Most recently updated on 6th March 2018
Hello! This is the questions, clarifications and corrections section of the Lost Connections website. As with my previous book ‘Chasing The Scream’, I’m really keen to make sure I have been entirely accurate, and I went through a detailed fact-checking and editing process. Once a month I’ll post an update here, and have any errors corrected for future editions. (You can see the corrections page for Chasing The Scream here to get a sense of what I’m talking about.)
I’m also very happy to have an open conversation about areas where some people think I have made an error and I consult the facts and disagree.
I was emailed and asked to respond to a few people’s queries and comments about the book.
SHOULD PEOPLE STOP ANTI-DEPRESSANTS COLD TURKEY?
I’ve been told that one person read my book, stopped their chemical anti-depressants cold turkey, and experienced some nasty physical withdrawal symptoms. As somebody who went through really deep and painful depression for thirteen years, I send her my love and support.
To take this step – quitting the drugs overnight – is to deeply misunderstand the message of the book in two very clear ways.
I warn in the book that 20 percent of people taking chemical anti-depressants will experience very severe withdrawal symptoms when they stop, which is why I stopped taking these drugs very slowly over the course of six months. I was on 60mg of Seroxat – so for a month I alternated 60mg one day and 30 mg the next; then for two months I took 30mg every day; then I alternated 30mg one day and 15mg the next; and so on, until I stopped entirely. My strong advice to anyone who wants to stop taking these drugs (and not everyone should, for reasons I’ll come to) is to cut back as I did, with a lot of consultation and monitoring with their doctor, for two reasons. One is the risk of physical withdrawal. The other is because – as I also explain in the book – the drugs give a mostly small but real amount of relief from depression to some people.
The fact that this reader experienced such severe physical symptoms shows how serious these drugs are: nobody should start or stop taking them lightly. For me, they caused a huge amount of weight gain and affected my sexual functioning while I was taking them, while giving me only an initial burst of relief from the depression itself that sadly wore off over time. Others experience low symptoms and bigger benefits (as one of my closest relatives has): I point out in the book that people who feel for them to benefits outweigh the side-effects should carry on taking these drugs.
Nobody should ever stop cold turkey, in any circumstances – that’s dangerous and unequivocally contrary to my advice.
I think there’s a deeper misunderstanding in responding to my book this way. ‘Lost Connections’ is emphatically not an argument for quitting drugs and just trying to cope with the agony. It is an argument that as a society we need to have a much broader menu of deep responses to the pain this reader, and so many other people like her, are going through. It argues – in line with the advice of the leading medical body on earth, the World Health Organisation – that we need to deal with the deep underlying reasons why people are depressed, and give them far more support and love, and far more options for changing their lives. That – along with the option of continuing chemical anti-depressants for as long as she feels she needs them – is what this reader deserves.
This reader, alas, didn’t try any of the alternative solutions I suggest, and didn’t receive any of the extensive social solutions I say are necessary to deal with depression and anxiety. Instead, she stopped overnight, and faced the extreme unpleasantness of physical withdrawal alone. None of this is what the book recommends, and my heart goes out to her for what must have been a truly horrible experience.
I believe both these points – physical withdrawal is a big risk; we need much more extensive care and support for people with depression – are clear in the book. I’m going to add an extra paragraph to future editions, stressing even more emphatically that stopping cold turkey is an absolutely terrible idea and I implore people not to do it.
RESPONDING TO DEAN BURNETT
The other people I am responding to in this section have raised serious scientific questions in a spirit of serious scientific debate, which I am happy to engage in. With Dean Burnett, who has written twice about my book in blog posts for the Guardian, the situation is slightly different: he has made a series of provably false claims about what I say, which leave his readers with a deeply misleading impression. To be fair to Burnett, he admits he has not read the book, which may explain how he has so profoundly misunderstood what it says, in such a broad range of ways.
I’d like to go through his claims one by one: I’d urge readers to look at his claims, and then the factual record, and compare them using your own judgement. In his blog posts, he makes eight claims:
Claim one: Burnett has written an entire article imploring people not to quit their anti-depressants overnight in response to my book. He admits two-thirds of the way in that I have never said they should, but he then insinuates this is somehow my position anyway.
Response one: It is blatantly false to suggest I have ever implied to anyone, ever, that they should ever stop taking chemical anti-depressants. On page 37 of the book, speaking of these drugs, I say the exact opposite, unequivocally, to people taking these drugs: “If you feel helped by them, and the positives outweigh the side effects, you should carry on.” Some of the people I most love take chemical anti-depressants, and I have never once urged them to stop.
I have repeatedly stated that anti-depressants have a real benefit for some people, and for the people who are experiencing benefits on them, I offer only love and encouragement. I have repeatedly stated that I want to expand the menu of options for depressed people – not take anything off the menu. I have also repeatedly said that if people for whom they are not working decide to stop, I would in the strongest possible terms urge them never to stop abruptly, but instead to do what I did: cut back very slowly, under the supervision of their GP, over a period of six months.
I am puzzled about why Burnett is reacting this way to my wider point about anti-depressants – that they are good for some people, but we need a wider debate and better solutions because there are many people they don’t work for – since Burnett himself made exactly this argument less than a year ago. In an article, he stated: “It’s not surprising, then, that antidepressants don’t work, or even make things worse, for many patients.” As proof for the accuracy of his claim, he approvingly linked to a study entitled ‘Why Anti-Depressants Don’t Work For So Many,’ of which the subtitle is: “More than half the people who take anti-depressants for depression never get relief.”
Using Burnett’s logic – that pointing out any partial limitations to chemical anti-depressants is tantamount to urging everyone to abruptly discard them – I could just as easily write a piece implying Dean Burnett is telling people to stop taking their anti-depressants overnight and condemning him for putting people in danger. It would be wholly false; and his attempt to imply that about me is equally false.
Claim two: Burnett claims what I say about the grief exception in this article is inaccurate.
Response two: The leading expert on the grief exception in the world, Dr Joanne Caciatorre, has responded to him, explaining that the circumstances he claims cannot happen – immediate diagnosis of a grieving parent – in fact can happen, and she lays out the precise circumstances in which it can take place. She points to her scientific paper showing 9 percent of grieving parents are drugged in the first 48 hours. Dr Caciatorre writes:
“There is no bereavement exclusion anymore in the DSM [Diagnostic and Statistical Manual], thus a diagnosis of MDD [Major Depressive Disorder] can be made when a person has the normal symptoms of grief for two weeks. And a person could be dx’d [diagnosed] with MDD one minute after the death of a baby if he or she had symptoms of MDD for the prior two weeks (many pregnant women feel weepy, experience changes in sleep patterns, loss of energy, fatigued, have trouble concentrating, etc). Of course, any wise clinician would not diagnose MDD under such tragic circumstances even if those symptoms predated the birth and death of the baby by two weeks. That isn’t the point: the point is that there is no protection against such carelessness and it contributes to the mistreatment of families suffering grief. And so, grieving parents are diagnosed within days and weeks at their therapist’s or doctor’s discretion. For example, in one robust sample of 235 grieving parents, nearly 40% were prescribed psychiatric medications and of those 32% of prescriptions were written within 48 hours (44% within a week and 75% within a month) (Lacasse & Cacciatore, 2014).” [Thank you to Adrian Flynn for pointing out via email that, in my summary of this research here in the questions and corrections section, I got one of the numbers wrong for Dr Cacciatorre’s findings: that’s now been fixed.]
If Burnett has evidence that the leading expert in the world and her published record of scientific papers on this is incorrect, he should offer it.
Claim three: He says that Professor Irving Kirsch of Harvard University, is a marginal figure in the field and his findings on anti-depressants should not be taken seriously.
Response three: As I pointed out above, and it bears repeating: Burnett himself has written approvingly about, and linked to scientific reports by, scientists who are just as critical as Irving Kirsch’s, and he drew precisely the same point from the research. Burnett wrote last year: “It’s not surprising, then, that antidepressants don’t work, or even make things worse, for many patients.”
As proof for the accuracy of his claim, he linked to a study entitled ‘Why Anti-Depressants Don’t Work For So Many,’ of which the subtitle is: “More than half the people who take anti-depressants for depression never get relief.”
This is Kirsch’s point, and my point. Some people get relief from chemical anti-depressants: they deserve only love and encouragement. But we also need a much wider debate, because there are many people they don’t help. I am puzzled about why Burnett is so outraged by a Harvard professor (one of the leading experts in the world on this) and I pointing out the same facts he pointed out himself less than a year ago.
Claim four: Burnett argues I present some of my wider arguments – that there are deeper social and psychological causes of depression and anxiety which must be dealt with – as if they are new, when in fact they are mainstream and well-known within the scientific community.
Response four: I explicitly state in the article and book that these facts and arguments are well-known and mainstream in the field, writing: “This is radical, but it is not, I discovered, some maverick position. In its official statement for World Health Day in 2017, the United Nations reviewed the best evidence and concluded that “the dominant biomedical narrative of depression” is based on “biased and selective use of research outcomes” that “must be abandoned.”” For Burnett to claim I am saying I discovered these claims, when I explicitly attribute them to the World Health Organisation and to the dozens of scientists I write about, is bizarre.
My point is (as I say repeatedly in the book) not that these arguments are new to psychiatrists and researchers: they already know them. My argument is that they are new to the general public, who have never been told about them, and to the wider culture, which has not built a better system based on these insights.
Claim five: He says many of these insights have been known since the 1970s.
Response five: That’s correct – which is why in the article, I explain that Professor Michael Marmot made his discovery in the 1970s, and the book is full of the stories of discoveries made in the 1970s. He cannot have fully read the article he claims to be debunking.
Claim six: He says I claim that only one kind of treatment is available on the British National Health Service for depression, when in fact there are many.
Response six: Far from neglecting this topic, I have a whole chapter on the best of this NHS diversification in my book. (It’s chapter seventeen for anyone who wants to check it out).
Claim seven: Burnett claims that I have “cherry-picked” studies that find what I wanted to see, rather than dispassionately surveying the evidence.
Response seven: For more than a decade, I wrote articles and gave interviews defending the idea that depression is caused by a chemical imbalance and saying that the primary and most important response was to give people chemical anti-depressants. I believed it passionately. If I was “cherry-picking” studies that confirmed what I already thought, I would have looked for studies that said reinforced this belief.
In fact, what I did was the opposite of cherry-picking: I was ultimately persuaded by evidence that went against what I wanted to believe. I learned that chemical anti-depressants have a real but limited effect, and we need a much broader response. I explain all this very clearly in the book – a book which Burnett, to be fair to him, admits he hasn’t read. I also go through the reasons why I was persuaded by the particular trials I cite, especially the Star-D trial: because it is the study that most closely resembles how people are using chemical anti-depressants in the real world, for reasons detailed at length in the book.
Claim eight: Burnett argues that my book is somehow an attack on doctors and psychiatrists who are working hard and doing their best.
Response eight: Far from being opposed to psychiatry, I am hugely sympathetic to doctors and psychiatrists working day to day with some of the most distressed people in our culture, who – as the book explains – overwhelmingly work really hard to do the best for their patients. They are doing their best with the tools they are given. My own sister was, until very recently, a psychiatric nurse, and I am enormously proud of her and the work she did, which saved lives.
It is the wider society – all the rest of us – that need to do a better job of giving them better tools, of acting on the insights from the best research into mental health, and (most importantly of all) of changing the way we all live so that fewer people are left in a state of profound distress.
We don’t leave the job of dealing with car crashes simply to people who have already been mangled in car accidents and to doctors in emergency rooms. We know that the culture has to change to prevent it – through airbags and seatbelts and speed limits and bans on drunk-driving. We need a comparable cultural shift to deal with the nine deep causes of depression and anxiety I was able to find evidence for in ‘Lost Connections.’ I think people can see it is a deep misunderstanding to think that making this case is an attack on psychiatrists, any more than making the case for airbags is an attack on doctors doing the night-shift in the Emergency Room.
Unlike Burnett, there are two journalists at the Guardian who have in fact read my book. One is their Readers Editor, Paul Chadwick, who has taken the unusual step of issuing a clarification at the end of both Burnett’s blog posts, linking to my correction. Chadwick points out that I do not urge people to abruptly stop taking chemical anti-depressants – which runs contrary to the misleading implications of Burnett’s posts. The other Guardian writer who read my book – for their lead review of it – praises the book’s scientific and factual rigour, gives an accurate summary of the book that bears no relationship to Burnett’s, and strongly recommends people read it. You can read that review here.
Depressed and anxious people deserve a serious debate about the causes of depression and anxiety, not a series of straw men and fictitious claims. I am happy that serious debate is taking place, and these entirely false claims are not distracting from it.
A RESPONSE TO DR CARMINE PARIANTE
Dr Carmine Pariante wrote an article in the Independent entitled ‘As a psychiatrist, I know Johann Hari is wrong to cast doubt on anti-depressants’. Dr Pariante and I concur on a lot, and I admire his work. He wrote to me: “As a psychiatrist, I value your emphasis on the importance of social connections, and I hope that you will recognize in my response the many points on which I completely agree with you.”
We differ a little on some questions (not all) surrounding chemical anti-depressants. I want to go through his two key points separately:
Point one: Dr Pariante argues: “Antidepressants reverse some of the physical effects of depression: increasing production of new brain cells, and reducing inflammation.”
Response: I asked him to send me the study on which he was basing this conclusion, and I looked at it carefully and then asked Professor Kirsch for his analysis. (Again, I had discussed this question during my research with several scientists, but I wanted to return to it here with one of the most distinguished figures in the field to make sure I had understood it.) The study Dr Pariante sent over is here.
Professor Kirsch responded: “Pariante bases this conclusion on an uncontrolled study. With no control group, there is no way of knowing whether the effect was due to the antidepressant, rather than it being a consequence of improvement in depression brought about by the passage of time and/or the placebo effect. For example, using PET, Mayberg and colleagues found that successful treatment with an SSRI was associated with “metabolic increases involving the prefrontal, anterior cingulate, premotor, parietal, posterior insula, and posterior cingulate and metabolic decreases involving the subgenual cingulate, parahippocampus, and thalamus.” The hitch is that pretty much the same changes were observed among participants who had been successfully treated with placebo.”
Point two: Dr Pariante also argued: “Studies using the most rigorous approaches (supported by publicly funded bodies, such as the Medical Research Council, not just pharmaceutical companies as Hari suggests) show that antidepressants lift the pervasive sadness at the core of clinical depression, albeit with varying effects on other symptoms such as sleep or appetite problems.” (The study he sent me for this is here)
I respond to the argument about publicly-funded trials later – see below.
Concerning the argument that chemical anti-depressants lift the pervasive sadness at the heart of depression, Professor Kirsch responded: “Pariante bases this on a recent study by Hieronymus et al (2017) in which superiority of SSRI over placebo were found more consistently on a single item of the Hamilton depression scale than on the total score of the scale. There is a reason for constructing scales made of many items, and the reason is that multi-item scales are more reliable that single items in that scale. For example, in the supplementary material of the Hieronymus study, it was revealed that side effects were associated higher single-item depression scores on one of the two SSRIs studied (citalopram) but lower scores the other (paroxetine). Further, the single item on which these findings were based does not measure “the pervasive sadness at the core of clinical depression.” Here is what that the item actually says:
1 DEPRESSED MOOD (sadness, hopeless, helpless, worthless)
0 |__| Absent.
1 |__| These feeling states indicated only on questioning.
2 |__| These feeling states spontaneously reported verbally.
3 |__| Communicates feeling states non-verbally, i.e. through facial expression, posture, voice and tendency to weep.
4 |__| Patient reports virtually only these feeling states in his/her spontaneous verbal and non-verbal communication.
The mean score on this item was between 1 and 2, regardless of whether patients were given drug or placebo, meaning that both groups reported feeling sad, hopeless, helpless, and worthless after treatment, but those who had been given the SSRI were more likely to state them without being asked and those given placebo more likely to wait to be asked. Now I ask you, is this a clinically meaningful difference in outcome?”
I found these arguments by Professor Kirsch persuasive but this is an on-going scientific argument in which they are both far more expert than me, and I’m looking forward to continuing to follow it.
I’m grateful to Dr Cariante and to Professor Kirsch – who agree on a lot – for engaging in this way.
RESPONSE TO STUART RITCHIE
Stuart Ritchie at the University of Edinburgh has asked a question and put forward some studies which he argues contradict some of what I concluded from my interviews and research. He asked where the figure I put forward, that 65 to 80 percent of people taking anti-depressants become depressed again within a year. They are footnoted in the book. I initially learned about this claim from Dr Steve Illardi, Associate Professor at Clinical Psychology at the University of Kansas, in his book ‘The Depression Cure’ (see pages 44 to 45), as Dr Ritchie correctly surmises. I then read through the studies Dr Illardi cites, and discussed in depth this field of research with Professor Irving Kirsch, Professor John Ioannidis, Professor Joanna Moncrieff, Dr David Healey, Dr Lucy Johnson, Dr Sam Everington, Dr Vincent Felitti, Professor Michael Chandler, and with people who defend anti-depressants more strongly like Dr Peter Kramer.
Some of the studies Dr Illardi cites, which I also drew on, are: Corey-Lisle, P. K. et al., “Response, Partial Response, and Nonresponse in Primary Care Treatment of Depression,” Archives of Internal Medicine 164 (2004): 1197–1204; Trivedi et al., “Medication Augmentation after the Failure of SSRIs for Depression,” New England Journal of Medicine 354 (2006): 1243–1252.
In the book, I explain in detail why I was persuaded by the people I spoke to, and by my reading of the evidence, that the research from the Star*D trial – a specific investigation into the effects of anti-depressants – struck me as particularly important. Some studies that are worth looking at in relation to this: Diane Warden et al., “The STAR*D Project Results: A Comprehensive Review of Findings,” Current Psychiatry Reports 9, no. 6 (2007): 449–459; A. John Rush et al., “Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report,” American Journal of Psychiatry 163 (2006) : 1905–1917; Bradley Gaynes et al., “What Did STAR*D Teach Us? Results from a Large-Scale, Practical, Clinical Trial for Patients With Depression,” Psychiatric Services 60, no. 11 (November 2009), http://dx.doi.org/10.1176/ps.2009.60.11.1439; Mark Sinyor et al., “The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Trial: A Review,” Canadian Journal of Psychiatry 55, no. 3 (March 2010): 126–135, doi: 10.1177/070674371005500303 ; Thomas Insel at al., “The STAR*D Trial: Revealing the Need for Better Treatments” Psychiatric Services 60 (2009): 1466–1467 . Warden et al., “The STAR*D project results: A comprehensive review of findings,” Current Psychiatry Reports 9, no. 6 (Dec. 2007): 449–459. (Not every one of these studies is in agreement, of course.)
In the book I also discuss how the Star-D trial evidence is disputed by Peter Kramer, in a way I found unpersuasive: I explain to the reader that anyone who wants to look it up can find his critique in Ordinarily Well, 192–3.
I also refer people to the research Dr Ed Pigott has done which argues that 90 percent of people who take anti-depressants experience a relapse or stop taking the drugs because the side-effects are so severe. I thought his analysis, while making some important points, went too far, which is one reason why I went for the lower figure given by Dr Illardi.
In the book I explain why I found the evidence from many of the drug research trials unpersuasive. Stuart Ritchie puts forward four studies which he asks me to consider:
“This 2003 meta-analysis of 31 studies found a 1-year relapse rate of 19% with antidepressants (vs. 41% with placebo): https://www.ncbi.nlm.nih.gov/pubmed/12606176
This 2008 meta-analysis of 23 studies found a 1-year relapse rate of ~20% with antidepressants (vs. ~40% with placebo – see Figure 3): https://t.co/V8TawlMS1E
This 2009 meta-analysis of 11 studies found a 1-year relapse rate of 23% with antidepressants (vs. 51% with placebo):
This 2016 meta-analysis of 72 brief studies (~8 months) found a relapse rate of 23.3% with antidepressants (49.4% w/discontinuation); and of 37 longer studies (~2yrs) found a relapse rate of 24.5% (vs. 55.6% w/placebo):
I asked Professor Irving Kirsch of Harvard University, who has done so much to reveal the flaws in many of these trials, for his response to Dr Ritchie, and he wrote:
“The relapse prevention studies referred to [by Ritchie] are discontinuation trials. It’s what happens to people who improve on drug and then are either kept on the drug or switched to placebo. What this ignores is what happens when people improve on placebo and are kept on placebo. [Professor Kirsch sent me graphics which illustrate this.] Note that people started on placebo and continued on it have the same low relapse rate as those started on drug and continued on drug. Also see the other three slides. Unlike other treatments, those on drugs have to stay on drugs to avoid high rates of relapse. Also note that the STAR*D trial produced an exceptionally high rate of relapse (over 90% according to Ed Pigott’s analysis) even without discontinuation.”
I explain in the book: “The debate about whether chemical antidepressants work—for some other reason we don’t fully understand—is still ongoing. There is no scientific consensus. Many distinguished scientists agree with Irving Kirsch; many agree with Peter Kramer.”
Anyone who would like to read a more detailed analysis of the flaws in the drug testing trials – one that I find persuasive, some others may not – should check out Professor Irving Kirsch’s book ‘The Emperor’s New Drugs’, which goes into this scientific debate in much greater detail, and people who want to read a defence – one which has many good points but ultimately, for reasons I explain in the book, I was not persuaded by – should read Peter Kramer’s ‘Ordinarily Well.’
I’d also like to take this opportunity to reiterate my position. My argument is not that chemical anti-depressants are bad, or that people who feel benefit from them (including some of the people I love) should stop taking them. It is that their benefits are real but limited, and we need to expand the menu of help that is available, and change our culture to deal with the reasons people are feeling so bad. All sides of this debate agree – at the very least – that there is a very significant number of depressed and anxious people who are not helped by anti-depressants, and this is just one of many reasons why we need to have a much bigger debate about depression.
WHAT ABOUT PUBLICLY-FUNDED TRIALS OF ANTI-DEPRESSANTS?
Dr Ritchie has pointed out that there are some publicly-funded trials of anti-depressants which also indicate they are more effective than placebos. Many people understandably infer from this that this fact demonstrates their effectiveness, since there is no vested interest for publicly-funded bodies to back these drugs unless the effects are real. I found this point persuasive when I first learned about it in my research several years ago, and I explored it with some of the scientists named above during the research for the book, and I then looked at many of publicly-funded studies, including some of those cited by Dr Ritchie.
As I dug deeper, I was broadly persuaded by the analysis of these trials put forward by Professor Kirsch and others, and I touch on why in the book.
Before I quote the analysis Professor Kirsch offers, I have to step back for a moment to explain something. Scientists measure the depth of someone’s depression using something called the Hamilton scale, which was invented by a scientist named Max Hamilton in 1959. The Hamilton scale rages from 0 (where you’re skipping along merrily) to 51 (where you’re suicidal). To give you a yardstick: you can get a six-point leap in your Hamilton score if you improve your sleeping patterns.
Concerning the trials Dr Ritchie raises, Professor Kirsch explains: “About half of studies, regardless of funding, find support [for chemical anti-depressants] in the sense that they show a statistically significant difference between drug and placebo. The question is, are these differences clinically meaningful?”
When Professor Kirsch studied the data provided in private to the Food and Drug Administration (FDA) in the US when anti-depressants were first being submitted for release to the public, he found that the average improvement an individual experiences when they take them is 1.8 percent on the Hamilton Scale – which is a little less than a third of the improvement you get if you improve your sleep patterns. There is a real effect, but it is relatively small, on average. (There is a debate about whether it works better with people who have severe depression – I go through this debate in the book.)
Professor Kirsch argues that this improvement is too small to be regarded as clinically significant. Others think he has somewhat under-estimated the effect, and others argue that an improvement of 1.8 percent is worth the cost and side-effects of the drug.
Professor Kirsch adds: “Also, various design features can augment the apparent [small] effect. These include [trials which are]:
(a) Excluding people who are mildly or moderately depressed, which make up the majority of patients given antidepressant prescriptions
(b) Excluding patients who get better on placebo during the wash out period
(c) Replacing patients who fail to show improvement on the drug during the first two weeks (e.g., in the fluoxetine and sertraline trials submitted to the FDA)
(d) Breaking blind by patients and clinicians [This is a really important concept explained in detail in Professor Kirsch’s book ‘The Emperor’s New Drugs’] So even that small, clinically insignificant difference, may be an artefact.”
So: nobody disputes that publicly funded trials show some improvement over placebo. I explain this clearly in the book. The debate is – how big is the effect? Some people think it’s too small to solve the problem; others believe it is not, at least for some people.
(There is, of course, no dispute that in addition to this effect, the drug companies exaggerated the effects of these drugs in their trials. They had to make a huge pay-out in the US courts for doing this, following a detailed legal case, concerning the exact drug I took for thirteen years – for a little background on this, check out this, this, this, this, this, this and this.)
It was looking at this evidence, and much more, that led me to my conclusion about chemical anti-depressants: that they have some real effect, but for most people, it is modest, and we need lots of other solutions alongside the chemicals. This is why I am not opposed to these drugs, but I think they need to be complemented by many more strategies to solve depression and anxiety.
RESPONSE TO ZOE STAVRI
Zoe Stavri argues that I am wrong to draw on the work of Professor Irving Kirsch, for three reasons. I was aware during my research of these criticisms (not specifically from Stavri, but from others), and I was also aware of Professor Kirsch’s response to them, and I was broadly persuaded by Professor Kirsch’s arguments. I asked him to reiterate them specifically for this page.
Point one, from Stavri. She says: ‘Kirsch and colleagues didn’t find that antidepressants don’t work on the majority of people: they found that effectiveness of antidepressants are more effective for severe depression and less effective for mild or moderate depression. That’s a nuanced difference’
Response, from Professor Kirsch (the square brackets are from me): “We found no drug-placebo effect at all for mild or moderate depression and less than clinically significant differences for most people with very severe depression. Those who are depressed enough to show a clinically (as opposed to statistically) significant difference represent approximately 10% of patients presenting in practice with diagnoses of major depressive disorder. However, it is important to look at the criterion used for clinical significance. NICE [The National Institute for Clinical Excellence, the independent body which assesses the efficacy of drugs] set a 3 point difference on the HAM-D [the Hamilton scale, which measures depression] or an effect size of 0.50. Leucht and colleagues examined what changes in the HAM-D correspond to global clinical ratings of improvement. They found that a 3 point difference is equivalent to a clinician rating of “no change”. To get a rating of “minimally improved” you need a change of 7 points on the HAM-D. so far, no one has been able to find a drug-placebo difference anywhere close to that in any group of patients, no matter what the severity.”
Point two, from Stavri: “Other researchers analysed the same dataset as Kirsch and drew different conclusions. Using different statistical modelling, Fountoulakis and colleagues found antidepressants were better than placebo, at all levels of depression severity. Turner and Rosenthal’s interpretation of the data is different to Kirsch’s, suggesting that certain measures can be more important than disappearance of depression, such as quality of life, which has been overlooked in Kirsch’s study, and to be “circumspect but not dismissive” in considering the benefits of antidepressants.’”
Response, from Professor Kirsch: “They made statistical errors in there calculations, which we pointed out in our rejoinder. In any case, some meta-analyses show an association of drug-placebo differences with baseline severity; others do not. Others use unconventional cut-offs for classifying severity, and some use statistical techniques (e.g., grouping Ss into severe v not severe) that all statisticians say are unreliable, akin to throwing away at least 1/3 of the data, and therefore not having enough power to reliably show real differences. More important, no one finds an overall drug-placebo difference that is clinically significant even according to the NICE criteria. So if the effect is the same across levels of severity, then no one is getting a clinically meaningful effect from the drug compared to what they would get on placebo. We used the same measure used by the FDA to make approval decisions.”
Point three, from Stavri: “Kirsch only looked at certain types of antidepressants – four types of SSRIs; your comments re relating specifically to the serotonin hypothesis and don’t relate to antidepressants in general.”
Response three, from Professor Kirsch: “There are few if any differences between the effects of one type of AD [anti-depressant] vs another. Other researchers have used different ADs in their meta-analyses. All come up with the same basic findings as did we. No one gets an effect size above 0.35 (the NICE criterion is 0.50). This includes two meta-analyses done in-house at the FDA on all the clinical trials for which they had the data. The largest found the same 1.8 point difference that we reported in our meta-analyses. Note also, that one gets the same response to Tianeptine (an SSRE) as to SSRIs.”
WHAT ABOUT THE OXFORD STUDY?
In February 2017, a study was published by Dr Andrea Cirpriani and his colleagues. I’ve discussed some of these questions with Dr Cipriani on the BBC and we agreed on most things: he said that I was right to try to get people to talk more about, and deal with, the social and psychological causes of depression. (He disagreed with me on some other points). He has now co-authored this study that has found that chemical anti-depressants have a larger effect than just a placebo.
A few people on social media seemed to think this showed some aspect of my book was wrong. I assume they believe this because (as detailed above) a Guardian blogger named Dean Burnett claimed that my book tells people to stop taking anti-depressants and this idea got quite widely spread – but, as interviewers and psychiatrists who have read the book have explained, my book doesn’t say anything remotely like that. The readers’ editor at the Guardian has now issued a clarification at the end of Burnett’s blog posts. In fact the book says, on page 37 (and this is a point reiterated throughout the text): “I certainly don’t want to take away anything that gives anyone some relief. If for you the benefits outweigh the side-effects, you should carry on.” That’s been my advice to my own relatives, several of whom continue to take these drugs at my urging.
The book explores some nuanced points about chemical anti-depressants, which are not contradicted by the Oxford study. Depression is often measured by something called the Hamilton Scale. As I explain above – and I’ll reiterate here, for anyone who’s skipped down to here – it runs from 1 (where you’d be joyful) to 51 (where you’d be suicidal). To give you a sense of what movement on the Hamilton Scale looks like, if you improve your sleep patterns, you gain 6 points on the Hamilton Scale, and if your sleep patterns deteriorate, you lose 6 points on the Hamilton Scale. According to the leading expert at Harvard Medical School, Professor Irving Kirsch, chemical anti-depressants give you on average a boost of 1.8 points. It’s important to stress: that’s an average.
As I explain in the book, I initially got more than that, and over time got less than that. (Some other experts say Professor Kirsch is under-estimating the benefit on the Hamilton Scale – but not by a huge amount).
It’s clear that 1.8 points is not nothing, and it’s more than placebo. For people in terrible pain (as I was), it can offer real relief, and therefore has real value. But for huge numbers of people – more than 50 percent, according to this major study, cited by the very person who wrote the Guardian blog post attacking my position – it is isn’t enough to provide lasting relief for depression. You can read that study here.
I think this is a pretty common-sense position. 1.8 points is not nothing; these drugs give some real relief to some people and therefore have some value; but they don’t solve the problem for most of us. This is why 90 percent of my book is about how we need to expand the menu of options for depressed people, to include solutions that deal with the underlying problems. Nobody wants to take anything off the menu.
Professor Kirsch explains about the Oxford study, via email:
There is not much new in this study, despite the media hype, and it does not contradict what I have written in the past.
One. They find a statistically significant difference between drug and placebo. So have my colleagues and I in the various meta-analyses we have published [as Lost Connections reports]. The question is whether this difference has any clinical relevance [i.e. whether it gives the user a significant movement on the Hamilton Scale]. They do not address this issue. All of the meta-analyses addressing this issue, including those by proponents of antidepressive medication, have failed to find clinically meaningful differences, using the cutoffs proposed by the National Institute for Health and Clinical Institute for Health and Care Excellence (NICE). Furthermore, Joanna Moncrief and I have demonstrated that the NICE criteria are overly liberal, as they correspond to clinician ratings of no difference at all in depression.
Two. They have chosen to dichotomize scores into responders vs. nonresponders. This has been condemned by statisticians as producing biased results and tantamount to discarding 1/3 or more of the data. It also produces what Joanna Moncrieff and I have termed the “response rate illusion.” That is because the difference between a “responder” and a “nonresponder” can be as little as 1 point on whatever scale is used to measure depression. For example, a person who improves by 50% is called a responder, whereas one who improves by 49% is called a nonresponder. We have shown that a small difference in mean improvement scores corresponds to the kind of difference shown in the new Cipriani et al. study. This difference was 1.8 points on the Hamilton scale in both our meta-analysis and a more recent unpublished analysis of all the antidepressant data ever submitted to the FDA, the latter comprising patient-level data from 23,295 patients in 92 clinical trials. To put this into perspective, note that “minimal improvement” corresponds to a 7 point change on the Hamilton scale.
Three. They report an effect size (SMD) of 0.30 for drug v placebo. We found an SMD of 0.32. The NICE cutoff for clinical significance is 0.50. Using the criteria of “minimal improvement” you would need an effect size of 0.875.
This strongly suggests the more over-inflated claims made about the Oxford study are going too far. It confirms there is real value in these drugs, but if we get stuck at the debate ‘are chemical anti-depressants good or bad?’ we’re missing the point. They provide relief for some, and therefore have some value, but don’t solve the underlying problems for most and need to be part of a much bigger strategy. The conclusion I reached in the book – that we urgently need to deal with the deeper causes of depression, rather than just pathologizing our pain by saying chemical solutions should be the immediate response for most people – is the position of the leading medical body in the world, the World Health Organisation, and the United Nations. Take a look at what the UN’s leading doctor says on this here.
For something as devastating as depression – the worst thing I have ever been through – we need every strategy and tool on the table, as I make clear in my book. Everyone in this debate agrees, including Professor Kirsch and Dr Cipriani, that there are big social and psychological causes of depression – I write about seven in Lost Connections – and many of them are rising. We need to deal with these deeper causes urgently. We are in the middle of a depression and anxiety emergency. The Oxford study confirms that some depressed and anxious people will benefit from chemical relief (as I did for a time, as I explain in the book). That relief – based on the best evidence – will be mild for the average user. It’s not nothing – but it’s not a full solution.
All depressed people, by contrast, will benefit from us dealing with the deeper causes of depression. That’s our most urgent public health task now – and that is the subject of my book.
If you spot anything in ‘Lost Corrections’ that you think is not correct, the best way to contact me is to drop me a line at firstname.lastname@example.org – on the 12th of each month I’ll post an update on what I’ve received and respond to queries.