Current Treatment Options in Neurology

, 13:508

Treatment of Apathy in Huntington’s Disease and Other Movement Disorders


    • Maelor Hospital
  • David Craufurd
    • Manchester Academic Health Sciences Centre and Central Manchester University Hospitals, NHS Foundation TrustSt. Mary’s Hospital
Psychiatric Manifestations of Neurologic Disease

DOI: 10.1007/s11940-011-0140-y

Cite this article as:
Krishnamoorthy, A. & Craufurd, D. Curr Treat Options Neurol (2011) 13: 508. doi:10.1007/s11940-011-0140-y

Opinion statement

Apathy is one of the most prevalent neurobehavioral symptoms in Huntington’s disease (HD), occurring in approximately 70% of the symptomatic HD population. Apathy scores in patients with HD are highly correlated with duration of illness, suggesting that apathy is an inevitable consequence of advanced disease. Although less distressing than symptoms like depression and less disruptive than irritability or aggression, apathy has a considerable adverse impact on those affected with HD because it leads to a decrease of the goal-directed behaviors that contribute much to the day-to-day quality of life. As a neuropsychiatric syndrome, apathy is also common in patients with other neuropsychiatric disorders such as Parkinson’s disease, traumatic brain injury, cerebrovascular accident, dementia, and other neurodegenerative conditions. The nosologic status of apathy and lack of a clear definition has probably contributed to the paucity of therapeutic evidence in this area. Several different scales are available to measure apathy, including the Apathy Evaluation Scale, Apathy Inventory, Lilles Apathy Rating Scale, and the apathy items from the Unified HD Rating Scale, the Problem Behaviours Assessment for HD, and the Neuropsychiatric Inventory, but all are based on slightly different definitions of apathy, so the scores obtained may not be directly comparable. Assessment may also be complicated by overlap between the manifestations of apathy and other complications of HD such as depression, so the identification and treatment of these comorbid conditions is important. No adequate evidence currently supports any specific pharmacologic or psychological intervention for apathy in HD. Evidence can only be extrapolated from interventional studies done in other basal ganglia disorders such as Parkinson’s disease or other neurodegenerative disorders such as dementia. The neurobiology of apathy points towards three areas of functional connectivity: connections between the dorsolateral prefrontal cortex (PFC) and basal ganglia, orbitomedial PFC and basal ganglia, and dorsomedial PFC and basal ganglia. Pharmacologic interventions such as cholinesterase inhibitors, the dopaminergic antidepressant bupropion, amantadine, levodopa, bromocriptine, methylphenidate, and atypical antipsychotics have all been tried in other neurodegenerative disorders, but not in HD. Psychosocial interventions such as cognitive stimulation therapy and multisensory stimulation, which have been used in patients with dementia, have not been properly studied in HD. Individualized treatment should be considered, using a combination of methods, as there is no evidence to support one particular type of treatment. Multidisciplinary input, environmental modifications, improved psychosocial support, and psychoeducation programs designed to help caregivers to understand and compensate for the deficits caused by this symptom may all have a role to play in the treatment of apathy.


Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded trinucleotide repeat (CAG)n mutation in the coding region of the huntingtin gene on chromosome 4 [1]. Affected individuals display a combination of motor, cognitive, and psychiatric symptoms progressing eventually to a state of severe hypokinesia and dementia. Estimates of the lifetime prevalence of psychiatric disorders among HD patients vary between 33% and 98% [24], but a recent literature review reported the prevalence of depressed mood, anxiety, irritability, and apathy to vary from 3% to 76% [5].

A cross-sectional study of patients attending a multidisciplinary HD management clinic [6] reported the most common behavioral symptoms to be lack of energy and apathy, affecting more than 75% of patients; irritability was seen in 44% of patients and low mood in 33%. Principal-components analysis identified three factors (apathy, irritability, and depression) that together accounted for about 40% of the variance. Apathy scores were strongly correlated with duration of illness. A later study [7••] using the same measure, the Problem Behaviors Assessment for HD (PBA-HD), confirmed that apathy becomes more severe with advancing disease and established that there was no correlation between scores for apathy and depression. More recently, a factor analysis of data from the European Huntington’s Disease Network REGISTRY study [8], using the behavioral section of the Unified HD Rating Scale (UHDRS), identified four main clusters of psychiatric symptoms in HD:
  1. 1.

    Depression (depressed mood, low self-esteem, suicidal ideation, anxiety)

  2. 2.

    Drive/executive function (perseveration, compulsion, apathy)

  3. 3.


  4. 4.

    Psychosis (delusions and hallucinations)

Apathy is also reported to be common in patients with stroke, Parkinson’s disease, Alzheimer’s disease, and traumatic brain injury, but until recently there has been no agreed consensus on a definition for apathy, which may present differently in different disorders. One definition of apathy is “lack of emotional response or affective flattening” [9], but most would agree with Marin and Wilkosz [9] that the essential components of apathy also include a decrease in goal-directed behavior and associated cognitions. These authors defined apathy as a distinct psychiatric syndrome characterized by deficits in goal-directed behaviors, as manifested by the “simultaneous diminution in the cognitive and emotional concomitants of goal directed behavior.” Starkstein [10] modified this concept and proposed a set of diagnostic criteria for apathy (Table 1). Apathy is usually considered to be significantly associated with cognitive deterioration (executive dysfunction) and functional decline, but in Parkinson’s disease it could still have an association with depressive symptoms [11]. Although decreased motivation leading to lack of interest could be a central theme of both apathy and depression, people with apathy without depression rarely report anhedonia [12••], and apathy in HD is often present independent of depressive symptoms, as noted above [7].
Table 1

Diagnostic criteria for Apathy

(A) Lack of motivation relative to the patient’s previous level of functioning, or the standards of his or her age and culture, as indicated either by subjective account or observation by others.

(B) Presence for at least 4 weeks, during most of the day, of at least 1 symptom belonging to each of the following three domains:

 1. Diminished goal-directed behavior

 • Lack of effort or energy to perform everyday activities

 • Dependency on prompts from others to structure everyday activities

 2. Diminished goal-directed cognition

 • Lack of interest in learning new things, or in new experiences

 • Lack of concern about one’s personal problems

 3. Diminished concomitants of goal-directed behavior

 • Unchanging or flat affect

 • Lack of emotional responsivity to positive or negative events

(C) The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

(D) The symptoms are not due to diminished level of consciousness or the direct physiological effects of a substance.

Adapted from Starkstein and Leentjens [12••]

Neurobiology of apathy

The underlying neurobiology of apathy is not well understood. In 2006, Levy and Dubois [13] proposed three etiologic mechanisms:
  1. 1.

    Disruption of emotional-affective processing due to dysfunction in the orbitomedial prefrontal cortex (e.g., as a sign of frontotemporal dementia)

  2. 2.

    Impairment in cognitive processing: executive dysfunction due to lesions of the dorsolateral prefrontal cortex and related subregions such as the dorsal caudate nucleus

  3. 3.

    Auto-activation deficit: loss of spontaneous actions due to basal ganglia dysfunction.


Measuring apathy

The concept and nosologic status of apathy as a neuropsychiatric syndrome have changed over time, so different studies have used different methods to assess it. Among the measures available are the Apathy Evaluation Scale (AES), the Apathy Inventory, the Lille Apathy Rating Scale (LARS), and the apathy sections of the Neuropsychiatric Inventory (NPI), the UHDRS behavioral interview, and the PBA-HD. The nature of the symptom is such that patients with more severe degrees of apathy are likely to have limited insight, so collecting information from family members and carers as well as from the patients themselves becomes an integral part of assessment. It is also important to consider concomitant disorders when quantifying apathy, to avoid confounding the measurement with overlapping symptoms caused by depression or motor abnormalities.


  • On the basis of the current evidence, no clear recommendations can be made concerning treatment for apathy in HD. Though the concept of apathy has been widely seen as an important determinant of outcome in neuropsychiatric disorders, we do not yet know whether the neurobiology of apathy is different in different disorders. Most of the evidence for treatment of apathy comes from studies of patients with cognitive disorders or brain injury, and head-to-head trials comparing different medications are rare. In addition, apathy is a secondary outcome rather than a primary outcome measure in most studies. This problem needs to be addressed, and more studies are needed that focus on apathy as a primary outcome measure.

  • To date, there have been no randomized controlled trials for the treatment of apathy in HD. No medication is currently approved or licensed to use specifically for apathy in Huntington’s disease. Evidence for treatment of apathy therefore must be extrapolated from interventional studies in other areas of neuropsychiatric practice. In the summary of this evidence presented below, comparisons between studies and between different classes of medication are very difficult because the studies have used different measures of apathy, small sample sizes, and widely varying methods. Consequently, no clear recommendations can be made from the available evidence base.

Pharmacologic treatment

Cholinesterase inhibitors

  • Cholinesterase inhibitors are one of the most commonly researched medications for apathy in degenerative neuropsychiatric disorders. Apathy in HD has not been systematically evaluated as a primary end point in trials using cholinesterase inhibitors; it was a secondary outcome measure in all the studies mentioned below.

  • These medications inhibit the cholinesterase enzymes that degrade acetylcholine in the cortex and hippocampus, thereby increasing the availability of this neurotransmitter. Cholinesterase inhibitors are beneficial in improving cognitive function, but they also improve behavioral symptoms. The mechanism of the specific effect on apathy has not been delineated, but it is thought to be due to enhanced dopamine release in various areas [13].


Donepezil has been found to be significantly beneficial in reducing apathy and other noncognitive symptoms in Alzheimer’s disease. In a double-blind, placebo-controlled, randomized controlled trial in 290 patients with Alzheimer’s disease, apathy was one of the significantly improved neuropsychiatric symptoms [14, Class I]. In a recent pooled analysis of two randomized controlled trials, donepezil (10 mg/day) showed significant reduction in the emergence of apathy in 576 patients with mild to moderate Alzheimer’s disease [15, Class I]. In a sample of 30 patients with HD, donepezil did not produce any improvement in motor or cognitive symptoms, but apathy has not yet been studied [16, Class III].


In a prospective, open-label observational study with 4,460 Alzheimer’s disease patients, apathy significantly improved over a 12-month period of treatment with rivastigmine [17, Class IV]. One study in HD showed improvement in behavioral and cognitive symptoms in three patients [18, Class IV], but apathy was not assessed. A 2-year, open-label follow-up study of 11 patients showed improvement in cognitive and motor symptoms, but again, apathy was not included as an outcome measure [19, Class III].


In an open-label study, galantamine was shown to improve apathy in 229 patients with mild to moderate Alzheimer’s disease, over a period of 6 months [20, Class III]. However, galantamine has not been tested for apathy in HD, apart from a single case study.



This belongs to the class of CNS stimulants and has been studied as a treatment for apathy in a number of neuropsychiatric disorders. The results are not uniformly positive, but there have been positive effects in some studies.

Methylphenidate works by blocking the dopamine transporter, amplifies dopamine response duration, and activates postsynaptic dopamine receptors, thereby increasing the availability of dopamine in the synapse. It also inhibits noradrenergic reuptake, which is thought to be the main action responsible for its effect in attention deficit hyperactivity disorder (ADHD). Because of the effects on dopamine, methylphenidate has been tried for the treatment of apathy in various neuropsychiatric disorders.

In a randomized controlled trial, 13 patients with Alzheimer’s disease who were treated with methylphenidate showed significant improvement in apathy as measured by the AES [21, Class II]. Padala et al. [22•, Class III] reported a recent open-label study of 23 patients with Alzheimer’s disease: significant improvement occurred over a 12-week period with methylphenidate, and no patients dropped out because of adverse effects. In a case series of three patients, methylphenidate improved apathy associated with cerebrovascular accidents in various regions of the brain [23, Class IV]. In a single case report, methylphenidate (10 mg/day) drastically improved apathy in an 82-year-old patient with significant apathy [24, Class IV], whereas in a small case study of five patients studied as randomized blocks, methylphenidate improved apathy in dementia and depression, but the effect was not sustained [25, Class IV]. Methylphenidate also is frequently used to treat apathy in patients with traumatic brain injury, but there is little evidence to support this use.

The use of methylphenidate in HD has not yet been subjected to large-scale studies. In a single case report of methylphenidate use in juvenile HD [26], it exacerbated the motor symptoms and probably uncovered the illness in a family that was unprepared. No further case reports on the use of methylphenidate in HD have been published.


Atomoxetine is a presynaptic inhibitor of noradrenaline reuptake, which is thought to be the basis of its specific effect on ADHD.

Atomoxetine has not been widely tried for apathy. It improved executive dysfunction in Parkinson’s disease during an 8-week, open-label study in 12 patients [27, Class III], but it did not improve apathy or depression in a randomized, placebo-controlled trial in 55 patients with Parkinson’s disease [28, Class II].

In a double-blind, crossover trial in 20 patients with HD, atomoxetine did not improve either motor or psychiatric symptoms or inattention [29, Class III].


Modafinil is a wakefulness-promoting drug used in narcolepsy and sleep-wake cycle disorders. Its mechanism of action is unclear, but it is hypothesized to act on the dopaminergic and noradrenergic systems to promote wakefulness.

Modafinil improved apathy in a single case report of an elderly individual with dementia and depression [30, Class IV]. No further study on apathy has been done. Modafinil did not improve mood or cognition in a double-blind, placebo-controlled study of 20 patients with HD, but whether it had any effect on apathy has not been studied.

Dopaminergic drugs


Levodopa, a dopamine precursor, effectively increases brain dopamine concentrations. As dopamine is implicated in apathy, levodopa has been used in trials of motivation and stimulus-reward learning. In a study in which 23 patients with Parkinson’s disease were compared with 28 healthy controls, levodopa improved the patients’ apathy scores as measured by the Apathy Scale. This effect was seen in both the “on” state and “off” state [31, Class III].


Selegiline is a monoamine oxidase B inhibitor used in the treatment of Parkinson’s disease. In a case series of four patients with apathy following traumatic brain injury, selegiline significantly reduced apathy measured by the AES, and it also improved functional scores [32, Class IV]. Selegiline (at a dose of 15 mg/day) also improved apathy in a 30-year-old man with a severe head injury and a 7-year history of apathy following the injury [33, Class IV].


Amantadine is an antiviral agent that acts by NMDA antagonism and helps to reduce levodopa-induced dyskinesia and chorea. Amantadine improved apathy in a patient with traumatic brain injury in an N-of-1 trial [34, Class III]. In a study of 22 patients with chronic brain injury, 12 weeks of amantadine treatment improved executive functions, which were correlated with increased left prefrontal glucose metabolism [35, Class III].

In HD, 24 patients underwent a randomized, placebo-controlled crossover trial for 2 weeks. They did not show any improvement in chorea or cognitive function [36, Class II]. In another trial involving 24 patients with HD, chorea scores improved with amantadine at a dose of 400 mg per day, but cognitive scores were unchanged; apathy was not measured as an outcome [37, Class III].


Bromocriptine is a semisynthetic ergot derivative, which acts as a dopamine agonist and prolactin suppressant.

In combination with levodopa and benserazide, bromocriptine produced some improvement in apathy in a case series of five patients with postanoxic encephalopathy, but the changes were not significant [38, Class III].

Bromocriptine use improved involuntary movements in 12 patients with HD in a double-blind crossover trial, but no beneficial change in apathy was observed [39, Class III]. Currently, there is no evidence to support the use of bromocriptine for apathy in HD.


This atypical antidepressant acts mainly on dopamine and noradrenaline reuptake inhibition, increasing the availability of these neurotransmitters in the synapse. Bupropion is also widely used for smoking cessation. In addition, it increases dopamine levels in the ventral tegmental area projecting to frontal cortex by blocking noradrenaline transporters in the frontal cortex. This effect has evoked considerable interest, as this pathway has been implicated in reward mechanisms and motivation, which seem to be central to apathy.

A case series reported the beneficial effects of 300 mg per day of bupropion in three patients with apathy who had different neurologic conditions. One had poststroke psychosis and apathy, another had a cerebrovascular accident and hyperprolactinoma, and the third had major depression on a background of medical comorbidities [40, Class IV]. A further case series of bupropion use in HD reported significant improvement of apathy in one patient out of seven reported. Four patients dropped out, three because of increased irritability and one because of lack of efficacy. Apathy significantly improved over a 3-month period in one patient who received 300 mg/day of bupropion [41, Class IV]. A recent case report showed improvement of fatigue in a patient with multiple sclerosis, without improvement in sleepiness or depression over a 3-month period [42, Class IV]. Further large-scale randomized trials are needed to assess the efficacy of bupropion in managing apathy in HD.

Psychosocial management

  • Various forms of nonpharmacologic intervention have been tested in a range of neuropsychiatric populations, mostly patients with dementia or brain injury. The types of interventions include those directed at psychomotor activity (psychomotor therapy), interventions directed at sensory stimulation (multisensory stimulation), and interventions focused on cognitive stimulation (cognitive stimulation therapy, targeting specific aspects of cognitive function such as attention, retrieval of memory, calculation, and learning by reading, in order to improve general cognitive abilities).

Psychomotor therapy

  • A randomized, controlled trial of a psychomotor activation program consisting of sports, games, activities, and relaxation training in a group of 72 older people with cognitive impairment living in a care home did not show any significant improvement in apathy [43, Class II]. Of the 72 members of the experimental group, 27 dropped out, compared with 15 of 62 in the control group.

  • A recent crossover, randomized controlled trial in 146 institutionalized dementia patients showed a trend toward improvement, mainly in patients with moderate apathy. The therapy consisted of music therapy, art therapy, and psychomotor activity, and apathy was measured by the Neuropsychiatric Inventory Questionnaire (NPI-Q) and the Dementia Apathy Interview and Rating (DAIR). The beneficial effect seemed to extend beyond the therapeutic period [44, Class II].

Multisensory behavior therapy

  • A total of 24 participants (12 in each arm) with moderate to severe dementia received multisensory behavior therapy (MSBT) plus occupational therapy or occupational therapy alone. At the end of six sessions, participants in the intervention group had statistically significantly less apathy and agitation as well as improved activities of daily living [45, Class II]. The effect was measured by the Scale for the Assessment of Negative Symptoms in Alzheimer's Disease. The intervention included auditory, visual, and tactile stimulation in a controlled environment, following a schedule of reinforcement. Multisensory stimulation has been studied in disorders such as dementia, learning disability, autism, and chronic pain, but it has not been studied in basal ganglia disorders.

Music therapy

  • In a randomized trial of 30 patients with dementia, the experimental group received 30 music therapy sessions over a 16-week period; the control group received educational support or entertainment activities. At the end of therapy, all neuropsychiatric symptoms were significantly reduced in the intervention arm versus the control arm [46, Class II].

Cognitive stimulation therapy

  • In a randomized controlled trial, 16 patients with dementia were allocated to 10 weeks of cognitive stimulation therapy and were compared with 16 patients in a control group. there was significant improvement in apathy and the depression/dysphoria section of the Neuropsychiatric Inventory. There was no effect on other neuropsychiatric symptoms [47•, Class III]. In this study, the therapy included reality orientation, verbal fluency task, photo-story learning task, overlapping figure task (which focussed on reality orientation, fluency, encoding, and retrieval), and planning functions of cognitive domains. This type of therapy has not been studied in any movement disorders.

Future directions

  • In HD, the severity of apathy increases with disease progression. When developing new projects, a dimensional approach for the diagnosis and measurement of apathy, combined with a longitudinal analysis, would throw more light. Potential targets include dopaminergic levels in the frontal subcortical circuits, which may be increased by agents such as bupropion. Dopamine agonists also have not been evaluated in depth for the treatment of apathy in HD. Other agents that are undergoing randomized trials for disease-modifying treatment may show some effect on apathy.

  • Psychosocial interventions will need to focus on improving not only cognitive functions like memory and learning, but also executive function.

  • Formal psychoeducational interventions aimed at training family members and other caregivers to understand the nature of the underlying cognitive deficits—and to provide external prompts when required—may help to reduce the impact of apathy on the quality of life of affected individuals. Brief interventions using social support groups, scheduling mixed mastery and pleasure activities, and individualized behavior therapy interventions have not been tested.

  • Apathy includes goal-directed behavior, cognition, and emotion, so studies need to address all these areas, which are distressing to the patient and caregivers. A combination of pharmacologic and psychosocial treatment would be ideally placed to give a good effect size in intervention trials.


Conflicts of interest: A. Krishnamoorthy: honoraria for invited lectures from Pfizer, Shire, Novartis, and Eisai; D. Craufurd: payment from Amarin Neuroscience, Neurosearch, and Medivation for participation in clinical trials.

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© Springer Science+Business Media, LLC 2011