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Aggression in Huntington's Disease: A Systematic Review of Rates of Aggression and Treatment Methods

Authors:
  • The Royal Melbourne Hospital & The Melbourne Clinic

Abstract and Figures

Aggression is commonly reported in individuals with Huntington's disease (HD). While correlating factors for aggression are often speculated about, features that are associated with, and contribute to, aggression in this population have not been clearly determined. This systematic review investigates rates of aggression and treatment options for aggression in HD. A number of key findings were revealed. Studies reporting on rates of aggression revealed that its prevalence is high, falling between 22 and 66 percent in the majority of studies. Aggression may be more common in males with HD, and is also found in higher rates in individuals who experience frequent falls, have obsessive-compulsive symptoms and suicidal ideation. There is little research investigating antecedents for aggression in HD. A wide variety of psychotropic medications have been reported in the literature to treat individuals with HD and aggressive behaviour. However, due to methodological limitations, no treatment recommendations can be made, based on the current literature. Two non-medication therapies have been investigated, behaviour support and sensory modulation intervention. However, again, due to methodological limitations with these studies, further research is needed before they can be recommended as frontline interventions. This review highlights the need for further methodologically rigorous studies investigating the treatment of aggression in HD.
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Journal of Huntington’s Disease 3 (2014) 319–332
DOI 10.3233/JHD-140127
IOS Press
319
Review
Aggression in Huntington’s Disease:
A Systematic Review of Rates of Aggression
and Treatment Methods
Caroline A. Fishera,b,, Katherine Sewellb, Anahita Brownband Andrew Churchyardc,d
aChild and Youth Mental Health Service, Adolescent Inpatient Psychiatric Unit, Box Hill Hospital, Eastern Health,
Melbourne, Australia
bBrain Disorders Program, Royal Talbot Rehabilitation Centre, Austin Health, Melbourne, Australia
cHuntington’s Disease Service, Calvary Health Care Bethlehem, Melbourne, Australia
dSchool of Psychological Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University,
Melbourne, Australia
Abstract. Aggression is commonly reported in individuals with Huntington’s disease (HD). While correlating factors for
aggression are often speculated about, features that are associated with, and contribute to, aggression in this population have
not been clearly determined. This systematic review investigates rates of aggression and treatment options for aggression in
HD. A number of key findings were revealed. Studies reporting on rates of aggression revealed that its prevalence is high,
falling between 22 and 66 percent in the majority of studies. Aggression may be more common in males with HD, and is also
found in higher rates in individuals who experience frequent falls, have obsessive-compulsive symptoms and suicidal ideation.
There is little research investigating antecedents for aggression in HD. A wide variety of psychotropic medications have been
reported in the literature to treat individuals with HD and aggressive behaviour. However, due to methodological limitations, no
treatment recommendations can be made, based on the current literature. Two non-medication therapies have been investigated,
behaviour support and sensory modulation intervention. However, again, due to methodological limitations with these studies,
further research is needed before they can be recommended as frontline interventions. This review highlights the need for further
methodologically rigorous studies investigating the treatment of aggression in HD.
Keywords: Aggression, Huntington’s disease, prevalence, treatment, therapy
INTRODUCTION
Huntington’s disease (HD) is a neurodegenerative
genetic disorder with autosomal dominant inheritance
[1, 2] that is characterised clinically by motor abnor-
malities (chorea, falls) [3], cognitive impairment [4, 5]
Correspondence to: Dr. Caroline Fisher, Child and Youth Men-
tal Health Service, Adolescent Inpatient Psychiatric Unit, Box Hill
Hospital, Eastern Health, 5 Arnold Street, Box Hill, Victoria 3128,
Australia. Tel.: +61 3 9092 6725; Fax: +61 3 9348 2766; E-mail:
Caroline.Fisher@easternhealth.org.au.
and psychiatric disturbance [6]. High rates of aggres-
sion have also been reported. Aggression is one of the
primary causes of hospitalisation in this population [7],
is associated with higher rates of nursing home place-
ment [8] and places family members, carers and other
clients at risk of assault. While a number of previous
texts have speculated on factors that may contribute to
aggressive behaviour in HD [9–11] correlating clini-
cal symptoms and antecedents for aggression remain
unclear. There are also presently no recommended
clinical guidelines on how to manage aggression
effectively in Huntington’s disease.
ISSN 1879-6397/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved
This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License.
320 C.A. Fisher et al. / Aggression in Huntington’s Disease
This paper has two aims. The first is to review the
published evidence on rates of aggression in Hunting-
ton’s disease and identify correlating factors as well as
behavioural, situational or environmental antecedents
for this behaviour. The second is to review the pub-
lished evidence on treatment strategies for aggression
in HD, including both pharmacological and non-
pharmacological interventions. It is anticipated that
these investigations will provide a clearer understand-
ing of aggression in Huntington’s disease and help to
inform future research into this distressing behavioural
sequelae.
Identification and classification of studies
Aggression is an externalised behaviour that can be
directly observed and measured via observation from
carers, family members and hospital staff. In their
seminal text Bushmann and Anderson define aggres-
sion as a noxious stimuli that is delivered with the
intent to harm, threaten or reject the recipient [12].
For the purposes of this paper, aggression is defined
as: any behaviour that attempts to inflict uninvited
force, harm or damage to a person or inanimate object,
or verbal behaviour that is delivered in a intimidat-
ing manner (swearing, yelling, shouting, insults or
threats). Irritability has also been investigated in a
number of studies of HD sufferers [e.g. 13, 14] and
is sometimes grouped together in symptoms clusters
with aggression [15]. Irritability, however, is gener-
ally conceptualised as an internalised mood state [16]
that requires client participation to rate [17, 18], and
is not necessarily possible to monitor via observations.
As such, it is difficult to accurately gauge irritability
across all stages of HD as persons with advanced HD
may not be able to provide ratings of their internal
mood state and irritability levels, due to cognitive and
communication impairments. Due to the heterogeneity
between these clinical variables the review has focused
specifically on aggression as an overt, observable
behaviour.
To identify original studies reporting on aggres-
sion in Huntington’s disease a database search of
PubMed, Medline and PsycInfo to September 20th
2014 was performed. The search term “Huntington’s”
was combined with the terms “aggression”, “assault”
and “violence”. This revealed a total of 52 studies,
after duplicates were removed. A further 13 studies
were identified following reference section searches of
the papers initially obtained, as well as a three further
studies known to the authors. These 68 papers were
then examined and studies were included if they meet
at least one of the two inclusion criteria: I) original
research studies examining rates of aggression, cor-
relates with aggression or antecedents for aggression
in individuals with Huntington’s disease, II) original
research studies outlining treatment approaches for
aggression in Huntington’s disease. Fourteen papers
meet inclusion criteria I. Nineteen studies meet inclu-
sion criteria II. Studies were excluded if they: involved
animal rather than human subjects, if the HD par-
ticipants were included in a group study with other
disorders and the HD data could not be separated out, if
the data on aggression could not be separated out from
other sequelae (e.g. irritability), if they were review
papers not containing original research, if they did not
contain any subjects with Huntington’s disease, and if
they were not investigating aggression or the treatment
of aggression.
Rates of aggression in HD
Characteristics of studies
Of the studies that meet inclusion criteria I, fourteen
papers from thirteen individual studies are summarised
in Table 1 [7, 19–31]. The results of one study were
spread across two papers, and thus were combined so
that the reporting was not duplicated [7, 21]. A fur-
ther study [32], which reported on aggression only
as a correlate of suicidal ideation, rather than as an
individual variable of interest, was not included in the
table, but is reported in the Associations/Correlations
with Aggression section, below. For eleven of the
studies the sample sizes ranged between 27 and 250
participants. Of these studies the most common type
were case records reviews, followed by comparison
studies with another group, (i.e. Alzheimer’s disease
[23] or a control group [26]), monitoring studies [25,
28], a behaviour scale development study [27] and a
longitudinal symptoms monitoring study [30]. There
were also a further two studies of data reviews from
Huntington’s registries containing very large samples
[29, 31].
Gender ratios varied across the studies. Five studies
[22, 24–26, 30] contained a high percentage of female
participants (60.4 % or higher), while the remaining
studies had ratios ranging between 60:40 (in either
direction) and even 50:50 distribution. The average age
of the participants for the studies in which this figure
was reported (or was calculable via a mean weighted
average), ranged between 45.6 years and 57.2 years.
Four studies contained at least one participant with
juvenile onset Huntington’s (JHD) [19, 20, 23, 27]
and in one study JHD participants were excluded [26].
C.A. Fisher et al. / Aggression in Huntington’s Disease 321
Table 1
Studies on rates of aggression
First Author, Year,
[Reference number]
HD Participants Methodology % M/F Mean
Age
Functional
Capacity
Aggression
Overall
Aggression
Scale
Rating on
scale
Additional findings
Rosenbaum, 1941
[19]
46 hospital
admissions
Case records
review
58.7/41.3 65.2% 10.9% “attempted
homicide”
Tamir, 1969 [20] 32 clinic patients Case records
review
40.6/59.4 48 34.4% More aggression in M
(61.5%) vs. F (15.8%)
(p< 0.05)
Dewhurst, 1969 [21]
& 1970 [7]
102 patients
known to
clinicians
Case records
review
53.9/46.1 48.7125.5% More aggression early
in illness. 17.6%
violent crime
conviction
Tyler, 1983 [22] 92 inpatients and
outpatients
Questionnaire
survey
38.0/62.0 26% not
disabled, 37%
partially
disabled, 37%
totally
disabled
42.4% More aggression in M
(60%) vs. F (31.6%)
Burns, 1990 [23] 26 HD research
clinic patients
Comparison study 60.0/40.0 48.3 22.3 MMSE
mean
59% YAS mean 3.3 No signif. correlation
betw. aggress. &
MMSE
Pflanz, 1991 [24] 86 health service
referrals
Case records
review
39.5/60.5 44.0% PSE 9th Ed. Even M vs. F
aggression rates
Shiwach, 1993 [25] 27 nursing home
residents
Behaviour
monitoring study
29.6/70.4 45.6136% RAGE 25% mildly
aggressive
11% mod.
aggressive
Even M vs. F
aggression rates.
Weak signif.
correlation of
aggression with FRS
Jensen, 1998 [26] 250 HD register
cases
Comparison study
with registry data
39.6/60.4 57.213.6%1,2Higher rates of
convictions in M not F
Craufurd, [2001] [27] 134 outpatients Behaviour rating
scale study
47.0/53.0 50 5 TFC mean PBA-HD 40% v.aggress
22%
ph.aggress.
Aggression most freq.
8-9 yrs. post onset
Grimbergen, 2008
[28]
45 participants in
a prospective falls
study
Falls monitoring
study
48.9/51.1 51.919.71TFC
mean
UHDRS aggression
freq. mean
2.01,
aggression
severity mean
1.61
Fallers had higher
aggression frequency
(p= 0.01) and severity
scores (p= 0.02)
322 C.A. Fisher et al. / Aggression in Huntington’s Disease
Table 1
(Continued)
First Author, Year,
[Reference number]
HD Participants Methodology % M/F Mean
Age
Functional
Capacity
Aggression
Overall
Aggression
Scale
Rating on
scale
Additional findings
Anderson, 2010 [29] 1642 HD study
group participants
Registry data
review
49.6/50.5 8.2 TFC mean UHDRS mean 4.91SS with OCD Sx had
higher aggression
scores, (p< 0.001)
Thompson, 2012 [30] 111 HD research
clinic participants
Longitudinal
study
38.7/61.3 48 7.8 TFC mean PBA-HD 40% v.aggress
18%
ph.aggress.
Longitudinal rates
higher than point
prevalence
Hubers, 2013 [31] 2095 HD registry
participants
Registry data
review
50.9/49.1 50.3 TFC stages
1:33.3%,
2:33.0%,
3:25.5%,
4:7.0%,
5:1.2%
22.6% UHDRS Aggression correlated
with suicidal ideation,
(p< 0.001).
1Mean weighted average, 2Convicted of a violent crime, FRS – Functional Rating Scale, TFC – Total Functional Capacity, MMSE – Mini Mental State Examination, RAGE – Rating scale for
aggressive behaviour in the elderly, YAS – Yudofsky Aggression Scale, PSE - Present State Examination, PBA-HD – The Problem Behaviours Assessment for Huntington’s disease, UHDRS -
Unified Huntington’s Disease Rating Scale.
C.A. Fisher et al. / Aggression in Huntington’s Disease 323
The diagnosis of HD for participants, where reported,
was based on clinical categorisation in the majority of
studies [19, 20, 23, 24, 29], or inclusion on an HD reg-
istry [26]. Three studies contained confirmed HD gene
mutation carriers [27, 30, 31]. In one of these stud-
ies [31] 98 percent were motor symptomatic (thus,
up to two percent of this sample may have had pre-
manifest HD). Average CAG repeat mutations in these
three studies ranged between 44 and 46 (calculated
via the mean weighted average for Hubers, et al.).
As a number of the studies were case records reviews
(incorporating the patient’s behaviour over a number
of years) mean disease duration was often not reported.
However, where this was available, average disease
durations were 5.5 years [30], 5.7 years [31], 7.0 years
[28, 29], 9 years [27] and an estimate of 10 years [22].
A number of differing measures were used to calculate
the participants’ functional capacity, including Mini
Mental State Examination [33] and Total Function-
ing Capacity (TFC) [34] means, TFC stages and study
developed classifications [e.g. 22].
Rates of aggressive behaviour
Rates of aggression (any type) overall were high in
the majority of studies, ranging between 22.6 percent
and 65.2 percent, across eight studies [7, 19–25, 31].
The highest rate was reported in a case records review
study, that analysed patient file information, potentially
spanning many years for each client [19), followed by a
group comparison study that analysed the responses of
family/caregivers on a questionnaire about both current
and past behaviour [23]. The lowest rate was found in a
large registry data review study utilising scores on the
behavioural subscale of the Unified Huntington’s Dis-
ease Rating Scale (UHDRS) [31]. A low rate was also
found in a case records review study reporting the pri-
mary reason for admission to hospital in the HD cohort
[7, 21]. This data may represent an underestimation of
aggression, in total, in this cohort as others in the study
may also have exhibited aggressive behaviour that did
not result in a hospital admission. In one further study
[26] that only reported on convicted crimes, rates of
conviction for violent crimes were 3.6 percent. This
result differs significantly from reported rates of over-
all aggression in the other studies. It may indicate that,
at least in recent years, aggression perpetrated by HD
sufferers is either not commonly reported to the police,
or infrequently prosecuted.
Characteristics of the aggressive behaviour
A number of studies did not utilise a recognised
scale, or scoring system to rate or evaluate aggres-
sion [7, 19–22], making it difficult to draw any further
conclusions about the nature, severity or frequency
of aggression in these studies. When a rating scale
was used, the UHDRS aggression items were the most
common [28, 29, 31, 32]. The Problem Behaviours
Assessment for Huntington’s Disease (PBA-HD) [27,
30], Rating Scale for Aggressive Behaviour in the
Elderly (RAGE) [25], Yudofsky Aggression Scale [23]
and Present State Examination, 9th Edition [24], were
also utilised. Despite the comprehensive nature of
some of these scales in assessing rates, types and sever-
ity of aggression, the full findings were not always
reported, with overall subscale means for aggression
the most common type of data provided.
The UHDRS Behaviour Assessment [34] has a
Disruptive and Aggressive Behaviour subscale, with
descriptors that all relate to aggression. These include:
threatening behaviour, physical violence, verbal out-
bursts, and threatening, foul or abusive language.
The UHDRS rates these behaviours according to
both severity and frequency, but does not provide
information separately on the different types of aggres-
sion (physical, verbal and towards furniture/property).
Three papers utilised this scale. In a falls monitoring
study with 45 HD participants [28] the mean weighted
average for severity was 1.6 (rates between slight,
questionable and mild), and the mean frequency was
2.0 (consistent with a classification of sometimes). In
a large sample registry data review [29] the aggres-
sion score was calculated by multiplying the frequency
score by the severity score, providing a mean weighted
average of 4.9. Little further information can, thus,
be drawn about the severity, frequency or nature of
the aggression in this sample. In a second large sam-
ple registry data review [31], the authors indicated
that aggression was also calculated by multiplying the
frequency total by the severity total to produce an over-
all rating. This score does not appear to have been
reported, however. Instead aggression was reported as
the number of participants who exhibited aggression
in any form, at any level of severity (i.e. cases with
aggression 1), at a rate of 22.6%.
Two studies employed the Problem Behaviours
Assessment for Huntington’s Disease (PBA-HD)
[27, 30] to rate aggressive behaviour. This is a semi-
structured behavioural interview, which rates both
the frequency and severity of a range of problem
behaviours. Information is provided from both patients
and caregivers about behaviour over the preceding four
weeks. In the original development of the scale [27] the
items with a clear relationship to aggression are Tem-
per, verbal outbursts (appearing in subsequent studies
324 C.A. Fisher et al. / Aggression in Huntington’s Disease
as Verbal outbursts) and Threatening behaviour, vio-
lence (appearing in subsequent studies as Physical
aggression). The first study reported rates of verbal
outbursts as 40 percent and physical aggression as 22
percent [27]. In the second study [30], exact numer-
ical figures were not provided, but careful inspection
of the provided bar graph figure revealed point preva-
lence rates that appear to correspond with 40 percent
for verbal outbursts and 18 percent for physical aggres-
sion. Longitudinal ratings (reports of the behaviour at
any time point during the study) appear to correspond
to 75 percent for verbal outbursts and 49 percent for
physical aggression. The actual duration of the longi-
tudinal follow-up in this study is unclear, but appears
to be around 6.5 years (mean of five assessments per
participant, mean time between assessments 1.3 years).
More specific information about aggression frequency
and severity ratings are not provided in either study,
despite these variables being collected by the PBA-HD.
The RAGE [35] was another measure of aggression
employed in one of the studies [25]. Authors indicated
that this scale rates behaviour over a three-day obser-
vation period. It consists of 23 items. Nineteen of these
gauge observable behaviour, with some of these items
directly classifiable as overt aggressive behaviour (e.g.
shouted, yelled or screamed; attempted to bite, scratch,
pinch or hit others, etc.). Three items gauge con-
sequences of the aggressive behaviour (termed as
the non-behavioural items) and one item determines
a global judgement for overall aggressiveness. The
authors reported the data for 17 of the items on this
scale, by frequency (occurred once in three days,
occurred everyday in the past three days, occurred
more than once everyday in the past three days) in
the 27 participants. By far the most common form
of aggressive behaviour was found to be: shouted,
yelled or screamed (33% with positive ratings), with
the majority (29.6%) exhibiting this just once in three
days and a smaller number (3.7%, i.e. 1 out of 27 par-
ticipants) exhibiting it more than once a day, over the
three days. Attempting to bite, scratch, pinch or hit oth-
ers, was the most common form of physical aggression
(11.1% exhibited this at least once, with 3.7% exhibit-
ing this more than once a day). Destroying property
or throwing things around angrily occurred in 7.4%
of participants, at a frequency of once in three days
for all. The number of participants attempting to kick
(3.7%) or hit others (3.7%) was low, but when dis-
played, this behaviour was frequent (more than once a
day for both). Importantly however, not all the items
from the RAGE were included in the results table.
The results for “Pushed or shoved others” were not
included in the results table, although this behaviour
was reported as occurring in one in five participants,
in the text (pg. 45). Overall, 25% of participants were
rated as mildly aggressive, and 11.1% as moderately
aggressive.
One group comparison study utilised the Yudofsky
Aggression Scale. Information provided by the authors
[23] indicated that it is comprised of four components:
verbal aggression against self, physical aggression
against self, aggression against objects and aggression
against other people. During the data collection addi-
tional questions were also asked of relatives about: the
most recent outburst, what outbursts were usually like,
the frequency of the outbursts and any precipitating
factors. Despite this, only information about the mean
score on the scale, the number of participants above
a “cut-off point” for the presence of aggression (any
type) and the percentage of participants with aggres-
sive periods lasting longer than 24 hours (31%), were
reported. No information was provided about the types
of aggression (despite data being collected for this
within the scale). Information on precipitating factors
was also not analysed empirically, with only a gen-
eral statement provided, which indicated “Aggressive
outbursts were usually prompted by some event.. .
Typical precipitants in the HD group included argu-
ments with the spouse over money” (pg. 23). This was
the only study in which reference was made to the col-
lection of empirical data on precipitating, antecedent
or triggering events for the aggressive outbursts.
Finally, the Present State Examination, 9th Edition
[36] was also used to rate aggression in one study [24].
The measure is a semi-structured interview that rates
participants on 140 items, which can then be used for
diagnostic classification. It is unclear how many items
relate to the classification of aggression. However, as
presented in this study, the rating for aggression was
considered a unitary item, with no further information
provided other than prevalence rates, by gender (45%
in males and 44% in females).
Associations/correlations with aggression
A number of studies reported aggression results by
gender. In three studies [24, 25, 27] relatively simi-
lar rates of aggression were reported across males and
females. However, in a further three studies higher rates
of aggression were observed in males [20, 22, 26]. In
one study [7, 21] aggression was found to be more
prevalent in the early, rather than later stages of the ill-
ness (57.8% prevalence in the early phases; 9.8% in the
middle phases and 2.0% in the terminal phase). In a sec-
ond study [27] verbal aggression was found to be most
C.A. Fisher et al. / Aggression in Huntington’s Disease 325
prevalent in clients with 8-9 years illness duration,
with physical aggression also showing a small increase
at this illness stage compared to a relatively even
rate of prevalence for physical aggression at earlier
and later illness stages. Correlation analysis between
aggression and cognitive or functional status was con-
ducted in two studies [23, 25]. In one, no correlation
was found between Mini Mental State Examination
(MMSE) scores and aggression [23]. In the other [25],
a significant but weak correlation was found between
aggression and Functional Rating Scale scores (Pear-
son’s correlation coefficient of 0.45, p< 0.01). This
study does not explicitly state the direction of the cor-
relation, however, from the information contained in
the text it appears that poorer functional ratings were
correlated with higher rates of aggression. In regard to
physical variables, one study found significantly higher
rates of aggression frequency and severity in partici-
pants with a high rate of falls, versus those without
[28]. Psychiatric correlates of aggression were exam-
ined in three studies, all of which used the UHDRS
to rate aggression. One found that participants with
Obsessive Compulsive Disorder (OCD) symptoms had
higher aggression scores [29], while two others found
that rates of aggression were correlated with suicidal
ideation [31, 32].
Data was also provided about rates of criminal
behaviour that related to aggression in three studies. In
one study [19] it was reported that 10.9 percent of par-
ticipants had “attempted homicide” (pg. 95), indicating
a relatively high proportion of participants perpetrat-
ing physical aggression against others with force of
potentially lethal intensity. It was further stated in the
text that “In none was the homicidal attempt felt to be
due to paranoid ideas – rather was it (sic) attributed to
explosive irritability” (pg. 95). One study specifically
examined the rates of criminality in HD sufferers, first
degree relatives and the general population, by com-
paring HD and criminal registry data [26]. It found
that overall crime rates were significantly increased
in HD sufferers compared to first-degree relatives, but
only for males. The increased rate of violent offences
observed in male HD sufferers compared to both first-
degree relatives, and a matched control group, failed
to reach statistical significance (HD 6%; first degree
relatives 1.5%; matched controls 1%). This contrasts
somewhat with an earlier study [7] that reported high
rates of conviction for a range of offenses in their HD
sample (no control group), including assault (13%),
offenses against property (12.7%) cruelty to children
(8.8%), malicious damage (1.9%), blackmail (1%) and
arson (1%).
Summary
Of the 14 studies that met the criteria for inclusion in
this section of the review the majority were not specifi-
cally focused on examining aggression in HD. Rather,
rates of aggression were collected along with a wide
number of clinical variables, or measures of aggres-
sion were obtained as part of general Huntington’s
or psychiatric symptom scales and then analysed in
relation to the main variable of interest. The major-
ity of studies utilised clinical characterisation for the
diagnosis of HD, with only three including confirmed
gene positive cases, leaving the possibility open that
a proportion of included participants may not have
actually been afflicted with HD. The study method-
ologies ranged widely and the reporting of data from
the clinical variables was poor in a number of stud-
ies. Overall, only 64 percent of the studies utilised a
recognised HD, behavioural or psychiatric scale for
evaluating aggression.
Even with consideration given to these methodolog-
ical issues, the results do appear to indicate that rates
of aggression in HD are high, ranging between 22.6
percent and 65.2 percent in the majority of studies.
Little information is available regarding the nature of
the aggressive behaviour (e.g. verbal aggression, phys-
ical aggression, aggression to furniture/property). In
the three studies that did report on types of aggression
[25, 27, 30] both verbal and physical aggression were
found to occur, with verbal aggression having a higher
prevalence. Aggression to property was reported to
have been exhibited by just two participants in one
study [25]. Overall, no studies reported empirical data
on precipitating, antecedent or triggering events for the
aggressive behaviour. One study that did collect this
data (but did not report it empirically), indicated that
aggressive outbursts were often triggered by arguments
with spouses over money.
In the studies where gender differences were
observed aggression was more prevalent in males.
However, several studies reported even rates of aggres-
sion for both genders. Data on whether aggression
becomes more or less prevalent in HD sufferers as
the disease progresses is unclear. One study reported
considerably higher rates of aggression in the early
phases of the disease [7, 21], a second indicated higher
rates in the middle phase (8-9 years) [27], while
in another aggression was weakly, but significantly,
correlated with poorer ratings on a functional scale.
Psychiatrically, there is evidence that aggression is
more prevalent in clients with co-morbid OCD symp-
toms and also correlates with higher rates of suicidal
ideation. Physically, it may also be more prevalent in
326 C.A. Fisher et al. / Aggression in Huntington’s Disease
sufferers that are also frequent fallers. In contrast to
previous speculation [10, 11] there is presently lit-
tle evidence that aggression in HD is associated with
cognitive deterioration, irritability, personality factors,
depression, psychosis or mania. Such associations may
exist, but have yet to be thoroughly examined in the
literature. Future research that focuses on investigat-
ing these factors carefully, using systematic evaluation
of psychiatric symptoms and thorough cognitive and
functional evaluation would be useful, as the methods
employed thus far (e.g. MMSE, disease stage, FRS)
may lack sufficient sensitivity to detect important asso-
ciations. Finally, despite the high rates of aggression
reported in most samples, the reported conviction rates
for violent offenses in HD in the one recent study that
examined this [26] were relatively low. This may reflect
lower levels of reporting such episodes to police and/or
infrequent prosecution of HD individuals.
Treatment of aggression
Characteristics of studies
Nineteen studies met inclusion criteria II, and are
summarised in Table 2 [37–55]. All of the included
studies had small samples sizes (1 to 6 participants),
with eleven case studies [39, 41, 42, 44, 46, 48, 49,
51–54], seven case series [38, 40, 43, 45, 47, 50, 55]
and one very small group study [37]. The majority of
the studies were medication trials, with just two stud-
ies reporting non-medication interventions. Blass et
al. [48] included a structured behaviour support plan,
in addition to a poly medication trial, while Brown
and Fisher [55] utilised sensory modulation interven-
tion. Fifteen of the participants across the studies were
female and twenty were male. The majority of partici-
pants were aged in their 30 s to 50 s, with three younger
participants, aged 16, 19 and 22 years, and three older
participants, aged 60, 67 and 74 years, respectively.
Where reported, the duration of HD from the onset
of symptoms was variable. Participants who had been
symptomatic for 10+ years were reported in five stud-
ies [38, 43, 47, 50, 55] while the remaining timelines
reported were between 1 and 9 years. The functional
or cognitive capacity of participants was reported in
seven studies. In two studies intellectual capacity was
reported, with IQ scores at the time of the intervention
of 65 [51] and 89 [41]. Reported MMSE scores var-
ied considerably, from participants who were unable
to complete any MMSE tasks, scoring 0/30 [45, 48],
moderately impaired participants, scoring 20/30 [54],
to those who exhibited no difficulties on this measure,
scoring 30/30 [42]. One study utilised the Shoulson’s
Huntington’s disease rating scale [46], with the partic-
ipant in this study being classified as Stage V.
Characteristics of the aggressive behaviour
Only one study used a recognised behaviour scale,
the Cohen-Mansfield Agitation Inventory (CMAI),
to quantify the participant’s behaviour [53]. For all
remaining studies behaviour was categorised via the
authors’ descriptions. Nevertheless, there was suffi-
cient information provided in most studies, to allow
for the classification of the aggressive behaviour into
three major types (physical, verbal or against furni-
ture/objects), see Table 2. Physical aggression was the
most common type, with a high prevalence of verbal
aggression also reported. In only one study was aggres-
sion against property/furniture clearly described. The
majority of studies made no mention of antecedents
to the aggressive behaviour, with just three studies
providing specific information about this. One study
[55] outlined precursors for aggression individually for
each of the participants. This study reported that for
the female participant pacing, voicing hunger, verbal
aggression and intrusiveness, where signs that often
lead to behavioural escalation, whilst for the male par-
ticipant loud noise from the television or co-residents
was a precursor to verbal and physical aggression.
The second study [42] stated that the participant self
reported that her aggression was triggered by inter-
nal feelings of anger and irritability, which developed
rapidly following minor irritants or changes in her rou-
tine. In the third study [48] the authors reported that
the participant’s behaviour was initially believed to
be related to psychotic sequelae and delirium. How-
ever, following the implementation of a systematic
behaviour evaluation period, it was then identified
that the participant’s behaviour escalated when he was
asked to take medication or to interrupt a pleasant
activity, such as walking or watching television. Prob-
lematic touching of female staff members was also
found to occur during bathing or dressing activities.
Treatment efficacy
The quantification, measurement and evaluation of
the effect of the therapeutic agents on aggression were
generally poor. In just one study was an empirical mea-
sure of baseline behaviour provided [53] via a singular
pre-treatment rating on the CMAI of 78. This study
was also the only study to provide empirical outcome
measures, via two further CMAI ratings during the
medication treatment period with zuclopenthixole and
medroxyprogresterone (CMAI of 56 at six weeks, and
57 at ten weeks). However, the statistical significance
C.A. Fisher et al. / Aggression in Huntington’s Disease 327
Table 2
Treatment of aggression
First Author, Year
[Reference number]
N M/F Age (s) in years Aggression Type: Treatment type Medication Treatment
duration
Reduction in
Aggression
Adverse Effects
reported
Leonard, 1975 [37] 6 0/6 Physical Medication Lithium
carbonate+
Haloperidol
12 weeks Yess, physical
aggression only
Stewart, 1987a [38] 2 2/0 43, 41 Physical, Verbal Medication Amantadine 1) 4 mths No
2) 6 days
Stewart, 1987b [39] 1 1/0 67 Medication Propranolol+
Haloperidol
2 mths approx. No
Stewart, 1987c [40] 3 3/0 48, 44, 50 Physical, Verbal Medication Propranolol 3–12 mnths Yes
von Hafften, 1989
[41]
1 1/0 48 Physical, Verbal Medication Pindolol 10 days
approx.
No
Findling, 1993 [42] 1 0/1 16 Physical, Verbal Medication Buspirone not reported Yes
Byrne, 1994 [43] 2 2/0 58, 60 Medication Buspirone 1 mnth
approx.
Yes
Patel, 1996 [44] 1 0/1 19 Physical Medication Fluoxetine+
L-deprenyl
12 mths Yes
Ranen, 1996 [45] 2 1/1 52, 42 Physical, Verbal,
Furniture/ Objects
Medication Sertraline 1) 5 mnths Yes
2) not reported
Bhandary, 1997 [46] 1 1/0 74 Physical Medication Buspirone unclear Yes
Grove, 2000 [47] 2 1/1 39, 52 Medication Olanzapine+
Valproate
7–8 weeks Yes
Blass, 2001 [48] 1 1/0 32 Physical Medication+
Behaviour
Support Plan
Admiss. 1:
Clonazepam,
Carbamazepine
and Thioridazine,
Medroxyproges-
terone acetate
Admiss 2:
Haloperidol also
introduced
Admiss1:42
days, Admiss
2:13 days
Yes
Fogliani, 2003 [49] 1 0/1 51 Medication Trifluoperazine,
then Fluoxetine+
Olanzapine
4 mths approx. Yes, slight
improve-ment
with fluox.
328 C.A. Fisher et al. / Aggression in Huntington’s Disease
Table 2
(Continued)
First Author, Year
[Reference number]
N M/F Age (s) in years Aggression Type: Treatment type Medication Treatment
duration
Reduction in
Aggression
Adverse Effects
reported
Alpay, 2006 [50] 5 3/2 40, 40, 42, 34, 38 Medication Quetiapine 1-2 mths Yes
Soliman, 2007 [51] 1 0/1 48 Physical, Verbal Medication Risperidone+
fluvoxamine
4 mths Yes
Edlinger, 2013 [52] 1 1/0 39 Medication Olanzapine,
risperidone,
amisulpride+
aripiprazole, then
clozapine+
reboxetine
6 mths Yes, only with
aripip. intro.
Clozapine:
“sedation and
confusion”
Rej, 2013 [53] 1 1/0 58 Physical, Verbal Medication Zuclopenthixol+
medroxyproges-
terone
10 weeks Yessc Medroxyprogrest:
“fluid retention”
Ding, 2014 [54] 1 1/0 60 Physical, Verbal Medication Risperidone+
citalopram
1 month Yes
Brown, In press [55] 2 1/1 22, 31 Physical, Verbal Sensory
Modulation
not reported Yes
Yess= statistically significant reduction, Yes= reduction based on observational opinion only, Yessc = reduction in behaviour rating scale, significance level not reported.
C.A. Fisher et al. / Aggression in Huntington’s Disease 329
of the rate of change on this measure was not provided.
Multiple baseline data for aggression were not reported
in any studies. In one study [37] a placebo control
condition was used, as well as blinded nursing staff
who rated aggressive behaviour. However, the study
reports that ratings were made only once at the end
of each three week medication period, with no infor-
mation provided about whether episodes of aggressive
behaviour were recorded during the period (leaving the
ratings open to potential confounds of the raters’ mem-
ories over the entire three week period). This study
reported a statistically significant positive effect of
a combined pharmacotherapy approach [lithium car-
bonate and haloperidol) over placebo. This was the
only study in which statistical analysis was applied to
the behavioural data to determine the efficacy of the
intervention. For all remaining studies the information
provided about the efficacy of the treatment was based
on the observational opinion of the authors.
Within the context of these methodological issues
the majority of the studies reported positive effects
of the therapeutic agents at reducing aggression (see
Table 2). Antipsychotic medications were the most
commonly reported pharmacotherapies. Haloperidol,
a butyrophenone neuroleptic, was utilised with eight
subjects, across three studies [37, 39, 48]. In one study
it was reported to be effective at reducing aggres-
sion in six participants, when combined with lithium
carbonate. However, in a single subject case study
[39] no efficacious effect was reported on aggressive
symptoms when haloperidol was combined with pro-
pranolol, a nonselective beta-blocker. Haloperidol was
also introduced to a poly medication regime during a
second admission in a further case study [48]. Queti-
apine, an atypical antipsychotic, was also utilised in
one study [50] containing five HD participants and
was reported to have been affective at reducing aggres-
sion. Olanzapine, another atypical antipsychotic, was
utilised in three participants across three studies [47,
49, 52]. In all of these studies it was used as part of a
poly medication regime. It was reported as efficacious
when combined with valproate [48], an anticonvulsant
also with antipsychotic properties, and with fluoxe-
tine [49], an antidepressant, although the authors in the
later study attributed the small improvement in aggres-
sion primarily to the fluoxetine. Finally, olanzapine
was also used as one of five psychotropic medica-
tions in another case study [52]. However, in this study
the authors primarily attributed the improvement in
aggression to the introduction of aripiprazole, another
of the three antipsychotic agents employed in this case
study. Thioridazine, a peperidine typical antipsychotic
(now withdrawn in many countries due to cardiotoxi-
city and retinopathy at high does) was used in a poly
medication regime in combination with behaviour sup-
port modifications [48], making its effect on aggression
difficult to determine. Trifluoperazine, a phenothiazine
neuroleptic, had little effect on aggression in one single
case study [49], whilst zuclopenthixole, a thioxanthene
neuroleptic, was reported to be efficacious in combi-
nation with, medroxyprogesterone, a progestogen, in
another single case study [53]. However, the medrox-
yprogesterone is reported to have resulted in fluid
retention and abdominal bloating. Side effects from
the antipsychotic agent clozapine, were also reported
in one study [52] and were described as sedation and
confusion.
Two reported case studies combined the antipsy-
chotic agent risperidone with selective serotonergic
reuptake inhibitor antidepressants (SSRIs), specifi-
cally fluvoxamine [51] and citalopram [54]. In both
of these studies aggression was reported to have
decreased, following the introduction of the duo med-
ication regimes. SSRIs were also used in several other
studies. Sertraline was reported to improve aggres-
sive symptoms in two HD clients in one case series
study [45]. Fluoxetine was reported as the medication
primarily responsible for reduction in aggression in
one poly medication single case study [49], and was
also reported to be effective when combined with L-
deprenyl in another [44]. The anxiolytic buspirone has
also been utilised in four participants, across three stud-
ies with improvements reported in aggression in all
cases [42, 43, 46].
Beta-adrenergic blocking agents were mixed in their
effectiveness on aggressive symptoms in HD. Pin-
dolol was reported to be ineffective in one single case
study [41], as was propranolol, when combined with
haloperidol, in another [39]. However, in a second
study investigating the effect of propranolol alone,
improvement in aggression was reported in three
HD clients [40]. Finally, two medications generally
employed for the treatment of movement disorders
were also utilised. Amantadine alone did not improve
aggressive behaviour in two participants in one study
[38], whilst L-deprenyl when combined with fluoxe-
tine (as indicated above) was reported to be effective
in another [44].
In two studies, non-medication treatments were
investigated. In one of these a behaviour support plan
was instigated in conjunction with a poly medica-
tion trial over two separate inpatient admissions in
a single case study [48]. This involved a systematic
behaviour monitoring period, from which antecedents
330 C.A. Fisher et al. / Aggression in Huntington’s Disease
and precursors to problem behaviours were identified.
A clear behaviour support plan was then developed
involving a highly structured daily timetable routine,
the minimisation of behaviour triggers where possi-
ble, positive verbal reinforcement of desired behaviour
and rewards. The behaviour support plan was intro-
duced two weeks after the new medication regime
was commenced, and was reported to have resulted
in dramatically improved behaviour within five days
(in conjunction with the continued pharmacotherapy).
The behaviour plan was reportedly successfully trans-
ferred to the patients’ nursing home environment after
discharge. It was also reinstituted on the inpatient unit
when the patient was readmitted four months later,
after a second period of suspected medication induced
delirium.
In another study sensory modulation intervention
was administered in a two case series [55]. This
study reported on individual triggers for aggressive
behaviour in both of the patients, as well as their indi-
vidual sensory profiles. Sensory modulation treatment
plans were developed for each client, utilising vari-
ous sensory equipment (e.g. weighted blankets, puff
massagers, click-clack balls), which were provided to
clients to prevent the escalation of problem behaviour.
The duration of the intervention was not specified, but
was also reported to have resulted in a reduction in
aggressive behaviour in both clients.
Summary
A wide variety of psychotropic medications have
been reported in the literature to treat individuals with
HD and aggressive behaviour. However, the published
studies have very small sample sizes and poor mea-
surement and evaluation of the effect of the therapeutic
agents on aggression. No randomised controlled trials
were revealed by the search, and none of the case stud-
ies or case series reports employed multiple baseline
measures of aggression by frequency, type or sever-
ity. Two studies attempted to empirically quantify the
effect of the medication on behaviour, however, each
of these studies still contained methodological prob-
lems. Only two studies reported non-pharmacological
measures to treat aggression in HD. Sensory modu-
lation intervention was utilised in one study, whist
behaviour support intervention was used in another,
in conjunction with poly medication therapy. Overall,
no recommendations for specific treatments for aggres-
sion in HD can be made based on the currently available
literature. However, the information contained in this
review can be used as a starting reference point for
treating clinicians to help determine which medica-
tion and non-medication treatments may be suitable
for their clients. It can also be used to direct future
research with stronger methodological properties.
CONCLUSION
Aggression is a commonly occurring behavioural
sequelae in HD. Further research into the antecedents
and precursor “triggers” for this behaviour in HD is
required. Given the rarity of the disorder, it is not
surprising that treatment studies seeking to reduce
aggression in individuals with HD contain small
sample sizes. A large randomised controlled trial eval-
uating the efficacy of treatment for aggression in
HD may be difficult to conduct. However, case stud-
ies, case series and smaller group studies should be
conducted utilising scientifically rigorous methodol-
ogy. This should include the use of multiple baseline
measures of pre-treatment behaviour, quantification
of aggressive behaviour using a recognised scale or
clearly defined parameters, post treatment evaluation
of significance levels and follow-up data to determine
the efficacy of the treatment over longer time periods.
CONFLICT OF INTEREST
The authors do not declare any conflict of interest.
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Background Human embryonic stem cells (hESCs) transplantation had shown to provide a potential source of cells in neurodegenerative disease studies and lead to behavioral recovery in lentivirus transfected or, toxin-induced Huntington's disease (HD) rodent model. Here, we aimed to observe if transplantation of superparamagnetic iron oxide nanoparticle (SPION)-labeled hESCs could migrate in the neural degenerated area and improve motor dysfunction in an AAV2-Htt171-82Q transfected Huntington rat model. Methods All animals were randomly allocated into three groups at first: HD group, sham group, and control group. After six weeks, the animals of the HD group and sham group were again divided into two subgroups depending on animals receiving either ipsilateral or contralateral hESCs transplantation. We performed cylinder test and stepping test every two weeks after AAV2-Htt171-82Q injection and hESCs transplantation. Stem cell tracking was performed once per two weeks using T2 and T2*-weighted images at 4.7 Tesla MRI. We also performed immunohistochemistry and immunofluorescence staining to detect the presence of hESCs markers, huntingtin protein aggregations, and iron in the striatum. Results After hESCs transplantation, the Htt virus-injected rats exhibited significant behavioral improvement in behavioral tests. SPION labeled hESCs showed migration with hypointense signal in MRI. The cells were positive with βIII-tubulin, GABA, and DARPP32. Conclusion Collectively, our results suggested that hESCs transplantation can be a potential treatment for motor dysfunction of Huntington's disease.
... Caregivers of those with HD have reported higher levels of anxiety and depression and a greater negative impact on marital and other social relationships compared to caregivers of those with other progressive neurological disorders (PNDs) (McCabe et al. 2009;O'Connor et al. 2008). Caring for a person with HD may carry particular challenges arising from neuropsychiatric changes, such as loss of empathy (including for the caregiver's needs), limited insight into the extent of impairment, aggression and apathy (Fisher et al. 2014;Kaptein et al. 2007;Simpson et al. 2016;Williams et al. 2009). The lengthy course of illness and younger symptom onset may also contribute to cumulative losses and strains (Domaradzki 2015;Simpson et al. 2016). ...
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The psychosocial sequelae of caregiving in Huntington’s disease (HD) have been shown to be extensive, even in comparison with other progressive neurological disorders. Based on observed clinical need, this investigation aimed to identify psychoeducational and emotional support needs of male HD caregivers and to explore the feasibility and utility of a carer support group. Six male caregivers completed quantitative measures assessing depression, anxiety, carer burden, and carer support needs. The men participated in two education and support group sessions, four weeks apart, which were developed with consideration of male support preferences. Qualitative themes arising in these sessions were documented. Questionnaire results showed overall low levels of psychological distress and carer burden. Despite this, the group sessions facilitated disclosure of significant emotional, practical, and relationship challenges arising from HD. Further, a range of psychoeducational and emotional support needs were identified on quantitative and qualitative assessments. Participants strongly endorsed the format of the group and the benefits of participation, highlighting in particular the importance of meeting other men who understood the experience of living with a spouse with HD.
... However, the groups differed at baseline and the study may have struggled to detect effects given the small sample. More methodologically rigorous studies are needed for aggression (Fisher, Sewell, Brown, & Churchyard, 2014) and more research is needed more widely for irritability. ...
Technical Report
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This document was produced as part of Lancaster University’s Minds and Movement project funded by the British Psychological Society. Guidance on psychological interventions for psychological difficulties in individuals with Huntington’s disease, Parkinson’s disease, motor neurone disease, and multiple sclerosis was produced for the British Psychological Society and is available at www.bps.org.uk/news-and-policy/psychological-interventions-huntingtons-parkinsons-motor-neurone-multiple-sclerosis. The current document presents extended evidence, covering the literature reviewed more comprehensively than was possible for the BPS published guidance, and is referred to by that guidance.
... Both patients and caregivers reported that increased irritability in HD patients led to arguments with family members or coworkers. Aggression, which is differentiated from irritability by external, observable behavior with intent to inflict physical or verbal harm, was also reported in this sample (Fisher et al., 2014). Two caregivers related episodes of physical abuse from neuropsychiatric symptoms. ...
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Neuropsychiatric symptoms in Huntington disease (HD) are commonly encountered, but their effects on functional status are poorly understood. In this qualitative study guided by the Theory of Unpleasant Symptoms, 15 HD patients and caregivers completed semi-structured interviews regarding perceived effects of neuropsychiatric symptoms on functional status. Physical, cognitive, and social functional effects were reported, with negative effects on daily activities and social withdrawal being reported by the greatest number of subjects. Participants also reported improved function with intervention for neuropsychiatric symptoms. This study provides a novel description of the lived experiences of HD patients with neuropsychiatric symptoms.
... Then delay in diagnosing may cause delay in seeking help and finding appropriate support. In time, the most prominent symptoms of HD are motor symptoms, such as involuntary and uncontrolled movements (chorea), poor coordination, gait and balance problems, cognitive symptoms (e.g., impairment in organizing and planning), and behavioral symptoms (e.g., anxiety, disruptions of aggressive behavior, obsessions, compulsions and delusions) [8][9][10]. ...
... Data from an uncontrolled pretest-posttest study with two people with advanced HD also suggest that behavioural relaxation might be effective in reducing arousal in the short term, although not in the long run [60]. As more methodologically rigorous studies are needed to explore the concept of aggression [86], the consideration of alternative psychologicallyinformed models is currently warranted more widely to increase our understanding of irritability in pwHD. Inspiration for this may be drawn from the general literature on psychological interventions for people with anger and aggression, which currently identifies cognitive behavioural approaches as the most effective to address these difficulties (for a recent review, see [87]). ...
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Background: Although Huntington’s disease (HD) can cause a wide range of psychological difficulties, no review has ever been carried out on the range of psychological interventions adopted with this population. Objective: To scope the literature on psychological interventions for psychological difficulties in people affected by HD. Methods: A systematic scoping review was performed across MEDLINE, PsycINFO, CINAHL, Academic Search Ultimate, and Cochrane Library up to 1 March 2020. Results: From an initial return of 1579 citations, a total of nine papers were considered eligible for review. These included a qualitative investigation, three case studies, two case series, two uncontrolled pretest-posttest designs, and only one randomised control trial (RCT). Despite the wide range of psychological difficulties which can be experienced by people affected by the HD gene expansion, the adopted interventions only accounted for five main psychological outcomes (anxiety, apathy, depression, irritability, and coping). Further discussion and suggestions for future research are provided for each outcome. Conclusion: The current literature on psychological interventions in people affected by HD is extremely limited both in terms of methods and addressed clinical outcomes. Consequently, no conclusions can be offered yet as to which psychological therapy may help this population. As further more comprehensive research is urgently needed for this group, the ultimate aim of the present review is to act as a call to arms for HD researchers worldwide to help shed light on the most effective way to translate psychological theory into practice for the benefit of people affected by HD.
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Prior research suggests that sleep is associated with increased subjective stress and aggression, but important questions remain about the typical magnitude of these relationships, as well as their potential moderators. We therefore conducted the first meta-analysis of this literature. Across 340 associational and experimental studies, significant associations were identified between sleep with both subjective stress (r =.307, p <.001) and aggression (r =.258, p <.001) in individuals from the general population, as well as between sleep with subjective stress (r =.425, p <.001) in individuals with sleep disorders. Experimental sleep restriction also led to increased subjective stress (g = 0.403, p =.017) and aggression (g = 0.330, p =.042). These findings suggest that poorer sleep is associated with - and leads to - heightened levels of subjective stress and aggression. These findings, and their implications, are discussed in relation to neurobiological literature, which highlights the complex interplay between metabolic activity in the brain, hormonal changes, and behavior.
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We describe the management of post-traumatic stress disorder (PTSD) and obsessive-compulsive disorders (OCD), through Cognitive Behavioral Therapy (CBT) in a Huntington's disease (HD) patient.Even with a psychopharmacological treatment to manage PTSD and OCD, psychiatric disorders remained in the HD patient. We proposed CBT essentially based on progressive exposure. The symptomatology disappeared shortly after starting the psychotherapeutical treatment and was maintained over time. We discuss the benefits of CBT on this patient considering the therapeutical alliance and the cognitive disorders.This clinical case gives positive impetus for future research concerning the non-pharmacological management of psychiatric comorbidities in Huntington's disease.
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Striatal-enriched protein tyrosine phosphatase (STEP) is a signal transduction protein involved in the pathogenesis of neuropathologies. A STEP inhibitor (TC-2153) has antipsychotic and antidepressant effects. Here, we evaluated the role of STEP in fear-induced aggression using Norway rats selectively bred for 90 generations for either high aggression toward humans (aggressive rats) or its absence (tame rats). We studied the effects of acute administration of TC-2153 on behavior and STEP expression in the brain of these animals and the influence of chronic treatment with TC-2153 on the behavior and STEP expression in aggressive rats in comparison with classic antidepressant fluoxetine, which is known to exert antiaggressive action. Acute TC-2153 administration decreased the aggressive reaction to humans in aggressive rats, while having no impact on the friendly behavior of tame rats. Moreover, in the elevated plus-maze test, the drug had an anxiolytic effect on both aggressive and tame rats. Aggressive rats demonstrated elevated levels of a STEP isoform (STEP46) as compared to tame animals, whereas acute TC-2153 administration significantly reduced STEP46 protein concentration in the brain of aggressive rats. Chronic treatment of aggressive rats with either TC-2153 or fluoxetine attenuated fear-induced aggression. Chronic administration of fluoxetine enhanced the exploratory activity in the elevated plus-maze test and decreased the STEP46 protein level in aggressive rats’ hippocampus, whereas chronic TC-2153 administration did not affect these parameters. Thus, STEP46 can play an important role in the mechanisms of aggression and may mediate antiaggressive effects of TC-2153 and fluoxetine.
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Objective: Neuropsychiatric symptoms are common in Huntington's disease and have been considered its presenting manifestation. Research characterising these symptoms in Huntington's disease is variable, however, encumbered by limitations within and across studies. Gaining a better understanding of neuropsychiatric symptoms is essential, as these symptoms have implications for disease management, prognosis, and quality of life for patients and caregivers. Method: Fifty two patients with Huntington's disease were administered standardised measures of cognition, psychiatric symptoms, and motor abnormalities. Patient caregivers were administered the neuropsychiatric inventory. Results: Ninety eight per cent of the patients exhibited neuropsychiatric symptoms, the most prevalent being dysphoria, agitation, irritability, apathy, and anxiety. Symptoms ranged from mild to severe and were unrelated to dementia and chorea. Conclusions: Neuropsychiatric symptoms are prevalent in Huntington's disease and are relatively independent of cognitive and motor aspects of the disease. Hypothesised links between neuropsychiatric symptoms of Huntington's disease and frontal-striatal circuitry were explored. Findings indicate that dimensional measures of neuropsychiatric symptoms are essential to capture the full range of pathology in Huntington's disease and are vital to include in a comprehensive assessment of the disease.
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Abstract Statement of context: People with juvenile Huntington’s disease often experience difficulty engaging in occupations due to neuropsychiatric sequelae, such as impulse control difficulties, agitation and aggression. Occupational therapy using sensory modulation intervention strategies may be utilised to assuage behavioural symptoms in this population. Critical reflection on practice: Through case reports, this practice analysis explores changes in occupational performance for two young adults diagnosed with juvenile Huntington’s disease who received sensory modulation treatment. Implications for practice: These inspiring reports could encourage occupational therapists to consider sensory modulation intervention to decrease psychiatric disturbance, thus optimising performance capacity among this rare population. Keywords Sensory modulation, occupational performance, Huntington’s disease
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Elevated levels of irritability have been reported across a range of psychiatric and medical conditions. However, research on the causes, consequences, and treatments of irritability has been hindered by limitations in existing measurement tools. This study aimed to develop a brief, reliable, and valid self-report measure of irritability that is suitable for use among both men and women and that displays minimal overlap with related constructs. First, 63 candidate items were generated, including items from two recent irritability scales. Second, 1,116 participants (877 university students and 229 chronic pain outpatients) completed a survey containing the irritability item pool and standardized measures of related constructs. Item response theory was used to develop a five-item scale (the Brief Irritability Test) with a strong internal structure. All five items displayed minimal conceptual overlap with related constructs (e.g., depression, anger), and test scores displayed negligible gender bias. The Brief Irritability Test shows promise in helping to advance the burgeoning field of irritability research.
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We describe a case of a 51-year-old woman affected by Huntington disease who presented choreoatetosic movements that had appeared 4 years previously. She also experienced concentration and attention difficulties, agitation, aggression and insomnia that had begun 5 months earlier. She was treated with olanzapine at 5 mg daily that induced a slight improvement in her motor functioning. The drug was then increased to 10 mg/day. After this treatment she gradually also developed a subjective experience of illness and started to be aware of her involuntary movements with global functional improvement. We argue that olanzapine efficacy on cognitive impairment has similarity to its pharmacological effect on negative psychotic symptoms.
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The Unified Huntington's Disease Rating Scale (UHDRS) was developed as a clinical rating scale to assess four domains of clinical performance and capacity in HD: motor function, cognitive function, behavioral abnormalities, and functional capacity. We assessed the internal consistency and the intercorrelations for the four domains and examined changes in ratings over time. We also performed an interrater reliability study of the motor assessment. We found there was a high degree of internal consistency within each of the domains of the UHDRS and that there were significant intercorrelations between the domains of the UHDRS, with the exception of the total behavioral score. There was an excellent degree of interrater reliability for the motor scores. Our limited longitudinal database indicates that the UHDRS may be useful for tracking changes in the clinical features of HD over time. The UHDRS assesses relevant clinical features of HD and appears to be appropriate for repeated administration during clinical studies.
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Background Previous studies indicate increased prevalences of suicidal ideation, suicide attempts, and completed suicide in Huntington's disease (HD) compared with the general population. This study investigates correlates and predictors of suicidal ideation in HD. Methods The study cohort consisted of 2106 HD mutation carriers, all participating in the REGISTRY study of the European Huntington's Disease Network. Of the 1937 participants without suicidal ideation at baseline, 945 had one or more follow-up measurements. Participants were assessed for suicidal ideation by the behavioural subscale of the Unified Huntington's Disease Rating Scale (UHDRS). Correlates of suicidal ideation were analyzed using logistic regression analysis and predictors were analyzed using Cox regression analysis. Results At baseline, 169 (8.0%) mutation carriers endorsed suicidal ideation. Disease duration (odds ratio [OR]=0.96; 95% confidence interval [CI]: 0.9–1.0), anxiety (OR=2.14; 95%CI: 1.4–3.3), aggression (OR=2.41; 95%CI: 1.5–3.8), a previous suicide attempt (OR=3.95; 95%CI: 2.4–6.6), and a depressed mood (OR=13.71; 95%CI: 6.7–28.0) were independently correlated to suicidal ideation at baseline. The 4-year cumulative incidence of suicidal ideation was 9.9%. Longitudinally, the presence of a depressed mood (hazard ratio [HR]=2.05; 95%CI: 1.1–4.0) and use of benzodiazepines (HR=2.44; 95%CI: 1.2–5.0) at baseline were independent predictors of incident suicidal ideation, whereas a previous suicide attempt was not predictive. Limitations As suicidal ideation was assessed by only one item, and participants were a selection of all HD mutation carriers, the prevalence of suicidal ideation was likely underestimated. Conclusions Suicidal ideation in HD frequently occurs. Assessment of suicidal ideation is a priority in mutation carriers with a depressed mood and in those using benzodiazepines.
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This is a case of a 60-year-old man who presented with a 6-month history of increasing agitation and emotional volatility. His family brought him to the emergency room as they were concerned about his threatening and aggressive behaviour. The patient was initially incoherent and uncooperative. During the interview, the patient's family revealed that he had a previous diagnosis of Huntington's disease; there was also a family history of personality changes preceding Huntington's chorea. The patient was admitted to the psychiatric inpatient unit and started on low-dose risperidone. Consequently, there was marked improvement in his symptoms. Subsequent cognitive tests revealed deficits in multiple domains. After a month, the patient was discharged to a community home in stable state.