Cardiovascular Severe Hospitalization Stroke
*p < 0.02 □ Sertraline (n = 70) □ Placebo (n = 68)
Figure 23.4 The frequency of adverse medical events among patients treated for 1 year following acute stroke with sertraline or placebo. Cardiovascular events and hospitalization were significantly lower in the sertraline treated patients compared with the placebo group (from Rasmussen et al. 2003, reprinted with permission).
The frequency of adverse events was significantly influenced by the presence or absence of sertraline (Fig. 23.4). Using an intention-to-treat analysis, there was a significantly higher frequency of adverse cardiovascular events, including severe adverse events and rehospitalization for physical illness in the placebo, compared with the sertraline treated patients. Although this study did not report the death rate among sertraline versus placebo treated patients, it is unlikely that in a period of 1 year significant differences in treatment related death rate would have been discovered. This study is one of the most important studies to be reported in the treatment or prevention of poststroke depression because it is the first study to demonstrate both the ability of antidepressant treatment to prevent poststroke depression and decrease the frequency of comorbid physical illnesses particularly cardiovascular disorders. This finding is similar to that reported in patients with major depression following myocardial infarction in which the use of sertraline significantly reduced the number of adverse physical illnesses following myocar-dial infarction (Glassman et al. 2002).
The most recent prevention study was reported by Niedermaier et al. (2004). Patients with ischemic stroke received either mirtazapine (30 mg) (n = 35) or no medication (n = 35) in an open randomized design. Patients were started 1 day following stroke and re-examined 7,44,90,180,270 and 360 days later. Of the non-treated group, 144 of 233 completers (42%) developed DSM-IV major depression while only 2 of 31 (6%) completers in the treated group became depressed.
For many years, psychiatrists have been interested in prevention. There are numerous trials in the literature demonstrating the efficacy of antidepressant medication as well as psychological treatment in preventing recurrence of depressive disorder among patients who have had previous episodes of depression (Frank et al. 1990). This type of secondary prevention has been highly beneficial to patients with mood disorders. The ability to prevent the first onset of depression, however, has not previously been achieved in psychiatry because a high-risk population of patients could not be identified with sufficient risk to justify the administration of antidepressants in patients who had never experienced depression. Poststroke depression, however, represents a relatively unique population because of the high risk of developing depression within the first several years following stroke. The combined prevalence of major and minor depressive disorder as demonstrated in Chapter 6 is approximately 40% during the acute stroke period. In addition, among patients who have not developed a depression during the acute poststroke period, approximately 40% will develop depression between 3 months and 2 years following stroke (see Chapter 9 on delayed onset depressions). This indicates that over 2 years, there is a high risk for developing depression. Thus, the poststroke population is at sufficiently high risk for developing depression that primary prevention strategies are justified. The four studies presented in this chapter suggest that ser-traline, nortriptyline, mirtazapine and perhaps fluoxetine may be effective in preventing the development of depression in patients who would otherwise have developed poststroke depression. This represents the first time, to my knowledge, that primary prevention has been successful in psychiatry. As indicated in Chapters 13 and 14, successful treatment of poststroke depression improves both physical and cognitive recovery from stroke and as shown in Chapter 19, antidepressant treatment may reduce the death rate over 7 years following stroke by as much as 50%.
In summary, four studies have examined prevention of poststroke depression and three of the studies have provided evidence of the utility of preventing this disorder using nortriptyline, sertraline, mirtazapine or fluoxetine. Based on the adverse consequences of developing depression following stroke, these studies support the contention that all patients who have suffered an acute stroke should be placed on antidepressants to prevent the development of depression and enhance physical and cognitive recovery and reduce mortality. Furthermore the available data suggest that sertraline does not lead to adverse side effects or complication but, on the contrary, leads to fewer adverse events compared with the natural course of poststroke events. Thus, the benefit-to-risk ratio appears to be very large. Future studies will need to examine other pharmacological and non-pharmacological interventions to prevent the development of poststroke depression and to determine which treatments are most effective and have the greatest benefit-to-risk ratio. Treatments such as transcranial magnetic stimulation, psychological treatment (e.g., problem solving therapy), and a wide range of selective serotonin reuptake inhibitors or selective norepinephrine and serotonin reuptake inhibitors need to be examined to determine their efficacy in the prevention of poststroke depression. Prevention of poststroke depression may represent one of the major advances in the care of stroke patients.
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