interventions based on risk scores.

The biological side was not discussed in this study even though the database used probably contained all of the admission and discharge medications. It would be interesting to know if certain pharmacological interventions were more or less associated with suicides after discharge. It would also be very useful to know if there were any protective factors from inpatient treatment that could be discerned from the data both from the standpoint of psychosocial interventions and biological interventions like electroconvulsive therapy, transcranial magnetic stimulation, or treatment with ketamine.

I have included a reference to another study of post discharge suicide rates done in a Medicare sample and with a slightly different methodology (2).  In this case the researchers looked at a population of 770,643 patients with mental disorders compared with a 1,090,551 patients in a cohort with no mental disorders and compared suicide rates in the first 90 days after discharge. They found suicide rates that were 10-20 times higher in the mental disorder cohort.  The non-mental disorder cohort had a rate that was lower than the baseline suicide rate in the US at the time (11.6 versus 14.2 per 100,00 person years).  Like the Swedish study rates were the highest for mood disorders. Comparing both of these studies would be an interesting seminar for residents or journal club for staff psychiatrists interested in different epidemiological approaches to the same clinical problem.  I have included two references by Chittaranjan Andrade, MD and encourage the use of his series on statistics and epidemiological concepts in the Journal of Clinical Psychiatry.

From a clinical standpoint, the take-home message for clinicians is to make sure that deliberate self-harm prior to admission and the diagnosis are carefully explored. It is fairly common practice to consider adjustment disorders to be low risk in terms of brief hospital stays and discharge plans that do not include intensive outpatient treatment. This study suggests that at least some of those patients need more intensive intervention but there is no guidance on how to identify that group. The other high-risk groups of patients with psychosis that had deliberate self-harm prior to admission and any trained inpatient psychiatrist should admit those patients and treat them until there is clinical improvement that results in decreased risk.

My only concern about the current patient flow through emergency departments and onto psychiatric inpatient units is that many of these patients never get admitted and if they do they are discharged in a short period of time with the same symptoms that they presented with.  The inpatient environments in the US are also deteriorated to the point that they resemble correctional settings and patients want to leave as soon as possible.

These are not good ways to address the issue of post hospitalization suicide risk in a high risk population.

George Dawson, MD, DFAPA




Reference:

1:  Haglund A, Lysell H, Larsson H, Lichtenstein P, Runeson B. Suicide Immediately After Discharge From Psychiatric Inpatient Care: A Cohort Study of Nearly 2.9 Million Discharges. J Clin Psychiatry. 2019 Feb 12;80(2). pii: 18m12172. doi: 10.4088/JCP.18m12172. PubMed PMID: 30758922. (full text)

2: Olfson M, Wall M, Wang S, Crystal S, Liu SM, Gerhard T, Blanco C. Short-termSuicide Risk After Psychiatric Hospital Discharge. JAMA Psychiatry. 2016 Nov 1;73(11):1119-1126. doi: 10.1001/jamapsychiatry.2016.2035. PubMed PMID: 27654151. (full text)

3: Andrade C. Why odds ratios can be tricky statistics: the case of finasteride, dutasteride, and sexual dysfunction. J Clin Psychiatry.2018;79(6): 18f12641. Link

4: Andrade, Chittaranjan. Drug interactions in the treatment of depression in patients with ischemic heart disease. The Journal of Clinical Psychiatry 73.12 (2012): 1475-1477.