Antidepressant use and risk of suicide and attempted suicide or self harm in people aged 20 to 64: cohort study using a primary care database
BMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h517 (Published 18 February 2015) Cite this as: BMJ 2015;350:h517All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
To the Editor:
Coupland et al. reported recently a very informative pharmacoepidemiological investigation of antidepressant use and risk of suicide(1) Their main finding was that venlafaxine, mirtazapine and trazodone had stronger associations with suicide than SSRIs and tricyclics. The authors basically interpret this as a consequence of bias by indication (severity), i.e. these three may be more commonly used as second line antidepressants in more seriously ill patients. Furthermore, they found that the association to suicide for all antidepressants was strongest during the first 28 days of exposure and the first 28 days after stopping the medication. The authors did not suggest any interpretations of this observation.
I wish to address the paradigm on which conclusions from this well done study was based. The authors write in their introduction, “Rates of suicide and self harm are greatly increased in people with depression and reduction of these risks is a major consideration when treating such patients. Paradoxically, although antidepressants have been shown to be effective in reducing the symptoms of depression there is concern that rates of suicide and self harm may actually be increased by treatment, particularly in younger people.” This paradox, which is currently held as a “truth” by some, is based on very weak evidence(2). What if there is no paradox? What if, in fact, antidepressants actually decrease the risk of suicide(3). The interpretation of the same study results based on this paradigm would then be the following: “Venlafaxine, mirtazapine and trazodone appear to be less effective than SSRI’s or tricyclics in reducing the risk of suicide in depressed people. This might be due to their second-line use for more severely depressed patients.”
Two facts support the latter paradigm being the more appropriate framework for interpretation. First, the authors found the absolute suicide rate in this cohort of antidepressant treated depressed patients to be smaller than expected. It was in men and women only 3.5 and 2.4 times higher than in the general population. Systematic investigations of consecutive suicides have found depression in 50-80 % of the cases(4, 5). On the other hand, most epidemiological studies have found the point prevalence of Major Depression in the general population being about 2-5 %(6). Using 50-80 % as the numerator and 2-5 % as the denominator, suggests a 10 to 40-fold over risk of suicide in depressives. Thus the small 2- to 4-fold over risks found by Coupland et al. indicate that many depressed patients in the study cohort have been protected from suicide by their use of antidepressants. The second fact supporting the latter paradigm is that the risk of suicide rapidly decreased after 28 days of treatment. This is consistent with the known delay until antidepressant medications are expected to become fully effective.
The well-done study by Coupland et al. should not be used as support for misbeliefs that antidepressants increase suicide risk in depressed people.
1. Coupland C, Hill T, Morriss R, Arthur A, Moore M, Hippisley-Cox J. Antidepressant use and risk of suicide and attempted suicide or self harm in people aged 20 to 64: cohort study using a primary care database. Bmj. 2015;350:h517.
2. Isacsson G, Rich CL. Antidepressant drugs and the risk of suicide in children and adolescents. Paediatric drugs. 2014 Apr;16(2):115-22.
3. Isacsson G, Holmgren A, Osby U, Ahlner J. Decrease in suicide among the individuals treated with antidepressants: a controlled study of antidepressants in suicide, Sweden 1995-2005. Acta Psychiatr Scand. 2009 Jul;120(1):37-44.
4. Barraclough B, Bunch J, Nelson B, Sainsbury P. A hundred cases of suicide: Clinical aspects. British Journal of Psychiatry. 1974;125:355-73.
5. Cheng ATA. Mental illness and suicide. Arch Gen Psychiatry. 1995;52:594-603.
6. Henriksson S, Asplund R, Boethius G, Hallstrom T, Isacsson G. Infrequent use of antidepressants in depressed individuals (an interview and prescription database study in a defined Swedish population 2001-2002). Eur Psychiatry. 2006 Sep;21(6):355-60.
Competing interests: No competing interests
Potential “inadequacy” of antidepressant treatment in depression and suicidality
To the editor: A possible relationship between the use of antidepressants and suicidality that may be positive or negative has been a topic of hot debate and represents a clinical issue of high pertinence (1). Dr. Coupland and colleagues investigated this critical issue using a huge database of an adult population consisting of “fresh” cases of depression with a large number of relatively “rare” events in question, to find that some antidepressant medications were more associated with higher rates of completed suicide as well as suicidal attempt or self-harming behaviours (2). The authors remained justly conservative in relating the events to antidepressants in their text by commenting on relevance of residual and unmeasured confounders. Furthermore antidepressants are likely to represent only a tip of the iceberg contributing to complex suicidal actions, for which many psychosocial difficulties and adversities are certainly involved (3) that however were largely unaccounted for in this study. Unequivocally picking one “suspect” out from many is a challenging task (specific antidepressants in this instance).
Another view of the paper could consist of evaluating “adequacy” of pharmacological treatment, for which the selection of the antidepressant together with its dose as well as the duration of treatment critically matter, rather than trying to attribute suicidality to specific antidepressants whereby confounding by indication would play a substantial role that may well remain resistant to adjustments. As is shown in their text, while 87.7% of patients received at least one prescription of antidperessants, as many as 14.2% of patients received only a single prescription. Further merely 36.6% of patients received treatment for one year or more, and as few as 5.5% did so for more than five years for this frequently chronic condition during the median follow-up period of 5.2 years. It is highly unlikely that all of those who stopped antidepressants recovered enough to the extent where they no longer require them to maintain wellness. Increased risk of suicidality following cessation of antidepressants found in this study is a replication of the previous work (4), which underscores an importance of maintenance treatment with antidepressants for those who need them.
As for the dose looking at Tables 2 and 3, it is clear that an overwhelming majority of cases with the event had been treated with a dose less than one defined daily dose (DDD). This clearly highlights a possibility of “under or suboptimal treatment”, which should be seriously taken into account among those with relatively severe depression who have a potential to act on suicidal thoughts. For instance in Table 3 it is indicated that 305 of 365 patients (83.6%) treated with tricyclics and exhibited suicidal attempts were dosed at one DDD (equivalent to only 75mg in case of amitriptyline, which is conservative in dose for sicker people) or less. A similar situation was also true for all other antidepressnats. Although dose response relationships of antidepressants are not necessarily straightforward, such a dose may well be considered “low” for those at risk of suicide related behaviours (5). An intriguing question to ask is how many instances of suicide related actions could have been avoided had the dose of antidepressants been adequate during the highest risk period (i.e., within 28 days after initiation of antidepressants when doses of antidepressants would be titrated upwards depending upon treatment response).
References
1. Stone MB. The FDA warning on antidepressants and suicidality--why the controversy? N Engl J Med. 2014 Oct 30;371(18):1668-71. doi: 10.1056/NEJMp1411138.
2. Coupland C, Hill T, Morriss R, Arthur A, Moore M, Hippisley-Cox J. Antidepressant use and risk of suicide and attempted suicide or self harm in people aged 20 to 64: cohort study using a primary care database. BMJ. 2015 Feb 18;350:h517. doi: 10.1136/bmj.h517.
3. Almasi K, Belso N, Kapur N, Webb R, Cooper J, Hadley S, Kerfoot M, Dunn G, Sotonyi P, Rihmer Z, Appleby L. Risk factors for suicide in Hungary: a case-control study. BMC Psychiatry. 2009 Jul 28;9:45. doi: 10.1186/1471-244X-9-45.
4. Valuck RJ, Orton HD, Libby AM. Antidepressant discontinuation and risk of suicide attempt: a retrospective, nested case-control study. J Clin Psychiatry. 2009 Aug;70(8):1069-77. doi: 10.4088/JCP.08m04943.
5. Adli M, Baethge C, Heinz A, Langlitz N, Bauer M. Is dose escalation of antidepressants a rational strategy after a medium-dose treatment has failed? A systematic review. Eur Arch Psychiatry Clin Neurosci. 2005 Dec;255(6):387-400. Epub 2005 Apr 29.
Competing interests: No competing interests
Re: Antidepressant use and risk of suicide and attempted suicide or self harm in people aged 20 to 64: cohort study using a primary care database
Yolande Lucire lucire@ozemail.com.au
The predicaments for which doctors prescribe antidepressants are not available to persons doing epidemiological studies or meta-analyses, as they do not have access to this patient level information. Accordingly, the reason for prescription should not be assumed to be “depression” – even as understood in its common language meaning. Antidepressants have been trialled for “minor mental disorders”, otherwise known as common human unhappiness, and also approved for anxiety, obsessive-compulsive disorder and menopausal symptoms.
At the United States Food and Drug Administration (US FDA), approval must be granted if a drug can be differentiated from placebo, or sugar pill, in two clinical trials out of any number that have been done, based on whatever criterion of significance the drug company chooses. Approval by FDA guarantees neither safety nor efficacy.
Whether or not the person develops toxic symptoms, worsening depression and sucidality or physical side effects is not at all related to their previous mental state or socially-constructed psychiatric diagnosis. Toxic side effects are biological, and occur in persons treated for non-psychiatric conditions as well.
Adverse effects as listed in each drug’s product information are the outcome of antidepressant toxicity, above the “therapeutic window of opportunity”, and result from several factors, usually acting together.
These include diminishing mutations in metabolizing genes in the cytochrome P450 system, the dose of the drug, synergistic adverse effects, the age of the patient, the drug burden, general and hepatic health, drug-drug and drug-gene interactions resulting from co-prescription of CYP450 inhibitors or withdrawal of inducers and the rate at which the medication is increased or decreased.
Adverse effects correlate well with genotypes but poorly with drug blood levels, which do not necessarily reflect brain levels. Also, once sucidality has set in, it worsens if withdrawal is not undertaken very slowly and persists well after the culprit medication has been ceased, and cannot be detected in blood which is five half-lives of the drug at issue.
Competing interests: No competing interests