Clozapine Dopamine

Ahlenius, S. (1999) Clozapine dopamine D, receptor agonism in the prefrontal cortex as the code to decipher a Rosetta Stone of antipsychotic drugs. Pharmacology Toxicol 84 193—196. 

Youngren KD, Inglis FM, Pivirotto PJ et al (1999) Clozapine preferentially increases dopamine release in the rhesus monkey prefrontal cortex compared with the caudate nucleus. Neuropsychopharmacology 20 403-12... 

Neuroleptics or antipsychotics suppress the positive symptoms of schizophrenia such as combativeness, hallucinations and formal thought disorder. Some also alleviate the negative symptoms such as affective blunting, withdrawal and seclusiveness. Neuroleptics also produce a state of apathy and emotional indifference. Most neuroleptics block dopamine D2-receptors but some, like clozapine, also block dopamine D4-receptors or serotonin 5-hydroxytryptamine2A-receptors. 

Figure 17.8 Comparison of the antagonist potencies of some neuroleptics on different NT receptors. Data are shown for haloperidol (HAL), chlorpromazine (CPZ), clozapine (CLOZ) and risperidone (RISP) acting on dopamine Dj and D2, 5-HT2 (S2), alpha (0(2) adrenoceptors and cholinergic muscarinic receptors (M). The height of each column shows an average of the dissociation constants obtained from a number of publications (see Seeman 1990). The values, which can vary some fiftyfold, are expressed as the negative logarithms (i.e. 9 = 10 M,lnM) so that the higher the column, the more potent the compound. The order of potency of the four compounds at each receptor is shown alongside...

Dailey, JW and Webster, RA (1993) Dopamine-like effects of clozapine on spontaneously active neurons in the rat prefrontal cortex. J. Psychopharm. 1 A7. 

Pilowsky, LS, Costa, DC and Eli, PJ (1992) Clozapine single photon emission tomography and the D2 dopamine receptor blockade hypothesis of schizophrenia. Lancet 340 199-202. 

Seeman, P (1992) Dopamine receptor sequences therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4. Neuropsychopharmacology 7 261-284. 

With respect to other ethnic groups, African Americans may have a differential sensitivity to weight gain on clozapine (de Leon etal, 2007). They may also require lower doses than Caucasians (Kelly et al, 2006) and inter-individual as well as ethnic responsiveness maybe partly explained by differences in dopamine receptor polymorphisms (Hwang et al, 2005). It is conceivable that side effects may also be differentially expressed based on pharmacodynamic differences resulting from polymorphisms in other receptor types (histaminergic, muscarinic, etc.). This area remains largely unexplored with respect to ethnic differences in antipsychotic side effects. 

Hwang, R. et al. (2005). Association study of 12 polymorphisms spanning the dopamine D(2) receptor gene and clozapine treatment response in two treatment refractory/intolerant populations. Psychopharmacology, 181, 179-87. 

Malhotra, A. K., Goldman, D., Buchanan, R.W. et al. (1998). The dopamine D-3 receptor (DRD3) Ser-9Gly polymorphism and schizophrenia a haplotype relative risk study and association with clozapine response. Mol. Psychiatry, 3, 72-5. 

Rao, P. A., Packer D., Gejman, P. V. et al. (1994). Allelic variation in the D4 dopamine receptor (DRD4) gene does not predict response to clozapine. Arch. Gen. Psychiatry, 51, 912-17. 

Scharfetter, J., Chaudhry, H. R., Hornik, K. etal. (1999). Dopamine D3 receptor gene polymorphism and response to clozapine in schizophrenic Pakistani patients. Eur. Neuropsychophar-macol., 10, 17-20. 

Clozapine is the prototype of atypical antipsychotic drugs, and it has been used effectively to treat patients with schizophrenia who are unresponsive or intolerant to typical antipsychotics [7]. Clozapine is characterized as atypical by its preferential binding to serotonin (5-HT2) and dopamine D4 receptors (D4) relative to dopamine D2 receptors [8]. A recent body of work also suggests that atypicality may be defined by the rate at which clozapine dissociates from D2 receptors. Specifically, clo-... 

Ozdemir V, Masellis M, Basile VS, Kalow W, Meltzer HY, Lieberman JA et al. Variability in response to clozapine Potential role of cytochrome P450 1A2 and the dopamine D4 receptor gene. 

Shaikh S, Collier D, Kerwin RW, Pilowsky LS, Gill M, Xu WM et al. Dopamine D4 receptor subtypes and response to clozapine [letter]. Lancet 1993 341 (8837) 116. 

Shaikh S, Collier DA, Sham P, Pilowsky L, Sharma T, Lin LK et al. Analysis of clozapine response and polymorphisms of the dopamine D4 receptor gene (DRD4) in schizophrenic patients. American J ournal of Medical Genetics (Neuropsychiatric Genetics) 1995 60 541-545. 

Dopamine receptor blocking agents. Many of the neuroleptics used in the treatment of schizophrenia frequently produce parkinsonian symptoms as unwanted effects. Neuroleptics block dopamine receptors and their therapeutic effect seems to be related to this action. Although these drugs act on DA systems without distinction, some are more selective. Thioridazine, clozapine and molindone, for example, have electrophysiological effects in the limbic region of the brain but little action in the nigro-striatal area. This selectivity may be related to receptor subtype specificity (see Chs 12 and 54). 

Drew KL, O Connor WT, Kehr J, Ungerstedt U. 1990. Regional specific effects of clozapine and haloperidol on GABA and dopamine release in rat basal ganglia. Eur J Pharmacol 187(3) 385-397. 

By contrast, studies of the dopamine D -like receptors have found evidence for the association of the receptor with disease (66) these studies have been replicated (41,42). From among the multitude of these studies, only selected examples are reviewed here. For example, evidence both for and against the association of the dopamine D -like receptors with schizophrenia has been reported. Polymorphisms of the dopamine receptor, including the third intracellular loop VNTR, alter dopamine receptor expression. In addition to association with schizophrenia (3,67-70), the dopamine polymorphisms have been associated with the genetic basis of the variable efficacy of antipsychotics such as clozapine (or neuromuscular toxicity—tardive dyskinesia) (69,71,72). Similarly, promoter SNPs have been associated with altered clozapine efficacy (67,68,73). 

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