Neuropsychiatry of Huntington’s Disease and

Other Basal Ganglia Disorders

ADAM ROSENBLATT, M.D.

IRACEMA LEROI, M.D., F.R.C.P.C.

Degenerative diseases of the basal ganglia, such as Huntington’s disease (HD), Parkinson’s dis-
ease, and Wilson’s disease, are characterized by motor, cognitive, and psychiatric manifestations.
HD, in particular, can be considered a paradigmatic neuropsychiatric disorder that has all three
components of the “Triadic Syndromes”: dyskinesia, dementia, and depression. The authors ex-
amine the phenomenology, prevalence, and management of psychiatric disturbances occurring in
diseases of the basal ganglia. They address psychiatric conditions such as depression, mania,
psychosis, obsessive-compulsive disorders, aggression, irritability, apathy, sexual disorders, and
delirium, discussing subtleties of diagnosis, and making reference to more unusual disorders of
the basal ganglia, such as postencephalitic parkinsonism and Fahr’s disease.
(Psychosomatics 2000; 41:24–30)

dromes.”2 This label reflects the confluence of symptoms

T he degenerative diseases of the basal ganglia, such as
Huntington’s disease (HD), Parkinson’s disease (PD),
and Wilson’s disease, have traditionally been classified as
movement disorders, with associated cognitive and psy-
chiatric manifestations. However, HD, for example, might
just as easily be regarded as a dementia, or indeed a pri-
mary psychiatric condition, with associated motor symp-
toms similar to dementia with Lewy bodies. In fact, some
of the earliest descriptions of HD recognized as central
features were the involvement of affect and cognition in
addition to the motor manifestations.1 HD, as well as being
a prototypical basal ganglia disorder, is also a paradigmatic
neuropsychiatric condition.
One heuristic model of the complexity of the basal
ganglia disorders is seen in McHugh’s “Triadic Syn-
Received September 2, 1999; accepted September 2, 1999. From the De-
partment of Psychiatry and Behavioral Science, Neuropsychiatry and
Memory Group, Johns Hopkins University School of Medicine, Balti-
more, Maryland. Address correspondence and reprint requests to Dr. Ro-
senblatt, Department of Psychiatry, Johns Hopkins University, Meyer 2–
181, 600 N. Wolfe Street, Baltimore, MD 21287; e-mail: arosenba@
welchlink.welch.jhu.edu.
Copyright 䉷 2000 The Academy of Psychosomatic Medicine.
conceptualized as the three Ds: dyskinesia, dementia, and
depression.
The basal ganglia disorders encompass a wide range
of diseases. Among them are PD (which is covered exten-
sively elsewhere in this issue of Psychosomatics), HD, Wil-
son’s disease, progressive supranuclear palsy (PSP), Hal-
levorden-Spatz disease, idiopathic calcification of the basal
ganglia, familial calcification of the basal ganglia (Fahr’s
disease), neuroacanthocytosis, Sydenham’s chorea, and
postencephalitic parkinsonism. Genetically similar, and
phenomenologically related to HD, are a group of heredi-
tary neurodegenerative disorders caused by expanded tri-
nucleotide repeats in DNA (deoxyribonucleic acid), in-
cluding DRPLA (dentatorubral-pallidolysian atrophy;
Smith’s disease), Machado-Joseph’s disease (spinocerebel-
lar ataxia, type 3; SCA3), and the autosomal-dominant spi-
nocerebellar ataxias. Many of these disorders are so rare
as to preclude more than anecdotal characterizations of
their psychopathology. We will focus on the major neuro-
psychiatric complications of HD and provide an overview
of current treatment modalities. We will draw on specific
reports, where available, about other basal ganglia diseases

24 Psychosomatics 41:1, January–February 2000


and will consider how the experience with HD might be
generalized to anticipate and treat the psychiatric manifes-
tations of these conditions.
DEPRESSION
The prevalence of major depression in these disorders is
high. We believe that much of this is the direct result of
pathological changes in the brain, presumably activating
some final common pathway, that result in the clinical syn-
drome of major depression. In fact, some have suggested
that depression in neurological disorders affecting the basal
ganglia provides a model for generating hypotheses about
the neuroanatomic basis of “idiopathic” depression.3
George Huntington, in his original description of the
disease that bears his name, stated that there was “a ten-
dency to insanity and suicide.”1 Folstein and colleagues
found a lifetime prevalence of 38% for mood disorders in
patients with HD.4 Of these, 22% met criteria for major
depression. In retrospect, the depressive syndromes often
appear to have preceded the motor symptoms (although it
is hard to be sure, given the prevalence of depression in
the general population) but may occur at any stage of the
disease.5 The suicide rate for patients with HD is 4–6 times
higher than the general population. This rate is even higher
for those over the age of 50.6
The neuropathological basis for depression in HD
might be linked to early neuronal loss in the medial cau-
date, which has connections to limbic structures.7 The sub-
cortical structures affected in the basal ganglia disorders,
such as the caudate in HD, are linked to orbitofrontal and
prefrontal cortices via complex, parallel, frontal–subcorti-
cal circuits.8,9 Mayberg and colleagues10 found that de-
pression in HD is associated with reduced glucose metab-
olism in the orbitofrontal and inferior prefrontal regions.
This finding is consistent with positron emission tomog-
raphy (PET) results that show hypometabolism in the pre-
frontal cortex of depressed patients without a primary neu-
rologic disorder.11
In Wilson’s disease, also known as hepatolenticular
degeneration, excess copper deposition occurs in the len-
ticular nuclei.12 Depression has been reported to occur,
with a prevalence rate as high as 20% in Wilson’s disease.
Depression may also be the presenting symptom of PSP,
which includes degeneration of the basal ganglia, brain-
stem, and cerebellar nuclei. As cognitive impairments ap-
pear, depression, personality changes, and affective lability
may be seen in PSP.13
In our experience, depression is commonly under-
Psychosomatics 41:1, January–February 2000
Rosenblatt et al.
diagnosed in patients with basal ganglia disorders. Com-
munication may be impaired, preventing the clinician from
getting a detailed picture of the patient’s emotional state.
Neurologically mediated changes to cognition and person-
ality may result in an atypical presentation, with irritability,
agitation, or social withdrawal being the most prominent
symptoms. The situational aspects of living with a debili-
tating motor illness can give rise to demoralization, hope-
lessness, loss of self-worth, and expression of a wish to
die. This fact is intuitively obvious to clinicians, patients,
and families. Thus, the sense that depression in these cir-
cumstances is “understandable” sometimes leads clinicians
prematurely to assign a reactive explanation to the patient’s
symptoms, failing to undertake aggressive treatment.
In trying to decide between a “reactive” and an “or-
ganic” etiology, the clinician should consider prior history
of depressive episodes, history of depression in close rela-
tives, the proximity of specific losses and life changes to
the episode, “proportionality,” and the total number of
symptoms. Danger and severity of depressive symptoms
should be the trump card, lowering the threshold for di-
agnosis, pharmacotherapy, or hospitalization.
There is also a danger of overdiagnosis. Some of the
individual symptoms of these disorders may resemble a de-
pressive state. Physical changes, such as weight loss, sleep
disturbance, bradykinesia, restricted facial expressions, ap-
athy, and bradyphrenia, may be mistaken for a major de-
pressive episode, which may lead to unnecessary pharma-
cotherapy in patients who are specially vulnerable to the
central nervous system side effects of antidepressants.
We know of no randomized, controlled trials of the
treatment of depression in HD and the other basal ganglia
disorders. Therefore, clinical experience must guide the
choice of therapeutic agents, often by extrapolation from
principles developed in the treatment of depression in other
medically ill patients. For example, while no class of anti-
depressant has been found to be uniquely effective in these
disorders, patients with basal ganglia disorders are espe-
cially vulnerable to adverse effects, such as sedation, falls,
and anticholinergic-induced cognitive impairment. There-
fore, the tricyclic antidepressants, although more exten-
sively studied, should no longer be considered first-line.
We have generally found selective serotonin reuptake in-
hibitors (SSRIs) to be easier to manage and better tolerated.
Also, the SSRIs may be useful in treating some of the psy-
chiatric symptoms seen in some of these disorders that may
not fit into a well-defined syndrome, such as irritability,
apathy, and obsessiveness, which may be due to these
drugs’ putative role in improving “frontal function.” We
25
Huntington’s Disease and Basal Ganglia Disorders
have also had success in treating HD patients with many
of the other newer antidepressants, such as bupropion
(Wellbutrin), venlafaxine (Effexor), and nefazodone (Ser-
zone), but it remains to be seen whether these agents pos-
sess all of the less-specific benefits of the SSRIs.
If the patient’s depression is accompanied by delu-
sions, hallucinations, or significant agitation, it may be nec-
essary to add an antipsychotic medication. Some strategies
are provided in the section on psychotic disorders. In cases
in which the patient is dangerously suicidal, not eating or
drinking, or is unresponsive to several trials of medication,
electroconvulsive therapy (ECT) should be considered. De-
pressed patients with HD respond to ECT, which they typ-
ically tolerate well. However, there is probably an in-
creased risk of delirium from ECT in the setting of
subcortical dementia.14,15
When a depression is believed secondary to some spe-
cific medical cause, such as hypothyroidism or exogenous
steroids, correction of the underlying problem may be all
the treatment that is needed. In the case of Wilson’s disease,
for example, timely treatment with penicillamine will usu-
ally reverse the neurologic symptoms and may ameliorate
the psychiatric symptoms. However, if a depression re-
mains, standard antidepressant therapy, as outlined earlier,
is warranted. Once again, the severity or duration of the
depression may mandate the initiation of treatment, what-
ever the suspected cause.
MANIA
Although depression is the most common specific psychi-
atric diagnosis in HD, a smaller number of patients become
manic, displaying elevated or irritable mood, impulsive-
ness, overactivity, decreased need for sleep, and grandi-
osity. Some may even have a classical bipolar disorder,
alternating between episodes of depression and mania. In
his review of the subject, Mendez looked at seven studies
and estimated an average rate of mania (with variable def-
initions of “mania”) of 4.8%.16 Folstein found hypomania
and manic episodes in up to 10% of HD patients.5 There
are few reports of mania or hypomania in other basal gan-
glia disorders, although emotional lability and irritability
have been reported in Wilson’s disease and PSP.12,17
Patients with mania or a bipolar mood disturbance in
the context of a basal ganglia disorder should probably be
managed with a mood stabilizer other than lithium. Clinical
experience, and a small amount of literature, suggest that
HD patients with manic or hypomanic symptoms respond
less well to lithium and may be more susceptible to toxic
26
effects. It may be that “mania” in patients with HD is not
the same neurophysiologic entity as mania found in idio-
pathic bipolar disorder, that something about the disorder
limits the response to this drug, or simply that lithium is
poorly tolerated in patients vulnerable to delirium and
dehydration. The same caveat has been expressed about
patients with “AIDS mania.”18
Divalproex sodium and carbamazepine are good alter-
natives to lithium, starting with the lower doses than would
be used with robust patients. Liver functions and blood
counts should be routinely monitored, because these med-
ications carry a risk of liver-function abnormalities (par-
ticularly divalproex sodium) and blood dyscrasias (particu-
larly carbamazepine). Finally, manic patients who have
delusions and hallucinations and therefore are very agitated
(e.g., requiring hospitalization), or who may not fully re-
spond to mood stabilizers, may require an antipsychotic.
The judicious use of benzodiazepines for immediate con-
trol of these symptoms may also be helpful. ECT may also
be considered should other treatments fail.
PSYCHOTIC DISORDERS
A link between basal ganglia pathology and primary psy-
chotic disorders such as schizophrenia has been hypothe-
sized. For example, many of the symptoms of PD, includ-
ing poverty of speech, flattened affect, and psychomotor
retardation, resemble the negative symptoms in schizo-
phrenia.19 It has also been established that schizophrenia
patients who are antipsychotic-naive may have extrapyra-
midal signs similar to PD.20 These lines of thinking suggest
a role for the basal ganglia in psychosis and schizophrenia-
like presentations.
A recent review of 11 studies of HD patients found an
increased frequency of psychosis in HD, ranging from 3%
to 12% of patients.16 The psychotic presentations included
poorly systematized paranoia, isolated delusional states,
and psychotic states resembling various types of schizo-
phrenia.21,22 Those with an early age at onset of HD seem
to be at an increased risk of such psychoses.23 Overall,
these psychiatric symptoms in HD presented early in the
course of the illness and declined as the cognitive impair-
ment became more profound.16
The underlying neuropathology leading to psychosis
in HD is not well understood. However, it is possible that
the relative hyperdopaminergic state, resulting from selec-
tive degeneration of other neurotransmitter-containing neu-
rons, superimposed on faulty subcortical circuits, may lead
to the development of psychotic symptoms.24 Also, there
Psychosomatics 41:1, January–February 2000

appears to be an anterior bihemispheric decrease in metab-
olism, as seen by PET in psychotic HD patients. This
change is similar to the relative hypofrontality seen on PET
in patients with schizophrenia.25 Finally, since psychosis
often occurs early on in the disease, and the early patho-
logical changes include atrophy of the medial caudate, it
is possible that the caudate may have a role as well.26
In Wilson’s disease, psychosis is less common. In the
series of 195 cases surveyed by Denning and Berrios,12
fewer than 2% of the patients had such symptoms. The
most common problems among the 20% of patients with
psychiatric disturbances were a mixture of behavioral dis-
turbances (“incongruous behavior,” recklessness, disinhi-
bited behavior); poor school performance; personality
changes; irritability; emotional lability; anxiety; anorexia
nervosa; antisocial behavior; and alcohol abuse.27
Postencephalitic parkinsonism (PEP), which manifests
with microscopic foci of inflammation in the gray matter
and basal ganglia, may also present in a “psychotic
form.”28 This effect was first described in von Economo’s
1929 classic paper.29 During the acute phase, the patient
may present with acute confusion, depression, hypomania,
catatonia, and psychosis, along with, or instead of, the
more commonly recognized motor and ophthalmologic
symptoms. The effects may have been a delirium rather
than a “pure” psychosis. Chronic sequelae have been re-
ported to include personality changes and a full range of
schizophrenia-like presentations. Davison and Bagely30
found 15%–30% of a sample of 40 patients with PEP to
have paranoid–hallucinatory psychoses. Another 10% of
the same sample had symptoms indistinguishable from
what was described as “dementia praecox” at the time.
Finally, Fahr’s disease, or familial idiopathic calcifi-
cation of the basal ganglia, a disorder characterized by
parkinsonism or choreoathetosis, subcortical dementia, and
focal cortical deficits such as dysphasia, may present with
a psychosis. Cummings et al.31 identified two types of pre-
sentation. In early-onset cases, psychosis is a more com-
mon presenting feature, whereas in later-onset cases, motor
and cognitive symptoms predominate. More recent re-
viewers, however, have disputed this assertion. Flint and
Goldstein32 concluded that the schizophrenia-like presen-
tations seen in Fahr’s disease may simply be due to a
chance association.
The new onset of psychotic symptoms, even in pa-
tients with basal ganglia disorders, should prompt a search
for specific causes or precipitating factors. Such symptoms
may be caused by mood disorders, delirium, substance in-
toxication, and withdrawal or medication effects, particu-
Psychosomatics 41:1, January–February 2000
Rosenblatt et al.
larly if antiparkinsonian medications are being used. Psy-
chosis could then result from either a hyperdopaminergic
state or an anticholinergic delirium. Once these possibili-
ties have been considered and excluded, therapy aimed
specifically at the psychosis may be attempted.
The use of neuroleptics in basal ganglia disorders is
complicated by the risk of worsening the underlying move-
ment disorder. Small doses of high-potency neuroleptics,
such as haloperidol and fluphenazine, are often used in
mild-to-moderate cases of HD and other conditions such
as Tourette’s syndrome (TS), to suppress chorea and tics.
Therefore, in the earlier phases of the illness, an agent tar-
geting both hyperkinesis and psychotic symptoms may be
preferable. In more advanced cases of HD and in other
basal ganglia disorders, dystonia and parkinsonism is a
more significant problem, and may be worsened by the
high-potency agents. In these situations, the newer, “atyp-
ical” agents, such as olanzapine (Zyprexa), risperidone
(Risperdal), or quetiapine (Seroquel) are generally better
tolerated. In fact, the advent of the atypical antipsychotics
has revolutionized the treatment of several of these disorders.
Attention must be paid to the development of tardive
dyskinesia, because these superimposed movements may
be difficult to tease out from the underlying movement dis-
order. Risperidone and olanzapine may also precipitate ma-
nia, particularly in those with vulnerable brains, (Leroi et
al., unpublished) and quetiapine is sometimes excessively
sedating. Finally, if the psychosis is refractory to treatment
with neuroleptics and the patient poses a significant risk,
ECT is an option. There has been one report of the use of
ECT for psychosis in HD, and success with ECT in panic
disorder with psychosis has also been reported.33,34
OBSESSIVE-COMPULSIVE DISORDER
Obsessive-compulsive disorder (OCD) has been reported
in HD and is common in TS, another disorder in which
basal ganglia pathology is implicated.35,36 Cummings and
Cunningham, in 1992,35 reviewed several studies of pa-
tients with compulsive symptoms complicating neurologic
disorders that affected the caudate nucleus and globus pal-
lidus. The management of OCD in basal ganglia disorders
should follow the same lines as treatment for idiopathic
OCD, namely, with serotonergic antidepressants being the
first line. Cognitive and behavioral psychotherapy may also
be helpful, but cognitive impairment tends to limit their
effectiveness. Patients may have difficulty understanding
the treatment, and impulsiveness and memory impairment
make it hard to build on previous successes.
27
Huntington’s Disease and Basal Ganglia Disorders
AGGRESSION, IRRITABILITY, AND APATHY
Symptoms ranging from irritability to intermittent explo-
sive anger have been reported in HD and Wilson’s dis-
ease.12,16 Aggression is a common reason for psychiatric
hospitalization in patients with HD.37 Irritability and ag-
gression may be due to multiple causes, including person-
ality changes accompanying HD, and other psychiatric dis-
orders, such as depression, mania, and psychosis.
Compared with a matched sample of patients with Alzhei-
mer’s disease, HD patients have been shown to be signifi-
cantly more aggressive when measured on a scale of apathy
and irritability.38 There did not seem to be any interrela-
tionship among the variables of apathy, irritability, and ag-
gression in this study, although a correlation between pre-
morbid “bad temper” and irritability was seen in the HD
group. One of the reasons for irritability in some basal
ganglia disorders may be the development of “rigidity” of
thinking. This trait causes patients to perseverate relent-
lessly on a particular desire or idea, resulting in outbursts
when perceived needs are not met.
The key to management of aggression and irritability
is to place each in its proper context, and to detect and
avoid precipitants. This step will prevent premature use of
medications. Factors that may precipitate an irritable epi-
sode include hunger, thirst, pain, inability to communicate,
frustration with failing abilities, boredom, and an unex-
pected change in routine.38 If there is a potential for vio-
lence, or if conservative measures fail, there are several
medication options. Important treatment principles include
focusing on reversing the underlying cause of the symptom
and frequent medication reviews, thus avoiding enduring
treatment for what is usually an episodic symptom.
Although there are no published studies of efficacy of
psychotropic medication in HD-related aggression and ir-
ritability, clinical experience has shown that antipsychotics,
mood stabilizers, and antidepressants may be helpful.
Mood stabilizers may be more effective in cases in which
the irritability appears to have an affective basis, and anti-
psychotics may have limited efficacy in cases in which
there is no psychosis.39 In our clinical experience, the
SSRIs are among the most helpful agents for these prob-
lems, perhaps because of their frontal activity. There are
also several reports of the efficacy of beta-blockers in the
treatment of aggression in HD.40–43 These are generally
well tolerated, although there have been two descriptions
of paradoxical aggression.42,44 Side effects of hypotension
and bradycardia may complicate the use of propranolol,
but pindolol, a partial beta-agonist, seems to be relatively
28
safe in this regard.43 Doses must be individually titrated,
and contraindications to use, such as bronchospastic dis-
ease and congestive heart failure, must be noted. There
have been no reports of the worsening of the movement
disorder with beta-blockers. Also, there is some evidence
to support the use of the SSRIs, clomipramine, clonaze-
pam, and hydroxyzine for use in HD-related aggression.38
In addition to irritability and aggression, apathy is of-
ten noted as part of the “personality change” that occurs
with the progression of HD. In the aforementioned sample
of HD patients, apathy was detected in up to 48%.37 Apathy
may be secondary to depression or the use of antipsychotic
medications, but often takes the form of an independent
symptom. Apathy may manifest as withdrawal from social
situations, decreased initiative and motivation, and a dis-
regard for personal hygiene and appearance.16 This symp-
tom has also been called “situational apathy,” because it
tends to improve in structured or stimulating environ-
ments.45 There are few specific treatments for apathy. In
many cases, the best response is to educate the patient’s
family about this symptom and to avoid conflict over minor
issues. When the apathy is severe, however, a number of
agents have been useful in our experience, including
SSRIs, amphetamines, and dopaminergic agents, such as
amantadine and bromocriptine. These latter agents may
worsen chorea in some disorders.
DELIRIUM
Delirium is common in HD and the other basal ganglia
disorders. Patients in the later stages of these conditions
may have severely aberrant movements, which can impede
mobility and oral intake. Hence, patients are particularly
vulnerable to delirium resulting from volume depletion,
poor nutrition, medical complications, metabolic distur-
bances, and medication effects. Delirium is often multifac-
torial. For example, a patient who is no longer able to swal-
low may become volume-depleted and therefore more
vulnerable to toxicity from his or her medication. Respi-
ratory infections and, particularly, urinary tract infections
should be ruled out, as they are a frequent cause of delirium
in these patients.
Delirium often mimics other psychiatric disturbances. It
may be accompanied by hallucinations, paranoia, or mood
lability. Both the hyperaroused, as well as the more somnolent
obtunded manifestations of delirium should be recognized.
The latter is often mistaken for depression, but, when ques-
tioned carefully, the patient will not report a low mood.
In the management of any acute change in mental
Psychosomatics 41:1, January–February 2000

status, a full medical workup and review of medications is
indicated. The definitive treatment for a delirium is reversal
of the underlying cause. However, low doses of neurolep-
tics may be helpful in the short-term management of a pa-
tient who is agitated because of the delirium.
SEXUAL DISORDERS
Changes in sexuality have been well documented in HD.
Disorders of sexual functioning, such as hypoactive sexual
desire and inhibited orgasm, have been reported in men,
with rates of 63% and 56%, respectively.46 In female pa-
tients, 75% had hypoactive sexual desire, and 42% had
inhibited orgasm. Also, sexual aberrations, such as sexual
assault, promiscuity, incest, indecent exposure, and voy-
eurism, have all been described in HD.37,47 The etiology of
these abnormalities may be related to specific psychiatric
syndromes prevalent in HD, such as mania, to the under-
lying neurotransmitter deficits of HD, or to medication ef-
fects.24 There is some evidence that male HD patients with
both inhibited orgasm and increased sexual interest are at
higher risk for developing paraphilias.47
There have been no studies systematically examining
the management of inappropriate sexual behaviors in pa-
tients with HD. Treating an underlying psychiatric condi-
tion, such as a depression, may ameliorate the sexual symp-
toms. A short trial of an antipsychotic may also be useful.
If these measures fail, treatment with an antiandrogen
agent, such as leuprolide acetate, can be attempted. Leu-
prolide is a gonadotropin-releasing hormone agonist,
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CONCLUSIONS AND DISCUSSION
We have sought to make several facts clear: that the basal
ganglia disorders are neuropsychiatric disorders, that they
have certain features in common, and that the psychiatric
disturbances are amenable to rational treatment. In attempt-
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