Adding Antipsychotics Worsens Outcomes in Psychotic Depression

Outcomes were worse for all, with young people on combination therapy twice as likely to experience rehospitalization or death by suicide than those on antidepressants alone.


Antipsychotics for psychotic depression? Not a great idea, according to a new study. Adding an antipsychotic drug to antidepressant treatment increased the risk of death and rehospitalization for people with the psychotic depression diagnosis.

“Our findings do not indicate any advantage of adding antipsychotics as adjunctive to antidepressants as maintenance treatment. Considering the wide use, known side effects, and the current lack of evidence supporting the benefit, further studies on the effect of antipsychotics in the maintenance phase of psychotic unipolar depression are urgently warranted,” the researchers write.

The research was conducted by Ahmed Al-Wandi and Axel Nordenskjöld at Örebro University, Sweden, and Mikael Landén at Gothenberg University and the Karolinska Institutet, Sweden. The study was published in Acta Psychiatrica Scandinavica.

Illustration of man sitting on a red and white pill. He holds his head with pain symbols in the air above him.The researchers note that it is common practice to give antipsychotic drugs (in addition to antidepressants) to those with psychotic depression, and their results bear this out; in their study, twice as many people got combination therapy. Indeed, the American Psychiatric Association guidelines for treatment of psychotic depression list combination therapy as a first-line intervention, along with electroconvulsive therapy (ECT). Sounds good on the surface, right? If people have “psychosis,” add an “antipsychotic.”

But sometimes things that sound good on the surface are actually harmful. The results speak for themselves: after two years, 42.3% of those in the combination group were either readmitted or died by suicide, while slightly fewer (36.6%) in the antidepressants-alone group met this outcome. That is, adding antipsychotics didn’t help prevent this outcome, it increased the risk.

The researchers used Swedish national registries to identify patients who were hospitalized with a diagnosis of psychotic unipolar depression between 2007 and 2016. There were two groups: 1,419 people received antidepressants alone, while 2,972 people got both antidepressants and antipsychotic drugs.

Because the argument could be made that these results were confounded by other factors, including baseline severity, the researchers controlled for a variety of factors that could have influenced the results. Moreover, the researchers noted that at baseline, the two groups were similar in all ways, except that the antidepressants-alone group was more likely to have received ECT during the initial hospitalization (36.4% versus 26.7%). Therefore, in further analyses, the researchers controlled for ECT, as well as other possible confounds including sex, age, prior admissions, comorbidity, and other pharmacological treatments. This did not change their results.

In terms of specific outcomes, significantly more in the combined treatment group ended up rehospitalized: 41.8% versus 35.9% in the antidepressants-alone group. This puts to rest the notion that antipsychotics prevent relapses. Instead, it seems that they make relapse more likely.

People in the combined group were also more likely to die of any cause (other than suicide): 3.5% versus 2.4% in the antidepressants-alone group. There was no difference in deaths by suicide between the two groups.

In another analysis, the researchers searched for any subgroup of patients for whom combination therapy was actually helpful. They did not find any.

They did, however, learn that for young people (18-30 years old) combination therapy was even more dangerous than for older people. Young people on combination therapy were about twice as likely to reach the main outcome of rehospitalization or death by suicide.



Al-Wandi, A., Landén, A. M., &  Nordenskjöld, A. (2023). Antipsychotics in the maintenance phase for psychotic depression. Acta Psychiatrica Scandinavica. Published online November 6, 2023. (Full Text)


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  1. I was wondering who were able to stay home after breakdown in this study. I have been through a lot of illness and medicine. I have noticed environment plays a big part. Where you live and if your life was made easier. Please do more research.
    If nothing improves then you will go to hospital again!! Also you build resistance and must change medicine from time to time. At two years my meds had to change. Illness since 1995.

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  2. “Adding an antipsychotic drug to antidepressant treatment increased the risk of death and rehospitalization for people with the psychotic depression diagnosis.”

    Well, as anyone who has actually, honestly, researched into psychopharmacology, with the goal of finding the truth, would know. Since both the antidepressants and antipsychotics are anticholinergic drugs, that can cause anticholinergic toxidrome poisoning … which can make a person “psychotic.”

    Of course, combining the anticholinergic drugs will make people worse.

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  3. This is was a purely observational study – although an attempt to control for confounding factors was attempted, it was still correlational. To come to the conclusion urged here, it would be necessary to randomly divide treatment groups in “antidepressant only” and “antidepressant + antipsychotic” groups. Why are researchers urging that antipsychotics be withheld unwilling to try such an obvious study?!

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  4. So called antidepressants are bad enough. Adding a major tranquilizer to the mix for someone who is already miserable? Perhaps not surprisingly…

    People got worse. Many…especially the younger set…became demonstrably worse in the very ways that the pills are supposed to prevent.

    My own personal problem with this study? I highly doubt many psychiatrists will listen. If they do listen it won’t affect their prescribing habits. And so…

    Once again the information is available and straightforward. And once again most psychiatrists will continue on as usual because their toxic so called treatments are based more on dogma and current trends than data or anything remotely scientific.

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  5. Peter,
    Antipsychotics increase histamine and new research points to histamine as being a critical player in the pathology of depression and a cause of antidepressant nonresponse.

    “spikes in brain histamine following stress likely drive neurochemical changes in monoaminergic systems. Indeed, elevated histamine can result in increased activation of H3 heteroreceptors on 5HT terminals in the hippocampus, resulting in blunting of neuronal serotonin release and producing a reduction in extracellular serotonin.”

    Inflammation-Induced Histamine Impairs the Capacity of Escitalopram to Increase Hippocampal Extracellular Serotonin

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