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Day # 20: Clozapine

Today we are going to discuss one medication: clozapine. Clozapine deserves at least one full day of our attention due to its unique properties, side effects, and specific prescribing guidelines. Let's jump right in.

Today's Content Level: Intermediate; Advanced

Introduction and Mechanism of Action

•As we discussed previously, clozapine is consistently shown in the literature to be the most effective antipsychotic medication and is the first choice in treatment resistant schizophrenia (symptoms do not respond sufficiently to adequate, sequential trials of two or more antipsychotic drugs). 1

•Because of the significant side effects and other unique aspects of this medication it is typically reserved for treatment resistant cases.

•The biological basis for the superior efficacy of clozapine is uncertain, however it has been hypothesized that it may be due to it's broad mechanism of action. Clozapine is an antagonist at serotonin (5HT2A), dopamine (D1, D2, D4), histamine (H1), muscarinic, and alpha-1 receptors. This also provides an explanation for the significant side effect profile.

•Clozapine is metabolized by specific enzymes in the liver called cytochrome P450 enzymes. This family of enzymes is responsible for the metabolism of many different medications. Specifically, it is metabolized by CYP1A2 and 3A4.

•Of note, fluvoxamine (SSRI) blocks 1A2 (slows metabolism) and cigarette smoking induces 1A2 (increases metabolism) which both effect drug levels of clozapine. What this means practically, for example, is that a smoker will metabolize this drug more quickly leading to lower medication levels and thus the dose will need to be increased.

•In male smokers who cannot achieve therapeutic plasma levels, metabolic inhibitors (fluvoxamine or cimetidine), can be co-prescribed but extreme caution is required.

Side Effects

•Most of this was already covered in two previous posts: day 15 and 17.

•As a reminder, here are some of the highlights:

  • Less likely to cause tardive dyskinesia and EPS in general.

  • Can cause tachycardia and hypersalivation. Can treat hyper salivation with glycopyrrolate.

  • Most severe anticholinergic side effects.

  • Significant constipation. Can lead to toxic megacolon / ogilvie syndrome.

  • Very sedating.

  • Clozapine and olanzapine most severe weight gain and metabolic syndrome.

  • Higher risk of hypotension among SGA's (along with quetiapine and risperidone).

  • Small risk of myocarditis.

  • 1% incidence of agranulocytosis. Highest risk during first 6 months of treatment. Risk also increases with age. Must be stopped if ANC drops below 1,500/microliter.

  • 4% incidence of seizures (highest of all antipsychotics). Increased risk at higher doses and fast titrations.

•Clozapine has five black box warnings.

  • Agranulocytosis

  • Seizure

  • Myocarditis

  • Orthostatic hypotension with syncope or cardiorespiratory arrest

  • Increased mortality in elderly patients with dementia-related psychosis


•Before prescribing clozapine, consider the following potential contraindications. If any of these are present, exercise extreme caution. 2

•History of seizures, significant cardiac disease, unstable diabetes, paralytic ileus, blood dyscrasia, NMS or other disorder that increases the risk of serious adverse effects (initiation with close monitoring in hospital may still be possible).

•Previous severe adverse effects on titration of clozapine or other antipsychotics.

•Unreliable or chaotic lifestyle that may affect adherence to the medication or the monitoring regimen.

•Significant abuse of alcohol or other drugs likely to increase the risk of adverse effects (e.g. cocaine).


•When first prescribing clozapine:

  • Physical examination

  • Complete Blood Count (CBC). Requires ANC of at least 1500 for routine prescribing.

  • Liver function tests (LFT)

  • BUN and electrolytes (BMP)

  • Lipids

  • Glucose/HbA 1C

  • ECG – particularly to screen for evidence of past myocardial infarction or ventricular abnormality echocardiogram if clinically indicated.

  • Other labs not required but consider in certain circumstances: troponin, C‐reactive protein (CRP), beta‐natriuretic peptide, erythrocyte sedimentation rate (ESR) as baseline for further tests.

•After first dose is given check pulse, postural blood pressure, and temperature between 30mins and 6 hours after the dose.

•Continued monitoring

  • Required weekly blood draws for the first 6 months (CBC with diff / ANC) .

  • Every 2 weeks for the remainder of the first year.

  • After that usually done monthly.

  • See this 4-minute video for an excellent summary of ANC monitoring and considerations.

  • Inform the patient's primary care doc that he/she is on clozapine and provide education.

  • Consider monitoring plasma troponin, beta‐natriuretic peptide and CRP weekly in the first 6 weeks of treatment, particularly where there is any suspicion of myocarditis.

  • For further continued monitoring true of all antipsychotics, see the table below taken from the Maudsley's Prescribers Guide.

Dosing and Titration

•Many of the adverse effects of clozapine are dose-dependent and associated with speed of titration.

•Adverse effects also tend to be more common and severe at the beginning of therapy. Slow titration is particularly important to minimize the risk of seizure, syncope, and sedation.

•Clozapine should normally be started at a dose of 12.5 - 25 mg once per day at night. If tolerated, the dose can be increased by 25 - 50 mg per day until dose of 300 mg per day is reached. Further dosage increases should be made slowly in 50 - 100 mg each week. Target dose is typically 300 - 450 mg per day with max dose of 900 mg. The total dose should be divided (usually twice daily) and, if sedation is a problem, the larger portion of the dose can be given at night.

•The blood levels of clozapine should also be checked for dosing changes.

  • The target serum level range is 200-350 μg/mL.

  • 50-150 μg/mL is often ineffective.

  • Upper limit of levels is 300-450 if continued symptoms.

  • Levels above this are associated with increased seizure risk.

•Clozapine has linear pharmacokinetics: this means that double the dose = double the blood level.

•If patient stops taking the medication or misses doses there are some important considerations. If less than 48 hours, can restart previous dose, otherwise, especially after 72 hours, will need to restart the titration schedule.

Miscellaneous Clinical Pearls

•All prescribers and patients must be registered in clozapine REMS. Patients entered into database -

•Clozapine is the only antipsychotic shown to reduce the risk of suicide 3. Remember the risk of suicide is 20x greater in patients with schizophrenia.

A quick word on clozapine augmentation:

  • The evidence for augmentation with various agents is growing but remains insufficient for a specific algorithm or schedule of treatment options.

  • In practice the result of clozapine augmentation is often disappointing and substantial changes in symptom severity are rarely observed. Studies showing a very small effect overall. Source.

  • The following agents have at least some evidence for limited effects: amisulpride (risk of increased cardiac effects), aripiprazole (can also reduce weight and LDL cholesterol), haloperidol, lamotrigine, omega-3 triglycerides, risperidone, sulpride, and ziprasidone, ginkgo biloba, and memantine. Can also consider the use of mood stabilizers and/or antidepressants if mood disturbance is thought to contribute to symptoms. Also consider augmenting with ECT or TMS.

  • Augmentation attempts should be carefully monitored and, if no clear benefit is seen, abandoned after 3-6 months.


Congratulations! This was the last blog post in our current theme (intro to psychotic spectrum disorders). On Monday we will have a review quiz and after that we will start our next theme (depressive disorders).

Resources for this post include embedded articles as well as:

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