Addition of antipsychotics worsens psychotic depression outcomes

Antipsychotic drugs for mental depression. Not a great idea, according to new research. Adding an antipsychotic to antidepressant treatment increased the risk of death and rehospitalization in people diagnosed with psychotic depression.

“Our findings do not indicate any benefit of adding antipsychotics to antidepressants as adjunctive treatment as maintenance treatment. “Given the widespread use, known side effects, and the current lack of evidence supporting benefit, further studies of the effects of antipsychotics in the maintenance phase of bipolar depression are urgently needed,” the researchers wrote.

The research was carried out by Ahmed Al-Wandy and Axel Nordenskjöld at the University of Örebro in Sweden and Michael Landen at the University of Gothenburg and Karolinska Institutet in Sweden. The study has been published Acta Psychiatrica Scandinavica.

The researchers note that it is common practice to give antipsychotics (in addition to antidepressants) to people with psychotic depression, and their results support this; twice as many people received combination therapy in their study. Indeed, American Psychiatric Association guidelines for the treatment of psychiatric 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 “antipsychosis”.

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, compared with slightly fewer (36.6%) in the antidepressant-alone group. That is, adding antipsychotics did not help prevent this outcome, it increased the risk.

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

Because it could be argued that these results were confounded by other factors, including baseline weight, the researchers controlled for a number of factors that could have influenced the results. Furthermore, the researchers noted that the two groups were similar in all respects at baseline, except that the antidepressant-alone group was more likely to receive ECT at initial hospitalization (36.4% vs. 26.7%). Therefore, in subsequent analyses, the researchers controlled for ECT as well as other potential confounders, including sex, age, prior admissions, comorbidities, and other pharmacologic treatments. This did not change their results.

Regarding specific outcomes, significantly more rehospitalizations occurred in the combination treatment group, 41.8% compared to 35.9% in the antidepressant alone group. This puts to rest the idea that antipsychotics prevent relapse. Instead, they seem to make relapse more likely.

People in the combination group were also more likely to die from any cause (except suicide); 3.5% versus 2.4% for antidepressants alone. There was no difference in suicide mortality between the two groups.

In another analysis, the researchers looked for any subgroups of patients for whom the combination therapy actually benefited. They did not find it.

They found, however, that the combination therapy was even more dangerous for young adults (ages 18-30) than for older adults. Youth who received combination therapy were twice as likely to die from rehospitalization or suicide.


Al-Wandi, A., Landén, AM, & Nordenskjöld, A. (2023). Antipsychotics in the maintenance phase of mental depression. Acta Psychiatrica Scandinavica. Published online November 6, 2023. (Full text)

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