Neuropsychiatry
J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2019-320646 on 13 October 2019. Downloaded from http://jnnp.bmj.com/ on October 16, 2019 at Stella Welsh - Periodicals
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Correspondence to
Professor Clement T Loy, Brain
and Mind Centre, University of
Sydney, Sydney, NSW 2006,
Australia; ​clement.​loy@​sydney.​
edu.a​ u
An earlier version of this
work was presented at the
Neuropsychiatric Syndromes
symposium of the International
Society to Advance Alzheimer’s
Research and Treatment
(ISTAART) Professional Interest
Area day at the Alzheimer’s
Association International
Conference (AAIC) on 13 July
2019 in Los Angeles, USA.
Received 15 February 2019
Revised 13 June 2019
Accepted 14 August 2019
© Author(s) (or their
employer(s)) 2019. No
commercial re-use. See rights
and permissions. Published
by BMJ.
To cite: Connors MH,
Teixeira-Pinto A, Loy CT. J
Neurol Neurosurg Psychiatry
Epub ahead of print: [please
include Day Month Year].
doi:10.1136/jnnp-2019-
320646
Research paper
Psychosis and longitudinal outcomes in Huntington
disease: the COHORT Study
Michael H Connors ‍ ‍ ,1,2,3 Armando Teixeira-Pinto,4 Clement T Loy4,5,6
Abstract
Objective  Huntington disease (HD) is an autosomal
dominant neurodegenerative disease involving motor
disturbances, cognitive decline and psychiatric symptoms.
Psychotic symptoms occur in a significant proportion of
patients. We sought to characterise the clinical outcomes
of this group of patients.
Methods  Data were drawn from the Cooperative
Huntington Observational Research Trial, a prospective,
multi-centre observational study. 1082 patients with
HD were recruited. Measures of cognition, function,
behavioural disturbance and motor function were
completed annually over 5 years.
Results  Overall, 190 patients (17.6%) displayed
psychotic symptoms. These patients demonstrated worse
cognition, function and behavioural disturbances than
patients without psychosis over time. Patients with
psychosis also demonstrated lower levels of chorea
than patients without psychosis, despite adjusting for
concurrent antipsychotic and tetrabenazine use.
Conclusions  Psychosis in HD is associated with
poorer outcomes in cognition, function and behavioural
symptoms. Patients with psychotic symptoms may
also have less chorea. Altogether, the findings suggest
patients with psychosis have a distinct clinical course.
Introduction
Huntington disease (HD) is an autosomal domi-
nant neurodegenerative disease that is character-
ised by motor disturbances, cognitive impairment
and psychiatric symptoms.1 2 Onset is typically in
mid-life, though can occur at any age, and motor
disturbances, particularly chorea (involuntary, jerky
movements), are often the first signs of the disease.3
The disease results from an unstable expansion of
the cytosine–adenine–guanine (CAG) repeat in the
Huntingtin gene4 and the number of these repeats
correlates with the disease’s onset5 and progres-
sion.6 HD occurs in approximately one in 10 000
people7 and there is no known prevention or cure.
Given its relative rarity, there are limited data on
whether features in its clinical presentation predict
subsequent disease progression.8
Psychotic symptoms occur in 3%–11% of
patients9–11 and it remains unclear whether these
patients experience a different clinical course to
those without such symptoms (for simplicity, we
refer to psychosis—delusions and hallucinations—
as symptoms, though they may also be considered
to be signs). In other neurodegenerative disor-
ders, psychosis is associated with a more rapid
decline in cognition and function over time.12–15 In
Connors MH, et al. J Neurol Neurosurg Psychiatry 2019;0:1–6. doi:10.1136/jnnp-2019-320646
Alzheimer’s disease and frontotemporal dementia,
there is also evidence for distinct genetic underpin-
nings of psychotic phenotypes.16–20 It is unclear if
similar findings hold in HD. In cross-sectional anal-
yses, psychotic symptoms in HD have been asso-
ciated with lower functional ability, greater motor
disturbance, longer duration of illness9 and lower
cognition.21 These findings, however, are limited
by the relatively small number of patients with
psychotic symptoms in the respective samples and
longitudinal outcomes remain unknown. In addi-
tion, psychotic features in HD have been found to
aggregate in families22–25 and appear to be unrelated
to the number of CAG repeats in the Huntingtin
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gene.9 25–29 These latter findings are consistent with
the possibility of a psychotic endophenotype with a
distinct genetic basis, though specific genetic modi-
fiers have yet to be identified.
Against this background, we attempted to
characterise the clinical features of the psychotic
phenotype in HD. We examined the longitudinal
outcomes of a large sample of patients with HD
and compared those with psychotic symptoms to
those without psychotic symptoms. We drew on
data from the Cooperative Huntington Observa-
tional Research Trial (COHORT),30 which assessed
cognitive ability, functional ability, motor distur-
bances and behavioural symptoms at baseline and
over the following 5 years. We considered chorea
and other motor disturbances—such as dystonia
(involuntary muscle co-contractions that produce
abnormal posturing), rigidity and balance—sepa-
rately given evidence of distinct neural underpin-
nings and different trajectories over time.2 8 31 We
hypothesised that psychosis would be associated
with poorer cognitive, functional and motor abil-
ities, and worse behavioural symptoms.
Methods
Design
Participants were from the COHORT study,30
a prospective, multi-centre observational study
involving 44 separate testing sites across Australia
(n=2), Canada (n=4) and the USA (n=38). The
study recruited four groups of participants: (1) indi-
viduals with a clinical diagnosis of HD; (2) individ-
uals at high risk of HD according to DNA testing
but who did not have clinically diagnosed HD; (3)
first-degree and second-degree relatives of individ-
uals from the first two groups and (4) spouses or
caregivers of individuals from the first two groups
(controls) who had no genetic risk for HD. The
study collected blood for genetic analyses at enrol-
ment and behavioural measures annually for up to
1
 Neuropsychiatry

5 years. All participants provided written informed consent. The
current paper represents a retrospective analysis of the study
data; it was conceived after data collection was complete, so
there was no risk of recall bias.
Participants
Our analyses focused on patients with a diagnosis of HD at base-
line or who received a diagnosis during the course of the study.
This was based on the motor subscale of the Unified Huntington
disease Rating Scale (UHDRS),32 which requires the clinician to
rate whether they believe with a confidence level of ≥99% that
the subject has manifest HD. In addition, all patients were
required to have a CAG count greater than 35. Psychosis was
defined by either the presence of psychotic symptoms at that
time point (according to the UHDRS behavioural assessment,
items 34 and 35) or a previous history of psychotic symptoms
(regardless of when this occurred relative to patients’ diagnosis
of HD).
Measures and procedure
At baseline, participants completed a medical history and gave
a blood sample for DNA testing and Huntingin CAG repeat
genotyping. At baseline and each visit, participants completed
J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2019-320646 on 13 October 2019. Downloaded from http://jnnp.bmj.com/ on October 16, 2019 at Stella Welsh - Periodicals
(combining scores for gait, tandem gait and postural instability;
range: 0–12) were also examined. Cognition was assessed using
the Mini-Mental State Examination33 (MMSE, range: 0–30;
higher scores indicate better cognition). Function was assessed
using the UHDRS measures of total functional capacity (TFC;
range: 0–13; higher scores indicate better function) and inde-
pendence (range: 0–100; higher scores indicate better func-
tion). Behavioural disturbance was assessed using the UHDRS
total score of behavioural disturbance excluding delusions and
hallucinations (range: 0–144; higher scores indicate more severe
and frequent behavioural disturbances). A list of patients’ medi-
cations, including antipsychotics (typically prescribed for both
psychosis and chorea) and tetrabenazine (typically prescribed for
chorea), was also compiled.34
Statistical analyses
The baseline characteristics of all patients—including both those
with HD at baseline and those subsequently diagnosed—were
compared according to whether they ever experienced psychosis
(both prior to baseline or during the study). Data were compared
using logistic regression to control for time since clinical diag-
nosis. The relationship between number of CAG repeats and age
of onset of psychotic symptoms was examined using Spearman’s

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a detailed physical and neurological examination. Motor distur-
bance was assessed using the UHDRS ’99,32 which provides a total
score of motor disturbance (range: 0–124, higher scores indi-
cate more severe symptoms). The subscores for chorea (range:
0–28), dystonia (range: 0–20), rigidity (range: 0–8) and balance
rank-order correlation coefficient.
Longitudinal data were analysed using linear mixed models
with normally distributed random intercepts and random effects
for time. We restricted the analyses to the first 4 years of data
due to the relatively small number of patients returning for the

Table 1  Characteristics of patients at baseline (including both patients with Huntington disease at baseline and patients who were subsequently
diagnosed during the study)
Statistical comparison†
Overall Psychosis* No psychosis
(n=1082) (n=190) (n=892) OR P value
Demographics
 Age 51.64 (11.75) 52.15 (11.47) 51.54 (11.82) 1.00 0.650
 Sex (female) 572 (52.9%) 101 (53.2%) 471 (52.8%) 1.00 0.982
 Education (tertiary) 444 (41.1%) 66 (35.1%) 378 (42.4%) 0.74 0.075
 CAG 44.30 (4.12) 44.05 (3.91) 44.35 (4.16) 0.98 0.370
 Time since diagnosis 7.95 (6.22) 9.19 (6.90) 7.57 (5.96) 1.03 0.191
Function
 Total functional capacity 8.23 (3.40) 6.98 (3.71) 8.50 (3.28) 0.87 <0.001
 Independence scale 18.89 (6.00) 73.37 (17.59) 81.15 (15.74) 0.97 <0.001
Cognition
 MMSE 25.12 (4.45) 24.19 (4.96) 25.32 (4.31) 0.95 0.007
Behavioural symptoms
 Behavioural total score‡ 13.31 (14.79) 20.11 (17.40) 11.87 (13.77) 1.03 <0.001
Motor symptoms
 Total motor score 38.64 (18.76) 40.24 (19.75) 38.30 (18.54) 1.00 0.425
 Chorea 9.99 (5.14) 9.13 (5.29) 10.18 (5.09) 0.96 0.005
 Dystonia 3.46 (3.81) 3.42 (4.03) 3.46 (3.76) 0.99 0.581
 Rigidity 1.36 (1.59) 1.53 (1.68) 1.32 (1.56) 1.07 0.168
 Balance 3.90 (2.76) 4.29 (3.03) 3.82 (2.70) 1.06 0.073
Medications
 Antipsychotics 376 (34.8%) 108 (56.8%) 268 (30.0%) 1.70 0.050
 Tetrabenazine 58 (5.4%) 10 (5.3%) 48 (5.4%) 0.75 0.581
Function, motor and neuropsychiatric symptoms measured using Unified Huntington Disease Rating Scale. Summary figures are means for continuous variables or numbers for
categorical variables. Numbers in brackets indicate SD for continuous variables and percentages for categorical variables.
*Psychosis includes all participants who experienced psychotic symptoms in the past or during the study.
†Statistical comparison between patients with psychosis and patients without psychosis, adjusted for time since clinical diagnosis.
‡Excluding delusions and hallucinations.
CAG, number of cytosine–adenine–guanine repeats; MMSE, Mini-Mental State Examination.

2 Connors MH, et al. J Neurol Neurosurg Psychiatry 2019;0:1–6. doi:10.1136/jnnp-2019-320646

 Neuropsychiatry

J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2019-320646 on 13 October 2019. Downloaded from http://jnnp.bmj.com/ on October 16, 2019 at Stella Welsh - Periodicals
5-year follow-up (see online supplementary appendix 1). Only
Table 2  Linear mixed models for measures of function
patients with a current motor diagnosis of HD were included in
the analyses (patients diagnosed with HD during the study were Parameter Estimate 95% CI Sig
only included once they had received their diagnosis). Psychosis TFC
was defined as a time-varying variable, such that patients were  Time effect for no psychosis*† −0.50 −0.53 to −0.46 <0.001
categorised as having psychosis once they showed active symp-  Time effect for psychosis*‡ −0.42 −0.49 to −0.36 <0.001
toms or if they had a previous history of psychosis. Outcome  Psychosis (at time of diagnosis) −1.18 −1.64 to −0.71 <0.001
measures were cognition (MMSE), function (TFC), motor  CAG −0.27 −0.33 to −0.21 <0.001
disturbances (total score, chorea, dystonia, rigidity and balance)  Age −0.07 −0.09 to −0.05 <0.001
and behavioural disturbances (total behavioural score excluding  Sex (female) −0.62 –0.95 to −0.28 <0.001
delusions and hallucinations). Time was measured in years from Independence scale
the patients’ clinical diagnosis.  Intercept§ 165.50 150.19 to 180.81 <0.001
For each outcome, separate models included the following  Time effect¶ −2.56 −2.74 to −2.38 <0.001
predictors: age, sex, number of CAG repeats and the presence  Psychosis −4.97 −6.49 to −3.44 <0.001
of psychosis. For behavioural disturbances, use of antipsychotic  CAG −1.27 −1.53 to −1.00 <0.001
medications was included as a dichotomous time-varying vari-
 Age −0.35 −0.44 to −0.26 <0.001
able. Likewise, for motor disturbances, use of antipsychotic
 Sex (female) −2.72 −4.26 to −1.18 <0.001
medication and tetrabenazine were included as dichotomous
Numbers in bold indicate p values <0.05.
time-varying variables. For all outcomes, interactions between *The interaction between time and psychosis had a p value of 0.014 and was
psychosis and time were included in the model to check if the retained in the model. As such, separate time effects for the presence and absence
effect varied over time and were retained in the model if p<0.10. of psychosis are reported while the intercept term is not reported.
If statistically significant interactions involving a categorical vari- †Random effect with mean −0.50 and SD=0.22.
able were statistically significant, separate effect estimates of the ‡Random effect with mean −0.42 and SD=0.22.
§Random effect with mean 165.50 and SD=10.43.

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interaction were reported for each value of the categorical vari-
able. Models were selected on the basis of the Akaike informa-
tion criterion. Statistical significance was set at p<0.05 for all
statistical tests of main effects given the exploratory nature of
the analyses.
Two sensitivity analyses were conducted. First, to examine
the possibility that differences between patients with psychosis
and those without psychosis represent long-standing pheno-
typic traits that antedate overt psychotic symptoms, analyses
were repeated defining psychosis as time-invariant (including all
patients who had a history of psychosis or displayed psychotic
symptoms at any point over the study). Second, to examine the
contribution of active psychotic symptoms to the findings, anal-
yses were repeated distinguishing active psychotic symptoms
as a time-variant variable from both previous psychosis and no
previous psychosis. All analyses were completed using SPSS V.25
(IBM Corporation, Armonk, New York, USA).
Results
Over the course of the study, 1082 patients with HD were
recruited (994 patients had HD at baseline; a further 88 were
diagnosed with HD during the study). Of these, 190 (17.6%)
demonstrated psychotic symptoms at some point during the
course of their disease (97 patients had a history of psychosis
before the study and 141 displayed psychotic symptoms during
the study; 48 displayed such symptoms both before and during
the study). Of the patients who developed psychotic symptoms
during the study, 121 (85.8%) developed delusions and 39
(27.7%) developed hallucinations; 19 (13.5%) developed both
symptoms.
The characteristics of patients at enrolment—including both
those with HD at the baseline visit and those subsequently
diagnosed—are shown in table 1. Patients with either active
psychosis or a past history of psychosis did not differ from
those without psychosis in terms of age, sex, education or CAG
repeats. Patients with psychosis, however, exhibited worse func-
tion, cognition and behavioural symptoms than patients without
psychosis. Patients with psychosis also had less chorea than
patients without psychosis. The sample size across the study is
Connors MH, et al. J Neurol Neurosurg Psychiatry 2019;0:1–6. doi:10.1136/jnnp-2019-320646
¶Random effect with mean −2.56 and SD=1.28.
CAG, cytosine–adenine–guanine; TFC, total functional capacity.
shown in the supplementary material (see online supplementary
figure 1).
Data about age of onset of psychotic symptoms were avail-
able for 138 (72.6%) patients. For these patients, the mean age
of onset of psychotic symptoms was 51.38 years (SD=12.29).
The mean time between clinical diagnosis and onset of psychotic
symptoms was 3.58 years (SD=4.81); 21 patients (15.2%)
exhibited psychotic symptoms prior to their HD diagnosis; 21
(15.2%) had psychotic symptoms at the time of their HD diag-
nosis and 96 (69.6%) developed psychotic symptoms after their
HD diagnosis. There was a negative correlation between number
of CAG repeats and age of onset of psychosis, rs(136) = −0.66,
p<0.001.
In linear mixed model analyses, patients with psychosis demon-
strated worse cognition, function and behavioural disturbances
than patients without psychosis. For measures of function, there
was a significant interaction between psychosis and time using
TFC, but not the independence scale (table 2). In particular,
patients with psychosis had TFC scores 1.18 lower (p<0.001)
on average than patients without psychosis at the time of diag-
nosis in the model, but declined at a slower rate thereafter,
adjusting for patient’s age, sex and CAG repeats. Patients with
psychosis had independence scale scores 4.97 lower (p<0.001)
than patients without psychosis across the study on average
adjusting for other covariates.
For cognition, patients with psychosis had MMSE scores
1.26 units lower on average than patients without psychosis
(p<0.001) when adjusting for other variables (table 3). For
behavioural symptoms, patients with psychosis had behavioural
scores 8.55 units higher on average than patients without
psychosis (p<0.001) when adjusting for other variables (table 3).
There were no interactions with time for either cognition or
behavioural symptoms, indicating the differences between
patients with psychosis and patients without psychosis were
stable over time.
For movement disturbances, results varied according to the
type of disturbance. Patients with psychosis demonstrated less
3
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J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2019-320646 on 13 October 2019. Downloaded from http://jnnp.bmj.com/ on October 16, 2019 at Stella Welsh - Periodicals
Table 3  Linear mixed models for cognition and behavioural Table 4  Linear mixed models for motor disturbances
disturbances Parameter Estimate 95% CI Sig
Parameter Estimate 95% CI Sig Chorea
Cognition  Intercept* −2.45 −7.83 to 2.93 0.372

 Intercept* 45.52 41.02 to 50.02 <0.001  Time effect† 0.20 0.14 to 0.27 <0.001

 Time effect† −0.43 −0.49 to −0.38 <0.001  Psychosis −1.08 −1.70 to −0.45 0.001
 CAG 0.16 0.06 to 0.25 0.001
 Psychosis −1.26 −1.74 to −0.78 <0.001
 Age 0.09 0.06 to 0.13 <0.001
 CAG −0.32 −0.40 to −0.24 <0.001
 Sex (female) 0.00 −0.54 to 0.53 0.993
 Age −0.08 −0.11 to −0.06 <0.001
 Antipsychotic 0.12 −0.33 to 0.56 0.597
 Sex (female) −0.41 −0.86 to 0.03 0.070
 Tetrabenazine 0.40 −0.33 to 1.13 0.280
Behavioural Disturbances‡
Dystonia
 Intercept§ 25.46 10.75 to 40.17 0.001  Intercept‡ −15.22 −18.93 to −11.50 <0.001
 Time effect¶ 0.00 −0.17 to 0.16 0.959  Time effect§ 0.30 0.25 to 0.35 <0.001
 Psychosis 8.55 6.72 to 10.39 <0.001  Psychosis −0.17 −0.62 to 0.28 0.451
 CAG −0.18 −0.43 to 0.07 0.160  CAG 0.31 0.25 to 0.38 <0.001
 Age −0.13 −0.22 to −0.05 0.003  Age 0.07 0.05 to 0.09 <0.001
 Sex (female) 1.71 0.27 to 3.15 0.020  Sex (female) −0.03 −0.40 to 0.34 0.882
 Antipsychotic 2.75 1.42 to 4.08 <0.001  Antipsychotic 0.58 0.26 to 0.90 <0.001
Numbers in bold indicate p values <0.05.  Tetrabenazine −0.32 −0.85 to 0.21 0.242
*Random effect with mean 45.52 and SD=2.76. Rigidity
†Random effect with mean −0.43 and SD=0.46.  Intercept¶ −5.42 −6.98 to −3.87 <0.001
‡Total behavioural disturbances excluding psychotic symptoms.  Time effect** 0.10 0.08 to 0.12 <0.001

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§Random effect with mean 25.46 and SD=9.67.  Psychosis 0.18 −0.01 to 0.38 0.060
¶Random effect with mean 0.00 and SD=0.00.
 CAG 0.12 0.10 to 0.15 <0.001
CAG, cytosine–adenine–guanine.
 Age 0.02 0.01 to 0.03 <0.001
 Sex (female) −0.16 −0.32 to 0.00 0.043
 Antipsychotic 0.16 0.02 to 0.30 0.024
chorea than patients without psychosis (p=0.001), scoring
 Tetrabenazine 0.01 −0.22 to 0.24 0.932
1.08 units lower on average after adjusting for age, sex, CAG
Balance
repeats, antipsychotic medication and time since onset of symp-
 Intercept†† −16.17 −18.73 to −13.61 <0.001
toms (table 4). Patients with psychosis also demonstrated worse
 Time effect‡‡ 0.32 0.29 to 0.35 <0.001
balance than patients without psychosis (p=0.025), scoring
 Psychosis 0.32 0.04 to 0.60 0.025
0.32 units higher on average after adjusting for other variables
 CAG 0.28 0.24 to 0.33 <0.001
(table 4). There were no significant differences between patients
 Age 0.11 0.09 to 0.12 <0.001
with psychosis and patients without psychosis in dystonia,
 Sex (female) 0.87 0.61 to 1.12 <0.001
rigidity and overall motor score (table 4). There were no interac-
 Antipsychotic 0.64 0.44 to 0.83 <0.001
tions with time for any of the motor score variables.
 Tetrabenazine 0.58 0.26 to 0.90 <0.001
The effects for all outcome variables were unchanged when
Motor disturbances overall
analyses were based on only psychotic symptoms that occurred
 Intercept§§ −90.77 −108.61 to −72.94 <0.001
during the study or when examining delusions and hallucina-
 Time effect¶¶ 2.45 2.25 to 2.66 <0.001
tions separately (results not shown).
 Psychosis 1.33 −0.43 to 3.09 0.139
A sensitivity analysis found similar findings when treating  CAG 2.01 1.71 to 2.32 <0.001
psychosis as a time-invariant variable—such that all participants  Age 0.56 0.45 to 0.67 <0.001
who developed psychotic symptoms during the study or who  Sex (female) 1.83 0.04 to 3.63 0.045
had a previous history of psychosis were considered together as  Antipsychotic 2.79 1.57 to 4.01 <0.001
a stable group, even if this preceded the onset of their psychotic  Tetrabenazine 1.54 −0.40 to 3.48 0.120
symptoms (see online supplementary tables 1 and 2). In partic- Numbers in bold indicate p values <0.05.
ular, patients with psychosis defined in this way displayed *Random effect with mean −2.45 and SD=3.67.
†Random effect with mean 0.20 and SD=0.25.
lower function (both TFC and independence), lower cognition ‡Random effect with mean −15.22 and SD=2.21.
and greater behavioural disturbances than patients without §Random effect with mean 0.30 and SD=0.32.
¶Random effect with mean −5.42 and SD=0.93.
psychosis. These patients also developed chorea at a slower rate **Random effect with mean 0.10 and SD=0.11.
than patients without psychosis, adjusting for antipsychotic and ††Random effect with mean −16.17 and SD=1.75.
‡‡Random effect with mean 0.32 and SD=0.17.
tetrabenazine use and other covariates. §§Random effect with mean −90.77 and SD=12.36.
A further sensitivity analysis distinguished patients with ¶¶Random effect with mean 2.45 and SD=1.41.
CAG, cytosine–adenine–guanine.
active psychotic symptoms at any time point from patients with
previous psychotic symptoms and patients who had never had
psychotic symptoms. Both groups of patients with psychotic Patients with previous psychosis also demonstrated less chorea
symptoms—those with active symptoms and those who had than patients who had never experienced psychosis (see online
previous symptoms—demonstrated lower function (both TFC supplementary tables 1 and 2).
and independence), lower cognition and greater behavioural
disturbances than patients who had never experienced psychosis. Discussion
Patients with active psychosis demonstrated worse rigidity and A significant proportion of patients with HD—approxi-
balance than patients who had never experienced psychosis. mately 18%—exhibited psychotic symptoms. These patients
4 Connors MH, et al. J Neurol Neurosurg Psychiatry 2019;0:1–6. doi:10.1136/jnnp-2019-320646

demonstrated lower cognitive ability, lower functional abilities
and greater behavioural disturbances compared with patients
without psychosis, and showed a different trajectory in function
over time. Psychosis was also associated with a different profile
of motor disturbances to patients without psychosis. In partic-
ular, patients with psychosis had less chorea and worse balance
than patients without psychosis, despite adjustment for antipsy-
chotic and tetrabenazine use. These differences in motor func-
tion remained stable over time and the lower levels of chorea
were apparent regardless whether psychotic symptoms were
actively present, suggesting the presence of a long-standing trait.
Altogether, the current findings indicate that patients with HD
with psychosis have a distinct clinical course.
The proportion of patients with psychotic symptoms was higher
than previous cross-sectional studies.9–11 The higher proportion
may be due partly to the lower threshold for psychosis used in
our analyses (we considered the presence of symptoms, rather
than only clinically significant symptoms), the regular assess-
ment of patients within the longitudinal design of the study, and
the recruitment of patients from HD specialists, which could
lead to more patients in the sample with challenging or unusual
presentations. Nevertheless, the finding that psychosis is asso-
ciated with cognitive and functional deficits is consistent with
previous research, which has found that patients with psychosis
have lower cognition21 and function9 in cross-sectional compar-
isons. The current study extends previous research by showing
these patients differ in terms of other behavioural symptoms and
such various differences exist longitudinally and after controlling
for demographic and clinical variables. The current study also
reveals that while the cognitive deficits associated with psychosis
may be stable over time, functional deficits—particularly when
measured using TFC—may progress more slowly in patients
with psychosis than patients without psychosis. These latter find-
ings may be the result of a floor effect: Patients with psychosis
may reach significant levels of impairment earlier in the course
of their disease and thereafter deteriorate more slowly. Alterna-
tively, these findings may reflect slower neurodegeneration and
disease progression in patients with psychosis.
By contrast, the finding that psychosis is associated with a
different profile of motor disturbances is less expected. This is
particularly the case given its dissociation from poorer cognitive
and functional outcomes and balance. Other research9 has found
that patients with psychosis have greater motor disturbances
overall, though did not distinguish types of motor disturbances
or control for antipsychotic medication and tetrabenazine use,
and was limited by the small number of patients with psychosis
in their sample. The lower levels of chorea in patients with
psychosis that was found in the current study have not been
previously reported. The current study further reveals that these
differences in motor function are stable over time and not due
to active psychosis or the presence or absence of medication.
Possible mechanism are unclear, though altered dopaminergic
activity has been implicated in both psychosis35 and chorea.36 As
far as we are aware, there have been no detailed neuroimaging
or neuropathological studies of psychosis in HD.
The current study had a number of limitations. First, the study
was limited by its convenience sampling of patients and the fact
that patients were volunteers recruited from HD specialists. As
such, patients may have come from a higher socio-economic
background and differ in the severity of their disease and rates
of psychosis to those seen in other clinical settings. Second,
data were available for 4 years, which is only a small propor-
tion of the course of HD, so longer-term trajectories are unclear.
Third, it was not possible to determine the duration of psychotic
Connors MH, et al. J Neurol Neurosurg Psychiatry 2019;0:1–6. doi:10.1136/jnnp-2019-320646
Neuropsychiatry
J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2019-320646 on 13 October 2019. Downloaded from http://jnnp.bmj.com/ on October 16, 2019 at Stella Welsh - Periodicals
episodes. Finally, analysis of medications was limited and lacked
a fine-grained approach to dosage and duration. While there
are a number of competing methods for standardising antipsy-
chotic doses in terms of their effect on psychotic symptoms in
schizophrenia,37 antipsychotics have different motor side effect
profiles and there is no established way of standardising doses
in terms of their effect on chorea or in a HD population. This
is significant given that a large proportion of patients without
psychosis received antipsychotic medications during the study,
presumably for their chorea. It is thus possible that patients with
psychosis received higher doses of antipsychotics than patients
without psychosis.
Despite these limitations, the current study provides evidence
that patients with psychosis have a distinct clinical course char-
acterised by more severe cognitive, functional and behavioural
deficits, yet also relatively less chorea. The findings, if replicated
in other cohorts, point to an important direction for future
research in terms of clarifying the genetic and neurobiological
underpinnings of this psychotic endophenotype.
Author affiliations
1
Sydney Medical School, The University of Sydney, Sydney, New South Wales,
Australia
2
Centre for Healthy Brain Ageing, The University of New South Wales, Sydney, New
Talbot Campus Library. Protected by copyright.
South Wales, Australia
3
Dementia Centre for Research Collaboration, The University of New South Wales,
Sydney, New South Wales, Australia
4
Sydney School of Public Health, The University of Sydney, Sydney, New South Wales,
Australia
5
Brain and Mind Centre, The University of Sydney, Sydney, New South Wales,
Australia
6
The Garvan Institute of Medical Research, Sydney, New South Wales, Australia
Acknowledgements  We thank the Huntington Study Group COHORT
investigators and coordinators, who collected data and/or samples for this study, as
well as all participants and their families, who made this work possible.
Contributors  MHC helped to conceptualise the paper, analysed the data,
interpreted the data and drafted the manuscript. AT-P helped to conceptualise the
paper, provided statistical advice, interpreted the data and revised the manuscript
for intellectual content. CTL contributed to acquisition of the data, helped to
conceptualise the paper, provided statistical advice, interpreted the data and revised
the manuscript for intellectual content.
Funding  MHC was partially supported by the Dementia Centre for Research
Collaboration, which is funded by the National Health and Medical Research Council
(NHMRC) in Australia. AT-P was partially supported by NHMRC program grant
633003 to the Screening & Test Evaluation Program (STEP). CTL was supported by
a NHMRC Dementia Research Development Fellowship (APP1107657). The CHDI
Foundation, a non-for-profit organisation dedicated to finding treatments for people
with Huntington disease, funded the COHORT study. The CHDI Foundation had no
role in the analyses, data interpretation or writing of this paper.
Competing interests  None declared.
Patient consent for publication  Not required.
Ethics approval  Ethics approval was obtained from institutional ethics committees
associated with individual testing centres (National Institute of Health clinical trials
registry number: NCT00313495).
Provenance and peer review  Not commissioned; externally peer reviewed.
Data availability statement  Data are available upon reasonable request. Data
may be obtained from a third party and are not publicly available.
ORCID iD
Michael H Connors http://​orcid.​org/​0000-​0002-​7224-​1896
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