Epistemic Injustice Is Misapplied to Psychiatry

Some of the greatest minds in psychiatry have emphasized the importance of philosophy in the field and done some excellent work in that area. Unfortunately philosophy can also be used to attack the field and when it is, some of that work is not very well done. Since I’ve been writing this blog there have been a couple of examples. The first was the argument that the DSM-5 was a “blueprint for living”. My counterargument is available at this link and you can read the subsequent dialogue. It should be evident from my argument that the DSM-5 is the farthest thing from the blueprint for living that a psychiatrist could imagine. The political context for that article in the New York Times was the supposed controversy about the DSM-5. It was being portrayed in the media as almost apocalyptic and this opinion piece fit right in.  I always viewed the DSM-5 as the non-event that it proved to be.

The second couple of articles focused on critical psychiatry. One was an opinion piece about critical psychiatry and the second was a summary of critical psychiatry written by a couple of critical psychiatrists. In the philosophy literature as it applies to psychiatry there is always a lot of hedging around the issue of whether philosophical critics are anti-psychiatrists or something else. Some authors for example refer to them as skeptics. I have no problem with the school that sees them as anti-psychiatrists and made the argument that if critical psychiatrists based their criticism on antipsychiatry philosophers they are in fact anti-psychiatrists.

The latest philosophical criticism of psychiatry is an opinion piece (1) called “Epistemic injustice in psychiatry.” It is written by an author who has a doctorate in philosophy and is a psychiatrist and two academic philosophers. Their main thesis is that epistemic injustice occurs to a number of people based on biases against them and this prejudice undermines their credibility in that context.  In the case of medical treatment, that means the patient is not taken seriously and their treatment plan would be more unilateral on the part of the provider rather than collaborative and seriously considering their input. But I don’t want to minimize the authors definition and so I am including it at this point below:

“Epistemic injustice is harm done to a person in her capacity as an epistemic subject (a knower, a reasoner, a questioner) by undermining her capacity to engage in epistemic practices such as giving knowledge to others (testifying) or making sense of one’s experience (interpreting). It typically arises when a hearer does not take the statements of the speaker as seriously as they deserve to be taken.”

They cite racism and sexism as good examples where prejudical stereotypes lead to the subjects information being discounted. They build on this idea and suggest that people with mental illness are subjected to similar biases. From there they extrapolate and say that physicians and psychiatrists in particular make these same biased assessments and discount what patients say to them. They acknowledge that there are some circumstances where the credibility the patient may be questioned. They also suggest that this epistemic injustice is more likely to happen with psychiatric patients than other patients with physical illnesses. They suggest this has a detrimental effect on psychiatric patients, funding psychiatric services, and public perception.

They describe three examples of “epistemic injustice in psychiatry”. In all three cases the patients were put on acute psychiatric holds. In the first case a man claimed to be related to a Soviet leader and that was seen as delusional when it was true. In the second case a woman had cultural beliefs and practices that were misinterpreted as delusions. In the third case the patient had chronic suicidal thinking and visited the same cliff numerous times. He was admitted on hold when he was at the cliff for an hour and the decision was eventually made to treat him as a chronic high-risk patient on a voluntary basis. In all three cases the patients were released from the hospital by the civil commitment authority.

There are several problems with these vignettes and the inferences. The first is that the patients are being held on legal basis and not because of a psychiatric diagnosis. At least that is what happens in the United States. In other words, people cannot be held on the basis of a diagnosis they also have to present an imminent danger to themselves or others. It is a contested legal process and that in itself blurs the diagnosis and inhibits communication. The vignettes also seem to say that people are never adequately assessed based on their history and released even before the legal hold is released. As an acute care psychiatrist I have had to assess and release thousands of people when we determined that the history they gave us was accurate. In other words we believed them and released them. Of all the people I assessed and treated I am not aware of anyone who was released by a court because I made in an inaccurate assessment by not listening to the patient.

The authors move on to talk about contributory factors for epistemic injustice.  They discuss a number of archaic stereotypes (for a psychiatrist) of people with mental illness such as believing substance use users have a “lack of willpower” and that they are responsible for their own particular problems. I have never really met a psychiatrist with these beliefs and doubt that people with those beliefs go into psychiatry. I have certainly met other medical specialists with these beliefs and in fact argue with them regularly about that. The authors do have a rare point when they point out that negative stereotypes and stigma lead voters and politicians to underfund treatment for mental illness but that has nothing to do with the way psychiatrists communicate with their patients.

They discuss the topic of hard versus soft evidence. They use this to develop the argument that health professionals have epistemic power because “only they have access to this evidence and have the training to interpret it”. They really stretch to come up with the statement that some psychiatrists think of their patients as "objects of epistemic inquiry" rather than collaborators. I wonder if the authors are familiar with the psychiatric concept of therapeutic alliance. In the therapeutic alliance the psychiatrist and the patient are active collaborators and both the psychiatrist and the patient focus on solving problems that the patient identifies. That is an active process that as far as I know is taught to all psychiatrists. It wouldn’t work if a psychiatrist was looking at the patient as an object of inquiry.

The third contributor to epistemic injustice is negative stereotypes. The common stereotype mentioned by the authors is that “people with a mental illness are responsible for their condition”. I don’t think any psychiatrists think this way but at the end of this section the authors go back to making an argument about how psychiatric services are inadequately funded because the public and politicians maintain these negative stereotypes. So in the end two of the three contributory factors have more to do with the public’s lack of knowledge about psychiatric disorders than how psychiatrists function.

They discuss dementia and schizophrenia as conditions where the patient’s input may be minimized because of cognitive factors or their psychiatric status. The main stereotypes mentioned are the dangerousness stereotype with schizophrenia and the hopeless case stereotype with dementia. It is very difficult to understand how either of these descriptions support their main argument. Psychiatrists are trained to weigh what the patient is telling them and whether or not it might be plausible. Compared to practically all people - psychiatrists should have the best framework for what might or might not be plausible in the area of human behavior.  I can recall being interrupted during team meetings with news that one of my patients had communicated some behavior that the staff in the room were discounting as implausible and I suppose that is congruent with the authors’ argument. Those behaviors range from self reports of severe self endangering behavior to behaviors with a high likelihood of aggression. In most cases I considered the patient report to be accurate.  I had no doubt that a very low frequency behavior had occurred based on that patient’s history and in those cases it was generally corroborated.

The authors do not elaborate on the case where the patient's statements are uncritically accepted by the treating physician.  That is a likely cause of overprescribing and unnecessary testing.   

The entire first section of the paper does not seem to reflect modern psychiatric practice. I just put up a post on about 50 different factors that can be discussed with the patient at the end of the interview and a few real life examples of what is discussed. All treatment planning is based on what the patient says in that interview. The authors examples are cases where psychiatry and psychiatric assessment is secondary to legal considerations and all the impaired communication that involves. So there appears to be no epistemic injustice at the level of psychiatrist talking to patients in an outpatient setting.  The only exception would be a psychiatrist with insufficient expertise or one under severe constraints.  Those constraints can include a lack of time with the patient and unrealistic productivity and paperwork demands by the bureaucracy. 

The authors move on to discuss ways to overcome epistemic injustice. They suggest changing training to emphasize the subjective perspective of patients. I don’t understand that argument because the psychiatric evaluation should be focused entirely on the subjective perspective of patients. If the psychiatrist has any technical expertise at all, empathy is used to communicate that the psychiatrist knows what the patient is going through. The best description of empathy comes from British psychiatry as follows:

“Empathy is achieved by precise, insightful, persistent and knowledgeable questioning until the doctor is able to give an account of the patient’s subjective experience that the patient recognizes as his own.” (2)

That hardly seems like an exercise in disbelieving or ignoring what the patient has to say. Further psychiatric assessment should be focused on the entire conscious state of the patient rather than just what they have to say. Psychiatrists should be adept at diagnosing and treating patients who are unconscious and comatose, delirious, cognitively impaired, and experiencing severe psychiatric symptoms. A psychiatric assessment is more than believing what is said. I have frequently been in the position of having to explain to the patient what was happening to them and helping them make sense of their current experience. That is a singular focus on the patient’s subjective state when they are confused and unable to describe it.

The authors suggest multidisciplinary teams with a focus on the emotional aspects of care. I don’t know if that happens in England but in the United States I had team meetings every day for 22 years. The emotional aspect of care including interpersonal dynamics with patients and among the staff was routinely discussed in those meetings.

The authors suggest that medical students should be “taught to believe what psychiatric patients tell them unless there is a good reason not to do so”. My hope would be that medical students are able to see how attending physicians approach evaluations and treat psychiatric patients much differently than other physicians. The main factors that lead to that different approach include therapeutic neutrality, a lack of bias toward people with severe psychiatric disorders and addictions, and an ability to talk to all people with those problems. There is a more technical point that might not be as evident and that is psychiatrists are the only physicians who are systematically trained to understand and analyze their reactions to the patient and what that might mean. That is what psychiatrists do and why they are consulted by other physicians and by everyone else when problems are significant.

A much better approach is to go after institutional countertransference or the collective emotional and interpersonal reactions that can be seen institution wide based on psychiatric and addiction diagnoses. This is the single most important factor in being able to provide quality care to people with these conditions. A negative institutional countertransference toward these patients is evident in most hospitals and clinics where I have worked.  Only one person - the director of an emergency medicine program was interested in addressing it and had me speak as a consultant at a Grand Rounds on the subject. These negative attitudes are driven to an extent by stereotypes but also by the neglectful way society and political systems treat these people. They have been cast as a burden on the medical system, always uncooperative, people who deserve minimal if any treatment, and their treatment resources are cut to the bone. Psychiatrists working in these settings and promoting a model of therapeutic neutrality facilitating appropriate care is one of the best solutions - but more cooperation outside of the psychiatric community is needed.

In summary, epistemic injustice appears to be another philosophical concept that is misapplied to psychiatry.   There is no doubt that people can be misdiagnosed. There is no doubt that things don’t always go well. There is a clear reason for that and that is everyone coming to see a psychiatrist has a unique conscious state. There is no catalog of every unique conscious state. The psychiatrist's job is to understand that unique conscious state and it happens through direct communication with that person.  That direct communication can happen only if the psychiatrist is an unbiased listener.

George Dawson, MD, DFAPA

References:


1: Crichton P, Carel H, Kidd IJ. Epistemic injustice in psychiatry. BJPsych Bull.  2017 Apr;41(2):65-70. doi: 10.1192/pb.bp.115.050682. PubMed PMID: 28400962;

2: Sims A. Symptoms in the Mind. Elsevier Limited; London; 2003; p 3.


Graphic Credit:

The above photo was downloaded from Shutterstock per their standard user agreement.  The title is
Joshua Trees in Mojave Desert, California by Dean Stanisavljevic.

Preliminary Look At Structured Treatment Planning

I recently posted an early view of an approach to look at the treatment planning discussion that occurs at the end of a psychiatric interview. I thought that the next step would be to see if this approach works in the real world.  My current real world involves doing 1 hour evaluations with anywhere from 15-20 minutes of that time focused on a discussion of the treatment plan and that does include the option of no psychiatric treatment and in many cases other suggested treatments.  For example, some people seek treatment for acute stressors including grief that generally resolve spontaneously or are more adequately treated by individual or group counseling.  In most treatment settings where there is a triage system, these people are frequently screened out and do not see psychiatrists. That consideration directly applies to the treatment planning discussion because it affects the discussion of diagnosis, medical complications, and suggested treatments.

The graphic above shows the results of 10 interviews and the distribution of what was discussed (indicated by the orange cells) varies with individuals and general headings. The graphic is more readable if you click on it and zoom.  For example there were 13 bullet points that were covered in all 10 discussions and those points have to do with a diagnosis and specific treatments are expected.   Some topics were less frequently discussed and that generally means there were less applicable or the discussion time was reduced by a more lengthy diagnostic interview.  I have found over the years that the length of an interview depends on getting the necessary transfer of information that can lead to a working diagnosis so that treatment planning can be started.  The information necessary can be compromised by a number of factors including the patient's emotional state, their ability to describe a history with enough detail, the ability to be relatively concise, and the ability of the physician to communicate based on eliciting the necessary information and empathic listening.  That can vary significantly from physician-patient dyad to dyad.

In terms of coverage of all 50 bullet points, 30-58% of them were covered in the discussions with patients.  I don't think there is an ideal number.  The people I talked with all have unique needs and there is no cookie cutter approach to either the diagnostic process of treatment planning.  In some cases my discussion may run a little over the 15-20 minutes but that is rare.  I have received some feedback that this seems like an ivory tower approach that can only be used by psychiatrists who have unlimited time with patients. All of these interviews were conducted the same way I have interviewed and talked with people for the past 30 years.  The interview was not modified in any way.  This is not research (yet) it is real world experience.

I am in the process of modifying the form based on suggestions from other psychiatrists so this is not the final version.  At some point I think it would be useful to consider research using this kind of format to document that points covered by setting, diagnosis, and time constraints.  A basic skill that all psychiatrists need is knowing when to depart from the original reason for consultation to a more urgent need - like the need for assessing an acute medical problems, a medical problem that might represent the cause of the psychiatric presentation, or a complication of treatment.

For now, I think it works as good evidence that psychiatry is not as easy as it has been depicted.  The original depiction was by the federal government when it suggested the structure of psychiatric evaluations and treatment were not like the rest of medicine.  There were separate codes and reimbursement for psychiatric treatment that did not take into account even one section of the above template.  The adaptation to that government and insurance company practice has been to reduce discussions to the amount of time congruent with the devaluation of the cognitive process. That also led to clinics scheduling patients too close together and for briefer appointments.  There is a lower limit to the time necessary to assess and treat patients. I don't think anyone who is doing new evaluations every 20 minutes while they are talking to patients and checking off templates in the electronic health record is going to be having lengthy treatment planning discussions. This form suggests that psychiatrists need time to do what they were trained to do.

The form when it is completed with provide not only a good estimate of what was discussed with the patient but will also provide guidance on what is relevant to document. 


George Dawson, MD, DFAPA

 

2000 Words About the Last Ten Minutes of a Psychiatric Evaluation

I do psychiatric interviews all week long. At this point I’ve been doing it for over three decades. I am always interested in improving the process. I came up with this idea recently and wish I had thought about it many years ago. My standard initial interviews are anywhere from 45 minutes to 60 minutes long and that includes a lot of information transfer. The actual amount of information transferred and whether it can be used come up with formulation and diagnosis is always an unknown variable. There are people who can come in and succinctly produce that information in 30 minutes or less. Other people will take several hours. At the end of every interview, I have to dictate a report that contains fairly standardized sections including a diagnosis and treatment plan.

When physicians are trained there is an implicit understanding that they will be able to adhere to a specific protocol and come up with a diagnosis and treatment plan. In the real-world things are never that linear. In inpatient psychiatry, the patient may not be able to produce a coherent history or any history at all if they are severely ill and the diagnosis needs to be pieced together by collateral information and the medical and behavioral presentation. In outpatient clinics, the format is much different. It is still possible to interview a patient who communicates low information content but it is much more likely that patients describe what is necessary for diagnosis and treatment. One of the main problems is the discussion at the end of the assessment. It is typically truncated by time constraints. Many patients leave the assessment and realize they should have mentioned specific concerns or asked more questions.  I often have people tell me that they are drawing a blank in the interview and want to know if they can call me if they have additional questions. I reassure them that they can.

These brief observations highlight the need for adequate time and structure following the diagnostic interview to facilitate the discussion and make sure that the patient can send and receive the communication that is both necessary and what they want beyond that. I came up with the structure over the past two weeks and I think is a good starting point. I also refer interested readers to the only post on this blog that was not made by me. It was written by Cedric Skillon, MD one of my psychiatric colleagues because I observed his superior treatment planning in all of his notes that I encountered.

This exercise assumes that any psychiatrist reading this as adequate time to do their work. I don’t think psychiatry can be reduced to a checklist and I don’t think it can be done in a short period of time. I realize that there are psychiatrists reading this who may have evaluations scheduled back to back in the morning and 15-minute appointments scheduled back to back all afternoon. We all know how that schedule gets accommodated and the outcomes are not good. What typically happens is there is very little emphasis on getting to know and understand patients and little emphasis on communicating with them about their problem. I also understand that the people who really control all psychiatrist practice these days don’t really care about quality treatment. The emphasis here is always on quality and the obvious fact that quality work is not easy and it takes time.

What follows is my proposed outline for the patient discussion. I think that in even moderately complex cases at least 25% of the allotted time should be for this discussion. I have not done it yet but I hope to hand an outline to the patient in order to facilitate discussion. I’m very interested in whether their psychiatrist have used this technique and also speculation on why it may or may not be a good idea.

1.  A discussion of the diagnosis and/or formulation

Of the people I talk with very few seem interested in the specific diagnosis. It does happen, and when it does, I think it is important to cover most likely diagnosis and complicating factors. For example, when seeing a patient to has been drinking excessively for 20 years and gives a history of anxiety and depression prior to the onset of that alcohol use and current anxiety and depression can there be a valid anxiety or depression diagnosis given the intervening alcohol use. This is a basic level of complexity that psychiatrists encounter. In covering the diagnosis, I will typically talk about a most likely diagnosis as well as the provisional or working diagnosis and my recommendations for clarifying the diagnosis. In some cases, people are interested in whether or not they have a severe psychiatric disorder. I encounter a lot of people at the end of the initial interview who asked me “So am I nuts/crazy Doc?” Some people have a specific diagnosis in mind that they either want or don’t want and I give them my best assessment. Some people have studied diagnostic features online or in the DSM and use that jargon during my interview. They may or may not be right.

I think a formulation is always necessary in addition to a psychiatric diagnosis. I was first impressed with rapid formulations done in brief psychodynamic psychotherapy. I also found several courses given at the annual APA conference in diagnostic formulations to be useful. The patient may have their own formulation or one that they worked on with the therapist that I would typically discuss in the original interview. I don’t think the formulation discussion has to be excessive or detailed and it may complement the diagnostic assessment. As example the case of the diagnosis of major depression, it is reasonable to discuss the interpersonal elements relevant to the depression as well as psychosocial stressors.

2.  A discussion of a no treatment option

A no treatment option should be explicit. It should be discussed as part of the informed consent process. The potential risks and benefits of no treatment should be discussed but in many cases no treatment is a viable option for people. The case that always comes to my mind is the person who consulted with me decades ago after receiving years long psychoanalytic treatment who wanted to know if he should find a new therapist and continue. After reviewing course of therapy and how his anxiety had improved over the years, he was very relieved to hear from me that he probably did not need to continue psychoanalysis. He had formally terminated with a psychoanalyst and no further treatment was recommended but he wanted a second opinion from a psychiatrist. Other people have mild anxiety and depression but are still functional and they had concerns about both medication and psychotherapy. With psychotherapy - the time, financial commitment, and past therapy experience are generally the determining factors. With medication the main concern is side effects and typically concerns about taking any medication. I commonly hear “Doc - I don’t like to take any medication, not even aspirin.” I think it is possible to discuss no treatment in a number of scenarios as well as the contingencies. The common contingency might be returning for reassessment if symptoms worsen or there are other complications.

3.  A discussion of potential medical treatments and medical concerns – especially those that may affect treatment

Outpatient psychiatrists are generally seeing patients after all the smoke has cleared. If they have access to an electronic health record (EHR) there are often laboratory results, ECGs, and imaging results and reports that the patient may or may not be aware of. After taking a complete medical history and review of systems I generally ask the patient if they had any questions about recent medical procedures or results and we have a discussion at that time.

The medical treatment of the identified disorder is reviewed. There are often several approaches to the problem and when I discuss all those approaches patients generally want my recommendation. I provide them with that, the necessary prescribing literature, and both short and long-term plans. I also talk about rare but serious complications of psychiatric pharmacology like antidepressant withdrawal, agranulocytosis, Stevens Johnson syndrome, priapism, serotonin syndrome, akathisia, suicidal ideation, and neuroleptic malignant syndrome. In a previous post, I describe some of the discussion. I generally want to make sure that the patient is aware of any black box warnings, contraindications, and warnings. I will often do a drug interaction search in front of the patient so that I can discuss it with them rather than doing it after the interview.

In some cases, my treatment will depend on my discussion with their primary care physician, cardiologist, or other specialist. It may also depend on me ordering tests that I view as critical and getting those test results.  

4.  A discussion of potential psychotherapy treatments

There are research proven psychotherapies that should be part of any informed consent discussion. I commonly inform patients with posttraumatic stress disorder (PTSD) that exposure therapy and the EMDR variant are very good approaches to the disorder and may be superior to pharmacotherapy. That does not mean that I won’t try to treat that patient for PTSD symptomatology, but I want to give them a clear message that the psychotherapy results may be much better. I have similar discussions regarding the psychotherapy of anxiety and depressive disorders specific to those conditions.  The psychotherapy may include supportive and crisis intervention approaches that occur right in the initial interview.  In psychiatry treatment interventions that involve psychotherapy can occur right at the time of the assessment. 

5.  A discussion of potential environmental/social approaches

One of the commonest problems in outpatient psychiatry is that there are clear environmental factors that are leading to anxiety, depression, insomnia, and substance use morbidity. Practically all of the people in those situations or consulting psychiatrists are looking for a medical treatment to address those environmental and social factors. I generally have detailed discussion about the evidence that medication works in those situations (there is very little) and what can be done.  I typically discuss examples like grief responses and the very common scenario of a stressful work environment or boss. I want to be sure that I emphasize the point that medical treatment of these acute and chronic stressors is almost always not enough to solve the problem.

6.  General treatment parameters

If the patient and I decide to proceed with treatment – a discussion of the general parameters of treatment needs to occur.  That would include indications for calling me and how to address potential medical and psychiatric emergencies.  In this day of external control of medical treatment – prescription refill policy can be discussed and how insurance company denials or prescriptions (prior authorization) will be handled.  In large systems of care, a discussion of who has access to the information in the chart and systems that deal with emergency and crisis calls can be a topic for discussion.  In the current Internet age modes of communication (email, texts, calls) also need to be discussed especially if there is no formal EHR portal.  Limitations on privacy are typically part of the general permission to treat but may require additional explanation like the CFR42 regulations for drug and alcohol treatment.

7.  Definition of the treatment alliance

As part of the general treatment discussion, definition the treatment alliance can be useful for many people.  Physical appearance and the appearance of one’s office can be a projective test for people entering treatment.  When I started out, I would get a lot of comments like: “You seem to be too young to be a doctor!”.  Now that I am an old man, my introduction has stayed the same.  Within a few minutes people know how long I have been in practice.  Most people can get past that and engage in a dialogue, but some people are overly deferential and seem intimidated.  Others decide to challenge the old man to see what he knows or if he can be pushed around. Both of those scenarios can be a topic of discussion but that might be too confrontive for most and lead to more problems in communication.  A more neutral approach is to discuss the typical diagnostic interview and treatment alliance. I find a basic definition that works for most people is: “You and I working on a problem or set of problems that you identify to see if we can find the solutions.”   

There have been entire books written on this topic, but most don’t focus on the ten or 15 minutes at the end that should be for the benefit of the person seeking help. That is my outline so far. Over the years I have had these discussions but not in a structured way. It de-emphasizes the diagnostic template or checklist and puts the emphasis on information that is directly useful for the patient. I plan to take the headings, add bullet points, and see if it adds to the discussion. I think it will because it will at least define the boundaries of the discussion, what I hope to communicate, and provide more solutions to people coming in to see me. And mostly I hope that it will counter the implicit assumption that all psychiatrists do is prescribe medications and that it is an easy thing to do.

George Dawson, MD, DFAPA




Supplementary 1:

The preliminary form described above is contained in the 3 PNG files below. There are 49 bullet points so far. I have it as a Word file and a PDF so if you are interested in it send me an email and I will send you the format you want.  I consider this to be a work in progress. Click on the files below to enlarge for easy reading.

Supplementary 2:

As a preliminary screen - I looked at one day of intakes in my practice and discovered that I am routinely covering 30-36% of the bullet points on this form. That seems like a sufficient number but it would be a good idea to run a trial looking at the baseline for a number of clinicians (rated by independent observers) and then a second rating after the patients were provided the form ahead of time.

Reward Prediction Error At The Gas Pump

A couple of years ago I was driving up to Minnesota resort country when I noticed something happened at gas stations. For decades, gas pump choices were arranged linearly with the lowest octane fuel on the left and the highest on the right.  The only difference was the occasional pump with diesel or racing fuel options and they were typically on the far right.  To illustrate I took this photo of a gas pump display on the way home form work yesterday.  Three years ago the display would have been (left to right) 87-88-91.  In this case, in addition to the octane shuffle there is a price dissociation.  Motorists have been trained for year to expect that 87 octane to be the least expensive and now it is not - 88 octane is the least expensive.  These changes at the pump reminded me of a paper I had read a few years ago by Wolfram Schultz one of the world experts in reward prediction error. 

Reward prediction error is basically the difference between a prediction about the nature of the reward and what really happens. See all of the definitions in the diagram below that are taken directly from Schultz.  Reward is clearly defined as well as predictions to both the positive and negative sides.

In the paper of interest Dr. Schultz introduces it by being confronted with a vending machine where he cannot read the language (Japanese).  There are 6 choices and his expectation is low that he will get his preferred choice so he pushes the second button.  He is surprised that it delivers exactly what he wants - black current juice. He points out that this experience will keep him pressing this second button until the machine is loaded differently and he does not get his expected juice.  He uses this as an example of positive reward prediction error (RPE) or the difference between his low expectation and the ideal outcome that resulted.  RPE systems are set up to optimize positive reward prediction error.  When the eventual negative outcome results in negative prediction error decision making will change in order to return to the positive RPE scenario and then no reward prediction error scenarios.

Getting back to the gas pumps. They appear to have been designed to defeat RPE at two levels.  First, the position of the buttons after everyone was conditioned to push the one at the far left.  The second, is the dissociation of gas price from button position.  There is no longer a linear correlation between octane and price.  I am not sure if both of these trends have been occurring over time or just recently. I do know from studying various gas pumps that the button positions do not necessarily reflect linear price or octane changes, but in some cases they still do. The good news is that they can both be overcome by carefully studying the octane button position and posted per gallon price rather than depending on the old learned patterns.  The other interesting aspect of the gas pump problem is that there don't have to be a lot of predictions.  The prediction error occurs only if the purchaser depends on old patterns without paying close attention to details. 

The neurobiology of RPE is more fascinating than the descriptive aspects. We know that the neurobiology of reward in the human brain is heavily dependent on dopaminergic systems in the ventral striatum.  Dopaminergic neurons code reward in the form of prediction error even  in complex tasks.  What is even more interesting  is that the coding is not in terms of quantifiable measures but subjective ones.  Utility functions incorporate subjective measures and can be used to determine the potential values of the reward.  Dopaminergic neurons code the utility of the received reward minus the utility of the predicted reward.  Looking at a computational model of the addictive process, Redish (7) discusses a value function V[s(t)] dependent on the state of the world s(t) and presents it as the calculation of expected future reward discounted by the expected time of reward:

As noted the value of delayed rewards are reduced and the actual discounting applied is based on empirical work on discounting in human and animal models.  The author in this case goes on to develop a computational model of addiction in this case that is based on reward prediction error and the fact that cocaine produces direct phasic increases in dopamine (DA).  The model is termed a temporal-difference reinforcement learning (TDRL) model.  According to RPE increases in DA occur after unexpected natural rewards. Over time DA release decreases, learning stops, and instead is paired with the cues for the reward.  That does not occur with a pharmacological reaction at the level of the dopaminergic neurons.  In that case, a drug like cocaine will release DA independent of the expected reward.  That produces a final state where a unexpected natural reward, a cue for a learned reward, and cocaine will all produce DA.

The Redish paper also looks in detail at a couple of associated issues. The first is rational addiction theory defined as the user maximizing value or utility over time. Long term rewards for quitting are discounted more than the short term penalties and therefore the user remains addicted.  In the author's model "the maximized function entails remaining addicted." (p 1946).  TDRL theory suggests that addiction is always irrational because the pharmacological effects of cocaine (in this case) always outweigh the associated DA surges from the universe of value functions available in the real world. Addictive drugs will produce an increase in DA, so that the user will not be able to encounter and learn a value function that is associated with an equal or greater DA surge than is produced by the drug.  Therefore the user remains addicted.  This has been taught in addiction seminars for years as the Hijacked Brain Hypothesis - meaning that the dopamine signal produced by addictive drugs overwhelms the dopamine signal produced by natural stimuli like eating, drinking water, sexual behavior, and social affiliation.  Both RPE and TDRL theory offer more explanatory power than the Hijacked Brain Hypothesis. 

As I wrap up this post, I pulled down the latest editions of the two major addiction texts to see what they had to say about reward prediction error, computational models of addiction, and some of the authors referenced in this post, especially Wolfram Schultz.  There were no references at all and the sections on the actual function of DA neurons in addiction was surprisingly thin. On the other hand a lot of concepts used in the field like salience are the direct product of these systems. In order to produce a more coherent picture of the neurobiology of addiction it is important to outline these DA systems and how they work normally and in addictive states.

I am hoping that addiction texts for clinicians will contain some of this information in the near future and ideally the chapters will be written by the scientists that have been studying these processes in some cases for decades.


George Dawson, MD, DFAPA

Supplementary 1:

Getting back to the gas pump example, considering the 3 octane ratings and the three prices that may or may not correspond to the octane ratings means that there are 6 possible combinations at any pump that need to be considered.  Any real world actor at the pump needs to consider this carefully when the gas pump has undergone a transition from the expected correlation between increasing octane ratings and price to one where this relationship does not exist. The advantage to the actor in this case is that all of this information is explicit and that behavior is more likely to be affected by negative prediction error when automatic selection behavior results in the wrong octane or fuel cost being selected.  That is unlike Dr. Schultz's example in the Japanese airport when he randomly chose a beverage and was unexpectedly rewarded.


Supplementary 2:

I can't say enough about the writings of Wolfram Schultz.  They are only peripherally mentioned in the addiction literature and yet his theories and experiments are some of the more important that I have read with regard to the neurobiological theories of addiction.

Papers of Wolfram Schultz - Journal of Neurophysiology Page Link

Home Page of Wolfram Schultz Link - contain some of the best PowerPoint slides that I have ever seen.

References:




1: Schultz W. Dopamine reward prediction error coding. Dialogues Clin Neurosci.2016 Mar;18(1):23-32. Review. PubMed PMID: 27069377 full text

2: Schultz W. Reward prediction error. Curr Biol. 2017 May 22;27(10):R369-R371.doi: 10.1016/j.cub.2017.02.064. PubMed PMID: 28535383 full text

3: Stauffer WR. The biological and behavioral computations that influence dopamine responses. Curr Opin Neurobiol. 2018 Apr;49:123-131. doi: 10.1016/j.conb.2018.02.005. Epub 2018 Mar 2. Review. PubMed PMID: 29505948. full text

4: Takahashi YK, Batchelor HM, Liu B, Khanna A, Morales M, Schoenbaum G. DopamineNeurons Respond to Errors in the Prediction of Sensory Features of Expected Rewards. Neuron. 2017 Sep 13;95(6):1395-1405.e3. doi: 10.1016/j.neuron.2017.08.025. PubMed PMID: 28910622. full text

5: Keiflin R, Pribut HJ, Shah NB, Janak PH. Ventral Tegmental Dopamine Neurons Participate in Reward Identity Predictions. Curr Biol. 2019 Jan 7;29(1):93-103.e3. doi: 10.1016/j.cub.2018.11.050. Epub 2018 Dec 20. PubMed PMID: 30581025.

6: Tobler PN, Fiorillo CD, Schultz W. Adaptive coding of reward value by dopamine neurons. Science. 2005 Mar 11;307(5715):1642-5. PubMed PMID: 15761155.

7: Redish AD. Addiction as a computational process gone awry. Science. 2004 Dec10;306(5703):1944-7. PubMed PMID: 15591205.

8: Sweis BM, Thomas MJ, Redish AD. Beyond simple tests of value: measuring addiction as a heterogeneous disease of computation-specific valuation processes. Learn Mem. 2018 Aug 16;25(9):501-512. doi: 10.1101/lm.047795.118. Print 2018 Sep. PubMed PMID: 30115772.  

Policy Makers Are Always The Weakest Link In Healthcare

When it comes to solutions to the opioid epidemic - talk is cheap. The last 20 years everybody has “the solution”. The AMA came up with a new version of theirs entitled “AMA Opioid Task Force Recommendations for Policymakers.”  Inspection of this page shows that it is basically a rehash of everything we have known over the past 10 years or longer. The only new message is that the AMA is now suggesting that policymakers should follow these recommendations. In this era of patient empowerment, direct advice to patients is completely missing.

Drug legalization advocates have apparently vilified the Reagan era “Just Say No” campaign to the point that attempts at primary prevention of substance use are now politically incorrect and forbidden. How can you possibly stop opioid and methamphetamine epidemics when there is a large and vocal advocacy for legalizing all drugs emboldened by the cannabis campaign? There are few reasonable voices out there saying “You know you can really live a better life without drugs or alcohol”.

It should probably come as no surprise that real action on the drug epidemic cannot be expected from a government that is unable to end a decades long streak of mass shootings. We hear the familiar refrain that people were “in the wrong place at the wrong time” or that they are “fallen heroes” and that “now is the time to move on”. A real adaptive response to mass shooting like even slightly tougher gun laws would make a difference. Despite hearing that “this is the last time that our children can be victimized” the mass shooting saga drags on - courtesy of local and federal governments.

The resolution of the opioid epidemic is another example of how our government doesn’t work on serious public health issues.  The epidemic has been in place for the past 20 years.  Using deaths by overdose as a proxy measure suggests that things may be improving the last couple of years, but the epidemic is far from resolved.  The more recent problem has been that people who started using prescription opioids have changed to heroin or fentanyl – the supplies of both are plentiful and less expensive than the street value of typically prescribed opioid pain tablets.

A few words about the points the AMA has in their graphic:

1. MAT - medication assisted treatment for opioid use disorder is considered a major advance in treatment. That applies both to methadone maintenance treatment and more recently buprenorphine maintenance with various preparations. Sustained-release naltrexone injections are also an option but they are more controversial due to the longer induction and wait time until the patient is safely covered by opioid receptor antagonism. The current AMA position is to remove prior authorization from these treatments so that they are more readily available. Some treatments are more cost-effective than others. It is not clear from the statement how the AMA hopes to remove these barriers particularly since they have not been effective in removing them for the past 30 years of utilization management or prior authorization. They may be counting on political leverage in this case but I don’t see it happening. Regulators and politicians could easily make this an exception to the current utilization management and prior authorization statutes that they have on the books but it should be apparent from that statement that they are the problem in the first place.

2. Mental health - the document cites the well-known correlation between mental illness and substance use. The document also cites the Mental Health Parity Addiction and Equity Act (MHPAEA) as meaningful but the only way this law gets enforced is if civil action is brought against healthcare companies. These healthcare companies are protected by legislation and they basically do whatever they want. The AMA Task Force suggests that healthcare company should be “held accountable” but that hasn’t happened in the 10 years since the MHPAEA has been passed.  The document suggests that a number of addiction specialists should be in the networks of these healthcare providers, but for 20 years politicians have been rationing mental health services to the point that county jails are currently our largest psychiatric institutions. The mental health suggestion in this document seems like another wish.

3. Comprehensive pain care and rehabilitation access - I would really like to see the numbers on this one. If anything there has been a tremendous proliferation of freestanding or chains of pain clinics over the past 20 years. That proliferation correlates directly with increasing opioid prescriptions. As far as I can tell there has been no movement at all in terms of determining what constitutes a quality pain clinic versus something else. This may have to do with the politics that wrung the word “quality” out of the healthcare system 30 years ago. There is also an access problem. In other words there has always been “non-opioid alternatives” like physical therapy but healthcare systems ration their utilization.  This might be another area where education is important and convincing people that a course of physical therapy even if their healthcare company makes them pay for it is potentially more beneficial than taking opioids and getting deconditioned for a period of time.

4.  Maternal and child health - there is no doubt that punishment-based paradigms can intrude on the parental relationships with children and result in destabilization of families. This usually occurs on a county by county basis and there are no statewide standards and no specific treatment facilities. The problem is compounded by the fact that most states consider social services to be as expendable as mental health services and it takes more than a suggestion to reverse that 20-year trend.  Recently, the child protection issue as a result of substance use has become so bad that additional tax legislation is needed just to cover this problem.

5. Civil and criminal justice reforms - the most significant reform suggested in this section is that MAT is continued when a person is incarcerated and after they are released. This is a tall order considering how difficult it is for anyone to access MAT in an outpatient setting. Jails and prisons have the absolute worst record. The evidence for that is people who are acutely taken off of methadone, buprenorphine, or other psychiatric medications at the time of incarceration. That can lead to weeks of opioid withdrawal symptoms and intense physical symptoms.  Despite many county jails considering themselves to be psychiatric hospitals very few of these places are equipped to assess and treat psychiatric disorders or do medication assisted treatment of substance use disorders.

That is the AMA WishList and all of its deficiencies. I have not seen a realistic assessment of the problem and how to reverse it in spite of the fact that there are two documented opioid epidemics in the medical literature and suggestions about how they were resolved. I never heard anyone referencing them. Medication assisted treatment was one component but there are other significant factors that no one seems to be talking about at this time.

Working in a residential treatment facility provides me with unique perspective on the problem. The continuum of care ranging from residential treatment to intensive outpatient treatment to date treatment to self-help groups like Alcoholics Anonymous and Narcotics Anonymous depends on a number of factors to make it work. First and foremost is a competent staff in the facility with reasonable boundaries and a supportive environment. Most medical facilities do not have this because of significant bias against people with substance use disorders. There are some treatment facilities that have similar biases and they should not be allowed to admit people until that problem is resolved. The measures recommended by the AMA Task Force are medically weighted and that means that treatment facilities need to have medical staff. If the facility needs histories and physicals done medical staff need to provide that function as well as comprehensive detoxification, treating associated medical problems, and providing psychiatric care and MAT. There is no point in having residential or outpatient treatment programs in a network if they cannot provide that level of care. People who need MAT should not be treated in facilities where they cannot get medical assessment and treatment.

That basic fact seems to be missing from the AMA Task Force guidelines, state regulations, and any discussion at the federal level about what kind of treatment is needed for people with active opioid use disorders.

The AMA could be of more service referring people to appropriately staffed treatment programs and advising the public on the source of all of these obstacles of care. As I have been writing here for years now those obstacles are a product of pro-business government policy at both the state and federal level and how those rationing businesses are able to operate. Until that basic flaw is corrected - I do not anticipate any increase in access to treatment (at least effective treatment), increased access to appropriate social services, or sudden revision of county jails to suddenly make them functional psychiatric units.

There are some changes that would make an immediate difference in the opioid epidemic instead of the continued evidence-based platitudes.  If there are any policy makers or politicians out here that are serious about making some changes - here they are:

 1:  Hold physicians harmless for providing MAT:

The suggestion that more physicians should be providing MAT for opioid use disorder has gone from a suggestion to more of a demand.  Just this weekend there have been debates about why Emergency Department Physicians aren't providing MAT for every person with OUD that they see.  My first thought when I saw that was: "Are they serious?" People are not presenting to EDs with casual use.  They are not people coming into clinic intentionally in withdrawal to start buprenorphine induction. They are generally people with very serious use problems who end up in EDs because of a different problem. Many of them are polysubstance users with multiple drugs on board and in many cases drugs that are typically flagged as having potentially serious interactions with buprenorphine.  Add to that the dearth of buprenorphine prescribers that will accept referrals from an ED and it makes perfect sense that Emergency Medicine physicians do not want to send people out with buprenorphine.

The physicians are not the problem, the practice environment is.  The solutions seem obvious to me.  The first is to indemnify the physicians for providing care that is harm reduction to patients with high risk. This already happens in state statutes that cover Good Samaritan provisions, mandatory reporting of child and adult protection concerns, and civil commitment and guardianship proceedings that hold the petitioners harmless for good faith activity.  MAT is a very similar endeavor. But I would not just stop at a vague statutory requirement. I would tie it in with abbreviated training for MAT.  When I took that training, at least half of the patient case examples were high risk with limited resources, psychiatric comorbidity, and they were using high levels of multiple substances.  The answer in each of these scenarios was to prescribe buprenorphine as a way to assist the patient with the OUD aspect of the problem. 

2:  Open up addiction clinics:

The idea that primary care physicians are all going to start seeing large volumes of these patients will not materialize as long as there is a problem with cross coverage.  I have seen it happen many times. A well intended physician starts prescribing buprenorphine and even in a mutli-specialty clinic has nobody else to assist and is on-call 24/7 for years until they burn out.  There has to be a structure in place where there are clinics that can handle large volumes of patients including the referrals from all of the local EDs and correctional facilities and provide adequate cross coverage for the physicians prescribing buprenorphine. 

3:  Decrease the training requirement:    

Unlike others - I don't think it can be eliminated for the reason I cited above.  The physicians and other prescribers need to know the high risk scenarios that they can treat.  I think it could probably be done in two hours with a case book of treatment scenarios.  The case can be made for collaborative care/mentoring arrangements with experienced physicians, but the funding of those scenarios should be seriously considered.   

4:  Provide temporary housing programs to take people directly from the ED and crisis appointments: 

As a former acute care psychiatrist - I know the uneasy feeling of providing brief opioid detox services and discharging patients with OUD to the street with medications that have street value.  There is no surer path to immediate relapse.  If we are really serious about helping people get established on MAT, they need a stable environment where it can happen. 

5:  States need to license substance use programs only if they provide medical services and MAT:   

If we are all serious about the effects of MAT in OUD it is time to start acting like it.  There is no longer an excuse or reason for not offering MAT to all patients in residential, extended care, or outpatient treatment programs.  There are no religious or ideological grounds that justify not offering these services and the license of all treatment facilities should depend on it.

These are my ideas about stopping the opioid epidemic that stop all of the platitudes in their tracks.  There is a rational way to proceed that does not depend on physicians sacrificing to keep the irrational system afloat. The rational way will cost money, but it will also save money but not in the way politicians usually talk about healthcare savings. It will save money and resources by saving lives, not investing in inadequate treatment, and finally putting a dent in the large circulating pool of opioid and polysubstance users that are circulating between emergency departments, inpatient units, drug treatment programs without MAT, detox units, shelters, and jails.    

George Dawson, MD, DFAPA

Medical Cannabis Does Not Prevent Opioid Overdoses

The political aspects of medical cannabis are undeniable. The legalization of cannabis for recreational purposes had no traction with American politicians or voters until it was promoted as a miracle drug.  With that widespread promotion medical cannabis is now legal in 33 states and recreational cannabis is legal in ten.  The legalization arguments also suggested that the US was behind other countries of the world when there are only two countries – Canada and Uruguay – where it is completely legal for medical or recreational sale and purchase.  In the world, 22 of 195 countries have legalized medical cannabis with widely varying restrictions on its use. The Netherlands is often cited as an example of recreational cannabis use, but most Americans don’t realize that it is illegal for recreational use and tolerated for use and sale only in specially licensed coffee shops.  The promotion of cannabis as a solution to the opioid overuse and chronic pain problems can be seen as an extension of the political arguments for legalization that outpace any science to back them up.

There was probably no greater hype about the purported benefits of medical cannabis than early data suggesting that it might decrease the rate of opioid overdoses (1). The sequence of events was supposed to be opioid users tapering off of opioids or using lower equivalent amounts because of medical cannabis use.  The original study covered the time period from 1999-2010 and suggested that states with medical cannabis laws had a lower mean opioid overdose mortality and that the annual rates of overdose progressively decreased over time.  The authors conclusion was:  “Medical cannabis laws are associated with significantly lower state-level opioid overdose mortality rates.”

Despite the usual caveats suggested by the authors in the original study the results of that study were heavily hyped by all cannabis promoters as was the discussion of many Internet forums.  The lay press, public, and politicians saw it as another reason to promote medical cannabis and recreational cannabis by association.

A study came out today in PNAS (2), that is an extension of the original data and it no longer comes to the same conclusion.  In this new study the authors replicated the opioid mortality estimates from the original study but when the data was extended from 2010 to 2017 – the improved opioid overdose mortality rates not only did not stay constant but they reversed themselves to that they were now on the average from -21% to +23%.  They provide an even more valuable analysis of this effect as spurious rather than a true positive or negative effect based on the low penetration of medical cannabis in the population at large (2.5%).  The authors focus on the problem of ecological fallacy – that is conclusions about individuals are drawn from aggregate data across the entire population.They point out that the states with the medical cannabis laws have a number of characteristics separating them from other states.  A recent good example of this fallacy was the New England Journal of Medicine (3,4) report that per capita chocolate consumption correlated with the number of Nobel Laureates in a particular country.  

This is a valuable lesson in scientific analysis. The political approach to the problem is all that most of the public sees. That approach is to grab any information that seems to agree with your viewpoint and run with it.  Big Cannabis and cannabis promoters have been doing this for almost 20 years now. The process of science on the other hand is slower and more deliberate.  It is not a question of a right answer but a dialogue that hopefully produces the right pathway. The authors of this study have added a lot to the dialogue about cannabis but also statistics and how statistical descriptions may not be what they seem to be. 

George Dawson, MD, DFAPA

References:

1: Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in the United States, 1999-2010. JAMA Intern Med. 2014;174(10):1668–1673. doi:10.1001/jamainternmed.2014.4005 (full text)

2:  Shover CL, Davis CS, Gordon SC, Humphreys K.    Association between medical cannabis laws and opioid overdose mortality has reversed over time.  First published June 10, 2019 https://doi.org/10.1073/pnas.1903434116  (full text)

3: Messerli FH. Chocolate consumption, cognitive function, and Nobel laureates. NEngl J Med. 2012 Oct 18;367(16):1562-4. doi: 10.1056/NEJMon1211064. Epub 2012 Oct 10. PubMed PMID: 23050509.

4:  Pierre Maurage, Alexandre Heeren, Mauro Pesenti, Does Chocolate Consumption Really Boost Nobel Award Chances? The Peril of Over-Interpreting Correlations in Health Studies, The Journal of Nutrition, Volume 143, Issue 6, June 2013, Pages 931–933, https://doi.org/10.3945/jn.113.174813


Attribution:

Above figure is from the original article (reference 2): "This open access article is distributed under Creative Commons Attribution-Non Commercial No Derivatives License 4.0 (CC BY-NC-ND).y"  See this link for full conditions of this license.

Spare The Venlafaxine.....

Venlafaxine is a commonly prescribed second-generation antidepressant. It is well-known to psychiatrists because it is a second line medication if SSRIs fail and for many psychiatrists it is another first-line antidepressant. In some head-to-head comparisons with SSRIs venlafaxine has a more favorable side effect profile. It does have the risk of discontinuation symptoms and typical antidepressant side effects. I have noticed that the dose escalation with venlafaxine seems to be out of proportion with SSRIs, bupropion, and third-generation antidepressants.

Consider the following venlafaxine related scenarios:

1. A colleague comes into my office late in the day and asks me: “Have you ever heard of venlafaxine causing sedation at higher doses?” The patient in question was just increased from 187.5 mg to 225 mg - the suggested max dose according to the FDA approved package insert. 

2. I am asked to consult on patient who had extensive pharmacogenomic testing in a different facility where she was told that she may need to take 350 to 450 mg of venlafaxine per day based on that genetic profile. She wants to make sure that she gets an adequate dose of the antidepressant and is currently on 225 mg.  I reviewed the limitations of that approach with the patient and potential side effects and I let her know that the commonest side effect I see in people taking high-dose venlafaxine is excessive sedation or low energy in the daytime. As we start to follow the recommended dose increase she discloses that she has had sedation even at the 225 mg level. We decreased the dose to 150 mg and that side effect is gone.  Her depression is also gone.

3. I see a significant number of patients taking more than 300 mg per day of venlafaxine from the same geographic location in the United States. They all tell me that the target dose in that location is 350 mg per day and they are all experiencing numerous side effects. Many had dose escalations into that range in a week or two - much faster than any increase I have done.

What is wrong with this picture? Why are there a significant number of people taking more than the recommended dose of venlafaxine in some cases much more and appearing to have side effects? The roots of this prescribing behavior can be traced back to old-school psychopharmacology. Proponents of that approach suggests that there may always be a group of outliers that need to take higher-than-expected doses of medications - typically antidepressants but there has also been a history of excessive dosing of antipsychotic medications. People were generally more cautious with more toxic medications like tricyclic antidepressants, monoamine oxidase inhibitors, lithium, and various addictive compounds. They also seem to be more cautious with SSRI type medications at least initially. It took over a decade for me to see a dose of sertraline in excess of the maximum recommended dose.  While it is true that there are always outliers in terms of dose-response what is the best way to approach that problem.

I have attended medical education courses where the lecturer suggested titrating the medication to the point of toxicity and then reducing it back down to the next lowest dose. That particular lecture was focused on treating anxiety disorders with SSRIs. I don’t think that is the best approach. The best approach to me is one where the patient recovers from anxiety or depression and the process does not experience a single side effect. I know that can be done because I have been doing it for decades.

That also brings me to what I think is a good research article that looks at optimal dosage ranges. It is a very large meta-analysis of fixed dose randomized clinical trials that utilize the specific antidepressants - citalopram, escitalopram, fluoxetine, paroxetine, sertraline, venlafaxine, and mirtazapine.  The trials were identified by searching the literature and looking for unpublished studies specifically by searching national drug licensing agencies and requests directly to pharmaceutical manufacturers. Outcomes were noted at eight weeks of treatment and defined as a 50% reduction on an observer rated scale for depression.  Dose equivalence among medications was determined from previous studies and the recommendations of the manufacturer. The article is written by researchers that I consider to be world experts in meta-analyses and the analysis of large data sets in psychiatry.

77 studies were identified from a total of 24,524 published references and 4030 unpublished records.  27 were published, 21 or unpublished, and 29 were both published and unpublished. The study showed too hard when treatment groups across all of the medications of interest between the years 1986 and 2013.

The authors calculated dose response, dropouts due to adverse effects, and dropouts for any reason. Relative risks (RRs) were calculated for specific doses. The dose outcome relationships for venlafaxine are included in the figures below from the original article.  The Response figure shows the significant increase of up to about 150 mg and then a much more modest increase beyond that. The Dropout figure shows a similar increase up to the 150 mg range. The Dropout for any reason was less remarkable. The authors calculated that the 75-150 mg dose of venlafaxine was equivalent to 20 to 40 mg of fluoxetine (click to enlarge graphic)

The authors conclude that optimal acceptability of SSRIs and venlafaxine and and mirtazapine occurs within the lower end of the licensed dose range. They reconcile this with serotonin transporter (SERT) studies that show that 80% SERT occupancy occurs at the minimum doses of SSRIs or venlafaxine with further dose increases showing small increase in SERT occupancy.

In the case of venlafaxine they suggest that noradrenalin reuptake transporter (NET) may require higher doses of venlafaxine in the 225 mg to 375 mg per day range. Given the lack of efficacy of atomoxetine, a logical question might be whether NET blockade adds much to the antidepressant effect.

The authors review other dose-efficacy studies of antidepressants and point out that they are variable. The variability ranges from optimal doses of fluoxetine in the 21-40 mg per day range to doses at the recommended lower end of the range being superior. Response to doses in the higher range were variable in some studies. One study found a significant greater response for high-dose antidepressants but the dose of 40-50 mg fluoxetine equivalents showed the greatest efficacy.

The authors considered strengths and limitations their study. They thought that their state-of-the-art meta-analysis was a strength as well as the size of the data set. They also examined dose dependency for both efficacy and tolerability and acceptability. The limitations they discussed included patient selection and dosing not reflecting clinical practice. They also discussed the calculation of dose equivalency among antidepressants and how that might be problematic.

Another obvious strength of this study is the calculation of relative risks for response across SSRIs, venlafaxine, and mirtazapine. The figures are modest but favor antidepressants across all dosage ranges with the exception of mirtazapine at the 60 mg dose.  The authors don’t seem to mention it but it would seem that the optimal dosage ranges could be predicted from the regulatory information since that is based on dose ranging studies and tolerability studies. In that regard, the conclusion about dose ranges don’t seem to be that surprising but they may be needed given what is happening clinically.

Getting back to the issue with venlafaxine I see people respond to dosing within the lower and of the range from 37.5 to 75 mg in many cases. That same response rate continues up to the 150 mg dose and then starts to diminish between two or 25 and 375 mg. Over that same range there is a significant increase in dropout rates due to adverse effects.

How clinicians approach this new information will be interesting. There will still be people like me and the conservative camp looking for the first signs of side effects and toxicity and deciding at that point whether to stop dose escalation. I explicitly tell people that the goal is not to experience any side effects and that I doubt that people “get used to” side effects. There are clearly clinicians out there who are doing exactly the opposite and that is increasing the dose of venlafaxine and advising people to either tolerate the side effects or expect that they will go away.

The balance between therapeutic effect and side effects is a central issue in all branches of medicine. In many cases, the severity of adverse effects like an allergic reaction determines the decision. In the case of the medication like venlafaxine making that decision can be complex. Some of the side effects like sedation and lethargy at high doses can mimic symptoms of depression. At this point in time neither pharmacogenomics or most plasma level determinations guarantees either tolerability or efficacy.  

Detailed analysis of the situation by an expert with a bias toward preventing side effects is required as the first step in any dose increase.

George Dawson, MD, DFAPA

References:

1:  Furukawa TA, Cipriani A, Cowen PJ, Leucht S, Egger M, Salanti G.  Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis.  Published:June 06, 2019DOI:  https://doi.org/10.1016/S2215-0366(19)30217-2.

Attribution:

Above figure of the venlafaxine dose response and drop outs are directly from the paper in reference 1 and used per the Creative Commons Attribution 4.0 International Public License.

Attribution 4.0 International (CC BY 4.0)

Attribution 4.0 International (CC BY 4.0)