Secondary Schizophrenia (136 page)

to rapid copper mobilization, but persistent treatment
Cognitive disorders occur in somewhat less than
usually leads to remission (see the section on treating
25% of WD patients and cognitive impairments, mem-psychosis in WD, discussed later).

ory, and IQ can improve after WD is treated
[27, 30].

Associated neurological features in WD psychosis
WAIS-R IQ score impairments have been associated
have included parkinsonism
[50, 54, 56],
dysarthric
with neurological and hepatic features
[33].
Atten-speech
[51],
gait disorders
[50],
and upper motor neu-tional deficits are associated with dropping out of
ron signs (Babinski, hypertonia, hyperreflexia)
[56].

school and loss of employment
[27].
Diminished func-Radiological correlates of WD psychosis have included
tional capacity correlates with ataxia, tremor, and focal
bilateral putaminal cavitation with delusions
[51]
and
thalamic lesions
[58].

T1 and T2 hyperintensities in the putamen, caudate,
Mania, manic features including hypersexual-

and pallidum with delusions and auditory and visual
ity, hyperactivity, and aggression, emotional lability,
hallucinations
[56].

pathological laughing and crying, depression, anxi-ety, and substance abuse
[27,
40]
can develop in WD.

Other features of schizophrenia observed

Mania has been observed, as have isolated manic
behaviors, including hypersexuality, hyperactivity, and
in Wilson’s Disease

aggression
[27,
40].
Major depression occurs in at least
Beyond the typical positive symptoms of hallucina-30% of patients with WD, and may affect nearly all
tions, delusions, and thought disorders, a wide diver-patients at some point in the illness
[3, 26, 28,
32,

sity of psychiatric features are observed in schizophre-

59]
. Depression has correlated with cognitive impair-nia, and many of these are evident in WD. Wil-ment, parkinsonian rigidity, bradykinesia, gait disor-son observed prominent psychiatric symptoms in his
ders, and dilatation of the third ventricle
[3,
58, 59].

patients, including silliness, euphoria, sexual preoccu-Suicidal behavior has been documented in as many
pation, hebephrenia, catatonia, occasional hallucina-as 16% of patients across studies
[26, 27, 30],
with
tions, “hysterical” behavior, and “narrowing of mental
the risk potentially compounded by disinhibited and
horizons.” He concluded that “facility, docility, child-impulsive personality changes. Isolated manic symp-ishness, and emotional overaction form the chief fea-toms and some cases of depression improve with anti-tures of the more chronic cases”
[2]
. Other stud-copper treatment.

ies indicate that personality disturbances, irritability,
depression, and academic or employment failure are
common psychiatric manifestations
[27,
40].

Personality changes are the most common psychi-Treating psychosis in Wilson’s Disease
atric disorders in WD, occur in about half of patients
In using psychotropics to treat psychoses arising in
[30,
34],
and include mainly irritability and aggression,
WD, it is important to determine the origin of the
but also apathy, disinhibition, and impulsivity,
[2, 30],

psychotic features. For example, psychotic features
sometimes leading to marital disruption and crimi-may arise from primary psychiatric disorders coex-nality
[32]
, and tend to be associated with neurolog-isting with WD, from WD itself, from WD treatical or hepatic features
[33].
In a series of 34 consec-ment, or from secondary complications of WD such
utive patients with confirmed diagnoses of WD, irri-as delirium, dementia, bipolar disorder, depression,
tability correlated with the presence of neurological or
seizures (ictal or interictal psychoses), and so on. There
hepatic features of WD and was less apparent among
is some evidence that the benzodiazepine antagonist
asymptomatic WD patients
[33]
. Irritability, incon-flumazenil may have utility in the delirium of hepatic
341

gruous behavior, and personality disturbances have
encephalopathy
[60].

Organic Syndromes of Schizophrenia – Section 3

As in other neuropsychiatric illnesses, medicines
dysrhythmias, including tachycardia or bradycardia
should be started at low doses and gradually titrated
with reduced cardiac efficiency
[66].
EKG abnormal-upward to avoid evoking serious side effects. Con-ities occur in about 30% of patients with WD, and
trolled studies of psychotropic treatment in psychiatric
orthostatic hypotension and sudden death sometimes
WD have not been reported.

occur. Therefore, psychotropics with low dysrhythmo-The clinician must also stay alert for atypical pre-genic and hypotensive potentials will be critical in
sentations and atypical responses in WD. Neuroleptic-some cases
[65].
Bone marrow suppression can occur
refractory psychosis responding to lithium
[61]
and
with certain psychotropics as well as in WD. Attention
nortriptyline-refractory depression responding to lev-must also be given to drug-drug interactions. Given
odopa
[62]
have been reported in lenticular dis-the potentially lethal treatment effects, a thorough disease. Otherwise, conventional psychopharmacological
cussion of benefits, risks, and side effects should be
approaches should be applied with special considera-undertaken as part of the informed consent process.

tion of the effects of copper deposition on the brain,
The case report literature reveals that psychotic
liver, kidney, heart, and bone marrow.

features are sometimes unresponsive
[50, 52, 54, 56]

Basal ganglia cuprification may lead to a height-to or actually aggravated
[54]
by antipsychotic ther-ened susceptibility to psychotropic-induced dysto-apy, yet responsive to anticopper therapies
[26,
41,

nia and other movement disorders
[63].
Neurolep-

50, 51, 52, 53, 54].
Treatment failures have occurred
tic malignant syndrome, parkinsonism, and severe
with haloperidol
[54, 56],
chlorpromazine
[54],
thior-extrapyramidal reactions
[16]
are more likely in WD,
idazine
[56],
and a variety of other neuroleptics, pre-and atypical antipsychotics may be safer in this regard
sumably due to cuprification of circuits mediating
[53].
Cortical actions of atypical antipsychotics may
antipsychotic response. In the prospective study of
still be viable even when subcortical dopaminergic
Oder and colleagues
[26],
the authors noted that delu-systems are unresponsive to antipsychotics. Capaci-sions in their three patients responded well to anticop-ties to worsen cognitive impairment and gait disorders
per therapy. Catatonia has also responded to anticop-must be considered. Clozapine can attenuate parkin-per therapy
[54].

sonian and dystonic features in non-WD patients,
Case reports reveal occasional worsening of psy-although bone marrow suppression and seizure risks,
chosis after commencing anticopper therapies, anal-already intrinsic to WD, should be considered. A sin-ogous to WD treatment-related neurological exacer-gle case report indicated improvement in delirium and
bations
[41, 51]
. In one case, the patient developed
a persecutory delusion in WD during treatment with
de novo bizarre behavior, visual hallucinations, para-clozapine 100mg/d, which had failed to respond to
noid delusions, referential thinking, and heightened
penicillamine and zinc
[64].
Vigilance for cognitive
sensory awareness within several months of starting
impairment, cardiac dysrhythmia, and hypotension
penicillamine treatment
[41].
With persistent anticop-is of course necessary with antipsychotics possessing
per treatment, however, subsequent remission of psy-anticholinergic and alpha-blocking properties because
chotic symptoms occurred a number of months later
WD patients are already at risk for these conditions
[51].

due to the disease itself. Psychotropics that lower
WD patients with psychosis may be particularly
seizure threshold, such as clozapine, may increase the
prone toward extrapyramidal side effects
[53,
63].
At
likelihood of seizures in WD, especially during WD

times, extrapyramidal side effects have been refractory
treatment
[59].
Patients on anticonvulsants are at risk
to treatment with antimuscarinics
[53]
and dopamine
for the many drug interactions that can occur between
agonists
[53],
presumably related to putaminal cuprifi-these agents and psychotropics
[65].
Liver disease in
cation
[53]
or cuprous alteration of striatal muscarinic
WD hepatic and renal involvement may affect the
and dopamine receptor functions. Neuroleptic malig-metabolism of psychotropics, leading to dose accu-nant syndrome in WD has responded to dantrolene
mulation and toxic blood levels. Use of shorter half-and bromocriptine in at least some cases
[67].

lived drugs, lower doses, and drugs that are minimally
ECT should only be administered with extreme

metabolized before elimination may circumvent this
caution in WD, given the capacity for prolonged
problem. Renal dysfunction in WD may lead to ele-seizures
[57]
and the dearth of studies reporting safety
vated lithium concentrations. Cardiac copper depo-and efficacy
[55, 56].
In one case, ECT (six bifrontal
342

sition can affect conduction pathways and produce
treatments, sine wave pulse, 110 V, 0.8 s) along with
Chapter 27 – Wilson’s Disease

haloperidol 15 mg/d, were safe and effective in resolv-from restoring a more normal physiology to systems
ing auditory hallucinations, delusions, thought disor-involved in psychosis.

der, and suicidal ideation in a paranoid psychosis possibly ascribable to WD
[55].
In a second case, the first
Future directions

bilateral treatment (30 s seizure) markedly improved
Against this backdrop of unknowns described above,
muscular rigidity, and the second treatment (49 s
an agenda for research is offered. Pursuit of this agenda
seizure) led to normal ambulation and remission of
can produce information relevant to understanding
delusions and auditory command and visual halluci-and effectively treating psychosis in WD. It can also
nations
[56].
However, in another case, a single bilat-inform our understanding of pathogenetic mecha-eral brief pulse ECT (12.4 J of charge) resulted in a
nisms involved in schizophrenia and other primary
3-minute seizure and mania in a WD patient with
psychoses. A research agenda includes:

persecutory and control delusions, loose associations,
disorganized behavior, negativism, cognitive impair-1. Large multicenter studies to obtain adequate
ment, and major depression, suggesting the need for
sample size and to average out selection factors
extreme caution in patients with high copper levels
2. Prospective determinations of psychosis

[57].
WD itself carries an increased risk of seizures.

prevalence in WD, taking into account sample

selection and referral biases, with particular
Research considerations

attention to:

a) Visual, auditory, and other modalities of

Possible pathophysiological mechanisms

hallucinations

for psychosis

b) Specific types of delusions

c) Formal thought disorders

Much research is still needed before a tentative patho-d) Inappropriate affect
physiology of psychosis in WD can be formulated.

e) Bizarre or inappropriate behavior

Copper deposition in specific brain regions may play a
f) Catatonia

role. Candidate structures include the ventral tegmen-g) Negative symptoms
tal area, ventral striatum/nucleus accumbens, ventral
pallidum/internal pallidum, thalamic nuclei, temporal
h) Cognitive impairment

cortex, amygdala, other limbic structures, and other
i) Functional impairment in WD psychosis

regions, and copper deposition in regions such as
j) Psychotic syndromes using DSM-IV-TR

these should be evaluated in prospective studies. Cop-criteria and structured clinical interviews
per may affect energy metabolism, leading to reduced
3. Prospective evaluation of WD patients to