**8. Poststroke depression effect on morbidity and mortality**

Poststroke depression was found to be an independent predictor of symptom severity after a stroke, and difficulty with managing activities of daily living [35]. In a meta-analysis of seven studies, poststroke depression was found to have an association with increased mortality [39]. Specifically, patients that experienced early poststroke depression as defined to be within 3 months of stroke onset, were found to have 1.5 increased risk of death. A literature review by Robinson and colleagues, found that using the Hospital Anxiety and Depression scale (HADS), patients that had a score greater than 7 at 3 months had increased mortality than those with a score less than 7 [38]. These scores were evaluated up to 5 years poststroke, and the hazard ratio was found to be 1.41. It was seen that mortality was increased in patients with poststroke depression that were younger than 65 years old [38]. Their study also demonstrated that in greater than 50,000 veterans that suffered an ischemic stroke, those that developed poststroke depression had higher rates of mortality within 3 years of that acute event. The hypothesis behind this being that early poststroke depression can occur in a patient with a severe disability such as neurocognitive decline, paralysis, aphasia, or dysphagia [38]. Due to the severity of their post-stroke symptoms these patients may be at increased risk of death due to complications like pneumonia secondary to dysphasia or infection from decubitus ulcers. Another hypothesis is that patients that are suffering from poststroke depression may be less likely to be compliant with medical recommendations, such as healthy diet, avoiding tobacco, alcohol, drug use, scheduled follow up appointments and medication compliance [37, 38]. These factors can increase the risk of mortality. Another theory states that mortality associated with poststroke depression may be related to

cardiovascular mortality [38, 39]. There is an association between depression and myocardial infarction, where it was found that depressed patients had less heart rate variability. This finding was also seen in patients with poststroke depression. This could put these patients at risk for myocardial infarction and subsequently, death. This meta-analysis also highlighted the idea that pharmacologic antidepressants have a mixed response in poststroke depression [38].

#### **9. Treatment of poststroke depression**

In order to treat poststroke depression, it needs to be accurately diagnosed. Currently the DSM IV is used to diagnose this disorder, along with multiple depression rating scales such as the Hamilton Rating Scale for Depression, Beck Depression Inventory, Montgomery-Åsberg Depression Rating Scale, Center for Epidemiological Studies Depression Scale, Zung self-rating depression scale and the Post-Stroke Depression Rating Scale [5]. There are many challenges in diagnosing depression in a patient after an acute stroke. Many of these patients have a somatic component to their symptoms, like pain, fatigue, or limited speech after a cerebrovascular event. These symptoms can confound a depression scale that account for somatic symptoms like the Beck Depression Index [5]. Depending on which scale is used to measure depression in these patients, there may be an overestimation or underestimation of depression. Since the hypothesis that stroke results in disruption of the monoamine pathways, there has been a focus on antidepressants like selective serotonin reuptake inhibitors, or tricyclic antidepressants to target poststroke depression. However, the role of antidepressants has been debated. There are some studies that show efficacy and reduction in mortality, and some that show a minimal effect or even adverse side effects [38–40]. Selective serotonin reuptake inhibitors (SSRIs) are well tolerated and can lead to fewer symptoms of depression at 3 weeks of use [40]. It is one therapy that is thought to work well in all age groups, regardless of comorbid conditions. SSRIs are better tolerated in all populations, compared to tricyclic antidepressants (TCA) [39, 40]. One endpoint found that patients that were started on SSRI early had decreased risk of myocardial infarction and recurrent stroke [40]. In a meta-analysis by Robinson and colleagues, the use of nortriptyline or fluoxetine demonstrated improvement in activities of daily living in poststroke depression compared to patients on placebo [38]. This study also demonstrated that the continued use over 12 weeks resulted in improved cognition in patients with poststroke depression, where the effect could last up to 2 years. Not only do SSRI inhibit reuptake of serotonin, but it was demonstrated in rodent models that SSRIs can decrease infarct volumes, reduced inflammation and increase neuroplasticity by modulating BDNF expression [38]. SSRI was also found to increase neurogenesis in the hippocampus, and improve cerebral blood flow autoregulation which is thought to be related to the upregulation of BDNF [27, 38].

In the fluoxetine in motor recovery of patients with acute ischemic stroke (FLAME) trial, fluoxetine use for 3 months was tested to see if it would improve motor recovery in patients with hemiparesis [41]. This trial was used to assess if the use of fluoxetine would change the Fugl-Meyer motor scale (FMMS) score which is an index used to test motor recovery, with a score of 100 representing complete motor function without any deficit. Two groups were analyzed a fluoxetine dose of 20 mg was the placebo and a 40 mg dose was used as the test treatment. At 3 months there was a significant improvement in motor function among the patients in the treatment arm [41]. At 90 days modified rankin scale (MRS) scores were better in the treatment arm as well. The frequency of depression was lower in the treatment arm when assessed with the MADRS score at 90 days. Even in patients that did not receive intravenous thrombolysis, their FMMS scores at 90 days were higher in the

**267**

*Post Stroke Depression*

*DOI: http://dx.doi.org/10.5772/intechopen.86935*

initiation of treatment with antidepressants.

**10. Depression and stroke rehabilitation**

treatment arm. Patients that were assessed to be depressed at the onset of the trial, based on MADRS score, were excluded from this trial [41]. Pretreatment with SSRI prior to stroke was also an exclusion criterion. Although the FLAME trial seemed to be promising for improving motor function in poststroke patients and reducing depression within that 3-month period, newer studies have shown the use of SSRI

In a study by Etherton et al., it was found that the use of SSRI prior to an acute stroke was associated with a decrease in discharges back to the patient's home, and increasing need for ambulatory aids [8]. When examining the patients in the two groups: pre-SSRI/spread vs. non antidepressant, there were no significant difference in admission NIHSS or length of hospital stay. The authors thought this may be due to the possibility that patients that were on SSRI or antidepressants prior to admission for their stroke event may have suffered a stroke before or TIA, resulting in a larger stroke burden. Another ischemic event could cause recrudescence of old stroke symptoms due to an increased burden on that area that was receiving adequate blood flow, which could lead to the patient having more needs such as rehabilitation at discharge. Pre-SSRI use was also associated with increased mortality at 30 days, and worse stroke severity in patients with hemorrhagic stroke [8]. Another criticism for the use of SSRIs was due to the increase in the risk of major bleeding or death. In a meta-analysis of 31 case-controlled studies, it was found that SSRI use was associated with risk of major bleeding events, with the increased risk being 41% [40, 42]. This meta-analysis also examined cohort studies that evaluated the use of SSRI vs. non-SSRI in association with major bleeding risk of 36%. The pooled data from the meta-analysis found that SSRI was associated with major bleeding risk with an odds ratio of 1.41. Gastrointestinal bleeding accounted for the majority of these major bleeding events, with a few intracerebral hemorrhage cases [42]. The hypothesis behind the increased bleeding risk is that platelet activity is inhibited by serotonin. This hypothesis is strengthened by the idea that patients taking SSRI have less myocardial infarctions and fewer strokes. The major bleeding risk associated with SSRI are amplified with adjunct use of non-steroidal anti-inflammatory drugs (NSAIDS) [42].

Overall, antidepressants such as SSRI and TCA have been thought to be the best initial treatment for post-stroke depression. SSRI are overall better tolerated in all populations [40]. These antidepressants can help patients combat poststroke depression enough to allow them to participate in rehabilitation efforts. Psychotherapies such as cognitive behavioral therapy (CBT) have been studied to assess if it would be beneficial in the treatment of poststroke depression. Due to the small sample size of the studies, and other limitations there was no real effect seen with CBT [5]. It may be an area of adjunct therapy for patients with severe poststroke depression that need more than pharmaceutical treatment. However, the use of CBT should not delay the

Depression after stroke strongly affects the way patients participate in and respond

to rehabilitation. Depression has been linked with decreased participation in rehabilitation efforts which in turn results in more increased morbidity and mortality and decreased quality of life. In a Japanese study that evaluated poststroke depression in patients admitted to a rehabilitation center, their results demonstrated that the patients that were identified as having poststroke depression had less response to rehab and minimal improvement in activities of daily living and functional independence measures [32]. This study found that the level of independence in the activities of daily living at the time of discharge from rehab was related to the severity of poststroke

prior to stroke, was negatively associated with ambulation poststroke [8].

#### *Post Stroke Depression DOI: http://dx.doi.org/10.5772/intechopen.86935*

*New Insight into Cerebrovascular Diseases - An Updated Comprehensive Review*

a mixed response in poststroke depression [38].

**9. Treatment of poststroke depression**

cardiovascular mortality [38, 39]. There is an association between depression and myocardial infarction, where it was found that depressed patients had less heart rate variability. This finding was also seen in patients with poststroke depression. This could put these patients at risk for myocardial infarction and subsequently, death. This meta-analysis also highlighted the idea that pharmacologic antidepressants have

In order to treat poststroke depression, it needs to be accurately diagnosed. Currently the DSM IV is used to diagnose this disorder, along with multiple depression rating scales such as the Hamilton Rating Scale for Depression, Beck Depression Inventory, Montgomery-Åsberg Depression Rating Scale, Center for Epidemiological Studies Depression Scale, Zung self-rating depression scale and the Post-Stroke Depression Rating Scale [5]. There are many challenges in diagnosing depression in a patient after an acute stroke. Many of these patients have a somatic component to their symptoms, like pain, fatigue, or limited speech after a cerebrovascular event. These symptoms can confound a depression scale that account for somatic symptoms like the Beck Depression Index [5]. Depending on which scale is used to measure depression in these patients, there may be an overestimation or underestimation of depression. Since the hypothesis that stroke results in disruption of the monoamine pathways, there has been a focus on antidepressants like selective serotonin reuptake inhibitors, or tricyclic antidepressants to target poststroke depression. However, the role of antidepressants has been debated. There are some studies that show efficacy and reduction in mortality, and some that show a minimal effect or even adverse side effects [38–40]. Selective serotonin reuptake inhibitors (SSRIs) are well tolerated and can lead to fewer symptoms of depression at 3 weeks of use [40]. It is one therapy that is thought to work well in all age groups, regardless of comorbid conditions. SSRIs are better tolerated in all populations, compared to tricyclic antidepressants (TCA) [39, 40]. One endpoint found that patients that were started on SSRI early had decreased risk of myocardial infarction and recurrent stroke [40]. In a meta-analysis by Robinson and colleagues, the use of nortriptyline or fluoxetine demonstrated improvement in activities of daily living in poststroke depression compared to patients on placebo [38].

This study also demonstrated that the continued use over 12 weeks resulted in

lation which is thought to be related to the upregulation of BDNF [27, 38].

improved cognition in patients with poststroke depression, where the effect could last up to 2 years. Not only do SSRI inhibit reuptake of serotonin, but it was demonstrated in rodent models that SSRIs can decrease infarct volumes, reduced inflammation and increase neuroplasticity by modulating BDNF expression [38]. SSRI was also found to increase neurogenesis in the hippocampus, and improve cerebral blood flow autoregu-

In the fluoxetine in motor recovery of patients with acute ischemic stroke (FLAME) trial, fluoxetine use for 3 months was tested to see if it would improve motor recovery in patients with hemiparesis [41]. This trial was used to assess if the use of fluoxetine would change the Fugl-Meyer motor scale (FMMS) score which is an index used to test motor recovery, with a score of 100 representing complete motor function without any deficit. Two groups were analyzed a fluoxetine dose of 20 mg was the placebo and a 40 mg dose was used as the test treatment. At 3 months there was a significant improvement in motor function among the patients in the treatment arm [41]. At 90 days modified rankin scale (MRS) scores were better in the treatment arm as well. The frequency of depression was lower in the treatment arm when assessed with the MADRS score at 90 days. Even in patients that did not receive intravenous thrombolysis, their FMMS scores at 90 days were higher in the

**266**

treatment arm. Patients that were assessed to be depressed at the onset of the trial, based on MADRS score, were excluded from this trial [41]. Pretreatment with SSRI prior to stroke was also an exclusion criterion. Although the FLAME trial seemed to be promising for improving motor function in poststroke patients and reducing depression within that 3-month period, newer studies have shown the use of SSRI prior to stroke, was negatively associated with ambulation poststroke [8].

In a study by Etherton et al., it was found that the use of SSRI prior to an acute stroke was associated with a decrease in discharges back to the patient's home, and increasing need for ambulatory aids [8]. When examining the patients in the two groups: pre-SSRI/spread vs. non antidepressant, there were no significant difference in admission NIHSS or length of hospital stay. The authors thought this may be due to the possibility that patients that were on SSRI or antidepressants prior to admission for their stroke event may have suffered a stroke before or TIA, resulting in a larger stroke burden. Another ischemic event could cause recrudescence of old stroke symptoms due to an increased burden on that area that was receiving adequate blood flow, which could lead to the patient having more needs such as rehabilitation at discharge. Pre-SSRI use was also associated with increased mortality at 30 days, and worse stroke severity in patients with hemorrhagic stroke [8].

Another criticism for the use of SSRIs was due to the increase in the risk of major bleeding or death. In a meta-analysis of 31 case-controlled studies, it was found that SSRI use was associated with risk of major bleeding events, with the increased risk being 41% [40, 42]. This meta-analysis also examined cohort studies that evaluated the use of SSRI vs. non-SSRI in association with major bleeding risk of 36%. The pooled data from the meta-analysis found that SSRI was associated with major bleeding risk with an odds ratio of 1.41. Gastrointestinal bleeding accounted for the majority of these major bleeding events, with a few intracerebral hemorrhage cases [42]. The hypothesis behind the increased bleeding risk is that platelet activity is inhibited by serotonin. This hypothesis is strengthened by the idea that patients taking SSRI have less myocardial infarctions and fewer strokes. The major bleeding risk associated with SSRI are amplified with adjunct use of non-steroidal anti-inflammatory drugs (NSAIDS) [42].

Overall, antidepressants such as SSRI and TCA have been thought to be the best initial treatment for post-stroke depression. SSRI are overall better tolerated in all populations [40]. These antidepressants can help patients combat poststroke depression enough to allow them to participate in rehabilitation efforts. Psychotherapies such as cognitive behavioral therapy (CBT) have been studied to assess if it would be beneficial in the treatment of poststroke depression. Due to the small sample size of the studies, and other limitations there was no real effect seen with CBT [5]. It may be an area of adjunct therapy for patients with severe poststroke depression that need more than pharmaceutical treatment. However, the use of CBT should not delay the initiation of treatment with antidepressants.
