Click here to listen to the audio.

By Dennis Miller, BHC Senior Writer

A new study has found that SSRI antidepressants may help non-depressed stroke victims recover cognitive functions more quickly following a stroke. The study found that escitalopram (trade names Lexapro, Cipralex or Seroplex), used at relatively low doses, can help stroke patients regain cognitive functions such as verbal and nonverbal memory. The study was recently published in the Archives of General Psychiatry and funded by the National Institute of Mental Health.

Lead author Ricardo Jorge, M.D., an Associate Professor of Psychiatry at the Carver College of Medicine, University of Iowa, says the study focused on non-depressed stroke patients after researchers had noticed that stroke victims prescribed the medication for depression seemed to do better with cognitive functioning. Researchers decided to test whether a smaller dosage might have a similar effect for stroke patients who were not depressed. “We knew that a patient with depression had poorer outcomes. We knew also that antidepressants improved outcomes among depressed patients,” he explains. “But we really didn’t have (although we had a hint) evidence that antidepressants given in small doses — relatively small doses — would be able to modify the outcome of these patients, particularly the cognitive outcome.”

The results proved the hypothesis that the medication can improve cognitive functioning independent of their effect on depression. “What we found is that there was significant improvement in those patients who received escitalopram, particularly in memory function in both verbal and nonverbal memory. And that’s the main finding of the study,” says Dr. Jorge. “And in fact, the effect that we observed in cognition is independent of any other changing mood or depression.”

One group of patients among the study’s 129 subjects received 5 to 10 milligrams of escitalopram, about half of the drug’s standard dosage when used to treat depression. Two control groups received either a placebo or problem-solving therapy without medication. By the study’s end, results showed that those on the SSRI drug achieved much better scores on cognitive functioning tests. “The change in memory scores in this neuropsychological test for those patients who received the escitalopram was 11.3 points, against 2.5 points of positive change in patients who did not receive escitalopram,” says Dr. Jorge.

As for how the medication may work to achieve that result, Dr. Jorge says there are a number of theories, but no concrete explanation as of yet. “This is a complex issue, because there are several alternatives,” he explains. “One, and probably one that is quite appealing because this is related to the mechanism of antidepressants for treatment of depression, is that antidepressants have an effect called a neurotrophic effect. In a sense, that increases the expression of neurotrophic factors.”

There is also the possibility that the drug interacts with the brain’s regenerative functions, which are particularly active following a stroke as the brain works to creates new neuropathways to restore cognitive functioning. “There is evidence that it will increase the neurogenesis and the proliferation of primordial neurons in the hippocampus,” Dr. Jorge theorizes. “There are several trophic effects that help the brain reorganize itself. This is also important because the period immediately after a stroke is a period of greater plasticity in the brain, where the brain tries to compensate for its deficits. In not only a functional way but also in a structural way, there are changes in structure and changes in function that try to override the deficits brought by the stroke.”

A third possibility is more of a biochemical effect. “Those aren’t the only mechanisms that we can suspect. We know that adding this type of medications will alter the transmission in different aminergic pathways and also in other pathways, which are related to acetylcholine and also involved in memory” Dr. Jorge explains. “So we need to say that, although we have different alternatives and different mechanisms that may be related to this effect, we don’t know for sure which are the most important and should be an area of further research.”

As for any adverse effects associated with prescribing antidepressants to non-depressed patients. Dr. Jorge says his team checked and found few if any problems. “The most serious adverse events that we were considering were, first of all, the possibility of bleeding complications, particularly gastrointestinal bleeding. The other one was whether antidepressants will make this older and frail patient more vulnerable to falls and, for example, hip fractures,” he says. “In our experience, we didn’t have any difference in the frequency of these complications — bleeding complications or falls and fractures — between patients receiving escitalopram or patients receiving placebo.”

Much more research will be needed before there’s any official recognition of escitalopram’s validity as a treatment for cognitive impairment following a stroke, and Dr. Jorge is reticent at this point to even suggest it as a potential off-label indication for doctors to consider. “129 patients is still a relatively small study to analyze all the different possibilities in depth. And in fact, you cannot modify the current guidelines for treatment of stroke based on this interesting but preliminary finding,” he cautions. “This is a very significant public health problem and to make a change in how we treat patients, we definitely need more information and more in-depth studies.”

To listen to our complete interview with Dr. Jorge, click on the audio icon above. The following is a complete written transcript, edited for readability.

BHC: Tell us a bit more about the study and what it found.

RJ: Let me tell you a little bit about the history of this study. For more than twenty years, our lab, and in particular our head Dr. Robinson, has been working on a very common complication of stroke, which is post-stroke depression. And the last of his studies was on prevention of post-stroke depression. That is, treating patients immediately or very closely after a stroke who are not depressed, with the aim of preventing the onset of such a frequent complication.

And this design of a prevention study was also very attractive and appealing to study outcomes after stroke. We knew that a patient with depression had poorer outcomes. We knew also that antidepressants improved outcomes among depressed patients. But we really didn’t have (although we had a hint) evidence that antidepressants given in small doses — relatively small doses — would be able to modify the outcome of these patients, particularly the cognitive outcome.

So in the group of patients that were included in Iowa for this prevention trial, we analyzed cognitive outcomes. What we were more interested is not only a global outcome, but what happened with memory function and what happens with executive functions. So, this study was conducted over a year — that’s important if you’re studying very closely after a stroke and following treatment at low doses for a year. And the outcomes were basically [measured by] the difference of the change between the baseline evaluations and the one-year evaluations.

And what we found is that there was significant improvement in those patients who received escitalopram, particularly in memory function in both verbal and nonverbal memory. And that’s the main finding of the study.

BHC: How was this effect first theorized or detected? Was it that there were patients who had had strokes who were depressed and were given the medication for that and then this was noticed?

RJ: In this study, patients who had depression at baseline were excluded. These were non-depressed patients. And in fact, the effect that we observed in cognition is independent of any other changing mood or depression.

So it’s an effect that’s independent of the effects of antidepressants in improving mood or in treating depression.

BHC: Did the patients in the study receive the same dosage as patients would who were taking the drug for depression?

RJ: No, particularly in those patients over 65, who received five milligrams of escitalopram. And for those below 65 we were using ten milligrams. These are doses that are small doses compared with the doses that are usually employed to treat depression.

BHC: Is it difficult to tell if stroke patients are indeed depressed or simply suffering from cognitive deficiencies?

RJ: In fact, if you analyze what is the phenomenology of depression in these patients, for a psychiatrist at least it’s not difficult to differentiate the presence of depression in these patients. Although it is true that apathy, which is a psychiatric condition characterized as lack of motivation, is also frequent among stroke patients, and it might be associated with depression and it might not. But the core symptoms of depression are very clear and are the symptoms described in the DSM-IV or in the other versions of the DSM-III and in the medical literature.

The other differential diagnosis is emotionality. You know that there is, in some of these patients with stroke or cerebrovascular lesions, faulty regulation of emotions. Some patients have what’s been called pseudo-bulbar affect or has been called emotional expression disorder. For an experienced psychiatrist it is relatively easy to differentiate a depressive syndrome from apathy and from emotional lividity.

BHC: Is it possible to deduce from this study whether there are certain types of stroke patients that SSRI antidepressants would be most likely to help?

RJ: It’s not possible from this study, because if we analyze the effect either of the type of stroke or on the mechanisms of stroke in these patients, that will explain differences in improvement of cognition. And that was not significant. There was not an effect of different types or mechanisms of stroke.

Nevertheless, we need to remember that this is an important thing to take into account for all the studies, although 129 patients is still a relatively small study to analyze all the different possibilities in depth. And in fact, you cannot modify the current guidelines for treatment of stroke based on this interesting but preliminary finding.

BHC: Dr. Jorge, how dramatic was the difference in cognitive functioning among the patients who took the SSRIs?

RJ: If you analyze the changes in memory, the change in memory scores in this neuropsychological test for those patients who received the escitalopram was 11.3 points against 2.5 points of positive change in patients who did not receive escitalopram.

BHC: Do you have any theories on why and how the medication, the SSRI medication used, works to improve cognitive functioning among stroke patients?

RJ: Well, this is a complex issue, because there are several alternatives. One, and probably one that is quite appealing because this is related to the mechanism of antidepressants even for treatment of depression, is that antidepressants have an effect called neurotrophic effect. In a sense, that increases the expression of neurotrophic factors.

Also, there is evidence that it will increase the neurogenesis and the proliferation of primordial neurons in the hippocampus. There are several trophic effects that help the brain reorganize itself. This is also important because the period immediately after a stroke is a period of greater plasticity in the brain, where the brain tries to compensate for its deficits. In not only a functional way but also in a structural way, there are changes in structure and changes in function that try to override the deficits brought by the stroke.

So this is a special timing and a special biological window where the antidepressants may help these neurotrophic changes — building new connections, building new synapses and even, in some areas like the hippocampus that are also related to memory, increase the number of new neurons that are divided evenly in the brain.

That’s not the only mechanisms that we can suspect. We know that adding this type of medications will alter the transmission in different aminergic pathways and also in other pathways, which are related to acetylcholine and also involved in memory.

So we need to say that, although we have different alternatives and different mechanisms that may be related to this effect, we don’t know for sure which are the most important and should be an area of further research.

BHC: What are the next steps from here? Does this particular usage require further testing before there may be a potential FDA approval for this indication?

RJ: My impression, and is what I was telling you before, is that what I would like to see is a bigger study, a multi-center study, which focuses not only on cognitive outcomes but also on trying to reproduce outcomes in other measures of disability after a stroke. I think that we have sufficient information from previous preliminary studies to support such a study, but what we need is a bigger study with a bigger number of patients.

And in analyzing different types of outcomes, you know that there are indications that antidepressants may help with disability, may reduce disability and may even reduce cardiovascular morbidity and mortality.

BHC: Dr. Jorge, what about the potential risks of antidepressant use among stroke patients? Is that something you looked at in the study?

RJ: Yes. We were concerned about that, and basically I will tell you what has been our experience in previous trials also. The most serious adverse events that we were considering were first of all the possibility of bleeding complications, particularly gastrointestinal bleeding. The other one was whether antidepressants will make this older and frail patient more vulnerable to falls and, for example, hip fractures.

So those were serious events that are not common but have been observed with this. In our experience, we didn’t have any difference in the frequency of these complications — bleeding complications or falls and fractures — between patients receiving escitalopram or patients receiving placebo.

The other usual and more common complications that may be relevant is that SSRIs in this population are associated with gastrointestinal side effects — nausea, vomiting, diarrhea — and these are more frequent and less serious, but also may have a significant impact. Just to give you an example, in a previous study in stroke patients that were treated with Fluoxetine (Prozac), those patients treated with the SSRI — and in particular, they were treated for depression so they were treated at higher doses — had significant weight loss.

So those were the type of things that we were worried about and that’s the reason we also have chosen escitalopram, in the sense that it’s probably, among the SSRIs, the one that’s more gastrointestinally friendly. But fortunately, and that could be related to the type of dosing that we were using, there were no significant complications of using, at least this SSRI in this population.

BHC: Dr. Jorge, I really want to thank you for speaking with us today. Anything else you’d like to add in closing that we haven’t covered here?

RJ: The only thing is caution. Caution in the sense that this is a very significant public health problem and to make a change in how we treat patients, we need definitely more information and more in-depth studies.

Comments (0)

Subscribe to this comment's feed