Depression is the most highly prevalent neuropsychiatric syndrome across all neurologic illnesses (Fig. 5-1). The relationship between depression and neurologic illness is complex in several aspects, including pathophysiology, clinical presentation, and response to treatment. Depression may sometimes be the direct result of brain pathology, very much like other neurological manifestations, such as cognitive or motor disturbances. In other cases, a more complex interplay of neurobiological, environmental, and coping mechanisms appears responsible for the development of depressive symptoms (Box 5-1). Neurologic illness may produce signs and symptoms that mimic depression, such as psychomotor retardation, apathy, concentration deficits, and sleep disorders, making the diagnosis of depression in the context of neurologic illness challenging. However, the identification and treatment of depression in these individuals is of fundamental importance, as this tends to improve the prognosis of the neurological disease.
Mean risk of depression for selected illnesses (% prevalence for particular disease.)
BOX 5-1 IMPORTANT RISK FACTORS FOR DEPRESSION IN NEUROLOGICAL DISEASE
Personal or family history of depression
Alcohol and substance use disorders
Cortical and subcortical atrophy
Lesions of left frontal lobe, basal ganglia
Frontal and temporal lesions; atrophy and hypointense lesion burden (MS)
Other specific lesions (see Fig. 5-2)
Localization-based clinical phenomena underlying brain-behavior relationships in traumatic brain injury.
This chapter covers depression in the context of specific neurological disorders, such as dementia, cerebrovascular disease, Parkinson disease (PD) and other movement disorders, multiple sclerosis, traumatic brain illness, and epilepsy. Depression in the context of pain is covered in Chapter 21 and depression in the context of a sleep disorder is covered in chapter 22.
See Figure 5-1 and Box 5-1 for prevalence and risk factors of depression in different neurological illnesses.
“Dementia” refers to a syndrome characterized by cognitive deterioration, behavioral abnormalities, and possible personality changes that significantly affect daily functioning. A dementia syndrome can be caused by myriad etiologies, including neurodegenerative processes, such as Alzheimer disease (AD), dementia with Lewy bodies, and frontotemporal dementia, cerebrovascular disease, traumatic brain injury (TBI), infectious illnesses such as HIV, and other neurologic disturbances. This section covers depression in dementia secondary to a neurodegenerative process, with emphasis on depression in AD. Depression refers to clinically significant depressive symptoms, rather than particular subtypes as defined by Diagnostic and Statistical Manual of Mental Disorders (DSM) unless otherwise noted. Cerebrovascular depression and depression associated with PD are addressed later in this chapter.
Neuropsychiatric symptoms are common in dementia, and depression is one of the most frequent manifestations.1,2 Much of the research in this area has focused on the relationship between depression and AD. The reported prevalence of depression in the AD population (dAD) varies widely. This heterogeneity is in part due to differences in depression criteria, depressive subtypes included, study settings, and assessment methods used in various studies.3 Estimates range between 1% and 90%, but the majority fall between 30% and 50%3–5
There is very little published data on depressive subtypes within the dementia population. A 2010 study6 categorized patients with dementia into one of three groups by etiology: AD, vascular dementia, or unidentified dementia. Approximately 18.5% of patients with AD were depressed; 5.05% of that group met ICD-9 criteria for major depressive disorder (MDD), 1.93% for dysthymic disorder, 0.71% for adjustment disorder with depressive symptoms, and 0.20% depressive psychosis. An additional 12.8% were diagnosed with depressive disorder not otherwise specified.
In AD, the pathophysiological process is thought to begin many years before the clinical symptoms. In an initial stage, there may be asymptomatic cerebral amyloidosis without evidence of neurodegeneration. Later on, markers of neuronal injury, such as elevated CSF tau, cortical thinning/gray matter loss, and cortical hypometabolism may be present. After the preclinical stage, often a period termed mild cognitive impairment (MCI) during which a person experiences a subjective sense of intellectual decline without a change in functional ability precedes diagnosis. Ample evidence suggests that depression and dementia are inextricably linked. Whether depression is a risk factor, prodrome, or consequence of AD is an ongoing area of research. Several studies suggest a history of depression earlier in life approximately doubles the risk of developing dementia.7–11 On the other hand, late-life depression (usually defined as presenting at age 60 or older) may represent a prodrome of incipient dementia. Although a definitive pathophysiological link between depression and dementia has yet to be established, several theories have been proposed.12,13 These include dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, sequelae of chronic inflammation, and nerve growth factor derangements. See Box 5-2 for possible mechanisms for depression in neurological illnesses.
BOX 5-2 POSSIBLE MEDIATORS BETWEEN NEUROLOGICAL ILLNESSES AND DEPRESSION
Dysregulation of HPA axis
Nerve growth factor derangements
Direct brain insults
Depletion of neurotransmitters
Reaction to serious illness
Learned helplessness (e.g., epilepsy)
DYSREGULATION OF THE HYPOTHALAMIC–PITUITARY–ADRENAL AXIS
Major depression is associated with elevated cortisol levels, mediated by increased cortisol release and lack of sensitivity to normal negative feedback mechanisms. Excess cortisol is linked to hippocampal atrophy in animal models and human studies, an anatomical change that also occurs in AD.14 In addition, longitudinal studies suggest that chronically elevated glucocorticoids levels can adversely affect memory.15 Glucocorticoids can trigger apoptotic death in hippocampal neurons via activation of the glucocorticoid receptors.16 In animal models of AD, stress level glucocorticoid administration promotes beta-amyloid deposition.17
Both depression and cognitive decline may be mediated through inflammation. Depression is considered a proinflammatory state, with increased levels of cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor (TNF). These cytokines can (through a series of intermediary steps) reduce synaptic plasticity and hippocampal neurogenesis. Proinflammatory cytokines can also promote neurodegeneration by inducing neuronal apoptosis.18 Amyloid-β (Aβ) can activate microglia to release proinflammatory cytokines. Microglia activation can be found in patients even at the earliest stages of cognitive decline, such as MCI.19
Neurotrophins are essential in modulating synaptic plasticity and maintenance of neuronal health.20 Levels of certain neurotrophins, such as brain-derived neurotrophic growth factor (BDNF) and transforming growth factor (TGF), are reduced in both dementia and depression. Impaired BNDF signaling occurs in animal models of stress-induced depression, humans with depression, and individuals with AD. BDNF is essential in regulating hippocampal plasticity, and therefore likely involved in maintaining cognition and memory.
It bears mentioning that simply being aware of cognitive deficits, or being diagnosed with a neurodegenerative disorder, do not seem to necessarily result in a “reactive” depression. Several studies showed no correlations between awareness of cognitive deficits or diagnosis of cognitive impairment and depression scores.21–24
In general, depression in dementia presents similarly to major depression in the nondemented population. Regarding depression in the setting of earlier and milder cognitive deficits, the most common symptoms of depression in MCI may be excessive worrying, hopelessness, and crying spells.25,26 See Box 5-3 for symptoms commonly associated with depression in the different neurological illnesses.
BOX 5-3 DEPRESSION IN NEUROLOGICAL ILLNESSES: IMPORTANT ASSOCIATED SYMPTOMS
More typical in depression associated with cognitive impairment
Crying and affective lability
Psychomotor slowing and fatigue
More typical in depression associated with cerebrovascular disease
More typical in Parkinson disease
More typical in MS
Insomnia, other sleep disorders
Irritability and mood lability
More typical in TBI
More typical in epilepsy
Short lived symptoms associated with particular phase of the seizure (i.e., pre or post ictal)
Depression in AD is notable for a higher frequency of motivational disturbances such as psychomotor slowing and fatigue, whereas geriatric depression without cognitive impairment has a higher frequency of mood symptoms, such as depressed mood, anxiety, suicidality, and sleep and appetitive disturbances.27 Studies have also found that depression with AD is associated with higher rates of delusions and other psychotic symptoms than general geriatric depression.27,28 A 2011 study of AD patients found that within those with depression, sadness, loss of interest, and agitation/retardation were the most common among the depressive symptoms.29 Sadness, anxiety, suicidal thoughts, poor self-esteem, multiple physical complaints, and pessimism best distinguished the depressed patients from the nondepressed.
Depression is considered part of the behavioral and psychological symptoms of dementia (BPSD) spectrum, and is frequently found with other comorbid neuropsychiatric symptoms. These may include anxiety, apathy, psychotic symptoms, mood lability, agitation, or some combination thereof.30 In a 2013 study, Van der Mussele et al.31 found that a number of behavioral symptoms such as delusions, hallucinations, psychosis, activity disturbances, aggressiveness, diurnal rhythm disturbances, affective disturbances, and anxiety/phobia were more prevalent in depressed AD patients than nondepressed AD patients.
COURSE AND NATURAL HISTORY
Longitudinal studies of depression in patients with dementia suggest that mood symptoms may have an episodic, rather than chronic, course and that in a significant percentage of these patients symptoms may improve or remit in subsequent assessments.32–34 In each of these studies, patients with depression would have had access to, and in some cases received, antidepressant treatment. The prevalence of depression and associated complaints (sadness, suicidal ideation, low self-esteem, guilt, anxiety, crying, and hopelessness) in patients with Alzheimer dementia has been found to be highest in the moderately demented population, followed by the mild dementia population.35 Severe dementia is associated with the lowest prevalence of depressive symptoms. As dementia progresses from moderate to severe stages, patients may lose the ability to experience and communicate their psychological state. In addition, they may display other behavioral symptoms such as agitation, aggression, or anxiety, interfering with the identification of depressive symptoms.
While individuals with MCI and mild to moderate dementia may underestimate their cognitive deficits, they remain key informants on their subjective mood state.36 Caregiver input is needed on standard measures of depression, which require recall of sleep and eating patterns and engagement in activities; caregivers also have important observations on affect and behavioral manifestations, such as tearfulness and withdrawal. Although caregivers' reports may be influenced by their own level of distress, studies still show high concordance between clinician-rated, caregiver-observed, and patient-reported mood.36 The best practice for assessment is a clinical interview with both patient and caregiver.
There is substantial overlap between some of the depression criteria and symptoms of dementia (e.g., difficulties with concentration and memory, apathy, and fatigue). In 2001, using the existing criteria for major depression as laid out in the DSM-IV, an expert panel convened by the National Institute for Mental Health (NIMH) created a provisional set of diagnostic criteria for depression in patients with AD: the NIMH-dAD (Table 5-1).
TABLE 5-1Criteria for NIMH Depression of AD as Compared to MDD Criteria ||Download (.pdf) TABLE 5-1 Criteria for NIMH Depression of AD as Compared to MDD Criteria
|MDD ||Depression of AD |
≥ 5 of the following symptoms, present most of the day, nearly every day during a 2-week period and representing change from baseline functioning
Depressed mood most of the day, as either indicated by subjective report or observation of others
Markedly diminished interest or pleasure in all, or almost all, activities (either 1 or 2 are required)
Significant weight loss when not dieting or weight gain, or decrease or increase in appetite
Insomnia or hypersomnia
Psychomotor agitation or retardation
Fatigue or loss of energy
Feelings of worthlessness or excessive or inappropriate guilt
Diminished ability to think or concentrate
Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide
≥3 of the following symptoms, present during a 2-week period and representing change from baseline functioning
Clinically significant depressed mood (e.g., depressed, sad, hopeless, discouraged, tearful)
Decreased positive affect or pleasure in response to social contacts and usual activities (either 1 or 2 are required)
Disruption in appetite
Disruption in sleep
Psychomotor changes (e.g., agitation or retardation)
Fatigue or loss of energy
Feelings of worthlessness, hopelessness, or excessive or inappropriate guilt
Diminished ability to think or concentrate
Recurrent thoughts of death, suicidal ideation, plan, or attempt
Social isolation or withdrawal
Does not meet criteria for a Mixed Episode.
The symptoms are not better accounted for by bereavement.
All criteria are met for dementia of the Alzheimer type (DSM-IV-TR).
Symptoms are not better accounted for by other conditions, such as major depressive disorder, bipolar disorder, bereavement, schizophrenia, schizoaffective disorder, psychosis of Alzheimer disease, anxiety disorders, or substance-related disorder.
The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
The symptoms cause clinically significant distress or disruption in functioning.
The minimum number of symptoms required to diagnose depression in AD was decreased from 5 to 3 and the requirement that symptoms be present “most of the day, nearly every day” was eliminated in favor of relevant symptoms being present “during the same 2-week period.” Anhedonia, or decreased ability to take pleasure in normally enjoyable activities, was expanded to include loss of pleasurable affect or pleasure associated with social and other activities. In addition, “Markedly diminished interest in… activities” was thought to correspond too closely to apathy, a separate neuropsychiatric symptom seen in dementia, and was removed from the criteria. Finally, there were two additional criteria added: social isolation/withdrawal and irritability. The NIMH-dAD has been validated in a small cohort study37 where it is seen to have higher sensitivity and specificity for depression than the DSM criteria.
While much research continues to use DSM criteria for depression in dementia, the NIMH-dAD criteria may be more clinically useful when differentiating depression from age-related physiologic and cognitive changes.
There are several rating scales used to evaluate dementia in depression. Each has its benefits and drawbacks. The Cornell Scale for Depression in Dementia (CSDD) was designed specifically for assessing depression in patients who have cognitive impairments that may hamper answering questions about depressive symptoms. It comprises 19 caregiver and clinician-rated items, a strength as individuals with dementia may not be able to accurately describe their own mood or symptoms. The Geriatric Depression Scale (GDS) is commonly used in the clinical setting. There are 15-item and 30-item versions and the former generally takes 5 to 7 minutes to fill out. The GDS focuses on cognitive and affective aspects of depression, avoiding somatic and sexual symptoms that may return false positive in an older population. The Hamilton Depression Scale's (HDS) longer length and complexity renders it more useful for clinical studies than office use. It is interviewer-administered questionnaire better suited to monitor depressive symptoms and treatment efficacy, than to be used as a screening device (Table 5-2).13
TABLE 5-2Depression Rating Scales ||Download (.pdf) TABLE 5-2 Depression Rating Scales
| ||Cornell Scale for Depression in Dementia ||Geriatric Depression Scale ||Hamilton Depression Scale |
19 caregiver and clinician rated items
15-item version and 30-item version
21 item (although score based on first 17 items only), clinician administered scale
Designed for patients whose cognitive impairments interfere with answering questions about mood
Less emphasis on sexual and somatic symptoms that may lead to false positives in geriatric population
15-item version is short; can be completed easily during clinical appointments
Can be used to track symptom severity over time and monitor treatment efficacy
| || || |
Clinician needs to administer test
Length can make it unwieldy to administer in clinical visits
Any evaluation of mood in dementia requires careful assessment of contributing medical comorbidities, medications with sedating or cognitively dulling side effects, inadequately addressed pain, and metabolic disturbances. Relevant tests include chemistry profile, complete blood count (Box 5-4), liver function tests, thyroid panel, vitamin B12 and folate levels. Additional workup to be considered includes a urinalysis, chest x-ray, electrocardiogram, and neuroimaging. In cases where a patient has episodic changes in mood or alertness, an electroencephalogram may be useful.
BOX 5-4 COMMON COMORBIDITIES OF DEPRESSION IN DEMENTIA
Sedating medication, or medications that dull cognitive function
Inadequately treated pain
The reversible dementia of depression (formally termed “pseudodementia”) presents almost identically to a dementia caused by neurodegenerative processes. It is often diagnosed retrospectively, after successful treatment for mood symptoms results in resolution of cognitive deficits as well. Neuropsychological testing is considered the gold standard in distinguishing between the entities,38 although “poor effort” on testing in the severely depressed may limit its usefulness. Apathy is a common finding in AD, and can present early in the course of the disease. Apathetic patients may appear disinterested in activities they used to enjoy, resist participation in social or family events, and remain inactive for extended periods of time. While apathetic patients have many of the same motivational deficits seen in depression, the syndromes are dissociable.39,40 There are several scales designed to assess for apathy; these include, but are not limited to, the Starkstein Apathy Scale, the Lille Apathy Rating Scale and the Apathy Evaluation Scale. Another important differential diagnosis of dAD is pathological affective display.41 Individuals may present with sudden episodes of laughing or crying. The emotional reaction may be completely unrelated to the individual's state of mind or the current situation. At other times, it may be congruent with the individual's mood but out of proportion to the situation. It is important to note that while the crying may be a pathological display of affect, studies have found significantly higher levels of depression and anxiety in patients with pathological affect than in those without it.42 Thus, any individuals in whom pathological display of affect is suspected should be carefully screened for concomitant depressive symptoms (Box 5-5).
BOX 5-5 DIFFERENTIAL DIAGNOSIS OF DEPRESSION IN NEURODEGENERATIVE ILLNESS
Dementia of depression
Pathological affect (e.g., pathological crying)
There are compelling reasons to treat depression in patients with dementia as soon as possible. It has been demonstrated that depression is associated with earlier placement into a nursing home and a greater likelihood of being discharged earlier from an assisted living facility to a nursing home.43,44 It is also associated with greater rates of physical aggression toward caregivers.45 Finally, the caregivers for people with dementia and depression are at higher risk for depression themselves.46 Promptly identifying and treating depressive symptoms results in better outcomes for both dementia patients and their caregivers.47,48 Treatment may involve biological and psychosocial interventions. Box 5-6 summarizes treatment alternatives for depression in neurological illnesses.
BOX 5-6 TREATMENTS FOR DEPRESSION IN PATIENTS WITH NEUROLOGICAL DISORDERS
SSRIs: often well tolerated but may worsen apathy, agitation or insomnia. Watch for serotonin syndrome, QTc prolongation (rare), exacerbation of motor symptoms associated with particular neurological disorders (e.g., Parkinson's)
Bupropion: theoretical benefit in disease that deplete dopamine.
Seizure risk, esp. with IR formulation
TCAs: cardiac risks, anticholinergic side effects, orthostatic hypotension, make these less attractive alternatives.
Contraindicated in closed angle glaucoma. Seizure risk for some (e.g., clomipramine)
MAOIs: rarely used. Dietary effects may be reduced by using selegiline patch.
Adjunctive carbamazepine (e.g., in TBI)
ECT: risk of cognitive side effects
Psychotherapy: also helpful for caregiver burnout.
CBT, e.g., in Parkinson's, MS
Healthcare providers selecting a pharmacological intervention must take several factors into account, including medication's mechanism of action, side effect profile, interactions, cost and dosing schedule. Serotonin reuptake inhibitors (SSRIs) are generally well tolerated, but may induce agitation, worsening apathy, tremor or sleep disturbances. In addition, it is particularly important to monitor interactions due to the heightened risk for serotonin syndrome, and EKG due to risk for QTc prolongation. SNRIs are an alternative with the potential added benefit of their noradrenergic action, although there are no controlled studies for its use in this population. Tricyclic antidepressants (TCA) carry cardiac risks, including conduction problems and potential heart block. They can also have anticholinergic side effects that interfere with cognition, worsen confusion or cause delirium. Other side effects include orthostatic hypotension, dizziness, dry mouth, constipation, sedation, and urinary retention.41 TCAs should be avoided in patients with closed angle glaucoma. If a TCA must be used, nortriptyline and desipramine have the least severe anticholinergic side effects and one can follow plasma levels to avoid toxicity. Monamine oxidase inhibitors (MAOI) have the benefit of little anticholinergic side effects. They are generally quite well tolerated, but require adherence to a restrictive diet, as ingesting tyramine-rich foods while on an MAOI can cause a hypertensive crisis. One way to circumvent this risk is by using the selegiline patch at its lowest dose of 6 mg/24 hours.13
Research studies have not provided clear direction about which medications confer greatest benefit to depressed individuals with dementia. A 2007 meta-analysis reviewed dAD treatment with TCAs and selective SSRIs. Overall, antidepressant treatment was superior to placebo.48 However, a recent large community-based, multicenter, randomized/placebo-controlled controlled trial in patients with mild to moderate depression in AD showed no difference in patients treated with sertraline or mirtazapine as compared to placebo.49 The Work Group on AD and other dementias (convened by the American Psychiatric Association) suggests SSRIs as the first-line treatment. This is mainly due to SSRIs being better tolerated than other antidepressant classes. There is no clear consensus on which SSRI works best in the dAD population, but paroxetine should be avoided for its relatively greater anticholinergic effects. If patients with dementia develop intolerable side effects or fail to achieve remission, one can consider substituting bupropion, an SNRI such as venlafaxine, or mirtazapine.50
The use of antipsychotics in persons with dementia remains controversial. They do not have an indication for depression per se, but may be helpful in addressing comorbid agitation, aggression or psychotic symptoms. Conventional antipsychotics are generally avoided as older patients and those with neurodegenerative disorders may be especially vulnerable to side effects, such as tardive dyskinesias, parkinsonism, and increased risk of falling.51 Second-generation, or atypical, antipsychotics are better tolerated but several well-documented studies have shown that they may carry an increased risk of adverse cerebrovascular events and a higher rate of all-cause death in individuals with dementia.52 However, as most seasoned geriatric psychiatrists and behavioral neurologists can attest, these concerns must be balanced with the need to manage the neuropsychiatric symptoms of dementia that may be dangerous to the patient or their caregivers. In 2008, the American College of Neuropsychopharmacology (ACNP) published a white paper reviewing available evidence on antipsychotic drug use in the elderly with dementia.53 They provided several clinical recommendations, which included: ruling out medical etiologies of BPSD (e.g., delirium or pain), utilizing nonpharmacologic interventions, and involving caregivers and family members in informed decision making about when to use antipsychotics and the potential risks. If antipsychotic use is unavoidable, the authors recommended identifying target symptoms, monitoring for efficacy and side effects frequently, and discontinuing the medication if target symptoms did not decrease or resolve.
In regard to medication choice, the authors felt that there was not enough evidence to suggest one atypical over another. Whatever agent was used, they advocated for the lowest required doses for the shortest time possible.
Studies that looked at the efficacy of cholinesterase inhibitors for neuropsychiatric symptoms in dementia have demonstrated improvement in various mood symptoms (e.g., anxiety, apathy) but not depression.54–56 Similarly, randomized control trials of anticonvulsant mood stabilizers have provided mixed results at best.57 Stimulants have also failed to show conclusive effects on depression of dementia: while one study found improvement in depression scores in a small group of AD patients treated with methylphenidate,58 another suggests that this may be due to a reduction in negative symptoms rather than true remission of depressive symptoms.59
BRAIN STIMULATION THERAPIES
ECT can be considered to address depressive symptoms in dementia.60 In the elderly without dementia, it can be quite useful in treating depression with psychotic features. However, dementia patients are at heightened risk for adverse cognitive effects of ECT, especially those at later stages of a neurodegenerative process or with a heavy cerebrovascular burden. Often times, dementia patients have medical comorbidities rendering them vulnerable to anesthetic agents. Thus, ECT should be reserved for medication refractory cases, and the patient and/or family must be intensively counseled on the risks and benefits of ECT before providing consent.
There are a limited number of studies looking at other brain stimulation therapies' effects on depression in dementia. There is no consensus as to whether deep brain stimulation (DBS) has any effect on neuropsychiatric symptoms of AD, although its effects in PD are discussed later in this chapter. Vagus nerve stimulation (VNS) appears to be well tolerated in the Alzheimer population but has yet to demonstrate robust effects on mood symptoms.61,62 Transcranial magnetic stimulation (TMS) may have a mild antidepressant effect in depressed patients with AD63,64 and dementia with Lewy bodies.65
The psychosocial treatment of depression in dementia is discussed in a separate section below.
In summary, first-line pharmacologic treatment of depression in dementia should be an antidepressant. Among the various classes, SSRIs offer the best risk/benefit ratio, given their relatively benign side effect profile and lack of diet restrictions. SNRIs can be a useful alternative. If depressive symptoms are refractory, one can consider TCAs or MAOIs with careful patient and caregiver education. ECT remains an option for severe depression when medication truly cannot be tolerated or is ineffective. While newer brain stimulation therapies such as VNS and TMS appear to be well tolerated, they have yet to build a robust body of evidence to support their use in treatment depression in dementia.
PSYCHOSOCIAL TREATMENT OF DEPRESSION IN DEMENTIA AND OTHER NEUROLOGICAL DISEASES
While the main focus of this section is psychosocial treatment of depression in Dementia, many of the general principles discussed here can be applied to depression in other neurological conditions; this includes depression in the context of other neurodegenerative illnesses such as PD, and depression related to brain vascular illness. Often it is family members and not the patient him- or herself who request help with dementia diagnosis and treatment. It is important to help families understand that anosognosia represents impairment in the cognitive processes that support insight; in other words, “denial” is not purely a psychological defense.66 While there is variability in the response to dementia diagnosis, an overarching theme is the tension between preserving key aspects of identity and accommodating change; for people with dementia and their caregivers, dynamics of autonomy and independence are salient with conflicts often emerging around safety.67
Consensus has emerged in favor of “telling the truth in dementia” and current guidelines warn against providers' fear of inflicting harm and caregiver-expressed concerns about impact of diagnosis on patients; instead, the recommendation is for an early dialogue with the patient to elicit his or her preferences for information on diagnosis and prognosis and involvement in treatment decision-making.68 As preferences may change over time it is important to continue this conversation longitudinally, timing and tailoring the referrals according to the clinical needs and the range of resources available.
The majority of people with dementia live in the community with family caregivers who themselves are at risk for psychiatric morbidity (see Box 5-7).69 Rates of depression in dementia caregivers range from 23% to 85% in developed countries.69 The burden of care is highest in the presence of BPSD and neuropsychiatric symptoms, rather than cognitive impairment and needs for direct physical care, are more likely to prompt institutionalization (see Text box 5-7).70–72
BOX 5-7 RISK FACTORS FOR CAREGIVER STRAIN AND PSYCHOLOGICAL MORBIDITY
Neuropsychiatric symptoms of patient
Lack of financial resources
Poor relationship quality and low levels of past/current intimacy
Caregiver perception of “role captivity”
Emotion-based or confrontational coping/communication style
While there is evidence that support and counseling for caregivers reduces depression73 the most effective interventions add cognitive restructuring techniques74 and individually tailored behavioral management training.71,75
Given risk of MCI advancing to dementia, MCI caregivers are ideal targets for skill- and resource-building interventions.76 Spouse caregivers of people with early-onset Alzheimer's and frontotemporal degeneration are hard-hit as they are often raising young children and suffer financial losses during wage-earning years70; they are in need of more specialized information and support which may best be delivered by telephone and internet in remote areas where more specialized services are not available.77 Technology-based formats may also better reach caregivers in cultural minorities who have lower rates of resource use.78
The loss of language, memory, and insight inherent to dementia may be obstacles to the use of traditional psychotherapy. The number of randomized controlled trials of psychotherapy for depression in MCI and dementia is limited and the sample size in existing studies is small; however, research shows that psychotherapy can be adapted and is acceptable to people with MCI and early dementia.79–82 There is some evidence that long-term interpersonal psychotherapy protects against depression recurrent in older people with mild to moderate cognitive impairment.80 Even when adapted to include caregiver, short-term psychodynamic psychotherapy does not seem to produce measurable benefit.83 More research is needed to determine which specific cognitive abilities predict or preclude psychotherapy.
Problem-solving therapy (PST), an approach of inculcating skills to cope with everyday problems, has been adapted to the treatment of depression in elderly people with dementia and executive dysfunction, and is more effective that more emotionally oriented supportive psychotherapy in treating depression and reducing disability.84,85 It is important to note, however, that supportive therapy is a highly flexible approach that includes aspects of problem solving.86 Problem-solving and behavioral therapy have been adapted for intervention with caregivers of people with dementia. The caregiver is trained to initiate pleasant events, distract from negative thoughts, and alter the environment/routine. In two randomized controlled trials, problem-focused therapy with the patient and caregiver in the home was more effective than supportive therapy in reducing symptoms of depression in the person with dementia.87,88
The Alzheimer's association offers community-based support and education programs for patients and caregivers, especially in the vulnerable period after initial diagnosis.89 Participants meet with other newly diagnosed individuals in their community to share experiences and concerns, learn more about the disease, reduce feelings of isolation, and receive assistance in coping with lifestyle changes and developing long-term care plans. While some researchers caution that providing too much information too soon can increase depression for newcomers to groups,90 a waitlist-controlled clinical trial of an Alzheimer's Association Early Stage Memory Loss Support Group found significant reduction in depression symptoms for those enrolled in the group.91 A large-scale randomized controlled Danish trial of 12-month structured psychosocial intervention of counseling, education, and support to people with Alzheimer's and their caregivers found only a small positive effect on mood which was not sustained 24 months after the intervention ended.92,93 A similar Norwegian study found no effect.94 The lack of findings may be attributed to a floor effect as patients had minimal depression symptoms at the outset.92,93 These studies suggest that it is important to assess need and adjust level of intervention accordingly; doing so requires regular follow-up and the ability of providers to “prescribe interventions”95
Although mood is not the primary target of cognitive rehabilitation, training, and remediation, these interventions have secondary benefits likely mediated by increasing experiences of competence and decreasing experiences of frustration in everyday life.96,97 Incorporating cognitive behavioral interventions and motivational interviewing techniques may improve engagement and outcomes.98 A waitlist-controlled study combining activity planning, assertiveness training, relaxation techniques, stress management, motor exercise, use of memory aids, and motor exercise in group format for people with MCI showed improvement in mood.99 A randomized control trial of a cognitive-motor intervention consisting of reality orientation, ADL training, and psychosocial support produced mood and cognitive benefits in a people with Alzheimer's compared with patients treated with psychosocial support alone.100 Some of the highest-quality studies producing the most significant results combine different categories of intervention; this makes it difficult to determine the active ingredient but also suggests that a combination of interventions produces important synergies. Examples include a randomized controlled trial of 153 community dwelling people with AD which combined a home-based exercise program with caregiver training in behavioral management techniques and found significantly reduced rates of depression and delayed institutionalization.101 Psychosocial interventions can also be used in the treatment of depression and apathy in more advanced dementia and long-term care settings; these include multisensory stimulation, a variety of activities (music, dance, exercise), therapeutic conversation/reminiscence, pet therapy, cognitive stimulation (as distinct from rehabilitation)/reality orientation, and models of care. Individualized interventions that take into account characteristics and interests of the person with dementia and provide opportunities for meaningful activity are most effective in reducing symptoms of depression and apathy.102–107 Music may be most effective in more advanced dementia.104,108
There are various challenges to interpreting the robust meta-analytic literature on psychosocial interventions.72,75,79,81,109,110 Researchers use different terminology to label interventions, making it difficult to directly compare individual referenced studies. Inclusion criteria vary among the reviews, especially for control conditions, raising concern about the placebo effect of receiving stimulation and human contact regardless of the effectiveness of any specific method.111 Conversely, a finding of lack of effectiveness for a specific intervention may represent an artifact of difficulty validating an intervention.106
Despite equivocation about the effectiveness of specific interventions and various over-arching approaches, comparison of the meta-analytic literature yields strong support for interventions that are individually tailored, use multiple treatment components, include the caregiver, and include follow-up.72,75,111 There is particularly strong evidence for problem-solving approaches and modified cognitive behavioral therapy (CBT) intervening directly with a patient with MCI or early dementia or by training the family caregiver to deliver the interventions.109,110 In line with the correlation between neuropsychiatric symptoms (see Text box 5-8) and caregiver stress, improving caregiver skills to manage behaviors also benefits caregiver mood.
BOX 5-8 ANXIETY IN DEMENTIA
In patients with dementia and anxiety, restlessness, or agitation, important differential diagnoses to consider include discomfort due to pain or other somatic symptoms the patient cannot communicate, delirium and psychosis.
Patients with dementia may develop paradoxical anxiety as a reaction to benzodiazepines, antihistaminergic medications, and agents with anticholinergic properties. Rule out akathisia in patients on antipsychotics.
Anxiety is a common response to cognitive deficits. For instance, patients may feel anxious when they cannot communicate due to aphasia, or when they experience loss of control of their basic daily activities due to executive dysfunction or amnesia.
Anxiety can exacerbate cognitive deficits as it may negatively affect attention, executive function, encoding and retrieval of information.
Behavioral interventions such as reassurance, use of cognitive compensatory strategies such as calendars and notebooks, and clear and firm communications from trusted caregivers can be of help. Caregivers may benefit from psychoeducation and modeling by healthcare providers to effectively intervene in these situations. CBT interventions including relaxation training can be effective, preferably modified to allow for caregiver participation in treatment.
Medications that can help anxiety include SSRIs, SNRIs, buspirone, mirtazapine.
Avoid benzodiazepines and medications with high anticholinergic activity as they may worsen cognitive deficits.
Cerebrovascular disease is a significant contributor to late-life depression. The terminology in this section follows current usage in distinguishing poststroke depression from “vascular depression,” a term which in the past has been used to refer to depression related to both discrete infarcts and to the accumulation of subcortical microvascular ischemic changes. Poststroke depression is diagnosed based on the temporal relationship between a clinically apparent stroke and the onset of depression. Vascular depression is an evolving concept that arose from the observation of the correlation of depression and subcortical microvascular disease, which has become more widely appreciated in the age of increasingly available MRI. Unlike idiopathic MDD, poststroke and vascular depression primarily have onset late in life. They have modifiable risk factors, which coincide with the risk factors for cerebrovascular disease itself. Anticipation, recognition, and treatment of depression associated with cerebrovascular disease can reduce its morbidity, and improve outcomes related to vascular disease itself (see Text box 5-9 for a review of Anxiety and Cerebrovascular disease).112
BOX 5-9 ANXIETY AND CEREBROVASCULAR DISEASE
Anxiety after stroke occurs frequently, both independently and comorbid with depression.
Symptoms may include excessive worries and fears, somatic symptoms such as palpitations, muscle tension, restlessness, and insomnia.
Anxiety can worsen poststroke cognitive deficits and rehabilitation outcomes.
Pharmacological treatment options include SSRIs, SNRIs, buspirone, mirtazapine. Nortriptyline can also be of help, although it is not considered a first line of treatment due to its potential anticholinergic and other side effects.
Avoid benzodiazepines and medications with high anticholinergic activity as they may worsen cognitive deficits.
Stroke is the fourth leading cause of death in the United States, and it is estimated that 6.8 million Americans over the age of 20 have suffered a stroke, with an annual incidence of approximately 795,000113 Among the approximately 75% who survive a stroke, one-third will experience poststroke depression, with the greatest risk in the first year after the stroke.114 See Figure 5-1 for a comparison of the prevalence of depression in different neurological illnesses and Box 5-1 for risk factors for depression in neurological disease. The factors that increase the risk of depression after stroke include: personal or family history of depression, degree of subcortical atrophy prior to the stroke, and degree of physical or cognitive impairment after the stroke. Confounding the last factor, however, is the observation that the presence of poststroke depression worsens outcomes and increases the degree of residual disability after stroke.115
Several factors may mediate the development of depression in neurological illnesses (Box 5-2). The experience of stroke as a sudden loss of physical, verbal, or cognitive function, and the immediate onset of significant disability is a traumatic experience, and poststroke depression shares some of its origins in the reactive nature of depression that emerges in the wake of any significant medical diagnosis or illness. The fact that stroke is itself a brain injury, however, suggests that depression may arise from the infarction itself. This hypothesis has been borne out in the observation that the risk of poststroke depression is related to the location of the lesion. The ability of lesion location to predict poststroke depression remains debatable, but evidence suggests that infarcts in the left frontal lobe and basal ganglia are more likely to precipitate depression. Poststroke depression may correlate with the proximity of the infarct to the anterior pole of the left frontal lobe116 though this is not consistently observed, and may be more significant in the early phases of stroke recovery (2–6 months after the event).117
A depletion of monoamine neurotransmitters may also be involved in the development of poststroke depression. Multiple rodent models of stroke have shown ipsilateral depletion of serotonin, norepinephrine, and dopamine after stroke, and reduction of monoamine metabolites has been demonstrated in the CSF of human patients with poststroke depression. PET imaging of 5-HT2 receptors shows evidence of greater upregulation of serotonin receptors in the right hemisphere compared to the left in patients with poststroke depression. This difference in receptor expression after stroke may represent hemispheric differences in response to injury, and correlate with the lateralization of depression risk after stroke, as well as support the hypothesis of monoamine depletion leading to poststroke depression.118
Symptoms of poststroke depression do not significantly differ from those of idiopathic major depressive disorder. Because of overlapping symptoms of stroke and depression (e.g., changes in energy, sleep, appetite, libido, and cognition), several studies have examined the validity of DSM criteria for major depression in the setting of stroke. Adjusting diagnostic criteria, however, to account for the origin of neurovegetative symptoms (i.e., attempts to exclude symptoms judged to be direct sequelae of the stroke) does not improve the sensitivity or specificity of DSM criteria for major depressive disorder in the setting of stroke.119
DSM criteria for MDD are sensitive and specific for poststroke depression as well. The symptoms of poststroke depression do not differentiate it from other forms of late-life depression. The particular presentation of individual cases likely depends on the lesion location and the extent of disability, combined with the individual's reaction to the stroke due to the new and potentially traumatic onset of functional impairment.
COURSE AND NATURAL HISTORY
The course of poststroke depression has been examined in several longitudinal studies, but the conclusions have been inconsistent and the degree of treatment in most case series has not been clearly delineated. There is some consensus, however, that depressive symptoms that emerge rapidly, within hours to days of stroke, tend to peak within 3 to 6 months of onset and approximately 50% experience remission by 1 year. Patients who experience onset of depression 2 months after stroke or later, however, typically have a more protracted course, and up to 50% remain depressed 2 years after their stroke. One confounding factor is the degree of physical disability, which correlates with risk of depression; patients with greater disability tend to be overrepresented in the hospital and rehab settings where patients have been recruited for many of these studies.120
ASSESSMENT AND DIFFERENTIAL DIAGNOSIS
Lack of awareness of the high prevalence of poststroke depression, misattribution of depressive symptoms to physical consequences of the stroke, and perception that the patient's distress may be an “appropriate” reaction to stroke all likely lead to the underdiagnosis of poststroke depression. Recognition of this entity, however, is important, because appropriate treatment of depression can alleviate the suffering of the depressed patient as well as improve rehabilitation outcomes. As discussed, DSM criteria for MDD are sensitive and specific for poststroke depression. The defining characteristic of this entity is onset after a clinically apparent stroke. Other symptoms can emerge after stroke, however, that can complicate or confound the diagnosis of depression. The most common poststroke symptom that mimics depression is apathy. By definition, apathy is a reduction of motivation not attributable to emotional distress, cognitive impairment, or level of consciousness.121 Apathy is also a common feature of depression, and is included on the Hamilton Rating Scale for Depression. However, several studies and reviews demonstrate that apathy and depression are not always correlated and can be differentiated.122 A case series123 compared apathy and depression levels across stroke, AD, and idiopathic major depression. While the relationship between apathy and depression varied among the groups, patients with major depression or left-hemisphere stroke tended to higher depression scores and lower apathy scores. Patients with right hemisphere stroke had high levels of both apathy and depression, although these symptoms did not correlate with each other in this group. A longitudinal study of patients with poststroke depression found that within 3 months of a stroke, levels of apathy and depression did not correlate, but that a correlation emerged over time and was significant at 1 year. Both apathy and depression were predicted by the presence of dementia, but depression was independently predicted by psychosocial factors, such as not living with a family member. Although the correlation increased, there were a significant number of patients at 1 year who demonstrated apathy or depression, but not both.124
Although apathy likely shares with depression an origin in the disruption of frontal subcortical networks, distinguishing the two phenomena has treatment implications: failure to distinguish them can lead to treatment failure. Primarily studied in dementia, apathy has not been found to be responsive to antidepressants,125 whereas poststroke depression has (discussed below). When apathy occurs after stroke, careful assessment for other symptoms of depression is required to differentiate the two syndromes. If apathy coexists with depression, the treatment of both syndromes may be indicated.
Treatment of poststroke depression is important, as degree of depressive symptoms negatively correlates with rehabilitation potential112 and poststroke outcomes. See Box 5-6 for a summary of treatment of depression in neurological disorders.
Numerous studies comparing antidepressants against alternate agents or placebo have demonstrated widely varying efficacy in antidepressant treatment for poststroke depression. The range of study types, enrollment criteria, and means of assessment make it difficult to draw firm conclusions, but several studies have demonstrated efficacy of antidepressant agents in this population. The most commonly studied agents are SSRI and TCAs. In general, antidepressants from either class outperform placebo, although placebo response is high, which is typical for antidepressant trials. Nortriptyline has been shown to significantly outperform both fluoxetine and placebo.120 Use of tricyclic agents, while possibly more effective than SSRIs or SNRIs, is limited by their adverse effects. Patients with poststroke depression tend to be elderly and are more likely to have vascular disease. Anticholinergic effects and risk of cardiac arrhythmias may lead most clinicians to reject these agents in favor of SSRI antidepressants.
Several case series and chart reviews have demonstrated the safety and tolerability of psychostimulants in poststroke depression, but have not demonstrated efficacy. Nonetheless, the potential of stimulants to increase energy and physical activity level has led to their empiric use, particularly in the rehab environment.
BRAIN STIMULATION THERAPIES
Two retrospective chart reviews have demonstrated the safety and efficacy of ECT for poststroke depression, with some patients receiving treatment within 1 month of stroke.126 Repetitive transcranial magnetic stimulation (rTMS) has growing evidence for use in recovery of motor and cognitive stroke symptoms, but no published evidence to date addresses its use for poststroke depression.
Several of the principles discussed above, regarding the psychosocial treatment of depression in dementia, also apply to poststroke depression. Poststroke patients also struggle with issues of loss of function and many times loss of independence. They may depend from caregivers and the inclusion of caregivers in treatment may increase effectiveness of the interventions. On the other hand, in the context of a static brain lesion, the potential for rehabilitation changes the prognosis and the dynamics of the relationship with caregivers. Different approaches including cognitive behavioral therapy, mindfulness-based interventions, and acceptance and commitment therapy have been used. Unfortunately the evidence of benefit of psychotherapy in this population has been limited.127
In addition to significant physical disability stroke can also lead to depression, which can be an independent cause of disability and also exacerbate the residual physical symptoms of a stroke. Particularly in frontal lobe strokes, the lesion itself may injure regions of the brain involved in emotional regulation, leading directly to depression. Poststroke depression has been associated more with infarcts of the left frontal lobe than with other brain regions, but depression can emerge after an infarct in any location. The sudden onset of significant disability and loss of independence after a stroke can trigger a depressive episode. Patients with personal and family histories of depression are at higher risk. Recognition and treatment of depression in the wake of a stroke, particularly in the acute phase, can improve rehabilitation participation and outcomes. Although TCAs have more evidence for efficacy in poststroke depression their side effects may limit their use, particularly in elderly patients. SSRIs have demonstrated efficacy as well, and ECT has been used successfully used in severe and refractory depression.
Although cases of depressed elderly patients with atherosclerosis were described prior, “vascular depression” was first hypothesized as a distinct syndrome when Alexopoulos et al. described an association of late-life depression with impaired executive function and white matter hyperintensities on T2-weighted MRI.128 This suggested areas for further investigation including involvement of frontal subcortical circuits in idiopathic depression, and also evolved into a recognizable subtype of depression. However, there is not yet a consensus for criteria defining vascular depression, which complicates attempts to investigate the syndrome. Some investigators prefer the term “subcortical ischemic depression,” and others refer to “depression executive dysfunction,” which describes the syndrome symptomatically allowing for other causes. Despite terminology differences, most investigators agree that the triad of depression onset after sixth decade, white matter hyperintensities found on MRI, and executive dysfunction comprises the core features of vascular depression.
Estimating the prevalence of vascular depression is complicated by the general under-recognition of late-life depression and the requirement of imaging and cognitive assessment for diagnosis. In a large cross-sectional study vascular depression prevalence is estimated at 3.4% of Americans aged 50 and older, approximately 2.64 million people.129 However, the criteria in this study do not include imaging findings or measures of cognitive impairment, and include poststroke depression. Other salient findings include evidence of late-life depression under-treatment and increased morbidity of cerebrovascular disease-associated depression in which only 40% of the depressed respondents reported current treatment, and only 10% reported treatment considered adequate to guidelines. Respondents with cerebrovascular disease or risk factors reported significantly higher functional limitations across several domains, including cognitive, mobility, social, and overall role impairments.
See Boxes 5-1 and 5-2 for a summary of factors relevant to the development of vascular depression. Studies on the mechanism of vascular depression have centered on the white matter hyperintensities which represent microvascular disease. The amount of white matter hyperintensities correlates with age, regardless of the presence of depression. There is a correlation between the white matter disease burden in the frontal lobes and the incidence of depression. Periventricular hyperintensities appear equally prevalent in depressed and nondepressed subjects. Deep white matter hyperintensities, however, have consistently been found to be more prevalent in depressed subjects, and with late-onset depression in particular.130 These deep white matter lesions are thought to be disruptive to frontal-subcortical and to a lesser extent temporal lobe function in vascular depression.
The correlation of executive dysfunction with white matter disease and depression suggests disruption of dorsolateral prefrontal striatal circuits. Postmortem tissue analysis demonstrates that subcortical ischemia preferentially affects the dorsolateral prefrontal cortex in patients with late-life depression131 and that white matter hyperintensities in vascular depression are ischemic, rather than inflammatory.132
Vascular depression differs from other forms of depression in several ways, although there is significant overlap.133 Anhedonia as a major symptom is more common in vascular depression than subjectively depressed or low mood (Box 5-3). Vascular depression shares characteristics with frontal lobe syndromes, particularly those arising from dysfunction of medial or dorsolateral prefrontal cortices. Executive dysfunction, commonly seen in dysfunction of the dorsolateral prefrontal cortex or its connections, is a defining characteristic of vascular depression. Family history of mood disorder is less common in vascular depression than in idiopathic depression.
COURSE AND NATURAL HISTORY
The clinical course of vascular depression is similar to that of refractory major depression in that it generally becomes a chronic condition and tends not to respond to antidepressant treatment. Progression of white matter disease is a risk factor for the onset of vascular depression134 but it is not known whether progression of subcortical vascular disease in an individual patient correlates with worsened depression. Vascular depression is often comorbid with dementia, as microvascular disease causes subcortical vascular depression and also exacerbates dementia from other etiologies, such as AD.
ASSESSMENT AND DIFFERENTIAL DIAGNOSIS
The presence of executive dysfunction in vascular depression may lead to some confusion over whether a given patient's symptoms represent depression or dementia. The syndrome of “reversible dementia of depression,” also known as “pseudodementia,” has long been described, with deficits not only of memory but also of executive dysfunction (Box 5-5). Concern over this syndrome has been that clinicians often overlook depressive symptoms in the presence of cognitive impairment in elderly patients. Awareness of the entity of vascular depression, however, introduces a third consideration in addition to the possible diagnoses of idiopathic depression and dementia due to neurodegenerative process. Vascular depression comprises symptoms of both depression and executive dysfunction and shares features with depression and dementia of other etiologies. Diagnosis of vascular depression, however, implies the presence of microvascular disease, demonstrated by subcortical white matter hyperintensities on T2-weighted MRI. Brain imaging in this setting may help distinguish among idiopathic depression and vascular depression in elderly patients or patients with significant vascular risk factors.
The syndrome of apathy can also present a diagnostic challenge. Apathy and executive dysfunction may present as features of vascular depression, but also can signify the emergence of a neurodegenerative disorder or the sequelae of a stroke or other structural lesion. Differentiation of apathy from depression has been previously covered in the discussion of poststroke depression, and similar considerations apply with vascular depression.
Given its likely distinct psychopathology, it seems intuitive that the treatment profile of vascular depression would differ from idiopathic depression. Several studies have demonstrated variable response to SSRIs. Response to these medications seems to inversely correlate with the progression of white matter hyperintensities134 and degree of neuropsychological impairment. In a nonrandomized trial 33% of patients achieved remission over 12 weeks with SSRI treatment. The likelihood of remission, assessed by MADRS score, diminished with increasing deficits in overall executive function, language processing, episodic memory, and processing speed.135 A placebo-controlled trial of sertraline in elderly patients with depression (but not specifically with vascular depression) found that sertraline performed worse than placebo in patients with impaired executive function, as measured by response inhibition.136 This suggests that patients with executive dysfunction and depression, including vascular depression, may be subject to the side effects of antidepressants but not their benefits.
BRAIN STIMULATION THERAPIES
A study comparing rTMS of the prefrontal cortex to sham rTMS found a response rate of 39% and a remission rate of 27%,137 which are comparable to rates seen with antidepressants. Unlike antidepressants, however, response to treatment did not correlate with degree of cognitive impairment or executive dysfunction. There was a decreasing response to rTMS with increasing age and also with decreased volume of frontal gray matter. There is limited evidence regarding use of electroconvulsive therapy (ECT) in vascular depression, but one small series and several case reports suggest it is effective and generally well tolerated, although perhaps with increased risk of delirium compared to ECT in idiopathic depression.138
Given its usual age of onset, psychotherapy with patients with vascular depression shares characteristics with psychotherapy with the ill, elderly patient; please refer to Chapter 17 for discussion of this topic. An important role of psychotherapy with this population is to support the work patients need to do in sustaining positive health behaviors, to help decrease their vascular risk factors. Several of the aspects of psychotherapy in the context of dementia, discussed above, apply to this population as well; importantly, the inclusion of caregivers in the plan of care may augment treatment results.
Vascular depression is an increasingly recognized etiology of late-onset depression, often presenting with cognitive symptoms characteristic of subcortical dementia. The correlation of depression severity and cognitive dysfunction with the extent of subcortical microvascular disease seen on MRI suggests that disruption of subcortical networks is the common cause of both the depression and cognitive symptoms. Response to antidepressants appears to be poor in vascular depression. Attention, therefore, should turn to prevention. Although not proven, prevention of cerebral microvascular disease through blood pressure control, management of hyperlipidemia, and other vascular risk factors, may offer protection against vascular depression in addition to its known other cerebrovascular and cardiovascular benefits.
PD is a neurodegenerative illness resulting from deterioration and loss of dopamine-producing neurons in the substantia nigra of the midbrain. This results in decreased dopaminergic input to the basal ganglia, producing the characteristic motor symptoms of rigidity, bradykinesia, tremor, and postural instability. It is the second most common neurodegenerative disease after AD. Estimated prevalence in developed countries is 0.3% of the population and 1% of those 60 and older. Prevalence increases with age up to about 4% in the oldest cohorts,139 and nearly 1 million Americans have PD.
In addition to motor manifestations, psychiatric symptoms are common, with depression being the most frequent (Fig. 5-1). Estimates of depression rates in PD vary widely, but it is estimated that 17% of patients with PD meet DSM-5 criteria for MDD, with an additional 35% meeting criteria for dysthymic or subsyndromal depression.140
Rates of depression in patients who are ultimately diagnosed with PD are about double that of the general population.141,142 Mood symptoms can precede clinical motor parkinsonism for up to 20 years, but the peak is 3 to 6 years prior to onset of motor symptoms and PD diagnosis.143 It should be noted that most reports of depression onset rely in part upon patients' recall and thus are subject to some degree of reporting bias. However, an association between depression and PD is upheld by a retrospective cohort study of patients with depression that144 found a hazard ratio for developing PD of 3.13 among patients diagnosed with depression using International Classification of Primary Care (ICPC) criteria.
It is likely that some cases of depression associated with PD are reactions to the diagnosis and long-term prognosis of progressive disability (see Box 5-2). However, prevalence of depression in PD is as much as twice that seen in other conditions that produce equivalent disability145 suggesting that the pathophysiology underlying PD contributes to the development of depressive symptoms.
There is a correlation between depressive symptoms and certain motor symptoms, which supports the idea of a common pathophysiologic pathway. For example, there is a higher prevalence of depression in patients with predominantly akinetic-rigid motor symptoms versus tremor-rigid-bradykinetic symptoms.146
The primary pathophysiological process in PD is regression and loss of dopamine-producing neurons in the substantia nigra. The downstream effects of this include motor symptoms due to loss of dopaminergic input to the basal ganglia. The basal ganglia, in particular the ventral striatum, also have significant function in emotional processing, as part of the prefrontal-striatal-thalamic circuits. PET imaging of dopamine and norepinephrine transport receptors in patients with PD and depression147 shows that depression symptom severity, measured by Beck Depression Inventory (BDI), correlates with decreased dopamine and norepinephrine receptor binding in the ventral striatum. Patients with PD and depression have reduced binding in the locus coeruleus, mediodorsal and inferior thalamus, left ventral striatum, and right amygdala when compared to patients with PD and without depression. The latter group shows less binding in these areas compared to healthy controls. This suggests that depression in PD may be a consequence of a subset of the pathological processes of PD itself. It is not clear whether this is related to an underlying predisposition or vulnerability, or from idiosyncratic disease progression.
Structural and functional imaging studies further highlight the involvement of the mediodorsal, or “limbic” thalamus. In an fMRI and voxel-based morphometry study comparing patients with PD with or without depression, there is increased volume in bilateral mediodorsal thalami and reduced activation in the left mediodorsal thalamus and in the left medial prefrontal cortex in the depressed patients.148
Depression may emerge before diagnosis or in the early or late stages after diagnosis of PD. Somatic symptoms of depression may be masked or confounded by parkinsonian motor symptoms, such as bradykinesia and hypomimia (Box 5-3). Many patients with PD who do not have depression experience early waking and decreased energy, and psychomotor retardation is nearly universal. Other symptoms, however, such as decreased appetite and libido, increased sleep latency and overnight waking, and nonsomatic depression symptoms such as low mood, anhedonia, feelings of guilt, and preoccupation with death are generally attributable to depression.149 PD patients on levodopa may experience dysphoria and/or anxiety, combined with their motor fluctuations, as part of the “on/off” cycle: In most cases the effect of levodopa gradually wears off a few hours after each dose. During this “off” period the patient experiences exacerbation of the PD motor symptoms, and may also become more depressed and anxious. After the following levodopa dose, in the “on” period, the patient's mobility increases—possibly with added dyskinesia—and the mood improves.
COURSE AND NATURAL HISTORY
Evolution of depressive symptoms in PD tends to mirror the motor symptoms. A longitudinal study of nonmotor symptoms150 shows that depressive symptoms decrease over the first 2 years after PD diagnosis as dopaminergic therapy is initiated and titrated. As neurodegeneration progresses, however, depressive symptoms return and become more refractory, as do the motor and autonomic symptoms.
Depression in PD can exacerbate the disability produced by motor symptoms, and itself can be considered a marker of disease severity. Depression is independently correlated with degree of disability in PD, and in a cross-sectional study151 nonmotor symptoms (primarily depression and cognitive impairment) account for 37% to 54% of the total variance in disability among patients.
Patients recognize the morbidity associated with depression in PD. In a patient survey,152 patients with early (<6 years) PD rate “mood” as the sixth most bothersome symptom. Patients with more advanced illness (>6 years) however, rate “mood” as the second most bothersome symptom, behind medication-related symptom fluctuations.
ASSESSMENT AND DIFFERENTIAL DIAGNOSIS
There are no specific criteria for diagnosis of depression in PD, and DSM criteria are generally used. Marsh149 has suggested modifying DSM criteria somewhat to be more inclusive of the range of depressive symptoms found in PD. She recommends disregarding the “etiologic” criteria of DSM and considering symptoms based on observation rather than presumed etiology. Another recommendation is to carefully assess anhedonia to distinguish it from apathy, which may appear in patients with PD who are not depressed. Last, diagnosis of minor depression or dysthymia in PD is encouraged, as these “subsyndromal” depressive symptoms can cause significant distress and functional impairment in PD, without rising to the level of major depression.
Depression scales may be useful in PD to monitor the progression of symptoms or to screen for unreported or difficult-to-detect depression. The BDI153 and the Hamilton and Montgomery–Asberg rating scales154 are valid instruments for diagnosing and assessing severity of depression in PD, although the cutoffs for clinical significance tend to slightly overdiagnose depression because of the confounding effect of motor symptoms.
Because of its inherent morbidity and association with greater functional impairment, diagnosis of depression in PD is as important as it can be difficult. The overlap of motor symptoms with depression symptoms can easily lead to depression being overlooked. In one prospective study, diagnostic accuracy of the treating neurologist was 35%.155 Routine screening of PD patients for depression and other nonmotor symptoms should be commonplace and is effectively done using self-report checklists, such as the BDI.
Treatment of depression in PD has evolved in recent years (Box 5-6). Even in the absence of controlled trials, clinicians have used antidepressants to treat the observed symptoms of depression in patients with PD, with some anecdotally encouraging results. As most psychiatrists switched from TCAs to the better-tolerated SSRIs, most neurologists and neuropsychiatrists also switched to SSRIs for their patients with PD who were depressed. There have been limited controlled trials of antidepressants in this population and results have been inconsistent. A study in 2009 that compared nortriptyline with paroxetine for depression in PD shows significant advantage of nortriptyline,156 although this study had several limitations including its brief duration, relatively small size, and a high dropout rate.157
There is some concern over the potential exacerbation of motor symptoms by SSRIs, however the evidence remains inconclusive.158,159 A randomized, double-blind, placebo-controlled study demonstrates that both the SNRI venlafaxine and the SSRI paroxetine may improve depression in subjects with PD.160 The use of another SNRI medication, duloxetine, has benefit in a small series.161 The positive effects of SNRIs are not surprising, as the increase in both serotonergic and noradrenergic tone produced by these medications is similar to the actions of TCAs. Bupropion, an antidepressant which inhibits reuptake of norepinephrine and dopamine (NDRI), should theoretically be of benefit in PD, given its dopaminergic mechanism of action. It has been reported effective anecdotally and in a single published case report, and recommended for further study because of its low likelihood of worsening, and potential for ameliorating, motor symptoms.162,163
Treatment of PD itself, with dopaminergic medications, can also treat concomitant depression. MAO inhibitors, while they have fallen out of fashion as antidepressants, continue to be used to treat PD, typically providing benefits in reducing “on/off” motor fluctuations. Most commonly used are the selective MAO-B inhibitors selegiline and rasagiline. One trial comparing two doses of rasagiline in 22 patients with PD and depression shows significant improvement in motor symptoms, without significant differences between patients receiving 1 or 2 mg/d. All patients also showed improvement in depression symptoms, however, the patients receiving the higher dose show significantly greater improvement in depression as measured by the Hamilton Depression Rating Scale.164 This suggests that the antidepressant benefits of rasagiline are independent of its motor benefits, and that this medication may be particularly useful in patients with PD who are depressed. Dopamine agonists such as pramipexole, commonly used to treat PD's motor symptoms, may also benefit PD depression. The evidence from controlled studies is still insufficient to recommend these agents as a first line of treatment.
BRAIN STIMULATION THERAPIES
While there has not been a randomized controlled trial of ECT for depression in PD, there are numerous noncontrolled studies reporting efficacy and tolerability. ECT should certainly be considered as a treatment for medication-refractory or severe depression in patients with PD. rTMS has shown promising results in patients with PD and depression. In addition, beneficial effects on motor and cognitive symptoms have also been reported.165
DBS has emerged as an important treatment option for PD, particularly in patients with advanced disease or with side effects that limit the usefulness of dopaminergic medications. The most common sites for stimulator placement in PD are the subthalamic nucleus (STN) and the globus pallidus interna (GPi). The effects of DBS for PD are most clearly seen in the improvement of motor symptoms, but changes in mood have been observed as well. The evidence has been mixed, with some early reports of increased incidence of depression following DBS surgery and subsequent larger randomized trials showing little difference in mood outcomes of DBS versus medical management of PD.166 Although some reports have suggested greater risk of depression following DBS placement in the STN as compared with GPi, a study designed to compare these sites using mood and cognitive measures as primary endpoints failed to find a significant difference.167 Stimulation of STN often allows for reduction of dopaminergic medication due to less prominent motor symptoms, but dose reduction of levodopa or dopamine agonists may exacerbate underlying depressive symptoms which these medications had been treating as well. Although premorbid well-controlled depression is not a contraindication to DBS, surgery can be associated with a relapse of depression, and all DBS patients should be monitored postsurgically for emergence or evolution of depressive symptoms.168
Nonpharmacological treatments appear useful for depression in PD as well. A randomized controlled trial of CBT for depression in PD adapts CBT to the unique needs of patients with PD to include exercise, behavioral activation, thought monitoring and restructuring, relaxation training, worry control, and sleep hygiene. CBT for patients with PD was supplemented with individual caregiver sessions designed to equip caregivers with the skills necessary to facilitate practice of CBT at home.169 In comparison with the control group, which received clinical monitoring alone, the treatment group shows significant improvement in measures of depression. Further, this study reveals that caregiver participation rather than patient factors (motor disability, psychiatric comorbidity, and executive function) predicts treatment response.170
There is some evidence for group therapy in the treatment of depression in PD. A small-scale randomized waitlist controlled trial of group therapy demonstrated a significant reduction in depression in group participants; the group therapy used psychodrama methods (e.g., role play; emotional expression) in 12 sessions, also providing education on Parkinson's and information on coping skills and adaptive resources.171 Patient Education Program Parkinson (PEPP) which is a standardized program using CBT techniques administered to small groups of patients and caregivers also shows that mood improves significantly for the treatment group.172
A review of psychosocial treatments for depression and anxiety in PD points out that interventions that primarily target symptoms of PD have secondary mood benefits.173 A study of multidisciplinary rehabilitation including individually administered physical, occupational, and speech therapies, group relaxation exercises, expert lectures, and caregiver groups showed significant improvement in mood, although the benefits were not sustained 6 months after termination.174,175 This suggests the need for longer-term interventions or maintenance sessions to address the continuing needs of patients and the progressive nature of PD itself.
PD is a neurodegenerative illness whose core pathology is loss of dopaminergic neurons in the nigrostriatal pathway. The reduction in dopaminergic tone in the ventral striatum is associated with emergence of depression in patients with PD. The diagnosis of, and the progressive symptoms and disability from, a neurodegenerative process also can be psychologically destabilizing and trigger depression symptoms or a major depressive episode. Depression, therefore, is prevalent among patients with PD and can lead to significant additional morbidity. Recognition of depression in PD can be challenging, due to the overlap of neurovegetative symptoms of depression and motor symptoms of PD. Because the effects of depression can exacerbate functional deterioration of patients with PD, routine screening of this population for depression is important. Multiple treatment modalities are beneficial, including TCAs, SSRIs, SNRIs, bupropion, and nonpharmacological treatments such as individual and group CBT for both patients and caregivers. Treatment of PD with levodopa and dopamine agonists will often ameliorate depression. In addition, MAO-B inhibitors, such as rasagiline, can be used to treat both depression and motor symptoms in patients with both PD and depression. ECT should be considered for severe or medication-refractory depression (see box 5-10 for a review of Anxiety in Parkinson's Disease).
BOX 5-10 ANXIETY IN PARKINSON DISEASE
Anxiety symptoms are common in Parkinson disease (PD), both independently and comorbid with depression.
Patients may experience any of the classic anxiety symptoms typical of primary anxiety disorders.
In addition, anxiety symptoms more typical of PD include fear of falling and “freezing,” and anticipatory anxiety about the “wearing off” of the anti-parkinsonian drugs.
Anxiety symptoms may fluctuate during the day, in correlation with fluctuations in the individual's dopaminergic state. PD patients on levodopa may experience anxiety, usually combined with dysphoria, when the effect of levodopa wears off. Mood and anxiety (as well as mobility) tend to improve with the subsequent levodopa dose.
PD patients may also experience anxiety about social situations where their motor and cognitive symptoms become evident
Pharmacological treatment options include SSRIs, SNRIs, and Nortriptyline. Judicious use of benzodiazepines in cases of severe anxiety resistant to monotherapy with these agents can be also considered, with attention to their potential side effects.
Working in collaboration with the patient's neurologist, focusing on reducing the on–off fluctuations may address many of the anxiety symptoms. This can be accomplished through different strategies, including the addition of dopaminergic agonist or COMT inhibitors.
CBT may be effective as well for management of anxiety in patients with PD.
Huntington disease (HD) is a genetic, autosomal dominant, progressive, neurodegenerative disease with motor and psychiatric features. Although the movement disorder associated with HD has been considered its core feature and the disease was previously known as Huntington chorea,176 its psychiatric symptoms have been observed and reported since its initial description.177 Psychiatric disturbances, including depression, anxiety, mania, and psychosis are now considered one of the triad of core symptoms of HD, along with movement disorder and cognitive decline. HD is progressive, with a uniformly poor prognosis. Mean survival after diagnosis ranges from 10 to 15 years, typically with an extended period of severe disability and loss of independent function.
The prevalence of HD varies by ethnicity and geographic location. It is estimated to occur in 5.7 per 100,000 in people of Northern European ancestry, and is less prevalent in populations with non-European roots.177 Diagnosis is most often made after the emergence of motor symptoms, although genetic testing can identify the disease before any symptoms are apparent. The movement symptoms of HD typically have onset in the fourth or fifth decade, although earlier and even juvenile onset cases are seen. There is some evidence that psychiatric symptoms, particularly depression, and cognitive impairment can precede motor symptoms for years. Most attempts to quantify the length of prodromal mood symptoms are hampered by recall bias and a retrospective approach. A cross-sectional study comparing 55 HD gene carriers without motor symptoms, 85 gene carriers with motor symptoms, and 56 noncarrier first-degree relatives of HD carriers with the general population178 shows that gene carriers, both symptomatic and presymptomatic, have a significantly increased prevalence of MDD. The evidence for depression in clinically evident HD is unequivocal (Fig. 5-1). MDD affects up to 40% of patients, increasing up to 60% when subsyndromal depression is included.179
HD180 results from a mutation on the short arm of chromosome 4, in a gene for the protein product huntingtin. This gene contains a series of CAG repeats of variable length, whereas the normal allele contains 10 to 35 repeats. Alleles carrying 40 or more repeats are considered positive for the mutation, whereas carriers with 36 to 39 repeats are considered “indeterminate” and may show some symptoms due to incomplete penetrance, or remain asymptomatic. As in other trinucleotide repeat disorders, an increased number of repeats does not clearly correlate with severity of symptoms but does correlate with earlier age of onset.
The role of the huntingtin protein in normal neuronal function is unclear, but the abnormal protein forms intranuclear and cytosolic inclusions. This leads to impaired neuronal function and cell death.181 The striatum is preferentially affected and structural imaging shows caudate atrophy with increasing severity as the disease progresses. The damage to the striatum causes the movement symptoms of HD, and likely also contributes to the depressive symptoms. The caudate has connections with multiple frontal-subcortical circuits, important for emotional regulation. The medial caudate has rich limbic connections as well. Downstream effects from damage to the caudate affect function of orbitofrontal and prefrontal cortices, demonstrated by reduced glucose metabolism in these areas in depressed patients, including depressed patients with HD.182 Evidence that the pathophysiology is itself a cause of depression, rather than a reactive or adjustment response to a neurodegenerative disorder, is demonstrated by the increased prevalence of depression in HD as compared with AD.183
Depression and other psychiatric symptoms often predate the emergence of motor symptoms, and the diagnosis of HD. In a prodromal analysis, 42% of presymptomatic carriers were taking psychiatric medication at the time of the study, compared to 5% of noncarrier relatives.168 Despite the elevated index of suspicion for depression among clinicians treating patients with HD, depression may still be challenging to diagnose. Bradyphrenia, apathy, and constitutional symptoms such as sleep disturbance and weight loss are features of HD seen even in the absence of depression.
Other psychiatric symptoms can emerge in HD, sometimes in addition to depression. Anxiety is common, notably obsessive-compulsive disorder.184 Psychosis, primarily paranoia or delusions and less commonly hallucinations, is seen at times, with up to 11% reporting at least one psychotic symptom during the course of illness.185 Irritability is a common feature early in the course of HD, and this can progress along with motor and cognitive symptoms. Impaired impulse control and behavioral disinhibition can also occur.
COURSE AND NATURAL HISTORY
Left untreated, depression can become chronic in HD, particularly given the inevitable increase in physical and cognitive disability of this illness. The presence of depressive symptoms at baseline is a predictor of more rapid functional decline.186 In one small study, severity of depression does not appear to advance in correlation with severity of motor symptoms, and does not correlate with number of CAG repeats.187 Suicide attempts are a significant source of morbidity and mortality. An increase in the rate of death by suicide has been observed in HD patients for decades, and was noted in the original description of the illness. Analysis of records from one registry of patients with HD188 reveals that suicide was the proximate cause of death in 5.7% of patients, roughly four times the rate in the general population. In addition, 27.6% of patients report or were recorded as attempting suicide at least once. Identified risk factors for suicide in this population are prior suicide attempt and family history of suicide. It has not been determined whether the presence or severity of comorbid depression confers additional risk. It is clear, however, that screening for suicidal ideation is required during the treatment of these patients and of patients at risk for HD. There has been much debate over the ethics and consequences of testing asymptomatic patients for the Huntington gene. Up to one-third of patients at risk for HD reported suicide as a concern when approached with the option for testing. Approximately 10% to 20% of patients at risk for HD opt to receive genetic testing.189 Several studies have shown an increase in depressive symptoms experienced by patients receiving a positive test result (indicating they will develop HD) compared to those who receive a negative result. These differences, however, largely disappear when reassessed at 12 months.
ASSESSMENT AND DIFFERENTIAL DIAGNOSIS
As mentioned above, depression and HD have common symptoms. This presents a challenge both for the study of depression in HD and also for diagnosis and treatment. The BDI-II includes somatic symptoms that also can arise in patients with HD without depression such as loss of appetite, sleep disturbance, fatigue, and reduced libido. Because of this, it presents a lower specificity of 66% which renders it an appropriate screening tool, but not sufficiently accurate to distinguish the presence of depression in patients with HD. Two alternative self-report scales, the Hospital Anxiety and Depression Scale (HADS: sensitivity 100%, specificity 70%) and the Depression Intensity Scale Circles (DISCs: sensitivity 92%, specificity 82%) show adequate validity.190 Items on the BDI-II and the Hamilton Rating Scale for Depression (HAM-D) that refer to emotional rather than somatic symptoms correlate better with depression. Specific items include “Feel sad,” “discouraged about future,” “disappointed in self” and “feel like a failure”191 When using self-report depression inventories for patients with HD, the astute clinician will be able to make the diagnosis by reviewing the responses to individual items, rather than simply relying on the overall total score.
Though it is likely that pathophysiology of depression in HD differs from idiopathic major depression, specific treatments targeting depression in HD have not yet resulted. The list of treatments of depression in neurological illnesses shown in Box 5-6 may be useful in HD.
Several open label trials and case series and reports suggest the utility of antidepressant medications. One series of 26 patient reports significant improvement of depressive symptoms with venlafaxine.192 Published cases report positive results with fluoxetine193 and MAO inhibitors.194 There are few effective treatments for the motor symptoms of HD. The only agent approved by the United States Food and Drug administration is tetrabenazine, a presynaptic dopamine deplete which may provoke depression as a side effects. Other antidopaminergic agents that have been used to reduce chorea in HD include typical and atypical antipsychotics. Among these agents, the dopamine partial agonist aripiprazole may be the most beneficial in patients with significant motor symptoms and comorbid depression.195
BRAIN STIMULATION THERAPIES
Severe depression in HD has also been shown to respond to ECT,196 although the cognitive impairment of advanced HD may predispose patients to post-ECT delirium. While no randomized controlled trials have been published, the existing case reports and series suggest that ECT in HD is as effective and well-tolerated as it is in idiopathic major depression.
rTMS has been used as an investigative tool to study cortical excitability in HD. There are a small number of case reports with mixed results using rTMS for motor symptoms in HD.197 At present, there is no evidence for or against the use of rTMS for depression in HD.
While not focused on treatment of depression, one published case series of group therapy reports improved level of function and decreased behavioral outbursts in chronically hospitalized HD patients with Remotivation therapy. This therapy was designed to “motivate and engage nonverbal, withdrawn, and apathetic patients” in a hospital setting.198 It shows improvements in ADLs, level of interpersonal engagement, and participation in family and group activities.
Depression is a highly prevalent psychiatric symptom in HD. Because HD manifests with somatic symptoms that resemble neurovegetative symptoms of depression, misattribution of symptoms can occur and render the diagnosis of depression challenging. The pathogenesis of HD itself, with progressive neuronal dysfunction and loss that preferentially affects the striatum, may also cause depression more directly by disruption of frontal-striatal networks involved in mood regulation. Depression is associated with more rapid functional decline in HD. There are no randomized controlled trials of medications for depression in HD. Multiple published cases and anecdotal reports suggest some benefit in traditional antidepressants, including SSRIs, SNRIs, and MAO inhibitors. Aripiprazole, an atypical antipsychotic and dopamine partial agonist, may have benefits for both motor and nonmotor symptoms of HD, including depression. ECT remains an option for severe or refractory depression (see Text box 5-11 for a review of Anxiety in Huntington's Disease).
BOX 5-11 ANXIETY IN HUNTINGTON DISEASE
Anxiety symptoms are common in Huntington disease and can be part of the prodromal phase of this illness.
Patients may experience any of the anxiety symptoms typical of primary anxiety disorders.
Fear of onset, preoccupation about illness progression, and fear of losing one's capabilities and independence are common.
Patients may discuss their preoccupation about other relatives, especially their children, developing the illness. Genetic counseling including the patient's family members is important aspect of treatment.
Depression is a frequent component of the clinical presentation of Multiple Sclerosis (MS) (See Fig. 5-1). Unfortunately, it is often unrecognized and undertreated.199,200 Its detection and treatment may bring substantial improvement to adherence to MS treatment, illness prognosis, and quality of life of patients with MS.201 MS most commonly affects young adults, and is more common in women. The lifetime prevalence of MDD in MS patients is 23% to 54%.202–205 In a community based sample, the 12-month period prevalence of MD in MS was 25.7% for those in the 18- to 45-year range.206 This was significantly higher than the rate of MD in both patients with other chronic illnesses and the general population. The point prevalence of depressive symptoms (as opposed to MD) ranges from 31.4% to 79% of MS patients207–210, Early onset of MS210 and severity of illness and resulting disability209 are both associated with increased depression risk. Adjusted for severity of illness, course of illness (relapsing-remitting, primary progressive, secondary progressive) does not seem associated with differences in the severity of depression. The presence of cognitive difficulties, lower education level, younger age, and lack of social support are all significantly associated with depression.
Patients with MS present an increased rate of completed suicide compared with the age-matched general population and with other neurological illnesses.211 A quarter of patients with MS may have lifetime suicidal intent.212 Risk factors for suicide intent in patients with MS include:
lifetime diagnoses of major depression or anxiety disorders
prior suicidal ideation or intent
comorbid depression and anxiety disorder
family history of mental illness
Males with MS are at higher risk of completed suicide than females. For males with MS, the factors associated with increased suicide risk include213,214:
early illness onset and diagnosis
less than 5 years since diagnosis
recent worsening of disease
significant level of disability
access to violent means of suicide
The pathophysiology of depression in MS is multifactorial (see Boxes 5-1 and 5-2). Premorbid factors, illness-related biological and clinical characteristics, the individual's response, and elements of the social environment all have a role and interact in the development and course of depression. The prevalence of major depression in individuals with MS is higher in those with a family history of major depression208 although this factor has less relative weight than in primary MD.215 Several studies evaluate the relationship between structural and functional brain changes in MS and depression. A study evaluating the potential negative effect of demyelination on mood found that the presence of lesions in the left arcuate fasciculus region is associated with depressive symptoms.216 Superior frontal and superior parietal hypointense T1 lesions predict the presence of depression, while superior frontal, superior parietal and temporal T1 lesions, third and lateral ventricles enlargement, and frontal atrophy predict the severity of depression in one study.217 Greater lesion volume in the left medial inferior prefrontal cortex, anterior temporal atrophy,218 and hippocampal atrophy—which may be concurrent with higher cortisol levels219,220—may also be associated with depression in MS. In summary, studies highlight the importance of frontal and temporal lesion volume—especially hypointense lesions—and atrophy in the development of MS depression. The global burden of brain lesion volume and atrophy also seems important. A potential conclusion is that atrophy and cortical-subcortical disconnection due to frontal, temporal, and parietal white matter destructive lesions may contribute to depression in MS. Depression does not appear to be related to hyperintense lesions. Hyperintense areas may be nonspecific for the extent of tissue injury and neuronal pathways may function sufficiently in the presence of less severe insults, while persistent mood changes are more likely due to chronic destructive brain changes represented by the hypointense lesions. The use of diffusion tensor imaging (DTI) highlights the importance of more subtle brain changes221 as reduced fractional anisotropy and higher mean diffusivity in left anterior temporal normal—appearing white and gray matter—as well as higher mean diffusivity in right inferior frontal hyperintense lesions-correlate with depression. The contributions from functional neuroimaging techniques include an early PET study where increased perfusion in limbic areas significantly correlated with depression.222 In a functional MRI study, nondepressed patients with MS show increased activity in the ventrolateral Pre Frontal Cortex (vl PFC) and lack of connectivity between the amygdala and PFC when processing emotional stimuli.223 These findings may suggest that patients with MS are particularly vulnerable to developing a mood disorder and that they may have an ongoing compensatory mechanism at work to maintain euthymic mood.
Immunological and inflammatory factors and dysfunction of the HPA have a role in MS-related depression.224 The increase in proinflammatory cytokines, activation of the HPA, and reduction in neurotrophic factors that occur in MS may each account for the increased rate of depression in this illness.225 Evidence supporting the role of a HPA axis dysfunction in MS-related depression includes the finding that evening cortisol concentrations do not decline in MS patients with depression.226 Raised cortisol levels may not be suppressed with exogenous steroids administration in these patients, finding which may correlate with enhanced brain lesions.227 The corticosteroids used to treat MS may contribute to depressive symptoms; some of the immune-modulatory agents used in MS treatment may also have a role in the development of depression, such as interferon beta-1b and Natalizumab.228–231 Of the first-line oral drugs used to treat MS, Teriflunomide, and Dimethyl fumarate do not appear to affect depression, while initial data suggests that Fingolimod may have potential benefits for depression.
From a psychosocial perspective, a stress and coping strategies model is useful in understanding the pathophysiology of depression in MS. Predictors of depression include stress, limited social support, loss of hope, uncertainty about prognosis, and use of emotion-focused coping strategies.205,232,233 Cognitively impaired patients with MS are more likely to use high levels of avoidance as a coping strategy, which also renders them at increased risk for depression.234 Decreased use of active coping strategies and increased avoidance may increase depression risk; increased use of active coping strategies may result in decreased depressed mood longitudinally.235
The phenomenology of major depression in patients with MS is similar to that described for this disorder in the general population. There is a significant overlap between several MS symptoms such as fatigue, sleep, and cognitive disturbances, and symptoms of depression (Box 5-3). As discussed in the assessment section, different strategies can assist in the diagnosis of depression in this context. Fatigue may be the most frequent symptom in MS with a prevalence of up to 80% of MS patients. It has a reciprocal relationship with physical disability and depression.236 Factors involved in its pathogenesis may include neuroconduction delay, monoamine disturbances, lesion localization, and immunomodulatory and inflammatory factors. Amantadine, modafinil and related agents, stimulants, and exercise programs are used for its treatment. Fatigue can also be secondary to sleep disturbances and to anxiety and depression, in which case addressing the primary disorder is important. Sleep disorders as a group may present in about 50% of patients with MS. These may include insomnia, nocturnal movement disorders, sleep-disordered breathing, narcolepsy, and REM behavior disorder. Sleep disturbances may be secondary to other MS symptoms such as pain, spasticity, and nocturia; they may be side effects of medications or secondary to neuropsychiatric disorders, such as depression and anxiety. Their management warrants a thorough clinical assessment with possible addition of a polysomnogram, and treatment according to the etiology. (see also Chapter 22).237 Cognitive deficits can occasionally be the initial presentation of MS.238 They may contribute to the development of depression, and in turn depression may worsen cognition further.239–242 Other commonly comorbid symptoms include apathy and anxiety, which may occur in about 30% and 20% of MS patients, respectively. Anxiety symptoms may present in the form of generalized anxiety disorder, panic, OCD, and social anxiety symptoms.
Patients with MS may present a wide range of mood and affect symptoms, many times in combination with depression. These manifestations may take the form of pathological or pseudobulbar affect, which is present in about 10% of patients with MS. Bipolar disorder, or related symptoms without the full bipolar syndrome, can be present. Anger, agitation, irritability, euphoria, and disinhibition may co-occur with depression at higher rates than in primary major depressive disorder, and without other associated bipolar symptoms.204,207,208
Some of these symptoms, including irritability, disinhibition, emotional lability, and apathy, may be sustained and become new personality traits secondary to the illness.
Patients with MS present an increased rate of suicide ideation and attempts; it is important to screen and monitor for suicidal risk in MS patients, including evaluation of the risk factors detailed above. Somatic pain is rated by as many as 32% of MS patients as one of their worst symptoms. Depression and pain may reciprocally potentiate each other and it is important to address both in the management of these patients.
COURSE AND NATURAL HISTORY
The heterogeneity of MS makes the course of this illness very variable. There are several patterns of progression: relapsing remitting, secondary progressive, primary progressive, and progressive relapsing. Illness exacerbations and progression contribute to the development of depression.243,244 The Kurtzke Expanded Disability Status Scale (EDSS) quantifies MS-related disability in eight functional systems (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral, other) and allows neurologists to assign a functional system score (FSS) in each of these. Higher levels of disability may be associated with higher levels of depression.209,245 Untreated depression, in turn, may negatively affect the course of MS. It can negatively affect the physical outcome and disease exacerbations, cognitive function, adherence to treatment, suicide risk, and quality of life of patients and their caregivers.201,246 MS can significantly affect families: Children whose parents have MS may present greater emotional and behavioral problems than children of parents in the general population.247 In turn, this may contribute to feelings of inadequacy and guilt in depressed MS patients.
ASSESSMENT AND DIFFERENTIAL DIAGNOSIS
Depression in MS is underdiagnosed and undertreated.200 Patients should be encouraged to report symptoms of depression and clinicians should screen for them.
To assist with the diagnostic challenge that several symptoms are shared by depression and a medical illness, some scales assign more weight to the presence of depressive beliefs. One of these self-administered scales, the BDI, is validated for use in MS patients.248 The 9-item self-administered patient health questionnaire (PHQ-9) may be useful in this population.249 The SCID-IV 2-Question can be used to screen for depression, and the center for Neurologic Study Emotional Lability Scale to screen for pathological or pseudobulbar affect. The 28-items General Health Questionnaire may be useful to screen for depression and other emotional disturbances.229
The treatment of depression in MS patients should be interdisciplinary and use an integrated biopsychosocial approach. (Box 5-6).250 Treating depression may bring several benefits to patients and caregivers, including enhancement of adherence to disease-modifying agents.231
There are limited quality studies evaluating pharmacologic options. One shows that sertraline and CBT are equally effective and superior to supportive group therapy.251 Desipramine shows a trend toward efficacy in a small, nonrandomized study.252 A study comparing paroxetine with placebo shows no significant differences in primary outcomes.253 Moclobemide and duloxetine may be effective according to evidence from small open trials.254,255 As discussed in pathophysiology, one of the MS disease-modifying drugs (DMA), fingolimod, may have benefits for depression; still, further research is needed for further characterization of the effects of DMAs in mood. Pathologic or pseudobulbar affect may be comorbid with depression. Different antidepressants including SSRIs and tricyclics may be effective. A combination of dextromethorphan and quinidine may be useful.256 as well.
BRAIN STIMULATION THERAPIES
ECT appears as an effective treatment for depression in MS according to the limited evidence available, which includes several case reports. It should be especially considered for patients with severe depression, acute suicidal risk, and those who have failed other first-line approaches.257,258 There has been concern, based on isolated case reports, that some patients with MS may suffer neurological deterioration after ECT. The presence of contrast-enhanced lesions may be a risk factor for disease exacerbation with ECT and the possible value of gadolinium-enhanced MRI for identifying high-risk patients has been discussed.259 A small randomized, sham-controlled study of the safety and efficacy of deep rTMS on fatigue and depression in patients with MS showed potential benefits.260
CBT may be effective for patients with MS and depression delivered in group261 or individual format251 and also when administered by phone.262 A computerized form of CBT may have low acceptability among MS users for several reasons including the logistics of computer use, the perpetuation of social isolation and the lack of human input during the intervention.263 A randomized trial shows that mindfulness training is effective to reduce depression and fatigue and improve quality of life.264
Depression is highly prevalent in MS. It affects the quality of life of individuals with MS and their families. It is associated with increased morbidity and mortality, and decreased adherence to MS treatment. The pathophysiology is multifactorial. Its biological components include the load and localization of brain lesions, degree of brain atrophy, inflammatory and immunological factors. Its psychosocial elements include levels of stress, lack or limited social support, and coping style. Its clinical presentation may be the same as that of primary major depression. Certain overlapping symptoms between depression and MS such as fatigue, sleep, and cognitive disorders may make the diagnosis challenging. Associated and comorbid symptoms may include apathy, anxiety, pain, irritability and pathological affect. Individuals with MS and depression have higher risk for suicide. It is important to proactively screen and treat depression in MS as it has a significant impact on the prognosis of this illness. The treatment should be multidisciplinary and address biological and psychosocial factors. There are limited quality studies supporting the use of specific antidepressants in MS, but antidepressants may be as effective as in primary depression. Different types of psychotherapy including CBT and mindfulness training may be effective. ECT should be considered in cases of severe and treatment-resistant depression (see Text box 5-12 for a review of Anxiety in Multiple Sclerosis).
BOX 5-12 ANXIETY IN MULTIPLE SCLEROSIS
Although less well studied than depression, anxiety disorders are very prevalent in multiple sclerosis (MS).
Anxiety is common early after diagnosis due to adjustment difficulties and fears about the potential changes this illness will bring to the patient's life.
It is also commonly present in acute MS relapses as the symptoms cause disruption to the individual's routine.
Uncertainty about the illness' potential course and prognosis is one of the factors involved in the development of anxiety.
Among the disease-modifying drugs, Glatiramer is most likely associated with anxiety as a side effect.
Patients may experience any of the anxiety symptoms typical of primary anxiety disorders.
Anxiety may be associated with increased somatic complaints. Collaboration with the patient's neurologist is important in situations where it is unclear if somatic symptoms are due to anxiety or represent an MS relapse.
There is limited specific information about treatment of anxiety disorders in MS. As in primary anxiety disorders, treatment may involve medications such as SSRIs and SNRIs, and psychotherapy approaches including CBT.
MDD is recognized as the most common psychiatric complication after TBI.265,266 The prevalence and incidence rates of MDD after TBI range from 18% to 61% and from 15% to 33%, respectively (see Fig. 5-1).267 The methodology of prevalence and incidence studies is varied. The postinjury time points at which prevalence is measured and the use of different instruments to assess for the presence of MDD make such investigations difficult to compare.
One of the largest studies to date reports 53% of patients meeting criteria for MDD at some point during the first year after TBI. Of the total sample, 23% experience depression for the first time after their TBI, while others with post-TBI depression were depressed at the time of the injury or experienced a recurrence of a primary preinjury MDD. The highest point prevalence is at 1 month following the injury (31%).268 Another study identifies 42% of subjects meeting criteria for MDD at some point during the first-year post-TBI.269 Of those, 26% present MDD during initial hospital admission for TBI, while17% have a delayed presentation. Other studies report new onset of depression in 18 to 33% of subjects within the first-year post-TBI.270–272
Studies also measure prevalence of MDD beyond the first-year post-TBI. An evaluation done on an average of 32.5 months post-TBI identifies 26% of patients with MDD at the time of the evaluation and an additional 28% with an already resolved post-TBI MDD episode.273 From 10 to 126 months post-TBI, 27% of patients meet five or more of the nine DSM MDD criteria.274 When the average time postinjury is 2.5 years, the prevalence rate is 42% at the time of the evaluation.267 When the average time postinjury is 8 years (range 1–37 years), 61% of the subjects meet MDD criteria at some point after TBI.275
Longer-term studies evaluate prevalence of MDD decades after TBI. A 30-year follow-up study265 identifies a MDD lifetime prevalence of 27%, with 10% meeting criteria at the time of the assessment. A MDD lifetime prevalence of 18.5% is reported in World War II veterans 50 years after a TBI, with 11% meeting criteria at the time of the evaluation. The lifetime risk of developing MDD in the veterans TBI group compared to a non-TBI one is 1.5-fold.276
A very large National Survey of Children's Health of 12 to 17 years old identifies a 3.3-fold greater risk of depression in those with a history of concussion.277 For retired football players, a history of three or more concussions is associated with a 3-fold increase in the development of lifetime depression, versus those with one or two concussions who have a 1.5-fold increased risk.278 In summary, MDD is a common occurrence after TBI. The highest prevalence is in the first year after injury, but high rates of depression continue several months or even decades after the TBI.
TBI is defined as an insult to the brain caused by an external force that produces one of the following: alteration of consciousness, altered mental state, any loss of memory of events surrounding the accident and/or focal neurological deficits. The biomechanical forces applied to the brain during the trauma can be either contact forces or inertial forces. Contact forces most commonly cause impact or contusions in the anterior and inferior frontal and temporal areas. Inertial forces, on the contrary, refer to acceleration and deceleration forces causing a stretch and strain of white matter tracks throughout the central nervous system (CNS), including the upper brainstem, corpus callosum and gray-white matter junctions of the cerebral cortex. The latter described process is termed diffuse axonal injury. Blast-related injuries directly affect air-filled organs, and it remains unclear if they can directly affect the brain, but may secondarily cause TBI effects through contact or inertial forces. Coupled with the mechanisms described, a cytotoxic cascade (calcium and magnesium dysregulation, calcium-regulated protein activation, mitochondrial dysfunction, free-radical formation) and neurotransmitter disturbances (dysfunctional elevations in cerebral glutamate, acetylcholine, dopamine, and norepinephrine) usually accompany the immediate effects following the injury.279
Injury to specific brain regions and the pathways connecting these regions may translate into specific clinical symptoms of TBI. Figure 5-2 illustrates the clinical phenomena that commonly occur with localized injuries.279
Few studies have looked at lesion localization in TBI and its association with depression. During the preimaging era information from neurosurgical notes establishes that right frontal damage is commonly associated to mood disturbance.280 A study on Vietnam War veterans with penetrating brain injuries identifies right orbitofrontal lesions as more likely to be associated with edginess, anxiety and depressive symptoms, while left dorsolateral prefrontal lesions are associated with greater anger and hostility.281 Left frontal lateral and left basal ganglia lesions are associated with higher rates of depression,282,283 with the difference between lateral and medial regions being more likely to distinguish depression during the first 3 months after the injury.283 A hypothesis based on a structural MRI study284 proposes that an imbalance of negative valence (mediated by frontal lobes) and arousal (mediated by right parietal lobe) may play a role in the pathogenesis of depression, with another study signaling a similar imbalance between right versus left and anterior versus posterior regions in post-TBI depression.285
Functional neuroimaging studies reveal altered functionality and connectivity between different brain regions in post-TBI neuropsychiatric disorders. An fMRI study of veterans with blast-related concussions shows that those with post-TBI depression have more heightened amygdala reactivity, lower activation of prefrontal cortex, and lower fractional anisotropy (FA), which signals disruption of white matter tracts, in several tracts including the superior longitudinal fasciculus compared to nondepressed patients.286 During an error-monitoring task, patients with post-TBI depression and a history of suicidal ideation show more activation of the anterior cingulate and prefrontal cortices.287 Magnetic resonance spectroscopy imaging (MRS) detects reduced N-acetylaspartate/creatine ratio and reduced choline/creatine in the right basal ganglia in patients with post-TBI depression compared to patients after TBI who were not depressed, signaling neuronal and axonal alteration in that area.285
Chronic traumatic encephalopathy (CTE) refers to the neurodegenerative disease associated with repeated concussive and subconcussive head injuries, and it was formerly known as dementia pugilistica given its former association to boxers. Pathological findings that characterize CTE include frontal and temporal atrophy, axonal degeneration, and hyperphosphorylated tau and TAR DNA-binding protein (TDP-43) pathology.288 CTE is clinically associated to depression and other psychiatric symptoms such as irritability, impulsivity, aggression, short-term memory loss and heightened suicidality, with onset after experiencing repetitive mild TBI 8 to 10 years before. The stages in CTE refer to the spread of p-tau pathology that goes from discrete foci in certain cortical regions (stage I) to most regions of the cerebral cortex and the medial temporal lobe (stage IV). Depression is described in all four pathology-confirmed stages of CTE.289
Other physiological consequences associated with TBI include posttraumatic epilepsy290 and pituitary injury291; they can both contribute to depression pathogenesis.
Most studies demonstrate that injury severity does not predict development of MDD268,292 although course may differ per severity subgroups.293
Psychosocial factors such as premorbid personality and psychiatric conditions, emotional reaction to the injury, inability to have a functional reintegration, environmental factors and compensation or litigation, can all have a significant impact in the development of post-TBI depression.280
History of premorbid depression is more common in patients with post-TBI depression compared to those who do not develop depression after their injury.268,292 Older age seems to be protective against post-TBI depression268,294 although contradictory results have also been reported.295,296 Lifetime history of alcohol abuse,268 fear of job loss, dissatisfaction with work situation,297 unemployment and poverty274 have been linked to the development of depression following TBI.
In sum, the development of post-TBI depression depends on the potential interactions of several biological and psychosocial factors, as illustrated in Figure 5-3.
Multiple risk factors and clinical presentation in post-TBI depression.
Development of post-TBI depression is dependent on a number of preinjury biological and psychosocial factors as well as injury factors. Postinjury factors also play a role in the development and perpetuation of depression. These same factors may play a role in the development of other cognitive, somatic or associated behavioral syndromes. Symptomatic presentation in post-TBI depression can be pleomorphic, involving cognitive, somatic, and accompanying behavioral symptoms. These need to be distinguished as either part of the diagnosis of depression or as separate clinical entities.
Most studies on post-TBI depression utilize the criteria listed by DSM to confirm the diagnosis. Usually the category of “mood disorder due to a general condition” with either “depressive features” (for those not meeting full MDD criteria) or “major depressive features” (for those meeting full criteria) is selected in clinical scenarios. A number of somatic, behavioral, and motivation symptoms can be present in post-TBI patients with or without depression, at times making the diagnosis of depression challenging.267 Still, DSM criteria are considered to have good sensitivity and specificity for the diagnosis of depression in patients after TBI.298
Fatigue, frustration, poor concentration, and sleep disturbance are some of the most commonly symptoms reported in post-TBI depressed patients, although they are not specific (Box 5-3).275 Other postconcussive symptoms, such as headaches, dizziness, and blurred vision are reported in increased number and severity by depressed patients.299 The Neurobehavioral Functioning Index has been used to detect depression in patients after TBI, and identifies specific symptoms that distinguish patients with depression. These symptoms include feeling sad or blue, feeling hopeless, frustrated, easily irritated, having difficulty enjoying activities, feeling uncomfortable around others, loss of interest in sex, and feelings of worthlessness. Somatic symptoms (poor appetite, trouble falling asleep) and cognitive ones (cannot get mind off certain thoughts, forget if done things, forget to do chores) can also identify patients with depression after TBI.300
Objective testing of cognitive function demonstrates more pronounced impairment in patients with post-TBI with depression, specifically in the domain of executive function.272,273 Verbal memory and processing speed may be more impaired in patients after TBI with depression versus patients after TBI without depression.272,273 It is noteworthy that roughly 50% of mild and moderate TBI patients without MDD still present objective evidence of impairment in at least one cognitive domain.260
While many symptoms listed in the MDD criteria may exist independently in patients after TBI, they should still be included in the DSM criteria used to diagnose post-TBI depression, as their report is usually elevated due to mood factors.
Anxiety is comorbid in up to 77% and aggression in up to 57% of patients after TBI who are depressed.272 Anxiety occurs eight times more commonly in patients after TBI with depression than those after TBI who are not depressed.268 Concurrent rather than sequential treatment of these comorbid conditions is recommended.
A history of TBI increases the risk of suicide attempt.301,302 TBI-related completed suicide is associated with a history of comorbid psychiatric and alcohol disorders,293 but increased risk of suicide attempt still exists when controlling for psychiatric comorbidities.302 Later stages of pathology-confirmed CTE are associated with higher rates of suicide.289 Aggression and hostility are predictors of suicide attempt and should always be screened for in patients after TBI as potential risk factors for depression and suicidality.301
Involuntary emotional expressions303 and apathy304 can exist comorbidly with post-TBI depression and should be distinguished as either separate or comorbid clinical entities.
Figure 5-1 illustrates the range of cognitive, somatic and behavioral disturbances that may be associated with post-TBI depression or may present as independent entities in the post-TBI population.
COURSE AND NATURAL HISTORY
Over the course of the first-year post-TBI, depression has an estimated mean duration of 4.7 months269 with the highest prevalence of post-TBI depression at 1 month after the injury.268
Individuals with mild TBI and prior psychiatric history tend to present with more persistent psychiatric problems, including affective disorders, than those with moderate and severe TBI with or without a prior psychiatric history. For those with moderate and severe TBI, the risk of psychiatric difficulties tends to be higher immediately following the insult with a following decline in symptom prevalence.305 See Table 5-3 for classification of TBI based on severity.
TABLE 5-3Classification of Traumatic Brain Injury Severity ||Download (.pdf) TABLE 5-3 Classification of Traumatic Brain Injury Severity
|Severity of TBI ||Mild ||Moderate ||Severe |
Period of loss of consciousness
30 min or less
30 min to 1 week
More than 1 week
Glasgow Coma Scale score
8 or less
24 hours-1 week
> 1 week
Approximate % of all TBIs
% that experience full recovery
Sleep difficulties soon after TBI predict severity of depression 1 year after the injury.306
Depression is associated with more pronounced psychosocial dysfunction and a stronger perception of disability.273,299 Post-TBI depression lasting more than 6 months is associated with deterioration in social functioning and activities of daily living during the first-year post-injury.292 The individual's perception of changes in daily functioning may impact the onset of depression.307 Severity of depression and anxiety is a strong predictor of health-related quality of life 12 months after a severe TBI.308
The return-to-work rate in TBI is low, with post-TBI unemployment rates of up to 70%309 A study finds no difference in the return-to-work rate between patients post TBI with and without depression,299 and another finds fatigue but not depression to predict the number of days to return-to-work.310
The presence of depression with or without head injury may account for the individual's report of postconcussive symptoms, including cognitive complaints.311 Treatment with the antidepressant sertraline shows improvement in cognitive measures and subjective perception of cognitive and health status in patients after TBI with depression.312
Post-TBI depression can evolve into a chronic condition for a subgroup of patients and its presence signals a decline in functional status. Appropriately addressing depression improves perception of health status and may also influence functional recovery. Figure 5-2 highlights the role of postinjury factors in both the development and perpetuation of depressive symptoms after TBI.
ASSESSMENT AND DIFFERENTIAL DIAGNOSIS
As previously mentioned DSM criteria are appropriate for diagnosis of post-TBI depression.298 Different instruments can be used to assess for the presence of MDD diagnostic criteria, including the Structured Clinical Interview for DSM-IV (SCID), or the Schedules for Clinical Assessment in Neuropsychiatry,313 although these are more commonly used in research settings. The BDI is a self-report measure that can be helpful to assess and monitor treatment progress of depression in the TBI population.314,315 However, its score may be influenced by nondepression-related problems and astute clinical correlation is recommended.316 The PHQ-9 is a valid and reliable self-report screening tool for post-TBI depression and is very easy to administer.317 The Neurobehavioral Functioning Index is another self-report measure that can be used in patients after TBI for the assessment of multiple problems or symptoms and can accurately distinguish depressed from nondepressed patients.300 Given the frequent comorbidity with anxiety, self-report measures that combine depression and anxiety ratings are useful. The Depression, Anxiety and Stress Scale (DASS) and Hospital Anxiety and Depression Scale (HADS) are validated in the post-TBI population.318 Because of the potential discrepancy found in TBI patients between self-report and objective measures319,320 use of clinician-rated measures, such as the Hamilton Depression Rating Scale (HDRS), may be useful for the assessment of depression.
Cognition and level of functioning should be assessed periodically in patients after TBI, as the severity of cognitive and functional impairment may fluctuate over time and may inform treatment course. Within the first-year postinjury, the Rancho Los Amigos Levels of Cognitive Functioning Scale is a widely accepted measure of the clinical, cognitive and functional impact of the TBI and helps identify those patients that will most likely benefit from rehabilitation services.321
A number of clinical conditions that present with affective symptoms need to be distinguished from post-TBI depression. Pathological laughing and crying (PLC), defined as uncontrollable episodes of laughing or crying triggered by a stimulus that would not normally cause such a response, has a prevalence of 10.9% during the first year following a TBI.303 PLC is associated with higher severity of depression, which calls for a careful assessment and distinction of both conditions. Another important distinction is the presence of apathy. One study assessing post-TBI affective changes reports 11% of subjects with apathy without depression, 11% with depression without apathy, 60% with both depression and apathy and 18% with neither syndrome.304 The Apathy Evaluation Scale can distinguish apathy from depression and anxiety.
Anxiety should always be screened for. In addition to comorbid depression and anxiety, an anxiety disorder may be present in about 20% of nondepressed post-TBI patients.272 Generalized anxiety disorder, panic disorder and posttraumatic stress disorder (PTSD) are the most common anxiety disorders present in post-TBI depression.
PTSD following TBI should be considered as part of the differential diagnosis and as a comorbid condition in post-TBI depression. Although there may not be a PTSD prevalence difference between those individuals sustaining a closed head injury versus those being exposed to other traumas,322 PTSD occurs in post-TBI patients, even without a cohesive recall of the event, and is associated with higher depression scores.268,323
Post-TBI aggressive behaviors occur in 57% of post-TBI depressed patients versus in 23% of post-TBI nondepressed patients.272 Aggression is present in 34% of post-TBI patients during the first 6 months postinjury and its presence is correlated with depression.324 In a cohort of aggressive versus nonaggressive men, aggression is significantly associated with a prior history of closed head injury.325 As previously stated, aggression may increase the risk for suicidality.
History or presence of mania or hypomania that may signal a premorbid or post-TBI bipolar disorder, comorbid substance abuse and of other medical conditions should always be part of a comprehensive assessment in patients after TBI. Post-TBI mania has been identified in 9.1% of patients during the first year following the insult.326
Some self-report instruments are validated in the post-TBI population, but objective corroboration is always necessary for an accurate diagnosis. A solid clinical assessment of depression relies on the clinician's expertise and ability to distinguish and identify comorbid conditions, such as PLC, apathy, anxiety, aggression and others as discussed above. The post-TBI population is particularly susceptible to suicidality, which should be screened for regardless if depression is deemed present or not.
See Box 5-6 for a summary of treatments of depression in neurological illnesses.
Given that the onset of post-TBI depression tends to occur soon after the traumatic event and may evolve into a chronic illness, it is always recommended that treatment takes place immediately after mild depressive symptoms are recognized, even if this occurs during the recovery from TBI's physical sequelae. See Table 5-4 for a summary of studies conducted on psychopharmacologic treatment of post-TBI depression. One study evaluating the role of early administration of the antidepressant sertraline in patients after TBI without depression as a prophylactic treatment327 finds a significant reduction of depressive symptomatology in those receiving sertraline compared to placebo; however, the effects were not sustained when the drug was discontinued at 3 months.
TABLE 5-4Summary of Psychopharmacological Studies in Post-TBI Depression ||Download (.pdf) TABLE 5-4 Summary of Psychopharmacological Studies in Post-TBI Depression
|Authors ||AAN Evidence Level ||N ||TBI Sample Severity Level ||Depression Instruments ||Design and Intervention ||Results and Conclusions |
Ashman et al. (2009)
Different severities of TBI
17 ± 14 yr post-injury
DB, RCT of sertraline (25–200 mg/d) or PB for 10 wks
Significant improvement from pre- to post-treatment in depression, anxiety, and QOL measures, but no group differences.
Lee et al. (2005)
Mild to moderate TBI
DB, RCT of MPH (5–20 mg/d), sertraline (25–100 mg/d), or PB for 4 wks
Both drugs improved HDRS scores more than PB; MPH improved cognition and alertness more than sertraline.
Dinan and Moyabed (1992)
13 mild TBI depressed patients vs. 13 non-TBI depressed controls
Open trial of amitriptyline (up to 250 mg/d) for 6 wks
4/13 persons with mild TBI vs. 11/13 non-TBI depressed controls showed significantly improvement.
10 mild TBI patients vs. 12 non-TBI depressed controls
Open trial of amitriptyline (200–300 mg/d) for 4 wks; nonresponders had trial of phenelzine (60–90 mg/d) after 3–7 day washout
No response with either drug in TBI subjects; all depressed controls improved on amitriptyline.
Wroblewski et al. (1996)
DSM-IIIR 9-item symptom checklist
Blinded, randomized crossover study of desipramine (150–300 mg/d) vs. PB.
Six of 7 study completers on desipramine had significant improvement.
Fann et al. (2000)
Mean 10.6 mo post-TBI
Nonrandomized, single-blind trial of sertraline (15–150 mg/d) vs. placebo for 8 wks
Significant improvements in depression, psychological distress, post-concussive symptoms by week 8 of sertraline.
Horsefield et al. (2002)
Different severities of TBI
Open trial of fluoxetine (20–60 mg/d) for 8 mo
Significant reduction in mood and cognitive measures.
Khateb et al. (2005)
Moderate to severe TBI
Open trial of donepezil for 3 mo
Nonsignificant reduction in HADS depression scores; significant improvement in processing speed, learning and attention.
Kanetani et al. (2003)
Mild to moderate TBI
Open trial of milnacipran (30–150 mg/d) for 6 wks
Response rate was 66.7% and remission rate was 44.4%; significant improvement in cognition on MMSE
Newburn et al. (1999)
TBI severity not noted
Open trial of moclobemide (450–600 mg/d)
HDRS reduction was 81%; irritability scores dropped by 57% and pain scores dropped by 39%
Perino et al. (2001)
Open trial of citalopram (20 mg/d) plus carbamazepine (600 mg/d) for 12 wks
Significant reductions in depression and behavioral disorders.
Rapoport et al. (2008)
Mild to moderate TBI
Open trial of citalopram (20–50 mg/d) for 6 and 10 wks
Similar response rate as seen in patients with major depression without TBI: at 10 wks, 27% remission and 46% response.
There is no psychotropic agent that carries an FDA approval for use in patients after TBI with depression. A randomized, double-blind, placebo-controlled study shows that both sertraline and placebo may improve mood, anxiety and quality of life measures, but there was no statistically significant difference between the groups.328 Another randomized, double-blind trial comparing the efficacy of sertraline, methylphenidate and placebo finds reduction in HDRS for both patients treated with methylphenidate and sertraline compared to those treated with placebo. Both methylphenidate and placebo treatment significantly improves measures of cognitive function, specifically reaction time, and postconcussive symptoms, though sertraline treatment does not.329
A nonrandomized, placebo run-in trial of sertraline for 8 weeks in 15 patients after mild TBI shows improvement in depression severity, psychological distress, postconcussive symptoms, cognitive functioning and quality of life.330 Other SSRIs with efficacy in open trials include citalopram, either as monotherapy,331 or in combination with carbamazepine,332 and fluoxetine.333 The use of the TCA desipramine is supported by a study with a placebo cross-over design.334 Amitriptyline seems less effective in treating depression in this population.335,336 The efficacy of other antidepressants, including the serotonin-norepinephrine reuptake inhibitor milnacipran,337 and the selective monoamide oxidase inhibitor moclobemide,338 as well as the cholinesterase inhibitor donepezil339 for post-TBI depression in open trials is summarized in Table 5-4340 Citalopram does not seem to provide protection toward depression relapse for post-TBI patients with depression in remission.341
BRAIN STIMULATION THERAPIES
ECT may be effective for patients after TBI with depression.342 While ECT is not contraindicated in post-TBI patients, when indicated and administered, the use of the lowest effective energy and nondominant unilateral currents are recommended given the potential for cognitive side effects.
A randomized controlled trial of individual CBT plus cognitive remediation compared to a wait list group shows significant improvement in depression severity. Improvements are more pronounced one and 3 months after treatment.343
CBT delivered in groups or by phone may reduce depression and anxiety344 with sustained benefits 6 months following treatment.345 The CBT protocol was adapted to the specific needs of patients after TBI, including their cognitive impairment.
A 6-week Internet-based online CBT program for patients after TBI shows improvement in mood symptoms, but with poor adherence, likely influenced by the sample's cognitive impairment.346 A controlled 10-week mindfulness-based cognitive therapy (MBCT) study shows improvement in depression severity, which is maintained after 3 months.347
In contrast, a noncontrolled CBT-based coping skills group intervention for 5 weeks shows improvement in adaptive coping, but no changes in depression severity compared to baseline.348
Exercise, including swimming, has positive results in the treatment of depressive symptoms in patients after TBI, in small or uncontrolled trials.349,350 A large trial comparing aerobic exercise to relaxation training for 12 weeks in patients with recent and severe TBI shows no difference between the groups, but does show reduction of depression and anxiety in both groups.351 A randomized controlled trial of light therapy for treatment of fatigue in patients after TBI shows no effect of this intervention in depression severity, a secondary outcome measure.352
Meta-analyses of depression treatment in patients with TBI shows an overall effect size of 1.89 (95%CI = 1.20–2.58) for pre- and posttreatment comparisons of psychopharmacological and nonpsychopharmacological interventions. However, meta-analysis evaluating only controlled studies identifies an overall effect size of 0.46 (95% CI = −0.44−1.36), favoring the control interventions.353
Depression is the most common psychiatric complication after TBI. Preinjury history of depression and alcohol abuse are risk factors for the development of post-TBI depression, as are other premorbid environmental factors, such as unemployment, poverty, and dissatisfaction with work situation. Contusions in the frontal and temporal areas and diffuse axonal injury are mechanisms commonly associated with TBI. Repetitive trauma can evolve into a neurodegenerative process highly associated to depression. Structural and functional alterations specifically associated to post-TBI depression have been detected in studies, with alterations in the structure and function of the prefrontal cortex and its connectivity being the most consistent findings. The clinical presentation of post-TBI depression can be challenging, as a number of somatic, behavioral and motivational symptoms tend to be present. DSM-5 criteria should continue to be used to establish the diagnosis clinically, and a number of screening instruments such as the PHQ-9 and BDI are validated in post-TBI depression. Frequently comorbid conditions should be considered when evaluating post-TBI depression, and these include anxiety, apathy, pathological affect, aggressive behaviors and cognitive deficits. The highest prevalence of post-TBI depression occurs within the first year of the injury, but delayed presentations beyond the first year are not uncommon. Mild severity of the injury and prior psychiatric history seems to increase the risk of persisting post-TBI psychiatric difficulties. Evidence-based treatments for depression in patient's post-TBI include the use of antidepressants, cognitive-behavioral therapy, and MBCT. The use of exercise, which many times is part of the rehabilitation process, can exert a positive effect on mood (see Text box 5-13 for a review of Anxiety and Traumatic Brain Illness).
BOX 5-13 ANXIETY AND TRAUMATIC BRAIN ILLNESS
Anxiety is comorbid in up to 77% of patients who have depression after traumatic brain illness (TBI). It occurs eight times more commonly in patients with post-TBI depression compared to those who are not depressed.
In addition to their comorbidity with depression, anxiety disorders may be present in about 20% of nondepressed patients.
Patients may experience any of the anxiety symptoms typical of primary anxiety disorders.
Generalized anxiety disorder, panic disorder, and post-traumatic stress disorder are the most common anxiety disorders post-TBI. Obsessive-compulsive disorder and phobias may also develop post-TBI.
PTSD may occur even in patients without a cohesive recall of the traumatic event.
Anxiety may be present as part of a postconcussion syndrome.
Screening for and treating anxiety in patients with TBI may markedly improve their prognosis.
Depression is common among patients with epilepsy (Fig. 5-1), and patients with both epilepsy and depression are at risk for developing a more severe seizure disorder.354 Recent meta-analyses demonstrate a pooled prevalence of active depression (within the last 12 months) in persons with epilepsy (PWE) of just over 23% (range 13.2–36.5%) and a lifetime pooled prevalence of 13.0% (range 4.1–32.5%). Odds ratio (OR) of active depression in PWE relative to persons without epilepsy is estimated at 2.77 pooled, with the range of individual adjusted OR models varying from 1.1 to 3.49, and overall OR for lifetime depression of 2.2 with a range of 1.48 to 3.96355 Heterogeneity in individual study prevalence estimates is likely driven by variations in the method of diagnosing depression.355 The increased risk for depression in PWE is not accounted for solely by the presence of chronic disease: a population-based analysis comparing rates of neuropsychiatric comorbidities accompanying epilepsy versus other conditions (asthma, diabetes, migraine) finds the highest prevalence rates for depression in epilepsy (9.6%) with an adjusted OR of 2.7356 Despite significant heterogeneity in epilepsy subtypes in this discussion they are treated as one entity, except where noted.
Additionally, depression and suicide attempt independently increase incident risk of developing epilepsy.357 Conversely, a diagnosis of epilepsy increases the incidence risk ratio for depression and suicidality both before and after diagnosis.358 Thus, depression appears to be both a risk factor for developing epilepsy and, frequently, comorbid with it. In addition, comorbid depression is associated with diminished treatment-responsiveness.359
There is relatively little data regarding the contribution of family history to depression in epilepsy, but at least one study of children and adolescents with epilepsy finds family history to be highly statistically significant in contributing to depression.360
Genetics may play a role as well. There is a rat model of hereditary absence epilepsy with comorbid behavioral correlates to human depression.361 Future study may reveal genes conferring a high risk for both conditions. Population-based study of the genetics of epilepsy is demonstrating that specific gene dysregulation can have pleiotropic effects: copy number variation (CNV) is a form of genetic variability that arises when segments of DNA are duplicated or deleted during meiosis or recombination. Certain recurrent CNVs are associated with epilepsy as well as with neuropsychiatric conditions, such as autism, schizophrenia, and ADHD. That is, these CNVs convey an increased risk for a range of neuropsychiatric disorders including epilepsy.362 Future research may also shed more light on the genetic underpinnings of epilepsy and depression, whether by way of a common CNV leading to increased risk for both conditions or via some other mechanism.
The neuropsychiatric origins of depression in epilepsy are likely multi-factorial (Box 5-2) and reflect both diathesis and stress contributors. Etiology can then be understood at the levels of both psychological mechanism and neurobiological pathophysiology. Among the contributing psychological mechanisms, special attention should be paid to the ways in which living with epilepsy parallels a “learned helplessness” experimental model for inducing depressive behavior: recurrent seizures are aversive events that occur at unpredictable intervals largely outside the control of the individual experiencing them.363 In addition, the burden of living with a chronic illness with its associated injuries, effects on functioning, and social stigma create chronically high levels of psychological distress in epilepsy patients that are known to contribute to depression.364 That said, it is not the burden of chronic illness alone that raises depression risk in PWE: epilepsy is associated with a risk of depression and other neuropsychiatric disorders that exceeds the risk associated with other chronic illnesses (both asthma and diabetes).356
On a neurobiological level, epileptic seizures are marked by paroxysmal hypersynchronous neural discharges that result from cortical hyperexcitability. Shared pathophysiology may be related to alterations in cortical excitability. There are several leading mechanisms by which underlying pathophysiology has been hypothesized to predispose to both depression and epilepsy, including (1) a hyperactive HPA, (2) structural and functional abnormalities of cortical structures, (3) increased glutamatergic and decreased GABAergic and serotonergic activity, and (4) immunological abnormalities.351
Alterations in hormonal milieu, especially over-activation of the HPA axis, appear to be one shared contributing mechanism. In rats, treatment with high-dose corticosteroids prior to epileptogenic kindling accelerates seizure appearance and leads to higher amplitude hippocampal cell spiking even when serum corticosteroid levels are no longer elevated.365 Chronic low-dose corticosteroid supplementation, perhaps more akin to the physiological elevations seen with chronic depression, also leads to accelerated kindling in rats, albeit in an amygdala model of epilepsy.366 Blocking the glucocorticoid receptor prevents amygdalar kindling in these rats,367 indicating that the corticosteroid supplementation is critically involved in the development of epilepsy in this setting. It is thought that perhaps the elevated cortisol contributes to cortical hyperexcitability via neurotransmitter effects, for example by producing excessive synaptic glutamate and decreasing serotonin activity.364
Changes in hippocampal volume and neurogenesis are noted in animal models of both persistent temporal lobe epilepsy (TLE) and enduring depression.364 In addition, functional changes (decrements) in serotonin receptor binding in limbic regions, as seen on PET scanning, are much more pronounced in patients with both depression and TLE than in those with TLE alone,368 pointing toward a possible shared mechanism.
Abnormal neurotransmitter levels appear to be involved in the common pathophysiology of depression and epilepsy. Adequate serotonin levels in the hippocampus protected an animal model from pilocarpine-induced seizures369 perhaps via neuronal hyperpolarization mediated by the 5-HT1A receptor.370 Insufficient synaptic serotonin seen in both depression and epilepsy may therefore represent a common mechanism and a model by which they each can exacerbate the other. Enhanced CSF glutamate, on the other hand, is seen in depression associated with a failure of glutamate transporter proteins and resultant neuronal hyperexcitability and death,364 and NMDA antagonism has been associated with therapeutic effects on amygdalar kindling and status epilepticus as well as stress-induced depression phenotypes in animal models,371 supporting a role for excessive glutamate in common pathophysiology. Diminished region-specific GABAergic activity occurs in both animal and human models of depression and seizure disorders, and enhanced GABA functioning produces both antidepressant and anticonvulsant effects.364,371 Alterations in the acetylcholine, norepinephrine, and dopamine systems may contribute to common pathogenesis of epilepsy and depression as well.371
Release of proinflammatory cytokines in depression may be a further contributor to exacerbation of seizure risk: IL-1β has proconvulsant properties by promoting extracellular glutamate.364
Based on animal models of postictal depressive symptoms (e.g., reactive aggression) mitigated by morphine pretreatment and exacerbated by naloxone pretreatment, endogenous opioids released during seizures are thought to play a role in the mood-elevating effects of ECT, and postictal aggressive behavior is postulated to represent endogenous opioid withdrawal.372,373 As such, there may be a role for seizure-related fluctuations in endogenous opioids in the pathogenesis of depressive disturbances in humans with epilepsy as well.
It is also possible that seizure focus has an influence on depression risk in epilepsy. Of particular interest is the distinction between temporal lobe and non-TLE. Mesial temporal sclerosis (MTS), gliosis, and volume loss associated with mesial TLE is a risk factor for depression with inconsistent findings. One study374 finds that MTS significantly increases the risk for depression over nonlesional epilepsy or epilepsy with lesions elsewhere in the brain. This is in contrast with prior data indicating that nonlesional epilepsy poses a significantly greater risk for depression over lesional, including epilepsy associated with MTS.375 Diagnostic methods, inclusion criteria, and analysis of confounding variables may be contributing to the discrepancies in the data; clearly more research is needed to clarify the relationships between lesions, location of epileptic focus, and depression.
Paradoxically, although seizures and depression appear to have common pathophysiological mechanisms, and in some respects each disorder can potentiate the other, ECT, which is seizure induced with an externally applied electrical stimulus, has long been used as an effective treatment for depression. Moreover, seizures can be anticonvulsant.376
ECT may act via a number of potential mechanisms, including the inhibitory and monoamine neurotransmitter systems, neurogenesis, and the endocrine system.377 Depletion of cortical gamma-aminobutyric-acid (GABA) during ECT, leading to a compensatory increase in the function of inhibitory (GABA) neurotransmission, is proposed as one source of the treatment's antidepressant and anticonvulsant properties. ECT enhances serotonergic (5-HT1A) receptor function and striatal dopamine receptor (D1 and D3) binding and decreases the number of alpha-2 receptors in noradrenergic neurons in the locus coeruleus, suggesting that effects on these neurotransmitter systems may contribute to the effects of ECT.377
ECT also increases proliferation of precursor cells in the monkey hippocampus; neurogenesis is thus also postulated as a mechanism for the antidepressant effects of seizures.377
Electrically induced seizures are accompanied by marked acute changes in endocrine function: prolactin, oxytocin, and growth hormone all increase. However, there is no evidence suggesting these alterations are a mechanism for clinical improvement.377 On the other hand, normalization of derangements in the HPA axis correlates with clinical response, suggesting this too may represent a mechanism of antidepressant action for ECT.378 Additional research will help to elucidate the complex pathophysiological mechanisms involved in epilepsy and depression and to clarify the seemingly contradictory effect of seizures on mood disorders.
Depression is a syndrome affecting mood, activity level, and somatic rhythms. In addition to major depression, depressive disorders in epilepsy can include a range of presentations: less pervasive symptomatology (minor depression, or depressive disorder not otherwise specified), less severe symptoms combined with longer duration of disturbance (persistent depressive disorder, formerly dysthymic disorder), and symptoms that interleave with periods of mania or hypomania (bipolar spectrum disorders). Appropriate and self-limiting reactive symptoms (e.g., to a failed temporal lobectomy) must be attended to and distinguished from a disorder of affect. In addition, patients with epilepsy (PWE) can be affected by a range of peri-ictal depressive symptoms (Box 5-3).
Preictal depressive symptoms may present as prodromal dysphoria, irritability, and low frustration tolerance beginning hours to days before seizure onset.379 Self-reported low mood and negative life events prior to seizure events are both independently associated with the occurrence of seizure, suggesting that depressed mood may represent a prodromal aspect of seizure.380 A boost in mood may occur following seizure events.380
Ictal depressive symptoms—those that represent actual manifestation of seizure activity itself—are the second most common ictal affect after fear and are associated with both temporal and diffuse epileptic localizations.381 Distinguishing characteristics of ictal depressive symptoms include a stereotyped depressive reaction, short-lived experience, lack of contextualizing factors for the low mood, and association with other clearly ictal phenomena including evolution to altered consciousness. Unfortunately frequency of this seizure semiology has not been definitively studied and so prevalence data are limited.379
Postictal depressive symptoms may represent the appearance of affective symptoms in the postseizure period (in 5–7 days after) or the exacerbation of a preexisting affective disturbance; indeed these symptoms appear to be more common in those with a prior history of depression or anxiety.373 A study of postictal depressive symptoms in patients with refractory partial epilepsy found that these lasted a median of 24 hours and were quite prevalent (>20% for each symptom)382; the symptoms reported were the same as those reported for major depression.
Interictal symptoms may meet criteria for one of the standard depressive disorder diagnoses referenced above; however, some find that these criteria incompletely describe the clinical affective syndromes seen interictally. The interictal dysphoric disorder (IDD), an entity described as having eight key components including depressed mood, anergia, pain, sleep disturbance, irritable explosive affect, sudden euphorias, fear, and anxiety383 is put forth as one alternative diagnostic category to capture these clinical syndromes, with an emphasis on the chronicity of the dysthymia and the paroxysmal nature of the other components.
A description of the clinical presentation of depression in epilepsy would not be complete without mentions of the other comorbid psychiatric conditions that frequently present along with it: these include anxiety, psychosis, and elevated mood states (See Box 5-14).
BOX 5-14 ANXIETY AND EPILEPSY
The prevalence of anxiety disorders is high in patients with epilepsy, both comorbid with depression and standing alone.
Patients may experience any of the anxiety symptoms typical of primary anxiety disorders.
Importantly, anxiety symptoms may overlap with those of a seizure disorder. For instance fear, feelings of depersonalization and derealization, dizziness and paresthesias may be present as manifestations of a panic attack or represent ictal phenomena.
The clinical differential diagnosis between “primary” anxiety symptoms and those secondary to seizures may be challenging. Anxiety symptoms secondary to ictal activity tend to be stereotypic (occur the same way or similar each time); they are more likely to present with alterations in consciousness and automatisms. EEG including long-term monitoring may be needed to reach an accurate diagnosis in the most challenging cases.
Patients with epilepsy may experience anxiety about the unpredictability of seizure recurrence, especially in situations that would imply danger (driving; holding a baby) and in situations that may cause embarrassment.
Treating anxiety in patients with epilepsy may markedly improve their prognosis and quality of life.
As in primary anxiety disorders, the treatment tools include SSRIs, SNRIs, and psychotherapy including CBT.
Benzodiazepines are not a preferred treatment for these patients. In addition to their known side effects, patients with epilepsy may be at increased risk for seizures caused by withdrawal. Furthermore, patients with epilepsy who develop tolerance to benzodiazepine may be less likely to respond to these agents when used as “rescue” medications to terminate an acute seizure episode.
COURSE AND NATURAL HISTORY
The presence of depression, current or prior, negatively impacts the course of epilepsy, and is associated with a higher likelihood of treatment resistance. There is an odds ratio of 2.26 for psychiatric diagnosis (of which depression accounted for 85%) and refractory epilepsy.359 Depressive symptoms and seizure frequency mutually influence each other over time.384 Older work on the effect of psychotropic treatment on seizure frequency suggested that improvement in psychiatric symptomatology is associated with improvement in epilepsy control.385 However, more recent analyses386 show that changes in the course of epilepsy during antidepressant treatment could be related to effects on the underlying processes involved in epileptogenesis. Additional data on the effect that course of depression has on prognosis in epilepsy will help to clarify whether both depression course and neurobiological treatment are independent predictors.
The management of epilepsy, regardless of effectiveness of outcome, may also affect the prognosis of depressive illness. Patients with epilepsy have an increased risk of suicide (up to 10-fold) when compared with a general population and a high lifetime prevalence of suicidal thoughts, plans, and attempts.363 There is increased risk for suicide in a number of epilepsy sub-groups, including newly diagnosed epilepsy, tertiary care settings or epilepsy institutions, TLE, and postsurgical treatment for epilepsy including temporal lobectomy.387 Interestingly, resective epilepsy surgery may be associated with a higher risk of death by suicide than nonsurgical epilepsy management, even when good seizure control is achieved.388 It may be that the burden of adjusting to life unencumbered by seizures produces a host of new stresses that could prove intolerable and lead to suicide.389 Conversely, failed epilepsy surgery may provoke a feeling of hopelessness in that the last resort has been tried, and thereby lead to suicide.363
ASSESSMENT AND DIFFERENTIAL DIAGNOSIS
Depression in patients with epilepsy can be assessed clinically using the standard criteria outlined in the Diagnostic and Statistic Manual of Mental Disorders and some combination of observation, clinical interview, or a depression checklist such as the Hamilton Depression Rating Scale (HAM-D). Self-administered screening tools such as BDI or PHQ-9 can circumvent the issue of time limitations in brief clinical encounters and enable assessment of depressive symptoms in more patients. However, some depression screening instruments rely heavily on somatic symptoms, which in patients with epilepsy can be associated with the disease itself or with antiepileptic medications. A brief (6-item) neurological disorders depression inventory for epilepsy (NDDI-E) minimizes these confounding sources and demonstrates high specificity for a diagnosis of major depression as well as a better positive predictive value than either the BDI or the PHQ-2.390
Clinically, it can be difficult to differentiate neurovegetative and cognitive symptoms of depression from side effects of some antiepileptic drugs (AEDs), which can include lethargy, weight changes, and poor concentration. In these cases, the presence or absence of anhedonia can help clarify whether a depressive disorder is present.391
While some recommend that practitioners disregard the presence of epilepsy in making a depression diagnosis,363 it is a questionable practice given seizure-related effects on mood and affect regulation. In particular it may prove important to distinguish premorbid or interictal depressive disorders from postictal mood disturbance given that the latter may not respond to pharmacotherapy, even though the two may only be distinguishable based on the shorter duration of postictal mood phenomena.373 Blumer et al.383 advocate for the use of an 8-item subset from the Seizure Questionnaire assessing aspects of mood, irritability, pain, euphoria, anxiety/fear, energy, and sleep to establish a diagnosis of IDD.
Given the risks of suicidal behavior in patients with epilepsy, there is also interest in specific screening tools for suicidality in epilepsy. A comparison of three instruments—the MINI International Neuropsychiatric Interview (MINI), Columbia Suicide Severity Rating Scale (C-SSRS), and Interactive Voice Response System CSSRS (E-CSSRS)—finds that slightly more suicidal behavior was reported with the E-CSSRS than C-SSRS, suggesting the E-CSSRS may be optimal for detection of suicidality in epilepsy.392
Treatment of depression in people with epilepsy needs to take into account the possible risks of depression and suicidality associated with medical and surgical management of epilepsy, the possible risks of lowered seizure threshold associated with some antidepressants, and the psychosocial factors unique to this population (Box 5-6).
As stated above, surgical management of epilepsy, even when successful, is associated with a risk of suicide even with excellent postoperative seizure control. This could be related to new or compounded deficits associated with the surgery, but may be related to the “burden of normality,” the sudden pressure of adjusting to life as a well person. Thorough psychosocial assessment to understand the meaning of the patient's epilepsy to the patient, identify postcure expectations, and otherwise assist with transition to a well state is proposed as one way to reduce that risk.393
Medical management of epilepsy may carry its own risks of behavioral disturbances. In 2008 the FDA issued an alert regarding a 1.8-fold increased risk of suicidality in patients on all AEDs for different indications, including epilepsy, based on data from a meta-analysis of 199 clinical trials of 11 AEDs involving over 43,000 patients. Patients with epilepsy were found to have a higher risk of suicidality on AEDs than patients with psychiatric or other disorders who were taking AEDs. However, as several authors have noted,354,393 trials without suicidality—that is, two-thirds of them—were excluded from the analysis and the suicidality data were not prospectively collected, increasing the risk of reporting bias. Moreover, the risk was assumed to apply to the entire class of AEDs despite very varied mechanisms of action rather than focusing on the AEDs (lamotrigine and topiramate) with a statistically significant increase in suicidality risk or noting that some AEDs (carbamazepine and valproate) had a nonsignificant protective effect on suicidality.394 A recent case-control study of 44,300 epilepsy patients treated with AEDs attempted to account for these variables by studying suicidal behavior prospectively and by class of AEDs. The results show that newer AEDs with a high risk for causing depression (levetiracetam, tiagabine, topiramate, and vigabatrin) are associated with an increased risk of self-harm/suicidal behavior but others, including the barbiturates, valproate, lamotrigine, carbamazepine, oxcarbazepine, gabapentin, phenytoin, and ethosuximide, are not.395 A massive cohort study involving 5.13 million patients examines associations between AED use, epilepsy, depression, bipolar disorder, and suicide or suicide attempt. In the subgroup analysis, while some subgroups' use of AEDs is significantly associated with suicide-related events, the subgroup of patients with both epilepsy and depression shows no significant increase in suicide-related events.396 Given these contradictory findings, an expert consensus reminds practitioners of the multivariable nature of suicidality in epilepsy, the significant morbidity and mortality associated with failing to treat epilepsy with AEDs, and appropriate strategies for risk management in these patients including screening, psychiatric referral, adjustments to AED regimen, and close communication regarding emergent suicidality.397 Awareness of specific antiepileptic medications' propensity to cause depression and suicidality, along with attention to enzyme induction and inhibition properties of specific antidepressants and antiepileptics to maintain appropriate serum levels, should guide selection of drug regimen but not prevent appropriate management of seizures out of concern for inducing suicidality.
Many clinicians have avoided treating patients with epilepsy and depression with antidepressants because of concerns that these medications may lower seizure threshold. TCAs, and to a lesser extent SSRIs, were thought to be proconvulsant, but more recent data suggests that seizure frequency is not negatively affected, and may even be helped, by the addition of antidepressant therapy. With the notable exceptions of clomipramine and bupropion, antidepressants appear to be safe for use in epilepsy (Table 5-5).379,398,399,400–402
TABLE 5-5Seizure Risk by Antidepressant (for Doses Within the Therapeutic Range) ||Download (.pdf) TABLE 5-5 Seizure Risk by Antidepressant (for Doses Within the Therapeutic Range)
|Seizure risk ||Antidepressant |
|Low to moderate ||bupropion SR, citalopram, escitalopram, duloxetine, fluoxetine, nefazodone, mirtazapine, venlafaxine, phenelzine, tranylcypromine, fluoxetine, paroxetine, sertraline, and trazodone |
|High ||clomipramine, bupropion IR, maprotiline, amoxapine |
An analysis of seizure incidence in clinical trials demonstrates increased risk for seizures associated with bupropion and clomipramine, as well as with some antipsychotic medications (clozapine, quetiapine, olanzapine) but an overall lower risk for seizures among those taking antidepressants compared to placebo.399 Evaluation of the effects of extracellular hippocampal serotonin and dopamine in an animal model shows anticonvulsant effects of both neurotransmitters within a range many times above baseline levels; however, elevation above this protective range, as well as D-2 and HT-1 receptor blockade, is associated with proconvulsant effects.369 This is consistent with the observation that antidepressants tend to be associated with seizures primarily in overdose, and even raises the question of whether pro-serotonergic antidepressants should be given a trial as antiepileptic medications in their own right.389 That even relatively safe antidepressants can represent a proconvulsant risk in overdose does bear on treatment recommendations for those patients with epilepsy thought to be at high risk for suicide attempts: one clinical resource indicates elevated risk for seizures in overdoses of some tricyclics (desipramine, nortryptiline, imipramine) as well as other drugs (amoxapine, maprotiline).400 SSRIs remain the first-line treatment for depression in epilepsy given their superior safety profile even in overdose and their efficacy in treating irritability and other atypical depressive symptoms; those with minimal effect on the CYP450 enzymes such as citalopram and sertraline are preferred in patients taking hepatically metabolized AEDs in order to minimize pharmacokinetic interactions.379
As with any attempt to treat a depressive disorder, assessment for propensity to mania or hypomania is a necessity. If mood stabilizing treatment is indicated, it is essential to attend to the properties of the mood stabilizing agents considered. Lithium, for example, can be proconvulsant even at therapeutic doses and normal serum concentrations.379,401,402 Several AEDs including valproate, lamotrigine, carbamazepine, and oxcarbazepine have mood stabilizing properties and should be considered as a first line of treatment in those cases.
BRAIN STIMULATION THERAPIES
ECT holds some potential as a treatment for depression in patients with epilepsy, but limited supporting data have been gathered so far. Case reports have demonstrated safety and efficacy.403–405 A small retrospective chart review of patients with epilepsy and depression who underwent ECT, most of whom were on antiepileptic medication, shows mean seizure length commensurate with published norms for nonepileptic patients and that ECT is an effective treatment for depressive symptoms.406 The authors note two challenges associated with use of ECT in patients with epilepsy: first, the risk of inducing spontaneous seizure activity, especially if antiepileptic doses are lowered to allow planned seizure induction, and second, that of seizures being difficult to induce or of inadequate length. They concluded that epilepsy was not a contraindication to treatment with ECT, and that treatment can proceed with existing AED regimen in place, albeit with ongoing discussion with managing neurologists about how to proceed if seizure induction proves difficult and ongoing monitoring for spontaneous seizures. If AED dose reductions prove necessary to complete ECT, AEDs should be returned to pretreatment regimen following ECT.406 Others recommend holding AEDs on the morning of ECT treatment except in those patients with recent generalized seizures or at high risk for status epilepticus.407
TMS, which uses brief, rapidly changing magnetic field induction over the scalp to induce a focal electrical current in the underlying cortex, appears to be potentially useful in the treatment of mild to moderate treatment resistant depression, and it has the advantage of being noninvasive and well tolerated.408 While definitive studies demonstrating benefit have not been done, it is speculated that the ability of TMS to decrease cortical excitability might make it beneficial in epilepsy if the seizure focus is sufficiently close to the brain surface. It is further hypothesized that TMS of an epileptic focus could reduce its inhibitory inputs to other areas, such as the prefrontal cortex, and thereby improve mood.409 More research will be needed to see whether these hypothetical benefits for depression in epilepsy are borne out.
DBS utilizes intracerebrally implanted electrodes attached to a neurostimulator to stimulate nearby neurons. A Cochrane review of randomized controlled trials of deep brain or cortical stimulation for epilepsy found that anterior thalamic DBS, responsive ictal onset zone stimulation, and hippocampal DBS were all associated with a moderate reduction in seizure frequency in refractory epilepsy patients, but that anterior thalamic DBS was associated with higher rates of depression.410 Although there have been some limited reports of efficacy of DBS for the treatment of depression, placebo-controlled trial data are lacking. As such, it is too early to say whether DBS will be a beneficial treatment for patients with epilepsy and depression, have no effect, or do harm, but target site will likely have an impact and differential effects based on DBS target will need to be carefully characterized.
VNS uses an electrical stimulator attached to a programmable pulse generator to stimulate the patient's left vagus nerve. A randomized, open-label study of best medical practices for pharmacoresistant focal epilepsy versus best medical practices plus VNS found that seizure frequency was significantly improved in the group getting VNS, but depression scores did not change (as measured by the Centre for Epidemiologic Studies Depression scale and the Neurological Disorders Depression Inventory in Epilepsy).411 These results are suggestive of benefit for VNS in epilepsy but not in associated depressive symptoms, though not conclusive.
Transcutaneous vagus nerve stimulation (tVNS), in which the vagus nerve is stimulated noninvasively via the ear (somatic sensory territory of the vagus nerve), has been proposed as a treatment for treatment-refractory epilepsy that avoids the risks of invasive nerve stimulators.412 A randomized controlled trial of tVNS versus sham stimulation (in a region not part of the vagus nerve territory) for treatment-refractory epilepsy patients found statistically significant reductions in seizure frequency with tVNS treatment. In addition, statistically significant improvements in depression (as measured by the Self-Rating Depression Scale) were found in the treatment but not the control group patients. A review of the use of tVNS for neuropsychiatric disorders found benefit for major depression compared with sham-stimulated patients as well as benefit in pharmacoresistant epilepsy413 but was limited by small numbers of existing trials and their inherent biases. In summary, tVNS appears promising for the treatment of epilepsy and depression, as well as their comorbid appearance, but more research needs to be done to establish benefit.
Given the ways in which living with epilepsy parallels a “learned helplessness” model for depression, therapies aimed at altering cognitions, especially those concerning locus of control, may be helpful. CBT, behavioral activation, and acceptance and commitment therapy (ACT) are all helpful, with only a few hours of ACT showing a benefit to quality of life measures.363 CBT seems to help prevent depression in adolescents with a new diagnosis of epilepsy, and is demonstrated on MRI to improve neural activation in regions showing reduced activity in patients with depression and epilepsy.363 However, high-quality data are mixed.
A review414 of existing randomized controlled trials of CBT for depression in epilepsy (6 trials involving 247 patients) shows mixed results; it seems that a focus on coping and reducing depression accounts for the positive efficacy trials whereas a focus on seizure control is more associated with a lack of efficacy. Individual therapy rather than group treatments as well as therapy “booster” sessions to revise and practice CBT skills are associated with the trials finding in favor of CBT efficacy,414 suggesting a focus for implementation. These data must be interpreted cautiously however, taking note of RCT limitations such as small sample size and unclear or inconsistent diagnostic and outcome measures.
Depression is a risk factor for epilepsy, and vice versa. The presence of one also exacerbates the course of the other. Taking into account specific treatment considerations, including future information on the effects of AEDs on depression and suicidality as it becomes available, depression in epilepsy should be aggressively treated. Further research clarifying neurobiological predispositions to both conditions will be essential in clarifying the bidirectionality of the depression and epilepsy link (see Text box 5-14 for a review of Anxiety and Epilepsy).
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