Antipsychotic Augmentation Increases Risk of Death

A new study finds that adding an antipsychotic to existing antidepressant treatment is associated with a 45% increased risk of early 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).

“Augmentation with newer antipsychotics in non-elderly patients with depression was associated with increased mortality risk compared with adding a second antidepressant,” the researchers write.

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:

“The findings support careful consideration of this risk in relation to the limited known benefits of newer antipsychotics as adjuvants in treatment-resistant adult depression. The results further suggest the use of newer antipsychotics only after non-response to evidence-based treatment options that are less risky.”



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. (Link)


  1. A study found “antidepressants” increase mortality risk by 33%. The most used drug classes have higher mortality rates.
    If pre-medicated depression was adjusted for the increased mortality from the drugs would be larger.

    Adding a second antidepressant increases mortality risk by 33% while adding an “antipsychotic” increased the mortality risk by 45% on top of that. Both those options are on top of the 33% increased mortality risk from the first antidepressant.

    That is a lot of dead people who were never informed of how deadly the drugs are. If a “medical profession” doesn’t follow the medical principles of “first do no harm” and “informed consent” are they really a medical profession?

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  2. Thank you Peter for your ongoing persistence in exposing harm.
    Don’t give up or in.

    It should be illegal to pass these chemicals off as “treatments”.
    And I hope the public starts to care since this WILL affect their grandchildren,
    their great grandchildren.

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  3. Those numbers are absolutely dismal.

    I think we’re going to see some huge lawsuits in the near future over neuroleptic use in people diagnosed with depression and/or anxiety disorders. It’s the big new thing to prescribe and it is astonishing to see just how much it’s pushed. I see the commercials all the time.

    Now there are commercials for tardive dyskinesia awareness. They make it out to seem like it’s always very mild and can be completely managed by taking another drug. Those drugs are, unsurprisingly, developed and sold by the very company that makes those commercials! Wow! What a coincidence! That’s totally not suspicious or anything!

    In my case, I had two neuroleptics (Zyprexa and Risperdal) prescribed for an OCD diagnosis. Without being told that there was a (decent) chance that any drug from that class could *worsen* obsessions and compulsions. Not to mention the side effects…

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  4. Medicine does kill people. The third leading cause of death is usually attributed to “pharmaceuticals.” All drugs cause side effects and some are extremely dangerous. All you need to do is listen to the “drug ads” where despite the rosy, happy pictures, in the background the announcer is listing only some of the side effects. And, usually, they end the commercial, with something like, “please check with your prescriber or pharmacist, because, of course, there are more. And, wait until the next commercial, which will be from some eager lawyer, who will try to convince you that you have a case against the drug company for the harm done to you by a certain drug. Tragically, it is the person prescribed the drug who is victimized. This is across the board and does not just include “psychiatric drugs.” And, this is only the tip of the iceberg.
    I believe someone mentioned the ads regarding “patients” who found out they had “td” that arose from the drug and this is “normal.” Well, there is nothing “normal” about this. This really is nothing but science for profit and control and we suffer. Aldous Huxley warned us about this in “Brave New World.” Drugs do harm and kill. The topsy-turvy world is that which allegedly is supposed to be good for you will actually harm or kill you. As, in my case, I am lucky to have gotten out of this morass, Alive! Thank you.

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    • We were all lucky to escape alive. And combining the antidepressants and antipsychotics should be a crime, since all doctors are taught in med school that combining the anticholinergic drugs can result in anticholinergic toxidrome – a medically known way to create “psychosis.” And making people “psychotic” shouldn’t technically be the goal of the psychiatrists.

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