Unique Effects of Clozapine: A Pharmacological Perspective

Abstract

Schizophrenia is a heterogenous and severe neuropsychiatric disorder that affects nearly 1% of the population worldwide. Antipsychotic drugs are the mainstay of treatment, but not all patients with schizophrenia respond to treatment with these agents. Clozapine, the first atypical antipsychotic, is a highly effective medication for patients with schizophrenia who do not respond to other antipsychotics. Although clozapine tends not to produce extrapyramidal symptoms, other side effects of the drug (e.g., agranulocytosis, myocarditis, seizures) limit its widespread use. This chapter reviews clozapine's unique clinical effects and unusual pharmacological profile. In addition to its effects in treatment-resistant schizophrenia, clozapine has been shown to decrease suicidality, which occurs at an increased rate in patients with schizophrenia. Still preliminary, but consistent data, also suggest that clozapine limits substance use in these patients, an important effect since substance use disorders are common in patients with schizophrenia and are associated with a poor outcome, including an increased risk for suicide and poor response to treatment. We have suggested, from animal studies, that clozapine's apparent ability to limit substance use may occur through its actions as a weak dopamine D2 receptor antagonist, a potent norepinephrine α-2 receptor antagonist and a norepinephrine reuptake inhibitor. Using animal models, we have built combinations of agents toward creation of safer clozapine-like drugs to reduce substance use in these patients. Future research into the mechanisms of action of clozapine toward the development of safe clozapine-like agents is of great public health importance.

Polypharmacy in schizophrenia

“…4 Clozapine is a third-line compound as a consequence of the risk of severe side effects, including a need to follow standardized blood monitoring due to a 0.9% risk of agranulocytosis. 5 It is a substantial problem in schizophrenia treatment that marked delays are often observed before clozapine is introduced to treatment-resistant patients. Observational data point to a mean delay of almost 50 months 6 before treatment-resistant patients are offered clozapine despite well-established evidence of its superior efficacy in this patient group.…”

“…The only exception is clozapine with firm evidence of superior efficacy in patients with schizophrenia not having responded to ≥2 previous antipsychotic agents (ie treatment resistance) . Clozapine is a third‐line compound as a consequence of the risk of severe side effects, including a need to follow standardized blood monitoring due to a 0.9% risk of agranulocytosis . It is a substantial problem in schizophrenia treatment that marked delays are often observed before clozapine is introduced to treatment‐resistant patients.…”

Focus on Clozapine Withdrawal- and Misuse-Related Cases as Reported to the European Medicines Agency (EMA) Pharmacovigilance Database

“…Clozapine is a dibenzodiazepine designated as a Multi-Acting Receptor-Targeted Antipsychotic (MARTA), deriving its therapeutic effects from its action across various neurotransmitter systems [4,5]. In fact, a combination of pharmacological effects is unique to clozapine: (1) although the molecule presents with affinity levels for a range of dopamine/DA receptors (e.g., D1, D2, D3, D4, and D5; [6]), the blockade of dopamine 2 and 4 receptors is particularly relevant, with a preferential affinity for D4 over D2 receptors; this blockade seems to be effective in reducing positive symptoms of psychosis and stabilizing affective symptoms [4]; (2) 5-hydroxytryptamine/5-HT 2A receptor antagonism, causing enhancement of DA release in certain brain regions, and thus reducing motor side-effects and possibly improving cognitive and affective symptoms associated with schizophrenia [4]. Conversely, the clinical effects of the reported interactions at 5HT2C; 5HT1A; 5-HT6; and 5-HT7 receptors [6] might be less clear; (3) α2C-adrenergic receptor blockade; this may contribute to the clozapine-related improvement of cognitive function [7]; (4) significant antimuscarinic and antihistaminergic H1 effects, which may well contribute to the central effect [8]; and (5) possible modulatory actions on a dysfunctional glutamatergic system, improving schizophrenia symptoms and contrasting illness progression [1,4,[9][10][11].…”

“…Substance use disorders (SUDs), typically involving alcohol, cannabis, and cocaine, commonly occur in patients with schizophrenia, supposedly due to epidemiological and genetic determinants of risk for both psychosis and addiction [1,16]. This co-occurrence ('dual diagnosis') has a negative effect on the course of schizophrenia, due to increased rates of hospitalization, decreased compliance with medication, increased violence and suicide, general deterioration of the patients' condition, and overall increased societal costs [1,17]. In particular, the positive symptoms of schizophrenia are generally exacerbated by the intake of stimulant drugs, such as cocaine, amphetamine derivatives [24], and synthetic cathinones [25].…”

“…Clozapine was first synthesized in 1959 [1] and made available on the European market in 1971 for the treatment of schizophrenia [2]. If compared with remaining first-generation antipsychotic agents, clozapine is characterized by a lack of extrapyramidal side-effects [2].…”