Maintenance treatment of psychotic depression: Is antipsychotic medication needed?

A.J.R. has received grant or research support from Janssen, Otsuka, Compass Pathways, and the Irving S. and Betty Brudnick Endowed Chair in Psychiatry; is a consultant to Daiichi Sankyo, Inc., Sage Therapeutics, Xenon Pharmaceuticals, Neumora Therapeutics, Zydus Pharmaceuticals (USA), Inc., Sandoz, Inc., and Lupin Pharmaceuticals, Inc.; and has received royalties for the Rothschild Scale for Antidepressant Tachyphylaxis (RSAT)®, Clinical Manual for the Diagnosis and Treatment of Psychotic Depression, American Psychiatric Press, 2009; The Evidence-Based Guide to Antipsychotic Medications, American Psychiatric Press, 2010; The Evidence-Based Guide to Antidepressant Medications, American Psychiatric Press, 2012, and from UpToDate®

Major Depression with psychotic features (psychotic depression) is a serious psychiatric illness that presents with a combination of depressed mood and psychosis. The psychotic features commonly manifest as nihilistic-type delusions with overly self-critical beliefs, severe guilt, paranoia, and often the belief that “bad” things are about to happen.¹ The presence of psychosis in major depression presents a higher lifetime risk for completed suicide and doubles the risk of a suicide attempt in the acute phase of the disorder.^{2, 3} Studies have shown that psychotic depression is not uncommon,⁴ however because the diagnosis is frequently missed, the true prevalence of the disorder may be greater than reported.⁵

Currently, not a single medication has a Food and Drug Administration (FDA) indication for psychotic depression.⁴ However, there is a substantial evidence-based research, including meta-analyses, demonstrating the efficacy of combination treatment with an antidepressant and an antipsychotic or electroconvulsive therapy (ECT) for an acute episode of psychotic depression.^6-8

A perplexing question has been how long should a patient with psychotic depression successfully treated with an antidepressant and an antipsychotic stay on the antipsychotic medication? Little is known about the efficacy and tolerability of continuing antipsychotic medication for patients with psychotic depression in remission. The question is one of profound clinical importance as the clinician is faced with a conundrum: premature discontinuation has the potential risk of relapse of a severe, life-threatening disorder versus unnecessary continuation exposing the patient to potential serious adverse effects.

In the current issue of Acta Psychiatrica Scandinavia, Al-Wandi and colleagues, using data obtained from Swedish national registries and data bases, compared antidepressant monotherapy and antidepressant/antipsychotic combination treatment for the maintenance phase of unipolar psychotic depression.⁹ The primary outcome measure was hospital readmission due to any psychiatric disorder, suicide attempt, or completed suicide. The authors identified 4391 patients, of which 2972 were in the antidepressant/antipsychotic combination therapy group, and 1419 were in the antidepressant monotherapy group. A total of 1777 patients (40.5%) reached the outcome within 2 years. A significantly higher proportion of patients reached the composite outcome (readmission due to a psychiatric disorder, suicide attempt, or completed suicide) in the combination group than in the monotherapy group (42.3% vs. 36.6%; p < 0.01). The majority of the first events were readmissions, with a significantly higher proportion in the combination group (41.8% vs. 35.9%; p < 0.01). A significantly higher proportion of patients died from other causes in the combination group (3.5% vs. 2.4%; p = 0.04).

Al-Wandi and colleagues concluded that their findings do not indicate any advantage of adding antipsychotic medications as adjunctive to antidepressants for maintenance treatment of unipolar psychotic depression.⁹ While an important contribution to our understanding of the best treatment for patients who suffer from psychotic depression, their findings need to be put in context of previous work. The Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II), a prospective, multicenter randomized double-blind placebo-controlled trial, assessed the benefits and risks of continuing antipsychotic medication in patients with unipolar psychotic depression once the episode of psychotic depression has responded to treatment with sertraline and olanzapine.¹⁰ The study included 126 patients with unipolar psychotic depression between the ages of 18 and 85 years. The study had three phases: acute treatment, an 8-week stabilization phase, and randomization. Participants who still met full-remission or near-remission criteria at the end of the stabilization phase were eligible for the third phase, a 36-week randomized controlled trial (RCT). All participants continued to take open-label sertraline for the duration of the trial. During the RCT, they were randomized under double-blind conditions to either continue olanzapine or switch from olanzapine to placebo over a 4-week taper of olanzapine. Of the 126 randomized participants, 13 of 64 (20.3%) randomized to olanzapine and 34 of 62 (54.8%) to placebo experienced a relapse (hazard ratio, 0.25; 95% CI, 0.13–0.48; p < 0.001). The conclusion of the authors was that continuing the combined treatment with sertraline plus olanzapine compared with sertraline plus placebo reduced the risk of relapse over 36 weeks, with a number needed to treat of 2.8.

The findings of the Al-Wandi and colleagues' study, that antidepressant monotherapy for the maintenance treatment of psychotic depression was significantly associated with a lower risk of a relapse than combination antidepressant/antipsychotic therapy over a two-year period, is the opposite of what was observed in the STOP-PD II 36-week RCT.^{9, 10} Of note, approximately half of all the relapses in the Al-Wandi study occurred in the first 6 months. There are several significant differences in methodology, outcome measures, and patient characteristics between the two studies. The STOP-PD II study was a prospective, 36-week RCT, whereas the Al-Wandi and colleagues' study was a 2-year study using high quality registries to identify patients with unipolar psychotic depression and to identify what medications the patients collected from the pharmacy. The registry methodology allowed for a larger sample size than an RCT but has the limitation of not knowing whether the patients were compliant with treatment. The registry methodology also did not provide information as to what treatment the patients received during the index episode which may have had an impact on long-term outcomes.

The Al-Wandi and colleagues' sample included patients who received ECT and antidepressant monotherapy as treatment for the index episode of unipolar psychotic depression, which the STOP-PD II study did not.^{9, 10} It is somewhat surprising to me that an acute episode of unipolar psychotic depression would be treated with antidepressant monotherapy. This could be explained by the fact that the sample in the Al-Wandi and colleagues' study was from 2007 to 2016. Certainly today, based on the two meta-analyses,^{7, 8} published in 2012 and 2021, this would not, in my opinion, be advisable. Finally, as Al-Wandi and colleagues' point out, a study in the United States and Canada reported that after the successful treatment of a patient with unipolar psychotic depression with ECT, the most common choice among psychiatrists for maintenance treatment was the combination of an antidepressant and an antipsychotic.¹¹

In the Discussion, Al-Wandi and colleagues write that “at present, there does not seem to be a clear consensus among clinical practitioners about what the first line of treatment should be” for psychotic depression and cite a study by Leadholm and colleagues.¹² The survey data cited by Al-Wandi and colleagues of Danish psychiatrists was from a questionnaire that was distributed to participants at the annual meeting of the Danish Psychiatric Association in March 2011. Hopefully, approximately 12 years later, based on the two meta-analyses (7.8), there is a clearer consensus that the combination of an antidepressant and antipsychotic is more effective than either antidepressant monotherapy or antipsychotic monotherapy.

An interesting finding in the Al-Wandi and colleagues' study was that the 192 patients who also received lithium had significantly better outcomes.⁹ Lithium has been shown in a few small studies to be a possible treatment for psychotic depression¹³ and augmentation with lithium is recommended by some expert guidelines when the combination of an antidepressant and antipsychotic fails to achieve full remission of psychotic depression.¹³

As Al-Wandi and colleagues⁹ point out in their discussion, a relapse may occur without being readmitted or committing suicide. Although the STOP-PD II study¹⁰ had multiple different criteria for relapse, one can look at the same primary outcomes as the Al-Wandi study using data from the STOP-PD II Study: suicide, suicide attempts, or admission to hospital. In the STOP-PD II study, during the 36-week RCT, the sertraline + olanzapine group had no patients with completed suicides, suicide plan or attempt and 3 patients who were psychiatrically hospitalized.¹⁰ In contrast, in the sertraline plus placebo group, there were no suicides, 3 patients with a suicide plan or attempt, and 11 patients who were psychiatrically hospitalized.¹⁰ Thus, the findings in STOP-PD II are in the opposite direction of the findings of the Al-Wandi and colleagues' study.

Al-Wandi and colleagues are to be commended for adding to our knowledge and understanding of the maintenance treatment of unipolar psychotic depression. I agree with Al-Wandi and colleagues that more studies are needed to ascertain the best treatment for the maintenance phase of psychotic depression. To that end, the STOP-PD group has been working on identifying clinical and biological predictors of relapse following antipsychotic discontinuation which would allow some precision when deciding which individuals can be safely withdrawn from antipsychotic medication after remission of psychotic depression. To date, we have found that lifetime number of depressive episodes, severity of residual depressive symptoms, and degree of psychomotor disturbance¹⁴ are associated with an increased risk of relapse. In contrast, residual or re-emergent impaired insight into delusions following remission was not predictive of relapse.¹⁵ In studies of possible biological markers, higher mean diffusivity on Magnetic Resonance Imaging was significantly associated with a greater probability of relapse in the each of the following tracts: corpus callosum, left striato-frontal, left thalamo-frontal, and right thalamo-frontal.¹⁶

In conclusion, more research is needed as to the role of antipsychotic medications for the maintenance treatment of psychotic depression and how long patients should take antipsychotic medications once in remission. The benefits of antipsychotic medications in preventing relapse needs to be balanced against potential adverse effects. Hopefully, research into clinical and biomarker predictors of relapse will 1 day aid clinicians in their treatment of this serious disorder.