Expectancy effects in antidepressant withdrawal studies

Zhang et al (2024) have published a systematic review and meta-analysis of the incidence of antidepressant withdrawal symptoms. More than 40% experienced such effects. This figure is higher than the 15% estimate from another recent systematic review (see previous post). As I pointed out in that previous post, so-called withdrawal symptoms also occur in the continuation arm of randomised controlled trials (RCTs), when such withdrawal symptoms wouldn't necessarily be expected in this group as participants are still taking their antidepressant. This could be said to demonstrate how expectation can influence the experience of antidepressant withdrawal, as participants may have expected adverse reactions on withdrawal, thinking they were being withdrawn from antidepressant even though they were in the blinded control group. Zhang et al report that the incidence in the discontinuation group is significantly higher than the continuation group. What I want to challenge is their claim that this significant difference therefore necessarily excludes such expectancy, or nocebo, effects as an at least partial, if not complete, explanation of antidepressant withdrawal symptoms.

I want to emphasise that I'm not saying such nocebo effects are not real. They are felt and experienced as true medication effects. It may well be difficult for people who experience withdrawal effects to understand that they could be nocebo effects. However, in my experience, people do generally appreciate that people may become dependent on antidepressant medication. It was the basis for me writing my BMJ letter that led to my special interest in antidepressant withdrawal (see eg. my book chapter). A drug that is thought to improve mood may well be expected to be difficult to give up because of, for example, a fear of relapse. Psychological dependence with antidepressant medication is not surprising (see eg. previous post). What people find difficult to accept is that such nocebo effects can be so powerful that they can cause the severe and longstanding effects that they do. But, again for example, if the taking of antidepressants is associated with the belief that the medication is correcting a brain problem, even though this is the wrong way of understanding how mental health problems are corrected, then it's not surprising that it may take some time to come to terms with managing without the drug because of the complex set of meanings that the medication has acquired. Undoing these beliefs is not easy, particularly perhaps if the experience of taking antidepressants initially seemed to help.

Of course using placebos in clinical trials of efficacy is designed to exclude placebo effects. In the same way in discontinuation trials, having a control group which continues antidepressant is designed to control for nocebo effects. How effective these control methods are in preventing placebo/nocebo effects depends on how well blinded the participants are from knowing to which group they have been allocated. There is considerable evidence that people are not completely blinded in antidepressant efficacy trials (see eg. previous post). As far as I know, there has been no attempt to measure unblinding in an antidepressant withdrawal study. If unblinding occurs in antidepressant efficacy studies, I think it is also likely to occur in antidepressant withdrawal studies. As the blind can be broken in antidepressant efficacy trials, it cannot be said that expectancy effects have been eliminated.  So my case is that it cannot be said that expectancy effects have been eliminated from antidepressant discontinuation RCTs, because I think there is also likely to be significant unblinding in these withdrawal studies as well.

Habituation to antidepressants is to be expected (see eg. previous post). It helps to explain why people take them for such long periods of time. Psychological mechanisms causing antidepressant withdrawal symptoms should not be dismissed. I have considerable doubts about antidepressants being more than placebo in their antidepressant effect (see eg. previous post). Those that argue that antidepressants cause organic physical dependence tend to say that the sense that antidepressants have stopped working, which can occur, sometimes colloquially called the "poop-out" effect, is evidence that there is tolerance with antidepressants. As I don't think antidepressants are "effective" in the sense of being more than placebo, this explanation doesn't make sense to me. I am at least consistent in my scepticism about the effects of antidepressants, which for their apparent benefit I put down to placebo, and for their withdrawal effects I am inclined to think could be due to nocebo. To emphasise again, this does not mean I am saying any experienced benefit for antidepressants is not real. Nor am I saying that the experience of antidepressant withdrawal is unreal. What brought me into the area of antidepressant withdrawal years ago was my critique of mainstream psychiatry for denying the reality of such symptoms. I just don't think that there's necessarily been much progress since in understanding the mechanisms of such withdrawal effects, and it worries me that psychological mechanisms seem to be being ignored, even within the Critical Psychiatry Network (see previous post). 

Thinking differently about mental health

I’ve changed the name of this blog before (see eg. previous post). I’m not convinced it’s really made much impact in terms of attracting more readers (see eg. another previous post). I’m making another attempt to see if expressing what this blog is about in more everyday terms, avoiding the use of ‘psychiatry’, makes a difference. As mentioned in another previous post, ‘mental health’ has come to mean the conditions and practices that maintain mental health. There is general acceptance that mental health needs to be rethought (see eg. yet another previous post).

Psychiatry struggles to cope with its inherent uncertainty

Terry Lynch, who wrote a chapter for my Critical Psychiatry edited book, has posted a video asking why doctors pay so little attention to trauma in the lives of people with psychiatric diagnosis. As Terry says, Robert Spitzer, Chair of the DSM-III taskforce (see eg. previous post), when asked in an interview whether psychiatric diagnosis shouldn't always take into account a person's life circumstances replied "If we did that then the whole system falls apart".

As I've said before (eg. see previous post), psychiatry is a cultural system. The belief that primary mental illness is brain disease clothes psychiatry with an aura of factuality, even though that belief is incorrect. As I also keep saying, biomedical psychiatry is more like a faith than a science (see eg. previous post). That includes what's often called the biopsychosocial approach to psychiatry, which can be more of an eclectic mix of biological, psychological and social in psychiatric assessment, regarding these aspects as more or less equally relevant in all cases and at all times. This understanding of ‘biopsychosocial’ makes psychiatry merely a weakened, ill-defined form of the biomedical model (see eg. another previous post), rather than truly anti-reductionistic in the way originated by George Engel (see eg. yet another previous post).

Psychiatry is sustained by its professional institutions, such as the American Psychiatric Association (see eg. previous post) and the Royal College of Psychiatrists (see eg. previous post). These professional bodies can’t always be relied on for information (see eg. another previous post). In fact, they are biased and do not take a pluralistic and integrated position to psychiatry, despite claims that they do (see eg. previous post). They tend to think that primary mental illness is brain disease or at least is caused by biological factors to some extent, whereas it is not a structural brain but functional personal problem. The American Psychiatric Association is responsible for the Diagnostic and Statistical Manual (DSM) which has resulted in a dead-end in its 5th version (see eg. previous post), building on the direction started by Spitzer.

The biomedical model gives a sense of direction and purpose to psychiatry. The trouble is it induces certain dispositions and ways of understanding in psychiatrists that can lead to them treating patients more as objects than people. It provides a worldview that, if psychiatrists did not accept and believe in it, would make their practice too uncertain for most. I think that’s what Spitzer meant. He was so panicked that psychiatric diagnosis may be unreliable that he took psychiatry, particularly American psychiatry down the DSM route to its dead end in DSM-5 (see eg. previous post and my 2002 article). 

Mad studies and critical/relational psychiatry

I’ve mentioned before the chapter written by key members involved in the foundation of the Critical Psychiatry Network (see previous post). The book for which it was written has now been published: Mad Studies Reader, edited by Brad Lewis (who has written a guest post for this blog) et al. My chapter with Ameil Joseph in Mat Savelli et al’s edited book highlights how mad studies, critical psychiatry, anti-psychiatry, and decolonizing activism contribute to mental health education and transformation.

Do antidepressants cause emotional numbing?

George Dawson (mentioned eg. in a previous post) and Ronald Pies (also mentioned eg. in another previous post) argue in a Psychiatric Times article that antidepressants do not work by numbing emotions. They wrote the article to counter the claim by Joanna Moncrieff and Mark Horowitz, members of the Critical Psychiatry Network (CPN), that one of the pharmacological actions of antidepressants is emotional numbness and that is how they “work”. This hypothesis builds on Jo’s differentiation of a disease-centred and drug-centred understanding of the mechanism of drug action (see previous post). Psychiatric drugs do not necessarily work because they are correcting a disease process (disease-centred model) but because they have drug effects that may be useful in managing the illness (drug-centred model). Emotional numbing is hypothesised to be of benefit when using antidepressants for depression. 

Also being a member of CPN, I have some concerns about Jo and Mark’s claim. I accept that emotional numbing is a common side effect of antidepressants, particularly in long-term use. I don’t think it’s usually a very immediate consequence of taking antidepressants, for example within the short-term (often about 6 weeks) clinical trials that are used to make claims about the effectiveness of antidepressants. So, I don't quite see how emotional numbing can explain any significant difference between antidepressant and placebo demonstrated in these trials over the short-term. 

But over the longer-term, people often complain that antidepressants seem to have stopped them really dealing with their problems and complain of a flattening of emotional responses which includes feelings of being ‘dulled’, ‘numbed’, ‘flattened’ or completely ‘blocked’, as well as descriptions of feeling ‘blank’ and ‘flat’, affecting their relationships with others and how they see themselves (see previous post). If antidepressants have seemed to help, even if more because of a placebo effect than true antidepressant action, then it's not surprising that people may feel that a physical rather than psychosocial approach to their depression has not really helped. They may express that as emotional numbness and not being in touch with their feelings. They might even still have the same underlying personal and social reasons that led to their depression, which haven't really been dealt with, as such, by mere taking of an antidepressant.

The trouble is that there is only a limited literature about emotional numbing caused by antidepressants that does not allow proper assessment of its significance and mechanism. One study that is commonly quoted is Goodwin at al (2017). They found that emotional blunting is reported by about half of people on antidepressants and is correlated with their depression score ie. a poorer quality of remission is associated with more blunting. However, the screening method used a leading question ‘To what extent have you been experien­cing emotional effects of your antidepressant?’, and followed this up with an explanation that ‘emotional effects vary, but may include, for example, feeling emotionally "numbed" or "blunted" in some way; lacking positive emotions or negative emotions; feeling detached from the world around you; or "just not caring" about things that you used to care about’. Those that gave a positive response were asked to complete a fuller questionnaire about emotional blunting. 

As the paper admits, the data is very much affected by subjective factors. People were guided by the methods used in the study into essentially having a wide understanding of the meaning of emotional numbness or blunting. I tend to think what's meant by emotional numbing is more to do with people feeling antidepressants are masking the real problem and thereby preventing them having their full range of experiences, rather than a direct physiological effect of the drug. Jo and Mark disagree with me about this, but I'm not convinced they've got the evidence for their view. People commonly, at least initially and maybe over time if they can sustain having stopped the antidepressant despite withdrawal symptoms, say that they feel more alive and in touch with their feelings after stopping the drug. That may not be surprising, as there must be relief, at least, that they do not have to take the antidepressant. There must also be a sense that emotions are no longer being controlled by the antidepressant. Trouble is that it's not always very easy stopping antidepressants, perhaps particularly if they were started when there didn't seem to be much alternative and the person has been misled into thinking that there must have been something wrong with their brain. This means that they get stuck in a vicious cycle of wanting to stop antidepressants but fear relapse and withdrawal symptoms if they've previously experienced them. Withdrawal symptoms are very common (see eg. previous post).

It worries me how the notion that antidepressants work by emotional numbing seems to be catching on, perhaps particularly with patients. As I've said, I'm not convinced there's the evidence for the hypothesis. As I've commonly said, I tend to think antidepressants are no better than placebo (see eg. previous post). That doesn't mean that I think they're inert. In fact, the reason I think antidepressants are no better than placebo is because I think the significant difference between antidepressant and placebo found in short term trials may be a methodological artefact. This arises, for example, because trials are not as double-blind as is commonly assumed. Trial participants may well be able to break the blind in randomised controlled trials because of side effects, so I'm not saying antidepressants are inert.

But I do worry that critics of biomedical psychiatry may be creating another myth, like the serotonin hypothesis, that antidepressants work by emotional numbing. In fact, because I don't think antidepressants probably work any better than placebo, in a way I'm saying they don't "work". There's no need, therefore, to even have an explanation of how they "work"! That's not meant to undermine the people that feel that antidepressants have helped (see eg. another previous post) but the limitations of medication do need to be acknowledged. The trouble is that mainstream psychiatry is committed to supporting the use of antidepressants because they are seen as effective.