Biological and behavioral correlates of stroke and depression.

Introduction

Stroke is the third leading cause of death in the United States (US). An estimated 500 000 to 600,000 Americans suffer a stroke each year and 150,000 die following the event.[10,15] The incidence of stroke is increasing among young adult drug users but remains highest

One of the most widely accepted definitions of stroke is that it is "an acute neurological dysfunction of vascular origin with sudden (within seconds) or at least rapid (within hours) occurrence of symptoms and signs corresponding to the involvement of focal areas in the brain" (p. 1412).[14] mortality from stroke has declined in the past two decades due to better acute care, reduced stroke seventy as well as earlier and more accurate diagnosis.[15,31]

More individuals are surviving a stroke which has important personal, financial and societal implications. There are currently over 3 million stroke survivors in the US with an average cost of $22,000 per patient for rehabilitation.[1,9,10] It was recently estimated that the direct and indirect lifetime cost of a first ischemic stroke occurring in 1990 was $90,981 with an aggregate cost of $29 billion.[35] There are significant physical and psychological consequences in addition to the economic considerations. Investigators have identified that between 25% and 60% of stroke survivors experience/clinically significant depression.[3,4,6,38] Stroke survivors can be left with significant physical disability and depression can compound morbidity as it can interfere with rehabilitation, mentation and recovery of functional ability.[26]

A better understanding of the biological and behavioral correlates of stroke and depression will assist neuroscience nurses to decrease the morbidity in this expanding population of stroke survivors. This article summarizes the current literature on the biological and behavioral correlates of stroke and depression. Discussion of the biological correlates includes anatomical and neurochemical links suggested by current research. Depression, while not the only behavioral correlate following stroke, is the major focus. Implications of the biological and behavioral correlates for assessment and newer treatment options are discussed.

Biological Factors

The biological factors that link stroke and depression include anatomical and neurochemical correlates. Anatomical correlates include the ongoing debate about whether patients who have a stroke in the left hemisphere of the brain show more depression, those with a stroke in the right hemisphere are more depressed. or neither. Additional anatomical correlates include specific areas of the stroke lesions that researchers have found to be highly associated with depression. Research findings in each of these areas are summarized.

Anatomical Correlates

Early studies linking stroke and depression suggested that patients with left hemisphere damage had a greater incidence of depression. A group of investigators headed by Robinson at John Hopkins in Baltimore has been interested in the relationship of laterality and depression since the early 1970's. This group has consistently reported that the severity of depression was significantly increased in patients with left hemisphere lesions when compared to any other location.[24,27-29] Instruments used by this group to measure depression include the Hamilton Depression Rating Scale (HDRS), the Zung Depression Scale (ZDS) and the Present Examination Scale (PES). There are several limitations of these studies. They were conducted before the wide-spread availability of computed tomography (CT) or magnetic resonance imaging (MRI) scans to give investigators reliable information on the site of the lesion. The samples were restricted in that participants were excluded for failure to complete the depression measures.[22] At the same time subjects were not excluded for a prior history of dysthymia.[22]

More recent studies have continued to suggest a relationship between left hemisphere lesions and increased rates of depression. Astrom conducted a three year longitudinal study of 80 patients following an acute stroke.[3] The mean age of participants was 73 years. The prevalence of major depression, defined according to the DSM-III symptom criteria, was 25% at the acute stage, 31% at three months, 16% at 12 months, 19% at two years and 29% at three years.[3] One of the most important predictors of immediate major depression was a left anterior brain lesion.[3]

Patients with strokes in the right hemisphere are thought by many to be characterized by indifference and an apathetic mental state associated with cheerfulness.[38] Ross and Rush reported three cases of depression in patients with right hemisphere strokes characterized by dysphoria that interfered with verbal cognitive set in all cases and vegetative behavior in two cases.[30] This was a case report article in which depression was diagnosed by clinical interview and no standardized measures of depression were utilized.

In a study of 20 stroke patients reported by Folstein, Maiberger and McHugh, patients with a right hemisphere stroke were found to display a syndrome of irritability, loss of interest, difficulty in concentration and depression of mood.[13] Instruments used included the HDRS, The Visual Analogue Mood Scale, the PES and the Mini-Mental State Exam (MMSE).[13] Limitations of this study included a small sample size; in addition the main focus was mood disorders, not depression.

Bacher, Korner-Bitensky, Myo, Becker and Coopersmith conducted a study of 48 stroke patients in rehabilitation to examine the course of poststroke depression and the relationship between depression and physical and cognitive functioning over a year.[4] of depressed patients, 64% had lesions in the right hemisphere.[4] Only the ZDS was used to determine depression in this study.[4] Selection bias was also a limitation of this study as only rehabilitation patients were included thereby excluding the most severely or mildly-impaired patients.

Williams, Little and Klein investigated the relationship between depression and stroke laterality in 100 rehabilitation patients.[40] Using the ZDS it was found that approximately 30% of subjects were clinically depressed, regardless of the side of the lesions.[40] Sinyor, Amato, Kloupek, Becker, Goldenberg and Coopersmith examined poststroke depression in a rehabilitation program.[34] Depression was evaluated in this study using patient self-report measures and staff rating.[34] No overall differences in rate of depression were found between patients with right or left hemisphere lesions.[34] Whitney, Burn, Frederic and Lowery also reported no relationship between laterulity and depression in their study of stroke survivors.[38] Two depression measures, the Geriatric Depression Scale (GDS) and the Beck Depression inventory (BDI) were used to assess depression in 80 subjects four weeks and three months after a stroke.[38]

Investigators have explored other anatomical correlates with depression besides laterality. Robinson, Starr, Lipsey, Rao and Price studied 103 stroke patients over two years in an attempt to determine the variables that were associated with the development of depression.[29] Three and six months after the stroke there was a strong relationship between severity of depression and distance of the lesion on CT from the frontal pole.[29] The closer a left hemisphere lesion was to the frontal pole, the more severe the depression. This study used three instruments to measure depression: the HDRS, the ZDS and the PES.

Herrman et al conducted a study of poststroke depression in 47 patients with a single demarcated unilateral lesion.[17] The researchers concluded that patients with lesions in the left basal ganglia scored higher in the Cornell Depression Scale (CDS) and the Montgomery-Asberg Depression Rating (MAS) (Mann-Whitney U test p [is less than] .05).[17] Limitations included a highly select patient population that was over-represented by males and young patients and therefore not generalizable to the population of stroke patients.

In summary, studies attempting to correlate laterality, or a specific anatomic site, with prevalence rates of depression contain many methodological problems. Many early studies were conducted before the widespread use of CT and MRI that allowed investigators to identify with certainty the size and anatomical location of the lesion. Sampling issues include small sample sizes as well as differences in patient selection criteria.[17] Some studies have an additional sampling problem in that not all patients were screened for a history of psychiatric and substance abuse problems. Uniform time spans from onset of stroke to investigation were not utilized and differing definitions of depression were measured with different scales, making comparison of different studies impossible.[17,26]

There may or may not be different prevalence rates of depression following stroke depending -- the side of the lesion or other specific anatomical locations. Carefully controlled, well-designed research studies are still needed to answer this question. Clearly, neuroscience nurses working with stroke survivors should be alert for signs and symptoms of depression in all stroke patients. An intriguing alternate explanation for depression following stroke is that depression is due to neurochemical changes in the brain irrespective of anatomical location.

Neurochemical Correlates

For many years clinicians felt that depression following stroke was a psychological reaction to the residual disability. More recently, investigators have hypothesized that it may, in fact, be a direct result of neurochemical changes caused by the brain lesion.[2]

When a stroke occurs there is reduced blood flow and oxygen supply at the lesioned area.[41] There is evidence that these alterations lead to hypersecretion of cortisol and disruption in neurotransmitter systems.[17,33] Each of these mechanisms is discussed but it is essential to keep in mind that within the brain information processing is integrated, ongoing and occurs on several different levels simultaneously. Thus the systems are interconnected and influence one another.

Hypercortisolism is common in the first weeks and months following a stroke.[33] initial increases in cortisol represent a normal stress response but prolonged elevation can lead to deleterious effects. There is evidence that the increased cortisol following stroke is due to increased secretion and disturbed negative feedback.[33] Subsequent therapies are thus aimed at decreasing cortisol levels and correcting the disturbed feedback loop.[33]

An additional element of hypercortisolism is that it is interconnected with the neurotransmitter systems. The possible mechanism of enhanced glucocorticoid associated neurotoxicity is displayed in Figure 1. The cycle begins with either (A) a decrease in hippocampal neurons, or (B) decreased expression of glucocorticoids (GR) and mineralocorticoid (MR) by neurons and the sensitivity of the hippocampus becomes increased. This leads to elevated glucocorticoid levels that increase the vulnerability of remaining hippocampal neurons. This brings the pathway full cycle to further neuronal loss, perhaps in cells with the highest glucocorticoid levels. This complex mechanism has been deduced from research on the aging brain and is thought to be applicable to the brain following a stroke.[33] It is of particular importance in attempting to understand depression following stroke as the hippocampus plays an important role in memory, mood and behavior.[33]

[Figure 1 ILLUSTRATION OMITTED]

An alternate, or perhaps interconnected, explanation for the disturbance in neurotransmitter function is that the reduction in blood flow following a stroke causes a marked increase in extracellular adenosine, a global and long-lasting modulator of brain activity.[41] A massive release of excitatory amino acids (EAAs) also occurs following stroke. The principal EAAs are glutamate and aspartate. The increase in adenosine, and subsequently EAAs, is thought to cause the ischemic damage following stroke. These excess substances also disrupt the calcium channels, causing the neurotoxicity thought to result in a direct depletion of biogenic amine neurotransmission thereby leading to poststroke depression.[41] Serotonin and norepinephrine (NE) are the two neurotransmitter systems that appear to be disrupted.

The serotonin and NE neurotransmitter systems contain a number of steps in their synthesis and utilization pathways. The steps in each pathway include synthesis, vesicular uptake, transmitter release, receptor binding, cellular uptake and transmitter metabolism.[39] Each step in the pathway offers a potential target for pharmacological intervention. NE is synthesized from tryrosine.[39] Clonidine is thought to act at the receptor binding site and desimipramine at the cellular uptake site.[39] These drugs increase the amount of NE and help combat poststroke depression.

The second neurotransmitter system implicated in poststroke depression is serotonin, but its exact role in poststroke depression is not clearly understood. This neurotransmitter is widely distributed throughout the central nervous system. The neurons that produce serotonin are located in the median and dorsal rapine nuclei of the brainstem with ascending projections to the cortex.[2,20] There is evidence both that excessive and depleted serotonin have a role in depression.[16,33] Some researchers suggest there may be an insufficient amount of upregulation of serotonin, while another suggested mechanism is reduced postsynaptic serotonin receptors.[20,25] Several clinical trials suggest the beneficial effect of serotonin reuptake inhibitors as a treatment modality.[2,11] However, the exact role of serotonin and subsequent treatment of depression following stroke with serotonin reuptake inhibitors needs further study in well-designed clinical drug trials.

Of even greater interest than drug trials are studies of stroke patients using positron emission tomography (PET) that are yielding valuable information about the role of serotonin following stroke. A PET technique has been developed to assess cortical serotonin receptor density levels. This beginning research suggests that receptor densities vary according to the site of stroke and that the ipsilateral temporal cortex receptor density is inversely correlated with severity of depression.[20] Researchers who studied 26 patients suggest that cognitive performance following stroke may also be influenced by changes in the serotonergic system.[20] The important relationship between cognition and depression is beginning to be investigated. PET is an expensive study and not universally available, however, this new technology provides an important method to further investigate the link between serotonin binding and severity of depression thereby furthering the development of new knowledge in this area.

Overall, current knowledge concerning neurochemical correlates between stroke and depression is derived from information about the neurochemical changes that occur with normal aging or during depression alone.[33] It is not clear what neurochemical changes can be attributed to stroke, aging or depression alone or more importantly in combination. Exploration of neurochemical correlates between stroke and depression is an exciting, wide open area.

Behavioral Correlates

Behavioral manifestations occurring after stroke include apathy, anxiety,[6] indifference, inappropriateness, pragnosia, depression, mania,[22] and uncontrolled crying.[26] Depression is by far the most common psychosocial complication reported in 25-60% of patients and appears to have the most profound consequences.[16] Depression interferes with rehabilitation as well as mentation,[26] possibly leads to dementia[22] and may be responsible for poor functional outcome.[19]

There is an ongoing debate as to actual prevalence rates associated with left and right-sided lesions in stroke. However, it is clear that patients with left hemisphere (LH) lesions and right hemisphere (RH) lesions have very different behavioral manifestations, especially with respect to the manifestation of depression.

The left hemisphere of the brain is dominant for language and therefore it is no surprise that patients who have had a LH stroke suffer significant disturbances that impede expression and receptive abilities.[22,36] Aphasia in LH stroke has been reported in as many as 73% of patients.[22] Other neurological deficits in LH stroke include right hemiparesis; right-sided sensory loss; right visual field defect; poor right conjugate gaze; dysarthria. and difficulty in reading, writing or calculating.[36]

Nelson et al conducted a longitudinal study of emotional dysfunction in 7 LH poststroke patients.[22] Emotional dysfunction was measured using the variables of indifference, inappropriateness, depression, pragnosia and mania. Depression was measured using the BDI. Patients showed the maximum amount of emotional dysfunction at two weeks following stroke with steady improvement in all five variables over the six-month course of the study. Limitations of this study included a small sample size and although the authors called it a longitudinal study, it took place over only a six-month time course.

The right, or nondominant, hemisphere of the brain has primary functions of visual and spatial perception. Common neurological deficits that occur in patients who have a RH stroke are neglect of the left visual space, left visual field, left hemiparesis, left-sided sensory loss, poor left conjugate gaze, extinction of left-sided stimuli, dysarthria and spatial disorientation.[36] In addition there is a high degree of emotional dysfunction, indifference and denial.[66]

In a six-month longitudinal study of 10 RH patients, Nelson et al reported a trend toward increased indifference beginning two weeks following the stroke, and peaking at six months.[22] The onset of indifference was felt to be a component of endogenomorphic depression.[22] Limitations of the study include a small sample size and a relatively short follow-up time of six months. Some suggest that poststroke depression lasts years.

Further well-designed research is needed on behavioral manifestations following stroke. This beginning body of knowledge helps neuroscience nurses increase their understanding of the behavioral manifestations associated with LH and RH strokes.

Assessment of Depression Following Stroke

The Agency for Health Care Policy and Research (AHCPR) clinical practice guidelines for poststroke rehabilitation include recommendations for diagnosing and treating depression following stroke.[15] clinicians should have a high index of suspicion for depression in all stroke rehabilitation inpatients. Appropriate measures also need to be taken to determine the presence as well as the cause of depression.[15] Furthermore, the recommendation states that a diagnosis of depression depends primarily on the clinical examination and is supplemented, when needed, with the use of selected depression scales.[15] Although the AHCPR guidelines focus on in patient rehabilitation, acute care and outpatient practitioners should also be alert to signs and symptoms of depression. The key to obtaining a referral for psychiatric evaluation during any phase of care is a complete nursing assessment using both subjective and objective data.[6-8]

Subjective data are obtained by interviewing the patient and/or family members. Data need to be Collected on appetite, bowel, or sleep disturbances; loss or change in energy level; anxiety; difficulty concentrating; level of participation in therapy and feelings of hopelessness.[7,23] Observations need to include the patient's affect, interactions with family and friends and level of participation in care.[7] Caution should be used in assessing affective symptoms such as indifference, as these may be misinterpreted as depression.[13,16] An additional area for investigation is whether there is a history of substance abuse, depression or other psychiatric problems in the patient as well as any family history.[21]

There are many objective measures of depression, the most common being instruments that can be used by the nurse to measure level of depression. Table 1 summarizes some of the many instruments currently available to assist in depression assessment. Although use of standardized scales can assist the nurse in recognition of depression one must keep limitations in mind. For example, Bacher warns that depression scales must be used with caution on physically-impaired individuals.[4] Many scales contain items such as sleep pattern changes, weight loss and change in physical activity that may be more a result of the physiological changes of the stroke itself.[4] Self-administered tests or scales should be used with caution as the results will depend on the patient's energy level, motivation, understanding and ability to handle the test. Each of these components can be affected by the stroke and/or depression.[26] Price suggests that having a nurse administer these types of tests to patients who are not aphasic; using visual aids to assist the patient to pick the best answer will improve reliability.[26]

Table 1. Instruments for Measuring Depression

Cornell Depression Scale (CDS)(25)
Composite Depression Index (CDI)(24)
Composite International Diagnostic Interview(CDI)(39)
Center for Epidemiological STudies Depression Scale(CES-D)(13)
Beck Depression Index (BDI)(13,14,20,38)
Beck Hopelessness Scale (BHS)(24)
Geriatric Depression Scale(GDS)(14,40)
Hamilton Depression Rating Scale (HDRS)(17-19,38)
Hopkins Symptom Checklist (HSCL)(24)
Montgomery-Asberg Depression Rating Scale(MAS)(25)
Nurses' Rating Scale (NRS)(24)
Present State Examination (PSE)(17-19)
Zung Self-rating Depression Scale (ZDS)(12,17-19,23,24)

A biological test would be a helpful Objective measure to assist in identifying patients with depression, especially in aphasic patients. The dexamethasone suppression test (DST) has been used in some studies as a biological marker.[7,30] The DST is performed by administering one mg of dexamethasone orally at midnight, then measuring serum cortisol levels at eight AM, four PM, and eleven PM the following day.[17,30] Nonsuppression, or an excess cortisol level, is found in 60-80% of psychiatric inpatients with depression. Nonsuppression reverts to normal suppression with antidepressant treatment in Psychiatric patients. Some investigators have found this test useful as a marker of depression following stroke.[30] Others report that the DST is not sensitive enough to identify all depressed patients and not specific enough because patients with large infarcts may have nonsuppression even when not depressed.[26]

The cornerstone of assessment remains the collection of subjective and objective data. Investigation continues in the search for a sensitive and specific biological marker for depression following stroke.

Current Treatment Modalities

The current AHCPR poststroke rehabilitation clinical practice guidelines states that the choice of treatment for depression should depend on the cause and severity of symptoms.[15] Different treatments are suggested for mild and severe depression. Interventions for each are

Mild depression has a shorter average duration following stroke and a wide range of interventions has been suggested.[8,21] Recommendations include increased attention and encouragement from staff and family members, changes in environment (providing a positive milieu), as well as active participation in therapeutic activities.[15,32] Providing social support to stroke survivors and their families is advocated, as is poststroke education and counseling.[12] AS of yet, no well designed intervention studies have identified optimal intervention strategies for mild depression.

Severe, or major, depression has been recognized to have a longer duration and is also treated with a wide range of modalities.[8,21] Antidepressant medications as well as cognitive, interpersonal or behavioral psychotherapy are commonly utilized.[15] Table 2 contains a partial list of the wide range of antidepressant medications used to treat depression following stroke. There is general agreement that drug treatment for depression should be used with caution as adverse effects are common, especially when using tricyclic antidepressants.[7,15] The anticholinergic effects are a concern, especially for the stroke patients who may have bladder, bowel and cardiac problems.[23] Dosages should be the smallest possible in this elderly population. The newest class of drugs, the selected serotonin reuptake inhibitors (SSRI), may have fewer adverse effects.[23]

Table 2. Drugs Used in the Management of Depression
Following Stroke

Tricyclic Antidepressants(7,15)
   Amitriptyline (Elavil, Endep, Etrafon, Limbitrol, Triavil)(7,30)
   Doxepin (Sinequan, Adapin)(7)
   Impramine (Tofranil, SK-Pramine, Janimine)(7,30)
   Desipramine (Norpramin, Perfofrane)(7,30)
   Protiptyline (Vivactil)(7)
   Nortriptyline (Pamelor)(7,15,24,27)
   Amoxaprine (Asendin)(7)

Tetracycline
   Maprotiline (Ludiomil)(7,11)

Selective Serotonin Reuptake Inhibitors(15)
   Fluoxetin(11)

Other
   Trazodone (Desyrel)(7,15,24)
   Dexedreine(23)
   Methylphenidate(23)

Summary

Many questions and uncertainties remain surrounding the biological and behavioral correlates of stroke and depression. Newer technologies, in the form of state of the art imaging equipment, should assist those involved in these research areas to address questions about the anatomical and neurochemical connections between stroke and depression. More well-designed research studies are needed on the behavioral manifestations following stroke. Although the many assessment tools currently available are helpful, the identification of a biological marker would further enhance the assessment of depression following stroke.

Neuroscience nurses, as well as other health professionals, are becoming more aware that poststroke depression is underrecognized and undertreated.[16,26] It is currently seen as more than just a normal reaction to the loss associated with stroke. These changing attitudes, will hopefully lead to increased treatment for this important problem along with some well-designed clinical trials testing pharmacological as well as nonpharmacological interventions for patients who are depressed following a stroke.

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Questions or comments about this article may be directed to: Janice Hinkle, RN, MSN, CNRN, 775 N. 24th Street, Philadelphia, Pennsylvania 19130.

She is a doctoral candidate at the University of Pennsylvania School of Nursing.