https://orcid.org/0000-0002-0694-8674
Schizophrenia is a chronic and severely debilitating mental disorder that requires prompt and appropriate treatmentCitation1 at the very first signs of a psychotic episodeCitation1. Furthermore, the clinical, social, and economic burden of treatment-resistant schizophrenia is increasing globallyCitation1. Importantly, the increased mortality rate of patients with schizophrenia compared with the general population indicates disturbing inequalities in health outcomes that deserve serious attentionCitation1–3.
We enjoyed reading the recent article entitled, “The burden of disease in early schizophrenia - a systematic literature review” by Crespo-Facorro et al. published in this journalCitation4. The authors demonstrated the presence of multiple burdens in patients with schizophrenia compared with healthy controls, including increased mortality, psychiatric comorbidities, such as substance abuse and depression, poor social integration and functioning, and increased levels of unemploymentCitation4. Despite the clinical and epidemiological relevance of this studyCitation4, we would like to add some thoughts about the possible role of sudden unexpected death in schizophrenia (SUDS).Citation2,Citation3
Patients with schizophrenia have a 2 to 3-fold increased risk to die prematurely compared with those without this mental illnessCitation2,Citation3. By far, this excess of mortality is due to a combination of several risk factors, including life style, suicide, premature development of cardiovascular (CV) disease, pre-existing cardiomyopathy, high prevalence of metabolic syndrome, high risk of stress cardiomyopathy and neuroleptic-induced cardiotoxicityCitation2,Citation3. One of the factors contributing to this excess mortality but not so often mentioned is SUDSCitation2,Citation3. In this context, a recent study evaluated consecutive cohort data of 391 schizophrenia individuals who died suddenly and unexpectedlyCitation5. The circumstances regarding death and autopsy examination findings were investigatedCitation5. Briefly, the majority of deaths (64.2%) were caused by comorbidities, 12.0% deaths were accidents, 11.5% deaths were suicides, and 9.7% deaths were homicidesCitation5. The cause of death was undetermined in 38 cases (9.7%)Citation5. Of the 251 natural deaths, 198 cases (78.9%) were attributed to CV diseasesCitation5. Moreover, cause of death was listed as cardiac arrhythmia in 11 casesCitation5. Importantly, the authors calls closely monitor the high risk factors of SUDS5. Since cardiac stress may differ it would be interesting to assess the rate of SUDS among the various subtypes of schizophrenia. Cardiac stress may be particularly high in patients with paranoid schizophrenia or maniac disease. Increased cardiac stress carries the risk that these patients may develop stress cardiomyopathy (Takotsubo syndrome)Citation6. Thus, one pathogenic factor of SUDS could be non-reversible stress cardiomyopathy.
In fact, patients with schizophrenia have a much shorter life expectancy than the general population and SUDS is now widely recognisedCitation2,Citation3,Citation5. A series of studies clearly reported that schizophrenia patients had a 3-fold likelihood to experience sudden unexpected death compared with the general population, accounting for up to 20% of mortality in this specific populationCitation2,Citation3,Citation5. The lack of autopsy studies and the rarely witnessed or monitored cases of SUDS do not allow an accurate discussion regarding its precise definitionsCitation2,Citation3,Citation5. SUDS could be defined as sudden unexpected death in a patient with schizophrenia without any satisfactory explanation of cause of death as determined by autopsy studiesCitation2,Citation3,Citation5. The exact pathophysiological cause of SUDS remains poorly understood, but it is probable that cardiac arrhythmias play an important roleCitation2,Citation3,Citation5. Since there is clear evidence that individuals with schizophrenia are at high risk for CV disease, and that some antipsychotics may be associated with CV adverse events (e.g. QT-prolongation), it is plausible that schizophrenia patients experience QT-prolongation, ventricular tachycardia, torsades de pointes or SUDSCitation2,Citation3. In parallel, haematological and pulmonary causes have also been implicated as causes of SUDS, including agranulocytosis leading to sepsis, deep vein thrombosis leading to pulmonary embolism and aspiration pneumonia leading to sepsisCitation3.
Overall, SUDS represents one of the most severe outcomes of schizophrenia, for which no evidence-based prevention is available. Obviously, it would be interesting to conduct preventive studies in schizophrenia patients that assess risk factors for premature mortality. Following this line of reasoning, some general recommendations deserve to be emphasized: (1) since there is an educational problem with SUDS, it is time to improve education, reinforcing whether and when to talk about premature mortality to individuals, family members, and caregivers. In this context, it would be appropriate to establish a task force that discusses issues related to SUDS to answer these questions (2) psychiatrists, cardiologists, and other multidisciplinary team members should closely collaborate in assessing and establishing the state of knowledge about SUDS and (3) Current evidence suggests that omega-3 polyunsaturated fatty acids (n-3 PUFAs) are beneficial for schizophrenia patientsCitation2. In recent decades, there is effective literature suggesting that n-3 PUFAs protect against CV morbidity and mortality and might effectively prevent SUDSCitation2.
Although still controversial, evidence from large trials now suggests that n-3 PUFAs supplementation may have a dose-related antiarrhythmic effectsCitation7. Probably, these antiarrhythmic effects attributed to n-3 PUFAs include direct modulation of ionic channels, improvement of structural and electrical remodeling, and the sympatho-vagal balanceCitation8. Thus, the clinical usefulness of n-3 PUFAs in SUDS may be related to these mechanisms.
Finally, while these strategies are not fully realized, comprehensive CV screening protocols, including routine ECG, stress tests, long-term ECG recordings, echocardiography, cardiac MRI, and myocardial scintigraphy could be helpful and pertinent to prevent SUDS in patients with schizophrenia.
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Declaration of funding
Our studies are supported by the following grants: FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo); CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).
Declaration of financial/other relationships
The authors report no conflicts of interest. The peer reviewer of this manuscript has no relevant financial or other relationships to disclose.
Acknowledgements
None reported.
References
- Charlson FJ, Ferrari AJ, Santomauro DF, et al. Global epidemiology and burden of schizophrenia: findings from the global burden of disease study 2016. Schizophr Bull. 2018;44(6):1195–1203.
- Scorza FA, Cysneiros RM, Terra VC, et al. Omega-3 consumption and sudden cardiac death in schizophrenia. Prostaglandins Leukot Essent Fatty Acids. 2009;81(4):241–245.
- Li KJ, Greenstein AP, Delisi LE. Sudden death in schizophrenia. Curr Opin Psychiatry. 2018;31(3):169–175.
- Crespo-Facorro B, Such P, Nylander AG, et al. The burden of disease in early schizophrenia - a systematic literature review. Curr Med Res Opin. 2021;37(1):109–121.
- Sun D, Li L, Zhang X, et al. Causes of sudden unexpected death in schizophrenia patients: a forensic autopsy population study. Am J Forensic Med Pathol. 2019;40(4):312–317.
- Zoltowska DM, Kalavakunta JK, Subramaniyam PS, et al. Takotsubo cardiomyopathy in a patient with bipolar disorder. BMJ Case Rep. 2018;2018:bcr2018226452.
- Parish S, Mafham M, Offer A, et al. Effects of omega-3 fatty acid supplements on arrhythmias. Circulation. 2020;141(4):331–333.
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