Clinical trials
Olanzapine plus sertraline as first-line pharmacotherapy for MDD with psychotic features. Meyers et al11 reported on a double-blind randomized comparison of olanzapine plus placebo vs olanzapine plus sertraline in 259 patients with MDD with psychotic features. An unusual feature of this trial is that it included a similar number of younger and older participants (ages 18 to 93): 117 participants were age <60 (mean age [standard deviation (SD)]: 41.3 [10.8]) and 142 were age ≥60 (mean age [SD]: 71.7 [7.8]). The same dose titration schedules based on efficacy and tolerability were used in both younger and older participants. At the end of the study, the mean dose (SD) of sertraline (or placebo) did not differ significantly in younger (174.3 mg/d [34.1]) and older participants (165.7 mg/d [43.4]). However, the mean dose (SD) of olanzapine was significantly higher in younger patients (15.7 mg/d [4.7]) than in older participants (13.4 mg/d [5.1]).
In both age groups, olanzapine plus sertraline was more efficacious than olanzapine plus placebo, and there was no statistical interaction between age, time, and treatment group (ie, the trajectories of improvement were similar in older and younger patients receiving either olanzapine or olanzapine plus sertraline). Similarly, drop-out rates because of poor tolerability did not differ significantly in younger (4.3%) and older participants (5.6%). However, in a multinomial regression, older participants were more likely to discontinue treatment because of poor tolerability.22 Older participants were significantly less likely to experience weight gain (mean [SD]: +3.3 [4.9] vs +6.5 [6.6] kg) or an increase in fasting glucose and more likely to experience a fall, pedal edema, or extrapyramidal symptoms.11,22-24 Cholesterol and triglyceride increased significantly and similarly in both age groups. The incidence of symptoms of tardive dyskinesia (TD) over the 12-week trial was low (<5%) in both younger and older participants, and clinically diagnosed TD was reported in only 1 (older) participant.25
Venlafaxine plus aripiprazole for treatment-resistant MDD. In the largest double-blind randomized study of augmentation pharmacotherapy for late-life treatment-resistant depression published to date, Lenze et al21 compared venlafaxine plus aripiprazole vs venlafaxine plus placebo in 181 patients age >60 (mean age 66, with 49 participants age >70) with MDD who did not remit after 12 weeks of treatment with venlafaxine (up to 300 mg/d). After 12 weeks of augmentation, remission rates were significantly higher with aripiprazole than with placebo: 40 (44%) vs 26 (29%); odds ratio (95% confidence interval [CI]): 2.0 (1.1 to 3.7). The median final aripiprazole dose was 7 mg/d (range 2 to 15 mg/d) in remitters and 10 mg/d (range 2 to 15 mg/d) in nonremitters.
Five of 90 participants (5%) discontinued aripiprazole (1 each: suicide, jitteriness/akathisia, worsening parkinsonism; and 2 withdrew consent); 8 of 90 (9%) discontinued placebo (2 each: lack of efficacy, headache; 1: worsening parkinsonism; and 3 withdrew consent). The completed suicide occurred after 5 weeks of treatment with aripiprazole and was judged to be “neither due to emergent suicidal ideation nor to aripiprazole side-effects, but was concluded by investigators to be a result of the individual’s persisting and long-standing suicidal ideation.”21 Including the suicide, there were 4 serious adverse events (5%) in those receiving aripiprazole (1 each: suicide, congestive heart failure, mild stroke, and diverticulitis) and 2 (2%) in those receiving placebo (1 each: myocardial infarction, hospitalized for vomiting due to accidentally taking extra venlafaxine). In 86 participants receiving aripiprazole and 87 receiving placebo, the most frequently reported adverse effects were increased dream activity (aripiprazole: 23 [27%] vs placebo: 12 [14%]), weight gain (17 [20%] vs 8 [9%]), and tremor (5 [6%] vs 0). Akathisia and parkinsonism were observed more frequently with aripiprazole than with placebo (akathisia: 24 [26%] of 91 vs 11 [12%] of 90; parkinsonism: 15 [17%] of 86 vs 2 [2%] of 81). Akathisia was generally mild and resolved with dose adjustment; however, it was associated with a transient increase in suicidality in 3 (3%) participants receiving aripiprazole vs 0 receiving placebo and persisted at the end of the trial in 5 (5%) participants receiving aripiprazole vs 2 (2%) receiving placebo. Participants receiving aripiprazole had a significantly larger increase in weight (mean [SD]: +1.93 [3.00] vs +0.01 [3.15] kg), but there were no differences between aripiprazole and placebo in changes in body fat, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, glucose, insulin concentration, or QTc.
Citalopram plus risperidone for treatment-resistant MDD. Alexopoulos et al26 reported an analysis of data from 110 patients age ≥55 years (mean age [SD]: 63.4 [4.8]), among 489 mixed-age patients with MDD. Participants (n = 110) who did not respond to 1 to 3 antidepressants (venlafaxine, sertraline, mirtazapine, fluoxetine, paroxetine, or bupropion in >90%) during their current depressive episode completed 4 to 6 weeks of treatment with citalopram up to 40 mg/d; 93 did not respond and were treated with open-label risperidone (0.25 to 1 mg/d) augmentation for 4 to 6 weeks. Sixty-three (68%) of these 93 patients remitted and were randomized to 24 weeks of double-blind continuation treatment with citalopram plus risperidone vs citalopram plus placebo. Neither the median times to relapse (105 vs 57 days) nor the relapse rates (risperidone: 18 of 32 [56%] vs placebo: 20 of 31 [65%]) differed significantly. During the open-label risperidone augmentation, the most common adverse events were dizziness and dry mouth (n = 9 each, 9.7% of 93). During the continuation phase, headache (n = 3; 9.1% of 32) was observed with risperidone but not with placebo (n = 0). There was no incident parkinsonism or abnormal movements noted, but risperidone was associated with weight gain during both the open-label risperidone augmentation phase (mean [SD]: +0.9 [2.1] kg) and the continuation phase (risperidone: +0.8 [3.5] vs placebo: −0.3 [2.8] kg).
Quetiapine XR monotherapy for MDD. Katila et al27 reported on a placebo-controlled RCT of quetiapine XR (median dose, 158.7 mg/d; range, 50 to 300 mg/d) in 338 patients age ≥66 years (mean age [SD], 71.3 [7.5]) presenting with MDD and a major depressive episode with a duration <1 year and no history of failed antidepressants trials from 2 classes (more than two-thirds of participants had not received treatment). After 9 weeks, the reduction in depressive symptoms on the Montgomery-Åsberg Depression Rating Scale was significantly larger with quetiapine XR than with placebo (mean [SD]: −16.0 [9.3] vs −9.0 [9.9]). There were congruent, significant differences between quetiapine and placebo in terms of response rate (quetiapine XR: 105 of 164 [64%] vs placebo: 52 of 171 [30.4%]) and remission rate (92 of 164 [56.1%] vs placebo: 40 of 171 [23.4%]). The drop-out rates for all causes were similar, but the drop-out rate attributed to adverse events was higher with quetiapine than placebo (16 of 166 [9.6%] vs 7 of 172 [4.1%]). Most quetiapine drop-outs were attributable to dizziness, headache, and somnolence (n = 4 each), and placebo drop-outs were because of headache (n = 2). Consistent with the profile of quetiapine, adverse events with a rate that was at least 5% higher with quetiapine than with placebo included somnolence (64 of 166 [38.6%] vs 16 of 172 [9.3%]), dry mouth (34 [20.5%] vs 18 [10.5%]), and extrapyramidal symptoms (12 [7.2%] vs 4 [2.3%]). Changes in weight and laboratory test results (eg, glucose, lipid profile) were minimal and not clinically meaningful.
Other clinical data. The efficacy and relatively good tolerability of aripiprazole in older patients with treatment-resistant depression observed in the RCT by Lenze et al21 is congruent with the earlier results of 2 small (N = 20 and 24) pilot studies.18,19 In both studies, the remission rate was 50%, and the most prevalent adverse effects were agitation/restlessness/akathisia or drowsiness/sedation. Similarly, in a post hoc pooled analysis of 409 participants ages 50 to 67 from 3 placebo-controlled randomized trials, the remission rate was significantly higher with aripiprazole than with placebo (32.5% vs 17.1%), and the most common adverse effects were akathisia or restlessness (64 of 210 [30.4%]), somnolence (18 [8.6%]), and insomnia (17 [8.1%]).20