Review

Changes in mental state and behaviour in Huntington’s

disease
Clare M Eddy, Ellice G Parkinson, Hugh E Rickards

Changes in mental state and behaviour have been acknowledged in Huntington’s disease since the original Lancet Psychiatry 2016;
monograph in 1872 provided evidence of disinhibition and impaired social cognition. Behavioural problems can 3: 1079–86
manifest before obvious motor symptoms and are frequently the most disabling part of the illness. Although Published Online
September 20, 2016
pharmacological treatments are used routinely for psychiatric difficulties in Huntington’s disease, the scientific
http://dx.doi.org/10.1016/
evidence base for their use is somewhat sparse. Moreover, effective treatments for apathy and cognitive decline do S2215-0366(16)30144-4
not currently exist. Understanding the social cognitive impairments associated with Huntington’s disease can assist BSMHFT National Centre for
management, but related therapeutic interventions are needed. Future research should aim to design rating scales Mental Health, Birmingham,
for behaviour and mental state in Huntington’s disease that can detect change in clinical trials. Generally, UK (C M Eddy PhD,
communication and understanding of behaviour and mental state in Huntington’s would be enhanced by a clear E G Parkinson MSc,
Prof H E Rickards MD); and
conceptual framework that unifies ideas around movement, cognition, emotion, behaviour, and mental state, Institute of Clinical Sciences,
reflecting both the experience of the patient and their underlying neuropathology. College of Medical and Dental
Sciences, University of
Birmingham, Birmingham, UK
Introduction started in human beings, while a variety of new
(C M Eddy, Prof H E Rickards)
In George Huntington’s original 1872 paper,1 hereditary compounds have become available for testing in clinical
Correspondence to:
chorea is mentioned almost in passing at the end of the trials. The availability of second-generation antipsychotics Mrs Ellice G Parkinson, Research
article as “merely as a medical curiosity”, highlighting its has also contributed substantially to management. and Innovation, BSMHFT
rarity. Huntington noted a tendency towards insanity and Although mental and behavioural symptoms have National Centre for Mental
suicide in patients with chorea, who were mainly to be always been described in Huntington’s disease, they have Health, Edgbaston, Birmingham
B15 2FG, UK
found in a cluster in the Long Island area of New York, usually taken second place in the overall narrative of the ellice.parkinson@bsmhft.nhs.
USA. Additionally, he noted the hereditary nature of the condition, behind motor symptoms. A number of reasons uk
condition and its clear manifestation in midlife. His brief might explain this focus: motor symptoms tend to be
clinical descriptions imply disinhibition and impaired more specific, measurable, and are perhaps less likely to
social cognition: “I know of two married men, whose lead to stigma than mental symptoms. Motor symptoms
wives are living, and who are constantly making love to are also more likely to worsen gradually as brain pathology
some young lady, not seeming to be aware that there is worsens. By contrast, mental and behavioural changes
any impropriety in it…They are men of about 50 years of are unspecific in two distinct ways. First, changes occur
age, but never let the opportunity to flirt with a girl go initially on a spectrum within the variation of normal
past unimproved.” Other than this statement, description human behaviour. For instance, irritability, low mood,
of the illness beyond that of chorea, the insidious onset poor social awareness, and apathy are all common human
and gradual progression, and the familiality of the experiences in the absence of any pathological condition.
condition is scarce. Even in their pathological forms, these symptoms are
Patients with Huntington’s disease were often cared non-specific because they occur in a range of diseases.
for in asylums for most of the 20th century, because of Second, many of the mental and behavioural changes do
their symptoms of irritability, aggression, apathy, and not track the disease process well; they do not tend to
occasionally psychosis. Diagnosis was not always worsen as the disease worsens (one of the few exceptions
accurate, and these patients were often noted to have could be apathy).6 Nonetheless, in terms of their
had a grandparent who resided in an asylum with a importance to the patient and the family, mental and
diagnosis of schizophrenia.2 In the late 20th century, behavioural changes are commonly cited as the most
with the closure of mental hospitals in many countries, concerning for carers, and they reduce the quality of life
people with Huntington’s disease have found themselves substantially.6 Behavioural changes could affect multiple
without adequate care, leading to some countries areas of functioning, from aspects of family life such as
building new private asylums on a somewhat smaller parenting,7 to sustaining education or employment.8
scale than that of the Victorians. Some symptoms, especially those relating to poor social
Important landmarks in the history of Huntington’s cognition and apathy, might not be directly bothersome to
disease were the initial discovery of the gene location the patient but are devastating to close relatives. Indeed,
in 1983,3 and the characterisation of the gene in 1993.4 discrepancies in ratings of frontal behaviours between
The past decade has seen a notable increase in research carriers of the mutated gene and their spouses are
into Huntington’s disease, such that much more is now apparent 10 years before conventional motor onset.9
known about the epidemiology, clinical course, and Clinicians started to measure and classify abnormal
overall biology of the disease. Genetic modifiers have mental status with the advent of the United Huntington
been located,5 and the first gene suppression trials have Disease Rating Scale (UHDRS) in 1996, developed by the

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 Review

Most commonly prescribed Alternatives Estimated level of

pharmacological agents evidence (for efficacy)
Anxiety SSRIs, mirtazapine, pregabalin, venlafaxine Olanzapine, benzodiazepines, propranolol, buspirone 4 or 5
Depression or suicidality SSRIs, mirtazapine, venlafaxine Electroconvulsive therapy, tricyclic antidepressants 4 or 5
Perseveration SSRIs—eg, clomipramine To be investigated 4
Irritability SSRIs, atypical neuroleptics (olanzapine, Anticonvulsants (lamotrigine, carbamazepine, valproic 4 or 5
risperidone, sulpiride, tiapride) acid), clomipramine, tricyclic antidepressants, buspirone,
propranolol
Apathy No current trend Ongoing trial of buproprion 5
Psychosis Olanzapine, risperidone, haloperidol, sulpiride, Clozapine, quetiapine 4 or 5
tiapride, injectable antipsychotic medication

For the Oxford Centre for Based on the Oxford Centre for Evidence-Based Medicine levels of evidence for clinical studies. Most of the available evidence is around level 4 (lower quality cohort, case series or
Evidence-based Medicine levels case-control studies); or 5 (expert opinion without explicit scientific appraisal, or based on physiology, bench research, or first principles). Randomised, controlled trials (level 1),
of evidence see http://www. ecological studies, outcomes research, systematic reviews of cohort studies, or high-quality case-control studies (levels 2 and 3) are scarce.
http://www.cebm.net/oxford-
centre-evidence-based- Table 1: Available treatments for mental state and behavioural changes in Huntington’s disease
medicine-levels-evidence-
march-2009
US Huntington Study Group.10 This scale contains items
on all of the major changes seen in Huntington’s disease,
apart from those relating to social cognition. More
recently, since 2001, behavioural assessment is commonly
conducted in clinical trials using the Problem Behaviours
Assessment (PBA).11 The PBA has excellent inter-rater
reliability, clearer descriptors, and an important
distinction between obsessive-compulsive symptoms,
which are rare, and perseverative behaviours, which are
common. However, the reliability of the PBA is
dependent on administration by well trained and
experienced raters. The PBA and UHDRS measure the
breadth of pathology, although their ability to measure
change within clinical trials is unclear because neither
scale measures an underlying construct.12 Cognitive
function was initially rated within the UHDRS using the
Verbal Fluency Test (FAS type),13 the Symbol Digit
Modalities Test,14 and the Stroop interference test15
(Huntington Study Group, 199611). More recently, in 2014,
the more thoroughly validated Cognitive Assessment
Battery for Huntington’s disease was published, which
combines feasibility, reliability, and sensitivity to change
in Huntington’s disease.16
This narrative review aims to summarise literature
pertaining to the major psychiatric and behavioural
symptoms of Huntington’s disease, including anxiety,
depression, suicidality, irritability, apathy, perseveration,
disinhibition, and deficits in social cognition. Impairment
in social cognition is included because this aspect has
strong interpersonal impact (eg, poor understanding of
other people’s mental states), and difficulties with
emotional reasoning might underlie or interact with
multiple aspects of behaviour and function in
Huntington’s disease.
Changes in mental state and behaviour in
Huntington’s disease
The most commonly prescribed medications for changes
in mental state and behaviour in Huntington’s disease,
and levels of evidence, are summarised in table 1.
Anxiety
Anxiety disorders have a lifetime prevalence estimated to
be between 16·7% and 24% in patients with Huntington’s
disease,17,18 compared with 16·6% in the general
population worldwide.19 Generalised anxiety disorder and
panic disorder are the most prevalent types of anxiety
experienced in patients with Huntington’s disease, with
estimated lifetime prevalences of 11% for generalised
anxiety and 8% for panic disorder,17 compared with 6·2%
and 1·2%, respectively, in the general population.19
Notably, the prevalence of anxiety symptoms is the same
for men and women who have Huntington’s disease,
unlike in the general population, in which it is more
common in women.20 Anxiety in Huntington’s disease
has been found to peak around the time of predictive
testing, but then decreases over the following 5 years.21 At
stage 2 of the disease, when mild-to-moderate symptoms
become apparent, anxiety increases again, before
gradually decreasing as the disease progresses.22
Stage 2 of Huntington’s disease is when activities of daily
living (eg, managing finances and employment demands)
become more difficult, and the individual starts to
require more assistance from others.23
Higher levels of anxiety are associated with more
symptoms, more pain, and lower belief in control over
treatment of symptoms.24 No randomised controlled
trials of anxiety treatment have been done in patients
with Huntington’s disease. However, 5 mg olanzapine
per day substantially improved anxiety symptoms in
five people with Huntington’s disease in a 6-month
open-label pilot study.25 A European case registry study
found that clonazepam and lorazepam were most
frequently prescribed for anxiety symptoms in patients
with Huntington’s disease.26 Anxiety symptoms have
been reported to be significantly reduced from baseline
to post-intervention, with a mean difference of 2·75 on
the Hospital Anxiety and Depression Scale (HADS),27 as
a result of an intensive multidisciplinary team
programme in early-stage and mid-stage Huntington’s
disease.28 A patient education programme trialled for

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4 weeks with 59 people carrying the mutated Huntington’s
disease gene showed reduced anxiety in those with
manifest (but not premanifest) disease when compared
with their baseline anxiety scores.29
Depression
Major depression has been reported to have a lifetime
prevalence of 20–56% in people with Huntington’s
disease.17,30 These symptoms often precede clinical onset
and peak during the early stages of the disease.17 For
example, one report found that major depression is most
prevalent in the 10 years before clinical onset, and
reduces by two-thirds in the following 5 years.17 As the
disease progresses into the later stages, depressive
symptoms occur less frequently.22,31
Depression in Huntington’s disease presents
differently from depression in the general population.
Unlike in the general population, in which depression is
more prevalent in females than in males, no gender
difference has been noted in Huntington’s disease.20
Furthermore, the age of onset of depressive symptoms
has been reported to be 14 years later in people with
Huntington’s disease than in a control group of people
with major depressive disorder.30 Depressive symptoms
peak at stage 2 then decrease through the later stages of
the illness.32 Depressive episodes tend to be more
short-lived and frequent in carriers of the mutated
Huntington’s gene than in the general population, and
thus might not meet diagnostic criteria for major
depressive disorder.30 One difficulty with diagnosing
depression is that changes in vegetative function, such as
weight loss, inactivity, and apathy, might be considered
intrinsic to Huntington’s disease.
Treatment is typically required because depression is
linked to poorer quality of life in people carrying the
mutated Huntingtin gene,33 and increases the risk of
suicide in these patients.34 However, no randomised
controlled trials have been done, and no expert consensus
algorithms have been devised for treating depression
in patients with Huntington’s disease. A study analysing
prescription patterns from the European REGISTRY
study found that European clinicians most frequently
prescribe citalopram and paroxetine for depression
in these patients.35 Mirtazapine was also identified as one
of the most frequently prescribed medications for treating
depression in Huntington’s disease in the European case
registry study.26 One uncontrolled, open-label study found
that after administering venlafaxine for 4 weeks to
26 patients with Huntington’s disease, depressive
symptoms were substantially reduced compared with
those at baseline.36 However, one in five patients in
this study sample developed side-effects, such as
irritability and nausea.36 Electroconvulsive therapy was
well tolerated and improved symptoms in nine cases of
severe depression in Huntington’s disease.37,38 Finally, a
prospective, open-label, non-randomised study featuring
an intensive multidisciplinary team programme reported
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Review
improvements in depressive symptoms in Huntington’s
disease, with a mean reduction of 2·75 points on the
HADS after a 12-month intervention.27,28 Evidence of
alterations in the serotonergic brainstem raphe nuclei in
individuals with Huntington’s disease and depression
supports the use of SSRIs in these patients.39
Suicidality
George Huntington recognised suicidality as a
psychiatric manifestation of Huntington’s disease in his
original paper.1 5–10% of deaths in Huntington’s disease
are attributed to suicide,22,40,41 with a meta-analysis42
reporting a standardised mortality ratio of 290%. One
study found that the frequency of suicidal ideation
increased from 9·1% in people at risk of Huntington’s
disease with no neurological signs to 19·8% in those at
risk with soft neurological signs, and to 23·5% in people
with motor signs that were indicative of possible
Huntington’s disease.43 The same study found that for
individuals already diagnosed with Huntington’s
disease, prevalences of suicidal ideation were 16·7% at
stage 1 after receiving a formal diagnosis, 21·6% at
stage 2, then diminishing with further disease
progression (9·8% at stage 5).43 Depression at a later
stage might reflect loss of independence, but could
involve factors additional to psychological stressors. In
summary, two critical periods have been proposed for
increased risk of suicidality: immediately before
receiving a formal diagnosis, and during stage 2.
Although the proportion of patients having suicidal
thoughts reduces after stage 2, the severity of suicidal
thoughts seems to increase with disease progression.22
Thoughts of suicide might serve a comforting purpose
in Huntington’s disease, rather than a distressing one,
because it can help individuals to maintain a sense of
control over the illness.44
Suicidal ideation is predicted by the presence of
depressed mood, previous suicide attempt, aggression,
anxiety, and shorter disease duration, with depression
being the most reliable predictor.40 Other related factors
include anxiety, aggression, irritability, and substance
abuse, which predict increased severity of suicidal
ideation in Huntington’s disease.45 Although suicidal
ideation is routinely assessed by clinicians during the
predictive genetic testing process, it can be easily
overlooked during the typical neurological assessment.22
Because of the prevalence of suicidal ideation in
Huntington’s disease, it should be considered routinely
in this population.40,41 Notably, caregiver quality of life is
negatively associated with the frequency of a patient’s
suicidal thoughts.32
Perseveration
Perseveration is defined as the tendency to continue
behaviour, even when it ceases to be effective or rewarding.46
Perseveration in Huntington’s disease differs from the
repetitive compulsive behaviours of obsessive compulsive
1081
 Review
disorder—ie, individuals carrying the mutated Huntingtin
gene might not always show insight into the repetitive
thoughts and behaviours they have (probably due to
cognitive inflexibility)—and thus they do not try to control
these thoughts and behaviours.44 By contrast, repetitive
behaviours in obsessive compulsive disorder are frequently
distressing, despite appearing more goal directed. Few
studies have trialled treatments for perseverative behaviour
in Huntington’s disease, although one study reported a
beneficial effect of 10 mg buspirone twice daily in two
patients with perseveration and aggression.47 International
consensus supports the use of SSRIs (including
clomipramine) as first choice of treatment.48
Disinhibition
Disinhibition has been infrequently studied in
Huntington’s disease, although it can manifest as
impulsivity and emotional lability.49 Disinhibited
behaviours can include speaking out of turn, inappropriate
sexual remarks, other embarrassing remarks, and childish
behaviour,50 but hypersexual behaviour or exhibitionism
can be particularly problematic.51 One study reported
disinhibition in 34·6% of patients with Huntington’s
disease, and this factor was significantly associated with
the presence of delusions, irritability, and agitation.52 This
raises the probable overlap between disinhibited behaviour
and the other more specific psychiatric and behavioural
problems frequently described in Huntington’s disease,
which could extend to perseveration or socially
inappropriate behaviours. Notably, disinhibition has been
reported to be negatively correlated with age.52 The
PREDICT-HD study9 found that individuals with the
mutated gene showed substantially more disinhibited
behaviours than gene-negative individuals 10 years before
diagnosis of Huntington’s disease. The Frontal Systems
Behaviour scale53 includes a measure of disinhibition,
which can be used in Huntington’s disease.54 Treatment
options include behavioural therapy and SSRIs, or other
pharmacological options used for behavioural problems
in frontotemporal dementia could be considered.55
Irritability
Irritability has a point prevalence of 38–73% among
people who carry the Huntington’s disease mutation.52,54,56
The presence of irritability is not linearly linked to
disease progression,17,57 increasing from stage 1 of the
disease through to stage 3, before plateauing.31 Stage 3 is
generally when employment terminates and tasks such
as managing finances and doing household chores are
no longer manageable.23 The course and presence of
irritability in Huntington’s disease has been suggested
to be familial.29 One factor analysis found that irritability
in this population is related to impulsivity and
aggression.11 These results are in accordance with the
finding that carriers of the mutated Huntingtin gene
who have underlying anxiety are predisposed to
developing irritability.57
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Quality of life in people with Huntington’s disease is
negatively associated with irritability.33 Irritability can be
managed initially by reducing cognitive load, creating
distraction, and by carers responding calmly to this
symptom.48 In terms of pharmacological treatment,
expert consensus supports the use of SSRIs, such as
citalopram, sertraline, and paroxetine, when irritability is
accompanied by depression, anxiety, or perseverative
behaviours.48 Antipsychotic medication is favoured when
irritability is accompanied by aggression, hypersexuality,
or impulsivity.49 Citalopram, paroxetine, and sulpiride
were most frequently prescribed for treating irritability
according to a European case registry study.26
Apathy
Apathy can be defined as diminished motivation not
attributable to a decreased level of consciousness,
cognitive impairment, or emotional distress,58 and is a
separate condition to depression,59 despite some apathy
symptoms being difficult to distinguish from depressive
symptoms. In Huntington’s disease, apathy has a point
prevalence of 34–76%.11,56 One longitudinal study31 found
that almost all their sample population of individuals
with the Huntingtin mutation displayed some apathy
symptoms throughout the study period, and importantly,
apathy is the only psychiatric symptom of Huntington’s
disease that correlates with disease progression. Gene
mutation carriers with apathetic symptoms are more
likely to be men, have poor global functioning, and a
higher use of neuroleptics and benzodiazepines than
those without apathetic symptoms.60 Further research is
therefore needed to establish whether these drugs could
worsen apathy symptoms.
Patients with Huntington’s disease report a worse
quality of life when apathy is more frequent and severe.33
Despite the impact of apathy, no randomised controlled
trials into the specific treatment of apathy in these patients
have been published and no drugs have been licensed
specifically to treat apathy. Methylphenidate, atomoxetine,
modafinil, amantadine, and bromocriptine have all been
documented in the literature as being trialled for the
treatment of apathy in Huntington’s disease, with little
success.61–64 However, one case series found that bupropion
substantially improved apathetic symptoms for one out of
their seven patients, over 3 months of receiving 300 mg
per day.65
Psychosis
Psychosis is one of the least prevalent psychiatric
manifestations of Huntington’s disease, with a lifetime
prevalence of 10·4% in this population,66 compared with
3·48–11·6% in the general population.67,68 Point prevalences
of 10·0–11·5% for delusions and 1·9–3·0% for
hallucinations have been reported in patients with
Huntington’s disease.31,52 In a large-scale European cohort
study,32 psychosis was most prevalent in stage 3 of the
disease. Some neuropsychiatric symptoms have been
www.thelancet.com/psychiatry Vol 3 November 2016
 Review

previously underestimated in Huntington’s disease reported associations between theory-of-mind task

research,31 and patients with psychosis could have been performance and deficits in executive functions85,87 or
under-represented in some samples, which underline the spatial perspective taking.85 However, carriers of the
need for longitudinal prospective studies, such as Huntington’s disease gene mutation have been shown to
Enroll-HD (IRAS ID 129743). answer unconventionally to theory of mind tasks despite
Although randomised controlled trials for psychotic performing very well on concurrent assessments of
symptoms in the Huntington’s disease population are executive function.88,89 Emotional reactivity might also be
scarce, risperidone has been reported to be effective in altered in Huntington’s disease90 such that these patients
four separate case reports when administered at doses of could show changes in the recognition or experience of
0·5 mg twice daily, 1 mg twice daily, 2 mg twice daily, and fear and anger.91
4 mg once daily.69–72 Aripiprazole administered at 10 mg Alexithymia refers to difficulties in reflecting on,
daily, and then increased to 20 mg daily, substantially consciously interpreting, and describing one’s own
improved psychotic symptoms for a patient who had emotional experience.92 Such impairments could be
been admitted to an acute psychiatric ward with associated with a range of changes in social cognition,
persecutory delusions, displaying violent behaviour.73 including poor empathy and recognition of emotions in
Olanzapine and risperidone were most frequently others. One recent study88 reported substantial levels of
prescribed to treat psychosis in a European case registry alexithymia in patients carrying the mutated Huntingtin
study.26 Other antipsychotic medications, such as gene with or without signs of manifest Huntington’s
haloperidol and tiapride, are frequently prescribed in disease who were impaired on some measures of theory
Europe to treat psychosis, when chorea is also of mind. The increased likelihood of alexithymia in
problematic to the patient.74 A lower prevalence of Huntington’s disease could reflect decreased attention to
psychosis than of other symptoms in Huntington’s or salience of emotional reactions, difficulty linking
disease might be due to the use of antidopaminergic internal emotional states to meaning, or be associated
medications for motor symptoms in this population. with more general problems with language and
Although these agents might have additional benefits in communication: further work is needed to establish
relation to weight or sleep, they might have a small risk which features are operative here.
of side-effects such as tardive dyskinesia.75 Some studies have emphasised a link between
alexithymia and interoception.93 Indeed, both intero-
Social cognition and behavioural problems in ception and emotional awareness have been associated
Huntington’s disease with the anterior insula,94 which can be affected in
Early studies investigating the social abilities of people premanifest Huntington’s disease.95 Alexithymia could be
with Huntington’s disease found that these patients had related to the suggested loss of insight in these patients
substantial difficulty recognising emotional expressions in (eg, patients report that they are functioning well, but this
people’s faces.76,77 They also reported that the understanding
of body language,78 and emotional vocal tone,79 can be Difficulties in Huntington’s disease Behavioural problems that could be
affected, and the recognition of disgust77 or anger80 might linked to these difficulties
be disproportionately affected. Subsequent studies have Understanding of Some patients miss simple cues that Reduced attention to relevant social
argued for more generalised impairment in the recognition intentionality from subtle indicate social interaction stimuli; poor appreciation of subtle
non-verbal cues (eg, biological motion) and prompt social communications; odd or
of emotional expressions81 extending to fearful, angry, and theory of mind in healthy controls inappropriate social behaviour
surprised facial expressions.82 Emotional recognition can Emotion recognition from Impaired recognition of expressions Poor behavioural flexibility in social
also be affected in premanifest Huntington’s disease.83 human faces, tone of voice, and non-verbal communications, situations; antisocial or aggressive acts
Several studies have since shown that patients’ and body postures which might signal poor emotion linked to misunderstanding of
difficulties extend beyond the interpretation of emotional contagion, or mirror neuron communication
dysfunction
expressions by others, into the realms of more abstract
Affective and cognitive Difficulty understanding other’s Paranoia due to poor understanding of
forms of perspective taking and theory of mind—ie, the theory of mind beliefs and emotions, poor others’ motives and intentions;
ability to reason about mental states such as beliefs and reasoning about socially consequential emotional upset,
emotions. For example, patients with Huntington’s inappropriate behaviour arguments, and aggression; lack of
empathy; offensive or disinhibited
disease might have difficulties recognising complex behaviours
mental states, reasoning about socially inappropriate Spontaneous everyday Patients report a reduced tendency Egocentric perspective, behavioural
behaviours,84,85 and inferring intentions.86–88 Some of these perspective taking to consider other people’s points of inflexibility; socially inappropriate
studies have associated theory-of-mind impairment with view behaviour and lack of insight
motor symptoms,85,88 and functional capacity.85 Therefore, Interpretation, experience, Alexithymia, reduced emotional Seemingly unprovoked anxiety, anger,
social cognition could deteriorate as Huntington’s and expression of emotion reactivity, or unusual emotional and emotional dysregulation; blunted
responses to stimuli (eg, anger emotional reactivity could present as
disease progresses, although there are no longitudinal reaction rather than fear) apathy; greater vulnerability to
studies in this area. risk-taking behaviours
Problems with social reasoning could reflect underlying
Table 2: Social cognitive skills and how alterations in these might affect behaviour in Huntington’s disease
cognitive or emotional changes. A few studies have

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 Review
Panel: Future research directions
• Longitudinal study of behavioural and mental state
changes in Huntington’s disease
• Assessment of appropriate psychiatric rating scales to
measure meaningful change in clinical trials
• Identification of the neural correlates of social cognitive
deficits in Huntington’s disease
• Genome-wide association studies in relation to the
psychiatric phenotype
• Development of effective interventions for apathy and
impairments in social cognition
• Study of the interactions between more general cognitive
deficits and the psychiatric phenotype
Search strategy and selection criteria
We searched the following databases: PubMed, Allied and
Complementary Medicine Database, British Nursing Index,
CINAHL, Embase, Health Business Elite, Health Management
Information Consortium, PsycINFO, and Web of Science
between October, 2015, and February, 2016. The search terms
used were “huntington*” and any of the following terms:
“theory of mind”, “emotion”, “social cognition”, “quality of
life”, “treatment”, “anxiety”, “depress*”, “psychosis”, “apathy”,
“suicid*”, “disease progress*”, “disinhibit*”, “irritab*”,
“perseverat*”, “neuropsychiatric symptoms”, “behaviour”,
“mental disorders”. There were no publication date
restrictions, but only publications in English were selected.
Selection was based on manual appraisal and not specific
exclusion criteria. We reviewed the reference lists of papers to
find additional relevant studies.
is strongly disputed by close family members). A few
studies have highlighted this problem with self-awareness
in manifest Huntington’s disease, showing that patients
might overestimate their own competence in areas such
as emotional and behavioural control.96 Alexithymia might
reflect a specific problem with the patient’s insight into
their own emotional and mental states, which should be
remembered when doing psychiatric assessments on
these patients. Psychiatric and behavioural features that
could be more likely to be associated with impairment in
social cognition are proposed in table 2.
Summary and conclusions
Mental and behavioural changes are frequent
throughout the course of Huntington’s disease and can
predate the onset of specific motor symptoms. These
changes are commonly more disabling to patients
than are motor symptoms. Although most mental and
behavioural changes do not alter in a linear fashion with
disease progression, apathy might be an exception.
Overall, good quality clinical trials showing the
effectiveness of any intervention for mental and
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behavioural problems in Huntington’s disease are
scarce. Anecdotal evidence suggests that depression,
anxiety, and irritability are readily treatable, whereas
apathy and social cognitive problems are not. Future
trials are needed to test these hypotheses objectively.
Indeed, symptoms such as apathy and disinhibited
behaviour raise treatment challenges in many
neuropsychiatric disorders, and are a point of concern
for the health-care system in general. Other important
directions for future research are shown in the panel.
Assessment of psychiatric problems in Huntington’s
disease can be complex. Importantly, the nature of these
behavioural changes might not fit well with existing
diagnostic schemata such as DSM-5. Some changes,
including deficits in social cognition or apathy, might not
be noticed by patients but are severely distressing for
carers. Patient insight could pose a barrier to diagnosis in
general, however health-care workers should not
underestimate the impact that a carer’s own psychiatric
and emotional state might have on their report about the
patient’s functioning.
The impact of social cognition on the psychiatric profile
of Huntington’s disease is gaining recognition. Manifest
Huntington’s disease is more clearly associated with
deficits in emotion recognition and theory of mind,
although premanifest gene mutation carriers might
show impairments on more sensitive measures.
Alexithymia is an important influential factor and might
be quite common across the Huntington’s disease
population, in association with lack of insight and poor
social relations. Further work is needed to establish how
social cognition is related to disease burden, and the
relationship between laboratory-assessed deficits and
everyday problem behaviours. Additionally, no existing
rating scales have been validated to measure social
cognition in Huntington’s disease.
We need to refine our ability to measure changes in
mental state and behaviour in Huntington’s disease
clinical trials and to focus attention on those symptoms
that are the most impairing for the majority of patients
and their families. Social cognitive deficits have been
largely neglected until recently, despite being particularly
widespread, and having the potential to underlie a range
of problem behaviours in Huntington’s disease. Finally,
clinicians and researchers should develop their language
to integrate the mental, behavioural, cognitive, emotional,
social, and motor facets of Huntington’s disease. A clear
conceptual framework uniting these aspects will improve
communication and understanding, and reflect the
phenomenological reality of patient life and the objective
impact of Huntington’s disease on both the brain and
behaviour.
Contributors
All authors contributed to literature search, data collection, and writing
and editing of the manuscript.
Declaration of interests
We declare no competing interests.
www.thelancet.com/psychiatry Vol 3 November 2016

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