Combination treatment with olanzapine plus sertraline was associated with a greater remission rate than olanzapine monotherapy among patients with MDpsy. The benefits of the combination became more apparent over time during the twelve-week trial with separation favoring olanzapine/sertraline from week eight to the end of the trial. The higher categorical remission rate observed with olanzapine/sertraline compared to olanzapine/placebo was consistent with the significantly greater decreases in Ham-D scores observed with combination therapy.
Our hypothesis that pharmacotherapy would be more efficacious in the younger group was not supported. The greater efficacy of olanzapine/sertraline was comparable in both age groups; furthermore, the subgroup analyses demonstrated the efficacy of combination treatment compared to olanzapine alone in both the younger adults and geriatric subjects.
The rates and severity of adverse events were similar in the two treatment groups. Older subjects did not demonstrate poorer overall tolerability. With the exception of a greater frequency of pedal edema, older subjects were not more likely to experience falls, sedation/somnolence, or have greater extrapyramidal symptoms.
Both age groups experienced significant increases in weight and in both triglyceride and cholesterol levels. Fasting glucose levels increased significantly among younger adults only. The observed metabolic changes are consistent with those reported during olanzapine treatment among younger adults with schizophrenia53
. In the absence of reliable measures of premorbid weight, we are unable to estimate how much of the weight gained during the trial was due to the recovery of weight lost during the depressive episode. Our finding that older age was associated with less weight gain is consistent with other reports with atypical antipsychotic medications54
and with olanzapine specifically55,56
. In an analysis of data from a subgroup of subjects from this trial, we have shown that the lower weight gain experienced by older subjects is partially explained by their lower cumulative olanzapine dose57
The positive findings must be considered in relation to the absence of an antidepressant monotherapy arm and previous combination pharmacotherapy trials for MDpsy. Although most studies 12-14,16, 58-60
report poor response rates of MDpsy to TCA monotherapy, positive trials exist in patients with mood congruent delusions treated with high doses of amitriptyline61
. The generally poor responsiveness to TCA monotherapy has contributed to the conceptualization of MDpsy as a distinct entity15,35,59
and the recommendation for combination therapy10,11
, including in geriatric patients64
. Nevertheless, a meta-analysis of the only two trials comparing combination therapy to antidepressant monotherapy did not demonstrate the superiority of combination treatment. Although this meta-analysis did demonstrate greater efficacy for combination therapy compared to antipsychotic monotherapy21
, only one of the two trials that used an atypical antipsychotic medication19
was positive. Therefore, these results confirm and extend the results of the meta-analysis.
The TCA studies cited above were shorter then the twelve week duration of STOP-PD. It is possible that longer antidepressant monotherapy trials would result in higher remission rates. The present trial also differed in applying a two consecutive assessment criterion to assure that remission was sustained, which may have contributed to the absence of separation between olanzapine/sertraline and olanzapine/placebo before week eight. Nevertheless, the Ham-D analysis demonstrated that combination treatment was statistically superior on Ham-D scores from week two to week twelve without differences between the treatment arms in changes of SADS delusional scores at any time points. Therefore, the benefit of adding sertraline to olanzapine was specific for the rate of improvement of depressive symptoms.
The possible efficacy of SSRI monotherapy for unipolar delusional depression was suggested by a reported ITT remission rate of 72% with 150 mg/day of sertraline compared to only 27% for 40 mg/day of paroxetine28
. Methodological limitations in the trial design65
and a separate report that patients with MDpsy had a markedly lower response rate to 200 mg/day of sertraline than patients with nonpsychotic depression66
, highlight the need for additional trials to compare the efficacy of antidepressant monotherapy to combination treatment.
We have reported that pre-study antidepressant therapy was common among the first 100 study participants but that combination therapy was not24
. Without accounting for pre-study treatment, we cannot assess whether resistance to prior antidepressant therapy influenced response to either treatment.
Illness severity of participants, with most recruited as inpatients, rendered randomization to placebo only, and use of a placebo lead-in, impractical. The low placebo response rates in previous MDpsy trials (0%66 to 24.5%19) supported not including a placebo arm. Furthermore, the low early remission rate (<10% at week two) decreases the likelihood that a carry-over from pre-trial treatment contributed to these results.
Although patients with major depression associated with hallucinations but not delusions meet DSM IV criteria for MDpsy, the STOP-PD study required the presence of delusions. Therefore, we are unable to assess the efficacy of combination therapy for MDpsy associated with hallucinations only. Also, the study focused on patients with unipolar MDpsy and systematically excluded patients with histories indicating periods of either mania or hypomania. Therefore, the results cannot be generalized to bipolar psychotic depression.
The 45.2% rate of attrition is a limitation. Attrition was comparable to the 48.1% reported in placebo controlled antipsychotic trials68
, but higher than the approximately 35% overall rate estimated for antidepressant studies of nonpsychotic depression69
. Although the severity of illness among study participants, with 69.1% entering as inpatients, presumably contributed to the high rate of attrition, the lack of systematic follow-up data from subjects who prematurely discontinued the study limits both generalizeability and our ability to apply the results to inform clinical practice69, 70
. Mixed effects logistic regression was applied as the primary analytic strategy to allow for the use of all available data under the assumption of ignorable missingness69
The significantly higher attrition rate among olanzapine than olanzapine/sertraline subjects may be attributable to both more frequent discontinuations by investigators due to insufficient response and earlier self-withdrawal by individuals who were responding poorly to monotherapy. Also, considering symptoms as due to study medications rather than MDpsy may have contributed to the numerically greater frequency of discontinuation attributed to “intolerable side effects” in olanzapine/placebo subjects. The observation that 75.2% of instances of attrition occurred during the first six weeks indicates that the twelve-week trial length does not explain the high attrition rate
This trial applied an innovative and rigorous approach to defining remission in MDpsy. The two consecutive assessment remission criterion has been used in a previous MDpsy trial19
and a two week remission Ham-D cutoff of ≤10 has been used in ECT studies that included MDpsy subjects31,73
. The current study added a systematic assessment to assure delusions were resolved as a criterion for remission. In the absence of studies that assessed for the absence of delusions at more than one assessment, determination that delusions were not present at the second Ham-D remission assessment was considered an appropriately stringent remission criterion.
The remission rates of greater than 30% at week eight that rose to 41.9% at week twelve are comparable to those in studies summarized in recent meta-analyses comparing duloxetine71
to SSRI's for nonpsychotic depression. The potential benefit of acute combination pharmacotherapy relative to ECT, which is generally considered the treatment of choice for MDpsy, warrants consideration. The efficacy of ECT has been well-established, with a response rate of 87% when bilateral ECT is administered in academic centers31
. The public health significance of the acute efficacy of ECT is tempered by the rapid increase in depressive symptoms that occurs within days of completing a course of ECT73,74
and the markedly lower ECT remission rates (i.e., 30%-47%) reported in community settings75
. Therefore, evidence that a pharmacological treatment is efficacious offers physicians an alternative to ECT that may be preferred by some patients for reasons of stigma and practicality. Nevertheless, the adverse metabolic effects of atypical antipsychotic medications are problematic. Further study of the optimal duration of continued combination therapy is needed to balance the high risk of early relapse of MDpsy76,77
against the metabolic abnormalities and significant weight gain associated with atypical antipsychotic medications.