From the Editor
They are popular, but are they safe?
It’s the question that patients often ask about antidepressants. Though SSRIs have been on the market for decades – and older antidepressants for much longer – people continue to question their overall safety. Online forums relate stories of problems; news articles have linked them to suicidal thoughts in youth and other issues; regulatory agencies have acted on their doubts – the FDA, as an example, issued a black box warning for SSRIs use in adolescents.
This week, in our first selection, we consider a new paper from Linköping University’s Elena Dragioti and her co-authors. In this JAMA Psychiatry paper, the authors use a systematic umbrella review, drawing on meta-analyses of observational studies. “This study’s findings suggest that claimed adverse health outcomes associated with antidepressants may not be supported by strong evidence and may be exaggerated by confounding by indication; no absolute contraindication to the use of antidepressants was found to be currently supported by convincing evidence.”
We discuss the paper and the methodology.
In the second selection, we draw from the recently revised UK NICE guideleines, which provide advice on withdrawal symptoms and tapering strategies. “There is substantial variation in people’s experience…”
“Association of Antidepressant Use With Adverse Health Outcomes: A Systematic Umbrella Review”
Elena Dragioti, Marco Solmi, Angela Favaro, Paolo Fusar-Poli, Paola Dazzan, Trevor Thompson, Brendon Stubbs, Joseph Firth, Michele Fornaro, Dimitrios Tsartsalis, Andre F. Carvalho, Eduard Vieta, Philip McGuire, MD, Allan H. Young Jae Il Shin, Christoph U. Correll, Evangelos Evangelou
JAMA Psychiatry, 2 October 2019 Online First
Accumulating evidence suggests a sharp growth in antidepressant use worldwide. Up to 8% to 10% of adults in the United States take at least 1 antidepressant drug, which is ranked third among prescribed and fourth among sold medications. Antidepressants are indicated and used for depressive disorders, anxiety disorders, posttraumatic stress disorder, premenstrual dysphoric disorder, obsessive-compulsive disorder, bulimia nervosa, and binge-eating disorder, among others.
The safety profile of antidepressants is controversial. Since the US Food and Drug Administration introduced the black box warnings that associated selective serotonin reuptake inhibitor (SSRI) use with a higher risk of suicidal behavior in children and adolescents, the debate about the efficacy, acceptability, and safety profile of antidepressant medications has gradually increased. Evidence from randomized clinical trials (RCTs) of antidepressants’ efficacy and acceptability has been well documented in both meta-analyses and network meta-analyses,but safety assessment is inherently biased by certain methodological weaknesses of RCTs. These weaknesses include small and unrepresentative samples, rare and inconsistent reporting of adverse outcomes, and short duration of exposures…
In this umbrella review, we graded the evidence from published meta-analyses of observational studies. These studies tested the association between antidepressant use and risk of adverse health outcomes.
So begins a paper by Dragioti et al.
Here’s what they did:
- The authors “searched PubMed, Scopus, and PsycINFO from database inception to April 5, 2019, to identify systematic reviews with meta-analysis of observational studies of the association between any adverse health outcome and exposure to antidepressants.”
- They used a combination of search terms related to antidepressants and adverse health outcomes.
- Two of the authors chose eligible studies from the search, and only included meta-analyses of observational studies with a cohort or case-control study design.
- Excluded studies included meta-analyses of RCTs.
- Data was extracted, and statistical analyses were done. “We assessed the credibility of the evidence per association provided in meta-analyses by applying several criteria in concordance with previously published umbrella reviews.”
Here’s what they found:
- “In total, we identified 4 471 studies, scrutinized 252 full-text articles, and ultimately included 45 meta-analyses (17.9%) in this umbrella review…”
- All had a control group, spare one.
- “Forty-five eligible meta-analyses described 120 associations, including 1 012 individual study estimates of adverse health outcomes associated with exposure to antidepressants… Seventy-four (61.7%) of the associations concerned maternal and pregnancy-related adverse health outcomes…” See figure below.
- “Thirty-three meta-analyses (73.4%) met the moderate-quality level… and 8 (17.8%) were of low quality.”
- Convincing evidence: “Among the 120 associations, 3 (2.5%) were supported by convincing evidence, namely, the association between SSRI use and increased risk of suicide attempt or completion in children and adolescents as well as the association between exposure to any antidepressant before pregnancy and SSRIs during pregnancy and autism spectrum disorder.” The suicide risk work was analyzed to be of high quality. (!)
- Highly suggestive evidence: “Eleven associations (9.2%) had highly suggestive evidence of the association between any antidepressant use and increased risk of adverse health outcomes. The adverse outcomes were attention-deficit/hyperactivity disorder in children, cataract development (associated with TCAs), severe bleeding at any site, upper gastrointestinal tract bleeding, postpartum hemorrhage, preterm birth, lower Apgar score at 5 minutes, osteoporotic fractures (1 associated with TCAs and 1 with SSRIs), and risk of hip fracture.”
- Suggestive evidence: “Suggestive evidence was found for 21 additional associations (17.5%) between antidepressant use and increased risk of adverse health outcomes…”
They go on to argue:
We reviewed 45 meta-analyses of observational studies and found that only a few of the 74 statistically significant associations between antidepressants and adverse health outcomes were supported by convincing evidence in the main and sensitivity analyses, namely, the association between antidepressant use and increased suicide attempt or completion in individuals younger than 19 years (SSRI studies), autism risk in the offspring, preterm birth, and neonatal adaptation. However, the few with convincing evidence associations did not reflect causality, and none of them remained at the convincing evidence level after accounting for confounding by indication. Overall, the results showed that the association between antidepressant use and adverse health outcomes was not supported by robust evidence and that the underlying disease likely inflated the findings in a relevant way.
A few thoughts:
- This is a good study.
- The authors’ conclusions are reasonable.
- The approach is interesting and somewhat new. The authors concisely explain: “Umbrella reviews make it feasible to summarize the evidence from multiple meta-analyses on the same topic and enable the ranking of evidence (as convincing, highly suggestive, suggestive, weak, or not significant) according to sample size, strength of the association, and assessment of presence of biases.” In a recent and highly readable paper on umbrella reviews for Evidence-based Mental Health, Paolo Fusar-Poli and Joaquim Radua, both of King’s College London, argue that umbrella reviews “represent one of the highest levels of evidence synthesis currently available.” They note their increasing popularity in the literature. The figure below shows the web of knowledge records containing “umbrella review” up to April 2018:
I would add, though: any synthesis is open to biases. So while we can recognize that this is an established approach, we can also recognize its limitations.
The EBMH paper can be found here: https://ebmh.bmj.com/content/21/3/95.full
- Will this convince the sceptics? The paper is published in an important journal, drew on a significant literature with a published protocol, and included established researchers. There are, of course, limitations here, including the decision to exclude RCTs. (!)
- Still, a consistent pattern has emerged over the decades – antidepressants are safe for practically all clinical uses in adults. The question itself is a bit deceptive. After all, the prescription of antidepressants in, say, pregnancy needs to be weighed against the risk of not using antidepressants for pregnant women with major depressive disorder. The point is not that antidepressants should be used without consideration, but that a full clinical picture appreciating the risks and benefits of prescribing and not prescribing are needed.
- Other controversies exist for antidepressants, including how patients should stop these medications. The next selection offers practical advice.
“Continuation and relapse prevention”
National Institute for Health and Care Excellence, 2019
Advise people taking antidepressant medication that, before stopping it, they should discuss this with their practitioner.
The NICE guidelines mention several possible symptoms of withdrawal symptoms: “restlessness, problems sleeping, unsteadiness, sweating, abdominal symptoms, altered sensations (for example electric shock sensations in the head), altered feelings (for example irritability, anxiety or confusion)…”
How to advise patients about withdrawal symptoms?
Explain that whilst the withdrawal symptoms which arise when stopping or reducing antidepressants can be mild and self-limiting, there is substantial variation in people’s experience, with symptoms lasting much longer (sometimes months or more) and being more severe for some patients.
And how to taper?
When stopping an antidepressant, gradually reduce the dose, normally over a 4-week period, although some people may require longer periods, particularly with drugs with a shorter half-life (such as paroxetine and venlafaxine). This is not required with fluoxetine because of its long half-life.
A few thoughts:
- Like many NICE recommendations, the writing is clear, concise, and thoughtful.
- This update is something of a break from the past, where withdrawal symptoms were perhaps minimized. In the last version, from 2009, the authors had written that these symptoms are “usually mild and self limiting over about one week.” I highlight the new phrasing: “much longer (sometimes months or more) and being more severe for some patients…”
- The BMJ has a nice article of this summary. Paul Chrisp, who oversees NICE guidelines, is quoted: “We have amended the guideline to recognise the emerging evidence on the severity and duration of antidepressant withdrawal symptoms.”
You can find the BMJ paper here: https://www.bmj.com/content/bmj/367/bmj.l6103.full.pdf
Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.