Find out what psychiatry's favorite critic does in his practice
Dr. Aiken: David Healy is both a critic and a practitioner of psychopharmacology, and today he shares what he actually does in practice.
Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. And my co- host Kellie Newsome, is out on vacation this week.
David Healy is a psychopharmacologist whose career spans back to the early 1980’s, where his early research furthered our understanding of the monoamine system and the norepinephrine and serotonergic antidepressants that work through it. In the 1990’s he realized that many of the pioneers of psychopharmacology would not be with us long, and he collected interviews with them which he turned into a series of key texts on the history of psychopharmacology.
Since then, he has written critical texts exploring the broader effects of psychiatric meds and diagnoses on culture, all the while continuing to practice. He spoke with us about some of his views on the field, and shared a rare glimpse of how he works with patients.
But first, a preview of the CME quiz for this episode.
1. Which effect of SSRI antidepressants was not well known when they were first released
A. Anxiolytic or anti-anxiety effects
B. Antidepressant effects
C. Sexual dysfunction
D. Metabolic effects
Dr. Aiken: Randomized controlled trials are the “gold standard” for figuring out whether a medication works. What are we missing when we rely on RCTs?
Dr. Healy: Well the guy who did the first randomized controlled trial, Austin Bradford Hill said…in essence what he was saying was to play golf you need to have a full set of clubs in the bag. You don’t just want one good club which you love using. And RCTs are a bit like that. They’re useful to evaluate one obscure effect a drug often has. I mean you know use it if a drug clearly works. When you’re not sure if it really works or not, that’s when it can be really helpful to tee up an RCT to look at one thing.
But while you’re teeing up the RCT to look at one thing, you miss all of the other things that the drug may be doing. For instance, in the case of the SSRI group of drugs, they were fairly weak antidepressants. In fact, they’re not really antidepressants; they’re more anxiolytic. But the companies back in the late ‘80s figured there’s no way to try and bring an anxiolytic on the market at least in places like the U.K. and Europe where the benzodiazepines had got a really bad name. People were being hooked on them. And the average family doctor, who is the one who is giving out these drugs, wasn’t going to buy the idea that this is an anxiolytic that people can’t get dependent to. So the whole idea of having an anxiolytic brought on the market...
And back then most people viewed the problems they were having, not as a mood problem, but as stress, nervousness, anxiety. But it seemed from a marketing point of view a better idea to bring these drugs, which in every trial they’d been put into compared to tricyclic antidepressants, lost out and came out as inferior, you know. It seemed a better idea to bring them on the market as antidepressants.
But what you’re doing when you’re bringing them on the market as antidepressants is you’re setting up kind of an odd situation which is they are not awfully good antidepressants and it’s hard work to try and tease out do they actually work at all in clinical trials. It can often take a full six weeks before there’s a clear differentiation between the drug and placebo.
Dr. Aiken: I’ll differ with you there a touch. The SSRIs are not very effective in anxiety disorders, but they do work very well in patients with neurotic traits – people who have difficulty managing stress and tend to react with intense emotions and certainly anxiety is high among them. But you’ve also written that – besides their anxiolytic effects – the most reliable effect of SSRIs may be to lower sex drive.
David Healy: We all assume the mood effect is the commonest thing the drug does. It’s much more common than things which are idiosyncratic or may appear outside the time frame of the clinical trial. But in fact, no, there are things that are probably a lot more important to the people we put on these drugs happening in every single one of them.
Dr. Aiken: Can you put all this in practical terms – how does it affect what you do with the patient?
Dr. Healy: What is it that would be a helpful thing to do that might lift their mood? I mean if you’re looking closely at the patient and thinking about them closely you might think well, this is a person where an anxiolytic might help. So an SSRI might help. But this is a person where maybe a stimulant might help so a drug that’s more acting on the norepinephrine system or an outright kind of stimulant might help, you know. Or you might think well, they’re very agitated so one of the things I maybe need to do is throw in an antipsychotic into the mix also.
What we have instead as opposed to thinking – and this isn’t just a thing that’s confined to mental health; this is all of medicine these days – instead of thinking about it, we just figure let’s give an antidepressant.
And if the first one doesn’t work we give another and another. And I see people – I’m unsure about you – who are on six to ten psychotropic drugs and on the basis that apparently they all work so there can’t be any problem giving you ten drugs that work. You know you’ve obviously got a very severe mood disorder by this stage. It looked mild to begin with, but you know we didn’t realize there were clearly deep roots and you need ten drugs.
Whereas the other way of thinking was well okay this particular drug – this particular drug that gets labeled an “antidepressant” which is really more an anxiolytic hasn’t worked in your case, and rather than adding drugs into the mix maybe we should halt that one and begin a different kind of drug.
At the end of the day, the best evidence we have comes from the patient’s mouth. And part of the problem we’ve got is in clinical settings because of time constraints and things like that, and you know the bias you and I might have in that we don’t want to think we’ve harmed people, we actually make it very hard for people to speak up and say, “Well, look you know there is also this other odd thing that’s actually been happening to me.” But that’s the best evidence there is.
Dr. Aiken: So we moved from a culture of do no harm to see no harm.
Dr. Healy: Yes, we’ve moved from a culture where we figured, where we knew, and a lot of the people that we knew or that we gave pills to also knew that we were giving them poison out of which we hoped to bring good.
And we do the job well when we remember that we’re giving you poison and when you know that you’re actually having a poison or the first hint of things going wrong that we both say, “Well this could be the pill” to giving sacraments which are things that can only do good. Even we’ve gone beyond the Catholic Church that recognizes the Eucharist can cause problems and have made it gluten free, but now the pills we have can’t cause problems. I mean there are clearly some doctors who can recognize that the pills are causing problems but most of them don’t.
And part of the problem here for me in all this is that if you don’t think the pills can cause problems and if you think they work wonderfully well and you’re seeing a bunch of patients, it becomes a heartsick job: the people who are not responding or know things aren’t going right, or you know you’re feeling stressed and burdened when they turn up, and you see the clinic list and you say, “Oh, you know there’s gonna be three or four awkward people here.”
If you turn it the other way around and figure the people who can tell us the most about these pills are the people that we put on them and come to see us, well, all of sudden we have a hundred free research assistants if you encourage them to google things and come back and talk about issues.
Dr. Aiken: Doctors aren’t the only ones who are driving this. We have a consumer medicine culture and it’s often the patients who are asking for more medication.
Dr. Healy: We’ve moved into a health universe. I mean why the patient wants more drugs is a little bit like why the Catholic rather than going to mass once a week goes daily and wants the Eucharist daily? Health has replaced holiness and we think that the more sacraments we get the better and, “I’m entitled to get to heaven and you’re saying ‘no’ to me!” It’s a bit like a priest saying, “Hey, you know, you don’t really want to be coming along to church quite this often. It’s not that healthy.”
Dr. Aiken: As you talk I’m thinking about many of the things that SSRIs do which many of us did not believe they did when they first came out. They lower sex drive, the can cause a withdrawal syndrome, and there are rare cases of suicidal ideation on them. You helped bring attention to these problems, and lately you’ve written about persistent sexual dysfunction after stopping SSRIs – something that is recognized by European regulators but not by the FDA. Any other examples of rare side effects you’ve seen?
Dr. Healy: the case that I always come back to when I make this point is a lady I had who was put on Paxil because she got anxious. She choked on some food at her father’s funeral, became anxious, and found it hard to eat again, was put on Paxil which cleared the problem up beautifully. And also she was a nervous driver and Paxil cleared that up too and she was feeling great: “This pill is working wonderfully well for me.”
And then a few months later, about a half year later she gets told by a friend, “You know you were drinking very heavily last night and behaving oddly” and this really didn’t make sense to her. She couldn’t recall it. And when she gets told it a few times she begins to wonder. And when she has a crash in a car she begins to wonder as well, and goes back to the doctor and says, “Look you know I think this Paxil is causing me to drink.” And he laughs at her but is a little more gentle than most of us and writes the company and says, “Could this happen?” And they write back, of course, and say, “No, it couldn’t. We’ve got no reports of this.”
But he does agree to change her. And she knows so little about these pills; she’s got no background in healthcare; she’s left school early, and he’s changed her from one SSRI to another and she doesn’t know that’s what he’s done. She just knows he’s changed the pills and the problem keeps going. He refers her to AA and she says at AA, “Look I think my pills are causing me to drink and AA tell her, “This just proves you’re an alcoholic. This is typical alcoholic thinking,” okay. And she ultimately loses her job and things like that. And she goes on the Internet and begins to research these things. And I’ve got a PhD on the serotonin system and she ends up telling me things about the serotonin system that I didn’t know and comes up with an answer. “Change me to mirtazapine which is what the doctor does, and the problem clears up.”
And the only thing the people around the place at that time – this happened about ten years or so – that agreed with her that SSRIs can make you alcoholic...I mean they were useful; we all thought they were helpful for people who are depressed, who drink because they’re depressed, and that may be true for some people that we treat, but there’s clearly a group of people who become alcoholic on them, and I’ve got hundreds of reports of this now, but the people who agreed with her were the pharmaceutical companies who were working on 5-HT3 antagonists as potential treatments for alcoholism.
Dr. Aiken: Are psychiatrists more likely to see these rare reactions because they get referred to us?
Dr. Healy: Well, good question. Yeah, there gonna send it to us expecting us to add more diagnoses and add more drugs. They’re not going to recognize it as an adverse event, and the chances are that we’re not going to recognize it either. And we have a problem, which is if we tell the PCP this is an adverse event on the drug, lots of PCPs aren’t going to be terribly happy with this message and nor is the patient which is, “I did something wrong and we now have an expert saying I did something wrong, am I in legal trouble?”
Dr. Aiken: How do you know if a drug is causing a rare side effect?
Dr. Healy: Well, a lot of it hinges on the plausibility of the person who comes into us. And clearly working in mental health, there is going to be a bunch of people who are going to try to fool us and we’ve got to take that into account. They may be keen to talk issues up in order to get disability payments; there are all kinds of incentives for them not to tell us the truth.
But in the case of a person who’s got an adverse event on a drug where they’re beginning to think this is an adverse event, there is no great incentive for them to do that. So it’s worth paying heed to, and there’s a good chance in your case and my case that we’re gonna be told something that just doesn’t compute; you know it’s very hard to see how this drug could be causing that problem. But in a sense that’s where the fun in the job comes from you know and then maybe ending up saying that…I mean there’s a bunch of patients I’ve seen recently where it has been the drug. You’ve got people who have raw and painful mouths. You know how does that happen on a psychotropic drug? And to me it really wasn’t obvious, but it turns out when we look at the drugs the person has been put on there are things like lamotrigine or topiramate or whatever which are linked potentially to this kind of thing. You know it’s the kind of thing you can conceive of.
Dr. Aiken: OK so walk us through the steps when we see something in practice that may be a rare reaction to a drug, how do we evaluate that?
Dr. Healy: Well, one of the key things is going to be if it’s possible and it’s always possible when the person is on six or eight drugs to stop one of them. Like, for instance, let me give you an instance. I inherited a patient who was on four or five drugs; she was bipolar - in fact two from one of my colleagues who was ill - and both of these people came in to me. And they both had been treated for bipolar disorder and they had the shakes. And they were on standard treatment, which is lithium and lamotrigine and one or two other drugs. And the obvious thing in the case of one of them, which my colleague had done, was to say, “Well it’s probably a tremor caused by lithium, so let’s stop the lithium.” And the other lady, I said when she came to me said, “It’s obviously caused by lithium, let’s just hold it and see what happens.” In both cases, the tremor went on.
So this opened up the question…I was looking at two patients on lamotrigine, which I in essence never use okay. So you’ve got two people who had tremors on it, which I thought were likely to be caused by lithium, which you’d have thought was the obvious thing but weren’t – if you go to reports to FDA and look at lamotrigine and what are the problems people have reported to the FDA on it, you find tremor is there as very frequently reported. So it opens the possibility…
Dr. Aiken: Does it help to search the medical journals on pubmed?
Dr. Healy: Well no I don’t know that PubMed is going to get you anywhere. It has to be an adverse event reporting system. MedWatch is useful, but I just happened in that case to use it, but you don’t need to do that. If you’re left with…you know the person’s only on two or three drugs, you’ve got rid of the one that’s mostly like to cause a tremor, and that didn’t clear the problem up, the next thing is to remove the other one and see what happens.
Dr. Aiken: Why did you say that pubmed is not helpful in these cases?
Dr. Healy: No. This is awfully hard to do. It’s gotten harder and harder which was journals like The New England Journal of Medicine and The BMJ use to operate with case reports up until the early or mid-1990s. Industry did a good job of selling them evidence-based meds in which you only want to be publishing RCTs which we are also going to be paying you for reprints of; we’re not going to be buying reprints of case reports of problems on our drugs.
Dr. Aiken: You said the pharmaceutical companies have gotten around this mandatory reporting. How did they do that?
Dr. Healy: Yeah, they’ve outsourced the drugs to other companies. Like, for instance, Zoloft in the case of Pfizer, they hung onto a generic Zoloft. If you now try to report a person becoming suicidal on the drug to Pfizer they say, “Well, we aren’t the company that holds it anymore. There’s a holding company, a different company that now has”…I mean when a drug comes off patent, companies often produced branded generics. So there was a Zoloft generic drug okay, and you could report the problem to Pfizer because the person - even though the drug was off patent it was still a Pfizer drug, but it is no longer a Pfizer drug.
Dr. Aiken: You are known as a critique of psychopharmacology but you’re also a psychopharmacologist.
Dr. Healy: I’m a psychopharmacologist who figures that part of the skill is knowing when not to use a drug.
Dr. Aiken: And yes – I think your work is sometimes misunderstood as being anti-psych meds, but in reality you seem to be saying what a lot of us agree with which is that many of our psych meds are not strong enough. They have effect sizes of 0.2 or 0.3, which is barely noticeable to the naked eye. I mean that about the SSRIs and the latest – Cariprazine (Vraylar) – whose latest trial puts its effect size at 0.22 in depression and yet still got FDA approved to augment antidepressants.
Dr. Healy: Yeah. Well there are two things here. First of all, general speaking across the board, the drugs that we brought on the market during the 1950s and early ‘60s without RCTs are more potent than the ones that we’ve brought on since because if you are giving them as doctors you have to see the benefit, whereas with an SSRI you can produce a statistical benefit that no one can see.
Dr. Aiken: So what are the more powerful medications you rely on?
Dr. Healy: Well if I was going to treat a person who had melancholia I would always reach for a tricyclic antidepressant you know. They’re the only drugs that have been shown…I mean I’ve seen in clinical practice people respond to them, okay, in a way you don’t see with SSRIs, and the trials that have been done show that they are more potent than SSRIs.
Dr. Aiken: Melancholic depression is characterized by mood that is distinct from ordinary sadness. Emotions are flat, anhedonic, and don’t respond to external events although they may be worse in the morning. These patients also tend to wake up early in the morning, have low appetite, and pronounced psychomotor changes like slowing or agitation.
Dr. Aiken: And what about in bipolar?
Dr. Healy: I figure lithium can be very helpful for a lot of people. I’m much less persuaded by the anticonvulsants generally.
Dr. Aiken: In schizophrenia?
Dr. Healy: Well, in terms of the antipsychotic group of drugs, I’m probably more likely to use the first generation rather than you know the second generation. Haloperidol if need be, but not particularly, maybe perphenazine: the group of drugs that we had in Europe which haven’t really got over here like sulpiride and amysulpride.
Dr. Aiken: Thank you Dr. Healy. And where can people go to learn more?
Dr. Healy: The issues that concern me; if patients want to chase a bit further the book which is called The Shipwreck of the Singular: HealthCare’s Castaways. which does have all my concerns particularly the concern that doctors are going to go out of business if they don’t wake up and realize the goal – the value is in the interactions between their patients and them, you know.
Dr. Aiken: David Healy is a Professor of Psychiatry at Bangor University in England. He is a former Secretary of the British Association for Psychopharmacology, and has authored more than 220 peer-reviewed articles and 25 books, including The Antidepressant Era, The Psychopharmacologists I-III, his latest book Shipwreck of the Singular, documents how the improvements in medicine which increased life expectancy have now turned inside out and are leading to shortened life spans.
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