A 46-year-old man with schizophrenia is brought to the surgery by one of his carers. His current medication includes clozapine and procyclidine. His carer reports that for the past few weeks he has been more tired than usual and generally unwell. She also thinks he may have put on weight. What is the most important test to perform?
The most important complication of clozapine therapy to exclude is agranulocytosis. Weight gain is common in patients taking an antipsychotic.
Blood sugar41%Full blood count44%Urea and electrolytes6%Urine dipstick for protein5%Liver function tests4%
The most important complication of clozapine therapy to exclude is agranulocytosis. Weight gain is common in patients taking an antipsychotic.
Clozapine (neutropenia and agranulocytosis)
Neutropenia refers to a decrease in circulating neutrophils. The term agranulocytosis is used to communicate a more severe subset of neutropenia. Agranulocytosis refers to a virtual absence of neutrophils in peripheral blood.
Neutropenia
Around 2.7% of patients treated with clozapine develop neutropenia. Of these, half do so within the first 18 weeks, and three-quarters by the end of the first year (Maudsley, 2012).
Risk factors for neutropenia include:-
- Race (Afro-Caribbean 77% increase in risk)
- Age (decrease in risk as age increases)
- Low baseline white cell count
Note: Risk is NOT dose related
Agranulocytosis
Agranulocytosis is defined as an absolute neutrophil count (ANC) of less than 0.5 * 10^9/L. It is estimated to occur in 0.8% of patients. It can be fatal if not detected early.
With adequate monitoring the case fatality rate appears to be around 3% (of those who develop agranulocytosis 3% will die).
Clozapine must not be used alongside other drugs known to cause agranulocytosis e.g. carbamazepine.
Lithium has been shown to independently raise the white cell count and has been used in this way successfully in combination with clozapine. Use of this combination can enable patients to continue on treatment when they develop neutropenia. Having said that there are case reports suggesting that the combined use of lithium and clozapine can result in toxicity and so this combination must be used with caution.
Risk factors for clozapine induced agranulocytosis include:-
- Age (increasing age increases risk)
- Ethnicity (Asians are 2.4 times more likely than Caucasians to develop agranulocytosis on clozapine)
Note: the risk factors for neutropenia and agranulocytosis are quite different!
Rechallenge
One-third of patients who stop clozapine due to neutropenia or agranulocytosis will develop a blood dyscrasia on rechallenge. In most cases, the second reaction will occur more rapidly, be more severe, and will last longer than the first (Maudsley, 2012).
NOTE: Not all risk factors are the same for agranulocytosis and neutropenia; this implies that there may be distinct mechanisms for the two disorders.
Maudsley Guidelines (2012) 11th Edition p.85.
