Antidepressants Improve Post-Stroke 'Thinking Outside Box'

Antidepressant treatment appears to help stroke survivors with the kind of complex mental abilities often referred to as "thinking outside the box," according to a University of Iowa study.

The antidepressants' effects on study participants' abilities were independent of any changes in depression. In addition, the improvements in complex mental abilities were not seen immediately but during the course of 21 months after the treatment ended. The study results appear in the March 2007 issue of the British Journal of Psychiatry.

Antidepressant treatment already was known to improve mood in depressed post-stroke patients, but such therapy had not been examined on executive function in people with clinically diagnosed stroke, said Sergio Paradiso, M.D., Ph.D., the study's corresponding author and assistant professor of psychiatry at the UI Carver College of Medicine.

"We found that people diagnosed with stroke who often have a decline in 'executive function', that is, those mental abilities that enable us to respond appropriately to unfamiliar or complex situations, and support several cognitive, emotional and social capacities, showed improvement after receiving a 12-week treatment with antidepressants," Paradiso said.

Executive functions come into play, for instance, when we plan to take an alternative route home due to unexpected detours. This brain function involves stopping ingrained behavior, such as trying to take your usual route home. People with stroke often show impairments in executive function and may not be able to respond well to non-routine situations. This impairment may affect rehabilitation efforts.

The UI team included Kenji Narushima, M.D, Ph.D., UI resident physician in psychiatry, who contributed significantly to the study.

The study began with 47 patients who had had a stroke during the previous six months. These individuals were divided into three groups and randomly assigned (with the exception of those with certain medical conditions) to take the antidepressant fluoxetine (Prozac), the antidepressant nortriptyline (Aventyl or Pamelor) or a placebo (inactive substance).

Their executive functions were assessed using standard neuropsychological tasks at the end of 12 weeks of treatment, and again two years after the study had started. A total of 36 patients completed all the evaluations.

No significant differences were found between the antidepressant and placebo groups at the end of treatment. However, 21 months after the treatment ended, the placebo group showed continued worsening of the executive functions, whereas the group treated with antidepressants had clear and significant improvement, regardless of how their depressive symptoms changed.

"We were somewhat surprised to initially not find any difference after the first 12 weeks of treatment. It took another 21 months after the initial treatments for the antidepressants to have a detectable effect," Paradiso said.

The investigators hypothesize that antidepressants may foster recovery of neural tissue not directly destroyed by the stroke, yet because the process is slow, it takes months.

"Drugs such as antibiotics start working right away to kill germs. However, antidepressants may be reorganizing brain structure and re-establishing neuronal connections that were lost because of the death of neurons due to the stroke," Paradiso said. "We expect this regeneration to happen in longer, rather than brief, periods of time.

"We really appreciate the patients who made the commitment to participate in this two-year-long study while they were in their post-stroke recovery. The information we've learned will help us develop new studies," he added.

The researchers plan to examine individuals who responded favorably to the antidepressants and look noninvasively for brain changes.

"We can do functional and structural brain imaging studies using different technologies, including relatively new techniques that quantify chemicals in the brain," Paradiso said.

In addition to Paradiso and Narushima, the study involved UI researchers in psychiatry: David Moser, Ph.D., associate professor; Ricardo Jorge, M.D., assistant professor; and Robert G. Robinson, M.D., department head and the Paul W. Penningroth Professor of Psychiatry.

The study was supported in part by grants from the National Institute of Mental Health, part of the National Institutes of Health. Paradiso is additionally supported by the Edward J. Mallinckrodt Jr. Foundation and an NIH Institutional Career Development Award (K12).