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Pericarditis and Polyserositis as a Side Effect of Clozapine in an Adolescent Girl Emil Branik, M.D. and Meike Nitschke, M.D. ABSTRACT A case report describes an adolescent girl with a treatment-resistant bipolar disorder, who de- veloped pericarditis and polyserositis while being treated with clozapine. The sparse litera- ture about this rare, severe side effect of clozapine is discussed. Clinical recommendations with regard to monitoring are given. If myocarditis/polyserositis occurs, clozapine has to be discontinued immediately. 311 JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Volume 14, Number 2, 2004 © Mary Ann Liebert, Inc. Pp. 311–314 INTRODUCTION AND DISCUSSION T HE INDICATION FOR THE convincingly effective atypical neuroleptic, clozapine, is defined relatively strictly because of its most critical side effect—life-threatening agranulocytosis (AACAP 2001; Bryden et al. 2001; Kumra et al. 1996; Remschmidt et al. 2000). For 10 years, the literature has reported rare cases of polyserosi- tis and pericarditis as a further severe side ef- fect of clozapine. According to Kilian et al. (1999), clozapine-associated myocarditis or car- diomyopathy occurred in 1 of approximately 400 treatments in Australia. Other estimates are 1 in 10,000 cases (Warner et al. 2000). Eighty- five percent (85%) of cases of myocarditis re- ported to the manufacturer occurred in the first two months of therapy (Wooltorton 2002). The time of occurrence of this side effect was het- erogenic in the cases reported to date. It ranged from the first week (Catalano et al. 1997) to nine years (Malhotra et al. 2002) after begin- ning clozapine medication. The chief clinical symptoms were described as shortness of breath, heart palpitations/pains, diminished endurance, and thoracic pains. In the majority of cases, electrocardiogram (ECG) changes, pericardial effusion, pleural effusion, and non- specific signs of inflammation were found, but no evidence of pathogens or rheumatic dis- eases was found on laboratory tests or other procedures. So far, reports of clozapine-associated poly- serositis in adolescence have been extremely rare (Kay et al. 2002). In the following, a fur- ther case of an adolescent girl with therapy- resistant mania within the scope of a bipolar disorder is described: The girl developed peri- carditis and polyserositis 14 days after begin- ning the clozapine therapy (the details have been sufficiently changed so that the patient described is not recognizable). At the time of admission, a 17-year-old ado- lescent girl became symptomatic with opposi- tional-defiant provocative behavior. Within the last three years, an emotional instability

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Page 1: Pericarditis and Polyserositis as a Side Effect of Clozapine in an Adolescent Girl

Pericarditis and Polyserositis as a Side Effect ofClozapine in an Adolescent Girl

Emil Branik, M.D. and Meike Nitschke, M.D.

ABSTRACT

A case report describes an adolescent girl with a treatment-resistant bipolar disorder, who de-veloped pericarditis and polyserositis while being treated with clozapine. The sparse litera-ture about this rare, severe side effect of clozapine is discussed. Clinical recommendationswith regard to monitoring are given. If myocarditis/polyserositis occurs, clozapine has to bediscontinued immediately.

311

JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGYVolume 14, Number 2, 2004© Mary Ann Liebert, Inc.Pp. 311–314

INTRODUCTION AND DISCUSSION

THE INDICATION FOR THE convincingly effectiveatypical neuroleptic, clozapine, is defined

relatively strictly because of its most criticalside effect—life-threatening agranulocytosis(AACAP 2001; Bryden et al. 2001; Kumra et al.1996; Remschmidt et al. 2000). For 10 years, theliterature has reported rare cases of polyserosi-tis and pericarditis as a further severe side ef-fect of clozapine. According to Kilian et al.(1999), clozapine-associated myocarditis or car-diomyopathy occurred in 1 of approximately400 treatments in Australia. Other estimates are1 in 10,000 cases (Warner et al. 2000). Eighty-five percent (85%) of cases of myocarditis re-ported to the manufacturer occurred in the firsttwo months of therapy (Wooltorton 2002). Thetime of occurrence of this side effect was het-erogenic in the cases reported to date. It rangedfrom the first week (Catalano et al. 1997) tonine years (Malhotra et al. 2002) after begin-ning clozapine medication. The chief clinical

symptoms were described as shortness ofbreath, heart palpitations/pains, diminishedendurance, and thoracic pains. In the majorityof cases, electrocardiogram (ECG) changes,pericardial effusion, pleural effusion, and non-specific signs of inflammation were found, butno evidence of pathogens or rheumatic dis-eases was found on laboratory tests or otherprocedures.

So far, reports of clozapine-associated poly-serositis in adolescence have been extremelyrare (Kay et al. 2002). In the following, a fur-ther case of an adolescent girl with therapy-resistant mania within the scope of a bipolardisorder is described: The girl developed peri-carditis and polyserositis 14 days after begin-ning the clozapine therapy (the details havebeen sufficiently changed so that the patientdescribed is not recognizable).

At the time of admission, a 17-year-old ado-lescent girl became symptomatic with opposi-tional-defiant provocative behavior. Withinthe last three years, an emotional instability

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with alternating depressive and hypomanic af-fects was noted by the parents and by the girlherself.

Retrospectively, the description correlatedwith the ICD-10-diagnosis of cyclothymia. Atthe time of admission, she met the StructuredClinical Interview for DSM-IV (SCID) criteria ofmajor depression. A few weeks after she hadbeen hospitalized, the symptoms of depressionweakened, even without medication. After a pe-riod of feeling and behaving moderately de-pressed, she developed a typical manic phase,fulfilling the ICD-10-criteria of mania. She dis-played elevated drive, increased psychomotoricagitation, affective irritability, distractibility, ag-gressive behavior, pressure of speech, flow ofideas, sleep disturbance, lack of distance, disin-hibition, thoughts of grandiosity, and elevatedaffect. Over months, this proved to be resistantto lithium and carbamazepine despite therapeu-tic blood levels, and even when combined. Theadditional administration of typical and atypi-cal neuroleptics (risperidone, haloperidol, andclopenthixol)—each for several weeks—did notbring about a remission, either. At times, the pa-tient reported auditory hallucinations in theform of voices speaking dialogues and makingcomments. After a few days, however, she dis-associated herself from the voices. In spite ofstrong sedation, she remained driven; the af-fectivity tended to be irritated-aggressive andincreasingly childish. There were eruptionsof aggressiveness without any identifiablemotivation. Additionally, a psychopathologicalsyndrome gradually developed, consisting ofeccentricity, lack of perseverance, and inade-quate relations, with childish affectivity and thebehavior of a social outsider. When after 6.5months of therapy the mania had not abated,therapy with clozapine was initiated. Because ofthe possible side effects on the bone marrow andthe known interaction, which results in a sub-stantial drop in the level of clozapine when car-bamazepine is administered at the same time(Schulz et al. 1997), carbamazepine was previ-ously replaced by valproate (up to 1500 mg/day, accompanied by serum-level controls).Fourteen (14) days after beginning the clozapinemedication, the patient complained of epigastricpains that moved into the right hypogastricregion, nausea, and vomiting. She had a fever of

up to 39.5°C, with a rectoaxillary difference of0.9°C and rebound tenderness (Blumberg’ssign) in the hypogastric region. Presumingappendicitis, she was transferred to the surgicalclinic, where a laparascopic appendectomy wascarried out. The clozapine dosage was, by theway, continued throughout. However, the pa-tient continued to have febrile episodes, a C-reactive protein (CRP) increase, leukocytosiswith 17 G/l, with a considerable left-shift. Therewere also watery diarrheas. The hemocultureand the feces were negative as regards to patho-gens. An abdominopelvic computer tomogra-phy (CT) revealed enterocolitis. In spite ofantibiotics and clinical improvement, the mod-erate leukocytosis and diarrhea did not regress.After transferring the patient back to our psy-chiatric clinic for children and adolescents, thefever rose once again and she complained aboutretrosternal pains, so that she had to be trans-ferred to the medical clinic. There, the ECGidentified a T-flattening with inversion, and theechocardiography revealed a pericardial effu-sion (maximum posterior 7–10 mm diastolic).The stool bacteriology and hemoculture wereonce again negative. Chemical tests in the labo-ratory showed troponin-T, CRP, and gammaglutamyltransferase were increased, while theblood count indicated a slight normochromic,normocytic anemia, thrombocytosis with 568G/l, leukocytosis with 11.9 G/l, and eosino-philia of 13%. In the immunological clarificationof the infection, the CFR titers against CoxsackieB1–B3 were slightly increased at 40 and forB4–B6 at 20, and also, the CFR titers againstother enteric viruses (Picorna) at 20. With nega-tive Anti-Neutrophilic Cytoplasmic Antibodies(ANCA), CCP IgG, and rheumatoid factors,there were no indications of a rheumatologicalcause. Since the viral titers spoke against anacute infection as the cause, the clozapine wasconsidered a possible trigger of the symptomsdescribed above and was stopped. Just one dayafter discontinuing clozapine, the fever, theleukocytosis, and the pericardial effusion allregressed.

Remarkably, the psychopathological find-ings stabilized chronologically with the or-ganic complication. The multiform affectiveand behavior symptoms mentioned abovewere no longer identifiable. Under medication

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with valproate at 1500 mg/day and clopen-thixol at 5 mg/day, the patient remained stableat her relatively low level of psychosocialfunctioning already known before the devel-opment of an affective disorder, i.e., poor per-formance and perseverance considering therequirements of everyday life, lack of fields ofinterest, superficial peer relationships limitedon immediate-need satisfaction, and an incli-nation to interpersonal conflicts.

The superiority of clozapine compared toother typical—and perhaps also to atypical—neuroleptics, especially in the case of therapy-resistant schizophrenias and negative symptoms,is sufficiently known (AACAP 2001; Kumraet al. 1996; Tuunainen et al. 2002). Occasion-ally, a trend toward extending the range ofuse of clozapine is discussed (Klimke andKlieser 1995), for example, in manic episodesand bipolar disorders in children and ado-lescents (Remschmidt et al. 2000). However,the number of empirical tests is very meager.In an open study with a small number ofcases, Masi et al. (2002) reported on the effi-cacy of clozapine in the case of otherwisetherapy-resistant manic or mixed episodesin adolescence.

In the case of the above-described adolescentpatient, the manic symptoms continued for 6.5months, despite the partly successive andpartly common medication with two mood sta-bilizers, two typical neuroleptics, and one atyp-ical neuroleptic agent. Finally, clozapine wasadministered as part of an individual therapytrial; however, it had to be discontinued be-cause of the pericarditis/polyserositis, whichcould not be explained in any other way.

In addition to the agranulocytosis, peri-carditis and polyserositis must, therefore, betaken into consideration as a possible life-threatening side effect of clozapine and berecognized in time by means of appropriatemonitoring. It is easy to misinterpret corre-sponding complaints (see the above example,when an appendectomy was carried out onthe patient). According to the present lit-erature, in the case of clinical indications thefollowing laboratory tests are required inaddition to an ECG and echocardiogram: In-creased troponin I in the serum is consideredto be one of the most reliable biological mark-

ers for damage to the myocardium and isrecommended by a working group for moni-toring the cardiac side effects of clozapine(Kay et al. 2002). Further indicators seem tobe nonspecific signs of inflammation (fever,CRP, WBC, gamma glutamyltransferase, C 3level) that can neither be explained by an in-fection nor by a rheumatic type of disease.However, a trigger function of viral diseasesis not excluded in individual cases (Murko etal. 2002). The clozapine-induced fever (Jeonget al. 2002; Tham and Dickson 2002) is notan obligatory precursor of pericarditis. Itwas discussed as an allergic reaction to themedication, or as an expression of the im-munomodulatory effects of clozapine. Dis-continuing the medication when a feveroccurs without further indications of peri-carditis or polyserositis was not necessary(Jeong et al. 2002; Tham and Dickson 2002).However, in any case of fever during medica-tion with clozapine, infections resulting fromneutropenia or agranulocytosis need to beruled out.

CONCLUSIONS

At the present time, there are not yet anyconcluding findings about the immunomodu-latory effects of clozapine, specific patient-related risk factors, or the influence of theaccompanying medication. Besides the bloodcount, signs of inflammation and cardiacsymptoms should be taken into consideration.If myocarditis or polyserositis occurs whenusing clozapine, then according to presentknowledge, the medicament has to be stopped.Although the full picture of pericarditis withcontinued clozapine medication was in somecases initially subsided (Catalano et al. 1997;Kay et al. 2002), in most patients the symptomspersisted—as in the case of our adolescentgirl—until clozapine was discontinued.

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Address reprint requests to:Emil Branik, M.D.

Klinik SonnenhofKinder- und Jugendpsychiatrisches Zentrum

CH-9608 Ganterschwil SGSwitzerland

E-mail: [email protected]

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