Clozapine

Clozapine is an atypical antipsychotic medication [1]

Clozapine has been considered an atypical antipsychotic medication because of their therapeutic efficacy in the treatment of schizophrenic patients resistant to conventional neuroleptics. In addition, Clozapine has shown the effect on binding 5HT1c and 5HT2 sites with pKi values of 8.07 and 7.63, respectively. Besides, Clozapine has been reported to recognize all human dopamine receptor subtypes with Ki values of 80nM, 230nM, 89nM, 141nM and 250nM for D2, D3, D4, D1 and D5 receptor, respectively. Clozapine has been found to be the only drug to have a higher affinity for 5-HT1c sites than for the 5-HT2, D1 and D2 receptors [1].

References:
[1] Canton H1, Verrièle L, Colpaert FC. Binding of typical and atypical antipsychotics to 5-HT1C and 5-HT2 sites: clozapine potently interacts with 5-HT1C sites. Eur J Pharmacol. 1990 Nov 20; 191(1):93-6.

Comparative study of clozapine versus risperidone in treatment-naive, first-episode schizophrenia: A pilot study.[Pubmed:28361822]

Indian J Med Res. 2016 Nov;144(5):697-703.

BACKGROUND & OBJECTIVES: Clozapine may be more useful in treatment-naive patients with first-episode schizophrenia for better symptoms control and improving quality of life. The current study was carried out to compare the efficacy and tolerability of Clozapine versus risperidone in treatment-naive, first-episode patients of schizophrenia. METHODS: This was a comparative, open-label, six months prospective study of treatment-naive, first-episode patients with schizophrenia between the age group of 18 and 40 yr diagnosed as per the International Classification of Diseases-10 (ICD-10) criteria. A total of 63 patients were recruited and randomly assigned to Clozapine group or risperidone group using computer-generated random number tables. Eight patients were lost to follow up. The dosages of the respective drugs were kept in therapeutic range of 200-600 mg/day and 4-8 mg/day orally for Clozapine and risperidone, respectively. RESULTS: On general psychopathology score, after six months of intervention, Clozapine led to 60.32 per cent mean reduction in Positive and Negative Syndrome Scale (PANSS) for Schizophrenia total score while risperidone led to 56.35 per cent mean reduction in PANSS total score, which meant more improvement with Clozapine. Clozapine group was found to have significant improvement in quality of life (P = 0.04339). On Glasgow Antipsychotic Side-effect Scale, Clozapine was superior to risperidone. The most common side effects observed in Clozapine group were oversedation (78.96%) and dizziness (55.23%), and in risperidone group, common side effects were rigidity (62.36%), sedation (38.69%), tremors (65.69%) and menstrual irregularities in 80.25 per cent of female patients. INTERPRETATION & CONCLUSIONS: The findings of this preliminary study showed Clozapine as a better choice than risperidone in terms of efficacy, tolerability and better quality of life in treatment-naive, first-episode schizophrenia. However, further studies need to be done on a larger group of patients to confirm the findings.

Leukocytosis after Clozapine Treatment in a Patient with Chronic Schizophrenia.[Pubmed:28360774]

Noro Psikiyatr Ars. 2016 Mar;53(1):87-88.

Clozapine is an atypical antipsychotic drug that is approved by the US Food and Drug Administration (FDA) for the treatment of psychotic disorders. Agranulocytosis is a well-established side effect of Clozapine; Clozapine has also been associated with other blood dyscrasias like leukocytosis, albeit rarely. In this paper, we aim to report a case of possible Clozapine-associated leukocytosis in a 41-year-old woman.

Design, synthesis, and pharmacological characterization of N- and O-substituted 5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol analogues: novel 5-HT(2A)/5-HT(2C) receptor agonists with pro-cognitive properties.[Pubmed:23301527]

J Med Chem. 2013 Feb 14;56(3):1211-27.

The isoxazol-3-one tautomer of the bicyclic isoxazole, 5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol (THAZ), has previously been shown to be a weak GABA(A) and glycine receptor antagonist. In the present study, the potential in this scaffold has been explored through the synthesis and pharmacological characterization of a series of N- and O-substituted THAZ analogues. The analogues N-Bn-THAZ (3d) and O-Bn-THAZ (4d) were found to be potent agonists of the human 5-HT(2A) and 5-HT(2C) receptors. Judging from an elaborate pharmacological profiling at numerous other CNS targets, the 3d analogue appears to be selective for the two receptors. Administration of 3d substantially improved the cognitive performance of mice in a place recognition Y-maze model, an effect fully reversible by coadministration of the selective 5-HT(2C) antagonist SB242084. In conclusion, as novel bioavailable cognitive enhancers that most likely mediate their effects through 5-HT(2A) and/or 5-HT(2C) receptors, the isoxazoles 3d and 4d constitute interesting leads for further medicinal chemistry development.

Dopamine receptor pharmacology.[Pubmed:7940991]

Trends Pharmacol Sci. 1994 Jul;15(7):264-70.

Dopamine receptors are the primary targets in the treatment of schizophrenia, Parkinson's disease, and Huntington's chorea, and are discussed in this review by Philip Seeman and Hubert Van Tol. Improved therapy may be obtained by drugs that selectively target a particular subtype of dopamine receptor. Most antipsychotic drugs block D2 receptors in direct correlation to clinical potency, except Clozapine, which prefers D4 receptors. D1 and D2 receptors can enhance each other's actions, possibly through subunits of the G proteins. In schizophrenia, the D2 and D3 receptor density is elevated by 10%, while the D4 receptor density is elevated by 600%. Therefore, D4 receptors may be a target for future antipsychotic drugs. While antipsychotics originally helped to discover dopamine receptors, the five cloned dopamine receptors are now facilitating the discovery of selective antipsychotic and antiparkinson drugs.

The involvement of dopamine D1 and D2 receptors in the effects of the classical neuroleptic haloperidol and the atypical neuroleptic clozapine.[Pubmed:1678712]

Eur J Pharmacol. 1991 Apr 10;196(1):103-8.

There is increasing evidence that classical neuroleptics (neuroleptics that induce so called extrapyramidal side effects) and atypical neuroleptic drugs (neuroleptics that do not induce these side effects) have different mechanisms of action. It has been suggested that atypical neuroleptics may work at least partially through the dopamine D1 receptor whereas classical neuroleptics are generally considered to work via the dopamine D2 receptor. In order to test this hypothesis we evaluated the role of D1 and D2 receptors in the effects of haloperidol and Clozapine in the paw test. This test has been shown to be a good animal model for both the therapeutic efficacy of classical and atypical neuroleptics as well as for the extrapyramidal side effect potential of classical neuroleptics. The present results show that the effects of haloperidol in the paw test are antagonised by a dopamine D2 agonist but not by a D1 agonist, whereas the effects of Clozapine are reversed by a D1 agonist but not by a D2 agonist. These data suggest that haloperidol produces its therapeutic and extrapyramidal side effects via blockade of dopamine D2 receptors, whereas Clozapine produces its therapeutic effects via blockade of dopamine D1 receptors.

Binding of typical and atypical antipsychotics to 5-HT1C and 5-HT2 sites: clozapine potently interacts with 5-HT1C sites.[Pubmed:1982659]

Eur J Pharmacol. 1990 Nov 20;191(1):93-6.

We determined the affinity of several typical and atypical antipsychotics for the 5-HT1C and 5-HT2 sites using radioligand binding assays. Most of the antipsychotics tested appeared to bind to 5-HT2 sites with affinities that were fairly high (i.e. pKi values between 7 and 9) and significantly higher than for 5-HT1C sites. In contrast, Clozapine was found to have a significantly higher affinity for 5-HT1C than for 5-HT2 sites. Clozapine had the highest affinity for 5-HT1C sites of all the compounds tested. These findings are consistent with the hypothesis that an interaction with 5-HT2 receptors may be relevant to the clinical activity of typical antipsychotics. The findings also suggest, however, that an interaction with 5-HT1C sites may be relevant to the mechanism of clinical action of Clozapine and, perhaps, of other atypical antipsychotics.

Clozapine (HF 1854) is an antipsychotic used to treat schizophrenia. Clozapine is a potent antagonist of dopamine and a number of other receptors, with a Ki of 9.5 nM for M1 receptor. Clozapine is also a potent and selective agonist at the muscarinic M4 receptor (EC50=11 nM).

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