Clozapine

Clozapine (Brand name Clozaril) is considered the most efficacious antipsychotic. While it works in many cases where others have failed and can be life altering in positive ways, it is not used first line because of the more intense ECG & lab monitoring required, which we will get into below. If you are interested, please watch this video of patients giving their thoughts on what clozapine has done for them. Here is a second video of a psychiatrist interviewing his patient about their experience with clozapine. 

Clozapine benefits may take longer to recognize than other antipsychotics, so we should give it at least 6 months before making a final decision on its effectiveness as a solo agent for the psychotic symptoms. 

When is a clozapine trial recommended? 
-It is used after 1 or 2 other antipsychotic medications have been tried to treat psychotic symptoms associated with schizoaffective disorder or schizophrenia. 

In what domains is clozapine considered better than the other medications in its class? 
-Much more effective at treating psychotic symptoms 
-It is one of 2 medications in psychiatry shown to directly decrease suicidal thinking (Lithium being the other)
-Less chance of longterm movement disorders (called tardive dyskinesia)
-Less chance for tremor or changes to gait that mimic the effects seen in Parkinson’s disease  
-Less chance of restlessness 
-Less chance of a muscle dystonic reaction 

What are the screening tests that need to be done prior to starting clozapine? 
-ECG to rule out any arrhythmia or prolonged QTc interval (clozapine can lead to some arrhythmias in rare cases). 
-Blood count with differential (CBC with diff) because clozapine can affect the production of white blood cells, which we monitor over time. 
-Liver function tests: in very rare cases clozapine can cause liver toxicity, so we will monitor that periodically. 

What are the more common side effects to watch for? 
-Sedation, so we usually give all, or the majority of it, at night 
-Constipation occurs in up to 50% of patients so we may need to consider dietary changes and stool softeners. Please read here for more on remedies for constipation, if needed. 
-Increase in salivation (sialorrhea) in up to 21% of patients; this is thought to happen because patients have a decreased impulse to swallow. It is not considered dangerous but can be annoying. 
-Weight gain in 15% of patients. As weight increases we need to watch for metabolic syndrome such as higher blood pressure and insulin insensitivity.   
-Orthostatic hypotension (lower blood pressure when quickly standing) in 10% of patients, so stand up slowly to avoid dizziness. 
-Tachycardia (increased heart rate) in less than 15% of cases; it usually subsides after 1-2 months. Sometimes a beta-blocker is needed to help lower heart rate. 
-Less than 5% of patients complain about restlessness, increased sweating, and/or decreased sex drive.

What are the more rare and more intense side effects patients should know about? 
-Less than 1% of patients will develop agranulocytosis, or a decrease in the production of granulocytes (granulocytes are a key part of our innate immune response and if these get too low, then it puts the patient at higher risk of bacterial infections). We minimize this risk by doing frequent lab testing. 95% of these cases occur within the 1st 6 months of treatment. See below for laboratory testing. 
-Myocarditis occurring in 2/5000 patients— look for chest pain, fever, and shortness of breath. This is extremely rare and if it occurs it usually does so in the first few months of treatment. 
-Arrhythmias, especially prolonged QTc (which is why we do ECGs).
-Seizures— more common in those with seizure disorders but the risk increases as doses go above 600mg per day. 
-Paralytic Ileus or subileus: occurs when the intestines stop compressing which causes food to stop moving through. Presents as GI pain and constipation. 
-Neuroleptic Malignant Syndrome: rare problem with all antipsychotics in which the medicine causes an altered mental status, fever, muscle rigidity, and autonomic dysfunction. 

How frequently are labs drawn to monitor patients' absolute neutrophil count? 
-They need to occur weekly for the 1st 6 months, then every 2-4 weeks after that. 
-Note that we look at the neutrophil count because they are the most prevalent subtype of granulocyte. 
-The government has instituted a "REMS Program" which allows pharmacies to make sure these lab tests are done prior to giving the prescription to the patient.

How frequently should we get an ECG to watch for arrhythmias? 
Weekly while adjusting the dose and then with each dose increase.

How is clozapine dosed? 
-We start at 12.5mg at bedtime on day one and 25mg at bedtime on day 2. If there are no major side effects we increase the daily dose by 25mg each night. If there are too many side effects as we go up, we can slow down this titration to every 2 to 3 days, or even every 7 days. 
-Once we get to 200mg at night, we will check the serum level of clozapine/norclozapine before going higher (usually the serum level is at 350 ng/ml at this point). 
-The average target dose is 300mg to 600mg daily. At doses above 400mg we start adding a morning dose (splitting the dose). 

How long will it take for clozapine to work? 
30% of patients will respond by 6 weeks.
20% of patients will respond by 3 months. 
10-20% of patients will respond by 6 months.
Some patients will take more than 6 months to respond. 
A trial of clozapine monotherapy of 6-12 months is reasonable.

When do we check a clozapine level?
-We usually check a level when the patient gets to 200mg at bedtime. 
-We would check again for any patient receiving more than 600mg/day as there is an increased risk of seizure above that dose. 
-A therapeutic window of 0.35 mg/L - 0.5 mg/L (or 350 to 500 ng/ml) is suggested by the Maudsley Prescribing Guidelines but the maximum level is 0.75 mg/L, after which toxicity is more likely (especially above 1.0 mg/L).  

Is it ok to suddenly stop clozapine after a patient has been on it for more than 2 weeks? 
No, abrupt discontinuation can often lead to rapid relapse that is worse than the initial episode, so discuss with your practitioner to come up with a plan to wean off of clozapine. In cases where there are very serious side effects, then suddenly stopping is warranted. 

What if a patient misses 2 or more days of clozapine?
We should restart at the 12.5mg dose and titrate up. 

What are the reasons we stop clozapine? 
Neutropenia or agranulocytosis, thrombocytopenia, severe electrocardiogram (ECG) changes, QTc prolongation (>500ms), tachycardia, atrial flutter, myocarditis, cardiomyopathy, fever, syncope, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma, neuroleptic malignant syndrome, ileus, liver enzyme elevation and seizure.

What medications & other substances should be avoided when taking clozapine? 
-Be careful when taking benzodiazepines such as lorazepam and clonazepam together with clozapine because both can be sedating. 
-Avoid lamotrigine and carbamazepine 
-Avoid diphenhydramine and hydroxyzine, both of which can be anticholinergic and lead to worsening constipation which can cause paralytic ileum. 
-Smoking cigarettes greatly reduces the level of clozapine in the body (it causes the liver to break it down faster).