Antipsychotic Augmentation Increases Risk of Death

When a prescription for antidepressants doesn’t result in improvement, what do doctors do? It’s a common situation, and often-used strategies include switching antidepressants, augmenting with a second antidepressant, and augmenting with an antipsychotic drug.

However, a new study has found that adding an antipsychotic to existing antidepressant treatment is associated with a 45% increased risk of early death (compared with adding a second antidepressant).

The research was led by Tobias Gerhard at Rutgers University and published open access in PLOS ONE.

Most people do not experience remission after using an antidepressant. In the STAR*D trial, a massive multi-site study designed to evaluate clinical outcomes in real-life patients with depression, less than a third (28%) of the participants recovered after taking their first course of antidepressant drugs. More than half (53%) did not experience any noticeable improvement at all.

Unfortunately, even these results look rosy compared to the long-term outcomes. By the end of the STAR*D trial, after up to four different courses of switching, augmenting with another antidepressant, and receiving cognitive-behavioral therapy, only 108 (3%) of the 4041 participants remained in the study and were considered “in remission.”

Increasing the dose of an antidepressant also does not appear to improve results, according to a meta-analysis in the Journal of Clinical Psychiatry.

Because of this lack of effective treatments for depression, the strategy of augmenting with antipsychotics has been implemented. Research has shown that this strategy is little if any, better than adding another antidepressant. It also results in high levels of adverse effects, such as weight gain, sedation, akathisia, tardive dyskinesia, and parkinsonism.

Nonetheless, clinical practice guidelines in the US suggest using this strategy when antidepressants alone don’t result in remission.

Now, Gerhard’s new study has clarified the most serious risk of all—death.

Gerhard and the other researchers found that “an adjusted hazard ratio of 1.45 (95% confidence interval, 1.02 to 2.06) indicated increased all-cause mortality risk for newer antipsychotic augmentation compared to antidepressant augmentation.”

Because the researchers only compared two forms of augmentation (without a control group), this may underestimate the risk of death—for instance, if adding an antidepressant also increases the risk of death compared with no augmentation.

The study was a real-life, observational study rather than a randomized, controlled trial. The researchers looked at the records of 44,301 people on Medicaid with a depression diagnosis across the US. The researchers excluded people with other antipsychotic drug use indications, including people with diagnoses of bipolar disorder, psychotic depression, schizophrenia, autism, and dementia.

Of the study participants, 25,172 had an add-on prescription for antipsychotics, while 19,129 received a second antidepressant. 105 people died in the antipsychotic group (0.42%), while 48 people died in the antidepressant group (0.25%).

Interestingly, women had a 72% increased risk of death when prescribed an antipsychotic rather than a second antidepressant, but the risk of death for men was not different between the two drugs.

Additionally, the risk of death increased in older populations. For the older adult group of patients, the risk of death was 61% higher if prescribed antipsychotics than when prescribed a second antidepressant.

The researchers also provided statistics about which antipsychotics were associated with a higher risk of death—but because the sample of people who died was so small, that data was exploratory and needs further verification.

The researchers reported controlling for a number of potential confounding variables and conducting sensitivity analyses to ensure that their results were robust. According to the researchers, any unknown confounding factor would have to have been “strong and prevalent” to change their findings.

Gerhard writes:

 

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Gerhard T, Stroup TS, Correll CU, Setoguchi S, Strom BL, Huang C, et al. (2020) Mortality risk of antipsychotic augmentation for adult depression. PLoS ONE 15(9): e0239206. https://doi.org/10.1371/journal.pone.0239206 (Link)