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Affect refers to the external expression of emotions, whereas mood refers to the internal expression or feeling of emotions. Typically, affect and mood are congruent.1 However, in some conditions, they may be dissociated: Individuals with pseudobulbar palsy may have bursts of laughter or crying, which do not reflect how they feel at the time, whereas individuals with parkinsonism who do not have a depressed mood may appear depressed because of limited facial expressions. Mood has many manifestations, ranging from depression to euphoria.

Neuropsychiatric manifestations, such as changes in mood and affect, are very common in neurological conditions such as neurodegenerative diseases (Alzheimer’s disease: apathy, agitation, depression, irritability, anxiety, psychosis; Parkinson’s disease: depression, anxiety, psychosis; frontotemporal dementia: disinhibition, apathy), cerebrovascular disease (depression, apathy, psychosis), epilepsy (depression, psychosis), and multiple sclerosis (depression, eutonia, irritability, anxiety).2 These manifestations have a significant effect on individuals’ quality of life and caregiver burden.

This chapter focuses on dysphoria (sadness) as the main feature of depression and elevated mood (exaggerated feeling of happiness) and expansive mood (expression of feelings without restraint and exaggerated sense of self-importance) as aspects of mania.1 We also discuss the personality change seen with apathy (lack of motivation). We provide information about prevalence, characteristics, course, and precipitating factors of mood changes in neurological conditions. The neuroanatomical localization of mood changes—commonly involving the basal ganglia and the frontal and anterior temporal regions—is reviewed. Finally, issues concerning treatment of mood changes in neurological conditions are discussed, and practical treatment algorithms are offered. A discussion of primary mood disorders and miscellaneous neurological conditions with mood changes, such as pseudobulbar palsy, Klüver-Bucy syndrome, ictal affect, hypothalamic lesions, and catastrophic reactions, is beyond the scope of this chapter.


Depression is a common feature of many neurological conditions, but it is often underdiagnosed and undertreated. It can manifest as a symptom or as a syndrome complex such as a major depressive episode. Mood changes in depression consist of sadness and inability to experience pleasure (anhedonia), putatively mediated by the limbic system. They are often accompanied by feelings of worthlessness and hopelessness (mediated by the dorsolateral prefrontal cortex), guilt, helplessness, and, in extreme situations, suicidal ideation. Affective changes in depression include changes in facial expressions (reduced or immobile expression [hypomimia], sad expression, or furrowed brow), crying, and avoidance of eye contact. Reduced interest in or reduced initiation of new activities is often present (mediated by the anterior cingulate cortex and related structures). Cognitive changes include reduced associations and executive and visuospatial dysfunction. Changes in verbal expression include increased speech latency, slow rate and reduced volume of speech, decreased spontaneous speech, and lack of emotional inflection (dysprosody). Neurovegetative changes mediated by the hypothalamus include appetite alterations, sleep disturbances, libido loss, and diurnal mood variations. Motor changes include slumped shoulders and head, decreased gestures, slowing of movements and gait, and catatonia (mediated by the basal ganglia).3,4

Depression in neurological conditions occurs most commonly with the involvement of the frontal region (orbitofrontal and dorsolateral prefrontal cortices), temporal region (anterior temporal and paralimbic cortices), and basal ganglia (usually the caudate), mediated by the frontal-subcortical circuits. Lesions of the left hemisphere more commonly cause depression than do lesions of the right hemisphere (Fig. 19-1).2,5,6

Neurological conditions often can mask depression. Aphasic patients may not be able to voice their depressive feelings, whereas patients with dysprosody caused by basal ganglia or right hemisphere involvement may not be able to inflect their voice to convey their mood. In contrast, there are conditions that can imitate depression. Apathy, which is a common symptom in many neurological conditions, is commonly mistaken for depression. Patients with pseudobulbar palsy, parkinsonism, multiple sclerosis, and lesions causing emotional facial paresis may appear depressed without being so.3,7

The diagnosis of depression in neurological conditions is usually based on the criteria proposed for primary depression in the Diagnostic and Statistical Manual of Mental Disorders1 and is often classified as major depression or minor depression (according to the criteria for dysthymic disorder). Alternatively, the presence of depression is assessed with specific rating scales such as the Neuropsychiatric Inventory8 or the Geriatric Depression Scale.9

Depression can herald the onset or occur during the course of neurological conditions as a neurobiological component of those conditions or simply as a psychiatric comorbid condition. Cognitive changes seen in primary depression may sometimes imitate dementia, whereas depressive symptoms seen in dementia may sometimes imitate primary depression.3 The different presentations of depression in neurological conditions are described in the following sections and are summarized in Table 19-1. Table 19-2 lists neurological agents and psychotropic medications associated with depression.

TABLE 19-1 Neurological Conditions Manifesting with Depression

Condition Prevalence of Depression Specific Features and Localization
Alzheimer’s disease MaD: 1%-23% Milder depression and irritability greater functional deficits; depression heralds diagnosis of Alzheimer’s disease; frontal and parietal involvement
MiD: 14%-34%
DS: 20%-55%
Parkinson’s disease MaD: 8%-38% Anxiety, greater motor fluctuations, greater cognitive impairment, akinetic-rigid variant; frontal (left) involvement
MiD: 10%-32%
DS: 34%-47%
Stroke MaD: 8%-34% More common in women than in men; depression associated with larger lesions; frontal, temporal, caudate involvement
Vascular dementia MaD: 29%-45% Increases with time, lower education level, and greater functional deficits
DS: 30%-34%
Epilepsy MaD: 6%-30% Increased suicide rate among patients with ictal and interictal forms; temporal (left), frontal involvement
Multiple sclerosis MaD: 16% (lifetime, 50%) Irritability, frustration, increased suicide rate; arcuate fasciculus (left) involvement
DS: 79%-85%
Traumatic brain injury115,116 MaD: 17%-33% Anxiety, aggressive behavior, lower education level, alcohol abuse, executive dysfunction; frontal (left) involvement
Huntington’s disease94,117 MaD: 22% Increased suicide rate; medial caudate, orbitofrontal involvement
Frontotemporal lobar degeneration107 DS: 30% Depression in semantic dementia is worse than in frontal variant of frontotemporal dementia
Wilson’s disease94 MaD: 20% Lenticular nuclei

DS, general depressive symptoms; MaD, major depression; MiD, minor depression.

TABLE 19-2 Neurological Agents and Psychotropic Medications Associated with Depression3,78,82

Antiparkinsonian drugs Amantadine
Anticonvulsants Phenobarbital
Sedative-hypnotics Benzodiazepines
Chloral hydrate
Neuroleptics Butyrophenones
Psychostimulants Amphetamines
Miscellaneous Acetazolamide
Cholinesterase inhibitors
Interferon-β1b/interferon-βa (possibly)

Alzheimer’s Disease

Alzheimer’s disease is the most common form of dementia and produces cognitive impairment, functional deterioration, and behavioral changes. Among patients with Alzheimer’s disease, the prevalence of major depression has been reported as 1.1% to 23%1015; that of minor depression, 13.9% to 34%10,1315; and that of general depressive symptoms, 20.1% to 54.9%.1620 As demonstrated, the reported rates of depression in Alzheimer’s disease have a wide range because of the different measures and criteria used. The criteria in the National Institute of Mental Health Provisional Diagnostic Criteria for Depression in Alzheimer’s Disease reflect the generally more mild depression in Alzheimer’s disease, requiring the presence of only 3 (of 11) depressive symptoms (rather than 5 as in primary major depression), including irritability and social withdrawal as symptoms, and not requiring the presence of symptoms to be nearly daily over 2 weeks.21,22

Depression in Alzheimer’s disease is associated with greater functional deficits, wandering behavior, agitation, anxiety, apathy, disinhibition, and irritability.14,18,2325 Depressed Alzheimer’s disease patients often complain more about difficulties in thinking and concentration than about depressed mood and neurovegetative changes.26,27 Depressive symptoms tend to be episodic and recur frequently in Alzheimer’s disease.28,29 Frequency of mild depressive symptoms is correlated with severity of cognitive impairment15,30,31 but is not related to self-awareness of cognitive deficits.32 Depressive symptoms tend to occur early in the course of Alzheimer’s disease and may precede the diagnosis.15,3335 Risk factors for developing depression in Alzheimer’s disease include female gender, lower education level, early-onset disease, family history of depression, and possibly premorbid history of depression.15,25,31,33,36,37

Depression in Alzheimer’s disease has been correlated mostly with frontal and parietal dysfunction. Functional imaging studies showed localization of associated lesions to the bilateral superior frontal and left anterior cingulate cortices38 or the parietal lobe,39 and quantified electroencephalographic recording pointed toward abnormalities of the parietal lobes.40 Pathological and neurochemical studies of patients with Alzheimer’s disease and depression demonstrated greater involvement of the locus ceruleus (noradrenergic system) and, to a lesser degree, the substantia nigra (dopaminergic system) and dorsal raphe nucleus (serotonergic system), with relative preservation of the nucleus basalis of Meynert (cholinergic system).4144

Mild cognitive impairment is often a transitional stage between normal aging and dementia. The prevalence of depressive symptoms among patients with mild cognitive impairment has been reported as 9.3% to 47%.16,17,4547 One study reported that 85% of depressed patients with mild cognitive impairment went on to develop dementia, which again emphasizes the importance of depression in heralding the diagnosis of Alzheimer’s disease.46

Parkinson’s Disease and Parkinsonian Syndromes

Parkinson’s disease is the second most common neurodegenerative disease (after Alzheimer’s disease) and has a range of motor manifestations, cognitive impairment, and behavioral disturbances. Among patients with Parkinson’s disease, the prevalence of major depression has been reported as 7.7% to 38%4850; that of minor depression, 10% to 32%48,50; and that of general depressive symptoms, 34% to 47%.49,5155 Depression in Parkinson’s disease is associated with less self-punitive ideation, more anxiety, dysautonomia, and greater motor fluctuations (“on-off” phenomenon). It is correlated with advanced stage of disease and greater cognitive impairment.4951,54,5659 Depression is more common in the akinetic-rigid Parkinson’s disease variant than the classic tremor-predominant type.48,51 Risk factors for depression in Parkinson’s disease include premorbid history of depression, greater functional deficits, lower cerebrospinal fluid levels of 5-hydroxyindoleacetic acid, early-onset Parkinson’s disease, more left hemisphere involvement, and, possibly, female gender.50,51,57

Depression in Parkinson’s disease is associated with frontal lobe dysfunction, often of the left hemisphere, and is correlated with involvement of the dopaminergic, noradrenergic, and serotonergic systems.50,51,60 Neuropsychological studies show a relationship with disruption of frontal-lobe related tasks.61 Functional imaging studies show a localization of depression-related dysfunction in the bilateral medial prefrontal and anterior cingulate cortices62 or caudate and inferior orbitofrontal cortex.63

Depression has been reported in other parkinsonian syndromes. Among patients with dementia with Lewy bodies, the prevalence of major depression has been reported as 19% to 33.3%12,64 and that of general depressive symptoms, 47.5%.12 Among patients with progressive supranuclear palsy, the prevalence of general depressive symptoms has been reported as 18% to 25%,53,65 whereas that among patients with corticobasal degeneration has been reported as 73%.65

Cerebrovascular Disease

Depression in cerebrovascular disease has been described in the context of vascular depression, discrete strokes, and vascular dementia. Patients with vascular depression have clinical or imaging evidence of cerebrovascular disease, as well as vascular risk factors.66 In comparison with patients with primary depression, patients with vascular depression are older at onset of mood changes and have greater functional disability and cognitive impairment (mostly in verbal fluency and naming), greater psychomotor retardation, greater anhedonia, less agitation, lesser feelings of guilt, less insight, and less family history of depression.66,67 Vascular depression is associated with single or multiple lesions that disrupt the striatopallidothalamocortical (prefrontal) pathways.66,68

The prevalence of major depression among patients who have suffered strokes has been reported as 8.3% to 33.6%.6971 Poststroke major depression is more common in women (23.6%), in whom it is associated with more left hemisphere lesions and a history of psychiatric disorder and cognitive impairment, whereas in men (12.3%), it is associated with greater functional deficits.72 Depression has been shown to be more common with larger lesion volumes.71 Lesions in the frontal and temporal lobes, basal ganglia (especially the head of the caudate), and ventral brainstem circuitry are associated with depression.70,73 However, there is a tendency for depression after the acute poststroke period to be related to lesions of the left frontal region, whereas depression in the chronic poststroke period is associated with lesions of the right posterior region.4,74

Vascular dementia is the second most common dementia and is associated with executive dysfunction, motor symptoms, and significant behavioral changes. Among patients with vascular dementia, the prevalence of major depression has been reported as 29% to 45%,64,75 and that of general depressive symptoms, 29.7% to 34.2%.19,75,76 Depressive symptoms in vascular dementia tend to increase with time and are related to lower education level and greater functional deficits.25,76


Epilepsy is common and is associated with significant behavioral disturbances. The prevalence of major depression among patients with epilepsy has been reported as 6% to 30%.77,78 Depression in epilepsy is associated with decreased quality of life and increased suicide rate (5 to 10 times higher than in the general population).7779 Ictal and interictal forms of depression have been reported in epilepsy: The “interictal dysphoric disorder” resembles dysthymia and consists of depressed mood, low energy, pain, insomnia, irritability, euphoria, fear, and anxiety, whereas ictal depression usually occurs as an “aura” for a seizure and consists of guilt, anhedonia, and suicidal ideation.77 Depression is more common in patients with temporal (often left) and frontal seizure foci, and the hippocampus and amygdala appear to play a role as well.77,80,81

Multiple Sclerosis

Multiple sclerosis is an autoimmune disease with widespread physical, cognitive, and behavioral changes. Among patients with multiple sclerosis, the prevalence of major depression has been reported as 15.7% (lifetime prevalence, 50%)82,83 and that of general depressive symptoms, 79% to 85%.84,85 Depression in multiple sclerosis is associated with discouragement, irritability, frustration, higher rate of suicide (seven times higher than in the general population), and greater volume of lesions and cerebral atrophy.82 Depression in multiple sclerosis has been associated with lesions of the arcuate fasciculus, more so on the left.86