Introduction:
I’ve said it before in previous videos, older medications are more effective and newer medications have fewer side effects.
The advent of SSRIs in the late 1980’s and early 1990’s was largely driven by safety and not efficacy. The same is true for antipsychotic medications. This may be the reason most people haven’t even heard about Clozapine (brand name Clozaril).
Efficacy
Clozapine is the single most effective antipsychotic available, and it works in treatment resistant schizophrenia where no other medication is proven to be effective.
The results speak for themselves, 30% of previously treatment resistant patients experience symptom reduction within 6 weeks and that number jumps to 60% after 6 months of treatment.
Clozapine has a slew of additional benefits including mood stabilizing prosperities (it can be used in bipolar disorder), reduction in psychogenic polydipsia and the hyponatremia associated with it, reduction in hostility and aggression, reduction in the risk of suicidal ideation, improvement in substance use, and it may even help patients quit smoking a difficult task in schizophrenia.
So why are most schizophrenic patients not on this medication if it’s so great?
Side effects, side effect, side effects
-Sedation: feeling tired this can largely be mitigated by dosing the medication at night before bedtime.
-Tachycardia: It’s worth getting an EKG in patients with preexisting heart conditions or those at high risk due to hypertension and hyperlipidemia
-Sialorrhea: excessive saliva production leading to drooling, no one wants this
-Dizziness
-Constipation: this should be addressed immediately if a patient complains about it as it can lead to serious complications. In many cases Senna and Colace will do the trick
-Orthostatic hypotension
-Weight gain
Serious and potentially fatal Side effects include:
-Agranulocytosis: decreased absolute neutrophil count which can result in increased risk for serious infection and the reason everyone on the medication gets weekly blood draws for the first 6 months
-Seizures: clozapine is known to lower the seizure threshold
-Myocarditis: inflammation of the heart usually due to a viral infection
The risk for agranulocytosis is highest when starting treatment, usually during the first year of treatment (0.8%) and the maximum risk is between 4 and 18 weeks (when 77% of cases occur), although it can still occur at any point in the treatment.
Agranulocytosis
Monitoring is thus very important, and each patient must be registered in the Risk Evaluation and Mitigation strategy (REMS) data base before starting the medication.
A CBC with differential must be drawn to calculate the absolute neutrophil count prior to starting treatment and then weekly for the first 6 months. Then monitoring continues every 2 weeks for the next 6 months and finally monthly after the first year of treatment.
If agranulocytosis occurs stopping clozapine allows majority of cases to recover within 14 days.
Now that we know that this medication is very effective but comes with a high side effect burden a natural next question might be why does the medication work?
Mechanism of Action
Clozapine has very low affinity for the D2 receptors which is unique as most other antipsychotics will bind strongly to D2 receptors. Clozapine had far greater D1 and D4 binding affinity, blocking both receptors.
Clozapine also has significant activity at other neurotransmitter sites. It blocks alpha receptors which may be the reason for orthostatic hypotension. It blocks histamine H1 receptors resulting in sedation and weight gain. It blocks 5-HT2A serotonin receptors and is highly anticholinergic resulting in constipation and urinary retention.
It has two unique properties; it influences the glutamate system by altering NMDA receptor sensitivity and increases the release of brain derived neurotrophic factor BDNF.
Metabolism And Drug Interactions
Clozapine is primarily metabolized by CYP450 1A2 and 3A4 and cigarette smoking will cause a reduction in clozapine levels due to induction of CYP 1A2.
Before Starting the Medication
Before starting clozapine, the ANC must be above 1,500. If neutropenia develops treatment will depend on the severity of the drop.
Mild Neutropenia: ANC 1,000-1,499, you would continue treatment and check an ANC three times weekly until it reaches 1,500.
Moderate Neutropenia: ANC between 500 and 999, stop treatment and check the ANC daily until it reaches 1,000 then 3 times weekly until it reaches 1,500 then weekly for 4 weeks before returning to the patients prior monitoring schedule.
Severe Neutropenia: ANC less than 500, stop treatment and check an ANC daily until it’s 1,000 then 3 times weekly until it’s 1,500. The patient should not be rechallenged without a hematology consult and clear benefits that outweigh the risks.
Dosing
Clozapine can be started at 12.5 to 25 mg at bedtime. The dose can be increased 25 mg/day inpatient and 25 mg per week in the outpatient setting as tolerated.
You can overlap prior treatment with another antipsychotic and tapper the old medication once clozapine dose reaches 100 mg or more.
Plasma Levels
Clozapine dose should be based on serum levels, with a target blood level of 200 to 300 ng/ml. If there are still symptoms present the target serum level is 450 ng/ml. There are no benefits to serum levels above 900 ng/ml.
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