# 243 - Clozapine uncommon or unusual adverse effects

# Clozapine: uncommon or unusual adverse effects

Schizophrenia and related psychoses
CHAPTER 1
Clozapine: uncommon or unusual adverse effects
Adverse effect
Time course
Comment
Agranulocytosis 
(delayed)1–4
Usually first 3 months 
but may occur at any 
time
Occasional reports of apparent clozapine-­related blood 
dyscrasia even after 1 year of treatment. Some suggest risk 
may be elevated for up to 9 years.5 It is very likely that 
clozapine is not the causative agent in most, if not all late 
cases6,7 (see section on clozapine: serious haematological 
adverse effects in this chapter).
Colitis/gastrointestinal 
necrosis8–15
Usually within the first 
month but may be any 
time16
Growing body of case reports. Any severe or chronic 
diarrhoea should prompt specialist referral as there is a 
substantial risk of death. Use of drugs with anticholinergic 
effects probably increases risk of colitis and necrosis.17
Delirium18–20
Any time
Reported rates vary (0.1–10%)18,21,22 but rarely seen in 
practice if dose is titrated slowly and plasma level 
determinations are used. Older age and medical comorbidity 
increase the risk of delirium. Ensure common causes of 
delirium are treated. Cholinergic rebound resulting from 
abrupt cessation of clozapine can cause delirium.
Eosinophilia23–25
First week,26,27 but can 
be any time
Reasonably common but significance unclear. Eosinophilia 
may predict neutropenia but this is disputed. Usually benign 
but investigate for signs of inflammatory organ damage28 
(myocarditis,29 interstitial nephritis,27,30 interstitial lung 
disease, hepatitis, pancreatitis).31 May be associated with 
colitis and related symptoms.15,32 DRESS syndrome described 
in case reports.33,34 Successful rechallenge is possible.35 
Concomitant antidepressants may increase risk.36,37
Heat stroke38,39
Any time
Two cases reported, both occurred during a heatwave. May 
be mistaken for NMS (CK was elevated in both cases).
Hepatic failure/enzyme 
abnormalities40–46
First few months
Benign changes in LFTs are common (up to 50% of patients) 
but worth monitoring because of the very small risk of 
fulminant hepatic failure.47 Rash may be associated with 
clozapine-­related hepatitis48 (see section on hepatic 
impairment in Chapter 8).
Hypothermia49
Any time
A few case reports and events in pharmacovigilance 
databases. Can be fatal.
Interstitial nephritis50,51
Usually first 3 weeks, 
possibly up to 
3 months27
A handful of reports implicating clozapine. Probably immune 
mediated. May occur after only a few doses. Symptoms include 
fever, tachycardia, nausea, vomiting, diarrhoea, raised creatinine, 
urinary difficulties and eosinophilia. The classic nephritis-­
associated rash may not be present.27 There are no published 
cases of successful rechallenge.27
Interstitial lung disease
Usually first few 
months, possibly later 
in treatment
Six case reports.52 May be caused by aspiration or an immune 
reaction. Symptoms are non-­specific: shortness of breath, 
fever, cough, fatigue. Pneumonitis has also been reported.53
Knee-­buckling54,55
Usually at the start of 
treatment
Several cases reported. May be mistaken for postural 
hypotension.
Ocular effects56
Any time
Single case report of ocular pigmentation,57 five of periorbital 
oedema.58 Clozapine may cause dry eye syndrome.59
(Continued)

246
The Maudsley® Prescribing Guidelines in Psychiatry
CHAPTER 1
Adverse effect
Time course
Comment
Pancreatitis60–69
Usually first 6 weeks, 
possibly later in 
treatment70
Several reports of asymptomatic and symptomatic 
pancreatitis. Symptoms include fever, abdominal pain and 
distension, nausea and vomiting, raised CRP and raised lipase 
and/or amylase. Concomitant valproate may increase the 
risk.27 The majority of attempts to rechallenge fail63,71–74 but 
one successful case is reported.75
Parotid gland 
swelling76–80
Usually first few weeks, 
but may occur later81
Several case reports. Unclear mechanism, possibly 
immunological or thickening of saliva leading to calcium 
precipitation. Can be recurrent. May resolve spontaneously.82 
Terazosin in combination with benztropine may be helpful.
Pericarditis and 
pericardial effusion69,83–90
Any time
Several reports in the literature. Symptoms include fatigue, 
chest pain, dyspnoea, orthostatic hypotension and 
tachycardia, but may be asymptomatic.91 Signs include raised 
inflammatory markers (specifically trop I) and pro-­BNP 
levels.91 Use echocardiogram to confirm/rule out effusion. 
Successful rechallenge possible.92–94
Stuttering95,96
Any time
Case reports only. Check plasma levels, consider dose 
reduction and/or antiseizure drugs – may be a warning sign 
for impending generalised seizures.97
Thrombocytopenia98–101
First 3 months
Few data but apparently fairly common (incidence over 1 year 
of 3102–8%103). Probably transient and clinically unimportant, 
but persistent in some cases104,105 and recurrent on rechallenge 
in others.106,107 Thrombocytosis also reported.108
Skin reactions109
Any time
Presence of skin diseases in general is higher in those with 
schizophrenia.110 Four reports of vasculitis111–114 in which 
patients developed confluent erythematous rash on lower 
limbs. One report of Stevens–Johnson syndrome,115 two of 
pityriasis rosea,116,117 one of a papular rash,118 one of 
exanthematic pustulosis,119 one of cholinergic urticaria120 and 
two of Sweet’s syndrome,121 one fatal.122 Rash is often 
reported in DRESS syndrome.123
Thromboembolism124–126
Any time127
Weight increase and sedation may contribute to risk. 
Mechanism may be increased platelet aggregation via 5HT2A 
receptor activation.128 Clozapine increases risk of pulmonary 
thromboembolism by 28 times compared with the general 
population.129 The risk may be dose related130 but cases are 
reported across the dose range.131,132 Consider prophylactic 
antithrombotic treatment where additional risk factors are 
present (surgery, immobility). Continuation of therapy after 
embolism may be possible133 but consult haematologist as 
without prophylactic antithrombotic treatment recurrence is 
likely134,135 and may be fatal.131,136
Polyserositis
Usually first few weeks, 
but can occur at any 
time
Case reports describe a wide variety of symptoms related to 
inflammatory processes, including flu-­like symptoms, fever, 
eosinophilia, diarrhoea, shortness of breath, tachycardia, 
thoracic pain.137 Other inflammatory conditions may be 
present (hepatitis, pancreatitis, dermatosis). Suggested to be 
either IgE-­mediated hypersensitivity or an immunomodulatory 
effect.138 All reported cases have resolved on discontinuation 
of clozapine.138
CK, creatine kinase; CRP, C-­reactive protein; DRESS, drug rash with eosinophilia and systemic symptoms; 
IgE, immunoglobulin E; NMS, neuroleptic malignant syndrome; pro-­BNP, pro-­brain natriuretic peptide.
(Continued)