Major depressive disorder is diagnosed in 5% to 26% of terminally ill patients. This disorder causes suffering, and is associated with suicidality, increased pain, and increased caregiver burden and caregiver depression. Treatment of depression in cancer patients in hospice and palliative care is complicated by shortened life expectancy. Currently-approved antidepressants take several weeks to become effective. Methylphenidate has been reported in case series and very small randomized trials in patients without cancer, as a rapidly effective treatment for depression in medically ill patients. There are no randomized controlled trials to test this agent in terminally ill cancer patients.
To determine the effectiveness and safety of methylphenidate for depression treatment in cancer patients receiving hospice and palliative care.
We conducted an 18-day randomized, double-blind, fixed-dose (10 mg bid), placebo-controlled clinical trial of methylphenidate for depression in eligible veteran and non-veteran cancer patients with advanced cancer in the following settings: inpatient and outpatient hospice and inpatient and outpatient palliative care. We documented the safety and tolerability of methylphenidate in these patients. Eligible patients who answered yes to the question "are you sad or depressed" were invited to participate. They completed measures of depression [Structured Clinical Interview for Diagnosis (SCID), Montgomery-Asberg Depression Rating Scale (MADRS) as primary outcome, Hospital Anxiety and Depression Scale as secondary outcome)], and cognition at baseline. MADRS score had to be greater than 19 and SCID positive for depression at study entry. Subjects were randomized to either methylphenidate plus an selective serotonin reuptake inhibitor (SSRI), or placebo plus an SSRI. Patients continued any previously prescribed SSRI, or were prescribed citalopram if untreated. Participants were evaluated with the same measures as baseline on days 3, 6, 12 and 18 of the study. Cox proportional hazard analysis was used to analyze the primary outcome.
Enrollment started February 1, 2005. Forty-six subjects were enrolled. Because enrollment was lower than anticipated, we added all cancer clinics at OHSU in order to increase subject enrollment. Seventy-eight percent of subjects were men, and their mean age was 64 years.
The mean time to remission of depression was 10.3 days (SE = 1.77) in the methylphenidate group and 8.1 (SE = 1.31) for the placebo group (p = 0.38, log rank test). The response to placebo was high, suggesting that even with larger number of patients our original analytic approach would not have been able to show a difference. For example, by day six of the study 69% placebo patients and 54% of the methylphenidate subjects no longer met depression criteria. However, after first remission, 5 placebo groups relapsed, where as only 1 methylphenidate patient relapsed to depression. By day 18, 84.6% of methylphenidate patients were in remission, compared to 60% of placebo patients (p = NS). On the HADS the mean score for each group was 10.4 on screening, but had declined to 6.8 on day 18 in the methylphenidate group and 8.1 on day 18 in the placebo group (p = NS).
Because of the correlated nature of the data, we tested for linear trend in the MADRS scores over time using Generalized Estimation Equation modeling. The overall test for linear trend in both the placebo and methylphenidate groups revealed a significant decreasing linear trend (p <0.0001). When restricting the analysis to the placebo group only, the linear trend test revealed a significant decreasing trend (estimated mean = -1.05; p = 0.0002). When restricting the analysis to the methylphenidate group only, the linear trend test also revealed a significant decreasing trend (estimated mean = -1.57; p = 0.0007). The mean decrease was slightly higher in the methylphenidate group.
Alternative study design may be needed to determine the effectiveness of psychostimulants for depression in advanced cancer.
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