Antidepressants Evidence Salutary Effects for Stroke Patients

July 1, 2007

The results of two recent studies suggest that antidepressant medication may have an expanded role in the management of stroke patients. Prophylactic use of antidepressants following stroke appeared in a meta-analysis to be effective in fending off depression, and a short course of antidepressants in a placebo-controlled study was associated with long-term restoration of executive function, independent of depressive symptoms.

The results of two recent studies suggest that antidepressant medication may have an expanded role in the management of stroke patients. Prophylactic use of antidepressants following stroke appeared in a meta-analysis to be effective in fending off depression, and a short course of antidepressants in a placebo-controlled study was associated with long-term restoration of executive function, independent of depressive symptoms.

Administering antidepressants before the onset of depressive symptoms to avert poststroke depression (PSD) should be considered along with vascular preventive strategies, according to the authors of a meta-analysis published in International Clinical Psychopharmacology.1 Yan Chen and colleagues from the University of Cincinnati College of Pharmacy note that depression often emerges after stroke and complicates rehabilitative outcomes but can be difficult to recognize in the presence of the impaired cognition, language, and functioning that may follow a cerebrovascular injury.

"Given this, as well as the high incidence rates and consequences of PSD," the authors suggested, "antidepressant prophylaxis in patients with stroke may represent a viable prevention strategy."1

In an earlier meta-analysis, Chen and colleagues2 had affirmed the effectiveness of antidepressant treatment in reducing poststroke depressive symptoms. In their current meta-analysis of 10 randomized clinical trials with 703 nondepressed stroke patients, poststroke depression developed in 12.5% of patients receiving antidepressants compared with 29% of controls.1

The data were insufficient, however, to discern whether earlier initiation of antidepressant treatment, within 4 to 6 weeks of a stroke, has greater prophylactic effect, as has been posited.3 It also remains unclear whether longer duration of antidepressant treatment, which has been associated with greater reduction in poststroke depressive symptoms,2 is also better for sustaining prophylaxis.

Chen and colleagues found reduced rates of PSD in patients who received either tricyclic or SSRI antidepressants, but added a cautionary note that the SSRIs have also been associated with bleeding complications from depletion of serotonin in platelets and should therefore be avoided in hemorrhagic stroke patients. The investigators noted that most studies of antidepressant treatment of PSD have involved patients who had sustained ischemic rather than hemorrhagic cerebrovascular injury, although there is no evidence that these conditions differ in their risk for depression.

Antidepressants enhance executive function


In a separate study published in the British Journal of Psychiatry, Kenji Narushima, MD, and colleagues,4 from the department of psychiatry at the University of Iowa in Iowa City, reported that antidepressant treatment improves executive function after stroke, independent of depressive symptoms. Narushima and Robinson5 had previously found that antidepressant treatment improved physical functioning for stroke patients. After reviewing evidence of antidepressant modulating effects on frontal cortical-subcortical circuits and possible effects on neurogenesis, their group undertook what they believe is the first study to determine whether antidepressants contribute to restoring executive function.

An executive function index was established with a battery of tests to assess initiation and psychomotor speed, conceptualization and problem solving, and attention and working memory; the tests included the Controlled Oral Word Association test, the Wisconsin Card Sorting Test perseverative errors, and the Wechsler Adult Intelligence Scale-Revised. Depressive symptoms were assessed with the 17-item Hamilton Rating Scale for Depression.

In this placebo-controlled study of 47 patients who had experienced a stroke during the prior 6 months, there was no apparent treatment effect on executive function at the end of a 12-week course with either the SSRI, fluoxetine (Prozac), or the tricyclic, nortriptyline (Pamelor, Aventyl). At the 24-month follow-up, however, those who had received either antidepressant demonstrated significantly improved executive function, while all but 1 patient who had received placebo were found to have deteriorated.

The apparent delay in treatment effect is not inconsistent with the time needed to restore neuron integrity and function and the putative mechanisms of antidepressants for remediation. The investigators cited evidence of antidepressant action, for example, in enhancing the effects of brain-derived neurotrophic factor (BDNF) on neuron development, survival, and function.6 The activation of BDNF and corresponding receptors has been found necessary for antidepressant effect and is posited as a basis for the delayed behavioral effects of antidepressants.

Impaired executive function is a common sequela of stroke, confounding the patient's capacity to respond appropriately to unfamiliar and complex situations and to progress in rehabilitation. Narushima and colleagues posit that antidepressants could preserve executive function by modulating frontal cortical-subcortical circuitry and/or enhancing neurotrophin-mediated mechanisms. Their findings that antidepressants both improve and prevent decline of executive function, they conclude, "have important implications for the neuropsychiatry of stroke and rehabilitation medicine."

References:

References

1.

Chen Y, Patel NC, Guo JJ, Zhan S. Antidepressant prophylaxis for poststroke depression: a meta-analysis.

Int Clin Psychopharmacol

. 2007;22:159-166.

2.

Chen Y, Guo JJ, Zhan S, Patel NC. Treatment effects of antidepressants in patients with post-stroke depression: a meta-analysis.

Ann Pharmacother

. 2006;40: 2115-2122.

3.

Anderson CS, Hackett ML, House AO. Interventions for preventing depression after stroke.

Cochrane Database Syst Rev

. 2004;2:CD003689.

4.

Narushima K, Paradiso S, Moser DJ, et al. Effect of antidepressant therapy on executive function after stroke.

Br J Psychiatry

. 2007;190:260-265.

5.

Narushima K, Robinson RG. The effect of early versus late antidepressant treatment on physical impairment associated with poststroke depression: is there a time-related therapeutic window?

J Nerv Ment Dis

. 2003; 191:645-652.

6.

Saarelainen T, Hendolin P, Lucas G, et al. Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects.

J Neurosci

. 2003;23:349-357.