Clozapine
Clozapine (CLZ) is a unique antipsychotic medication that can produce marked improvement in up to 30% of chronic schizophrenic patients unresponsive to other neuroleptics (Kane et al., 1988).
From: Techniques in the Behavioral and Neural Sciences, 1993
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Pathophysiology, Pharmacology, and Biochemistry of Dyskinesia
Peter N. van Harten MD, PhD, Diederik E. Tenback MD, PhD, in International Review of Neurobiology, 2011
By Switching to Clozapine
Clozapine does not or very rarely induce TD. In the few case reports suggesting that clozapine induces TD most of the patients had a history of long-term use of FGAs. In such cases switching to clozapine may reveal suppressed TD (Bruscas et al., 2007; Duggal and Mendhekar, 2007; Ertugrul and Demir, 2005; Li et al., 2009; Raguraman and Vijaysagar, 2007).
In one trial, clozapine was compared with haloperidol for the treatment of patients with TD. Clozapine produced significantly greater motor symptom benefit after 12 months of treatment than did haloperidol. Moreover, the dyskinesia rebound, which occurred equally in both drug groups at the beginning of the study, was sustained in the haloperidol group but disappeared in the patients treated with clozapine (Tamminga et al., 1994). These data suggest that dyskinetic symptoms decrease, along with dopaminergic hypersensitivity, with long-term clozapine treatment (Lieberman, 2007; Lieberman et al., 1991).
There are several open trials and case series or case reports suggesting a beneficial effect of clozapine on existing TD. It seems that clozapine is especially beneficial in those patients in which TD is combined with tardive dystonia (Louza and Bassitt, 2005; van Harten et al., 1996a).
Drug Monitoring and Clinical Chemistry
Philip B. Mitchell, in Handbook of Analytical Separations, 2004
10.4.2.3 Relationship between genotype and serum concentrations
Clozapine is metabolized by CYP1A2 and CYP3A4 to the relatively inactive compounds norclozapine and clozapine-N-oxide. Response to clozapine is therefore not predicted by the CYP2D6 genotype [88]. A recent case report has highlighted the role of CYP1A2 in clozapine disposition [89]. In that case study, clozapine levels were affected by: (i) ultrarapid metabolism due to a single nucleotide polymorphism in intron 1 of the CYP1A2 gene; (ii) the CYP1A2 actions of grapefruit juice (enzyme induction); and (iii) the antidepressantfluvoxamine (CYP1A2 inhibition). Consistent with this, clozapine population pharmacokinetics are distributed similarly to the indices of CYP1A2 activity found in community populations [90].
Pharmacogenetics of Drug Metabolism
David A. Flockhart, Zeruesenay Desta, inClinical and Translational Science, 2009
Clozapine
Clozapine is a prototypical atypical antipsychotic whose metabolism covaries with CYP1A2 activity. Because clinical studies indicate a positive association between clozapine plasma concentration and antipsychotic response and since the extent of antipsychotic response varies markedly among patients, polymorphism of CYP1A2, and/or its regulators (e.g., Aromatic Hydrocarbon [AH] receptor) have been studied in an attempt to individualize clozapine therapy through identification of responders and nonresponders to the drug. There appears to be an association between the CYP1A2*1F allele and enhanced clozapine clearance, increased dose requirement and nonresponsiveness, particularly in smokers, and increased plasma concentrations and adverse effects after discontinuation of smoking. A few studies did not find this relationship. CYP1A2*1C and CYP1A2*1D appear to be associated with increased clozapine exposure and adverse effects.
Pharmacogenetics of Drug Metabolism
Zeruesenay Desta, David A. Flockhart, inClinical and Translational Science (Second Edition), 2017
Clozapine
Clozapine is a prototypical atypical antipsychotic whose metabolism covaries with CYP1A2 activity. Because clinical studies indicate a positive association between clozapine plasma concentration and antipsychotic response and since the extent of antipsychotic response varies markedly among patients, polymorphism of CYP1A2 and/or its regulators [e.g., aromatic hydrocarbon (AH) receptor] has been studied in an attempt to individualize clozapine therapy through identification of responders and nonresponders to the drug. There appears to be an association between the CYP1A2∗1F allele and enhanced clozapine clearance, increased dose requirement and nonresponsiveness, particularly in smokers, and increased plasma concentrations and adverse effects after discontinuation of smoking. A few studies did not find this relationship. CYP1A2∗1C and CYP1A2∗1D (−2467delT) appear to be associated with increased clozapine exposure and adverse effects.
Dopaminergic Approaches to Antipsychotic Agents
John M. Schaus, Frank P. Bymaster, inAnnual Reports in Medicinal Chemistry, 1998
Clozapine and other multireceptorial aaents
Clozapine (1) is the first compound to have been identified as an “atypical” antipsychotic, that is, one which is effective in treating both the positive and negative symptoms of schizophrenia without also inducing EPS and hyperprolactinemia seen with the classical, “typical” antipsychotics. While clozapine is a remarkably effective agent, its utility has been tempered by the observation that 1-2% of treated patients develop agranulocytosis, a potentially fatal blood disorder (16). As a result, clozapine is reserved primarily for refractory patients and, in the US, its use is accompanied by mandatory blood monitoring.
Because of the unique efficacy of clozapine, a great deal of effort has been made to identify compounds with similar clinical efficacy but without its toxicologic problems. Clozapine binds to many different neurotransmitter receptors and it is not yet known which of these interactions are critical for its atypical profile. One approach to identifying new clozapine-like antipsychotic agents is to develop compounds with a similar, broad pharmacologic profile. The Table outlines neuronal receptor binding affinities of clozapine and a number of other antipsychotics either currently in clinical use or under development. Of these multireceptorial agents, olanzapine (3) has a binding profile most similar to that of clozapine (17,18). Like clozapine, upon chronic administration, olanzapine inhibits A10 dopamine firing without affecting A9 firing, suggesting antipsychotic efficacy without EPS liability (19). Indeed, clozapine, olanzapine, and quetiapine (5) are effective antipsychotics, produce minimal EPS and have a surprisingly benign side effect profile in spite of interaction with a number of neuronal receptors (20). Thus, compounds with similar multireceptorial interactions to clozapine are efficacious and well tolerated antipsychotics.
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Table. Affinities (K1, nM) of antipsychotic agents for neuronal receptors (21-23)
CompoundD1D2D3D4.25-HT2A5-HT2Cα1α2musc.H1Haloperidol2701.4211125>500019>50004670730Clozapine, 1540150360403.31323160342.1Risperidone, 26203.313160.16632.37.5>50002.6Olanzapine, 32501754281.97.160230263.5Sertindole, 42107.48.2210.851.31.81680>5000570Quetiapine, 54240310650160012038205887102019Ziprasidone, 63309.77.5390.31312390>50005.3Zotepine, 7841316390.912.93.49605503.4
A number of researchers have focused on development of clozapine analogues which retain its pharmacology but are less toxic. A series of clozapine analogues in which nitrogens in the diazepine and piperazinerings were replaced by carbon or oxygen was prepared and evaluated for affinity at dopamine and serotonin receptors (24,25). Analogues 8 and 9 possessed similar affinities for serotonin receptors as clozapine with 9 having higher dopamine receptor affinity than clozapine and 8 having lower affinity. The distal nitrogen of the piperazine was required for high affinity to dopamine and serotonin receptors. The tetrahydropyridyl analogues 10 and 11 were equipotent with clozapine at the serotonin and dopamine receptors tested. Compound 12 and other pyridine-containing clozapine analogues have similar pharmacology to clozapine (26-28).
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while replacement of the chlorine in clozapine with a trifluoromethanesulfonyloxy group (13) led to a significant decrease in receptor affinity, the analogous derivative of isoclozapine (14) is GMC1-169 (15) which had an in vitro and in vivo profile predictive of atypical antipsychotic activity (29).
The 9,10-methanodihydroanthracene system of ZD3638 (16) represents a departure from the dibenodiazepine nucleus of clozapine. Molecular modeling studies indicated that the aromatic rings of 16 are held in a geometry similar to that seen in both clozapine and conformationally restricted D1 and D2 receptor antagonists(30) and 16 has significant affinity for D1, D2 and 5-HT2A receptors (Ki = 13, 42, 39 nM, respectively).
Severe Neutropenia and Agranulocytosis
John Lally, Robert J. Flanagan, in Life-Threatening Effects of Antipsychotic Drugs, 2016
5.3.1 Clozapine-Induced Neutropenia/Agranulocytosis
Clozapine is recognized as a potential cause of neutropenia, which may progress to agranulocytosis (Box 5.9). The mandatory hematological monitoring that is undertaken with clozapine means that more is known about the blood dyscrasia related to this drug than about blood dyscrasia that occur in association with most other drugs. It should be emphasized that (1) neutropenia and agranulocytosis induced by clozapine may have different etiological mechanisms and (2) clozapine can have a range of other effects on blood components including anemia, eosinophilia, leukocytosis, lymphopenia, thrombocytopenia, and thrombocytosis (Herceg et al., 2010). In a 15-year naturalistic retrospective study of clozapine use, hematological side-effects accounted for 45% of all side-effect related clozapine discontinuations and 13% of all discontinuations were related to hematological indices (Davis et al., 2014), highlighting the heavy patient burden associated with these adverse effects. White males in the 40–49 year age range appear to be at higher risk of neutropenia (Demler et al., 2016).
Box 5.9
Clozapine and Blood Dyscrasia
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Clozapine well known to cause blood dyscrasia
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Risk of neutropenia 1 in 30 patients
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Risk of agranulocytosis 1 in 120 patients (1 in 1200 after 1 year)
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Increased risk of eosinophilia (eosinophil count>0.5 nL−1), especially in women (23%, men 7%)
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Typically occurs at between 3 and 5 weeks: resolves spontaneously
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If WCC<3.5 nL−1 monitor for possible agranulocytosis or myocarditis
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May also cause anemia, lymphopenia, leukocytosis, thrombocytopenia
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Genetic factors important, but likely to be dose-related and immunological components as well
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Risk of neutropenia/agranulocytosis highest at 6–18 weeks
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Likely that neutropenia due to toxic effect on mature neutrophils, while agranulocytosis due to bone marrow toxicity
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Reversible on stopping (2–3 weeks)
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Proactive hematological monitoring very successful in preventing deaths from agranulocytosis
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Risk of death estimated at 1 in 10,000 patients (2012)
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Can stimulate neutrophil production (lithium, G-CSF, GM-CSF), but may mask agranulocytosis
M.J. Marino, ... M. Williams, inComprehensive Medicinal Chemistry II, 2007
6.02.3.5 The Clozapine Hypothesis
Clozapine 12 is the prototypic atypical antipsychotic, which has broad spectrum efficacy in schizophrenia, being efficacious in the treatment of refractory schizophrenics, with potential efficacy in treating cognitive deficits and having a lower extrapyramidal side effects (EPSs) liability.20,21 These positive attributes are however limited by a high incidence of potentially fatal agranulocytosis that requires continuous monitoring in the clinical situation.
Based on the favorable therapeutic profile of clozapine, there has been an intense effort in the pharmaceutical industry over the past 30 years to identify clozapine-like new chemical entities (NCEs) that have the efficacy attributes of clozapine without the agranulocyotosis. This has led to a slew of second-generation atypical antipsychotics, discussed in detail below, none of which has achieved the efficacy seen with clozapine. This search has been largely based on the receptor binding profile of clozapine, in itself a challenge since, with each newly identified CNS receptor, the subsequent evaluation of clozapine tends to result in yet another potential pharmacological propertybeing added to the profile of the compound.22 Thus the chemist is challenged to synthesize compounds active at what are thought to be the primary molecular targets of clozapine, the DA D2 and 5HT2 receptors, anticipating that the binding profile will result in an approximation of the intrinsic activity and receptor ratios of clozapine at both the primary and the as-yet unknown ancillary targets, that lead to the unique antipsychotic profile of this molecule. A facile approach to the discovery of new antipsychotics has been to replicate the molecular properties of clozapine on a more or less trial-and-error basis. More recently, the N-desmethyl metabolite of clozapine 13, which functions as a muscarinic receptor agonist, has been proposed as the key to understanding the unique properties of the parent drug.23
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Kersti Seksel, in Small Animal Clinical Pharmacology (Second Edition), 2008
Miscellaneous antipsychotics – clozapine
Clozapine is an atypical antipsychotic and has markedly different clinical effects in humans, i.e. different humans react or respond in different or various ways to the drug.
Clinical applications
Experimentally clozapine has shown to be effective in treating aggression in animal models of self-abuse. However, its use in treating aggressive dogs has been disappointing.
Mechanism of action
Clozapine is classed as a dibenzodiazepine and seems to have minimal central antidopaminergic activity, in contrast to many antipsychotic drugs. This may account for the different clinical effects observed in humans compared with other neuroleptics used to treat schizophrenia.
Formulations and dose rates
A suggested dose in dogs is 1.0–7.0 mg/kg PO. However, reliable dose–response data have not been established in animals.
Pharmacokinetics
The pharmacokinetics of clozapine have not been determined in animals. However, in humans it is well absorbed orally and is subject to moderate first-pass metabolism. Peak blood levels occur in 2.1 h, with mean half-life of 12 h; 95% is bound to plasma proteins and it is almost completely metabolized prior to excretion.
Adverse effects
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Significant risk of agranulocytosis in humans.
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Clozapine should be used with care in patients with concurrent cardiovascular disease.
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In dogs clozapine caused excessive salivation and ataxia, and blocked avoidance behaviors.
Vahn A. Lewis, in Pharmacology and Therapeutics for Dentistry (Seventh Edition), 2017
Dibenzodiazepines
Clozapine (Fig. 10-4) is the only dibenzodiazepine available in the United States. Its chemical structure closely resembles that of loxapine, but in contrast to loxapine, it is a prototype for the atypical antipsychotic drug class in light of its low risk for producing EPS and other therapeutic advantages. Clozapine has greater affinity for the D4 rather than for D2receptors. In addition, it blocks muscarinic and 5-HT2A receptors and has fewer motor side effects. Because of adverse effects, however, clozapine has largely been replaced by other atypical antipsychotic drugs.
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FIG 10-4. Structural formula of clozapine.
A worldwide yearly survey of new data in adverse drug reactions
Alfonso Carvajal, ... Natalia Jimeno, in Side Effects of Drugs Annual, 2011
Cardiovascular
Clozapine has been associated with venous thromboembolism. The mortality rate associated with pulmonary embolism has been estimated to be about 28 times higher than in the general population of similar age and sex; it is not clear whether pulmonary embolism can be attributed to clozapine or some characteristic of its users [SEDA-28, 65]. A new case of pulmonary embolism has been reported [76A].
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A 45-year-old man became acutely confused after taking an overdose of clozapine, which he had previously been taking for 6 months. He had acute dyspnea due to bilateral pulmonary emboli. He was not overweight, but was a heavy smoker; plasma concentrations of clozapine are lower in smokers than in non-smokers [SEDA-31, 81].
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