Introduction

Clozapine (Figure 1) is a unique neuroleptic agent. Unlike other neuroleptics, it does not produce significant extrapyramidal side effects in treated individuals.Further, some patients with schizophrenia have improved with clozapine treatment who were previously refractory to other neuroleptics. Although clozapine was only recently approved for use in the United States, it has been available in other countries for many years. The reason for this discrepancy is that during the clinical trials with clozapine in the US in the mid 1970s, reports of agranulocytosis appeared in the European literature. This resulted in the withdrawal of clozapine in the US and the limiting of its distribution in other countries. Since the reintroduction of clozapine into the market in the late1980s, information regarding its pharmacokinetics and pharmacodynamics has been expanded. However, the routine monitoring of plasma neuroleptic concentrations by clinicians still remains to be established. A major factor that limits the everyday application of routine monitoring is the lack of information regarding the metabolic disposition of the drug.[1]

Pharmacodynamics

Clozapine is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives that is universally regarded as the treatment of choice for treatment-resistant schizophrenia. Although it is thought to mediate its pharmacological effect through antagonism of the dopamine type 2 (D₂) and the serotonin type 2A (5-HT_2A) receptors, research have shown that clozapine can act on various types of receptors.[2-3]

Patients should be counseled regarding the risk of hypersensitivity reactions such as agranulocytosis and myocarditis with clozapine use. Clozapine-induced agranulocytosis, which is a reduction in the absolute neutrophil count or white blood cell count, places the patient at an increased risk for infection.[4] Agranulocytosis is most likely to occur in the first 3-6 months of therapy, but it can still occur after years of treatment. The mechanism is thought to be a dose-independent and immune-mediated reaction against neutrophils.6 Patients are strictly monitored by lab testing (complete blood count with differential) to ensure agranulocytosis is detected and treated if it occurs.Testing is initially completed at one-week intervals but is expanded to two-week intervals at six months, and then four-week intervals at twelve months if lab results have been within an appropriate range. Monitoring parameters may change if there is any break in therapy. In Canada, the patient's lab values are reported to the manufacturer for hematological monitoring, and in the USA, the patient's lab values are reported to the REMS (Risk Evaluation and Mitigation Strategy) program.7 These programs function to notify the care provider of any significant drop in WBC/neutrophil count, or if there is a drop below a threshold level. Patients who enter the "Red" zone (WBC<2x10⁹/L or ANC<1.5x10⁹/L) should normally not be re-challenged.

Clozapine-induced myocarditis is a hypersensitivity reaction that usually occurs in the third week of clozapine therapy and about 2% of clozapine patients.[5] Monitor the patient's troponin, CRP, and ECG at baseline, and 28 days into treatment. Follow guidelines for appropriate next steps according to the patient's lab results. If myocarditis occurs, the patient should not be rechallenged with clozapine.

Mechanism of action

The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D₂) and the serotonin type 2A (5-HT_2A) receptors. Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic, and other dopaminergic and serotonergic receptors.

Clozapine demonstrated binding affinity to the following receptors: histamine H1 (Ki 1.1 nM), adrenergic α1A (Ki 1.6 nM), serotonin 5-HT6 (Ki 4 nM), serotonin 5-HT2A (Ki 5.4 nM), muscarinic M1 (Ki 6.2 nM), serotonin 5-HT7 (Ki 6.3 nM), serotonin 5-HT2C (Ki 9.4 nM), dopamine D4 (Ki 24 nM), adrenergic α2A (Ki 90 nM), serotonin 5-HT3 (Ki 95 nM), serotonin 5-HT1A (Ki 120 nM), dopamine D2 (Ki 160 nM), dopamine D1 (Ki 270 nM), dopamine D5 (Ki 454 nM), and dopamine D3 (Ki 555 nM).

Clozapine acts as an antagonist at other receptors, but with lower potency. Antagonism at receptors other than dopamine and 5HT₂ with similar receptor affinities may explain some of the other therapeutic and side effects of clozapine. Clozapine's antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects. Clozapine's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Clozapine's antagonism of adrenergic α1 receptors may explain the orthostatic hypotension observed with this drug.[6]

Clozapine's Side-Effect

Despite clozapine's superior efficacy, it has several lifethreatening side effects. Agranulocytosis (now called severeneutropenia) occurs when the absolute neutrophil count is <500/μl. The risks are estimated to be 0.8% for severe neutropenia and 3% for neutropenia. As agranulocytosis orsevere neutropenia can lead to death, the FDA instituted theclozapine Risk Evaluation and Mitigation Strategies (REMS)registry. All patients on clozapine must enter this registry withweekly blood monitoring of their absolute neutrophil countfor the first 6 months, every 2 weeks for the next 6 months,and then monthly for as long as the patient is on clozapine.The establishment of a national registry has dramatically reduced the expected deaths from clozapine. Myocarditis occurs in 1 out of 10,000 to 1 out of 500, with a mortality rate of up to 50%. Approximately 80% of the incidents of myocarditis occur within the first month and 90% by 2 months. Clozapine can also cause venous thromboembolism, with an estimated mortality rate of 44%. Close following of electrocardiograms, troponins, and C-reactive protein during the first 2 months can mitigate cardiovascular events. The risk of developing seizures can be up to 10% after 3.8 years. However, seizures arising from clozapine treatment are not a contraindication and clozapine can be continued with the co-administration of an antiseizure medication. Gastrointestinal hypomotility occurs in approximately 14% of patients with a mortality rate as high as 27.5%. A mean weight gain of 30 lb was observed in a 10-year cohort, with most weight gain occurring during the first 6 to 12 months. Finally, clozapine is also associated with a high risk of developing diabetes mellitus. Unfortunately, gastrointestinal hypomotility and metabolic disturbances remain problematic despite monitoring.[7]

References

[1] Jann MW, Grimsley SR, Gray EC, Chang WH. Pharmacokinetics and pharmacodynamics of clozapine. Clin Pharmacokinet. 1993;24(2):161-176. doi:10.2165/00003088-199324020-00005

[2] Li P ,Snyder GL,Vanover KE. Dopamine Targeting Drugs for the Treatment of Schizophrenia: Past,Present and Future. Curr. Top. Med. Chem. 2016,16,3385-3403

[3] Keating D, McWilliams S, Schneider I, Hynes C, Cousins G, Strawbridge J, Clarke M: Pharmacological guidelines for schizophrenia: a systematic review and comparison of recommendations for the first episode. BMJ Open. 2017 Jan 6;7(1):e013881. doi: 10.1136/bmjopen-2016-013881. 

[4] Kar N, Barreto S, Chandavarkar R: Clozapine Monitoring in Clinical Practice: Beyond the Mandatory Requirement. Clin Psychopharmacol Neurosci. 2016 Nov 30;14(4):323-329. doi: 10.9758/cpn.2016.14.4.323. 

[5] Ronaldson KJ, Fitzgerald PB, Taylor AJ, Topliss DJ, McNeil JJ: A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls. Aust N Z J Psychiatry. 2011 Jun;45(6):458-65. doi: 10.3109/00048674.2011.572852. Epub 2011 Apr 27.

[6] Clozapine. https://go.drugbank.com/drugs/DB00363

[7] Nucifora FC Jr, Mihaljevic M, Lee BJ, Sawa A. Clozapine as a Model for Antipsychotic Development. Neurotherapeutics. 2017;14(3):750-761. doi:10.1007/s13311-017-0552-9