**4. Poststroke depression etiology**

Poststroke depression has been defined as a mood disorder resulting from a general medical condition, by the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV, meaning it does not carry with it the same definition of major depression [16]. There has been some debate about the etiology of poststroke depression, where multiple hypotheses exist, including but not limited to disruption to monoamine pathways, inflammatory cytokines, and hypothalamic–pituitary axis within the brain that modulates mood. The other belief is based on a psychosocial model, where depression develops after a stroke due to inability to adjust to new life circumstances, inability to care for oneself, fear of recurrence, financial insecurity and carrying a new diagnosis [7].

#### **4.1 Localization of poststroke depression**

One question that has been analyzed extensively with no definite answers is the location of a stroke as a predictor of poststroke depression. These studies used techniques such as voxel-based symptom lesion mapping, diffusion tensor imaging (DTI), functional magnetic resonance imaging (MRI), and positron emission tomography (PET) scans [19]. Functional neuroimaging has sought to determine neuronal circuitry to discover how damage to these circuits results in mood or personality changes. These imaging modalities demonstrate that there is less activity in the frontal cortex, anterior cingulate, dorsolateral and caudate nucleus, in patients that are experiencing depression. In pilot studies using DTI, there has been some data demonstrating that damage to the fronto-striato thalamic pathway and pathways involving emotional control, reward systems and decision making can lead to increased risk of poststroke depression [19]. DTI changes were seen in stroke patients that had damage to the genu and splenium of the corpus callosum, frontal lobe white matter and anterior left corona radiata, resulting in increased levels of apathy [20]. A few theories about lesion location and depressive symptoms include-anhedonia as associated with the stroke volume affecting the hypothalamic-pituitary-adrenal axis, and increased risk for depression in patients with basal ganglia, and frontal lobe strokes [20]. A study by Paradiso and colleagues demonstrated that patients who had left hemispheric strokes were likely to have

**261**

*Post Stroke Depression*

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

more depressive symptoms [19]. They proposed that right hemispheric strokes experience fewer depressive symptoms due to anosognosia. If the patient is unaware of his or her deficits, they will less likely feel depression related to their loss of function. Left hemispheric strokes have also been seen to have an earlier onset of

One of the models that have been proposed is that subcortical strokes like those in the basal ganglia, and strokes in the frontal lobes can result in disrupted serotoninergic and norepinephrinergic pathways that can be associated with poststroke depression [21]. The belief is that strokes that affected the amine-containing axons between the brainstem and specifically the left cerebral cortex would result in decreased production of serotonin (5-HT) and norepinephrine [22]. A reduction of these neurotransmitters in the frontal and temporal lobe limbic structures, and in the basal ganglia could result in difficulty with mood regulation [19]. This theory was supported by the finding that there were low levels of the 5-HT metabolite,

Inflammatory cytokines were also thought to be related to the development of poststroke depression [23, 24]. Jioa and colleagues found that interleukin (IL)-6 was elevated in patients with post-stroke depression, even after controlling for confounders, with a confidence interval of 95% [23]. The elevation of IL-6 in patients that have strokes could possibly predict the development of poststroke depression [23, 24]. In another meta-analysis, brain-derived neurotrophic factor (BDNF) was found to be involved in the development of depression and poststroke depression [25, 26]. In these studies, a low serum level of BDNF in the acute phase after a stroke was associated with the development of poststroke depression. BDNF is inherently involved in hippocampal plasticity and memory [27]. One study found a significant negative relationship between BDNF and NIHSS [25–27]. In rodent models, low levels of BDNF in the hippocampus that had an acute stroke exhibited depressed behavior, however if BDNF was overexpressed there was a marked decrease in depressed behavior [21]. Increased BDNF in the rodent model also resulted in reduced infarct size and improved functionality of the rodent [25]. Increased serum level of C-reactive protein (CRP), neopterin, ferritin, and glutamate could also be related to poststroke depression [24]. Proinflammatory markers such as tumor necrosis factor (TNF)-α, interleukins (IL)-1β, IL-6, IL-1, and interferon gamma (IFN-γ) were associated with the development of poststroke depression [23, 24]. Additionally, inflammatory cytokines can activate the hypothalamic pituitary adrenal axis [24]. Activation of the HPA access can also lead to the downstream release of glucocorticoids, which can also result in increased blood glucose levels, and potentially diabetes if this is a chronic process. After an acute stroke, patients often exhibit increased levels of serum adrenocorticotropic hormone, and cortisol. These hormones result in higher mortality and worse neurologic outcome [23]. Increased cytokine activity could also result in greater expression of genes involved in the metabolism of tryptophan such as indoleamine 2,3 dioxygenase (IDO) [27]. If IDO expression increases, tryptophan will be converted to kynurenine and not 5-HT. The downstream effect could result in decreased levels of 5-HT in the limbic system, temporal lobes, frontal lobes, and basal ganglia, which could potentially result in depression [27].

poststroke depression, usually in the first 6 months poststroke [13].

5-hydroxyindoleacetic acid in the cerebrospinal fluid (CSF).

**4.2 Biomarkers associated with poststroke depression**

**4.3 Genetic association with poststroke depression**

There have also been studies that have shown a genetic contribution to poststroke depression. Multiple studies have evaluated the 5-HT gene located on

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

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

pituitary access. This will be discussed later in the chapter.

perceived stress and more depressive symptoms [18].

**4. Poststroke depression etiology**

insecurity and carrying a new diagnosis [7].

**4.1 Localization of poststroke depression**

shown that at 3 months after an acute stroke, patients with diabetes were more likely to develop poststroke depression. This was an independent risk factor for the development of poststroke depression at or after 3 months [17]. The hypothesis behind this is based on the pathophysiology behind both diabetes and poststroke depression, which involves the inflammatory pathway, and the hypothalamic

Preexisting psychiatric disorders such as depression, anxiety, and bipolar disorder can also predispose patients to worse poststroke depression in the subacute phase, which is within 3 months [17]. One meta-analysis that looked at predictors of poststroke depression found that of the patients that had a preexisting mood disorders such as dysthymia, major depression, minor depression, anxiety, agoraphobia and adjustment disorder were all associated with increased risk of worsening depression after a stroke. Of 1058 patients with reported depression prior to their stroke, 27% had worse depressive symptoms after the acute ischemic event [18]. Premorbid anxiety was also predictive of worsening anxiety after the stroke. Anxiety poststroke results in impaired response to adverse events increased

Poststroke depression has been defined as a mood disorder resulting from a general medical condition, by the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV, meaning it does not carry with it the same definition of major depression [16]. There has been some debate about the etiology of poststroke depression, where multiple hypotheses exist, including but not limited to disruption to monoamine pathways, inflammatory cytokines, and hypothalamic–pituitary axis within the brain that modulates mood. The other belief is based on a psychosocial model, where depression develops after a stroke due to inability to adjust to new life circumstances, inability to care for oneself, fear of recurrence, financial

One question that has been analyzed extensively with no definite answers is the location of a stroke as a predictor of poststroke depression. These studies used techniques such as voxel-based symptom lesion mapping, diffusion tensor imaging (DTI), functional magnetic resonance imaging (MRI), and positron emission tomography (PET) scans [19]. Functional neuroimaging has sought to determine neuronal circuitry to discover how damage to these circuits results in mood or personality changes. These imaging modalities demonstrate that there is less activity in the frontal cortex, anterior cingulate, dorsolateral and caudate nucleus, in patients that are experiencing depression. In pilot studies using DTI, there has been some data demonstrating that damage to the fronto-striato thalamic pathway and pathways involving emotional control, reward systems and decision making can lead to increased risk of poststroke depression [19]. DTI changes were seen in stroke patients that had damage to the genu and splenium of the corpus callosum, frontal lobe white matter and anterior left corona radiata, resulting in increased levels of apathy [20]. A few theories about lesion location and depressive symptoms include-anhedonia as associated with the stroke volume affecting the hypothalamic-pituitary-adrenal axis, and increased risk for depression in patients with basal ganglia, and frontal lobe strokes [20]. A study by Paradiso and colleagues demonstrated that patients who had left hemispheric strokes were likely to have

**260**

more depressive symptoms [19]. They proposed that right hemispheric strokes experience fewer depressive symptoms due to anosognosia. If the patient is unaware of his or her deficits, they will less likely feel depression related to their loss of function. Left hemispheric strokes have also been seen to have an earlier onset of poststroke depression, usually in the first 6 months poststroke [13].

One of the models that have been proposed is that subcortical strokes like those in the basal ganglia, and strokes in the frontal lobes can result in disrupted serotoninergic and norepinephrinergic pathways that can be associated with poststroke depression [21]. The belief is that strokes that affected the amine-containing axons between the brainstem and specifically the left cerebral cortex would result in decreased production of serotonin (5-HT) and norepinephrine [22]. A reduction of these neurotransmitters in the frontal and temporal lobe limbic structures, and in the basal ganglia could result in difficulty with mood regulation [19]. This theory was supported by the finding that there were low levels of the 5-HT metabolite, 5-hydroxyindoleacetic acid in the cerebrospinal fluid (CSF).

#### **4.2 Biomarkers associated with poststroke depression**

Inflammatory cytokines were also thought to be related to the development of poststroke depression [23, 24]. Jioa and colleagues found that interleukin (IL)-6 was elevated in patients with post-stroke depression, even after controlling for confounders, with a confidence interval of 95% [23]. The elevation of IL-6 in patients that have strokes could possibly predict the development of poststroke depression [23, 24]. In another meta-analysis, brain-derived neurotrophic factor (BDNF) was found to be involved in the development of depression and poststroke depression [25, 26]. In these studies, a low serum level of BDNF in the acute phase after a stroke was associated with the development of poststroke depression. BDNF is inherently involved in hippocampal plasticity and memory [27]. One study found a significant negative relationship between BDNF and NIHSS [25–27]. In rodent models, low levels of BDNF in the hippocampus that had an acute stroke exhibited depressed behavior, however if BDNF was overexpressed there was a marked decrease in depressed behavior [21]. Increased BDNF in the rodent model also resulted in reduced infarct size and improved functionality of the rodent [25].

Increased serum level of C-reactive protein (CRP), neopterin, ferritin, and glutamate could also be related to poststroke depression [24]. Proinflammatory markers such as tumor necrosis factor (TNF)-α, interleukins (IL)-1β, IL-6, IL-1, and interferon gamma (IFN-γ) were associated with the development of poststroke depression [23, 24]. Additionally, inflammatory cytokines can activate the hypothalamic pituitary adrenal axis [24]. Activation of the HPA access can also lead to the downstream release of glucocorticoids, which can also result in increased blood glucose levels, and potentially diabetes if this is a chronic process. After an acute stroke, patients often exhibit increased levels of serum adrenocorticotropic hormone, and cortisol. These hormones result in higher mortality and worse neurologic outcome [23]. Increased cytokine activity could also result in greater expression of genes involved in the metabolism of tryptophan such as indoleamine 2,3 dioxygenase (IDO) [27]. If IDO expression increases, tryptophan will be converted to kynurenine and not 5-HT. The downstream effect could result in decreased levels of 5-HT in the limbic system, temporal lobes, frontal lobes, and basal ganglia, which could potentially result in depression [27].

#### **4.3 Genetic association with poststroke depression**

There have also been studies that have shown a genetic contribution to poststroke depression. Multiple studies have evaluated the 5-HT gene located on

chromosome 17q11.1-17q12, which encodes the serotonin transporter [25–27]. In a meta-analysis of 7 studies, there was a significant relationship between 5-HTTLPR polymorphism and the development of poststroke depression symptoms. 5-HTTLPR is an exon of the 5-HT transporter gene polymorphism [25, 26]. The hypothesis is that this gene polymorphism responds to the increased activity of the amygdala when responding to negative stimuli. An increase in 5-HTTLPR serum level has been positively associated with threefold increased risk of developing poststroke depression [25–28]. Another 5-HT polymorphism that has been analyzed is the STin2 VNTR, which is located within intron 2. It has variable number tandem repeats 9, 10, or 12. Repeats of the 9-allele have been well documented to be associated with multiple psychiatric disorders such as bipolar disorder, and major depression [25–28]. Repeats of the twelfth allele have been linked to the development of schizophrenia and bipolar affective disorder. It has been demonstrated that patients with variable tandem repeats of 9/12 and 12/12 were likely to have more depression after a stroke [25–28].

## **4.4 Psychosocial association with poststroke depression**

Lastly, psychosocial factors must be considered when assessing who is at risk for poststroke depression. After suffering a life-altering event such as a stroke, even if there are no severe deficits, patients can undergo an adjustment period. They may feel depressed about the new diagnosis of a stroke. There is also the concern of getting back to their normal life routine such as working, caring for dependents, and caring for their own activities of daily living (ADLS) [11, 12]. Patients that do not have good social support tend to experience more depression after a stroke due to feeling helpless, and alone. Patients may also experience anxiety, related to the fear that another stroke may occur. Financial costs of health care also play a role in postacute stroke depression. If a patient is unable to work there may be a concern about medication compliance, affording medication, affording postacute special services like physical therapy or occupational therapy [11, 12].
