Although universal preventive intervention has been a long-standing goal in psychiatry, there has not been a double-blind study that has demonstrated prevention of a psychiatric disorder. However, this study has demonstrated that depression can be significantly decreased in frequency by preventive use of escitalopram compared with placebo over the first year following an acute stroke, using double-blind methodology. In an open treatment group, we also found that problem-solving therapy significantly increased the time to onset of depression during the first year following stroke. Based on these results, we calculated that 7.2 stroke patients would need to be treated with escitalopram or 9.1 patients with problem-solving therapy to prevent 1 case of depression. This could be compared with preventive intervention in cardiology in which 40 male patients with hypercholesterolemia would need to be treated with pravastatin for 5 years to prevent 1 myocardial infarction.38
Before discussing the implications of these findings, the limitations of this study need to be acknowledged. First, the patients selected for the study did not include all patients with acute stroke. Patients with life-threatening comorbid physical illness, such as cancer or severe cardiac arrhythmia, were excluded. Similarly, patients with severe impairment in verbal comprehension or patients who had already developed a depressive disorder were excluded. Thus, our findings might not be applicable to all patients with stroke. However, as noted in , we included patients with multiple system illnesses and a representative range of stroke mechanisms and severity.
Second, the study included a relatively small sample size and the number of incident depression cases was also relatively small. Thus, further studies of prevention of poststroke depression are needed.
Third, our psychological treatment group could not be blinded except that the rater did not administer the treatment. Furthermore, there was no appropriate control for problem-solving therapy to account for the nonspecific effects of time and attention. It is possible, therefore, that some treatment bias may have influenced our findings with the problem-solving therapy group.
A fourth limitation is that the majority of patients were enrolled in Iowa (ie, 74%) and therefore the Iowa data had the greatest effect on outcomes. However, we found no statistically significant effect of treatment site on outcome.
A fifth limitation of this study is that a total of 51 patients out of the 200 who signed the informed consent form dropped out before receiving any treatment. Furthermore, following initiation of treatment, 15 of 149 patients (10.1%) dropped out during a 1-year treatment protocol. Thus, the loss of 33% of our study population may have influenced our results. This overall dropout rate, however, was lower than the 48.9% dropout rate in the study by Rasmussen et al12
and the 45.9% dropout rate in the study by Almeida et al11
and appears to have given us the statistical power needed to show a treatment effect.
Given these limitations, what are the implications of the current findings? Perhaps the first question is why this prevention trial worked while others failed to show a significant preventive effect. The mean age of the treated patients in the study by Rasmussen et al was 72 years (SD=9.1) and in the study by Almeida et al was 67 years (SD=13) while the mean age of our escitalopram-treated group was 62 years (SD=13). Although the measures of physical impairment in those studies were different from ours, the severity appears somewhat greater than ours. Thus, it is possible that our population differed from those of the other studies, which could explain the differences in prevention rates. Conversely, our increased sample size, as well as the medication selected and the dosage prescribed, may have led to successful preventive treatment in this population that was elderly and sometimes very frail. For example, Andersen et al39
demonstrated that citalopram was superior to placebo in the treatment of acute poststroke depression. Patients aged 65 years and older were given 10 mg of citalopram and those younger than 65 years were given 20 mg of citalopram. These relatively low doses of citalopram may have been particularly well suited for this patient population. Furthermore, in our previous study of treatment of poststroke depression,40
we used doses of as much as 40 mg of fluoxetine for all patients in that treatment group and found no effect of fluoxetine vs placebo for depression, but did find that fluoxetine produced a mean (SD) weight loss of 6.8 (3.6) kg, which was not seen with nortriptyline or placebo.40
The rates of gastrointestinal effects in the current study were not significantly different from placebo. It should also be acknowledged that the current study included a problem-solving therapy group that the other prevention studies did not have. It seems unlikely, however, that this influenced the overall study results. A recent 8-week nonblinded study of problem-solving therapy for preventing depression in older adults with macular degeneration also reported positive results for this treatment.41
The effects of problem-solving therapy, however, were lost over a 6-month follow-up period.41
In contrast to our study, the macular degeneration prevention protocol did not include reinforcement sessions. Thus, some form of maintenance problem-solving therapy may be necessary for long-term prevention.
The second logical question is what may be the consequence of prevention of poststroke depression? Since 1993, there have been at least 4 reports demonstrating an association of poststroke depression with increased mortality.42–45
For example, we reported in a 10-year follow-up of 103 patients with acute stroke that patients with acute-onset major or minor depression were more likely to die than patients who were without depression after the acute stroke, even after controlling for age, sex, marital status, socioeconomic status, cognitive impairment, activities of daily living impairment, previous and comorbid physical illness, stroke type, and stroke volume (adjusted OR, 3.7; 95% CI, 1.1–12.2; P
Subsequently, House et al44
examined 448 patients with acute stroke and found that at 2 years follow-up, patients with 1 or more symptoms of depression on the General Health Questionnaire46
were significantly more likely to have died compared with patients with no depressive symptoms even after controlling for older age, lower Mini-Mental State Examination scores, lower Barthel score, prior stroke, and urinary incontinence (OR, 2.2; 95% CI, 1.2–4.0; P
=.009). In a recent study of 104 acute stroke patients with or without depression, however, we found that 12 weeks of treatment with fluoxetine (20–40 mg) or nortriptyline (50–100 mg) significantly reduced the mortality rate at 7 to 9 years follow-up even after controlling for age, stroke type, comorbid physical illness, and diabetes mellitus.47
Whether prevention of post-stroke depression might lead to increased survival is an important issue for further investigation.
Although the mechanism by which escitalopram and problem-solving therapy were able to decrease the frequency of poststroke depression is unknown, it is possible that the mechanism for the treatment of acute depression may be different. Antidepressants have been associated with enhanced recovery in executive function,48
as well as recovery in activities of daily living49
independent of depression. In addition, it has been hypothesized that antidepressant effects on neuroplasticity50
mediate both recovery from depression as well as motor and cognitive recovery through different mechanisms.51
Perhaps prevention of depression may be another example of this alternative mode of action. Alternatively, one might also hypothesize, based on the study of macular degeneration, that regaining ability to facilitate valued activities may have led to a preventive effect on depression in patients receiving problem-solving therapy.41
In conclusion, this study has demonstrated that poststroke depression can be effectively prevented in a significant number of patients by administering escitalopram or problem-solving therapy during the first year following stroke. To our knowledge, this may be the first demonstration of selective prevention of a psychiatric disorder with adequate blinding for 2 of the 3 treatment groups. The 9 patients with prior history of depression clearly had maintenance intervention. However, the majority of patients had no prior history of mood disorder and this intervention protected them from depression. One might also question whether preventive intervention in all stroke survivors is superior to early detection and treatment. Although only a randomized controlled trial would answer this question, the major obstacle to early detection is that studies that have examined the detection of depression during standard stroke care have found that the vast majority of depression cases were overlooked by the treating physicians.52,53
The clinical implications of our findings are that patients who are given escitalopram or problem-solving therapy following acute stroke may be spared depression and perhaps its adverse consequences.