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Pathophysiological mechanisms in post-stroke depression. Psychosocial and economic implications of patient rehabilitation.


A cerebrovascular accident (CVA or stroke) is an acute loss of brain function, with a sudden onset, that occurs after a disorder of the blood supply to the brain. It can be caused by stenosis, occlusion or the rupture of an artery in the brain, and can result from a variety of predisposing factors. The clinical manifestations of the stroke indicate the installation of a temporary or permanent brain dysfunction (1). In most cases, patients who become physically disabled following a stroke will also suffer from other of its complications (2). Worldwide, 15 million people are affected by CVA each year. For at least 5 million people, the stroke is fatal, and another third remain with post-stroke sequelae (3). Over half of the 10 million survivors have reported an overwhelming fatigue and a permanent lack of energy (4). Decreased vitality, as a general consequence, will weaken the patients' ability to regain lost functions. Similarly, most of these patients have depressive elements (post-stroke depression) that considerably affect their quality of life (5).


Depression is a disabling psychiatric condition, characterized by negative hyperthythmic mood, anhedonia, hypobulia, fatigue, attention an memory deficits, feelings of worthlessness and guilt, decreased vitality and personal efficiency, and minimum involvement in daily activities, associated or not with suicidal ideation (6).

Many researches in the field have associated fatigue with post-stroke depression. In a study conducted in Sweden, 49% of patients with fatigue at 1 year after a stroke developed depression, compared with 39% in the control group (7). Similarly, a study done in Korea found out that 34% of the patients diagnosed with depression were among those presenting fatigue about 15 months after the stroke (8).

In a research conducted by Changjuan and his collaborators, 368 patients were included for a first interview 14 days after they suffered a stroke. The second interview took place at three months after the stroke. The diagnosis of depression was established in the case of 19.3% of patients upon admittance to study and of 23.6% of them at three months after the stroke. For 23 of the 71 patients who developed depression in the acute phase of the stroke the symptoms disappeared, while for the other 48 of them depression persisted at three months after the stroke. Fatigue was documented for 23.4% of the patients admitted in the study and for 29.6% of them at three months from the stroke. Of the 86 patients who experienced fatigue during the acute phase of stroke, 28 returned to their original state, but for 58 of them the symptoms persisted. Moreover, 75.6% of the patients who initially developed fatigue were diagnosed with depression at three months after the stroke and 53.5% of those who initially experienced depression had developed fatigue at three months after the stroke. Depression has been associated with fatigue for 10.9% of patients upon admittance and for 12.2% of them at three months after the stroke (9). In the case of these patients, social support and adaptation mechanisms are considered important factors in the rehabilitation process.


The cerebral neurotransmitters, norepinephrine, serotonin and dopamine are biogenic amines which transmit information between nerve cells or between neurons and effector cells, integrating the overall coordination of body functions. If these neurotransmitters are functionally impaired, the nervous system is also affected, leading to depression. In the pathogenesis of depression, the function and content of these three neurotransmitters may be altered and affect the patient's disposition and emotional regulation in varying degrees (10).

Serotonin (5-HT) acts as a hormone and a neurotransmitter, being involved in mitogenic induction. In 1918, at the time of its discovery, 5-HT was considered to be a vasoconstrictor stored in platelets, therefore it was called "serotonin", after the Latin word "serum" and the Greek one "tonic". In 1937, 5-HT has been found in the enterochromaffin cells of the gastrointestinal tract, and was named enteramine because of its believed implications in the intestinal smooth muscle contraction. Scientists assigned a neurotransmitter role to serotonin in 1952 and associated it with mood, behaviour, sleep-wake regulation cycle and appetite (11).

Norepinephrine is the second neurotransmitter discovered, after acetylcholine, and was originally named sympathetin, because it was produced by the stimulation of the sympathetic nervous system and because it had acetylcholine-antagonism effects on the myocardium. Noradrenaline secretion is stimulated by stressful events, as well as by low blood pressure. As a result, heart rate is increased and blood is redirected to the muscles, with increased glycemic levels to ensure a greater supply of energy to the cells (10).

Dopamine, discovered in 1958, has numerous functions, including controlling, triggering and executing voluntary movements and the postural adjustment associated with them, and controlling emotional behaviour, pleasure, the brain's reward system, cognitive functions and short-term memory (12).

Dopamine and serotonin are considered to be responsible for the appearance of fatigue in Parkinson's disease. Regarding the localization of cerebral lesions, infarcts of the basal ganglia, the corona radiata and the internal capsule appeared to be randomly related to the emergence of fatigue at three months after the stroke, while injuries that occurred in the cerebellum showed no association with it. Previously, the dopaminergic neurons that take action over the rewarding system and are located in the ventral tegmental area were found to project fibres at the striatum Venti level (13). Experiments on animals have shown that the profuse serotonergic fibres of the raphe nuclei, located in the brainstem from which fibres leave both upward and downward, affecting many areas of the brain, especially the cortex, the limbic system, the thalamus and the hypothalamus are projected in the basal ganglia and in the cerebellum (14).

Coping mechanisms refer to the patient's cognitive and behavioural efforts to manage the internal and external demands in the social environment. Keeping in mind that stroke is considered a particular physical condition, involving neurological dysfunctions of varying impact degree, the coping mechanism can be considered a key psychological resource in the recovering process of the patient's quality of life (4).


In another study, Xiao and his colleagues induced a cerebral vascular accident on mice, adopting the method of occluding the left cerebral artery. The cerebrovascular physiopathological changes in the brain of those mice, as a result of the procedure, were similar to the clinical manifestations of stroke. The mice were divided in two groups: the reference group, that had poststroke depression, and the control group, which had only suffered a stroke. The poststroke depression has been induced by applying a mild chronic stress to each animal in the experiment. They observed a significant reduction in the levels of serotonin, norepinephrine and dopamine in the frontal cortex and in the hippocampus of mice with post-stroke depression, compared to the control group. These results can be associated with the direct division of the pathways involving serotonin and norepinephrine following a stroke (15). Neuronal cell bodies are located in the brainstem and their axons reach the frontal cortex and the hippocampus, passing through the thalamus and the basal ganglia, which play an important role in the regulation of emotions and dispositions. Damage on the paths involving serotonin and norepinephrine induce a decrease in the level of these neurotransmitters, resulting in the emergence of post-stroke depression (16).


The inflammatory hypothesis stipulates that depression is associated with the activation of the innate immune system, with the increase of pro-inflammatory cytokines and acute phase proteins. In support of this hypothesis, numerous studies have detected significantly elevated levels of inflammatory markers, more importantly IL-6 and IL-1b interleukins, alpha tumour necrosis factor (TNF-[alpha]) and C-reactive protein, in patients diagnosed with depression compared to healthy groups (17).

The presence of depressive symptoms is not only a negative prognostic factor for patients with known cardiovascular disease, but it is also a risk factor for developing cardiovascular disturbances in the case of healthy individuals. However, the underlying mechanisms are not fully known yet. Several explanations have been proposed, including changes at the level of clotting factors, genetic factors that increase the risk of having both depressive and cardiovascular disease symptoms, and changes in the metabolism of glucose. Inflammation is a physiological mechanism often mentioned in studies regarding the underlying processes of developing depressive symptoms in the evolution of cardiovascular diseases (18).


Several neurotrophic and growth factors, such as the vascular endothelial growth factor (VEGF), the fibroblast growth factor-2 (FGF-2) and the insulin-like growth factor-1 have been implicated in the etiopathology of major depressive disorder. Particular attention was paid to brain-derived neurotrophic factor (BDNF), which is a molecule with a wide range of biological activities. Numerous studies have reported low levels of BDNF at the hippocampal level in various stressful situations (19). Moreover, after analyzing post-mortem brains of patients, low levels of BDNF were found, especially in the case suicidal patients and those with depressive mood disorders. Stress and hypercortisolism would induce the atrophy of the hippocampus and reduced synaptic plasticity, by shortening the dendrites. Chronic antidepressant treatment increases the effect of neurotrophic factors, neurogenesis and the hippocampal volume, which would explain the several weeks long latency for the antidepressant effect to appear (20).

The fibroblast growth factor plays an important role in the development of the neocortex and in the survival and growth of neurons in adults. The essential role that FGF occupies in the brain is regulating neuronal proliferation, and the migration, differentiation and survival of glial cells. Precursors of neural plate cells have the capacity to differentiate into dopaminergic and serotonergic neurons, and are believed to be associated with neural plasticity. The abnormal expression of FGF may cause depression (21). FGF-2 protects ischemic tissue by activating the anti-apoptotic protein (22). Although experiments on mice showed an association between post-stroke depression and low levels of monoamine neurotransmitters and FGF-2, the link between FGF and depression is not clearly established yet (16).

Finally, a stroke involves neurodegeneration. The vascular hypothesis posits that even the small lesions that disrupt important neural pathways can precipitate the occurrence of depression. For example, ischemic brain injuries may directly disrupt upward monoamine projections from the midbrain and the brainstem. In addition, the gradual accumulation of multiple vascular lesions may eventually pass a critical threshold, beyond which the risk of depression occurrence is very high (23).

In 1980, Robinson and his colleagues demonstrated for the first time that there is a correlation between a high depression score, calculated using the Hamilton and Zung scales, and left-frontal injuries, indicating that there is an association between the specific location of an injury and mood fluctuations in the case of patients who suffered a stroke (24, 25).

Psychopharmaceutic therapy provides an effective treatment for post-stroke depression. New clinical trials suggest that treatment with a selective serotonin reuptake inhibitor, applied in the subacute phase, can have multiple beneficial effects, that extend far beyond mood fluctuations, in recovering from a stroke. For example, the FLAME multicenter study demonstrated that the early prescription of fluoxetine (starting five to ten days after the CVA) to patients with ischemic stroke and moderate to severe motor deficit, but with no form of depression, significantly accelerated motor recovery after three months. Moreover, double-blind studies have reported an increase in the survival rate of both patients with depression and the control group who followed an antidepressant treatment for a period of 12 weeks during the immediate recovery phase (26).


Inflammation, cognitive disturbances and depression are distinctive elements that appear after a stroke. To alleviate their clinical expression, many researchers have studied ways to control these phenomena. Orexins--also known as hypocretins, are neuropeptides synthesized in the posterolateral hypothalamus, and are represented by Orexin A and Orexin B. They have widespread projections and implications in regulating metabolism and the sleep-wake rhythm. Three remarkable roles of orexins have been described after stroke: 1) they control the inflammation by regulating the expression of immune mediators, such as pro-inflammatory cytokines; 2) they improve memory, promote hippocampal neurogenesis and protect the neural pathways from damage caused by poststroke oxidative stress; 3) they alleviate depression by accelerating the secretion of neurotrophic factors. Although studies on the post-stroke role of orexins are still in the preliminary stages, further research may reveal their clinical value as effective therapeutic modulators, given their preventive role over the emergence of new, secondary strokes.


Aphasia has a prevalence of 31% in the case of a first stroke and persists in a proportion of 60% at 12 months after it. As a consequence, important psychosocial and lifestyle changes occur, such as reduced professional performance or even the inability to work, impaired relationships with others and social withdrawal. The incidence of depression after aphasia is estimated to be at 62%-70%, which is higher than in the case of stroke survivors who don't develop aphasia. Family members of patients with aphasia are also prone to develop depression, as well as to suffer a variety of psychosocial consequences. Due to communication difficulties, people with aphasia have reported difficulties in accessing existing mental health services, interventional programs or support groups that could meet their needs (27).

Patients older than 55, females and those with poor lifestyle choices have been identified as demographic categories with increased risk factors in the onset of depression. In support of the need to improve the quality of life of patients with aphasia in the long term, an intervention program called Aphasia Action Success Knowledge (Aphasia ASK) has been developed. It addresses patients that are within 6 months after the stroke, and includes explanatory concepts regarding the stroke and aphasia, elementary communication strategies regarding the management of mood fluctuations and strategies for creating social support networks. Preliminary results showed a significant improvement in the quality of life and a lower incidence of depression among participants and their family (28).


Patients with stroke show constant changes regarding their mood, ranging from simple emotional reactions, such as low motivation, indifference and frustration, to more severe depressive symptoms, such as appetite loss, insomnia and feelings of being useless. Depression is the most common psychiatric problem encountered after a stroke, and can occur from few days up to several months post-CVA. Several risk factors for the occurrence of post-stroke depression have been identified, such as age, sex, social background, but also patients' comorbidities and the presence of aphasia.

The diagnosis of post-CVA depression, however, is still a challenge, the symptoms often remaining unrecognized or untreated. The families of these patients are also at risk of developing depression, which leads to important consequences, from both a social and an economical point of view.

The physiological mechanisms involved in the onset of post-stroke depression haven't been fully elucidated yet. On the other hand, preliminary studies in this field seem to open up new ways in developing more efficient therapeutic strategies.

Finally, it is widely accepted that early recognition and management of depression is an important aspect at any stage of post-stroke rehabilitation. Thus, the development of support groups, educational, preventive, and interventional programs play a key role in the recovery process of these patients and in their social reintegration.


Authors state that there are no declared conflicts of interests regarding this paper.


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Raluca Mihaela FRINCU-Ph. D. Student, Department of Psychiatry, "Gr. T. Popa" University of Medicine and Pharmacy, Fourth Year Resident, "Socola" Psychiatry Institute of Iasi, Romania

Livia Andreea LUPSA-First Year Resident, "Socola" Psychiatry Institute of Iasi, Romania

Cristinel STEFANESCU-Prof., Ph. D., "Gr. T. Popa" University of Medicine and Pharmacy, Chief M. D., Residency coordinator, Section V, "Socola" Psychiatry Institute, Iasi, Romania



Ph. D. Student, Department of Psychiatry, "Gr. T. Popa" University of Medicine and Pharmacy No. 16 Strada Universitatii, zip code 700115, Iasi, Romania Fourth Year Resident, "Socola" Psychiatry Institute of Iasi, No. 36 Soseaua Bucium, zip code 700282, Iasi, Romania


Tel.: +40 742 795 086

Submission: April, 11th, 2016

Acceptance: May, 18th, 2016
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Author:Frincu, Raluca M.; Lupsa, Livia A.; Stefanescu, Cristinel
Publication:Bulletin of Integrative Psychiatry
Article Type:Report
Date:Jun 1, 2016
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