Clozapine in the Treatment of Psychosis

Introduction

Clozapine is an atypical (second-generation) antipsychotic primarily used in the treatment of treatment-resistant schizophrenia, and recurrent suicidal behaviors in schizophrenic/schizoaffective patients.[1]

Mechanism of Action

The mechanism by which clozapine exerts its effects involves the blocking of 5-HT2A/5-HT2C serotonin receptors and the D1-4 dopamine receptors, with the highest affinity for the D4 dopamine receptor.[2]  As a serotonin and D4 dopamine antagonist, clozapine is able to elicit its antipsychotic effects without inducing many of the extrapyramidal motor effects associated with D2 dopamine receptor antagonists.[3]

Dosing

Safety and efficacy have been established for the use of Clozapine primarily in adults with treatment-resistant schizophrenia. Initial dose beginning at 12.5mg taken orally once/day or every 12 hours.  After the initial dose, dosage increases by 25mg to 50mg depending upon patient tolerance. The goal is to achieve a target dose of 300-450 mg/day by the end of the second week.  Dosage may reach as high as 600-900 mg/day, although this higher dose increases the risk of adverse effects.[3]  Safety and efficacy have not been established for the pediatric population and is also approached with high levels of caution with the geriatric population.

Pharmacokinetics

The half-life of clozapine is approximately 12 hours, with a blood clearance rate of 250 mL/min. Upon ingestion, 97% of clozapine is bound to serum proteins and is metabolized by way of three hepatic P450 isoenzymes before being excreted through urine (50%) and feces (30%).[3]

Adverse Effects

Clozapine’s side effect profile ranges from mild symptoms (i.e. hypersalivation and an increased appetite) to more life-threatening conditions like agranulocytosis and myocarditis. In addition to the common adverse effects of atypical antipsychotics, clozapine can cause tachycardia and constipation.[3] Rarer side effects include dystonias, neuroleptic malignant syndrome, and seizures.[3]

Physical Therapy Implications

While treating, physical therapists must proceed with caution when encountering patients on clozapine.  Agranulocytosis, although a rare effect of clozapine, is an extremely dangerous condition that requires consistent monitoring of the patient’s blood cell count.[4] Drowsiness, dizziness, and tachycardia have implications regarding the patient's fall risk and level of perceived exertion.  Gastrointestinal distress from this medication can affect the patient’s ability to participate in therapy. The optimal time to treat these patients will vary, and proper scheduling will be pertinent to the level of care the physical therapist can provide.

For more information regarding clozapine please visit the FDA's medication guide: Clozaril (Clozapine).

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  1. Meltzer HY. Clozapine Treatment for Suicidality in SchizophreniaInternational Suicide Prevention Trial (InterSePT). Archives of General Psychiatry. 2003;60(1):82. doi:10.1001/archpsyc.60.1.82.
  2. Nucifora FC, Mihaljevic M, Lee BJ, Sawa A. Clozapine as a Model for Antipsychotic Development. Neurotherapeutics. 2017;14(3):750-761
  3. 3.0 3.1 3.2 3.3 3.4 Clozaril (Clozapine). Accessdata.fda.gov. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019758s062lbl.pdf. Published 2018. Accessed November 30, 2018.
  4. Uçok A, Gaebel W. Side effects of atypical antipsychotics: a brief overview. World Psychiatry. 2008;7(1):58-62.