Challenges in the Treatment of Major Depressive Disorder With Psychotic Features

Anthony J. Rothschild


Schizophr Bull. 2013;39(4):787-796. 

In This Article

Somatic Treatment of an Acute Episode of Unipolar Psychotic Depression

International Guidelines

While guidelines have been published for the treatment of unipolar psychotic depression, there are unfortunately no studies or guidelines that support specific pharmacological regimens for the treatment of psychotic depression in patients with bipolar disorder.[27] Several treatment guidelines recommend either the combination of an antidepressant and antipsychotic or electroconvulsive therapy (ECT) as the first-line treatment for unipolar psychotic depression.[28] These include the American Psychiatric Association (APA),[29] the Canadian Network for Mood and Anxiety Treatment (CANMAT),[30,31] the Texas Medication Algorithm Project (TMAP),[32] and the World Federation of Societies of Biological Psychiatry (WFSBP).[33] The South African Society of Psychiatrists[34] and the Royal College of Australian and New Zealand College of Psychiatrists (RANZCP)[35] recommend the combination of an antidepressant and an antipsychotic as first-line treatment and ECT as second-line treatment, while the Danish Board of Health[36] recommends ECT as the first-line treatment and the combination of an antidepressant and antipsychotic as second-line treatment. The National Institute for Health and Clinical Excellence (NICE)[37] and the Dutch National Steering Committee on Multidisciplinary Guideline Development in Mental Health (DNSC)[38] recommend antidepressant monotherapy as the first-line treatment. No treatment guidelines recommend antipsychotic monotherapy as a treatment option for psychotic depression.

The recommendation of antidepressant monotherapy (in contrast to the combination of an antidepressant and antipsychotic) for the acute treatment of psychotic depression in the NICE and DNSC guidelines may in part stem from a 2005 Cochrane review,[39,40] which concluded that there was a lack of statistical evidence for the superior efficacy of the combination compared with antidepressant monotherapy. However, a more recent meta-analysis, which included several randomized controlled clinical trials published since the 2005 Cochrane review, concluded that the combination of an antidepressant and antipsychotic was significantly more effective than either antidepressant monotherapy or antipsychotic monotherapy for the acute treatment of psychotic depression.[41]

In the United States, despite the APA Practice Guidelines having recommended the combination of an antidepressant and antipsychotic for the acute treatment of psychotic depression since 2000,[1] studies have shown that only 5% of patients with psychotic depression receive an adequate combination of an antidepressant and an antipsychotic.[3] These findings show a persisting low rate of adequate treatment (dose and duration of medications) of psychotic depression and little change from a study published a decade earlier, which also reported inadequate dose and duration of medication treatment.[42] This may be related to the under recognition of the psychosis in these patients[2] (discussed above).

Specific Combinations of Medications Studied for the Acute Treatment of Psychotic Depression

In a recent meta-analysis of antidepressant and antipsychotic trials for the treatment of psychotic depression, Farhani and Correll pointed out that efficacy has been demonstrated only for specific medication combinations (and not others) and that there is a need for further studies to help elucidate the effectiveness of different combinations of medications.[41] Given this, it is important to keep in mind that the studies discussed below may not be generalizable to all patients with psychotic depression or all combinations of antidepressant and antipsychotic medications. I was able to identify 7 studies in the medical literature that have compared the combination of an antidepressant and an antipsychotic (see Table 1 ) to treatment with antidepressant monotherapy, antipsychotic monotherapy, or placebo in well-designed, double-blind, randomized controlled trials.

Newer medications (selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor + second-generation antipsychotic)

  1. Venlafaxine plus quetiapine[43]

  2. Sertraline plus olanzapine[44]

  3. Fluoxetine plus olanzapine[45]

Older medications (tricyclic antidepressant + first-generation antipsychotic)

  1. Amitriptyline plus haloperidol, trimipramine[46]

  2. Nortriptyline plus perphenazine[47]

  3. Amoxapine, Amitriptyline plus perphenazine[48]

  4. Amitriptyline plus perphenazine[49]

Newer Medications

Venlafaxine Plus Quetiapine. Wijkstra and colleagues[43] reported on a double-blind, randomized controlled study of 122 hospitalized patients (aged 18–65 years) with psychotic depression at 8 sites in the Netherlands. The patients were treated for 7 weeks with imipramine (n = 42), venlafaxine (n = 39), or the combination of venlafaxine and quetiapine (n = 41). Dosages used were the following: imipramine (dose adjusted to adequate plasma levels of 200–300ng/ml), venlafaxine (maximum 375mg/day), or venlafaxine-quetiapine (maximum 375/600mg/day). The primary outcome measure was a response on the Hamilton Depression Rating Scale (HAM-D; ≥50% decrease and final score ≤14). Remission was defined as a final HAM-D of 7. Response rates for imipramine, venlafaxine, and venlafaxine-quetiapine were 22/42 (52.4%), 13/39 (33.3%), and 27/41 (65.9%), respectively. For the primary outcome measure of response, the venlafaxine-quetiapine combination was statistically significantly more effective than venlafaxine; there were no statistically significant differences in the response rates between venlafaxine-quetiapine and imipramine or between imipramine and venlafaxine. Remission rates for the venlafaxine-quetiapine combination (17/41, 41.5%) were statistically significantly more effective than imipramine (9/42, 21.4%), with no statistically significant difference compared with venlafaxine (11/39, 28.2%) and no significant difference between imipramine and venlafaxine. The authors concluded that the combination of venlafaxine and quetiapine was more effective than venlafaxine alone on the primary outcome measure (response) and was well tolerated.[43]

Sertraline Plus Olanzapine. The largest study to date, the NIMH Study of the Pharmacotherapy of Psychotic Depression (STOP-PD) reported results that indicated that the combination of an antidepressant and an atypical antipsychotic medication was more efficacious than monotherapy with the atypical antipsychotic.[44] The study included 259 subjects with psychotic depression, 142 subjects 60 years old and 117 <60 years old. 129 subjects were randomized to combination treatment and 130 to olanzapine plus placebo. Remission was defined as a HAM-D score of 10 at 2 consecutive assessments without delusions, as classified by a schedule of affective disorders and schizophrenia delusion severity score of 1 at the second assessment when the 2-week HAM-D depression remission criterion was met. Subjects who achieved a HAM-D score of 10 for the first time at week 12 were assessed again at week 13 to determine whether the 2-week duration criterion for remission was met. The daily dosages of medications in the STOP-PD study were as follows: (1) 50mg sertraline/placebo and 5mg of olanzapine as tolerated, initially; (2) increased to 100mg sertraline/placebo and 10mg olanzapine by day 7; (3) increased to 150mg sertraline/placebo and 15mg olanzapine by day 14; and (4) 200mg sertraline/placebo and 20mg olanzapine allowed for residual symptoms. Treatment with olanzapine/sertraline was associated with higher remission rates during the trial than olanzapine/placebo (OR, 1.28; 95% CI, 1.12–1.47; P < .001). 41.9% of subjects who underwent combination therapy were in remission at their last assessment compared with 23.9% of subjects treated with monotherapy (Chi square = 9.53, P = .002). Combination therapy 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) adults. Overall, tolerability was comparable across age groups. Both age groups had significant increases in cholesterol and triglyceride concentrations, but statistically significant increases in glucose occurred only in younger adults. Younger adults gained significantly more weight than older subjects (mean [SD], 6.5 [6.6] kg vs 3.3 [4.9] kg, P = .001). Although the STOP-PD study did not include a sertraline monotherapy arm, a previous open-label study[50] reported that patients with major depression with psychotic features had a markedly lower response rate to 200mg of sertraline per day for 8 weeks than patients with nonpsychotic depression.

Fluoxetine Plus Olanzapine. In 2 randomized, placebo-controlled trials,[45] a combination of the selective serotonin reuptake inhibitor fluoxetine plus the second-generation antipsychotic olanzapine was compared with olanzapine monotherapy or placebo in 229 hospitalized patients with psychotic depression. These 2 studies are the largest randomized controlled trials for the treatment of psychotic depression that included a placebo arm. In both studies, patients were randomized to placebo, olanzapine (mean doses: 11.9 and 14.0mg/day) plus placebo, or olanzapine (mean doses: 12.4 and 13.9mg/day) plus fluoxetine (mean doses: 23.5 and 22.6mg/day) and followed for 8 weeks. The first trial showed a reduction in HAM-D score that was statistically greater in the combination group than in the olanzapine monotherapy group or the placebo group throughout the 8 weeks. The second trial failed to reveal any statistically significant differences between the 3 treatment groups except for the HAM-D score in the combination group that was statistically lower than the placebo group at the end of week 1. However, there were several aspects of the study design that were biased against the combination of fluoxetine and olanzapine. First, the study was powered to show a difference between olanzapine monotherapy and placebo and not the combination therapy, resulting in a small sample size in the combination group, which limited statistical power. Additionally, the study design limited fluoxetine dosing according to olanzapine dosing, such that most subjects received only a starting dose of fluoxetine (20mg/day). It is plausible that if higher doses of fluoxetine had been used, it could have produced greater reductions in depressive symptoms or higher response or remission rates.

Older Medications

Amitriptyline Plus Haloperidol. In a double-blind, randomized, multicenter trial, Künzel and colleagues[46] compared the effects of trimipramine monotherapy (n = 33) vs a combination of amitriptyline and haloperidol (n = 24) in patients with psychotic depression. At week 6, the mean dosages (±SD) were 356.1±61.2mg trimipramine, 184.0±23.6mg amitriptyline and 6.3±1.8mg haloperidol. No significant differences were found in rates of response and remission between the 2 groups. A possible explanation for the fact that no differences were found between the 2 groups is, as the authors themselves point out, that a high dosage of trimipramine was compared with a lower dosage of amitriptyline (combined with haloperidol).

Nortriptyline Plus Perphenazine. Mulsant and colleagues[47] compared in a double-blind trial the efficacy of nortriptyline plus perphenazine vs nortriptyline plus placebo in a group of older inpatients who presented with a major depressive episode with psychotic features. Fifty-two patients (mean age: 72) were included in the trial and started openly on nortriptyline that was titrated to yield a therapeutic plasma level (target: 100ng/ml; range: 50–150ng/ml). After 2 weeks, patients who had not responded were randomly assigned to addition of perphenazine (n = 17) or placebo (n = 19). The doses of perphenazine/placebo were titrated up to a maximum dose of 24mg/day (mean dose: 18.9mg/day) until patients showed therapeutic response or extrapyramidal side effects were detected. After patients had received nortriptyline for at least 4 weeks combined with either perphenazine or placebo for at least 2 weeks (median: 9 weeks), no statistical differences were observed on the HAM-D or the psychoticism subscale of the Brief Psychiatric Rating Scale (BPRS). Rates of response to nortriptyline plus perphenazine (50%) and nortriptyline monotherapy (44%) did not statistically differ among the 30 treatment completers (P =.99).

Amoxapine/Amitriptyline Plus Perphenazine. Anton and Burch[48] conducted a randomized, double-blind investigation that explored whether the efficacy of combination amitriptyline plus perphenazine could be matched by monotherapy with amoxapine, an antidepressant derivative of the antipsychotic medication loxapine, with dopamine antagonist activity. Using a 50% reduction in HAM-D score as criteria for response yielded response rates of 71% and 81% for amoxapine and amitriptyline plus perphenazine, respectively. Extrapyramidal symptoms were significantly more frequent in the amitriptyline plus perphenazine group than in the amoxapine treated patients.

Amitriptyline Plus Perphenazine. Spiker and colleagues[49] compared the combination of amitriptyline and perphenazine with amitriptyline alone and perphenazine alone in the treatment of patients with psychotic depression over a 5-week period. Using a 50% reduction in HAM-D and BPRS total scores and a final HAM-D score of less than 12 as response criteria, 14 of 18 patients (78%) treated with the combination responded, in contrast to 7 of 17 patients (41%) treated with amitriptyline alone, and 3 of 16 (19%) patients treated with perphenazine alone.

Augmentation Strategies. Lithium augmentation of antidepressants for nonpsychotic depression is a well-known strategy, particularly for partial responders.[51] However, lithium augmentation has not been adequately studied in the treatment of psychotic depression. In 4 small uncontrolled studies, lithium augmentation of the antidepressant/antipsychotic combination appeared to add additional efficacy, particularly in bipolar patients.[52–55]

The use of other augmentation strategies or the use of lithium augmentation with other combinations of antidepressant and antipsychotic medications has not been studied. Of note, augmentation with lithium is recommended by the APA, TMAP, and RANZCP guidelines when the initial pharmacological regimen fails to achieve full remission. The other guidelines do not mention lithium augmentation in the section that discusses the treatment of psychotic depression.

Electroconvulsive Therapy (ECT)

ECT is advocated by most guidelines for the treatment of psychotic depression as being at least equally as effective as the suggested pharmacological first-line treatment. Only NICE, RANZCP, and DNSC place ECT as a third and final option to be used when other treatments have failed, or if acute response is required due to medical comorbidities or suicidality.[28]

The literature on the relative efficacy of ECT compared with pharmacotherapies is limited by a lack of prospective, controlled trials. Meta-analysis may offer the best opportunity to synthesize published treatment outcomes; however, it is difficult to draw broad conclusions from these studies because the ECT treatment was often compared with several different combinations of medications at varying doses and for different periods of time.[56]

In a review of 17 prospective and retrospective studies comprising 597 patients with psychotic depression by Kroessler,[57] response rates were 82% for ECT and 77% for the combination of a TCA and antipsychotic, with considerably lower response rates of 51% and 34% for antidepressant monotherapy or antipsychotic monotherapy, respectively. A second larger meta-analysis, which included data from 44 prospective and retrospective studies published between 1959 and 1988,[58] found that ECT was significantly more effective than TCA alone, with effect sizes of 2.30 and 1.16, respectively. The combination of an antidepressant and antipsychotic was found to have an intermediate effect size of 1.56, which was not significantly different from the other 2 groups.[58] The early initiation of ECT within 5 days of admission has been reported to shorten lengths of stay and reduce treatment costs[59] although hospital treatment with ECT is associated with longer lengths of stay when treatment is not instituted rapidly.[59–61] Some studies suggest that ECT may be even more effective for psychotic depression than for nonpsychotic depression.[61–65]

In clinical practice in the community, much lower ECT remission rates have been reported than in clinical trials of ECT.[66] For example, the intent-to-treat remission rates from a large cohort of adults treated with ECT in community facilities were in the range of 30%–47%.[66] The low rates of remission are of particular concern given the poor outcomes of patients who do not remit with ECT.[66] The low remission rates in community practice might be explained by the fact that patients with comorbid psychiatric and medical conditions that are associated with poorer ECT outcome might represent a larger proportion of the clinical population than the patients studied in clinical trials of ECT.[66]

The use of ECT as a first-line treatment for psychotic depression appears to depend on whether the patient is suicidal. In a survey of Danish psychiatrists, 21% said they would use ECT as a first-line treatment in nonsuicidal patients with psychotic depression.[28] However, if the patient was at high risk of suicide, 59% would use ECT as the first-line treatment.[28]