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Study, Jan/19: Long-term harms from previous use of SSRIs: Systematic review


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The full title of this Danish study is "Long-term harms from previous use of selective serotonin reuptake inhibitors: A systematic review".








Millions of people are treated with antidepressants like selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). This clinical practice is based on short-term trials that have exaggerated the benefits and underestimated the harms. We also know too little about long-term harms.




To assess harms of SSRIs and SNRIs that persist after end of drug intake.




Systematic review of placebo-controlled randomised trials of any length in patients with a psychiatric diagnosis and a follow-up of at least six months. Our primary outcomes were mortality, functional outcomes, quality of life and core psychiatric events. We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials and checked the references for eligible articles. One researcher extracted data and another checked the data extraction.




Our searches returned 9,153 unique records. We included 22 papers for 12 trials on SSRIs. Median intervention and follow-up periods were 15 and 52 weeks, respectively. Median number of randomised participants was 51; only two trials had a drop-out rate below 20%.Outcome reporting was less thorough during follow-up than for the intervention period and only two trials maintained the blind during follow-up. All authors concluded that the drugs were not beneficial in the long term.All trials reported harms outcomes selectively or did not report any. Only two trials reported on any of our primary outcomes (school attendance and number of heavy drinking days).




The randomised trials currently available cannot be used to investigate persistent harms of antidepressants.


Full study here:




Excerpt from Discussion section:


It is well known that harms caused by SSRIs can be long-lasting [18] and there are indications that they can even be permanent, e.g. for sexual disturbances [39, 40]. Withdrawal symptoms are also drug harms, and they can also persist for a long time [18].


Even though the median publication year was 2013, and even though all the trials we reviewed had a follow-up of at least 24 weeks after the randomised phase, none of them reported adequately on persisting harms of SSRIs; in fact, the reporting was very poor and selective. The authors were not even interested in reporting withdrawal effects although they likely occurred in all the trials.


Two trials reported on our pre-defined primary outcomes [28, 35]. As noted above, school attendance was higher for previously treated adolescents compared to placebo recipients [28], but given the number of trials and outcomes, this is likely a chance finding. For heavy drinking days there was no difference between drug and placebo at end of the 12-month follow-up [35]. For our secondary outcomes, data were sparsely reported for the follow-up periods and therefore useless. Thus, the outcomes that are relevant to the patients were almost universally ignored. Based on the reported effect outcomes, the SSRIs seemed to be no better than placebo at follow-up, also in the original authors’ opinion. This is possibly an understatement, as the harms reporting was insufficient. In fact, it has been shown, based on clinical study reports obtained from the European drug regulators, that 12% more patients drop out during the randomised phase when they are on drug than when they are on placebo [41]. This suggests that placebo is a better pill than an antidepressant drug because the patients weigh the benefits against the harms when they decide whether to stay in a trial or to drop out.


A search on PubMed (31 May 2018) on “antidepressants AND placebo” limited to the article type      “Randomized Controlled Trial” yielded 5,233 references. Thus, it seems that none of the authors of the thousands of placebo-controlled trials have been interested in finding out what the more lasting harms are of treatment with antidepressant agents. This is very worrying, particularly considering that the patients often complain about harms long after they have come off the drugs [18, 40, 42].


Since the randomised trials are not helpful, we need to look at observational studies instead. A US national sample (n= 15,365) with a 9-year follow-up found that patients medicated for symptoms of major depressive disorder (measured on several parameters like the Instrumental Activities of Daily Living and the Composite International Interview short-form) had poorer long-term outcomes, based on symptom severity, than those who were not treated or used treatment other than medication [43]. Symptom severity could not be explained by covariates such as initial disease severity.


Another indication that long-term treatment with psychiatric drugs is unlikely to be beneficial is that, in all countries examined, the number of people on disability pension has gone up while usage of psychiatric drugs has also gone up [44]. By far the most used drug category is antidepressants.


Inadequate reporting of harms, even serious harms like deaths, is a general problem for psychiatric drug trials [6, 8, 45, 46], and the discrepancy between data in clinical study reports and in journal publications is disturbing [7, 12, 47, 48]. This means that psychiatrists are unable to choose drug treatment strategies that optimise the benefit-to-harm balance.


Compared to the above, the co-morbidity bias we found is of minor importance. The problem with representativeness of the results from clinical trials have been highlighted before, e.g. in a study that showed that only 41 of 346 (12%) outpatients would qualify for a clinical trial based on common inclusion and exclusion criteria for antidepressant efficacy trials [49].


Responder selection bias is also related to the representativeness of clinical trials. In eight of the included trials, there were problems related to this.

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