clozapine

introduction

a newer dibenzodiazepine antipsychotic agent which remains unique in its ability to alleviate the symptoms of patients with refractory illness (30%–40% of patients appear to be “resistant” to other anti-psychotic medications)
acts by:
- dopamine D1 antagonism
- dopamine D1 antagonism
- serotonin (5HT2) antagonism
- muscarinic (M1) antagonism
- H1 antihistamine
- peripheral alpha-adrenoreceptors antagonism
- gamma-aminobutryic acid (GABA) receptors antagonism
unfortunately it has a range of potential toxic effects (see below) which require close monitoring and may warrant withdrawal of the drug.

clozapine has a narrow therapeutic index
- efficacy in schizophrenia target is usually recommended as a trough steady-state clozapine concentrations of 350–400 ng/mL
- to increase compliance and reduce daily ADRs, a single administration at night can be used
- most adverse drug reactions to it appear to relate to high serum concentrations of the metabolite norclozapine eg. sedation, hypersalivation, constipation and seizures
- serum concentration of norclozapine do not contribute to antipsychotic efficacy since norclozapine has no antipsychotic activity
- average doses to reach 350 ng/mL with average clozapine metabolism:
  - a non-smoking US Caucasian female needs around 300 mg/day while a US Caucasian male smoker needs 600 mg/day
  - a non-smoking Asian female needs around 150 mg/day and a Asian male smoker 300 mg/day
- phenotypic clozapine poor metabolisers (PMs) have lower clozapine clearance and need dosage adjustment
  - 2-13% of Asians - presumably due to lower CYP1A2 activity - usually need HALF the usual dose for an Asian
  - acute inflammation or infections with fever or elevated CRP levels, female gender, geriatric age, non-smokers, severe obesity or taking CYP1A2 inhibitors (eg. theophylline, valproate, OCPs, ciprofloxacin and norfloxacin) are risk factors for developing phenotypic PMs ¹⁾
  - these patients may reach the target tough serum concentration of 350 ng/mL with lower than average doses (as outlined below) and thus are at high risk of ADRs if given “normal doses” for gender and ethnicity
clozapine has potential serious adverse reactions which need to be actively risk managed
- ensure CRP level is normal BEFORE starting clozapine
- where possible avoid use of CYP1A2 inhibitors (eg. theophylline, valproate, OCPs, ciprofloxacin and norfloxacin)
- ensure correct dosing for age, gender, ethnicity, smoking status and PM status with an initial slow, personalised titration even a start dose of 25mg/d may be too much initially for a PM and for such patients a start dose of 12.5mg/d followed by targets of 50 mg/day on day 7, 100 mg/day on day 14 and 150 mg/day on day 21 is generally recommended!
  - for Asians with severe obesity or with co-prescription of a CYP1A2 inhibitor, starting with 12.5 mg as the first dose, followed by targets of 25 mg/day on day 7, 50 mg/day on day 14 and 75 mg/day on day 21 has been recommended
- halve dose if fever or elevated CRP or taking CYP1A2 inhibitors
- watch for myocarditis (eg. ECG, troponin if chest pains), agranulocytosis (regular FBE checks), or potentially fatal bowel complications from hypomotility (eg. bowel chart and early imaging if concerns)

P/K

rapidly absorbed orally
effects occur within 4 hrs ingestion
Vd 0.5-3L/kg
metabolism in liver
excreted in urine and faeces as metabolites

adverse effects

agranulocytosis
- appears to be related to antibodies developing against neutrophils
- peak incidence occurs at 1 month of exposure and declines to negligible levels after 1 year of treatment
- prevalence of agranulocytosis of 0.4% with deaths caused by agranulocytosis being 0.05% (~2% mortality rate if develop agranulocytosis)
increased risk of respiratory infection perhaps by 50% increase (eg. pneumonia, TB, etc) and gastrointestinal infections even in the absence of agranulocytosis
- perhaps partly due to neutropenia but also aspiration from hypersialorrhoea / dysphagia / sedation and seems to be higher with co-administration of valproic acid or proton pump inhibitors
metabolic disorder (particularly hyperglycaemia, hyperlipidaemia and obesity)
- The metabolic syndrome, along with other cardiometabolic risks such as smoking and inadequate exercise, is more prevalent in people with schizophrenia than in population controls and is a predictor of early coronary heart disease and mortality (with up to 25 years of life lost prematurely)
- John et al in MJA Feb 2009 showed prevalence of metabolic disorder to be 67% in patients with bipolar disorder or schizoaffective disorder, and 51% in those with schizophrenia, prevalences double that of the general population.
seizures
potent sedation
hypotension
hypersialorrhoea - Rx by nocte dosing and ensure not over-dosing +/- local antimuscarinics but avoid oral antimuscarinics as these will worse constipation
central and peripheral anticholinergia
life-threatening gastric hypomotility
- consider imaging any patients with new constipation and monitor bowel activity
sudden death in elderly patients
clozapine can cause inflammation with fever and/or raised CRP which in turn increases toxicity of clozapine by reducing clozapine clearance (see above)
- cardiac complications such as myocarditis, cardiomyopathy and pericarditis
  - Australia appears to have almost 10–100 times more reported clozapine-induced myocarditis (with a 6% mortality rate) than European countries due to a 3% incidence rate of clozapine-induced myocarditis in Australia is explained solely by the intensive cardiac monitoring during titration, which is not practiced in other countries, whereas, in continental Europe, on the other hand, psychiatrists titrate their patients slowly and rarely diagnose clozapine-induced myocarditis - a Danish study showed only a 0.03% incidence during 1st 2 months titration phase with no mortality ²⁾
  - myocarditis has heterogeneous and non-specific presenting features, making it difficult to identify patients with clozapine-related myocarditis clinically. A high index of suspicion is required.
  - transthoracic echocardiography is a valuable, reproducible and widely available tool to assist in diagnosis of clozapine-induced cardiotoxicity.
  - the level of B-type natriuretic peptide, a hormone secreted in response to ventricular wall stress, may be useful for evaluating patients with clozapine-induced cardiac dysfunction and may in the future be useful for screening asymptomatic patients
  - the mainstay of treatment of clozapine-induced cardiotoxicity is cessation of clozapine and provision of supportive care.
  - Layland et al. MJA Feb 2009
- rarely, other inflammation (in addition to the more common myocarditis) resulting in raised CRP or fever:
  - serositis, pneumonitis/alveolitis, hepatitis, pancreatitis, nephritis, colitis and dermatological disorders

clozapine overdose

toxicity occurs within 4hrs ingestion and lasts ~24 hours
main toxic effects:
- confusion, sedation but rarely requires ventilatory support
- 5-10% develop seizures
- extra=pyramidal effects (esp. children)
- alpha-blockade results in hypotension and tachycardia
- QTc prolongation is rare
- anticholinergic effects
- paradoxical hypersalivation
- NB. myocarditis and agranulocytosis are due to chronic use not acute overdose

Mx of overdose

ABC's, including iv 0.9% saline to Mx the hypotension
cardiac monitor
consider IDC as risk of urinary retention
consider DVT prophylaxis
consider other co-ingestants
Rx seizures with iv midazolam as needed
if refractory hypotension despite fluid, consider inotropes such as noradrenaline / norepinephrine or metaraminol (Aramine)
- if still poor response, consider argipressin (vasopressin / ADH)
medically clear once:
- BP stable
- awake
- able to walk
- has passed urine independently
- has tolerated oral intake

references and resources

MJA Feb 2009 editorial

¹⁾ , ²⁾

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199914/

Table of Contents

clozapine

introduction

P/K

adverse effects

clozapine overdose

Mx of overdose

references and resources