Introduction
Major depressive disorder with psychotic features, or psychotic depression, is a serious psychiatric illness that presents with a combination of depressed mood and psychosis. The psychosis commonly manifests through nihilistic-type delusions with overly self-critical beliefs, severe guilt, paranoia, and the belief that bad things are about to happen ( ; ; ). Psychotic depression is considered a more severe form of depression with increased symptomatology, greater cognitive impairment, more brain atrophy, more pronounced psychomotor disturbance, increased hospitalizations, and greater morbidity and mortality ( ; ; ). The evidence in the current literature also suggests that 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 ( ; ), while baseline suicidality predicts poorer response to treatment in adults with psychotic depression ( ).
The lifetime prevalence of psychotic depression in the general population varies between 0.35% and 1% ( ), although the community rates in older adults have been reported to be between 1.4% and 3% ( ; ). However, the prevalence of psychotic depression is considerably higher among depressed individuals in the community or in hospital settings. A general population study found that 18.5% of respondents with major depression had psychotic symptoms ( ), and studies in inpatient settings have estimated that up to 53% of depressed adults are psychotic ( ). Despite the relatively high prevalence, the misconception that psychotic depression is not a common illness persists in part due to misdiagnosis ( ). reported in 2008 that 27% of patients with a diagnosis of psychotic depression were initially incorrectly diagnosed at four academic medical centers, with the rate thought to be a conservative estimate of the rate in the general clinical population as patients with comorbid conditions were excluded. Their findings suggest that clinicians are frequently missing the psychosis rather than the mood disorder, and in many cases they note the symptom (i.e., guilt, persecution, poverty) but do not recognize that the symptom is delusional.
In addition to frequent misdiagnosis or underdiagnosis, psychotic depression is subsequently often undertreated. Studies have shown a persisting low rate of adequate dose and duration of pharmacologic treatment of psychotic depression ( ; ). Andreescu and colleagues reported that only 5% of patients with psychotic depression received an adequate combination of an antidepressant and antipsychotic medication. Unfortunately, therapies are further limited by a lack of interest of the pharmaceutical industry in developing medications for the treatment of psychotic depression ( ). At the time of this writing, there are no Food and Drug Administration (FDA)–approved treatments for psychotic depression.
Evidence-based treatment of psychotic depression
The American Psychiatric Association (APA) Practice Guidelines recommend either electroconvulsive therapy (ECT) or combination pharmacotherapy with antidepressant and antipsychotic medications for the acute treatment of psychotic depression ( ). Meta-analytic evidence supports this recommendation ( ; ). In 2012, Farahani and Correll identified eight randomized, placebo-controlled acute-phase studies in adults with psychotic depression conducted before 2011 and yielded six antidepressant-antipsychotic combination treatment comparisons with antidepressant monotherapy and four comparisons with antipsychotic monotherapy. Their metaanalysis concluded that the combined use of antidepressants and antipsychotics was superior to either monotherapy strategy in the acute treatment of psychotic depression.
Based on these recommendations, we define treatment resistance in psychotic depression as failure to respond to an adequate trial of an antidepressant-antipsychotic combination and a trial of ECT. Of note, some groups have argued that patients with psychotic depression should not be labeled as treatment-resistant until they have had a full course of bilateral ECT ( ).
Combination pharmacotherapy with antidepressant and antipsychotic medications
In the paragraphs below, we discuss the three combinations of newer antidepressants and antipsychotic medications that have been studied in double-blind, randomized, controlled trials (see Table 24.1 ).
| Study | Sample size | Combination | Statistically significant results |
|---|---|---|---|
| 249 | Fluoxetine + olanzapine | Reduction in HAM-D score : Trial 1: Fluoxetine + olanzapine > olanzapine and placebo Trial 2: Fluoxetine + olanzapine = olanzapine = placebo | |
| 259 | Sertraline + olanzapine | Remission : Sertraline + olanzapine > olanzapine | |
| 122 | Venlafaxine + quetiapine | Response : Venlafaxine + quetiapine > venlafaxine Venlafaxine + quetiapine = imipramine Remission : Venlafaxine + quetiapine > imipramine Venlafaxine + quetiapine = venlafaxine |
Fluoxetine plus olanzapine
In 2004, Rothschild and colleagues reported on two multicenter randomized, double-blind, placebo-controlled trials that compared the combination of the selective serotonin reuptake inhibitor, fluoxetine, and the second-generation antipsychotic olanzapine with olanzapine monotherapy or placebo in 249 hospitalized patients with psychotic depression ( ). In both trials, the subjects were randomized to an olanzapine monotherapy group ( n = 43 and 47), a placebo group ( n = 50 and 44), or an olanzapine-fluoxetine combination therapy group ( n = 22 and 23). The olanzapine monotherapy group initially received an evening dose of 10 mg of olanzapine followed by a morning dose of placebo; olanzapine could be titrated up to 20 mg daily maximum. The mean daily doses of olanzapine were 11.9 and 14.0 mg/day in the olanzapine monotherapy group of each study. The olanzapine-fluoxetine combination therapy group initially received an evening dose of 10 mg of olanzapine followed by a morning dose of 20 mg of fluoxetine; olanzapine could be titrated at each visit up to 20 mg daily maximum while the fluoxetine dose remained fixed until week 3, when it could be increased by 20 mg at each visit if the subject had reached the daily maximum olanzapine dose. In the olanzapine-fluoxetine combination therapy group of each study, the mean daily doses of olanzapine were 12.4 and 13.9 mg/day, and the mean daily doses of fluoxetine were 23.5 and 22.6 mg/day. Treatment duration was 8 weeks. The primary outcome measure was the 24-item Hamilton Depression Rating Scale (HAM-D) total score.
The results of the first trial showed significantly greater endpoint improvement in depressive symptoms (− 20.9) among patients in the olanzapine-fluoxetine combination therapy group compared with the placebo group (− 10.4, P = .001). This significant difference was present within 7 days of treatment, and the effect was maintained at every subsequent visit for the duration of the 8-week trial. The olanzapine-fluoxetine combination group also had significantly higher response rate (63.6%) than the placebo (28.0%, P = .004) or olanzapine monotherapy (34.9%, P = .027) groups. Olanzapine monotherapy did not demonstrate statistically significant effectiveness on overall symptom improvement in psychotic depression.
The second trial did not reveal any statistically significant differences between the three treatment groups, although the numeric pattern was similar to the first trial, with the combination pharmacotherapy group having the highest response rate and the placebo group having the lowest. This finding may be in part due to the study design which limited fluoxetine dosing according to olanzapine dosing, such that most subjects received only a starting dose of fluoxetine (20 mg daily). Higher doses of fluoxetine might have produced greater reductions in depressive symptoms or higher remission rates. Additionally, the study was initially powered to show a difference between olanzapine monotherapy and placebo rather than olanzapine-fluoxetine combination therapy and placebo. This resulted in a small sample size of the combination pharmacotherapy group, which limited statistical power.
Sertraline plus olanzapine
The Study of the Pharmacotherapy of Psychotic Depression (STOP-PD) ( ) examined the tolerability and efficacy of combination pharmacotherapy using a serotonergic antidepressant (sertraline) and an atypical antipsychotic (olanzapine) in the acute treatment of psychotic depression. This NIMH-funded randomized controlled trial included 259 subjects with psychotic depression across a broad spectrum of illness severity; of those, 117 were younger than 60 and 142 were age 60 years or older. Participants were randomly assigned to combination treatment of sertraline plus olanzapine (129 subjects) or olanzapine plus placebo (130 subjects). Olanzapine was administered openly, while sertraline and placebo were administered under double-blind conditions. The daily dosages of medications were increased gradually as tolerated. Initially, subjects received 5 mg of olanzapine and 50 mg of sertraline/placebo per day (frail elderly subjects were started on 2.5 mg of olanzapine and 25 mg of sertraline/placebo per day); daily dosages were increased to 10 mg of olanzapine and 100 mg of sertraline/placebo by the end of week 1, followed by 15 mg of olanzapine and 150 mg of sertraline/placebo by the end of week 2, with maximum daily doses of 20 mg of olanzapine and 200 mg of sertraline/placebo allowed for residual symptoms. Treatment duration was 12 weeks. The primary outcome measure was a response on the HAM-D. Remission was defined as a HAM-D score of 10 or lower at two consecutive assessments and required the absence of delusions, as classified by the Schedule of Affective Disorders and Schizophrenia (SADS) delusion severity score of 1 at the second remission of depression assessment. Subjects who achieved a HAM-D score of 10 or lower for the first time at week 12 were assessed again at week 13 to determine whether the 2-week duration of remission criterion was met.
The STOP-PD study results showed that the combination pharmacotherapy of sertraline and olanzapine was associated with higher remission rates during the trial than olanzapine monotherapy (OR, 1.28; 95% CI, 1.12–1.47; P < .001) among patients with psychotic depression. The benefits of the combination pharmacotherapy became more apparent as the clinical trial progressed, particularly from week 8 to the end of the trial. 41.9% of subjects who underwent combination pharmacotherapy were in remission at their last assessment compared with 23.9% of subjects treated with olanzapine monotherapy (Chi square = 9.53, P = .002). Furthermore, combination pharmacotherapy was comparably superior in both younger (OR, 1.25; 95% CI, 1.05–1.50; P = .02) and older (OR, 1.34; 95% CI, 1.09–1.66; P = .01) participants. The two treatments had comparable tolerability across age groups. The older subjects were more likely to experience pedal edema than the younger subjects, but the older subjects were no more likely to experience sedation, somnolence, falls, or greater extrapyramidal symptoms. The younger subjects gained significantly more weight than the older subjects (mean (SD), 6.5 [6.6] kg vs 3.3 [4.9] kg, P = .001). Both age groups had significant increases in cholesterol and triglyceride concentrations, but statistically significant increases in glucose occurred only in the younger subjects. There were no differences in incident akathisia or tardive dyskinesia by age group.
Venlafaxine plus quetiapine
In a double-blind, multicenter randomized controlled trial in the Netherlands, compared the efficacy and safety of imipramine monotherapy, venlafaxine monotherapy, and venlafaxine plus quetiapine combination therapy among 122 hospitalized patients with psychotic depression. Participants were 18–65 years old. 42 subjects received imipramine monotherapy, 39 subjects received venlafaxine monotherapy, and 41 subjects received venlafaxine-quetiapine combination therapy. There was no placebo control group given the severity of patients’ symptoms. Daily dosages used were as follows: imipramine was initiated at 75 mg/day and adjusted to a plasma level of 200–300 μg/mL with a maximum daily dose of 450 mg; venlafaxine was initiated at 75 mg/day and gradually tapered up to 375 mg/day on day 17; quetiapine was initiated at 100 mg/day and gradually increased to 600 mg/day on day 10. Treatment duration was 7 weeks. The primary outcome measure was a response on HAM-D that showed a 50% or greater decrease in score from baseline to study end-point, and a final HAM-D score of 14 or less. Remission was defined as a final HAM-D score of 7 or less.
Results showed that, for the primary outcome measure of response, the venlafaxine-quetiapine combination therapy was significantly more effective than venlafaxine monotherapy (OR, 3.96; 95% CI, 1.53–9.75), while there were no significant differences between venlafaxine-quetiapine and imipramine (OR, 1.75; 95% CI, 0.72–4.25), or between imipramine and venlafaxine (OR, 2.20; 95% CI, 0.89–5.41). In contrast to treatment response, venlafaxine-quetiapine combination therapy was not significantly more effective than venlafaxine monotherapy in improving remission rates; however, the combination pharmacotherapy was significantly more effective than imipramine alone. There was also no significant difference between imipramine and venlafaxine. Based on these findings, Wijkstra and colleagues concluded that venlafaxine plus quetiapine combination therapy was more effective than venlafaxine monotherapy on the primary outcome measure of treatment response.
Electroconvulsive therapy
Electroconvulsive therapy is widely considered to be the most effective treatment in severe major depression ( ). It is particularly effective in patients with depression with psychotic features ( ; ; ). In their 2018 metaanalysis looking at predictors of ECT response and remission rates in major depressive disorder, van Diermen and colleagues showed that presence of psychotic symptoms had an OR of 1.69 ( P < .001) for response and 1.47 ( P = .001) for remission. Expert guidelines recommend ECT as a first-line treatment of acute psychotic depression ( ; ; ). Unfortunately, the relative efficacy of ECT compared with pharmacotherapies is not known due to a lack of prospective controlled trials.
In 2001, Petrides and colleagues provided data that quantified the efficacy of bilateral ECT in psychotic depression ( ) and confirmed that the presence of psychosis in patients with major depression is a predictor of a favorable outcome with bilateral ECT. These data came from the first phase of a collaborative study of continuation treatments after successful ECT courses by the Consortium for Research in ECT (CORE). The authors reported the results for 253 patients ( n = 77 psychotic, n = 176 nonpsychotic) who received bitemporal ECT three times a week until remission, defined as a 24-item HAM-D score of 10 or lower after two consecutive treatments, and a decrease of at least 60% from baseline. For the completers of the acute ECT course ( n = 217), the overall remission rate was 87% (189/217). The remission rate for the psychotic depressed patients was 95%, while for the nonpsychotic depressed patients it was 83% ( P < .01). The odds of becoming a remitter for all patients was two times higher among the psychotic depressed than among the nonpsychotic depressed patients (OR, 2.0; 95% CI, 1.02–3.96). Additionally, symptomatic improvement, as measured by the HAM-D, was more robust and appeared sooner in the psychotic patients compared with the nonpsychotic patients.
Despite the demonstrated efficacy of ECT for the acute treatment of psychotic depression, early relapse rates after successful ECT are high ( ), although not all studies are in agreement ( ). The remission rate with ECT in community settings has also been shown to be substantially less than that in controlled clinical trials ( ). Prudic and colleagues showed that the intent-to-treat remission rates from a large cohort of adults treated with ECT in various community facilities were in the range of 30%–47%, a marked difference from the 70% to 90% remission rate typically reported in clinical trials ( ; ). This disparity between clinical outcomes in research and community settings was more marked for remission than for response rates. The low remission rates in routine practice might be explained by greater rates of comorbid psychiatric and medical conditions that are associated with poorer ECT outcomes in the community than in the patient populations studied in the clinical trials.
Continuation and maintenance pharmacotherapy
Despite the demonstrated efficacy of ECT in the acute episode of psychotic depression, studies show high rate of relapse within days to weeks after the completion of ECT course, and patients with psychotic depression are more likely to relapse following ECT compared to patients with nonpsychotic depression ( ; ). Intensive pharmacotherapy has been shown to reduce post-ECT relapse rates ( ). The relapse rate in psychotic depression after ECT has been reported to be approximately 50% in studies where lithium was used after ECT (see later). reported on a randomized, double-blind study of maintenance pharmacotherapy of unipolar depression following a successful ECT course with nortriptyline monotherapy, nortriptyline plus lithium, or placebo. Over the 24-week trial, the relapse rate for placebo was 84% (95% CI, 70%–99%); the relapse rate for nortriptyline monotherapy was 60% (95% CI, 41%–79%); and for nortriptyline‑lithium combination therapy, the relapse rate was 39% (95% CI, 19%–59%). The parametric survival analysis indicated that across the treatment conditions, medication-resistant nonpsychotic patients had a higher relapse rate than patients with psychotic depression. The relapse rates were 50.0% for psychotic patients ( n = 28), 55.6% for nonpsychotic patients without medication resistance ( n = 9), and 72.2% for nonpsychotic medication-resistant patients ( n = 36). reported on a sample of 319 patients with an episode of major depression (either unipolar or bipolar) who were treated with moderate dosage bilateral ECT or high dosage right unilateral ECT; of those who met post-ECT remission criteria, 122 patients (including 25.41% = 31 with psychotic depression) were randomized to post-ECT continuation treatment with nortriptyline plus lithium or venlafaxine plus lithium. There was no difference in the relapse rates of those with psychotic depression or nonpsychotic depression with a 50% relapse in both groups within 6 months, regardless of what antidepressant lithium was combined with.
Few studies on continuation and maintenance pharmacotherapy for psychotic depression have been published to date. In 2001, Meyers and colleagues reported on a randomized controlled trial that compared the benefits and risks of antidepressant-antipsychotic combination pharmacotherapy (nortriptyline or sertraline plus perphenazine) with those of antidepressant monotherapy (nortriptyline or sertraline) during a 26-week period in 28 older patients with psychotic depression who had achieved symptom remission after completion of an ECT course ( ). Results showed that the relapse frequency was nonsignificantly greater in combination therapy than in monotherapy participants. However, participants in the combination therapy group were more likely to experience adverse effects of treatment, including 43% incidence of tardive dyskinesia after 6 months of perphenazine treatment.
The STOP-PD II multicenter randomized double-blind placebo-controlled trial (“Sustaining Remission of Psychotic Depression”) assessed the benefits and risks of continuing antipsychotic medication in patients with psychotic depression once the episode of psychotic depression has responded to treatment with sertraline and olanzapine ( ). The study included 126 patients between the ages of 18 and 85 years who met criteria for current major depressive episode with at least one associated delusion (with or without hallucinations) and scored 21 or higher on the 17-item HAM-D. The study had three phases: acute, stabilization, and randomization. In the open-label acute phase, participants received a combination of sertraline (median dosage was 150 mg/day, interquartile range was 150–200 mg/day) plus olanzapine (median dosage was 15 mg/day, interquartile range was 15–20 mg/day). As soon as the patients with psychotic depression met criteria for remission, defined as the absence of delusions and hallucinations and a 17-item HAM-D score of 10 or less for 2 consecutive weeks, participants entered the open-label sertraline and olanzapine 8-week stabilization phase. Participants who met criteria for near-remission, defined as the absence of delusions and hallucinations, a HAM-D score of 11–15 with 50% or more reduction in baseline HAM-D score, and being rated as “very much improved” or “much improved” on the Clinical Global Impression scale, were also eligible to enter the stabilization phase. Participants who still met full-remission or near-remission criteria at the end of the stabilization phase and who had a Mini-Mental State Examination (MMSE) score of 24 or higher 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. Participants were assessed weekly for the first 8 weeks and once every 4 weeks thereafter until study completion at week 36, relapse, or early termination. Risk of relapse was the primary outcome and required one of the following: (1) meeting criteria for major depressive episode; (2) 17-item HAM-D score of 18 or higher; (3) symptoms of psychosis (delusions or hallucinations); or (4) other significant clinical worsening, including having a suicide plan or attempting suicide, developing symptoms of mania or hypomania, or being hospitalized in a psychiatric unit. Secondary outcomes included anthropometric and metabolic measures such as weight, waist circumference, fasting cholesterol and triglyceride levels, fasting glucose, and hemoglobin A1c.
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 < .001). The effect of olanzapine on the daily rate of anthropometric and metabolic measures significantly differed from placebo for weight (0.13 lb.; 95% CI, 0.11–0.15; adjusted P < .001), waist circumference (0.009 in.; 95% CI, 0.004–0.014; adjusted P = .002), and total cholesterol (0.29 mg/dL; 95% CI, 0.13–0.45; adjusted P = .003) but was not significantly different for low-density lipoprotein cholesterol (0.04 mg/dL; 95% CI, − 0.01 to 0.10; adjusted P = .57), high-density lipoprotein cholesterol (− 0.01 mg/dL; 95% CI, − 0.03 to 0.01; adjusted P = .99), triglyceride (− 0.153 mg/dL; 95% CI, − 0.306 to 0.004; adjusted P = .25), glucose (− 0.02 mg/dL; 95% CI, − 0.12 to 0.08; adjusted P = .99), or hemoglobin A1c levels (− 0.0002 mg/dL; 95% CI, − 0.0021 to 0.0016; adjusted P = .99). The authors concluded 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. However, continuation of olanzapine was associated with weight gain. The study did not provide information on the optimal duration of treatment with olanzapine following remission of psychotic depression.
Options to consider for treatment-resistant psychotic depression
If both adequate trials of antidepressant and antipsychotic combination and ECT have been tried with limited efficacy, several other treatment options have been reported in the literature that may be worth considering (see Table 24.2 ).
| Treatment | References |
|---|---|
| Amitriptyline plus perphenazine | |
| Lithium | , , , , |
| Clozapine | , , |
| Ketamine/esketamine | , , , |
| Acetylcholinesterase inhibitors | |
| Transcranial magnetic stimulation (TMS) | |
| Psychotherapy | , , |
| Benzodiazepines | |
| Glucocorticoid antagonists | , |
a Mainly anecdotal case reports and case series except for the study which was a small RCT.
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