Does psychiatry keep making the same mistakes? Edward Shorter gives us a historical perspective.

KELLIE NEWSOME: “History never repeats itself, but it often rhymes,” wrote Mark Twain. Today, Edward Shorter plucks a few lessons from psychiatry’s past.

CHRIS AIKEN: Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

KELLIE NEWSOME: Since the 1980’s, Edward Shorter has chronicled the history of psychiatry through a skeptic’s eye, and today we asked him what psychiatrists can learn from our history. Brace yourself.

EDWARD SHORTER: Well you can take psychiatry and really divide it into two arms: there’s diagnosis and there’s treatment. And in both areas, history has important messages for psychiatrists, but they aren’t necessarily good messages. In essence, history has bad news for psychiatry so that’s what I’m gonna talk about a little bit.

Let’s start with the good news first okay? And the good news is that many psychiatrists are extraordinarily effective clinicians. They can make their patients reliably better which is something you could say of no other medical specialty with the possible exception of radiation oncology. So this is a big plus point. But psychiatrists are able to do this in a way that has relatively little scientific underpinning. And so it’s the failure of psychiatry to become a truly scientific discipline that’s the real message here that I want to get across.

Every encounter with a psychiatrist is a form of psychotherapy and that’s wonderful, but it’s not necessarily an application of medical science.  It’s interesting that in the neurosciences neurology is viewed as the affiliated clinical science – not psychiatry.  Neuroscience is a very scientific field, the neurosciences, and people in that field look with kind of a reserved eye at psychiatry and they prefer neurology for the nature of its own scientific basis. For psychiatry as a medical discipline this is a kind of crisis. The field lacks the kind of science that the rest of medicine has, and I’m a historian and so we can trace this historically okay.

So let’s talk first about diagnosis. And in psychiatry there are a number of diagnoses that do not correspond to real disease entities. There are some that do. So this isn’t entirely bad news. Psychotic depression, melancholia, catatonia, and mania – these are all real disease entities.

CHRIS AIKEN: That’s it? Just four diagnoses you think are valid?

EDWARD SHORTER: Well sure, that’s not the end of the list by any means…there are these other conditions and vascular depression would be a good example because there is a clear organic cause. 

If we get into pediatric psychiatry there are more; geriatric psychiatry – dementia there’s more, but in terms of mainline psychiatry the diagnoses that I mentioned that are real that exist in scientific terms are melancholia, catatonia and mania.

But we’re close to the end of the list now.

Psychotic depression is a form of psychosis and that is very real, and it’s important for clinicians to know about that because it absolutely does not respond to psychotherapy but it does respond exquisitely to ECT. So this is a diagnosis with great clinical important, for example, and it’s a scientific diagnosis for sure. But depression as a global entity is just too diffuse. There are just too many kinds of depressions and, unfortunately, research has gone toward studying major depression which is global depression rather than trying to break depression down. And industry has had a real role to play here because industry does not want to see depression broken down because they want a big global market.

CHRIS AIKEN: To clarify, neurasthenic depression is marked by high fatigue and anxiety. It fell out of the DSM but remains in ICD-10.

Dr. Shorter, you’ve walked us through some of the diagnostic problems in psychiatry. What do you see as the treatment problems?

EDWARD SHORTER: Well, if you look at the whole area of treatment, there’s a history of decline here: a decline in the efficacy of treatments okay? Because many of the treatments today are either largely inert such as the SSRIs or toxic in the wrong population such as antipsychotics in the pediatric population or the geriatric population both of which are contraindication for psychotic medication, but nonetheless they’re widely prescribed in the pediatric and in the geriatric populations. So it’s not that antipsychotics have lost their efficacy, but the indications for their use have been narrow. The indications for the use of antipsychotics are too broad.

KELLIE NEWSOME: By the 1960’s, medications were available with most of the mechanisms we use today: Monoaminergic antidepressants – the tricyclics and MAOIs; Gaba-ergic benzodiazepines; Dopamine blocking antipsychotics, and Dopamine enhancing psychostimulants. But they lacked a clear diagnostic system to match a patient with the right medication, and so they tended to prescribe based on symptoms.

Stimulants were called antidepressants because they boosted energy and motivation, and that use continued with the tacit approval of the FDA until the agency decided there was no evidence these drugs treated depression at all and pulled that indication in the 1970’s. The maker of Vyvanse staged a comeback in the 2010’s with two large trials that tested the drug as antidepressant augmentation, but it failed in both studies.

CHRIS AIKEN: Antipsychotics also went by a different name in the 1950’s and 60’s – neuroleptics – so called because of their ability to calm agitation and anxiety when used in mania and psychosis. That symptomatic effect lead psychiatrists to try them in anxious depression, and the industry responded with the Triavil, a combination of the tricyclic antidepressant amitriptyline and the low potency antipsychotic perphenazine, also called Etrafon. 

Antipsychotic-Antidepressant combos fell out of favor in the 1980’s for three reasons

1. Growing awareness of tardive dyskinesia, which is more common in patients with mood disorders

2. Recognition that dopamine depletion can cause depression, particularly with high potency traditional antipsychotics like haloperidol

3. Availability of other combination options. Before the 1980’s, psychiatrists were not able to combine antidepressants because of the only options available – tricyclics and MAOIs – caused a potentially fatal serotonin syndrome when combined. That changed with trazodone in 1981, followed soon after by buproprion and fluoxetine.

KELLIE NEWSOME: Unlike stimulants in depression, antipsychotics did stage a successful comeback, starting with the approval of the fluoxetine-olanzapine combo pill Symbyax for treatment resistant depression in 2003. Dr. Shorter argued that they’re use has once again spilled over into populations where the risks tend to override their benefits. Children and adolescents are much more vulnerable to metabolic effects of antipsychotics, older adults are more at risk for tardive dyskinesia, temperature imbalance, anticholinergic effects and stroke on them, and patients with mild depression probably shouldn’t start an antipsychotic at all. 

EDWARD SHORTER: Well the real problem here is that psychiatry is heavily subject to fads. They don’t have a way of disproving anything or you can take any of the fads in psychiatry – well psychoanalysis is a good example of a fad. You can’t disprove psychoanalysis; all you can do is turn the page and move on; move on to some other form of psychiatry, move on to chemotherapy, and then psychoanalysis which would sort of wither on the vine and die. So that would be the typical life cycle of a fad. It starts out as something that everybody wants to get in on because they’ve read all about it the journals and then it becomes widely popular, which is the story of psychoanalysis for sure, and then it’s replaced by another fad. And there are many aspects of psychopharmacology that are really sort of faddish. 

CHRIS AIKEN: Now can you define a fad because I want to be clear like suppose something is really great and healthy and wonderful and so we use it a lot, like that wouldn’t necessarily be like a fad; that would be like proper use right?

EDWARD SHORTER: Yeah I mean if the use has a scientific basis it’s not a fad. A fad is something that becomes popular for cultural reasons.

CHRIS AIKEN: Okay and what are the forces that drive fads? So clearly it’s not science, so what is driving the fad; tell us about that?

EDWARD SHORTER: What drives fads is therapeutic desperation. You want to make patients better but you’re at a loss as to how to do. Of course, you could try psychotherapy, but hey psychotherapy doesn’t really do the trick if they’ve got something serious. So what else are you gonna use? You’ve got a bunch of pills out there that your patient is not responding to. The pills are called antidepressants. And so what else are we gonna use? So then you have various fads that come along: ketamine, for example. Today ketamine is a fad because it’s not clear that ketamine which started out with an anesthetic is a wonderful antidepressant and yet it works in a number of otherwise unresponsive patients, and why it works is unclear why an anesthetic would be so effective in serious depression. And so the use of ketamine – in Toronto, ketamine hasn’t been approved yet by the Canadian FDA; it has been approved in the U.S. So ketamine is just at the beginning of its trajectory. And when it’s approved here in Canada that will then open the door to ketamine as a fad, and it’s already a fad in the U.S. because you see it referred to constantly, everywhere. And for the clinical population in which ketamine works, hey that’s great, but it doesn’t work for everybody for sure. Nothing works for everybody. But, nonetheless, it is being used in inappropriate ways as an example of a fad.

CHRIS AIKEN: Yeah, so one driving force is desperation. We’ve got people we can’t help. Is there also something from the patients’ side or do patients get caught up in the fad and ask for stuff and is there something in that, tell us about that.

EDWARD SHORTER: If patients have seen in on television then they might ask for it. And the rule is that if a patient asks you for a treatment you give it to them to keep them happy right. They don’t ask for ketamine if they’ve never heard of it.

CHRIS AIKEN: It seems there’s a strong tendency in people to seek betterment, I don’t know, have sharper cognition, less anxiety, better sleep. I’m talking about people who don’t have any discernible mental illness who come to psychiatrists and this seems to have been going on for years is my guess, can you tell us about that force in psychiatry?

EDWARD SHORTER: I think there are a lot of people whose basic problem is that they’re unhappy and they tend to define this unhappiness in mental terms: ‘If I’m unhappy it must be because I’m depressed’ because depressed patients are unhappy too, right? They cry a lot and so forth. 

So I define myself as depressed and I go to the family doc and the family doc; you know there is nothing he can do for this kind of unhappiness so he refers you to a psychiatrist. Or in the U.S. you can go to a psychiatrist directly, just call him up and make an appointment so this is self-referral. And in this way, a lot of unhappiness ends up in the office of the psychiatrist.

CHRIS AIKEN: I suppose we can all get caught up in fads without knowing it like obviously if we know it we’re not going to get caught up in it, how can we examine ourselves and think through this and realize when we’re getting caught up in a fad?

EDWARD SHORTER: This is where science comes in and this is what psychiatry so gravely lacks is a kind of firm scientific foundation. If you can point out to a mechanism of action, for example, then that would immediately establish a scientific foundation for your drug, but there are very few drugs the mechanism of which is known. And so that’s really asking for something that is unrealistic to know the mechanism of action. 

But if you can demonstrate in RCTs that your drug clearly beats placebo that’s real science there – a randomly-controlled trial (RCT) is the most scientific procedure available to psychopharmacology, and so if your drug has a reliable history of beating placebo in RCTs then that’s great. But a lot of these RCTs are done only for purposes of registration; they’re financed by industry; they are sort of poked up in one way or another and they aren’t really reliable. 

So the whole literature on RCTs is corrupted from the get-go. It costs a lot of money to fund an RCT and nobody who doesn’t have a commercial interest in a molecule is going to set one up. So that’s an example now of the kind of scientific verification that you as a clinician can ask for. Are there nonindustry RCTs that support this drug? And if so then I’m gonna give this to my patients because I know that this has a scientific foundation.

CHRIS AIKEN: To back up, when you said we don’t have a scientific foundation except for those few things I think a part of what you’re saying is that we don’t have a scientific understanding of the etiology and the pathophysiology mechanism of action is that right?

EDWARD SHORTER: Yes, that would be asking for a lot.

CHRIS AIKEN: Because we do have randomized controlled trials. I mean psychiatry has that – generalized anxiety disorder we have randomized controlled trials, but we can’t match up the mechanism and the etiology.

EDWARD SHORTER: The RCTs that we do have are almost all funded by industry because who else would have an interest in funding RCT? They cost hundreds of thousands of dollars if not millions, and it’s the only funding agency for RCTs.

KELLIE NEWSOME: We interrupt this podcast for a preview of the CME quiz. Click on the link in the show notes to earn CME for this episode.

1. According to Dr. Shorter, what is the primary driver of fads in psychiatry?

A. Therapeutic desperation

B. Financial profit

C. Insurance pressures

D. Lack of scientific nosology

CHRIS AIKEN: Are there other mistakes that you see patterns in the last hundred years that psychiatrists keep making?

EDWARD SHORTER: Well one mistake has been turning nosology – the classification of illness – over to the American Psychiatric Association, which is a trade guild; it’s not a scientific organization. And so they’ve come up with these manuals - the DSM series - that are just terribly inadequate in terms of the definition of real illness. 

Nosology should have been placed in the hands of a real scientific organization such as NIMH or the Karolinska Institute in Stockholm where they could have gone about this in a scientific manner differentiating one disease entity from another on the basis of systematic psychopathophysiology.

CHRIS AIKEN: Is your implication that a trade group like the APA has a vested interest that is not scientific that biases them?

EDWARD SHORTER: Well they are partially funded by industry and so they definitely have an interest in coming up with diagnoses that industry will find useful. Now the APA brass don’t directly control the DSM; this is done by the various task forces. But nonetheless, the product of the task force will be determined by the people that you put on it, and the people on the DSM task forces have heavy biological commitments, and their interest in psychopathology as such tends to be minimal. 

But if you’ve got to come up with a nosology, you have to be guided by an expert sense of psychopathology – figuring out how in pathological terms one disease is different from another disease. For example, we make anxiety strictly distinct from depression in the DSM world, but in fact in reality almost all cases of depression have lots of anxiety and vice versa. 

The most common clinical entity is mixed depression and anxiety and yet that has never gotten into DSM, and I think the underlying mechanism here is that there are huge commercial lobbies that want to keep anxiety separate from depression because these are separate drug classes and each one is very popular and if you merge them together then somebody’s going to lose money.

CHRIS AIKEN: I missed what you said earlier, you said the members of the committee have heavy biological interests; what did you mean there?

EDWARD SHORTER: Well they believe that biological psychiatry is the main approach to psychiatry as opposed to psychoanalysis or as opposed to seeing themselves as psychotherapists. They have a commitment to the notion that psychiatric illness is basically brain disease that can be treated with the means of psychopharmacology.

CHRIS AIKEN: Okay, and other mistakes or patterns of mistakes that you see through different eras of history?

EDWARD SHORTER: Well we haven’t talked very much about the DSM at all and I think this has been a major area where psychiatry has blundered into the wilderness. We’ve talked about therapeutics. Another area that has been very much abused is neurotransmitters. 

Neurotransmitters are heavily marketed as a concept even though in scientific terms we know that your clinical symptoms are not associated with a shortage of serotonin in your brain. Never has a link been proven between brain levels of serotonin and illness and yet it’s become almost gospel for the field to think of clinical illness as resulting somehow from an imbalance in neurotransmitters and thus elevating the study of neurotransmitters almost to gospel saying, “Well, you know we have a case of depression here that probably is caused by a lack of dopamine, a lack of serotonin – maybe both of them, so let’s prescribe agents that are dopaminergic, serotonergic.”

CHRIS AIKEN: This sounds quite unhinged from science, as you put it; hence it reminds me of when the conflict between the ego and the id was gospel.

EDWARD SHORTER: Right, in the days when unconscious conflict was seen as the mechanism of illness and the conflict would be between the ego and the id or the superego would somehow intervene – it’s not very clearly exactly how this happened – but nonetheless these were the basic psychopathological entities that were studied in the days of psychoanalytic psychiatry. Now, nobody believes anymore in any of this stuff. But we believe, at least there are a lot of clinicians who believe or who tell their patients, which is different, or who tell their patients that their problems may be associated with low levels of serotonin.

CHRIS AIKEN: Right, even if they don’t believe it, it gets them to take the medicine. Are you saying that psychiatrists tend to derive our notions of pathophysiology from whatever treatment we’re using rather than from taking an honest look at what is causing these illnesses?

EDWARD SHORTER: Well, in reality we don’t know really what is causing them, but we know that they are caused by a deficiency in neurotransmitters or by an imbalance of neurotransmitters. And I think most psychiatrists understand that depression is not associated with low serotonin, although maybe all don’t, although they tell their patients this. But it’s a wonderful story for patients and you can go through it in a minute or two: ‘You know we think you’re problems are caused by a deficiency of serotonin. I’m going to prescribe something that will restore this deficiency,’ and you write out a prescription for an SSRI, give it to the patient and she’s out of your office.

CHRIS AIKEN: Yeah, but you know if you say it too much you tend to believe it yourself. 

EDWARD SHORTER: Well, I think there is in the real world of psychiatry still credence in the belief that levels of neurotransmitters are associated with illness. In the professional literature, this belief is no longer reflected, but in the trenches of clinical psychiatry, I think this belief is still strong. As you say, if you're patient enough you’ll end up believing it yourself.

KELLIE NEWSOME: Edward Shorter is Professor and Hannah Chair in the History of Medicine at the University of Toronto. His 1997 book A History of Psychiatry from the Era of the Asylum to the Age of Prozac is a classic that traces the history of psychiatry up to the SSRIs. In 2021 Dr. Shorter followed that up with a history of the post- SSRI years: The Rise and Fall of the Age Psychopharmacology. He will join us again next week for a discussion of controversies in psychiatry.

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