Guide to Neuropsychiatric Therapeutics
1st Edition

Chapter 5
Disturbances of Mood, Affect, and Emotion
C. Edward Coffey
I. Background
A. Definitions
  • Mood refers to the feeling state that one is experiencing at a particular moment in time, and its qualities can be either positive (e.g., happiness, or relief) or negative (e.g., sadness, anger, disgust; apprehension, fear, terror, etc.).
  • The term “mood” is not synonymous with the term affect, which refers to the behavioral domain in which the mood is expressed. Affect can be conceptualized quantitatively by the range (flat or narrow to broad), intensity (shallow to deep), and stability of mood (rigid to labile), and qualitatively by the appropriateness (congruence with situation or thought content) and relatedness of the mood. Mood is the content of affect. Mood is to affect as weather is to climate.
  • Emotion may be defined as the moods, affects, and related physiologic states that are associated with specific thoughts, ideas, or stimuli (particularly reinforcing stimuli).
  • Emotions have many functions including interpersonal (e.g., communication, or social bonding), cognitive (e.g., by affecting a perception or cognitive evaluation, by facilitating storage or recall of a memory, etc.), and motivation and preparation for action (including elicitation of autonomic and endocrine responses), all of which have survival value.
B. Classification of mood syndromes and disorders
Disturbances of mood include depression, mania/hypomania, and anxiety. These terms can be used to describe a normal mood, a clinical syndrome, or a group of specific disorders (Table 5.1).
TABLE 5.1 Classification of Mood and Mood Episode Syndromes
Depression
  • Normal sadness
  • Adjustment disorder
  • Bereavement
  • Major depressive episode
       Secondary
       Primary
Elated Mood and Mania/Hypomania
  • Normal happiness
  • Manic episode
       Secondary
       Primary
  • Mixed episode
       Secondary
       Primary
  • Hypomanic episode
       Secondary
       Primary
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1. Depressed mood and the major depressive syndrome
  • As a normal (nonpathologic) ubiquitous mood state, feelings of depression are synonymous with feeling sad, blue, down, or unhappy. Such feelings are common following a loss or disappointment, and typically last only hours to days. More severe depressive symptoms may occur in the setting of significant stress. The term adjustment disorder is used when a recent (within 3 months) stressor produces symptoms that do not meet criteria for a mood disorder (see subsequent text). The loss of a loved one may result in even more severe depressive symptoms (this mood state is called bereavement), but in such settings would not be diagnosed as a major depressive disorder unless the symptoms are especially severe or prolonged. Bereavement that lasts longer than 12 months is called a pathologic grief reaction, and may be seen when the survivor was excessively dependent upon the deceased, or is unable to grieve adequately or to obtain emotional and other (e.g., financial) support.
  • The clinical syndrome of a major depressive episode is defined by either abnormal sadness or loss of interest or pleasure, occurring for most of the time for at least 2 weeks, together with four or more of the following symptoms: Weight loss or decrease in appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or inappropriate guilt, impaired concentration and thinking, and recurrent
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    thoughts of death or suicide. All these symptoms must cause clinically significant distress or functional impairment.
2. Elated mood and the manic/hypomanic syndromes
  • Elated mood states (elation, exaltation, euphoria, and ecstasy) are normal when life is going well, or when major goals are achieved, as well as in states of love, sexual pleasure, and religious fervor and transcendence.
  • The clinical syndrome of a manic episode is defined by abnormally elated (or irritable) mood lasting for at least 1 week, together with three or more of the following symptoms: Inflated self-esteem or grandiosity, decreased need for sleep, talkativeness, flight of ideas or racing thoughts, distractibility, increased psychomotor activity, and excessive involvement in pleasurable activities. All these symptoms must cause clinically significant distress or functional impairment.
  • Mania may present in a milder form (known as a hypomanic episode) or together with a major depressive episode (known as a mixed episode).
3. Mood disorders (Table 5.2)
  • Disorders of mood are conceptualized by their presumed etiology. Secondary mood disorders are those that are presumed to be a direct physiologic effect of either a substance (e.g., medication, toxin, or drug of abuse) or a general medical (including neurologic) condition. All other disorders are referred to as primary mood disorders.
  • Primary disorders of mood are classified as either depressive disorders or bipolar disorders (DSM-IV).
    • The essential feature of depressive disorders is one or more episodes of major depression without a history of either manic or hypomanic episodes. There are three
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      depressive disorders—major depressive disorder (characterized by one or more episodes of major depression), dysthymic disorder (characterized by at least a 2-year history of depressed mood that does not meet diagnostic criteria for major depression), and depressive disorder not otherwise specified (NOS) (Table 5.2).
    • The essential feature of bipolar disorders is the presence of one or more manic or hypomanic episodes, usually (but not always) with a history of major depressive episodes. There are three bipolar disorders–bipolar disorder with manic (type I) or hypomanic (type II) episodes (usually with major depression), cyclothymic disorder (characterized by at least a 2-year history of numerous hypomanic episodes and depressed mood that does not meet diagnostic criteria for major depression), and bipolar disorder NOS (Table 5.2).
TABLE 5.2 Classification of Mood Disorders
Secondary Mood Disorders
  • Substance-induced mood disorder
  • Mood disorder due to a general medical (including neurologic) condition

Depressive Disorders
  • Major depressive disorder
  • Dysthymic disorder
  • Depressive disorder NOS

Bipolar Disorders
  • Bipolar I disorder
  • Bipolar II disorder
  • Cyclothymic disorder
  • Bipolar disorder NOS
NOS, not otherwise specified.
4. Affective lability and dissociation of mood and affect
  • Although not classified as a syndrome in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), affective lability (“emotional incontinence”) is common in a manic episode and in several neuropsychiatric disorders, particularly in patients with mental retardation (see Chapter 16) or frontal lobe dysfunction (see Chapters 3 and 12). Patients with affective labililty are typically irritable and may shift rapidly from positive (happiness, or euphoria) to negative (sadness, or anger) mood states. These emotional outbursts are usually short lived, and the affect is congruent with the mood (e.g., the patient both appears and feels angry).
  • A lack of congruence between affect and mood is known as pathologic affect (or pseudobulbar affect), a condition which characterizes some neuropsychiatric disorders. These patient’s may laugh or cry excessively in a situation that is not consistent with such an emotional reaction, and when questioned will deny they feel the emotional intensity they are displaying. Dissociation of mood and affect is most commonly seen in patients with bilateral lesions of the upper brainstem and diencephalon. The pathophysiology of this condition is not known but may involve a disturbance in brainstem motor nuclei involved in emotional expression, and in regulatory neurons that project to the cortex.
5. Anxiety
These mood states and related disorders are common in neuropsychiatric disorders and are discussed in Chapter 6.
6. Apathy and emotional blunting
These mood states and related disorders are common in neuropsychiatric disorders and are discussed in Chapter 1.
C. Epidemiology
  • Depressive symptoms and syndromes are reported to be two to three times more common in patients with certain neurologic disorders than in control or reference populations (Table 5.3).
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    The precise prevalence rates are difficult to establish given wide methodologic variation in the published reports, but in general, depressive symptoms are more common than depressive syndromes in patients with neurologic illness.
    TABLE 5.3 Prevalence of Depression in Patients with Neurologic Disease
    Poststroke ∼5–40%
    Alzheimer disease ∼20–50%
    Parkinson disease ∼10–50%
    Huntington disease ∼40%
    Traumatic brain injury ∼33%
    Multiple sclerosis ∼25%
    Epilepsy ∼55%
  • Euphoria and mania/hypomania have been described in patients with a variety of neurologic disorders but again, the precise prevalence rates are difficult to establish given methodologic variation in the published reports, many of which are case reports or small case series. The highest rates of euphoria and mania/hypomania have been reported for patients with Huntington disease (∼9%), traumatic brain injury (TBI) (∼9%), multiple sclerosis (0 to 67%), and epilepsy (∼5%). Mania occurring for the first time in an elderly individual should raise suspicion of an associated medical or neurologic disorder.
D. Prognosis
Very little literature exists on the course and prognosis of mood disorders associated with a neurologic illness. These limited data are consistent, however, in suggesting that depression following a neurologic illness may persist for months and even years after onset, and its presence may increase both the morbidity and mortality of the illness (see subsequent text on discussion of specific illness). Even less is known about the course and prognosis of mania/hypomania associated with a neurologic illness.
II. Neurobiology and pathophysiology of mood
A. Normal emotion
The neurobiology of normal emotional behavior is not fully understood. One model posits that emotional experiences are mediated by interplay between subcortical regions (e.g., hypothalamus, or amygdala) and higher brain centers. In response to emotionally relevant stimuli, subcortical systems (particularly the hypothalamus) coordinate autonomic, endocrine, and skeletomotor responses (arousal) that alter the internal milieu and prepare the organism to respond appropriately (fight or flight). Cortical (prefrontal cortex, cingulate, or parahippocampal) systems respond by filtering the stimuli and assessing their significance to the organism. Although this assessment is presumably based on learning and memory, it may also be affected by the relative contributions to the assessment
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of the left (positive emotional valence) and right (negative emotional valence) cerebral hemispheres. Once the assessment is made, these cortical systems communicate with the subcortical systems to enhance or suppress the somatic responses (the right hemisphere appears to drive cortical arousal by activating the reticular activating system). This bidirectional processing between cortical and subcortical systems, may be mediated in part by the limbic system (particularly the amygdala), which is also critically involved in mediating both inborn and learned emotional responses. It is this “cross talk” between neocortical and subcortical systems together with the somatic feedback from the periphery, which appear to mediate the experience of a particular emotion.
The communication between these cortical and subcortical systems is accomplished primarily by chemical neurotransmitters, the activity of which may impact the emotional state because of mediation of arousal (norepinephrine), motivation and reward (dopamine), and mood and impulsivity (serotonin).
B. Depressive disorders
1. Major depression
The pathophysiology of major depression is not fully understood. Depression may be the result of genetically determined (primary mood disorders have a strong genetic predisposition) defects in neurotransmitter function (particularly serotonin and norepinephrine) that may occur de novo or in response to psychosocial stress (the stress-diathesis model). We do not understand the mechanisms that cause these presumed neurotransmitter disturbances. Depression is associated with a myriad of neurobiologic disturbances (sleep, neuroendocrine, neurotransmitter; immunologic, and cerebral structure, blood flow, and metabolism, particularly of frontal-subcortical regions), most of which are consistent with an exaggerated stress response. We do not know whether these changes reflect causal associations or epiphenomena.
2. Depression in patients with a neurologic illness
The pathophysiology of depression in patients with neurologic illness is not known, but is likely to be heterogeneous. Depression may reflect some combination of an emotional reaction to deficits from the neurologic illness (e.g., an adjustment disorder with depressed mood), a recurrence of a preexisting mood disorder, a result of other neurologic or general medical problems, or a direct effect of the neurologic illness on brain systems that mediate emotion.
Studies in patients with brain disease suggest a relation between depression and lesions of particular brain regions including the left frontal-subcortical regions (cerebrovascular disease, or TBI), the basal ganglia (Parkinson disease, or Huntington disease), and the anterior limbic system (complex partial epilepsy, or multiple sclerosis) (discussed in the subsequent text).
C. Mania/hypomania
1. Manic episode
The pathophysiology of mania/hypomania and bipolar disorder are not known. Most of what is known is similar to that described for major depression.
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2. Mania/hypomania in patients with a neurologic illness
Mania/ hypomania is seen much less frequently in association with brain disease than is depression. Studies in patients with brain disease suggest a relation between mania and lesions of the right cortical (orbitofrontal or basotemporal cortex) or right subcortical (thalamus, head of the caudate) regions (discussed in the subsequent text).
III. Management
A. Principles of management
In general, the management of mood disorders in patients with neurologic illness (regardless of whether the depression is considered to be “secondary” to the neurologic illness) should follow the Principles of Management recommended by the American Psychiatric Association (APA) (2000, 2002) for patients with primary mood disorders.
1. Perform a diagnostic evaluation
  • The diagnosis of a mood disorder in patients with neurologic illness is challenging. Some controversy exists about the most appropriate method for diagnosing mood syndromes in patients with neurologic or general medical conditions, because some of the signs or symptoms (e.g., weight loss, and insomnia) may result from the general medical or neurologic illness. Still, most data support the validity of an “inclusive” approach (i.e., counting depressive symptoms regardless of whether they may be related to the general medical illness). An additional diagnostic challenge relates to the assessment of symptoms that require verbal expression (e.g., sadness, hopelessness, etc.) in patients who cannot speak (e.g., due to an aphasia). In such cases, it may be necessary to give greater weight to clearly manifest signs of the mood disorder (e.g., crying, irritability, weight gain, sleep disturbance, etc.).
  • The mood disorder should be defined as being a depressive disorder, a bipolar disorder, an adjustment disturbance, or a mood disorder secondary to a neurologic illness. The judgment that the mood disorder is secondary to the neurologic illness requires confirmation of a neurologic illness, evidence that the mood disorder is a “direct physiologic consequence” of that illness, and evidence that the mood disorder is not better accounted for by another mental disorder (see differential diagnosis in the preceding text). Determining whether the mood symptoms are “a direct physiologic consequence” of the neurologic illness may be very challenging indeed, as there are no clear rules for establishing such an association. A potential relation is suggested by a temporal association between the neurologic illness’s onset, exacerbation, or remission and that of the mood disorder (e.g., the depression begins shortly after the stroke); atypical features of the mood disorder; or a well
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    established relation between the mood disorder and the neurologic illness.
  • Laboratory tests are indicated only to confirm the presence of a general medical disorder or substance use disorder (as suggested by the history or examination), or to characterize its status.
  • Evaluate and address comorbidity, particularly anxiety disorders, substance use disorders, and personality disorders.
  • Evaluate the safety of the patient and others. It is essential to assess the patient’s risk of suicide or homicide.
2. Implement a biopsychosocial treatment plan
  • Determine and continually evaluate the treatment setting (inpatient vs. outpatient) based on the patient’s clinical status, available support systems, and ability to care adequately for self and cooperate with treatment.
  • We do not know whether mood disorders in patients with a neurologic illness require treatment different from that for primary mood disorders. As such, treatment of these mood disorders generally employs established treatments for primary mood disorders, although the data supporting such use are limited (see subsequent text). We recommend a biopsychosocial model, that is the combined use of appropriate biologic (somatic) treatments (including acute phase and continuation/maintenance phase treatment), psychological treatments, and social interventions.
  • Evaluate and address functional impairments (e.g., in interpersonal relationships, work and living conditions, and other health-related needs).
  • Provide education and support to the patient and family.
  • Enhance treatment adherence (e.g., by simplifying the treatment regimen, minimizing the cost of treatment, education about side effects, etc.).
  • Address early signs of relapse.
  • Coordinate the care with other clinicians. Patients with a neurologic disorder will typically be receiving care from multiple clinicians, including an internist, a neurologist or neurosurgeon, a rehabilitation medicine specialist, a physical therapist, or speech therapist. Coordination of care among these many providers is essential to ensure that the care is safe and effective.
B. Management of depression in patients with neurologic illness
1. Post-stroke depression
a. Clinical background
  • The 1-year prevalence of depression in patients with stroke varies from approximately 5% to 40%, with half of them manifesting a full major depressive episode and the other half exhibiting less severe symptoms (“minor depression”).
  • The occurrence of post-stroke depression (PSD) appears to be related to a personal or family history of mood
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    disorder, premorbid cortical atrophy, stroke location (left frontal-subcortical), and degree of functional impairment.
  • The phenomenology of PSD is similar to that of a primary major depressive episode.
  • During the course and prognosis, depression appears to typically last approximately 9 to 10 months, but symptoms may persist for longer periods especially in patients with cortical lesions and marked functional impairment. PSD is associated with greater impairment in activities of daily living, greater cognitive impairment, and greater (three to five times) long-term mortality. Of interest, depressive symptoms are also a prospective risk factor for stroke. Effective treatment of depression appears to reduce mortality or improve the outcome after stroke.
b. Pathogenesis of post-stroke depression
The pathophysiology of depression in patients with stroke is not known, but is likely to be heterogeneous.
c. Diagnosis
  • The diagnosis is clinical and is based on the presence of criteria for a mood disorder. The diagnosis is often difficult, however, given the overlap of depressive symptoms with symptoms of stroke, or in patients with aphasia, denial, or severe dementia. Information from caregivers may greatly assist diagnosis.
  • Post stroke apathy syndromes have to be ruled out (see Chapter 1).
  • Hypothyroidism has to be ruled out.
d. Treatment
  • Optimize the physical health of the patient and ensure that all underlying general medical and neurologic disorders have been optimally treated, including the provision of pain management.
  • Optimize the patient’s environment and lifestyle, including the promotion of exercise and a regular sleep–wake cycle. Caregivers should be instructed in behavioral management of the patient’s behavioral problems, including prevention and modification of adverse behaviors. Caregivers should also be monitored closely for development of depression in themselves.
  • Consider brief, structured psychotherapy (e.g., cognitive-behavioral therapy or interpersonal therapy) in patients with mild to moderately severe depression and who are able to participate in the treatment. Although its effectiveness has not been formally studied in patients with PSD, it is very safe and its efficacy is well established for acute phase treatment in primary mood disorders.
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    TABLE 5.4 Selected Antidepressant Treatments
    Medication Starting Dose Dosing Range
    Selective Serotonin Reuptake Inhibitors
    • Citalopram (Celexa)
    10–20 mg/d Up to 100 mg/d
    • Sertraline (Zoloft)
    12.5–25 mg/d Up to 200 mg/d
    Tricyclic Antidepressants
    • Nortriptyline (Pamelor; Aventyl)
    10 mg at bedtime 50–75 mg (therapeutic serum level = 50–150 ng/mL)
    Others
    • Buproprion (Wellbutrin)
    75–150 mg buproprion/d Up to 400 mg/d
    • Venlafaxine (Effexor)
    25 mg two to three times daily Up to 375 mg/d
    Brain Stimulation Procedures
    Electroconvulsive therapy NA  
    Vagus nerve stimulation NA
    Transcranial magnetic stimulation Experimental
    Deep brain stimulation Experimental
    NA, not applicable.
  • Implement somatic therapy if depression is severe or persists despite the steps listed in the preceding text. There are no U.S. Food and Drug Administration (FDA)-approved somatic treatments for PSD. Therapeutic options are the same as for major depressive disorder, that is antidepressant (Table 5.4) or mood-stabilizing medication, or electroconvulsive therapy (ECT).
  • Treat initially with citalopram based on its safety and tolerability, as well as its efficacy as demonstrated in two small randomized controlled trials of patients with PSD. Sertraline is a reasonable alternative. It should be noted that serotonin reuptake inhibitors (SRIs) should be used with caution in patients with subarachnoid hemorrhage, where they are associated with vasospasm.
    Nortriptyline is a reasonable second-line agent (efficacy demonstrated in two small randomized controlled trials of PSD), provided there are no contraindications (e.g., heart block, cardiac arrhythmia, narrow angle glaucoma) or concerns regarding sedation or orthostatic hypotension.
  • Consider ECT in patients with PSD who are severely ill (e.g., melancholic, psychotic, suicidal) and in need of rapid clinical improvement, or who are unresponsive
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    to or intolerant of psychotropic medications. A small uncontrolled (primarily retrospective) clinical literature supports the safety, tolerability, and efficacy of ECT in such patients, although randomized controlled data are lacking. Several modifications in ECT technique may be required, however, based on the patient’s medical/neurologic status and concerns about cognitive side effects.
  • Give patients with psychotic symptoms an antipsychotic medication in addition to the antidepressant medication, although there are no controlled data on such use in patients with PSD. Atypical antipsychotic medications are generally preferred given their safety, but should be used sparingly given their small risk in the elderly of stroke and death (see Chapters 4 and 7).
  • Continue successful acute treatment (medication or ECT) for at least 6 to 9 months. Of note, antidepressant treatment of PSD is associated with a lower mortality over the ensuing 9 years.
References
1. American Psychiatric Association: Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry. 2000;157:1–45.
2. American Psychiatric Association: Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(Suppl 4):1–50.
3. Coffey CE, Kellner CH. Electroconvulsive therapy. In: Coffey CE, Cummings JL, eds. Textbook of geriatric neuropsychiatry, 2nd ed. Washington, DC: American Psychiatric Press; 2000:829–859.
4. Robinson RG. The neuropsychiatry of mood disorder. In: Schiffer RB, Rao SM, Fogel BS, eds. Neuropsychiatry, 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003:724–749.
5. Whyte EM, Mulsant BH. Post stroke depression: epidemiology, pathophysiology, and biologic treatment. Biol Psychiatry. 2002;52:253–264.
2. Depression in patients with Alzheimer disease
a. Clinical background
  • Depression is seen in approximately 20% to 50% of patients with Alzheimer disease (AD), with about half manifesting a full major depressive episode and the other half exhibiting minor depression.
  • No consistent risk factors have been identified. There is controversy over whether depression is more common early or late in the illness or in those patients with a family history of mood disorder, and whether it is related to the ApoE 4 or serotonin transporter genes.
  • The phenomenology of major depression in patients with AD appears to be characterized by more cognitive
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    disturbance, more psychotic symptoms, less sleep disturbance, and less feelings of worthlessness or excessive guilt, relative to patients without dementia.
  • The natural history of depression in AD is not fully known. Depression may be the initial symptom of dementia, and may even be a risk factor for later development of AD in the elderly and in those with mild cognitive impairment. Depressive symptoms in patients with AD may persist for months, and are associated with greater physical and cognitive impairment (and hence earlier placement in higher levels of care), increased mortality or suicide, and greater caregivers burden. Effective treatment of depression may therefore reduce mortality or improve the functional status of patients with dementia, although there are no definitive data on this issue.
b. Pathogenesis
  • The pathophysiology of depression in patients with AD is not known, but is likely to be heterogeneous.
  • Abnormal neurotransmission may be involved, in that postmortem studies of patients with AD have found a relation between depression and loss of noradrenergic neurons in the locus ceruleus, and with loss of dorsal raphe serotonergic nuclei.
  • Depression in patients with AD does not appear to be related to the severity of the dementia nor the patient’s insight into having AD.
c. Diagnosis
  • The diagnosis is clinical and is based on the presence of criteria for a mood disorder. The diagnosis is often difficult, however, given the overlap of depressive symptoms with symptoms of dementia, or in patients with aphasia, denial/neglect, or severe dementia. Information from caregivers may greatly assist diagnosis.
  • Apathy syndromes have to be ruled out (Chapter 1).
  • Hypothyroidism has to be ruled out (check thyroid-stimulating hormone [TSH] and thyroxine [T4]).
d. Treatment
  • Optimize the physical health of the patient and ensure that all underlying general medical disorders have been optimally treated, including pain management.
  • Optimize the patient’s environment and lifestyle, including the promotion of exercise and a regular sleep–wake cycle. Caregivers should be instructed in behavioral management of the patient’s behavioral problems, including prevention and modification of adverse behaviors. Controlled studies have shown that caregivers can be successfully trained to reduce patient depression.
  • Monitor caregivers closely for development of depression in themselves.
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  • Use psychotherapy which is supported by controlled data, including individual (particularly cognitive-behavioral therapy) and group (including formal support groups) psychotherapy.
  • Optimize the use of cholinesterase inhibitors (see Chapter 4). Controlled data suggest that these agents may improve neuropsychiatric symptoms (including depression) and functional status, as well as cognition.
  • Implement somatic therapy if depression is severe or persists after these initial steps. There are no FDA-approved somatic treatments for depression in patients with dementia. Therapeutic options are the same as for major depressive disorder, that is antidepressant or mood-stabilizing medication, or ECT.
  • Treat initially with sertraline or citalopram, based on their safety and tolerability, as well as their efficacy as demonstrated in a small number of randomized controlled trials.
    Venlafaxine is a reasonable second-line agent (given the well-described pathologic deficit in norepinephrine-producing neurons in patients with AD), but its efficacy in patients with dementia has not been demonstrated. Medications with anticholinergic side effects (e.g., tricyclic antidepressants) should be used cautiously, as their anticholinergic properties may worsen the memory impairment, in addition to other adverse effects.
  • Consider ECT in depressed patients with AD who are severely ill (e.g., melancholic, psychotic, or suicidal) and in need of rapid clinical improvement, or who are unresponsive to or intolerant of psychotropic medications. A small uncontrolled (primarily retrospective) clinical literature supports the safety, tolerability, and efficacy of ECT in such patients, but controlled randomized data are lacking. Several modifications in ECT technique may be required, however, based on the patient’s medical/neurologic status and concerns about cognitive side effects. ECT does not appear to worsen the underlying dementing process.
  • Give patients with psychotic symptoms an antipsychotic medication in addition to the antidepressant medication, although there are no controlled data on this issue. Atypical antipsychotic medications are generally preferred given their safety, but should be used sparingly given their small risk in the elderly of stroke and death.
  • Continue successful acute therapy for at least 6 to 9 months.
References
1. Coffey CE, Kellner CH. Electroconvulsive therapy. In: Coffey CE, Cummings JL, eds. Textbook of geriatric neuropsychiatry, 2nd ed. Washington, DC: American Psychiatric Press; 2000:829–859.
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2. Holmes C, Wilkinson D, Dean C, et al. The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology. 2004;63:214–219.
3. Lee HB, Lyketsos CG. Depression in Alzheimer disease: Heterogeneity and related issues. Biol Psychiatry. 2003;54:353–362.
4. Lyketsos CG, Olin J. Depression in Alzheimer disease: Overview and treatment. Biol Psychiatry. 2002;52:243–252.
5. Teri L, Gibbons LE, McCurry SM, et al. Exercise plus behavioral management in patients with Alzheimer disease. JAMA. 2003;290:2015–2022.
6. Zubenko GS, Zubenko WN, McPherson S, et al. A collaborative study of the emergence and clinical features of the major depressive syndrome of Alzheimer disease. Am J Psychiatry. 2003;160:857–866.
3. Depression in patients with Parkinson disease
a. Clinical background
  • Depression is the most common neuropsychiatric disturbance in Parkinson disease (PD), with a prevalence of approximately 10% to 50%. Roughly half of affected patients will meet criteria for major depression, with the remainder meeting criteria for dysthymia.
  • Risk factors for depression in patients with PD include psychosis and degree of cognitive impairment, but there are conflicting data on whether it is related to physical impairment. The incidence of hypothyroidism is increased in patients with PD (perhaps due to inhibited release of TRH by levodopa stimulation of the pituitary) and may contribute to both the depressive and cognitive symptoms. Testosterone deficiency, present in up to 25% of men over age 60, may also contribute to depression and other nonmotor symptoms in patients with PD.
  • The phenomenology of depression in patients with PD is similar to that in patients with primary major depression, except that the former may be less likely to experience guilt, self-blame, and a sense of failure. Psychotic symptoms may be seen in 20% or more of patients, with hallucinations more common than delusions. The potential etiologies of these symptoms are complex (see Chapter 9).
  • During the course and prognosis, depression may appear to precede the onset of the movement disorder by several years. Depression (both major and minor) in patients with PD is associated with more personal suffering, faster progression of physical symptoms,
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    greater disability, and greater decline in both cognitive skills and ability for self-care. The risk of suicide in depressed patients with PD has not been defined (patients with PD do not have an increased occurrence of suicide relative to the general population). Effective treatment of depression may improve the functional status of patients with PD, although there are no definitive data on this issue.
b. Pathogenesis
  • The pathophysiology of depression in patients with PD is not known, but is likely to be heterogeneous. Certainly, the stress of the illness and related disability is a contributing factor.
  • Brain imaging and neurochemical studies suggest that patients with PD and depression may have degeneration in dopamine and serotonin systems believed to be important in mood. Recent data suggest that the risk of depression is increased in patients with PD who have elevated plasma homocysteine levels or the low-activity allele of the serotonin transporter gene-linked polymorphic region 5HT-TLPR.
  • Hypothyroidism may be a contributing factor.
c. Diagnosis
  • The diagnosis is clinical and is based upon the presence of criteria for a mood disorder. The diagnosis is often difficult, however, given the overlap of depressive symptoms with symptoms of parkinsonism, or in patients with denial/neglect or severe dementia. Information from caregivers may greatly assist diagnosis.
  • Apathy syndromes have to be ruled out (Chapter 1).
  • Hypothyroidism has to be ruled out (check TSH and T4).
  • Deep brain stimulation of the subthalamic nucleus for PD is associated with acute, transient mood changes, as well as more persistent and severe depression (including suicide) in some patients. Patients with a personal or family history of suicide may be at high risk for this complication.
d. Treatment
  • Optimize the physical health of the patient and ensure that all underlying general medical disorders (particularly hypothyroidism, testosterone deficiency) have been optimally treated, including pain management.
  • Optimize the patient’s environment and lifestyle, including the promotion of exercise and a regular sleep–wake cycle. Caregivers should be instructed in behavioral management of the patient’s behavioral problems, including prevention and modification of adverse behaviors.
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    Caregivers should also be monitored closely for development of depression themselves.
  • Optimize treatment of the movement disorder (see Chapters 9 and 10). Dopamine replacement therapy is only a weak antidepressant, however, and it may cause other neuropsychiatric symptoms, most notably psychosis, delirium, and agitation.
  • Consider brief, structured psychotherapy (e.g., cognitive-behavioral therapy or interpersonal therapy) in patients with mild to moderately severe depression and who are able to participate in the treatment. Although its effectiveness has not been formally studied in patients with PD, it is very safe and its efficacy is well established for acute phase treatment in primary mood disorders.
  • Consider somatic therapy if depression is severe or persists after these initial interventions. There are no FDA-approved somatic treatments for depression in PD. Therapeutic options are the same as for major depressive disorder, namely, antidepressant or mood-stabilizing medication, or ECT.
  • Treat initially with citalopram or sertraline based on their tolerability and the results of prospective open label trials. Worsening of motor symptoms has been reported in a few patients on SRIs, however, and SRIs should be used with caution in patients receiving deprenyl (a selective inhibitor of MAO-B) given a potential risk of adverse reactions similar to serotonin syndrome or hypertensive crisis. Sexual side effects are common with SRIs and may worsen sexual dysfunction that is experienced by many patients with PD. If there is inadequate response to first-line treatment, then switching to buproprion is recommended, given its dopaminergic properties and its relatively lower incidence of sexual side effects. Venlafaxine is a reasonable alternative. Both amoxapine and lithium should be avoided because they can worsen parkinsonism.
  • Consider ECT in depressed patients with PD who are severely ill (e.g., melancholic, psychotic, suicidal) and in need of rapid clinical improvement, or who are unresponsive to or intolerant of antidepressant medications. A small uncontrolled (primarily retrospective) clinical literature supports the safety, tolerability, and efficacy of ECT in such patients, but randomized controlled data are lacking. Several modifications in ECT technique may be required, however, based on the patient’s medical/neurologic status and concerns about cognitive side effects. Of note, controlled studies
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    indicate that ECT may also improve the motor symptoms of parkinsonism, irrespective of its effect upon mood.
  • Base the treatment of concomitant psychotic symptoms in patients with parkinsonism, which is complex, upon a thorough assessment of the potential causative factors (e.g., medication-induced vs. depression with psychotic features vs. dementia with Lewy bodies, etc.) (see Chapters 7 and 9). Atypical antipsychotic medications are generally preferred given their safety, but should be used sparingly given their small risk in the elderly of stroke and death.
  • Continue successful acute therapy (psychotropic medication or ECT) for at least 6 to 9 months, although there are no controlled data on this issue.
References
1. Coffey CE, Kellner CH. Electroconvulsive therapy. In: Coffey CE, Cummings JL, eds. Textbook of geriatric neuropsychiatry, 2nd ed. Washington, DC: American Psychiatric Press; 2000:829–859.
2. McDonald W, Richard IH, DeLong MR. Prevalence, etiology, and treatment of depression in Parkinson disease. Biol Psychiatry. 2003;54:363–375.
3. Okum MS, Watts RL. Depression associated with Parkinson disease. Neurology. 2002;58(Suppl 1):S63–S70.
4. Troster AI, Fields JA, Koller WC. Pardinson disease and parkinsonism. In: Coffey CE, Cummings JL, eds. Textbook of geriatric neuropsychiatry, 2nd ed. Washington, DC: American Psychiatric Press; 2000:559–600.
4. Depression in patients with Huntington disease
a. Clinical background
  • The prevalence of mood disorders in Huntington disease (HD) is approximately 40%, with 30% developing major depression and 10% bipolar disorder (usually type II).
  • The phenomenology of depression in HD is similar to that of primary major depression. Conflicting findings have been reported regarding the relation of depression to the cognitive and motor symptoms of HD. In addition, depression may precede the motor manifestations of HD by several years, and may occur in patients with minimal motor symptoms who are unaware they are affected.
  • The impact of depression on outcomes in HD has not been well studied, but the occurrence of suicide is increased in patients with HD
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    relative to the general population. Effective treatment of depression may improve the functional status of patients with HD and reduce the risk of suicide, although there are no definitive data on these issues.
b. Pathogenesis
  • The pathophysiology of depression in patients with HD is not known, but is likely to be heterogeneous.
  • The early onset of depression in many patients suggests that it may be related to degeneration of the caudate nucleus and related circuits, because they are also affected early in the disease. Mood symptoms apparently do not correlate with CAG repeat length.
  • The stress of a fatal disease no doubt is a contributing factor, but other patients may develop depression before they are aware of the diagnosis or before they experience motor symptoms.
c. Diagnosis
  • The diagnosis is clinical and is based on the presence of criteria for a mood disorder. The diagnosis is often difficult, however, in patients with dementia or denial/ neglect. Information from caregivers may greatly assist diagnosis.
  • Apathy syndromes have to be ruled out (see Chapter 1).
d. Treatment
  • Optimize the physical health of the patient and ensure that all underlying general medical disorders have been optimally treated, including pain management.
  • Optimize the patient’s environment and lifestyle, including the promotion of exercise and a regular sleep–wake cycle. Caregivers should be instructed in behavioral management of the patient’s behavioral problems, including prevention and modification of adverse behaviors. Caregivers should also be monitored closely for development of depression in themselves.
  • Optimize treatment of the movement disorder (see Chapter 10).
  • Consider brief, structured psychotherapy (e.g., cognitive-behavioral therapy or interpersonal therapy) in patients with mild to moderately severe depression and who are able to participate in the treatment. Although its effectiveness has not been formally studied in patients with HD, it is very safe and its efficacy is well established for acute phase treatment in primary mood disorders.
  • Consider somatic therapy if depression is severe or persists after these initial interventions. There are no FDA-approved somatic treatments for depression in HD. Therapeutic options are the same as for major depressive disorder, that is antidepressant or mood-stabilizing medication, or ECT.
  • Treat initially with citalopram or sertraline based on their tolerability and efficacy as demonstrated in case
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    reports. Sexual side effects are common with SRIs and may worsen sexual dysfunction that is experienced by many patients with HD. Nortriptyline is recommended if the SRIs are ineffective.
    For patients with HD and bipolar depression, we recommend lamotrigine or valproic acid.
    Lithium is generally avoided because patients with HD are at risk for dehydration and may therefore develop lithium toxicity.
  • Consider ECT in depressed patients with HD who are severely ill (e.g., melancholic, psychotic, or suicidal) and in need of rapid clinical improvement, or who are unresponsive to or intolerant of psychotropic medications. A small-uncontrolled (primarily retrospective) clinical literature supports the safety, tolerability, and efficacy of ECT in such patients, but randomized controlled data are lacking. Several modifications in ECT technique may be required, however, based on the patient’s medical/neurologic status and concerns about cognitive side effects.
  • Continue successful acute therapy for at least 6 to 9 months, although there are no controlled data on this issue.
  • Treat concomitant psychotic symptoms in patients with HD with antipsychotic medications (see Chapters 7 and 10). Atypical antipsychotic medications are generally preferred given their safety, but should be used sparingly given their small risk in the elderly of stroke and death.
References
1. Coffey CE, Kellner CH. Electroconvulsive therapy. In: Coffey CE, Cummings JL, eds. Textbook of geriatric neuropsychiatry, 2nd ed. Washington, DC: American Psychiatric Press; 2000:829–859.
2. Paulsen JS, Ready RE, Hamilton JM, et al. Neuropsychiatric aspects of Huntington disease. J Neurol Neurosurg Psychiatry. 2001;71:310–314.
3. Ranen NG. Psychiatric management of Huntington disease. Psychiatr Ann. 2002:32:105–110.
5. Depression in patients with traumatic brain injury
a. Clinical background
  • The 1-year prevalence of depression in patients with TBI is at least 33%, and the lifetime prevalence has been estimated at approximately 18%.
  • Potential risk factors for depression in patients with TBI include a personal history of psychiatric disorder (mood and anxiety disorders), impaired social functioning, and lesions of the left basal ganglia and left dorsolateral cortex. There are conflicting data on the relation of depression to the severity of the TBI, or
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    to functional (including cognitive) impairment following TBI.
  • The phenomenology of depression in patients with TBI is similar to that in patients with primary major depression, except that the former may have higher rates of comorbid anxiety (∼75%) and aggressive behavior (∼55%).
  • The longitudinal course of depression following TBI is variable, with some patients experiencing only transient syndromes lasting a few weeks perhaps (a result of neurochemical changes provoked by the TBIs) and others experiencing a more persistent disorder lasting several months (perhaps more related to physical or cognitive impairment?). Major depression in patients with TBI is associated with cognitive impairment, as well as with significantly poorer social functioning at 6- and 12-month follow up. Treatment of depression may improve these outcomes, but there are no data on this issue.
b. Pathogenesis
  • The pathophysiology of depression in patients with TBI is not known, but is likely to be heterogeneous.
  • Stress related to the injury and its physical, cognitive, and emotional sequelae may be a contributing factor, particularly in those with a personal history of mood disorder or who develop depression several months after the injury.
  • Some have speculated that depression (particularly acute depression occurring after the brain injury) may also relate to the neuropathologic changes of TBI, including deactivation of lateral and dorsal prefrontal cortical regions, and increased activation of ventral lateral and paralimbic systems including the amygdala.
c. Diagnosis
  • The diagnosis of major depression in patients with TBI is clinical.
  • There may be considerable overlap of symptoms with those of the postconcussive syndrome, apathy syndrome (see Chapter 1), and personality syndromes (see Chapter 12).
  • Comorbid substance use/abuse is common.
d. Treatment
  • Optimize the physical health of the patient and ensure that all underlying general medical and neurologic disorders have been optimally treated, including the provision of pain management.
  • Optimize the patient’s environment and lifestyle, including the promotion of exercise and a regular sleep–wake cycle. Caregivers should be instructed in behavioral
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    management
    of the patient’s behavioral problems, including prevention and modification of the adverse behaviors. Caregivers should also be monitored closely for development of depression in themselves.
  • Consider brief, structured psychotherapy (e.g., cognitive-behavioral therapy or interpersonal therapy) in patients with mild to moderately severe depression and who are able to participate in the treatment. Although its effectiveness has not been formally studied in patients with TBI, it is very safe and its efficacy is well established for acute phase treatment in primary mood disorders.
  • Consider somatic therapy if depression is severe or persists after these initial interventions. There are no FDA-approved somatic treatments for depression in patients with TBI. Therapeutic options are the same as for major depressive disorder, namely, antidepressant medication or ECT.
  • Treat initially with sertraline, based on its tolerability and the results of a single placebo-controlled, single-blind, nonrandomized trial. Citalopram is a reasonable alternative. In patients who fail to respond, desipramine is an alternative (supported by a small randomized, single-blind, placebo-controlled trial), although its use may be associated with seizures (tricyclic antidepressants [TCAs] lower seizure threshold).
    Case reports and small clinical series also support the use of psychostimulants, including dextroamphetamine (8 to 60 mg daily), methylphenidate (10 to 60 mg daily), and pemoline (56 to 75 mg daily). These medications are given twice daily, with the last dose at least 6 hours before bedtime to prevent insomnia. Treatment is begun at lower doses, with gradual escalation. Patients should be monitored closely for evidence of abuse or toxicity, including anxiety, dysphoria, headaches, insomnia, irritability, anorexia, dyskinesias, cardiovascular symptoms, and frank psychotic symptoms.
  • Consider ECT in depressed patients with TBI who are severely ill (e.g., melancholic, psychotic, or suicidal) and in need of rapid clinical improvement, or who are unresponsive to or intolerant of antidepressant medications. A small uncontrolled (primarily retrospective) clinical literature supports the safety, tolerability, and efficacy of ECT in such patients, but randomized controlled data are lacking. Several modifications in ECT technique may be required, however, based on the patient’s medical/neurologic status and concerns about cognitive side effects.
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  • Give patients with psychotic symptoms an antipsychotic medication in addition to the antidepressant medication, although there are no controlled data on this issue. Atypical antipsychotic medications are generally preferred given their safety, should be used sparingly given their small risk in the elderly of stroke and death.
  • Continue successful acute therapy for at least 6 to 9 months, although there are no controlled data on this issue.
References
1. Coffey CE, Kellner CH. Electroconvulsive therapy. In: Coffey CE, Cummings JL, eds. Textbook of geriatric neuropsychiatry, 2nd ed. Washington, DC: American Psychiatric Press; 2000:829–859.
2. Fields RB, Cisewski D, Coffey CE. Traumatic brain injury. In: Coffey CE, Cummings JL, eds. Textbook of geriatric neuropsychiatry, 2nd ed. Washington, DC: American Psychiatric Press; 2000:621–653.
3. Silver JM, McAllister TW, Yudofsky SC. Textbook of traumatic brain injury. Washington, DC: American Psychiatric Press; 2005.
6. Depression in patients with multiple sclerosis
a. Clinical background
  • Depression is approximately twice as common in patients with multiple sclerosis (MS) relative to patients with other chronic illnesses (particularly for women), with an estimated 1-year prevalence of at least 25% and a lifetime prevalence of up to 50%.
  • Potential risk factors for depression in patients with MS include younger age, lesion volume on magnetic resonance imaging (MRI) (particularly in the left frontal region and left arcuate fasciculus), cortical (especially left anterior temporal) atrophy, and various psychosocial factors (stress, coping ability, social support, uncertainty about the future, etc.) related to disease severity and disability.
  • The phenomenology of depression in patients with MS appears similar to that of patients with primary major depression, although this issue has not been well studied.
  • The longitudinal course of depression in patients with MS has not been thoroughly studied. Major depression has a negative impact on quality of life and treatment adherence in patients with MS, and is a risk factor for suicide. The risk of suicide is high in patients with MS (up to seven times that of the general population), and is associated with major depression, alcohol abuse, and social isolation. Therefore, effective treatment of the depression may improve the functional status and well-being of patients with MS.
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b. Pathogenesis
  • The neurobiology of depression in patients with MS is not known, but is likely to be heterogeneous.
  • Stress is a contributing factor, as MS is a disease of the young, which is unpredictable, can cause devastating disability, and which is without cure currently.
  • Brain imaging studies implicate atrophy, lesion burden, and involvement of frontal-subcortical and anterior temporal systems.
  • Depression may also be related to treatment of MS, particularly with interferon or steroids.
c. Diagnosis
  • The diagnosis of depression in patients with MS is clinical.
  • All patients should be thoroughly and continuously assessed for risk of suicide.
  • Depression secondary to medications should be considered in the differential diagnosis, particularly in patients receiving interferon or corticosteroids. In patients with depression, glatiramer may be a preferred drug for treatment of relapse.
  • Affective lability (see subsequent text), fatigue syndrome, or apathy syndrome has to be ruled out.
d. Treatment
  • Optimize the physical health of the patient and ensure that all underlying general medical disorders have been optimally treated, including the provision of pain management.
  • Optimize the patient’s environment and lifestyle, including the promotion of exercise and a regular sleep–wake cycle. Caregivers should be instructed in behavioral management of the patient’s behavioral problems, including prevention and modification of the adverse behaviors. Caregivers should also be monitored closely for development of depression in themselves.
  • Consider psychotherapeutic interventions (supported by controlled trials), including disease education (particularly for caregivers), as well as individual (particularly cognitive-behavioral therapy, that is supported by an open study), group (including formal support groups), and family therapy.
  • Consider somatic therapy if depression is severe or persists after these initial interventions. There are no FDA-approved somatic treatments for depression in patients with MS. Therapeutic options are the same as for major depressive disorder, that is antidepressant medication or ECT.
  • Treat initially with sertraline, based on its tolerability and the results of open studies. Citalopram is
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    a reasonable alternative. In patients who fail to respond, desipramine may be considered (supported by a small randomized, placebo-controlled study).
  • Consider ECT in depressed patients with MS who are severely ill and in need of rapid clinical improvement, or who are unresponsive to or intolerant of antidepressant medications. A small uncontrolled (primarily retrospective) clinical literature supports the safety, tolerability, and efficacy of ECT in such patients, but randomized controlled data are lacking. Several modifications in ECT technique may be required, however, based on the patient’s medical/neurologic status and concerns about cognitive side effects.
  • Give patients with psychotic symptoms an antipsychotic medication in addition to the antidepressant medication, although there are no controlled data on this issue. Atypical antipsychotic medications are generally preferred given their safety, but should be used sparingly given their small risk in the elderly of stroke and death.
  • Continue successful acute therapy for at least 6 to 9 months, although there are no controlled data on this issue.
References
1. Mohr DC. Treatment of depression in multiple sclerosis: Review and meta-analysis. Clin Psychol Sci Prac. 1999;6:1–9.
2. Mohr DC, Classen C, Barrera M. The relationship between social support, depression and treatment for depression in people with multiple sclerosis. Psychol Med. 2004;34:533–541.
7. Depression in patients with epilepsy
a. Clinical background
  • Psychiatric disorders are common in patients with epilepsy, and of these disorders depression is perhaps the most common. Depressive symptoms may occur peri-ictally (before, during, or after the ictus), but typically these mood symptoms are brief and do not require treatment per se, as they will resolve with improvement in seizure control. Depressive disorders occur interictally, and include major depression, dysthymia, or rarely bipolar disorder.
  • The precise prevalence of interictal major depression is unknown, but may occur in 30% to 50% of patients with epilepsy. Of interest, the risk of epilepsy may also be increased in patients with depression.
  • No consistent risk factors have been identified for interictal major depression. Conflicting findings have been reported regarding the relation of depression to male gender, sinistrality, family history of mood disorder, psychosocial stressors, seizure frequency/severity, or presence of a neurologic disorder causing the epilepsy.
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  • The phenomenology of interictal major depression appears to differ from that of primary major depression, with fewer “neurotic” traits (e.g., anxiety, guilt, rumination, somatization, hopelessness, or low self-esteem) and more psychotic symptoms. Atypical pain symptoms may also be present.
  • The longitudinal course of major depression in patients with epilepsy has not been sufficiently studied. At least some patients tend to suffer from dysthymia between episodes of major depression. Depression in patients with epilepsy is associated with greater utilization of health resources and a poorer quality of life. Effective treatment of depression may improve the functional status and well-being of patients with epilepsy, although this issue has not been well studied.
b. Pathogenesis of interictal major depression
  • The pathogenesis of interictal major depression is not known. Several factors may be involved.
  • The importance of temporal lobe involvement is suggested by the higher frequency of major depression in patients with temporal lobe seizures and complex partial seizures, compared with patients with other forms of epilepsy. Laterality (left greater than right) of epileptic focus as a possible pathogenetic factor is controversial.
  • Abnormal neurotransmission may be involved in the comorbidity of epilepsy and major depression. In animal models, seizures are associated with low levels of norepinephrine and high levels of serotonin.
  • Depression may be related to treatment of the epilepsy, including polypharmacy with anticonvulsant medication, the use of certain anticonvulsant medications (particularly barbiturates, phenytoin, primidone, vigabatrin, and all y-aminobutyric acid [GABA] agonists), and folate deficiency resulting from most anticonvulsant medications (especially those that induce liver enzymes). Withdrawal of antiepileptic medications may also be associated with depression, as well as anxiety and psychosis. Depression may also occur after (typically 3 to 6 months) temporal lobe surgery for epilepsy, particularly in patients with a history of mood disorder, and especially if seizures persist. No consistent relation has been found between post-surgery depression and side of surgery.
  • Depression in patients with epilepsy is certainly related to numerous psychosocial factors, including the burden of chronic disease, the stigma of epilepsy, the loss of autonomy (e.g., driving, occupational limitations, etc.), and impaired interpersonal relations (e.g., anticonvulsant induced loss of libido).
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c. Diagnosis
  • The diagnosis is clinical and is based on the presence of criteria for a mood disorder.
  • Peri-ictal depressive symptoms have to be ruled out, as these do not typically require treatment (see preceding text).
  • Depressive symptoms secondary to antiepileptic medications have to be ruled out (see preceding text).
d. Treatment
  • Optimize the physical health of the patient and ensure that all underlying general medical disorders have been optimally treated, including the provision of appropriate pain management. In particular, the treatment of epilepsy should be optimized. Antiepileptic polypharmacy should be minimized, and the use of antiepileptics with relatively low dysphorogenic properties should be considered (see preceding text).
  • Optimize the patient’s environment and lifestyle, including the promotion of exercise and a regular sleep–wake cycle. Caregivers should be instructed in behavioral management of the patient’s behavioral problems, including prevention and modification of the adverse behaviors. Caregivers should also be monitored closely for development of depression in themselves.
  • Consider psychotherapeutic interventions, including disease education, as well as individual (particularly cognitive-behavioral therapy), group (including formal support groups), and family therapy, although the efficacy of such interventions has not been formally studied.
  • Consider somatic therapy if depression persists after these initial interventions. There are no FDA-approved somatic treatments for depression in patients with epilepsy. Therapeutic options are the same as for major depressive disorder, that is antidepressant or mood-stabilizing medications, or ECT.
  • Choose antidepressant medication guided by its side effect profile (particularly its effect on seizure threshold) and risk of interactions with concomitant medications, because it is assumed (although not proved) that all antidepressants are equally efficacious in treating depression in patients with epilepsy. We recommend sertraline, based on its apparent minimal impact upon seizure threshold and its low risk of pharmacokinetic interactions, as well as the results of several open clinical trials demonstrating efficacy for major depression in patients with epilepsy. Citalopram is an acceptable alternative. Venlafaxine is a reasonable second-line choice if sertraline or citalopram are ineffective. There is only
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    one published randomized controlled trial of antidepressant medication in epilepsy, and it found that 12 weeks of nomifensine (that is no longer available) was superior to amitriptyline.
  • Avoid certain antidepressants (buproprion, maprotiline, and amoxapine) as they are proconvulsant in particularly vulnerable patients. Tricyclic antidepressants may also lower seizure threshold, but their use does not appear to worsen seizure control unless plasma levels are high, the dose is escalated rapidly, there are concomitant drugs with proconvulsant properties, or the patient has either cerebral pathology, an abnormal electroencephalography (EEG), and personal and family history of epilepsy. Less is known about the effects of newer antidepressants on seizure threshold.
  • Consider pharmacokinetic interactions of antidepressant and antiepileptic drugs. Those anticonvulsants that induce liver enzymes (particularly phenobarbital, primidone, phenytoin, and carbamazepine) can lower plasma levels of paroxetine and the tricyclic antidepressants. Conversely, certain antidepressants (fluoxetine, fluvoxamine, and paroxetine) inhibit the cytochrome P-450 enzyme system and can induce toxic levels of phenytoin and carbamazepine. Sertraline and citalopram have far fewer pharmacokinetic interactions with antiepileptic drugs.
  • Consider ECT in patients with epilepsy and major depression who are severely ill (e.g., melancholic, psychotic, or suicidal) and in need of rapid clinical improvement, or who are unresponsive to or intolerant of psychotropic medications. A small uncontrolled (primarily retrospective) clinical literature supports the safety, tolerability, and efficacy of ECT in such patients, but randomized controlled data are lacking. Several modifications in ECT technique may be required, however, based on the patient’s medical/neurologic status and concerns about cognitive side effects. Of note, the anticonvulsant properties of ECT may help improve seizure control.
  • Manage bipolar depression in patients with epilepsy with lamotrigine or ECT. Lithium is a second choice, because of its proconvulsant properties and its propensity for inducing delirium especially when used in combination with carbamazepine. Mania in patients with epilepsy may be managed with a mood-stabilizing antiepileptic medication (e.g., valproic acid) and an antipsychotic medication, or with ECT.
  • Base the treatment of concomitant psychotic symptoms in patients with epilepsy and major depression upon a thorough assessment of the potential causative factors
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    (e.g., medication-induced vs. depression with psychotic features vs. other), as discussed in Chapter 8. Atypical antipsychotic medications are generally preferred given their safety, but should be used sparingly given their small risk in the elderly of stroke and death.
  • Continue successful acute therapy for major depression in patients with epilepsy for at least 6 to 9 months, although there are no controlled data on this issue.
  • In July 2005, the FDA approved vagus nerve stimulation (VNS) therapy as an add-on long-term treatment for adults with treatment-resistant chronic or recurrent depression. Whereas VNS may be considered as a treatment option for depression in patients with epilepsy, its role in patients with other neurologic illnesses remains to be defined.
References
1. Coffey CE, Kellner CH. Electroconvulsive therapy. In: Coffey CE, Cummings JL, eds. Textbook of geriatric neuropsychiatry, 2nd ed. Washington, DC: American Psychiatric Press; 2000:829–859.
2. Kanner AM. Depressive in epilepsy. Biol Psychiatry. 2003;54:388–398.
3. Krystal AD, Coffey CE. Neuropsychiatric considerations in the use of electroconvulsive therapy. J Neuropsychiatry Clin Neurosci. 1997;9:283–292.
4. Mendez MF. Epilepsy. In: Coffey CE, Cummings JL, eds. Textbook of geriatric neuropsychiatry. Washington, DC: American Psychiatric Press; 2000:655–667.
5. Prueter C, Norra C. Mood disorders and their treatment in patients with epilepsy. J Neuropsychiatry Clin Neurosci. 2005;17:20–28.
C. Management of mania/hypomania in patients with neurologic disease
  • Mania/hypomania has been described in patients with a variety of neurologic disorders, most commonly epilepsy (some studies suggest a relation to nondominant temporal lobe epilepsy), stroke (associated with a family history of mood disorder, premorbid mild subcortical atrophy, and stroke location [right basotemporal cortex]), TBI, multiple sclerosis, Huntington disease, and tumor. The occurrence of mania/hypomania in patients with neurologic illness in not precisely known, but appears to be rarer than depression.
  • There are no FDA-approved treatments, nor any randomized controlled treatment trials of mania in patients with neurologic disease.
    • Follow the APA guidelines for bipolar disorder (APA 2002), which call for treatment of mania with a mood stabilizer (valproate or lithium) and an antipsychotic
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      medication. Lithium is generally avoided in patients with epilepsy due to its potential proconvulsant properties, and antipsychotic medications should likewise be used cautiously because they also lower seizure threshold.
    • Concomitant psychosocial and psychotherapeutic interventions are also reasonable considerations, although these have not been studied.
    • ECT should be considered in manic patients with epilepsy who are severely ill and in need of rapid clinical improvement, or who are unresponsive to or intolerant of pharmacotherapy. Several modifications in ECT technique may be required, however, based on the patient’s medical/ neurologic status. Of note, the anticonvulsant properties of ECT may help improve seizure control.
    • Effective acute treatment should be continued for 6 to 9 months, although the antipsychotic medication should be discontinued unless required for control of persistent psychosis or prophylaxis against recurrence.
D. Management of affective lability (“emotional incontinence”) and pathologic affect
There are no FDA-approved somatic treatments for affective lability or pathologic affect associated with neurologic disorders, and only a few studies have examined this issue prospectively. Both nortriptyline and citalopram have been found to be effective in small randomized controlled trials of pathologic affect following stroke. Amitriptyline was found effective for pathologic affect in a randomized controlled trial of 12 patients with MS. A recent 17-center, double-blind, randomized, controlled clinical trial found that AVP-39 (a combination of quinidine 30 mg and dextromethorphan 30 mg orally) was effective in relieving pathologic affect and improving quality of life in patients with amyotrophic lateral sclerosis (ALS) (ALS). A similar study is under way in patients with pathologic affect and MS. Case reports support the use of tricyclic antidepressants, SRIs, levodopa, and mood stabilizers for pathologic affect in various neurologic disorders.
References
1. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(Suppl 4):1–50.
2. Brooks BR, Thisted RA, Appel SH, et al. Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine. Neurology. 2004;63:1364–1370.
3. Schiffer RB, Herndon RM, Rudick RA. Treatment of pathological laughing and weeping with amitriptyline. NEJM. 1985;312:1480–1482.