Antidepressants Prescribed in the US Ranked on 3 Safety Indices

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Selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants were deemed the safest classes of antidepressants in the event of excess dosing in an assessment of 14 antidepressants prescribed in the United States on 3 safety indices.¹

In addition to a fatal toxicity index (FTI) for overdoses, Zach Poliacoff, MD, of the Department of Psychiatry at the University of South Florida in Tampa, applied an index for serious morbidity (SMI) and a health care utilization index (HUI) for health care facility treatment required for adverse events.

“There have been only limited attempts to compare agents on nonlethal but significant adverse effects resulting from toxic exposure, which is a necessary consideration in risk assessments,” Poliacoff observed. “There have been no attempts to quantify the burden on the health care system of each agent in overdose.”

Poliacoff used the total number of prescriptions for the respective antidepressants in the study period for the denominator of each index. He notes that this approach particularly diverges from traditional fatality indices, for which the denominator is total exposures, commonly drawn from the National Poison Data System (NPDS).

“However, this method does not properly adjust for each agent’s prevalence in the population,” Poliacoff explained. “Using a measure of total prescriptions as the denominator would provide a more accurate picture of risk associated with each drug in the real world at the time of prescribing.… Per-prescription risk rather than per-exposure risk is used here because the goal of the study is to determine the relative safety of these agents when prescribing, rather than when treating an exposure.”

Poliacoff extracted data on antidepressant-related deaths, major adverse events, required treatment in health care facilities, and prescription quantity for the period between 2013 and 2020 from the NPDS and the Agency for Healthcare Research and Quality’s Medical Expenditure Survey. In total, the sample comprised 364,526 single-agent exposures and more than 1,844,877,361 prescriptions.

An adverse event was classified as a serious morbidity if it corresponded to NPDS criteria for “major,” when “the patient exhibited signs or symptoms that were life-threatening or resulted in significant residual disability or disfigurement.”

Agents were excluded from analysis if prescribed for fewer than 200,000 individuals in a year. Other agents not in the analysis included lithium, as it is primarily indicated for bipolar disorder rather than unipolar depression, and trazadone, as it is more commonly prescribed as a sleep aid than as an antidepressant.

Selection Diverges From Safety

Among the findings, bupropion was associated with comparable rates of mortality but higher morbidity and more use of health care facilities for adverse events than the tricyclic antidepressants (TCAs) nortriptyline and imipramine. The FTI of bupropion was approximately twice as large and its SMI about 5 times as large as venlafaxine, which is characterized as the next-highest modern agent.

Poliacoff reflected on the finding that bupropion appeared significantly more likely to lead to death, major adverse outcomes, or treatment in a health care facility than all other first-line agents. “It is therefore an open question whether its status as the second-most-prescribed antidepressant in this study is justified by its relative risks vs benefits,” he posed.

In the 4 TCAs included in the analysis, doxepin and amitriptyline had higher FTI, SMI, and HUI than those of imipramine and nortriptyline. For the 5 included SSRIs, escitalopram and paroxetine had the lowest FTI; however, the difference in FTIs among all 5 was not statistically significant. Among the SNRIs, duloxetine had a statistically significantly lower FTI, SMI, and HUI; although its FTI and SMI were comparable to those of the SSRIs, the HUI was significantly lower.

“It is not surprising that when comparing classes, SSRIs and SNRIs are overall safer than the alternatives,” Poliacoff remarked. “Within the SSRI class, the relative safety of paroxetine and escitalopram are notable, though the clinical significance of the absolute differences in FTI and SMI are questionable.”

Poliacoff also commented on amitriptyline having the second-highest FTI, SMI, and HUI while being prescribed “far more frequently” than other TCAs. “Its metabolite, nortriptyline, is significantly safer on all measures,” Poliacoff pointed out, “and, because of their structural similarity, may have similar benefit.”

In contrast, the TCA imipramine was determined to be both the safest of the TCAs as well as the least prescribed. “Imipramine was associated with no deaths in the NPDS data set during the study period,” Poliacoff pointed out.

“Overall,” Poliacoff concluded, “these results suggest that prescribing practices for antidepressants may not necessarily reflect the reality of their relative risk vs benefit profiles in several respects.”

Dr Bender reports on medical innovations and advances in practice and edits presentations for news and professional education publications. He previously taught and mentored pharmacy and medical students, and he provided and managed pharmacy care and drug information services.

Reference

1. Poliacoff Z. Three safety indices for the fourteen most prescribed antidepressants in the US, 2013-2020. Gen Hosp Psychiatry. 2024;90:1-5.