In this sample of nonresponders to escitalopram monotherapy, 50% of the depressed older adults responded fully to open-label duloxetine “rescue” pharmacotherapy by 16.5 weeks, and another 17.5% responded partially. Reported side effects as measured by the UKU decreased over time. Five of the 40 subjects (12.5%) discontinued duloxetine because of intolerable side effects or adverse events.
Our finding that 50% of the subjects responded to the rescue pharmacotherapy with duloxetine is consistent with reports that the majority of older depressed patients will eventually respond to stepped care with antidepressant pharmacotherapy.3,5,18,19
Indeed, our group has reported that 42% of older adults (N = 5) who were nonresponders to open-label treatment with paroxetine responded to open-label venlafaxine XR.4
It is notable that the median dose of duloxetine was 90 mg/day. This dose is in contrast to the package insert for duloxetine that states, “There is no evidence that doses greater than 60 mg/day confer any additional benefits.”20
The higher median dose in our study reflects the operationalized titration schedule used. However, our study suggests that higher doses and/or longer exposure may be necessary to achieve a response to duloxetine in older adults who do not respond to treatment with an SSRI and require rescue pharmacotherapy with a dual-mechanism agent. Our observations that higher doses may result in improved effectiveness and still be tolerated are consistent with work reported by Wohlreich et al.7
The observed decrease in anxiety scores in our duloxetine-treated cohort is consistent with the report by Nelson et al.6
that, among older adults with MDD, the difference on the anxiety subscale of the HAM-D-17 between the duloxetine-treated and placebo-treated groups neared statistical significance after 9 weeks of treatment (t = −2.00, p = .051). It is notable that anxiety symptoms predict diminished acute treatment response and increased recurrence in elderly patients with MDD. We previously reported, in this cohort using open-label escitalopram, that greater severity of anxiety symptoms (both psychological and somatic) and lower self-esteem predicted worse response status after 6 weeks of treatment even after controlling for other variables.21
Our group has also examined the effects of comorbid anxiety on both acute treatment: response and recurrence of MDD during 2 years of maintenance treatment with paroxetine or placebo.22
We found that patients with greater pretreatment anxiety took on average 4.3 weeks longer to respond to depression treatment and had higher rates of recurrence of depression during maintenance treatment.22
Within this context, 1 possible explanation for the success of duloxetine as a rescue agent may be that it provides greater anxiolysis than escitalopram, even though both agents have recently received approval by the U.S. Food and Drug Administration for the treatment of generalized anxiety disorder.20,23
We were unable to test the differential decrease in anxiety scores between the duloxetine responders and nonresponders without an additional available anxiety assessment instrument. Future work to assess anxiety over time using more sensitive and validated anxiety assessment instruments such as the Hamilton Rating Scale for Anxiety or the anxiety sub-scale from the Hospital Anxiety and Depression Scale24
In our study, the median time to response to duloxetine rescue therapy was 12 weeks. While 12 weeks may seem like an extended period of time to achieve response for an older patient suffering from depression, this delayed but robust response is consistent with an earlier report from our group, which found that older patients with MDD treated with nortriptyline appear to benefit as much as, but perhaps more slowly than, midlife patients treated with imipramine.19
It should also be noted that subjects in this report had been depressed for a mean duration of 251.8 weeks prior to starting treatment with escitalopram. Greater duration of depressive episode in nongeriatric adults is associated with longer time to response.25,26
Taken into context, for this sample, the median time to achieve antidepressant response after being switched to duloxetine was 5% of the mean duration of the index episode prior to seeking treatment.
Five participants (12.5%) discontinued duloxetine because of intolerable side effects or adverse events. This rate of discontinuation is consistent with that reported in a study using duloxetine at recommended doses (40–60 mg/day)27
and is less than what has been reported in a study utilizing higher doses (80–120 mg/day).7,28
Of note, there was a statistically significant decrease in reported somatic symptoms during treatment as measured with the UKU.
In a recently published article by Raskin et al. comparing duloxetine 60 mg/day with placebo in older adults with MDD,29
the rates of discontinuation due to adverse events were 9.7% versus 8.7% for placebo. It is possible that since all of our subjects received escitalopram immediately prior to treatment with duloxetine, they were less susceptible to the troubling side effects frequently encountered when starting an antidepressant de novo. This hypothesis is supported by a report that the rate of discontinuation caused by adverse events among patients switched to duloxetine from an SSRI or venlafaxine was significantly lower than that in patients initiating duloxetine therapy (6.3% vs. 16.1 %, p = .018).30
Despite the 12.5% discontinuation rate due to side effects and adverse events, neither the total nor any of the subscales of the UKU indicated more somatic problems during treatment. In fact, there was a decrease in severity between initiation and end of duloxetine therapy for the total score, psychological subscale, and other systems subscale, suggesting that the level of reported somatic preoccupation decreased during the course of treatment. To put these findings into context, in another sample of older adults treated with paroxetine, the mean UKU total score (minus the psychological subscale) at baseline was 8.8.3
Thus, the patients in this report may be a more somatically preoccupied sample. Our group has previously found similar improvements in the UKU scales in elderly subjects with or without comorbid anxiety receiving paroxetine or nortriptyline.17
Thus, it is unclear whether this decrease in UKU scores represents improvement in depression or a somatic benefit of duloxetine itself. This finding is important because older adults frequently present with depression comorbid with unpleasant bodily sensations and somatic preoccupation.31
There are several limitations to this analysis. We cannot rule out the possibility that subjects’ expectations may have inflated the rate of response in this open-label trial. In addition, because this report is of uncontrolled open-label data, we cannot rule out the possibility that response was due to spontaneous improvement of their depression unrelated to the medication. Descriptions of spontaneous response rates in older depressed patients are needed to put open-label findings into perspective. To our knowledge, such data have not been reported. Finally, the relatively small size of the sample may have resulted in unstable estimates of response rates.
In summary, our data suggest that duloxetine may be a good “rescue” pharmacotherapy for older adults who either do not respond to or do not tolerate treatment with escitalopram. Furthermore, duloxetine appears to be well tolerated even at the higher doses used in this study. Achieving response by switching antidepressant medications instead of augmenting3
or combining antidepressants, especially in older adults, may have several practical benefits. Among these are expense (the patient only has to buy 1 medication), safety (polypharmacy and the increased risks of side effects and adverse events are minimized), and increased adherence (fewer pills, fewer missed doses). The next step in evaluating the efficacy of duloxetine as a potent rescue pharmacotherapy is a randomized, double-blind, placebo-controlled trial to minimize the risk of expectation bias on the part of both subjects and investigators.