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Saturday, February 11, 2006

Pedal Edema Associated with Clozapine Use

Rimona Durst MD1, Sergey Raskin MD1, Gregory Katz MD1, Josef Zislin1 and Ronen Durst MD2

1The Jerusalem Mental Health Center, Kfar Shaul Hospital (affiliated with Hebrew University Hadassah Medical School) and 2Department of Internal Medicine, Hadassah University Hospital, Jerusalem, Israel

Key words: clozapine, side effects, pedal edema

Clozapine, widely recognized as an efficient agent for treating nonremittent schizophrenic patients, is associated with well-established adverse effects such as sedation, weight gain, sialorrhea, palpitations, seizures, and agranulocytosis. We report a case in which an additional possible negative side effect of clozapine was observed, namely pedal edema.

Case Description

This 24-year-old patient was known to suffer from schizophrenia for 6 years. Previous treatment by a variety of neuroleptics (including mood stabilizers) failed to produce longterm amelioration. In view of her frequent relapses, it was decided to initiate clozapine treatment as a sole anti-psychotic agent while maintaining her long-term valproic acid treatment. Clozapine was gradually increased to 400 mg/day with satisfactory results. However, 6 weeks after the commencement, the patient began to show signs of pedal edema and peri-orbital puffiness. No polydipsia was apparent.

Physical examination revealed no other abnormal signs. Albumin blood level, and thyroid and liver function tests indicated normal levels. No proteinuria was detected. Other laboratory tests including electrolytes yielded normal results, except for eosinophilia. Echocardiogram showed normal systolic and diastolic functions.

In view of the apparent association between the development of the edema and the initiation of clozapine, the clozapine dosage was reduced to 200 mg/day over a period of 10 days. Parallel to clozapine diminution, eosinophilia subsided and the pedal edema gradually diminished.


There have been reports of an association between clozapine and a host of
general medical conditions. These include: de novo onset or exacerbation
of preexisting diabetes mellitus, paradoxical hypertension, lactic acidosis
with fatal myocardial failure, acute pancreatitis [1], and pheochromocytoma-
like syndrome suggesting clozapine-induced sympathetic hyperactivity [2]. Eosinophilia has been attributed to clozapine treatment but whether it can serve as a reliable predictor for neutropenia — the main hazardous side effect of clozapine — remains controversial [3].

The attribution of the onset of pedal edema to clozapine treatment in our patient seems to be substantiated by the gradual development of the edema parallel to the initiation of the clozapine treatment, peaking after 6 weeks at 400 mg/day. Diminution of the dosage to 200 mg/day for 10 days led to the gradual disappearance of the edema. Although this may have been
purely coincidental, association between the two is indicated. The
possibility of water dysregulation — also known as the syndrome of psychosis,
intermittent hyponatremia, and polydipsia — is doubtful due to the absence of polydipsia or hyponatremia in the patient.

Moreover, clozapine has been shown to be effective for both the polydipsia and sodium dysregulation associated with water dysregulation syndrome [4]. Lack of any other explanation for the edema, as well as its resolution following dosage diminution supports our hypothesis that the edema was drug induced.

Although the possibility of clozapine-induced angio-edema is supported by the eosinophilia, the dose-related effects suggest otherwise. Clozapine affinity is mainly related to dopamine D1, D2 (relatively weak) and D4, 5HT2, α1 and α2, muscarine and histamine H1 receptors. Thus, the edema may reflect an antagonistic effect of clozapine on renal dopamine receptor type 4 (D4). This receptor, activated by dopamine and the sympathetic system, has natriuretic and diuretic effects. Clozapine has been shown to block this effect in animals [5]. The dose-related edema in this case could be attributed to increased blockage of the D4 receptor, the reduced natriuresis becoming clinically significant at high dosage levels.

A Medline search through January 2000 did not reveal similar cases of clozapine-associated pedal edema. It may be too early to determine whether the edema in this case is exclusively attributable to the clozapine treatment. However, pending further information regarding this side effect and its underlying mechanism, we feel that it is important that clinicians be alerted to the possibility of such a phenomenon.


1. Martin A. Acute pancreatitis associated with
clozapine use [Letter]. Am J Psychiatry 1997;
149: 714.
2. Li JK, Yeung VT, Leung CM, Chow CC, Ko
GT, So WY, Cockram CS. Clozapine: a mimicry
of phaeochromacytoma. Aust N Z J
Psychiatry 1997;31: 889–91.
3. Ames D, Wirshing WC, Baker RW, Umbricht
DS, Sun AB, Carter J, Schooler NR, Kane JM,
Marder SR. Predictive value of eosinophilia for
neutropenia during clozapine treatment. J Clin
Psychiatry 1996;57:579–81.
4. Spears NM, Leadbetter RA, Shutty MS JR.
Influence of clozapine on water dysregulation.
Am J Psychiatry 1993;150:9.
5. Sun D, Schafer JA. Dopamine inhibits AVPdependent
Na+ transport and water permeability
in rat CCD via a D4-like receptor. Am J
Physiol 1996;271:391–400.

Correspondence: Dr. R. Durst, Jerusalem
Mental Health Center, Kfar Shaul Hospital,
Jerusalem 91060, Israel. Tel: (972-2) 655
1559; Fax: (972-2) 642 6057; email:

Chaperone selection
Secretory and plasma membrane proteins begin their life
with co-translational translocation into the endoplasmic
reticulum (ER). Inside the ER, the correct folding of
newly synthesized proteins is assisted by a group of chaperone
molecules including binding protein (BiP) and the
lectins calnexin and calreticulin. Molinari and Helenius found
that chaperone selection occurs co-translationally and
describe some of the criteria that select for a particular
chaperone. The position of carbohydrate chains in the
nascent chain of the protein diverted it from an interaction
with BiP to an interaction with calnexin and caireticulin.
Science 2000:288:331.

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