Guide to Neuropsychiatric Therapeutics
1st Edition

Chapter 1
Apathy and Related Disorders of Diminished Motivation
James D. Duffy
Historical Context
During the eighteenth and nineteenth centuries, disorders of motivation represented the theoretical foundation for most psychiatric classifications. The Swiss psychiatrist André Matthey wrote in 1816 that psychiatric illness was a manifestation of “perversions of the will and the natural inclinations without obvious impairment of the intellectual functions.” Matthey distinguished between a behavioral disturbance caused by a physical etiology (délire) and a behavioral disorder produced by a disturbance of the individual’s free will (fureur sans délire). According to Matthey’s nosology, behaviors such as kleptomania, ennui, melancholia, and tigridoanie (an irresistible urge to spill blood) were all considered “disorders of the will.” Matthey’s seminal writings became the foundation for the development of nineteenth-century neuropsychiatry and a clinical approach that placed disorders of will as the primary derangement in pathologic behaviors.
The German neuropsychiatrist Heinroth (1818) rejected earlier explanations for mental illness such as “bile or worms or a hundred other irritations” and suggested, “there are many involuntary movements, but not a single involuntary action, for action cannot be imagined without willing.” Heinroth went on to write that pathologic behaviors occurred when “the will separates itself from reason and is no longer determined by feeling or intellect.” By distinguishing intellect from

emotion and motivation, Heinroth laid the foundation for the triad approach of Mood, Cognition, and Conation that became the basis for psychiatric classification for the most part of the nineteenth century. The term abulia appeared in psychiatric literature as early as 1847 and was defined in medical dictionaries as “absence of will, a type of insanity in which this symptom is dominant.” Ribot described abulia as a “pure disease of will” in which the individual’s ability to act was abolished and he or she was reduced to an individual of “pure intellect.” Although most neuropsychiatrists at the end of the nineteenth century agreed on the concept of abulia, there was considerable disagreement on whether the disorder was caused by a deficit in cognition or was a consequence of a dysfunction in a specific motivational system within the brain.
By the beginning of the twentieth century, abulia had become a household word and parents were even urged to “combat the evil of abulia amongst students.” Despite this, the neuropsychiatric concept of disorders of will fell quickly into decline and by the end of World War I they had essentially disappeared from psychiatric nosology. The reasons for this shift include (i) the rise of behaviorism that posited a simple reflex response that did not require an intervening variable; (ii) psychiatry’s preoccupation with psychoanalysis and its emphasis of psychodynamic predeterminism; (iii) the burgeoning field of neurology with its emphasis on somatosensory disorders; (iv) the emergence of postmodernism and its emphasis on individuality and self-determinism (v) the reassignment of disorders of free will to diagnostic concepts such as “negative symptoms” and “executive cognition.”
Definitions of Motivation
A universal definition of the term motivation remains elusive. This single issue represents the most important barrier to our scientific attempts to understand the neural basis of goal-directed behavior and clinical disorders of motivation.
From a theoretical perspective, motivation is the heuristic construct that describes the amalgam of forces acting within an organism to initiate and direct behavior. Motivation serves to influence the activation, persistence, and direction of an organism’s behavioral response across different levels of behavioral complexity.
From a neuropsychiatric perspective, motivation describes the neurologically mediated variables that energize and direct an individual’s response to the environment. These variables include the following:
  • The emotional response to a stimulus
  • The motor reactivity to the stimulus
  • The level of arousal elicited by the stimulus
  • The cognitive interpretation of a stimulus
This approach provides a simple framework for assessing the character and etiology of behaviors that are characterized by a decrease in the expected response to a particular stimulus. It also provides a heuristic framework that is inclusive of and consistent with each of the different approaches to motivation described in the preceding text and does not fall prey to Cartesian models that attempt to separate mind-driven behaviors (i.e., free will) from homeostatic drive theories and instinctual reflex behavior patterns.

Definition of Apathy
Apathy may be either a symptom or a syndrome. As a syndrome, Marin has proposed Diagnostic and Statistical Manual of Mental Disorders (DSM)-like criteria (see subsequent text). Although not yet formally accepted, these criteria do provide the framework for the clinical assessment of apathy.
As per Marin’s proposed criteria, apathy is defined as “A lack of motivation, relative to the patient’s previous level of functioning or the standards of his/her age and culture as evidenced by all three of the following”:
  • Diminished goal-directed overt behavior, as indicated by the following:
    • Lack of productivity
    • Lack of effort
    • Lack of time spent in activities of interest
    • Lack of initiative or perseverance
    • Behavioral compliance or dependency on others
    • Diminished socialization or recreation
  • Diminished goal-directed cognition as indicated by the following:
    • Lack of interests
    • Lack of concern about one’s personal, health, or functional problems
    • Diminished importance or value attributed to such goal-related domains as socialization, recreation, productivity, initiative, curiosity
  • Diminished emotional concomitants of goal-directed behavior as indicated by the following:
    • Unchanging affect
    • Lack of emotional responsiveness
    • Euphoria or flat affect
    • Absence of excitement or emotional intensity
Classification of Apathy and Disorders of Motivation
Apathy and the Diagnostic and Statistical Manual of Mental Disorders text revision (DSM-IV-TR)—The DSM glossary does not include the term apathy, but related symptoms such as indifference, emotional unresponsiveness, lack of symptoms, and lack of concern are included in the diagnostic criteria and symptoms of several disorders. Further examples of related symptoms in DSM-IV-TR include the following:
  • Major depressive disorder: “Diminished interest or pleasure in all, or almost all, activities”
  • Post-traumatic stress disorder: “Markedly diminished interest or participation in significant activities”
  • Schizophrenia: Catatonic behavior characterized by “decrease in reactivity to the environment;” negative symptoms include avolition, alogia, and affective flattening
Apathy is explicitly included as a diagnostic criterion in only the following four disorders:
  • Inhalant intoxication (criterion B—“maladaptive changes e.g., apathy”)
  • Opioid intoxication (criterion B—“euphoria followed by apathy”)
  • P.4

  • Apathetic type of personality change due to a general medical condition (i.e., predominant feature is apathy or indifference)
  • Postconcussional disorder (criterion C—“apathy or lack of spontaneity”)
Epidemiology of Apathy and Disordered Motivation
No data are currently available on apathy as a primary disorder. However, a considerable amount of research indicates that apathy is perhaps the most common behavioral syndrome associated with neurologic disease. A recent analysis of prevalence data revealed that neurologic diseases involving the cerebral cortex are associated with a point prevalence of apathy of approximately 60%, whereas disorders primarily involving subcortical structures are associated with a 40% prevalence of apathy.
  • Alzheimer disease: At least six studies have examined the prevalence of apathy in Alzheimer disease (AD) with a reported prevalence ranging from 37% to 86.4% (composite prevalence 55.5%). Apathy has also been reported to be the most common behavioral symptom in mild cognitive impairment (MCI) with a point prevalence of 39%. It is important to recognize that apathy may be a herald symptom in MCI and AD that antedates the onset of observable cognitive decline. The prevalence of apathy in AD appears to be higher in community-dwelling AD patients and may be the most important determining factor for patients’ families seeking medical evaluation.
  • Traumatic brain injury: Several studies have reported the prevalence of apathy in traumatic brain injury (TBI) to range from 46% to 71% with a composite average of 61%. One study reported that apathy occurred in only 13.8% of patients following a TBI.
  • Vascular dementia: Two studies have reported a combined prevalence of 33.8% in a sample of patients with vascular dementia.
  • Poststroke: The prevalence of apathy in a heterogeneous group of patients following cerebrovascular accidents ranges from 22.5% to 56.7%. Apathy appears to be most frequent following a lesion involving the posterior limb of the internal capsule and is slightly higher in patients with right hemisphere lesions.
  • Anoxic encephalopathy: A study including 14 subjects reported a prevalence of 78.6% in patients with postanoxic encephalopathy.
  • Parkinson Disease: Using self report or informant-based measures, several studies have reported that between 16.5% and 42% of patients with Parkinson disease (PD) exhibit apathy. Low serum testosterone has been found to be an independent variable predicting the presence of apathy in PD.
  • Huntington disease: One study reported that 38% of patients with Huntington disease exhibit apathy and depression, with 7% exhibiting apathy alone. Apathy was found to be a powerful predictor of activities of daily living (ADL) ability.
  • Multiple sclerosis: Apathy has been reported to occur in 20.5% of patients with multiple sclerosis (MS); however, 53.3% of MS patients with depression are apathetic.
  • Human immunodeficiency virus: Three studies in patients with human immunodeficiency virus (HIV) report a prevalence ranging from 29.8% to 50%.

    Interestingly, the presence of apathy does not appear to correlate with absolute CD4 count.
  • Nursing home residents: Probably as a consequence of the additive effect of severity of disease and impoverished social environment, nursing home residents have an extremely high prevalence of apathy. This finding has important implications for patient compliance and undoubtedly negative impacts on disease progression, morbidity, and mortality.
  • Although no data is available, given their pathophysiology, it is reasonable to assume that normal pressure hydrocephalus, sleep apnea, amyotrophic lateral sclerosis, Lyme disease, and thyroid disease are associated with atrophy.
  • Negative symptoms of schizophrenia: The overlap between apathy and the negative symptoms of schizophrenia is discussed elsewhere in this text.
  • Prescription medications: Although no data is available on prevalence, anecdotal reports indicate that apathy may occur as a side-effect of selective serotonin reuptake inhibitors (SSRIs), neuroleptics, metaclopramide, and felbamate.
Several studies have reported significant morbidity associated with the presence of apathy. Four studies in patients with Alzheimer dementia that utilized standardized assessment tools for the diagnosis of apathy, have reported an association between the presence of apathy and diminished performance on activities of daily living (independent of the presence of depression). Patients who are apathetic following a stroke have been reported to be more functionally impaired, with the comorbidity of apathy and depression having the greatest impact on functional capacity. A study of geriatric patients admitted to a nursing home found apathy to be an important predictor of functional capacity at discharge, independent of admission diagnosis.
Apathy appears to be associated with more rapid cognitive and functional decline in patients with AD. Apathy has also been reported to be an important predictor of poor prognosis in patients with major depressive disorders.
Apathy appears to be an important predictor of medication compliance in patients with schizophrenia, and in identifying those patients who are less likely to benefit from social skills training.
Although there is no data available to support the hypothesis, it is reasonable to suggest that apathy may contribute to patient medication and treatment noncompliance, thereby indirectly increasing the morbidity and mortality of comorbid disorders (such as diabetes, hypertension etc.) that may themselves produce apathy. Patients and caregivers often interpret the patient’s apathetic behavior as volitional and label the patient as lazy, passive aggressive, or ungrateful. This inevitably results in resentment or hostility toward the patient, thereby perpetuating a downward spiral of diminishing functional capacity and diminishing social supports. In this regard, apathy has been reported to be significantly correlated with caregiver distress in AD, thereby being an important determinant of nursing home placement.
The longitudinal clinical course of apathy remains unclear. One study in AD has reported that apathy is likely to persist and worsen over the course of the disease.

The Neural Substrates of Motivation
Since the construct of motivation describes the neurologically mediated variables that energize and direct an individual’s response to the environment, a discussion of the neural substrates of goal-directed behavior could conceivably include a description of the entire brain. However, understanding the neural substrates that serve the different components of goal-directed behavior does provide the clinician with a framework that is helpful in developing clinical hypotheses and effective treatment plans.
  • Subcircuit No. 1—Motivational working memory
  • Components: The ventral tegmental area (VTA)—nucleus accumbens (NA) and the ventral pallidum (VP).
  • Function: Provides “the neural template for motivational working memory” that allows the prioritization of motivational valencies across the temporal domain.
  • Subcircuit No. 2—Cognitive coordination
  • Components: VP, mediodorsal (MD) nucleus of thalamus, prefrontal cortex (PFC), NA, and VTA.
  • Function: Provides the cognitive coordination of motivational response.
  • Subcircuit No. 3
  • Components: VP, pedunculopontine nucleus (PPN), VTA.
  • Functions: Integration of arousal into motivational response.
    Subcircuit No. 4
  • Components: The ventral tegmentum, amygdala, and the NA.
  • Function: Integration of reward memory into motivation.
Neurochemical Aspects of Motivation
Although dopamine (DA) and glutamine appear to be the primary modulators of motivation, the neurochemical foundations of motivation are extremely complex and have not been fully elucidated. However, substantial experimental data indicates a pivotal role for DA and glutamate as the key modulators of goal-directed behavior.
In simple terms, one can state that DA is necessary for modulating relative motivational valency (i.e., the direction of behavior) while glutamate is primarily involved in the enactment of the behavioral response (the intensity of behavior).
The cholinergic system exerts a modulatory influence on motivational response through projections from the PPN (located in the mesencephalic locomotor region) to widespread targets that include the limbic system, extrapyramidal system, thalamic nuclei, and tectal and cortical regions. These ascending cholinergic projections influence locomotor goal-directed behavior through their stimulatory influence on DA efflux.
The serotinergic system appears to exert an inhibitory effect upon motivational response through its 5-HT1b modulatory activity of glutamate pathways in the NA and an inhibitory effect on DA release through 5-HT2 activation.

Clinical Implications of This Circuitry
The neural circuitry described in the preceding text provides the theoretical framework for a reasoned clinical approach to the assessment and treatment of disorders of diminished motivation. Dysfunction within particular subcircuits produces a predictable and specific disorder of diminished goal-directed behavior (Table 1.1). This approach suggests that rather than representing a single syndrome, the disorders of diminished motivation include at least four distinct behavioral syndromes. Each of these syndromes requires a treatment approach based on the particular characteristics of each syndrome.
It is important to be aware of other conditions and syndromes, the clinical presentation of which may overlap or mimic apathy and disorders of motivation.
Differential Diagnosis of Apathy
Although apathy may occur as a symptom of depression, several studies have demonstrated apathy to be a disorder distinct from depression. Although patients suffering from a depressive disorder often exhibit diminished goal-directed behavior, the hallmark of depression is the presence of depressed mood and neurovegetative symptoms. While apathetic patients fail to verbalize any subjective distress, depressed patients are usually characterized by negativism and despair. The depressed person typically and purposively avoids interpersonal contacts. In contrast, the apathetic patient is passive and will engage in interpersonal behaviors only if others initiate and facilitate the social engagement.
Lethargy, impersistence, distractibility, and diminished goal-directed behavior are all components of delirium. When these features dominate the delirious patient’s clinical picture the patient is described as suffering from “apathetic delirium.” Apathy, however, is not associated with the disorder of attention and arousal that represents the hallmark of delirium. In addition, while apathy is associated with diffuse background frequency slowing on electroencephalogram (EEG), apathy is not associated with any particular EEG abnormality.
Patients with specific agnosias may exhibit a diminished behavioral response to a specific sensory or categorical stimulus. In particular, anosagnosic patients manifest a “laissez-faire” attitude to their illness and its social and personal implications (in this respect, it is probably better defined as apathy, cognitive subtype).
Patients who are exhibiting akinetic mutism manifest no goal-directed motor behavior in the absence of any motor deficit or abnormal motor movements. In this regard, rather than a motor disorder, akinetic mutism may be regarded as apathy, motor type.
TABLE 1.1 Components and Functions of Motivational Circuitry
  Circuit No. 1 Circuit No. 2 Circuit No. 3 Circuit No. 4
Neuroanatomic components VT-NA-VP VP-MD-PFC-NA-VTA VP-PPN-VTA VTA-Amygdala-NA
Function Provides the neural template for “motivational working memory” that allows the prioritization of motivational valencies across the temporal domain Provides cognitive framework for response coordination Integrates autonomic state into motivational readiness Integrates the incentive value (reward memory) into motivational response
Clinical syndrome associated with lesion in circuit Diminished motivational flexibility and increased threshold of behavioral response to stimulus Diminished cognitive planning Diminished arousal in response to motivationally relevant stimulus. Diminished stimulus discrimination
Clinical syndrome Motor apathy Cognitive apathy Arousal apathy Emotional apathy
VT-NA-VP, ventral tegmental-nucleus accumbens-ventral pallidum; VP-MD-PFC-NA-VTA, ventral pallidum-mediodorsal-prefrontal cortex-nucleus accumbens-ventral tegmental area; VP-PPN-VTA, ventral pallidum-pedunculopontine nucleus-ventral tegmental area; VTA-Amygdala-NA, ventral tegmental area-Amygdala-nucleus accumbens.


Pathologic fatigue is increasingly recognized as an important determinant of diminished goal-directed behavior. Unlike apathy, fatigue is an ego-dystonic experience with the patient typically frustrated by the inability to function at his/her usual level.
Despair and Demoralization
These occur in response to experienced helplessness in the context of an apparently overwhelming stress. Unlike apathy, these are experienced as painful psychological states. Demoralized individuals will exhibit a negative emotional orientation regarding their future while apathetic patients will exhibit very little concern.
Substance Abuse
Although there is no data available, anecdotal experience suggests that the chronic abuse of marijuana and possibly amphetamines may produce a chronic behavioral state characterized by apathy.
Obtain a thorough history from the patient and his/her family or caregivers. Because apathetic patients will not be motivated to participate in the interview process, it is important to obtain historical data from both the patient and his/her family and/or social supports. Typically, apathetic patients will underestimate their lack of motivation and its social consequences. Neuropsychiatric treatment is therefore typically sought by family members and/or caregivers and not by the identified patient.
When obtaining the history, it is important to assess not only the content, but also the patient’s response style. Apathetic patients typically initiate very few spontaneous statements. The interviewer typically needs to drive the interview and provide increased motivational relevance by either being more persistent or raising the volume of the interaction. Make sure that the patient’s caregiver/family member does not compensate for the patient’s apathy by assuming a more active role in the conversation. Also, while attempting to obtain historical information, carefully assess the patient’s level of arousal and monitor for evidence of distractibility, impersistence, or perseveration (all signs of delirium that can mimic apathy).
When obtaining the history, particular attention should be given to the following:
  • Changes in goal-directed activities from premorbid level (it is important to realize that goal-directed behaviors usually diminish with advancing age)
  • Previous and current functional capacity (i.e., occupational status, recreational pursuits)
  • Overt evidence for cognitive slippage (i.e., has the patient exhibited memory loss, diminished organizational skills, or diminished work performance?)
  • The patient’s insight regarding his/her diminished goal-directed behavior and the amount of concern the patient exhibits about this decline
  • History of increased irritability and/or aggressive behaviors
  • Changes in gait, posture, falls, tremor, urinary incontinence
  • Neurovegetative signs and symptoms of depression
  • Past or present substance abuse
  • P.10

  • The patient’s living environment and its motivational implications (i.e., patients living in an impoverished environment such as nursing facilities will experience fewer motivationally relevant stimuli)
  • Current and past medical history with particular reference to a previous history of TBI due to neurologic disease
  • Any recent or past history of substance abuse (particularly marijuana, solvents, N-methyl-D-aspartate [NMDA], and designer drugs)
  • Consider administering a clinical assessment tool such as the Apathy Evaluation Scale (AES) (patient-rated and observer-rated versions) or neuropsychiatric inventory (NPI)
Perform a Thorough Neurologic Examination
Patients exhibiting diminished goal-directed behavior should undergo a full physical and neurologic examination. The general physical examination should make particular reference to clinical signs of thyroid disease and cerebrovascular disease, and other conditions that result in general asthenia. In patients exhibiting features of delirium, it is important to recognize that delirium may be the manifestation of a medical emergency. In addition to detailed neurologic examination, the examiner should evaluate the patient for any evidence of frontal release signs.
Perform a Cognitive Examination
As stated above, it is important to assess the patient for any behavioral features of delirium. In patients exhibiting altered arousal, distractibility, impersistence, and/or perseveration, it is important to immediately perform a formal assessment of the patient’s attentional status (i.e., digit span, reverse serial days and months). In addition to assessing quantifiable cognitive functions such as memory, language, math and so on, it is also important to formally assess the patient’s executive functioning (open and closed set word generation, insight, and abstraction). The cognitive examination typically provides important information regarding the etiology of the patient’s apathy. Formal neuropsychological assessment can be helpful in providing more sensitive and specific assessments of cognitive functioning.
Perform a Psychosocial Assessment
Apathy will inevitably produce very significant social dysfunction. It is important to evaluate the patient’s current functional capacity and determine any evidence for deteriorating work performance. Although patients may be able to continue in their premorbid work capacity, close questioning regarding performance evaluations will usually uncover evidence for employer discontent with the patient’s productivity.
Since family members will typically compensate for changes in the patient’s behavior, it is important to perform a detailed family assessment. In this regard, the approach of a system to family assessment that includes a review of the different domains of family functioning is particularly useful (i.e., role assignment, instrumental problem solving, affective problem solving, discipline, finances). This assessment is particularly helpful in developing an effective treatment plan.

Clinical Instruments for Assessing Apathy
Although there is no universal definition of apathy, several assessment tools are available. These instruments were developed to support research in disorders of motivation but they do, however, have clinical utility. In particular, they provide clinicians with a method for quantifying the patient’s level of motivation and monitoring the patient’s clinical course over time.
The AES (as well as its shortened version, the Apathy Scale) is the most widely used scale and has demonstrated specificity for distinguishing apathy from depression (see Table 1.1). There are three versions of the AES for use by the patient, i.e., self (AES-S), by an informant such as a family member (AES-I), or by a clinician (AES-C). They are essentially the same, with only the pronoun referring to the subject changed. However, the AES-C has patient and clinician/caregiver versions, with at least one study reporting that families may be more reliable in accurately reporting the identified patients’ goal-directed behavior. One major challenge when using the AES is to recognize that the cutoff score for a diagnosis of apathy is arbitrary and is not sensitive to premorbid functional capacity and/or age. In this regard, the AES is most helpful as a tool for assessing treatment response and disease progression.
The NPI includes several behavioral domains including apathy. As an observer rating scale, the NPI is simple to administer and has been utilized in several neuropsychiatric conditions. The scale, however, is not clear on the appropriate cutoff score for the presence of apathy.
Laboratory Investigations
  • EEG provides important diagnostic information in patients who exhibit attentional deficits suggestive of delirium.
  • Magnetic resonance imaging provides important information regarding subcortical and white matter disease.
  • Neuropsychological assessment provides useful quantitative data in different domains and may be particularly helpful in patients with a presumptive diagnosis of MCI.
  • Perform tests for thyroid function and serum testosterone on all patients. Other tests should be performed depending upon the patient’s clinical picture.
  • Consider a formal sleep study in patients with a history of body habitus (i.e., overweight, bull necked, etc.) consistent with sleep apnea.
  • Perform urine toxicology screen.
Effective treatment should include both psychopharmacological and psychosocial interventions. The efficacy of therapeutic interventions can be assessed utilizing ongoing clinical assessment tools such as the AES. When developing a treatment plan, it is important to appreciate that most apathetic patients are, by definition, not bothered by their behavior. Treatment goals should therefore be established on the basis of the needs of the patient and family and not on the basis of the clinician’s agenda.

When developing a treatment plan it is important to characterize the nature of the patient’s apathy syndrome and its etiology. Patients with apathy characterized by diminished cognitive planning are likely to respond to medications only if their PFC is intact (i.e., they have an intact end organ). For example, (i) a patient who has sustained prefrontal trauma will not benefit from DA agonist therapy whilst a patient with a ventral tegmental lesion will likely exhibit marked improvement at high doses of DA agonist, (ii) patients with motor apathy (e.g., parkinsonism) will benefit from strategies intended to enhance motor responsivity, that is, DA agonists, and (iii) patients with emotional apathy may benefit from a nonserotoninergic antidepressant—however, patients with lesions involving the medial temporal structures are unlikely to benefit from this approach.
Psychopharmacological Approaches
The following principles should be observed when treating a patient with apathy:
  • Optimize physical status.
  • Evaluate and modify psychosocial modifiers (see subsequent text).
  • Optimize endocrine status.
  • Optimize treatment of comorbid psychiatric conditions.
  • Discontinue medications that may produce diminished motivation, that is, metaclopramide, paroxetine (and possibly other SSRIs), felbamate, and neuroleptics.
  • In patients with AD, acetylcholinesterase inhibitors represent the first-line treatment for apathy. A meta-analysis of randomized clinical trials (RCT) demonstrated a significant benefit of metrifonate for treating apathy in AD. An RCT has also demonstrated positive response with tacrine and donezepil. An open study of rivastigmine reported benefit in a small sample of patients with Lewy body dementia. The author’s preference is to begin donezepil 5 mg daily PO. Intolerance to side effects limits the use of other psychostimulants in patients with AD—however, patients may tolerate and benefit from low doses starting with methylphenidate 2.5 mg at breakfast and lunchtime. Patients who will benefit from psychostimulant therapy are likely to do so quickly and at these low doses.
  • There are no RCTs to guide the treatment of apathy in other disease populations. Pharmacologic approaches are therefore largely anecdotal and dictated by the side effect profile and close monitoring of the response. In one open trial with bromocriptine (doses 10 to 120 mg daily) patients post-TBI reported increased motivation. Although there are no published data to support their use, the newer DA agonists (pergolide, pramipexole, selegiline) should theoretically have a therapeutic benefit in the treatment of apathy. Pramipexole, with its selectivity for limbic D3 receptors, may have some theoretical advantage. The author’s preference is to begin with bromocriptine starting at 5 mg and titrate dosage upward against the patient’s response and tolerance. Patients may require very high doses to drive their motivational responsivity.
  • Anecdotal case studies have reported benefit from amantadine (50 to 200 mg per day) in TBI patients. One study reported that nursing home patients who were taking amantadine for viral prophylaxis demonstrated increased social interaction, personal care, caloric intake and weight gain.
  • P.13

  • Although there are no RCTs, several case reports suggest that methyl-phenidate (doses up to 1 mg/day/kg body weight) and D-amphetamine have clinical utility as a treatment for apathy in patients with TBI.
  • There is considerable evidence to support the efficacy of novel antipsychotics in reducing the negative symptoms in schizophrenia. Their utility in improving motivation in other neuropsychiatric disorders has not been ascertained.
Psychosocial Approaches to Treating Apathy
It is probably true to state that at this time, psychosocial treatment approaches offer more benefit than medications in treating apathy. Unfortunately, the impact of these psychosocial interventions is frequently underestimated or completely ignored.
It is critical to engage family members and/or caretakers in all psychosocial interventions. In particular, they should be empowered to assume a very active role in shaping the patient’s behavior and supporting adaptive behaviors. It is important to clarify from the outset that the patient’s apathy is not intentional but a manifestation of neurologic disease. This simple interpretation typically frees family members from the vicious cycle of accusations and misattribution.
Apathetic patients are typically incapable of generating and sustaining novel behavioral repertoires. They therefore benefit from a repetitive structured daily schedule. Because apathy is frequently associated with irritability, they also benefit from a low expressed emotion environment. Unfortunately, family and caregivers have to walk a tightrope—supporting positive goal-directed behaviors while also avoiding overt frustration. It is important that caregivers recognize their own needs and identify other resources that will lower their caregiving burden, that is, daycare, volunteers, other family members, and inpatient respite. Failure to address the needs of the patient’s caregivers will inevitably result in their becoming demoralized, exhausted, angry, and being likely to relinquish their critical role in supporting the patient. It is important to realize that psychosocial treatment will inevitably be a long-term regular endeavor.
Apathy is not formally recognized as a distinct symptom or syndrome in current psychiatric nosology. The clinician should, however, remain alert to recognizing that disorders of diminished motivation are a common and potentially treatable cause of profound psychosocial disability. Utilizing targeted psychopharmacologic and sustained psychosocial interventions can significantly improve the quality of life for both patients and their caregivers.
Selected Readings
Marin RS. Apathy: A neuropsychiatric syndrome [Review]. J Neuropsychiatry Clin Neurosci. 1991;3(3):243–254.
Marin RS. Apathy: Concept, syndrome, neural mechanisms, and treatment. Semin Clin Neuropsychiatry. 1996;1(4):304–314.
Van Reekum R, Stuss DT, Ostrander L. Apathy: Why care? [Review]. J Neuropsychiatry Clin Neurosci. 2005;17(1):7–19.