ACUTE PANCREATITIS AND CLOZAPINE IN THE ELDERLY
K R NICHOLLS BSc MB ChB MRCPsych
and T S
ANANTHANARAYANAN FRCPsych DPM
SUMMARY
Clozapine is an atypical neuroleptic which is prescribed
increasingly for a number of indications, including tardive dyskinesias. Serious side
effects reported include potentially fatal agranulocytosis, requiring close monitoring. We
report a case of acute pancreatitis associated with clozapine, and review the evidence
that indicates this may be an important, if uncommon, adverse reaction to this drug
deserving wider recognition.
KEY WORDS: clozapine; pancreatitis.
Clozapine is an atypical antipsychotic which is beneficial
to about a third of the 10-20% of schizophrenic patients who are resistant to conventional
neuroleptics, improving negative as well as positive symptoms (Kane et al 1988).
Demonstration of its use in the treatment of (rather than masking) tardive dyskinesias has
been reviewed elsewhere. (Lieberman et al 1991).
In the elderly, clozapine has been shown to be useful in the management
of treatment-resistant psychoses; its use not restricted to schizophrenic patients.
(Frankenburg & Kalunian 1994). It may be particularly valuable for psychotic patients
with co-existing Parkinson's disease, apparently ameliorating the troublesome features of
this condition, possibly through poorly understood and paradoxical anti-dopaminergic
mechanisms, or alternatively by facilitating increases in L-dopa dosage without
exacerbating psychosis. (Arevalo & Gershanick 1993, Factor et al 1994).
Side effects of clozapine treatment include sedation and confusion,
which may be a particular problem in the elderly. Less frequently, serious side effects
occur, the best known potentially fatal agranulocytosis causing a fatality rate of
approximately 1 in every 300 people treated prior to its recognition some twenty years
ago. It appears that the maximum risk occurs between 6 and 18 weeks after commencement of
Clozapine treatment, and is not related to gender, age or dose.
Prescribing this drug now requires obligatory registration with the
Patient Monitoring Service to regularly check neutrophil counts. Other rare adverse
effects which occur include hepatic dysfunction, ECG changes and arrhythmias, and
pericarditis and myocarditis.
We report a case of acute pancreatitis which occurred following
commencement of clozapine to treat orolingual dyskinesia, and review the evidence that
this may also constitute an uncommon, but significant adverse effect which is not
adequately recognised.
CASE REPORT
A 70 year old woman was admitted for treatment of a progressive and
debilitating orolingual dyskinesia of obscure aetiology. There was no history of
neuroleptic use, though at the time of onset she was being treated for a first depressive
episode with fluoxetine which has been implicated in extra-pyramidal dysfunction. (Baldwin
et al 1991, Lipinski et al 1989, Meltzer et al 1979). However, minor cerebrovascular
accidents were also recorded over the relevant period, possibly compromising basal ganglia
function.
The depressive episode, and another two years later, both responded
well to courses of E.C.T. A neuropsychiatric opinion about the dyskinesia was obtained at
an early juncture, and a trial of tetrabenazine recommended. Doses of up to 12.5mg twice
daily were given for nearly a year without benefit. Low dose haloperidol and pimozide were
subsequently prescribed, also without success. Due to the progressive deterioration,
admission was arranged for initiation of clozapine treatment. Other medication was tailed
off, and an initial dose of 12.5mg given. Total WCC at this time was 5.12 x 109/(neutrophils
3.35 x 109/l).V
Some four weeks later the daily dose had increased to 50mg, and the
patient started to report subjective improvement, which was not apparent to observers.
From the fifth week of treatment, 'definite' benefit was claimed by the patient, and
improvement became obvious to relatives and staff. Marked remission of spontaneous and
continuous grimacing affecting the mouth and tongue occurred, with improved co-ordination
of voluntary movements including mastication and speech.
Progress was consolidated up until the eighth week, (daily dose
125mg/day) when an episode of sudden vomiting occurred. Examination revealed generalised
abdominal tenderness and blood testing measured an amylase titre of 423 U (normal range
15-90 U). Following the diagnosis of acute pancreatitis, transfer to a surgical ward was
arranged. Clozapine was stopped and conservative management with intravenous fluids and
analgesia initiated. (WCC was 7.45 x 109/l neutrophils 3.86 x 109/l).
Ultrasonography depicted a 'normal' liver and biliary tree. There was no evidence of
calculi, free fluid or inflammation.
Clinical recovery was rapid over a period of four days, and was
mirrored by falling amylase levels, which had decreased to 24 U after two weeks. The
dyskinesia returned over the same period to its previous severity, to the patient's
disappointment after being much encouraged by the treatment.
DISCUSSION
Acute pancreatitis in Britain is associated with biliary
disease in 50% of cases, and alcoholism in a further 20%. Aetiology in a large
proportion of the remainder remains undetermined, though can occur following renal
transplantation, and abdominal trauma or surgery, and occasionally after viral infections,
certain metabolic disturbances, and hypothermia. Overall mortality is significant, ranging
from 5% when oedematous changes only occur, to 50% if haemorrhagic
pancreatitis develops. Death occurs usually from catastrophic respiratory, circulatory or
hepatorenal failure. Drug induced pancreatitis is well described and has been associated
with corticosteroids and oral contraceptives. More recent reviews of drug induced
pancreatitis have listed other medications including salicylates, thiazide-diuretics,
valproic acid and vinca alkaloids (Frick et al 1993). Others which have been linked
include asparaginase, azathioprine, and tetracylines.
Agents described as having a 'probable' association with pancreatitis
now include clozapine (Underwood & Frye 1993) following two separate reports of single
cases (Martin 1992, Frankeburgh & Kando 1992).
The former reports a 40 year old man who developed acute pancreatitis
on a daily dose of clozapine of 150mg. Amylase levels rose to a peak of 343 U/ml, but the
patient's clinical condition 'rapidly returned to normal after discontinuation of
clozapine'. Frankenburg & Kando describe a 17 year old woman who developed acute
pancreatitis after receiving l00mg daily. Symptoms again rapidly subsided on cessation of
clozapine therapy, amylase levels peaking at 231 U/ml. This patient had also been on
valproate which, as already noted, has been implicated in causation of acute pancreatitis.
Although valproate had been stopped prior to starting clozapine in this patient to no
avail, the possibility of an aetiological synergism between the two drugs cannot be
dismissed. These authors noted recurrence of symptoms when the patient was treated again
with clozapine, and suggested that a concurrent eosinophilia indicates an allergic
mechanism. A similar case linking acute pancreatitis with eosinophilia to milk allergy has
been described. (de Diego Lorenzo et al 1992).
More generally, mechanisms mediating pancreatitis are heterogeneous
and, as well as pancreatic duct obstruction, probably include immune-suppression,
cytotoxicity, osmotic pressure dysfunction, arteriolar thrombosis, metabolic effects,
direct cellular activity and hepatic involvement. (Underwood & Frye 1993).
Although the frequency of drug-induced pancreatitis is generally low,
the associated morbidity and mortality makes timely identification of the causative agent
important. Many cases are associated with underlying conditions known themselves to induce
pancreatitis, and drugs are likely to act as a trigger or cofactor. (Frick et al 1993).
Various experimental models of pancreatitis have led to the hypothesis
that intra-acinar cell activation of zymogens by lysosomal hydroxylases may be an
important critical event. (Steer 1993). Improved definition of the disease in molecular
terms is probable in future. (Sarles 1991). It is known for instance that abnormal
pancreatic proteins are produced during pancreatitis which may serve as endogenous
antibiotics, and prove to be useful markers (Kleim et al), whilst free radical scavengers
may be able to mitigate deleterious pathomechanisms (Shoenburg et al 1992).
Clozapine related acute pancreatitis occurred, in the case described
above and the two cases reviewed, in the same dose range (100-150 mg/day) which may
reflect a critical threshold. All three cases recovered quickly over a few days, and this
may be seen as further evidence of a dose-related phenomenon, since it coincides with the
biphasic elimination of this drug whose mean half-life is 12 hours (range 6-26 hours),
thus serum levels would become negligible after the same period (a few days).
However, the disparate aetiology of pancreatitis, and the anecdotal
nature of these cases makes such a conclusion premature and potentially hazardous to
individuals who may be more vulnerable to the more serious consequences of this condition.
We suggest that greater awareness of this possible side effect would be advantageous, and
that until the related risks are clarified, pre-existing disposition to pancreatitis
should be evaluated in all patients being considered for treatment with clozapine.
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Correspondence to:
Dr K Nicholls
Consultant Psychiatrist
Shelton Hospital
Bicton Heath
Shrewsbury SY3 8DN
Tel: (UK) 01743 261000 Ext. 1246 / Fax: (UK) 01743 261279
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