Misrepresenting harms in antidepressant trials
BMJ 2016; 352 doi: https://doi.org/10.1136/bmj.i217 (Published 28 January 2016) Cite this as: BMJ 2016;352:i217
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I recently attended the CME accredited winter meeting of the Scottish Division of the Royal College of Psychiatrists.
One of the topics presented was antidepressant prescribing which is rising year on year in Scotland. It is now estimated that 1 in 7 Scots are on antidepressants.
The presenters went on to give evidence that prescribing rates are rising because antidepressants are prescribed chronically. The accepted view is that that such prescribing is “appropriate” (1). However, I wonder how many patients who are first started on antidepressants might have been told that they may well end up taking these long-term and perhaps even for life? It would be interesting to know of the experiences and reflections of those who have been taking antidepressants long-term. Perhaps we should also reflect on how such long-term prescribing of antidepressants fits with the now widely adopted “recovery model”?
In the recent Royal College meeting I was surprised that the potential harms of antidepressant medication were not mentioned. There was no mention of “discontinuation syndrome” and no mention of potential risks such as suicide (2). What was repeatedly mentioned was concern about public “myths” about antidepressant medication and that as a profession we needed to counter these myths.
Interestingly, in a poll of cards, it was estimated, before the presentation, that 3/4s of the audience of Scottish psychiatrists felt antidepressants were overprescribed. The result after the presentation was unchanged. This would suggest that Scottish psychiatrists are not comfortable with such high prescribing rates.
References:
(1) Cameron I. M, Lawton K, Reid I. C. Appropriateness of antidepressant prescribing: an observational study in a Scottish primary-care setting. Br J Gen Pract. 2009 Sep;59(566):644-9
(2) Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports Tarang Sharma, Louise Schow Guski, Nanna Freund, Peter C Gøtzsche. 352:doi 10.1136/bmj.i65
Competing interests: Conflict of Interest: I have petitioned the Scottish Government for a Sunshine Act to be introduced: http://www.scottish.parliament.uk/GettingInvolved/Petitions/sunshineact I prescribe antidepressants in my job as a psychiatrist but I try to do so with discussion of the current evidence, where uncertainties are shared and risks and benefits are treated as equally important.
I am interested to learn more about how adverse effects are elicited in clinical trials. I have learned from interviewing patients that people with obvious dry mouth (impaired articulation that is corrected by a sip and swish of water) are often unaware of something I can hear easily. Canadian product monographs for drugs said not to be anticholinergic (e.g. duloxetine) list substantially increased dry mouth (up to 13% ARI) and constipation (up to 11% ARI) versus placebo in multiple RCT. (1) Does this mean that only about 1:8 to 1:9 people has chronic dry mouth or constipation, or that only this proportion of people spontaneously mention it on a long questionnaire? For venlafaxine, the Canadian product monograph suggests that dry mouth is increased similarly. Yet nausea, with an ARI of about 25% (NNH = 4) is even more common. (2) How much is known about how long such symptoms endure during chronic therapy? Do they truly decline (how?) or do patients simply adapt to chronic toxicity?
There are many reasons to fear long-term anticholinergic effects, now including the possibility that such exposure causes dementia. (3)
Recording of adverse effects is probably also problematic for all other drug classes. While adverse effects (AE) are usually not equally important as serious adverse events (SAE), they can certainly relate to quality of life. If they presage long term problems such as GI hemorrhage, increased dental decay, or chronic bowel and bladder problems, how should reported rates from short term trials be interpreted without the context of corresponding long term implications?
Psychotropic drugs often engender pharmacological tolerance and dependence. Whereas the syndrome that affects people who cannot obtain opioids or alcohol is usually referred to as "withdrawal", a similar phenomenon affecting people who have used SSRIs is euphemized as "discontinuation syndrome". When relevant, should the tendency to become stuck on a drug be reported similarly to other adverse events? If so, how long does a trial of a psychotropic drug need to be to provide a reasonably reliable estimate of the risk of developing dependence?
Thomas L. Perry, MD
References:
1. Cymbalta (duloxetine) product monograph, accessed February 2, 2016 at: http://webprod5.hc-sc.gc.ca/dpd-bdpp/info.do?code=78682&lang=eng
2. Effexor XR (venlafaxine) product monograph, accessed February 2, 2016 at: http://webprod5.hc-sc.gc.ca/dpd-bdpp/info.do?code=60601&lang=eng
3. Gray SL, Anderson ML et al. Cumulative Use of Strong Anticholinergics and Incident Dementia: A Prospective Cohort Study. JAMA Intern Med. doi:10.1001/jamainternmed.2014.7663
Competing interests: No competing interests
I completely agree that the side effects of SSRIs have not been researched or explained adequately to either prescribers or patients, which is very concerning in the light of the seemingly exponential level of use in recent years.. From both an interest in evidence, and from personal experience, the one side effect that I would like to see researched and explored more openly in the media concerns a discreet subset of patients whose SSRI use leads to uncontrollable cravings for alcohol (often in previously very moderate drinkers) that reportedly can lead to life changing consequences in unfortunate individuals. Nowhere in the Patient Information Leaflet is this mentioned. Dr David Healy has a website where patients experiences are described and I urge medical prescribers to have a read of all the page submissions and mention this to patients before prescribing.
Competing interests: No competing interests
Re: Misrepresenting harms in antidepressant trials Should be a criminal offence.
Dear Peter Gordon,
If 3/4 of psychiatrists were at odds to say the least, with the presentations being given by the College of Psychiatrists, why did they not speak out? That they did not is quite shocking when 3/4 of the attendees could not have been silenced by the presenters,.The card ballot was a rather crafty way of keeping the issue under wraps - it needs to be shouted out collectively. You are the only person so far who has highlighted how it was dealt with.
It begs the questions - what are psychiatrists afraid of if they do speak their truth at conferences? What actions could they take collectively to stop over prescribing? And how trustworthy is the information given by the presenters and representatives? Any possible conflict of interests? Including thoughts of career prospects.
When so many practising psychiatrists are in breach of the legal obligation to 'do no harm' - by knowingly going along with over prescribing - it could, hopefully, in time lead to a group legal action. People who have taken antidepressants have for decades been reporting adverse effects and been fobbed off. The College should have the humility to acknowledge they have been arrogant in over-riding reports both by those prescribing and those who have suffered the negative effects of powerful and harmful psychiatric drugs. Obviously the pharmaceutical industry is not the only big bad wolf in this.
Competing interests: No competing interests