Nortriptyline vs. Fluoxetine in Post-Stroke Depression
ABSTRACT & COMMENTARY
Source: Robinson RG, et al. Nortriptyline versus fluoxetine in the treatment of depression and in short-term recovery after stroke: A placebo-controlled, double-blind study. Am J Psychiatry 2000;157:351-359.
Depression is common among patients who have suffered an acute stroke, with slightly more than 40% of patients meeting criteria for a major depressive episode. While clinicians are aware of this problem, there are limited data on the effectiveness of antidepressants in treating post-stroke depression.
The present study evaluated 104 patients with acute stroke who were randomized in double-blind fashion to receive nortriptyline, fluoxetine, and placebo for 12 weeks. In order to determine whether improved recovery could be mediated by mechanisms unrelated to depression, both depressed and nondepressed patients were enrolled. Patients assigned to nortriptyline were started on 25 mg/d and gradually increased to 100 mg/d. The fluoxetine patients were initiated at 10 mg/d and gradually increased to 40 mg/d. Response to treatment of depression for individual patients was defined as a greater than 50% reduction in scores on the Hamilton Rating Scale for Depression and no longer fulfilling diagnostic criteria for major or minor depression. Improved recovery for a treatment group was defined as a significantly higher mean score from baseline to end of the treatment trial, compared with patients treated with placebo, on measures of impairment in activities of daily living and levels of cognitive and social functioning.
Among the 104 patients enrolled in the study, 66 were diagnosed with depression. Of the 23 patients assigned to fluoxetine, 14 completed the 12-week trial. Of the 16 and 17 patients assigned to nortriptyline and placebo, respectively, there were 13 completers in each group. Although fluoxetine had a significantly higher dropout rate, it appeared equally tolerated compared to nortriptyline and placebo; several patients who had dropped out simply refused treatment. Among completers, the successful treatment rate was 10 of 13 (77%) for nortriptyline, two of 14 (14%) for fluoxetine, and four of 13 (31%) for placebo. Although there were no differences between fluoxetine and placebo at any time point, nortriptyline was superior to placebo and fluoxetine at 12 weeks of treatment and to placebo at nine weeks of treatment (P < 0.05). Nortriptyline was also significantly superior to fluoxetine and placebo in improving anxiety symptoms as well as in improving recovery of daily activities. There was no effect of nortriptyline or fluoxetine on recovery of cognitive or social functioning among depressed or nondepressed patients.
Comment by Michael F. Barber, PharmD
Clearly, in terms of efficacy, the results of this study favor nortriptyline over fluoxetine in post-stroke depression. Typically, fluoxetine is considered more tolerable than nortriptyline in elderly patients. Nortriptyline, a secondary amine tricyclic antidepressant (TCA), causes sedation, orthostasis, and anticholinergic effects; however, these effects are usually less pronounced than tertiary amines such as imipramine and amitriptyline. Usually, this difference in tolerability, as well as the potential for arrhythmias, seizures, and fatality in overdoses results in the selection of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, rather than a TCA for depressed patients. However, the results of this trial do not support this practice. Perhaps the initial dose of 25 mg/d and careful titration to a total daily dose of 100 mg enhanced the tolerability of nortriptyline. Moreover, fluoxetine tended to worsen rather than improve anxiety and depression scores in this trial. It is unclear whether this striking difference in efficacy would extrapolate to the other SSRIs. Although fluoxetine has recently been given approval for the treatment of geriatric depression, at this time it cannot be recommended for post-stroke depression.
In summary, more data are needed to be able to derive clear recommendations on the first-line therapy of post-stroke depression. Based on the available data, nortriptyline should be initially considered for post-stroke depression; if it is found to be inappropriate (i.e., patient with cardiovascular disease or suicidal intent), SSRIs other than fluoxetine may be considered.
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