CLINICAL CASE CONFERENCE This article addresses the Core Competency of Patient Care and Procedural Skills
From Yale University School of Medicine
The Spectrum of Psychiatric Symptoms in Wilson’s
Disease: Treatment and Prognostic Considerations
Paula C. Zimbrean, M.D., Michael L. Schilsky, M.D.
CASE PRESENTATION
A psychiatric consultation was requested by the internal
medicine inpatient service for a 39-year-old woman with
no past psychiatric illness who presented with several days
of disorganized behavior.
History of Present illness
Nine months earlier, the patient had presented to her pri-
mary care provider with mild neurological complaints. The
course of her physical symptoms and laboratory tests
leading to the diagnosis of Wilson’s disease are summarized
in Table 1, in the entries for months 0–8. For her Wilson’s
disease, the patient was started on a combination of the
copper chelator trientine and zinc. She soon developed
colitis, which was thought to be a side effect of the trientine.
To treat the colitis, prednisone was initiated at 40 mg/day,
and trientine was discontinued.
The psychiatric symptoms for which the formal eval-
uation was requested began approximately 3 days after
prednisone was started: the patient began exhibiting
insomnia, increased energy, and delusions of thought
control. She had been staying up at night working on two
computers and cooking at the same time. She claimed to
be a famous movie star. She was admitted via the emer-
gency department to the medical service.
Mental Status Examination and Pertinent
Physical Findings
Our psychiatric consultation team examined the patient
within 2 hours of admission. She appeared to be a
groomed woman looking her stated age, hyperactive, with
bizarre movements that she called “my special dance.”
Her affect was excessive, bizarre, and labile. She had
loose associations and delusions of thought insertion. She
could not participate in formal cognitive testing, but she
was oriented to person, time, and place and there were
no fluctuations in alertness. The neurological evaluation
revealed limitation of upward gaze, mild ptosis, reduced
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blink frequency, axial rigidity of the neck, reduced
smooth-pursuit eye movements, and a slight tilt of the
neck with the chin down and to the left. There was no
glabellar reflex, and no cogwheel rigidity. She had Kayser-
Fleischer rings.
Psychosocial History
The patient was married and had two children. She had
completed postgraduate education and had been working
as a freelance designer until she became ill. There was no
family history of psychiatric illness.
Laboratory Data
Basic serum chemistry values were within normal limits.
CBC was notable for a WBC count of 13.531000/mL, a
hemoglobin level of 13.3 g/dL, a hematocrit of 40.1%, and
a platelet count of 34531000/mL. Liver functions tests
were notable for normal direct and total bilirubin levels,
an AST level of 47 U/L, an ALT level of 159 U/L, and an
ALP level of 185 U/L. The patient’s albumin level was
3.1 g/dL and total protein 6.7 g/dL. Her prothrombin
time was 11.8 seconds, and her INR (international nor-
malized ratio) was 1.12. Repeated copper studies consistent
with her diagnosis of Wilson’s disease were ceruloplasmin
levels ,2 mg/dL, a total serum copper level of 0.25 mg/dL,
and a 24-hour urinary copper level of 187 mg. A brain MRI
showed nonspecific foci of increased signal in the last
centrum semiovale and white matter of the right parietal
lobe.
Treatment Course
A presumptive diagnosis of steroid-induced psychosis
was made. Prednisone was tapered off over the next 2 days
and the patient was given one dose of olanzapine, 2.5 mg,
after which she developed significant neck dystonia. The
olanzapine was discontinued and quetiapine was started.
The patient tolerated 25 mg/day of quetiapine, although
continued
Am J Psychiatry 172:11, November 2015

when the dosage was increased to 50 mg/day, she de-
veloped orthostatic hypotension and sedation, and the
dosage was reduced to 12.5 mg/day. She continued to be
psychotic and grandiose (she had plans to buy $50,000
worth of stocks and claimed she was the CEO of a com-
pany). Over 5 days, the quetiapine was titrated to a total
dosage of 75 mg/day, and her psychiatric condition im-
proved: she became calmer and cooperative. She was
discharged home.
While at home, the patient continued to be disorga-
nized and tangential; she developed paranoid delusions,
hallucinations, and pressured speech. She became aggres-
sive, which prompted readmission 3 weeks after dis-
charge. She had been off steroids for 6 weeks and had
continued the zinc for Wilson’s disease. Over the next 2 weeks,
the quetiapine dosage was increased to 400 mg/day,
with intermittent adherence. The patient remained dis-
organized, incoherent, and paranoid. She developed
Capgras syndrome and had vague thoughts of hurting her
family. She was deemed psychiatrically disabled and was
committed to the psychiatric inpatient unit. In parallel,
trientine was resumed and added to the zinc for treatment
of Wilson’s disease after a sigmoidoscopy and biopsy
showed no active colitis.
After the patient was transferred to the psychiatric
unit, quetiapine was discontinued and haloperidol was
initiated at 20 mg/day. The patient developed parkin-
sonian symptoms (Table 1, month 10). After 4 days of
psychiatric hospitalization, she returned to the medi-
cine service for bloody diarrhea, and trientine-induced
colitis was confirmed by endoscopy. She was started on
DISCUSSION
Background: Psychiatric Manifestations in
Wilson’s Disease
Wilson’s disease is an autosomal recessive illness attributed
to a defect of the gene ATP7B (on chromosome 13) leading to
excessive accumulation of copper in liver, brain, and other
tissues. Its lifetime prevalence is estimated at 1:30,000 (1).
A vast range of psychiatric symptoms has been described
in patients with Wilson’s disease, so many that the illness has
been called “a great masquerader” (2). In Wilson’s 1912 mon-
ograph describing the disease for the first time, eight of
12 cases had psychiatric symptoms (3). Psychiatric symptoms
have a higher prevalence among patients with Wilson’s dis-
ease than in the general population (4). Psychosis has been
described at various points in the course of Wilson’s disease
(5–8). Cases have been reported of patients carrying a dia-
gnosis of schizophrenia for years before being diagnosed with
Wilson’s disease (9).
The mechanism of psychiatric symptoms in Wilson’s di-
sease is not clear. Because symptoms can occur at the start
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CLINICAL CASE CONFERENCE
prednisone at 10 mg/day for 1 week, without worsening
of her psychosis. Her paranoia began to resolve. Her
thought process remained tangential. Over the next month,
her psychotropic medications were adjusted (Table 1,
month 10), initially on the medical unit and later on an
outpatient basis, to address her psychosis and haloperidol-
induced parkinsonism.
Over the next 5 months the thought disorder and
parkinsonian symptoms slowly resolved while quetiapine
and clonazepam were continued (Table 1, months 11–16).
Nine months after the start of the psychotic symptoms,
the patient showed no evidence of psychosis, had no
mood symptoms, and had resumed her freelance work.
Her family described her as being as fully engaged with
them as she had been before her illness. Her copper and
ceruloplasmin levels were consistent with treated Wil-
son’s disease (Table 1, month 17). In the subsequent
3 months, clonazepam was tapered and discontinued, and
shortly thereafter, quetiapine was tapered and discon-
tinued. Approximately 13 months after the beginning of
her psychotic episode, the patient presented with mod-
erate depressive symptoms triggered by the realization
of the “time lost due to the big W” (the nickname the
patient uses for Wilson’s disease). Sertraline was pre-
scribed for 6 months and discontinued when her symp-
toms resolved.
Four years after her initial psychiatric evaluation and
3 years after her last depressive episode, the patient has
remained asymptomatic off psychotropic medications.
She has continued to take zinc as maintenance treatment
for her Wilson’s disease.
of the illness, they are not fully explained by the psychosocial
impact of a medical condition. Initially it was thought that basal
ganglia abnormalities led to various psychiatric symptoms
through dopamine dysregulation. More recent studies have
explored the role of copper and other microelements in
schizophrenia and bipolar illness (10, 11).
Our patient’s initial presentation suggested steroid-induced
mania, with onset within days after starting prednisone and
a clinical picture that included elevated energy, decreased need
for sleep, and grandiosity. Other manic features, however, such
as pressured speech, flight of ideas, and psychomotor agitation,
were lacking. Over the course of the first month, the psychotic
symptoms became predominant, with delusions of being con-
trolled, Capgras syndrome, posturing, and tangential thought
process. Three factors suggest that steroids were not the primary
cause of her psychiatric illness. First, the psychosis persisted
months after the steroids were discontinued, whereas 90% of
cases of steroid-induced mania resolve within 6 weeks after
discontinuation of steroids (12). Second, there were no side
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TABLE 1. History of Present Illness in a Patient With Wilson’s Diseasea

Signs and Symptoms Medications
Gastrointestinal Laboratory and
Time Psychiatric Neurological and Hepatic Imaging Results General Psychotropic
Month 0 None Tingling of tongue, None Brain MRI shows None None
lips, fingertips diffuse area of
increased T2
signal in the white
matter of the pons
to the midbrain,
extending into the
midline cerebellar
white matter
Month 1 Depression All the above plus None EMG studies None Citalopram for 1 month,
decreased taste, normal; MRI no effect, discontinued
perioral burning, shows no interval
drooling, gait change in the
unsteadiness, brain lesions;
bladder urgency cervical spine MRI
and hesitancy normal; lumbar
puncture results
normal
Month 8 None All the above plus None Ceruloplasmin level None None
weakness in all ,2 mg/dL (ref.
extremities. range, 14–47.8);
Paresthesias on serum copper
head, slowed level, 0.25 mg/dL
speech, cognitive (ref. range, 0.75–
slowing 1.45); 24-hour
urine copper
level, 187 mg/dL
(ref. range, 15–60)
Wilson’s disease Trientine and zinc
diagnosis are initiated
Month 8.5 Psychosis Limitation of upward Diarrhea with Prednisone, Olanzapine, one dose,
(delusions, gaze, ptosis, neck blood in 40 mg/day, 2.5 mg; discontinued
grandiosity, tilt with chin down stools for trientine- because of dystonia.
thought and to the left secondary to induced colitis. Quetiapine at 50 mg h.s.
disorder); trientine. Trientine induced hypotension;
BPRS, 91 → 55 Diarrhea discontinued. dosage was decreased,
resolved Prednisone then titrated slowly
discontinued. to 400 mg, with
intermittent adherence
Month 10 Psychosis Severe parkinsonism: Diarrhea returns Trientine Psychiatric hospitalization,
worsening, shuffling gait, 3 days after resumed. 4 days. Quetiapine
Capgras cogwheeling, resuming Prednisone, discontinued.Haloperidol,
syndrome; bradykinesia, trientine 10 mg/day, 20 mg/day, 5 days.
BPRS, 78. drooling for colitis; no Haloperidol decreased
Psychosis (haloperidol exacerbation to 5 mg/day because of
starts induced) of psychosis parkinsonian symptoms.
resolving; Quetiapine reintroduced,
BPRS, 58 titrated to 150 mg/day.
Benztropine, up to 2
mg/day. Lorazepam
initially for insomnia, later
changed to clonazepam
Months Tangential Parkinsonism Zinc Haloperidol tapered
11–16 speech slowly improving off over 2 weeks;
resolving; benztropine tapered
insomnia. No off over 1 month.
delusions; Clonazepam, 0.5 mg
BPRS, 51 twice a day. Quetiapine,
150 mg/day
continued

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TABLE 1, continued
Signs and Symptoms
Gastrointestinal
Time Psychiatric Neurological and Hepatic
Month 17 Resolved; BPRS, Resolved
27
Month 21 Depression; None
BPRS, 29
Months None; BPRS 24 None
27–56
a
BPRS5Brief Psychiatric Rating Scale; EMG5electromyography.
effects with a second steroid challenge (albeit with a lower
dosage of prednisone). Third, our patient did not exhibit any
cognitive deficits, which occur in over 70% of cases of steroid-
induced neuropsychiatric side effects (13). The late onset of
psychosis, good premorbid psychosocial functioning, and
lack of prodromal symptoms militate against a chronic
primary psychotic disorder, and therefore a diagnosis of
psychosis secondary to a medical condition (Wilson’s disease)
was formally established.
Treatment and Prognosis of Psychiatric Manifestations
of Wilson’s Disease
Although it is well recognized that Wilson’s disease often
presents with psychiatric problems, little is known about the
treatment or the prognosis of these clinical manifestations.
Two treatment approaches to psychiatric symptoms in Wilson’s
disease patients have been described: 1) primary treatment
of Wilson’s disease directed at removal of pathological copper
deposition (chelation therapy or treatment with zinc) alone
leads to an improvement in psychiatric symptoms (14, 15); 2)
psychotropic medication or psychotherapy is used to address
specific psychiatric presentations independent of medical
therapy for Wilson’s disease. Trials of various psychotropic
medications have been reported, including lithium, haloper-
idol, tricyclic antidepressants, benzodiazepines, quetiapine,
risperidone, and clozapine, as well as trials of ECT (4, 8, 16, 17).
Our case illustrates three important aspects of treating
psychiatric symptoms in patients with Wilson’s disease.
Sensitivity to antipsychotic medications. High incidences of
neurological side effects caused by psychotropic medications
have been reported in patients with Wilson’s disease (e.g., 18).
Our patient developed significant side effects with minimal
dosages of atypical antipsychotics and severe parkinsonism
with haloperidol, which lasted weeks after haloperidol was
discontinued. Thus, our case supports the practice of select-
ing antipsychotics that are less likely to cause extrapyramidal
symptoms (such as quetiapine) and titrating the dosage slowly.
The setting where treatment is provided for psychiatric symptoms.
Patients with Wilson’s disease may have active medical
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Medications
Laboratory and
Imaging Results General Psychotropic
Ceruloplasmin level, Zinc Quetiapine, clonazepam
3 mg/dL; serum tapered off
copper level,
0.12 mg/dL; 24-
hour urine copper
level, 49 mg/L
Zinc Sertraline, 50 mg,
6 months, good results
Zinc None
problems (in our case ileitis-colitis) requiring prompt man-
agement that psychiatric units often are not equipped to
provide. Close collaboration with the medical team is essential
in the long-term management of these patients. Often a psy-
chiatrist in a consultative role follows patients with Wilson’s
disease when they are hospitalized on a medical unit. We were
fortunate to be able to continue the multidisciplinary treat-
ment in the outpatient setting, in our Wilson’s Disease Center
for Excellence. Co-located models of care have been reported
to improve the quality of life of patients with liver (19) and
neurological disease (20). This model, which implies the
presence of mental health professionals in the medical clinic,
needs to be considered for Wilson’s disease because of the high
prevalence of psychiatric symptoms.
For our patient, strong family support allowed her to avoid
extended hospitalization despite disabling psychiatric symp-
toms. Psychoeducation and/or referral to support organiza-
tions, such as the Wilson Disease Association, can ease the
burden on caregivers.
Duration and goal of treatment. For our patient, remission of
psychiatric symptoms was achieved after 9 months of treat-
ment. This slow recovery may have been due to the slow
reduction of copper levels in the brain, but it may also be
attributable to the fact that the patient’s psychotropic medi-
cations could only be adjusted slowly because of her sensitivity.
Full remission, once achieved, was maintained for 3 years
without psychotropic medications while continuing treat-
ment for Wilson’s disease. There are no data to guide the
duration of treatment with psychotropics in Wilson’s disease,
since there have been no systematic studies of the correlation
of biological markers with psychiatric symptoms in the dis-
order. We advocate close ongoing observation to identify
when the psychiatric symptoms resolve and the disease
markers are normalized. At that time, attempts should be
made to discontinue the psychotropic medications to reduce
short- and long-term side effects. The association of Wilson’s
disease with irreversible cognitive decline is no longer the
rule in the context of effective medical therapy for the dis-
order. Our case supports the notion that the goal of treat-
ment for patients with Wilson’s disease who develop
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psychotic symptoms is total remission and return to previous
functioning.
CONCLUSIONS
Treatment of psychiatric symptoms in Wilson’s disease
may require slower titration of psychotropic medications and
should accompany therapy for Wilson’s disease directed at the
prevention of accumulation and the removal of copper. Even
when severe psychosis is present, the aim of care should be
full recovery, since patients may maintain remission for years
after psychotropic medications have been discontinued.
AUTHOR AND ARTICLE INFORMATION
From the Departments of Psychiatry and Internal Medicine, Yale University
School of Medicine, and the Wilson Disease Center for Excellence, Yale
University Medical Center, New Haven, Conn.
Address correspondence to Dr. Zimbrean (paula.zimbrean@yale.edu).
Dr. Schilsky has served as a speaker for Gilead and as an adviser and in-
vestigator for Wilson Therapeutics. Dr. Zimbrean reports no financial
relationships with commercial interests.
Received March 24, 2015; revision received June 5, 2015; accepted June
15, 2015.
Am J Psychiatry 2015; 172:1068–1072; doi: 10.1176/appi.ajp.2015.15030371
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