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

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
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
  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).
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
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.

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
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
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.

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.