Startling lack of interest in confounding by withdrawal symptoms in this antidepressant discontinuation study in NEJM: Withdrawal symptoms in this discontinued group render this study uninterpretable. (1/n)
Withdrawal symptoms in the discontinuation group would have inflated the apparent rate of relapse in this group (2/n)
Patients on ADs for at least 9 months were taken off by halving for a month and then halving further for a month before stopping. Much quicker than the ‘months or longer’ recommended by RCPsych guidance and much faster than most patients can (3/n)
This caused withdrawal symptoms esp. at week 12. They measured modified withdrawal scale (15 symptoms) and found on average 3.1 in discon group vs 1.3 in maintenance group (but no measure of severity) (4/n)
Withdrawal symptoms include depressed mood, anxiety, anhedonia, disrupted sleep, fatigue and concentration problems. The rCIS-R measured depressed mood, anhedonia, fatigue, loss of concentration and sleep disturbance. (5/n)
Therefore withdrawal symptoms would have registered on the rCIS-R and increased the chance of registering as relapse. (6/n)
Drug doses were halved weeks 0-4 which has almost no effect on their receptor occupancy – no excess relapses were detected. Halved again (by second daily dosing) from weeks 4 to8 with some increase in relapses in the discon group. (7/n)
Drugs stopped at week 8. Almost entire separation between the lines occurred in the following 6-12 weeks the time at which withdrawal effects are most likely. (8/n)
At end of trial anxiety scores (GAD-7) were the same between maintenance and discon groups (3.0 vs 3.1, respectively) but they had been very different at week 12 (3.1 vs 5.3) the time at which withdrawal effects would have been most pronounced (4 weeks after stopping) (9/n)
The same was true for depression scores (PHQ-9). At 12 weeks maintenance versus discon was 4.1 vs 6.3 but by weeks 52 it was very similar 3.7 vs 4.0 (10/n)
Partial explanation for this was that patients who discontinued returned to their drugs but at end of trial only 44% of discon group was on ADs, while 89% in maintenance group were and they still had the same anxiety and depression levels. (11/n)
The pattern of anxiety and depression scores matches that of withdrawal effects: spiked at week 12, improving in weeks 24 through to 52. Differences between groups in PHQ-9 for week 12, 24, 39 and 52: 2,2, 0.8, 0.6, 0.3. For withdrawal symptoms: 1.8, 0.5, 0.9, 0.3. (12/n)
For GAD-7: 2.2, 0.7, 0.9, 0.1. (13/n)
Occam’s razor suggests rather than having 2 things going on: relapse and withdrawal symptoms it is more likely that increased anxiety and depression that correlate with the (mostly physical) withdrawal symptoms measured by the withdrawal scale is part of withdrawal syndrome(13/n)
If patients who scored significantly on withdrawal scale were excluded from registering as relapse then it is likely that the difference between rate of relapse in the discontinuation arm and the maintenance arm would be much less (14/n)
The failure to take into account mis-diagnosing withdrawal symptoms as relapse makes it difficult to interpret this trial and conclude as the authors do that people who stop antidepressants relapse more than those who do not. (15/n)
Would be similar to concluding that people who stop benzos have a relapse of anxiety more than those who continue (when anxiety is clearly a withdrawal symptom) or that people who quit smoking should continue in order to treat the anxiety that increases when they stop (16/n)
Ignoring confounding by withdrawal effects makes most discontinuation studies in psychiatry ‘uninterpretable’ to quote a very polite paper on the topic: And further analysis: (16/n)
To properly test the relapse prevention properties of antidepressants either very gradual tapering that prevents withdrawal symtoms from arising is needed or patients who experience significant withdrawal symptoms should be excluded from registering as relapse (17/n)
The media articles leaping to the conclusion that this study shows that people should be on these drugs long-term are very misleading to the public and are going to contribute to the ongoing and unnecessary use of these medications. (18/18)

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More from @markhoro

30 Sep
David Taylor says this about the NEJM study: "This study shows that discontinuing antidepressants in long term users leads to a greater risk of relapse than that seen in people continuing their medication. It seems to suggest that antidepressants are effective at (1/n)
preventing relapse. However, the speed and nature of antidepressant discontinuation is known to have a major effect on risk of relapse and this alone might explain the differences observed ..2/n
- patients were withdrawn over two months using a coarse linear dose reduction schedule which included alternate day dosing (even with short-acting drugs). ..3/n
Read 6 tweets
22 Jun
Enjoyed the @rcpsych IC session on deprescribing with @wendyburn David Taylor and Robin Murray. We had over 100 questions put to us - not seen so many before. Some very good questions from psychiatrists: 'Why is not a requirement of licensing these drugs that they are shown...1/n
to be safe to stop?'. 'Shouldn't we demand that manufacturers make medications in ways that make it easy to stop?' 'Why have academic psychopharmacologists, who should know best about this issue, both ignored and then minimised this problem?' 2/n
'Should we include a discussion about potential withdrawal phenomena when we are consenting something to start treatment?' 'Is there specific guidance for CAMHS/older age people?' 3/n
Read 9 tweets
22 Apr
Outline of the Cochrane study a bit for those scared of its length. Metro article: Lead author: the dauntless Ellen van Leuween. Co-author @tony_kendrick While there are hundreds of studies looking at starting antidepressants(1/n)
we found only 33 studies looking at stopping antidepressants, a therefore hugely neglected area 2/n
Most studies stopping antidepressants abruptly or in less than 4 weeks. This is not consistent with even the current lacklustre NICE guidance (stop over more than 4 weeks) and certainly nothing like the improved guidance from RCPsych (3/n)
Read 16 tweets
23 Mar
(Thread) Today we have published a paper on a way to reduce antipsychotics to minimise withdrawal effects and possibly relapse in @SchizBulletin. with thanks to co-authors Robin Murray, David Taylor, @sameerjauhar and Sridhar Natesan. (1/n)
It extends our work on risperidone to more antipsychotic drugs
It provides some examples of pharmacologically rational tapering regimes for haloperidol, risperidone, olanzapine, clozapine, quetiapine and amisulpride which takes into account 2/n
their pharmacological characteristics and clinical trials. We suggest reducing dose by 5 or 10 percentage points of D2 occupancy (equivalent to about one quarter or one half of the dose) every 3-6 months. (3/n)
Read 18 tweets
17 Mar
(Thread) With due respect to others who have contributed to my special edition I consider this one of the most important pieces. @Altostrata When I was coming off an antidepressant and in dire straits, I could not find any guidance on what was (1/n)
going on or how to navigate out of it from published literature. Without Adele Framer I would not have been able to get off my drugs; indeed I am not sure I would be alive. I have learnt a lot from her and now I am very glad that now other clinicians, patients (2/n)
and researchers will be able to learn from the wisdom she has gained over 15 years and deep study. She tells me she looked and looked for an expert to be able to help her and could not find one. Instead, she was forced to become one herself. (3/n)
Read 6 tweets
4 Mar
If you have been tapered off a psych drug too fast by a doctor, is it possible (after recovering) to go back and try to let them know what happened? Understand there may be a lot of anger. But could help others avoid the same fate. Terrible thing to have ask ppl to do I know
I ask this because in a focus group yesterday some ppl had done this. Know this takes a lot of energy. But ppl need to stop being told 'I have never seen this before', 'I don't know what to do'. At some point I am sure @rcgp will spring into action
It is also a numbers game. There are about 30,000 GPs in England. Based on this paper there are 10,000 English people just on a handful of facebook sites who know how to taper antidepressants. There are more ppl learning all the time
Read 4 tweets

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