Photo Credit: iStock.com/PeopleImages

A study suggests that failing to account for immortal time bias may misrepresent the mortality risks of psychiatric medications in schizophrenia.

Observational studies that fail to account for immortal time bias (ITB) misinterpret the association between antipsychotics, antidepressants, and benzodiazepines and all-cause mortality in patients with schizophrenia, suggests a study published in JAMA Network Open.

“This immortal time is the lag between the start of follow-up and the beginning of exposure, during which patients are necessarily alive and misclassified as exposed. This bias creates a scenario in which the exposed group appears to have a lower mortality rate than the unexposed group,” wrote corresponding author Sébastien Brodeur, MD, and colleagues. “Although widely recognized in the literature, this bias is not always addressed.”

The study investigated all-cause mortality and associations with low, moderate, and high exposure to antipsychotics, antidepressants, and benzodiazepines in 32,240 adults diagnosed with schizophrenia in Quebec, Canada, from 2002 to 2012. The mean age of participants was 46.1 years, and 61.3% were men.

During follow-up from 2013 to 2017, 1,941 patients (6.0%) died.

Researchers used two approaches to analyze data for the study: a time-fixed exposure that did not control for ITB, and a time-dependent exposure that did control for ITB. Findings, they found, differed with the employed approach.

“[N]ot controlling for ITB overestimated the protective association of antipsychotics and antidepressants,” the researchers wrote, “and underestimated the harmful association of benzodiazepine use at lower doses.”

Specifically, the time-fixed method found no dose-response association between antipsychotics and mortality. However, with correction for ITB, high-dose antipsychotic use was associated with increased mortality. The researchers reported an adjusted hazard ratio of 1.28.

Similarly, antidepressants were associated with reduced mortality risk when the time-fixed method was used. Nevertheless, correction for ITB showed reduced mortality only with high-dose antidepressant use (aHR, 0.86).

Benzodiazepines, meanwhile, were associated with increased mortality risk using either analytic method. Adjusted hazard ratios for mortality were 1.22 with the time-fixed method and 1.50 with the time-dependent method that controlled for ITB. Mortality risk increased with benzodiazepine doses in both methods but was higher with correction for ITB.

“The findings of this study do not dispute the known efficacy of antipsychotics in schizophrenia,” the researchers wrote, “but they call into question the magnitude of long-term mortality benefits.”