Adding antipsychotics worsens outcomes in psychotic depression


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.

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)


Editor’s Note: Part of MITUK’s core mission is to present a scientific critique of the existing paradigm of care. Each week we will be republishing Mad in America’s latest blog on the evidence supporting the need for radical change.

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Peter Simons was an academic researcher in psychology. Now, as a science writer, he tries to provide the layperson with a view into the sometimes inscrutable world of psychiatric research. As an editor for blogs and personal stories at Mad in America, he prizes the accounts of those with lived experience of the psychiatric system and shares alternatives to the biomedical model.