From Medscape CME Clinical Briefs
SSRI Shows Promise as Restorative Therapy Following Stroke CME
News Author: Caroline Cassels
CME Author: Désirée Lie, MD, MSEd

 
CME Released: 02/09/2010

February 9, 2010 — The selective serotonin reuptake inhibitor (SSRI) escitalopram appears to enhance cognitive recovery following stroke, suggesting this class of medications may be an effective restorative therapy for this patient population.

A randomized controlled trial conducted by investigators at the University of Iowa in Iowa City shows that nondepressed stroke patients who received relatively low doses of escitalopram experienced an improvement in global cognitive functioning, specifically in verbal and visual memory functions, compared with their counterparts who received placebo or who underwent problem solving therapy (PST).

"This study is important in the sense that it suggests that we may be able to increase the recovery of stroke patients — a clinical area where there are limited resources," principal investigator Ricardo Jorge, MD, told Medscape Psychiatry.

"However," Dr. Jorge added, "we have not yet proven that this is the case, and, therefore, while the results are quite promising, they merit replication in a larger patient population."

The study is published in the February issue of Archives of General Psychiatry.

Growing Interest in Restorative Therapies

According to Dr. Jorge, there is growing interest in restorative therapies that can be administered during the first few months following stroke — a period when the greatest degree of spontaneous recovery of motor and cognitive deficits occurs.

Although thrombolytic therapy has been a major advance in stroke treatment, said Dr. Jorge, its efficacy is limited because it must be administered within the first few hours of symptom onset.

"This means that not all stroke patients are treated with these agents. In fact, in the United States, only a minority of [stroke] patients receive thrombolytic therapy. So we are interested in exploring ways of assisting recovery in the subacute and chronic phases of stroke recovery which offer us a more prolonged therapeutic window," said Dr. Jorge.

One line of research has focused on antidepressant medications and "strongly suggests that antidepressants exert their therapeutic effects through complex signaling cascades that result in the increased expression of neurotrophic factors, the proliferation of neural and glial cell precursors, increased axonal sprouting, and the development of new synapses," the study authors write.

Enhancing Neuroplasticity

Immediately following stroke there is a period of spontaneous recovery where the brain reorganizes its networks in an attempt to compensate for deficits in areas damaged by ischemic injury.

"We wanted to investigate whether a safe pharmacological intervention would help this process of reorganization. We know that the effect of antidepressants, including their effect on mood, might be related to neuroplasticity by, for example, increasing the level of neurotrophic factors. So this makes possible the hypothesis that antidepressants in nondepressed stroke patients could possibly augment this recovery process," he said.

To examine the effects of escitalopram on cognitive outcomes, the investigators compared the drug to placebo and PST.

The study included 129 nondepressed stroke patients examined at the University of Iowa Stroke Center from July 9, 2003, to October 1, 2007. For the 12-month trial, patients were randomly assigned to 1 of the 3 treatment arms within 3 months following either a hemorrhagic or ischemic stroke.

Of these individuals, 43 were randomized to receive 5 to 10 mg of escitalopram daily, 45 to receive a daily placebo, and 41 to the nonblinded arm of PST.

The study's outcome measures included changes in scores from baseline to the end of treatment for the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and Trail Making, controlled Oral Word Association, Wechsler Adult Intelligence Scale III, and Stroop tests.

Independent Living

The results revealed a significant effect of escitalopram treatment on change in RBANS total score and the change in RBANS delayed memory score.

The researchers also note that participants in the escitalopram group were significantly more likely to show improvement in activities of daily living compared with subjects in the other 2 groups.

Further, the study showed that patients receiving placebo were more likely than those receiving escitalopram to live in a more structured environment. However, the difference was not statistically significant.

Dr. Jorge said the investigators chose escitalopram for the study because of its favorable safety and side effect profile and the fact that it has a more selective effect on the serotonin system than other SSRIs.

Although the study findings are positive, Dr. Jorge said more study is needed before altering treatment protocols in stroke patients is warranted.

"Restorative therapies are an important area to explore. We are hoping to conduct a similar but much larger study with at least 300 to 400 patients in each arm, and if we can replicate these results, then we can start thinking about adding this treatment — either alone or in combination with select rehab therapy — in stroke patients," said Dr. Jorge.

The study was supported by the National Institute of Mental Health. Dr. Jorge reports receiving 2 travel awards to participate in national meetings from the former Hamilton Pharmaceutical Company and Avanir Pharmaceutical Company. Disclosures of the other study authors can be found in the original paper.

Arch Gen Psychiatry. 2010;67:187-196.

Clinical Context

Stroke remains a major healthcare problem and is the third greatest cause of death in developed countries. Restorative therapies can be administered in the first months after stroke; they include physical therapy and pharmacotherapy. Treatment with antidepressants in the subacute phase of stroke has been shown to improve activities of daily living and cognitive functioning among patients with poststroke depression.

This is a 12-month randomized controlled trial comparing 3 strategies to examine the effect of escitalopram on cognition and functioning in patients with poststroke depression after mild to moderate stroke.


Study Highlights

Included were 129 patients who presented to 1 stroke center between 2003 and 2007 and were randomly assigned within 3 months of stroke to receive placebo, escitalopram, or PST.
Patients were aged 50 to 90 years, had imaging evidence of ischemic or hemorrhagic stroke and met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for major or minor depression or a Hamilton Scale for Depression score greater than 11.
Excluded were patients with severe comprehension deficits; stroke from an aneurysm, malformation, brain tumor, or myocardial infarction; and disabling conditions including cancer, neurodegenerative disease, Alzheimer's disease, or alcohol or substance abuse.
Patients underwent complete physical examination, and lesions were classified as right or left hemisphere, cerebellar or cerebral, or brain stem, and stroke type was classified as hemorrhagic or ischemic.
Patients were administered the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, at follow-ups of 3, 6, 9, and 12 months.
The Hamilton Scale for Depression, Hamilton Anxiety Rating Scale, and Functional Independence Measure were administered at baseline and at each follow-up visit.
Neuropsychological testing consisted of 5 tests.
The RBANS tested functioning in 5 domains (memory, visuospatial, language, attention, and delayed memory) evaluated by 12 subtests.
The Trail-Making Test Parts A and B assessed psychomotor processing speed and cognitive flexibility.
The Controlled Oral Word Association tested verbal fluency.
The Wechsler Adult Intelligence Scale-III Similarities tested abstract thinking.
The Stroop tests assessed selective attention and response inhibition.
117 of 129 randomized patients began treatment.
45 were randomly assigned to placebo, 43 to escitalopram, and 41 to PST.
Mean age was 64 years, more than 50% were men, half were married, and mean education was 13 years.
The 3 groups were similar in stroke severity and type and baseline functioning.
The escitalopram group showed a higher change in RBANS score than the other 2 groups.
After controlling for change in the Hamilton Scale for Depression score and stroke mechanism, the adjusted mean change in RBANS score was 10.0 for the escitalopram group and 3.1 for the other 2 groups (P < .01).
The delayed memory component of the RBANS score also showed a significantly greater change in the escitalopram group vs the other 2 groups (11.3 vs 2.5 for the other 2 groups; P < .01).
The immediate memory score component of the RBANS showed significantly greater change in the escitalopram group vs the other 2 groups (13.5 vs 5.3; P = .01).
There was no effect of treatment on change in RBANS attention, language or visuospatial domains, Trail-Making Test, Controlled Oral Word Association, Stroop Color-Word Trial, or Wechsler Adult Intelligence Scale-III Similarities scores before or after controlling for variables.
There was no effect of age, lesion, or location or type of stroke on the effect of escitalopram on cognitive function, and the changes were independent of depression symptoms.
The escitalopram group showed measurable improvements in function by the Functional Independence Measure scores vs the other 2 groups.
There was no significant change in occupational level before and after the treatment in the groups.
There were no differences in adverse effects in the 3 groups.
The authors concluded that escitalopram given to stroke patients with depression improved cognitive and functional outcome independent of depression outcomes.

Clinical Implications

Escitalopram improves global cognitive function, memory, and function in stroke patients with depression.
Improvements seen with escitalopram are independent of stroke type, depression, and age.

CME Test


Questions answered incorrectly will be highlighted.


Which of the following cognitive domains is most likely to be improved by escitalopram in patients with stroke and depression?

Attention
Language
Visuospatial function
Immediate memory

Which of the following variables is most likely to affect the impact of escitalopram on cognitive function in stroke patients with depression?

Depression
Patient age
Type of stroke
None of the above