Clozapine: 10 important facts to know

“Please do not discharge Jean Jacques on Clozapine. It will be a recipe for disaster.”  Dawn, Jean’s psychiatrist, articulated this request of Larny, the psychiatrist covering the Hope Hospital inpatient psychiatry unit, where Jean was admitted.

Dawn was trying to explain that Jean Jacques often gets lost from the shelter and there has been uncertainty about his medication dosing when he eventually returns.  She was also alluding to the need for a medication re-challenge after 48 hours of interrupted use.  (Re-challenge is essentially a re-dosing, as if it were being started for the first time).

We have discussed seven typical and five atypical, antipsychotic agents.  Clozapine is an atypical antipsychotic that has special characteristics, requiring dedicated attention here.

Below are ten important facts you need to know about Clozapine:

1. Agranulocytosis is only 1%:

Clozapine has trade or brand name Clozaril, and it is classified as an atypical antipsychotic agent.  It is indicated in the treatment of Schizophrenia.  A few special characteristics include the following:

1. It is reserved for treatment resistant Schizophrenia, and

2. It has also been shown to be helpful for patients with suicidality in the setting of Schizophrenia.

3. Another important, special feature, though not a positive one, Clozapine has the potential to cause agranulocytosis, a decrease in the number of white blood cells (WBCs); these cells serve the immune function in the body. While this side effect is well known and documented, its occurrence rate is only 1%, which means anyone taking Clozapine has a 1% chance of developing agranulocytosis and 99% of not developing it. This also means that for every 100 persons taking Clozapine, only 1 of them may end up developing agranulocytosis, while 99 will likely not.

Given this small risk, why then is there such attention given to Clozapine and agranulocytosis?  Remember, in agranulocytocis the white blood cells—the soldiers defending your body against “foreign” attacking agents and infections—decrease significantly.  This leaves you with little protection and the result can be death.

Because there is so much at stake, the US Food and Drug Administration (FDA), the US agency responsible for control and approval of medications in the US, requires a Black Box Warning (the strictest warning on the label of a medication) for Clozapine about agranulocytosis. Because of this life threatening side effect, the use of Clozapine is reserved for after a patient or client has failed a trial of two other antipsychotics.

2. Regular blood monitoring remains a barrier to treatment:

Once the criteria for taking Clozapine are satisfied, there are further requirements for regular blood monitoring.  Weekly blood tests are required for the first six months, then biweekly for the next six months, and then monthly, after one year of taking Clozapine.  This schedule happens only if there is no significant change in the white blood cells.  Neutrophils are the specific white blood cells monitored during these blood tests, more specifically, the absolute neutrophil count (ANC).  The normal range is 1500-8000 cells/uL (microliter), and lower than 500 cells/uL is known as neutropenia (low ANC).  Neutropenia is a condition that significantly increases the risk for infection, because of agranulocytosis.  This monitoring guideline is based on the fact that the 1% likelihood of developing agranulycytosis, which tends to occur in the first three months, will decrease to 0.01% after one year of taking Clozapine.  It is worth noting that children, adolescents, and the elderly are at higher risk for agranulocytosis compared to other age groups.

3. Some atypical side effects:

While Clozapine shares many of the same side effects seen with other atypical medications, including Metabolic Syndrome (weight gain, hypertension, diabetes, hypertriglyceridemia, or low HDL), the probability for extrapyramidal symptoms (EPS) is low, while the likelihood for other side effects, like seizure, hyper salivation, myocarditis (inflammation of the heart), and hypotension are well documented.  The risk of seizure, thought to be dose dependent, and the risk of hypotension can be significantly decreased with a slow titration (increase) of the dose, which I often recommend for medications, in general, not just Clozapine.

4. A history worth highlighted:

Another particular feature of Clozapine, it was synthesized in 1958, only eight years after the first antipsychotic agent, Thorazine.  This is especially notable, because the second-generation antipsychotics are generally more recent than Clozapine.  However, in 1975, it was withdrawn due to report of agranulocytosis but later on reappeared and was approved for use in treatment resistant schizophrenia.

5. Made it to the Model List of Essential Medicines:

Despite its Black Box Warning, Clozapine is one of only two atypical agents and one of the only five antipsychotic medications that have made it to the World Health Organization’s (WHO) Model List of Essential Medicines—the most effective and safest medication required in a health system.

However, on this list, Clozapine is part of the complementary items.

In my opinion, Clozapine is likely on the list of complimentary items, as opposed to the core items, due to the required additional infrastructure, like blood monitoring.  It also may be due to the fact that the risk of using Clozapine prior to trial of two other antipsychotics does not outweigh the benefits.

6. A secret weapon in dual diagnosis:

Another special feature of Clozapine worth mentioning and particularly significant for our dual diagnosis patients and clients, it lowers the incidence of relapse to substance use.  Part of this phenomenon is both straightforward and welcoming.  Due to their mechanism of action, the typical antipsychotics tend to mimic negative symptoms, and this has been found to be a contributing risk factor to using stimulants like cocaine and cigarette smoking.  Negative symptom-like side effects occur less with atypical antipsychotics, and even less with Clozapine. One of the major challenges with our patients and clients with dual diagnosis is active substance or drug use.  Having an antipsychotic that prevents the likelihood of relapse is for sure music to our ears.

Jean Jacques uses a variety of substances, including K2, and he becomes symptomatic even on injectable antipsychotics; but when he is on Clozapine, he is seen to be at his best.  Unfortunately, because he tends to leave his shelter and not come back until days later, his Clozapine needs constant re-challenge.  Since he may be administered the medication without proper re-challenge, Jean Jacques has a high risk for a fatal outcome.

7. Number 1 antipsychotic:

Clozapine is the most effective antipsychotic.  Yes, the 2013 study, Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: A multiple-treatments meta-analysis, published in the Lancet showed Clozapine as the number 1 antipsychotic in effectiveness.  It was found to be 33% more effective than Olanzapine and 50% more than Haloperidol.

8. Myocarditis Monitoring is required:

Few pay attention to myocarditis (Inflammation of the heart), which is another fatal side effect of Clozapine.  Like agranulocytosis, the risk for myocarditis increases early in treatment, particularly during the first month; and like seizure and hypotension, its risk also decreases with slow dose titration.  While it is common to have weekly ANC blood test monitor during the first six months, an EKG and weekly cardiac enzyme, like troponin, during the first month is part of the monitoring guidelines for myocarditis, though done less commonly.  Another recommendation involves caution with the use of Valproic acid; its use along with Clozapine has been shown to increase the risk of myocarditis.

9. Gastrointestinal hypo-motility is underrated:

Gastrointestinal side effects are too easily minimized.  Because Clozapine has strong anticholinergic properties, the function of the gastrointestinal system can be decreased and at times even compromised.  While agranulocytosis is more commonly known, and the gastrointestinal side effects, less, those on Clozapine are more likely to die form gastrointestinal hypo-motility (decreased movement and activities) than from agranulocytosis.

10. Higher Risk for Weight Gain and Metabolic Syndrome:

Weight gain and Metabolic Syndrome are relatively more likely than most of the other atypical antipsychotics.  In a previous article, Basic Knowledge of Antipsychotics: The Five Atypicals, I mentioned that Olanzapine was by far the most diabetogenic (diabetes causing) of all the antipsychotic agents.  Clozapine is a close second, and both of them have been shown to disrupt the body’s usual use of energy.  Instead of using carbohydrates (sugar), the body tends to use fat, leaving a high level of carbohydrates available, and this leads to insulin resistance and then to diabetes. One downside for sure of Clozapine is high likelihood of weight gain and Metabolic Syndrome that comes with its high effectiveness, a characteristic shared with Olanzapine.

“Please do not discharge Jean Jacques on Clozapine. It will be a recipe for disaster.” Dawn, Jean’s outpatient psychiatrist, articulated this request of Larny, the psychiatrist covering the Hope Hospital, inpatient psychiatry unit, where Jean was admitted. Larny totally agreed. Jean Jacques always does very well on Clozapine while in the inpatient unit.  But he often goes days without the medication and is at risk for death, if he goes back on his Clozapine without the proper re-challenge. Another challenge with Jean Jacques was the lack of the regular blood draw, required to obtain his ANC prior to renewing his Clozapine.

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