Treatment-resistant psychotic depression

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.