Dr Diane Mullins, RCSI Tutor in Psychiatry, St Itas Hospital, Portrane

Indications for and side effects of Clozapine therapy

Introduction
Patients on Clozapine must be registered with an approved monitoring system, i.e.
Clozapine Patient Monitoring Service (CPMS) or Zaponex Treatment Access
System (ZTAS)
Initiation of Clozapine is done either as an inpatient or where appropriate facilities
exist for monitoring (e.g. at a day hospital)
A normal leukocyte count (WBC > 3,500/mm 3, neutrophils > 2,000/mm3) must
precede treatment initiation
FBCs must be repeated (and results sent to CPMS) at weekly intervals for 18
weeks (when the risk of neutropenia/agranulocytosis is greatest) and then
fortnightly until 1 year. Blood monitoring continues monthly after 1 year of
treatment
Dose of Clozapine should be titrated up slowly. Need for close monitoring of vital
signs on initiation because of hypotensive effect
30% of patients who have previously been refractory to treatment improve
significantly after 6 weeks treatment with Clozapine and up to 60% respond after
1 year
Clozapine reduces suicidality

Indications
Treatment resistant schizophrenia (main indication)
Tardive dyskinesia
Psychosis in Parkinsons disease
Huntingtons psychosis
Resistant mania

NICE guidelines
Clozapine should be used in treatment resistant schizophrenia where there has
been a lack of a satisfactory clinical improvement despite the sequential use of
the recommended doses for 6 weeks to 8 weeks of at least two antipsychotics at
least one of which should be an atypical

Baseline investigations (before commencing Clozapine)

Bloods: FBC, fasting cholesterol, lipids & glucose level
ECG
Chest X ray
Weight

Mode of action
Clozapine mainly blocks D1 and D4 receptors its effects on D2 receptors are less
than traditional antipsychotics. The lower affinity of Clozapine for D 2 receptors
may partially explain its lack of EPSEs and hyperprolactinaemia
The superior efficacy of Clozapine in treating resistant schizophrenia may be due
to its additional blockade of 5-HT2 receptors

CMPS traffic lights

Green light: normal Clozapine may be administered to the patient

Amber light: caution further sampling advised by CPMS

Red light: STOP Clozapine immediately if either WCC <3,000/mm3 or the

absolute neutrophil count <1,500/mm3

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Dr Diane Mullins, RCSI Tutor in Psychiatry, St Itas Hospital, Portrane
Side effectsassociated with an extremely low incidence of EPSEs
Common side effects
o Anticholinergic: constipation, dry mouth, blurred vision, urinary retention
o Anti-adrenergic: hypotension, sexual dysfunction
o Other: sedation, weight gain, nausea, vomiting, hypersalivation, tachycardia,
hypertension, drowsiness, dizziness, headaches
Less common
o Seizures (dose related)
o Fainting
o Gastric discomfort
o Small involuntary muscle contractions
o Periodic catalepsy
o Enuresis
Rarer or potentially life-threatening
o Agranulocytosis (incidence: 0.8%) risk in older age & females
o Neutropenia (incidence: 3%)
o Thrombocytopenia
o Impaired temperature regulation, fever
o Dysphagia
o Circulatory collapse, arrhythmias, myocarditis, cardiomyopathy, pericarditis,
pericardial effusion, thromboembolism
o Pulmonary embolism
o Confusion, delirium
o Pancreatitis
o Pneumonia
o Neuroleptic malignant syndrome (NMS)

Dealing with Clozapine side effects

Problem Possible solution
Constipation High fibre diet
Fever Symptomatic relief
Check FBC & look for sources of infection
Hypersalivation Hyoscine hydrobromide (Kwells)
Hypertension Monitor closely
Slow rate or halt dose increase
If persists, consider use of hypotensive agent (e.g. atenolol)
Hypotension Advise caution when getting up quickly
Monitor closely
Slow or halt dose increase
Nausea Consider use of anti-emetic
Neutropenia/agranulocytosis Stop Clozapine
Admit to hospital
Nocturnal enuresis Avoid fluids in the evening
If severe, consider desmopressin
Sedation Reschedule dose to give smaller morning or total dose
Seizures Withhold Clozapine for 24 hours
Recommence at lower dose
Consider prophylactic anticonvulsant (e.g. valproate)
Weight gain Dietary and exercise counselling