The addition of antipsychotics worsens the outcomes of psychotic depression

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

Our findings do not indicate any advantage of adding antipsychotics in addition to antidepressants as maintenance treatment. Considering the widespread use, known side effects and current lack of evidence supporting 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 from Rebro University in Sweden and Mikael Landn from the University of Gothenburg and the Karolinska Institute, 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 support this; in their study, twice as many people received the combination therapy. Indeed, American Psychiatric Association guidelines for the 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 antidepressant-only group met this outcome. That is, the addition of antipsychotics did not help prevent this outcome, but rather 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 only antidepressants, while 2,972 people received both antidepressants and antipsychotics.

Because an argument could be made that these results were confounded by other factors, including baseline severity, the researchers controlled for a number of factors that could have influenced the results. Furthermore, the researchers noted that at baseline the two groups were similar in all respects, except that the antidepressant group was more likely to receive ECT during the initial hospitalization (36.4% vs. 26.7%). Therefore, in further analyses, the researchers controlled for ECT as well as other possible confounders, including gender, age, prior admissions, comorbidity, and other pharmacological treatments. This did not change their results.

Regarding specific outcomes, significantly more in the combined treatment group ended up rehospitalized: 41.8% versus 35.9% in the antidepressant-only group. This puts an end to the idea that antipsychotics prevent relapse. Instead, they seem more likely to relapse.

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

In another analysis, the researchers looked for any subgroups of patients for whom combination therapy was actually helpful. They didn’t find any.

However, they found out that for young people (18-30 years old) combined therapy is even more dangerous than for the elderly. Young people on combination therapy were about twice as likely to achieve the main outcome of re-hospitalization or death by suicide.


Al-Wandi, A., Landn, AM, & Nordenskjld, A. (2023). Antipsychotics in the maintenance phase of psychotic depression. Acta Psychiatrica Scandinavica. Published online 06 November 2023 (full text)

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