Selective Serotinin Reuptake Inhibitor (SSRI) Use and Delirium Occurrence in the ICU

Contributed by C. Adrian Austin, MD, MSCR, Divisions of Geriatric Medicine and Pulmonary Diseases and Critical Care Medicine, University of North Carolina School of Medicine, Chapel Hill, NC

Anxiety, depression and ICU delirium may be linked.1 Approximately 10% of the U.S. population takes an antidepressant, most commonly a selective serotonin reuptake inhibitor (SSRI).2 It remains unclear whether critically ill adults should be continued on a SSRI after ICU admission. We recently sought to clarify this question and examined the association between SSRI use and delirium occurrence in a cohort of critically ill adults.3

Our primary research question was whether SSRIs are associated with delirium in the subsequent 24-hour period after their administration. Secondly, we examined whether SSRIs are associated with delirium on the concurrent day of drug administration. We used the Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors (BRAIN-ICU) data set to answer this question.4 The BRAIN-ICU study examined the impact of ICU delirium on post-ICU cognitive function of survivors. It enrolled 821 critically ill patients with respiratory failure or shock between 2007 and 2010 and collected data on psychoactive medication administration (including SSRIs) and daily delirium assessments via the CAM-ICU.5

Our primary outcome of interest was presence of delirium or coma during each day in the ICU.3 Coma was defined as a Richmond Agitation Sedation Scale (RASS) score of -4 or -5. We considered seven potential confounding variables in our model. Both baseline (i.e., age, Charlson Comorbidity score, and SSRI prescription prior to hospitalization) and ICU (i.e., daily Sequential Organ Failure Assessment (SOFA) score, opiate dose in the preceding 24 hours, benzodiazepine dose in the prior 24 hours and number of days in the hospital) factors were examined.

Of the 821 patients, 233 (28.4%) received an SSRI at least once in the ICU.3 The median age was 61.2 years old (IQR 50.9-70.7) and 401 (48.8%) were female. Delirium was present in 606 (74%) of patients and coma in 32 (64.8%) of patients at some point during hospitalization. Most of the patients that received an SSRI during their ICU stay were prescribed them as outpatients prior to ICU admission [146 (67.0%)].

In our primary analysis, we found that SSRI administration was associated with a significantly decreased likelihood of delirium/coma the subsequent day (OR=0.60, 95% CI=0.48-0.76).3 SSRI administration was also associated with significantly lower odds of delirium/coma on the same day (OR=0.75, 95% CI, 0.58-0.97) (Table 1). After adjusting for the seven covariates, we found that SSRI administration was associated with a significantly lower odds of delirium/coma (OR=0.73, 95% CI, 0.55 to 0.96) the next day. An SSRI administered on the same day also significantly reduced the odds of delirium/coma (OR=0.64, 95% CI, 0.49 to 0.82).

To our knowledge, our study is the first to examine the association of SSRIs and ICU delirium.3 Our findings support the need for future clinical trials to evaluate whether continuing SSRI’s in patients who are taking them prior to ICU admission may be beneficial. Of note, one-third of patients administered a SSRI in the ICU were not prescribed an SSRI prior to ICU admission. This finding lends further support for future clinical trials to evaluate whether SSRI therapy in the ICU to may reduce delirium in patients not previously exposed to SSRI therapy.

While the mechanisms our findings remain unclear, we posit some hypotheses. First, while an antidepressant effect is not observed typically until weeks after SSRI initiation, SSRIs will increase serotonin levels shortly after their initiation.6 Given previously reported relationships between serotonin deficiency and delirium occurrence,7 SSRI use may have a delirium-protective effect. Alternately or additionally, it could be that SSRI administration provides an anti-inflammatory effect. A recent large randomized controlled trial examining the usage of fluvoxamine, an SSRI, for the reduction of hospitalization or emergency care in outpatients with COVID-19 found that fluvoxamine was associated with a reduced need for hospitalization or emergency care.8

The authors hypothesized the anti-inflammatory properties of SSRIs may have accounted for this finding. Given the importance of neuroinflammation in development of delirium, we hypothesize that the anti-inflammatory properties of our SSRIs may help to explain our findings, at least in part. All of these mechanisms are conjecture on our part, and we fully acknowledge that the pathophysiology of delirium is inherently complex and multifactorial. Future mechanistic studies will clearly be needed to test these hypotheses.

While our results are intriguing, they are limited by the biases, confounding by indication, and other sources of unmeasured bias found in any retrospective design. Our findings suggest that further exploration of SSRI usage in the ICU is justified, and randomized clinical trials of both continuing SSRI in those on them already and starting them anew should be tested in future studies. Our work lends support for a new line of clinical research into the use of SSRI for delirium prevention.

References

  1. Wu TT, Kooken R, Zegers M, Ko S, Bienvenu OJ, Devlin JW, van den Boogaard M. Baseline Anxiety and Depression and Risk for ICU Delirium: A Prospective Cohort Study. Crit Care Explor. 2022 Jul 21;4(7):e0743. doi: 10.1097/CCE.0000000000000743. PMID: 35923592; PMCID: PMC9307302.
  2. CDC. Antidepressant Use in Persons Aged 12 and Over: United States, 2005-2008 2011 [cited 2015 Sept 15]. Available from: http://www.cdc.gov/nchs/data/databriefs/db76.htm
  3. Austin CA, Yi J, Lin FC, Pandharipande P, Ely EW, Busby-Whitehead J, Carson SS. The association of selective serotonin reuptake inhibitors with delirium in critically ill adults: a secondary analysis of the bringing to light the risk factors and incidence of neuropsychologic dysfunction in ICU survivors ICU study. Crit Care Explor. 2022 Jul 19;4(7):e0740. doi: 10.1097/CCE.0000000000000740. eCollection
    2022 Jul.PMID: 35923593
  4. Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT, Brummel NE, Hughes CG, Vasilevskis EE, Shintani AK, Moons KG, Geevarghese SK, Canonico A, Hopkins RO, Bernard GR, Dittus RS, Ely EW, Investigators B-IS. Long-term cognitive impairment after critical illness. N Engl J Med. 2013;369(14):1306-16. doi: 10.1056/NEJMoa1301372. PubMed PMID: 24088092; PMCID: 3922401
  5. Ely EW, Margolin R, Francis J, May L, Truman B, Dittus R, Speroff T, Gautam S, Bernard GR, Inouye SK. Evaluation of delirium in critically ill patients: validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med. 2001;29(7):1370-9. doi: 10.1097/00003246-200107000-00012. PubMed PMID: 11445689
  6. Preskorn SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet. 1997;32 Suppl 1:1-21. Epub 1997/01/01. doi: 10.2165/00003088-199700321-00003. PubMed PMID: 9068931.
  7. Pandharipande PP, Morandi A, Adams JR, Girard TD, Thompson JL, Shintani AK, Ely EW. Plasma tryptophan and tyrosine levels are independent risk factors for delirium in critically ill patients. Intensive Care Med. 2009 Nov;35(11):1886-92. doi: 10.1007/s00134-009-1573-6. Epub 2009 Jul 9. PMID: 19588122; PMCID: PMC3673700
  8. Reis G, Dos Santos Moreira-Silva EA, Silva DCM, Thabane L, Milagres AC, Ferreira TS, Dos Santos CVQ, de Souza Campos VH, Nogueira AMR, de Almeida A, Callegari ED, de Figueiredo Neto AD, Savassi LCM, Simplicio MIC, Ribeiro LB, Oliveira R, Harari O, Forrest JI, Ruton H, Sprague S, McKay P, Glushchenko AV, Rayner CR, Lenze EJ, Reiersen AM, Guyatt GH, Mills EJ, investigators T. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial. Lancet Glob Health. 2021. Epub 2021/11/01. doi: 10.1016/S2214-109X(21)00448-4. PubMed PMID: 34717820; PMCID: PMC8550952
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