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Takotsubo Syndrome and Electroconvulsive Therapy: Time for Rigorous Assessment
To The Editor,
We followed with interest the recent debate ignited by several commentaries on Takotsubo Syndrome (TTS), adrenergic activation in mood disorder patients, and the associated clinical and public health implications appraised both in the Journal of Clinical Practice and Epidemiology in Mental Health (CPEMH) [1-4] and in other peer-reviewed sources [5, 6]. An important issue deals with the putative connection between Electroconvulsive Therapy (ECT) and subsequent TTS.
A burgeoning of case reports [7] published since the year 2009 [8], highlight the not-that infrequent occurrence of TTS soon after the delivery of a course of ECT.
In general, case reports, namely the detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of an individual patient, or (n=1, meaning one unique patient), and case series (up to n=10) represent timely, and essential study design in advancing medical and scientific knowledge, especially of rare diseases in the absence of systematic chart-review [9]. The European Union definition of a rare disease is one that affects fewer than 5 in 10,000 people (https:// www.eurordis.org/about-rare-diseases). However, no consen- sus exists about “how rare” a disease should be considered a “rare” one. This is particularly true for medical fields other than genetics, or whenever the “rare” condition is nonetheless life-threatening.
In recent years, case reports came under scrutiny and disfavor among some in the scientific publishing community, and case studies are frequently relegated to the lowest rank of the hierarchy of study design. Carey documented that 32% of journals do not publish case reports, and another 36% publish them in a modified format [10]. However, prestigious journals, including the New England Medical Journals, the Lancet, or those published by BioMed Central (with ad-hoc editorial destinations), to name a few, continue to publish even case reports [11]. CPEMH likewise does.
Generally speaking, case reports are prone to both “confounding bias” (factors, which we are unaware of may influence the observed outcomes), “chance”, and “causation” nexus (inferred in place of mere report of “association” between two events, e.g. ECT and subsequent occurrence of TTS).
However, as remarked above, the “rarity” of a condition remains an elusive concept, primarily when it is associated with major or life-threatening outcomes, as is the case with TTS. Also, multiple independent case reports, published consistently over a period of a decade or longer, coming from clinicians based in different geographic regions reasonably deserve attention; especially considering that “more rigorous” controlled clinical trials almost invariably exclude the most severe cases (of mood disorders, in this context) per protocol, thus undermining the chances of occurrence of infrequent events among the most sensitive individuals (read TTS outcome after ECT). Given the self-limiting dissemination of case-reports, and the reluctance of many journals to consider them, especially after previous similar reports on the matter, it cannot be excluded that the “association” (no causal inference made in contrast to “causation”) between TTS and ECT is even more frequently observed in clinical settings than appraised in the literature.
Several studies have now established a close association between mood disorders and cardiovascular disorders in general [12, 13], and TTS in particular [4], suggesting a rationale for a possible “vulnerable” condition for TTS, independently of ECT, in people with depressive and bipolar disorders. However, the pathogenetic hypotheses about the role of norepinephrine activation in TTS [2, 14] suggest a causal link between ECT and TTS, given the noradrenergic increase following electroconvulsive therapy [15]. Such claims reinforce the suspicion of a possible causal trigger between ECT and TTS that may occur among vulnerable individuals. Given the uneasiness of the diagnosis of TTS [14], it cannot be excluded that, in the absence of careful cardiologic workup, the TTS may have also been misunderstood or underdiagnosed, even among those patients exposed to ECT.
Several factors may inflate the rates of underdiagnosis of previous TTS in patients with severe mood disorders (as those that underwent ECT); especially considering that the consequences of TTS could be better-observed long-term, with rates of long-term mortality among TTS patients exceeding those expected in patients with ST-Elevation Myocardial Infarction (STEMI) [16]. The mortality rates seen among TTS patients are further inflated among those individuals whose severe mood disorders - often requiring intense ECT sessions [17] - already pose a significant mortality risk due to cardiovascular diseases [18].
In conclusion, we congratulate the Editorial Board of the Journal of CPEMH for posing emphasis even on single-patient reports about the intriguing, and clinically burdensome, plausible association between ECT and TTS, and we really hope that further research attention will be given to the topic by implementation of systematic registries and methodologically-rigorous research on the matter.
