IncreasesinC-Reactive Protein May

Predict Recurrenceof ClozapineInducedFever

A Case Study

Significance
First to associate a recurrence of clozapineinduced fever with known immunomodulatory
effects of the drug on cytokines and CRP levels
(Kohen and others, 2009, p. 145)
Provide another method for diagnosing clozapineinduced fever
Possibly predict occurrence or recurrence of
clozapine-induced fever

Background
C-reactive proteins
participates in systemic response to inflammation (Black
and others, 2006, p. 48487)
plasma concentration increases in inflammatory state
(Black and others, 2006, p. 48487)
might indicate major cardiovascular events (Black and
others, 2006, p. 48487)

Clozapine
atypical antipsychotic (Kohen and others, 2009, p. 144)
adverse effects include weight gain, hyperglycemia,
hypotension and mild to high grade fever (Kohen and
others, 2009, p. 144)
rare adverse effects include agaranulocytosis, myocarditis
(Kohen and others, 2009, p. 144)

Background
Clozapine-induced fever
usually benign (Young and others, 1998, as cited in
Kohen and others 2009, p. 143)
may subside even after continued use of clozapine
(Kohen and others, 2009, p. 144)
differential diagnosis must include agranulocytosis
and neuroleptic malignant syndrome (NMS) (Kohen
and others, 2009, p. 143)

Agranulocytosis
presents itself in 0.38-1.3% of patients. (Kohen and
others, 2009, p. 144)
may lead to neutropenic sepsis (Kohen and others,
2009, p. 144)

Background
Neuroleptic malignant syndrome
10% mortality rate (Kohen and others, 2009, p. 144)
symptoms include hyperthermia, rigidity, changes in
consciousness (Kohen and others, 2009, p. 144)

Interleukin-6 (IL-6) and Tumor necrosis factor- (TNF)

cytokines that mediate primary host response (Kluger
and others, 1991, as cited in Kohen and others, 2009,
p. 144)
not detectable in healthy humans (Gudewill and others,
1992, as cited in Kohen and others, 2009, p. 144)
increase production of CRP (Kohen and others, 2009, p.
144)

Objectives
Investigate whether elevated CRP levels can
predict clozapine-induced fever

Review of Related
Literature

In the studies by Nittenson and others (1995), Tham

and others (2002), and Druss and others (1993), there
was no recurrence of fever after clozapine therapy was
restarted (as cited in Kohen and others, 2009)
Tremeau and others (1997) report fever recurrence
after restarting the patient on clozapine (as cited in
Kohen and others, 2009)
Jeong and others (2002) and De Leon and others
(2003) suggest dosage reductions instead of
discontinuation of clozapine (as cited in Kohen and
others, 2009)
Study by Jeong and others (2002) indicate that
clozapine-induced fever is linked to IL-6 and TNF- (as
cited in Kohen and others, 2009)

Methodology
Patient admitted
to psychiatric
hospital
Recurrence of
fever. Clozapine
stopped
Patient started on
another drug and
discharged

Patient developed
fever
CRP levels
returned to
normal. Clozapine
therapy restarted

Full body exam

was conducted

Clozapine
discontinued

Results
Patient developed a fever on day 15 of clozapine
therapy (Kohen and others, 2009, p. 143)
No abnormalities were detected by tests (Kohen and
others, 2009, p. 143)
No irregularities detected by ECG(Kohen and others,
2009, p. 143)
Temperature peaked at 38.7oC (Kohen and others,
2009, p. 144)
Time
frame

Onset of
Fever

Clozapine
discontinu
ed

Clozapine
treatment
restarted

WBC count

12, 600 L

8, 900 L

12, 800 L

CRP level

3.96 mg/L

0.60 mg/L

4.36 mg/L

Discussion
Patient had elevated WBC count negating the diagnosis
of agranulocytosis (Kohen and others, 2009, p. 144)
Patient suffered no muscle rigidity nor hyperthermia.
Peak temperature reached 38.7 oC (Kohen and

others, 2009, p. 145)

IL-6 and TNF- caused an inflammatory response with
acute phase reaction elevation in CRP (Kohen and
others, 2009, p.145).
fever and elevated CRP levels indicate clozapineinduced fever (Kohen and others, 2009, p. 145)

Conclusions
Symptoms did not match diagnostic criteria of
agranulocytosis nor neuroleptic malignant
syndrome (Kohen and others, 2009, p. 145)
Fever and increased C-reactive protein levels were
probably related to clozapine (Kohen and others,

2009, p. 145)

Recommendations
Evaluate whether the data can be generalized to
patients with schizophrenia and other psychotic
disorders (Kohen and others, 2009, p. 145)
Determine whether an increase in C-Reactive
Protein levels may predict emergence or
recurrence of clozapine-induced fever (Kohen and
others, 2009, p. 145)

Determine whether different dosages would

induce clozapine-associated fever

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