Clozapine (Blood)

Diagnostic Use

Clozapine is an atypical antipsychotic indicated for patients with treatment-resistant schizophrenia. Side effects of clozapine include agranulocytosis, myocarditis and cardiomyopathy, constipation, intestinal obstruction, drowsiness and seizures.

Although clozapine levels can vary between individuals and are affected by factors such as gender, age, smoking status and weight (2), routine measurement of clozapine levels is not indicated in every day practice for the following reasons:

1.  A significant proportion of patients (approximately 1/5 th ) respond to clozapine treatment even if the serum concentration is below the therapeutic interval quoted above (1) .
2. Following a change in dose, patients with poor initial response at 6 weeks may respond by 4-6 months.
3. There is no agreed toxic threshold for clozapine related CNS toxicity. Seizures can occur at or even below the therapeutic interval in some patients. The risk of toxicity is increased at clozapine concentrations > 3000 nmol/L.
4. Haematological and cardiac side effects (e.g. agranulocytosis, myocarditis and myopathy) are not dose related.  A full blood count should be checked on regular basis and if signs of infection are present. Patients should be regularly assessed for symptoms and signs of heart failure.

Please review your local DHB guidelines with regards to routine monitoring and frequency of blood tests.

Indications for serum clozapine levels (3,4): 

1. Monitoring the compliance of clozapine:

• Therapeutic ranges derived from large studies may aid in the interpretation of clozapine levels but these studies are subject to the limitation of being retrospective analysis of laboratory data. (2, 5).
• Serum levels should be interpreted with previous measurements where available.
• Individual variations of clozapine and desmethylclozapine have been derived from regional data (Labplus).
• The within-subject variation of clozapine is about 20% which means that the ratio will vary by up to +/- 41% from the mean on 95% of occasions in a stable patient on a same dose.  A change of > 60% is needed between two trough levels to show there has been a significant difference.
• The within-subject variation of desmethylclozapine is about 18% which means that the ratio will vary by up to +/-36% from the mean on 95% of occasions in a stable patient on a same dose.  A change of > 53% is needed between two trough levels to show there has been a significant difference

2. Signs of toxicity or adverse effects that may be linked to serum levels (e.g. seizures), special caution should be paid to patients in the following categories:

• When increasing dose of clozapine in patients on an existing high dose
• Sudden onset of side effects (or other situations suggestive of irregular compliance)
• Acute inflammatory states may lead to an increase in clozapine levels (6)
• Constipation is a common side effect of clozapine which can affect the degree and rate of clozapine absorption. The GI hypomotility caused by clozapine can result in delayed absorption. Once the bowel moves after a period of constipation, some of the retained but not yet absorbed clozapine in the gut may only get absorbed then. Thus, it is crucial to beware of the cumulative dose of clozapine when the bowel movement pattern changes.

3. Patients suspected or known to have liver disease

4. Co-prescription with CYP450 medications

• Increased clozapine levels: e.g. caffeine, ciprofloxacin, erythromycin, fluoxetine
• Decreased clozapine levels: e.g. carbamazepine, phenobarbitone, phenytoin, rifampicin

5. Lack of improvement under recommended doses

6. Relapse during maintenance

7. Elderly patients (> 65y)

8. Patients with renal impairment

Interpretation

Interpretation of desmethylclozapine levels and clozapine/desmethylclozapine ratios:

Desmethylclozapine is the major metabolite of clozapine formed by the enzymatic action of CYP1A2. It has no efficacy as an antipsychotic but it may assist the interpretation of the clozapine level.

There is considerable variation in the clozapine ratio between different people due to genetic variations in metabolism. Based on published articles (4,5,7) and Labplus data review, clozapine/ desmethylclozapine ratios in adults are usually  1 – 3 in trough samples taken from compliant patients at steady state. Higher plasma clozapine concentration tends to have a higher clozapine/desmethylclozapine ratio as the major metabolic pathway for clozapine exhibits saturable kinetics.

With regular, stable dosing and lifestyle (e.g. smoking habits), the ratio is expected to remain largely stable for an individual patient.  Based on Labplus data, the within-subject variation of the ratio is about 16%.  This means that the ratio will vary by up to +/- 33% from the mean on 95% of occasions in a stable patient on a same dose.  A change of > 48% is needed between two trough levels to show there has been a significant difference.  However, a new baseline ratio will likely occur with a change in long-term lifestyle habit (e.g. starting/stopping smoking).

Possible causes for a rise in clozapine/desmethylclozapine ratio

• Not a trough sample – absorption of clozapine from the last dose has not been completed at the time of sampling
• Enzyme saturation -the clozapine metabolism is saturated with a high clozapine level (usually >3000nmol/L)
• Addition of an enzyme inhibitor e.g. Fluvoxamine
• Stopping smoking

 Possible causes for a drop in clozapine/desmethylclozapine ratio 

• Poor adherence in preceding days
• Addition of enzyme inducer, e.g. starting smoking

Reference Intervals

Therapeutic range

Clozapine:   1050 to 1800 nmol/L

Therapeutic control can be achieved at levels less than 1000 nmol/L in some patients.

Reference intervals stated are for trough (pre-dose) levels.  They are only a guide, and there is significant variability in both clinical response and likelihood of side effects. Some side effects, e.g. cardiac and haematological, are not dose related.

Both clozapine and desmethylclozapine (the major metabolite) are reported. In pre-dose samples, the metabolite normally has a concentration of between 25 and 90% that of clozapine concentration.

Elimination half-life: Plasma level peaks typically after 1-3 hours and half-life is usually 8-16 hours at steady state (1).

Conversion factors

Clozapine: nmol/L = ug/L x 3.06

Desmethylclozapine : nmol/L = ug/L x 3.20