Challenges in the Treatment of Major Depressive Disorder With Psychotic Features

Anthony J. Rothschild


Schizophr Bull. 2013;39(4):787-796. 

In This Article

Continuation and Maintenance Treatment of Major Depressive Disorder With Psychotic Features

Determining the optimal continuation and maintenance therapy for psychotic depression is of special concern due to the high rate of relapse observed in naturalistic follow-up studies of psychotic depression, including relapse after ECT.[80–82] Other concerns include a relapsing or chronic course,[83] high mortality rates,[83,84] a high risk of extrapyramidal symptoms and tardive dyskinesia with first-generation antipsychotics,[85] risk of metabolic syndrome with atypical antipsychotics,[44] an increased use of healthcare services,[15] and a high rate of disability.[15]

There is only 1 published randomized controlled trial of continuation pharmacotherapy for psychotic depression.[86] In this study, the benefits and risks of combination pharmacotherapy with nortriptyline or sertraline plus perphenazine were compared with those of antidepressant monotherapy with nortriptyline or sertraline during a 26-week period in 28 older patients with psychotic depression who had remitted after being treated with ECT. Overall, 25% of patients relapsed during the 26-week trial, 33% in the combination therapy group, and 15% in the monotherapy group. The difference was not statistically significant most likely due to the small sample size.

In an open-label maintenance study, Rothschild and Duval[87] assessed

the effect of discontinuing the antipsychotic medication in patients with psychotic depression. Thirty patients with the diagnoses of unipolar major depression with psychotic features who responded to the combination of fluoxetine and perphenazine were studied. If the patient was stable for 4 months on the combination, the patient was then gradually tapered off the perphenazine. After tapering of the perphenazine after 4 months of treatment with fluoxetine and perphenazine, 22 of the 30 patients (73%) did not exhibit signs of relapse over the next 11 months while remaining on fluoxetine monotherapy.

In another open-label maintenance study, Flint and Rifat[88] followed a group of patients older than 60 years with major depression with and without psychotic features for 2 years after remission of their index episode. The 68 patients with nonpsychotic depression were maintained on the treatment they had responded to in the acute phase (ie, a therapeutic dose of nortriptyline with or without lithium augmentation), while 15 of the 19 patients in the psychotic depression group were treated with ECT and then switched to nortriptyline. Patients with psychotic depression were significantly more likely to suffer a relapse or a recurrence than the nonpsychotic group (47% vs 15%, respectively, P = .005).

Wijkstra and colleagues[89] reported on a 4-month open-label follow-up of 59 patients with DSM-IV-TR major depressive disorder with psychotic features, aged 18–65 years, who had completed as responders an acute double-blind, 7-week trial with imipramine, venlafaxine, or venlafaxine plus quetiapine. Relapse rate was low (3.8%; 2/53). Six patients dropped out during the 4-month follow-up.

Taken together, these studies suggest that in a patient with psychotic depression who has responded to the combination of an antidepressant and antipsychotic, it would seem prudent to continue the treatment for maintenance. Once an episode of nonpsychotic major depression responds to antidepressant medication, it is recommended that the antidepressant be continued to prevent relapse and recurrence of depression.[90–92] However, it is not known whether the antipsychotic medication needs to be continued once an episode of psychotic depression has responded to combined antidepressant-antipsychotic treatment. On the one hand, premature discontinuation of antipsychotic medication has the potential risk of relapse of a severe, disabling disorder. On the other hand, the unnecessary continuation of antipsychotic medication exposes a patient to potential adverse effects. An NIMH study to address the question as to how long a patient with psychotic depression who is in remission needs to stay on the antipsychotic medication is currently underway[93] at Weill Medical College of Cornell University, the University of Pittsburgh School of Medicine, the University of Massachusetts Medical School, and the University of Toronto Department of Psychiatry (NCT01427608).

Unfortunately, despite the demonstrated efficacy of ECT in the acute episode of psychotic depression, there is often a rapid increase in depressive symptoms within days to weeks after the completion of a course of ECT66,81,94 and much lower ECT remission rates (ie, 30%–47%) reported in community settings than academic medical centers.[65] In a randomized, double-blind study of maintenance pharmacotherapy of psychotic depression after successful ECT,[81] in which patients were assigned to maintenance therapy with nortriptyline monotherapy, nortriptyline plus lithium, or placebo, 50% of the patients relapsed within 6 months.

The one exception to the high rate of relapse in patients with psychotic depression successfully treated with ECT was a study in the Netherlands,[95] in which 29 responders to ECT were followed for 1 year. The frequency of relapse after 4 and 12 months was 3/28 (11%) at 4 months and 4/27 (15%) at 1 year.