Variability in response to clozapine: Potential role of cytochrome P450 1A2 and the dopamine D4 receptor gene

Vural Ozdemir*, Mario Masellis, Vincenzo S. Basile, Werner Kalow, Herbert Y. Meltzer, Jeffrey A. Lieberman, James L. Kennedy

*Corresponding author for this work

Research output: Contribution to journalReview article

20 Citations (Scopus)

Abstract

Clozapine is a prototype atypical antipsychotic drug and displays efficacy in 30% to 60% of schizophrenia patients who do not respond to traditional antipsychotics. There is considerable evidence supporting a concentration-response relationship for clozapine. A plasma clozapine concentration >200 to 420 ng/mL increases the probability of antipsychotic effects. Approximately 70% to 80% of variability in clozapine plasma concentration can be attributed to variability in cytochrome P450 1A2 activity. Measurement of caffeine metabolites in plasma or urine can be used as an in vivo index of cytochrome P450 1A2 activity, since caffeine is primarily eliminated by oxidative metabolism through this cytochrome P450 enzyme. Caffeine-based tests may contribute to individualization of clozapine dosages and optimization of its antipsychotic effects in schizophrenia patients. There are several lines of evidence suggesting the potential involvement of the dopamine D4 receptor in pharmacodynamic effects of clozapine. Clozapine has a 10-fold higher affinity for the dopamine D4 receptor in comparison to the D2 and the D3 receptors. Moreover, the flee plasma fluid concentration of clozapine is comparable to its binding affinity for the D4 receptor in vitro. Blockade of the D4 receptor in the mesocorticolimbic region, a brain area implicated in the pathogenesis of schizophrenia, may contribute to efficacy of clozapine in negative symptoms. Moreover, the dopamine D4 receptor gene (DRD4) displays an unusual degree of genetic variation (polymorphism). In a recent preliminary study, we investigated the (G)(n) mononucleotide repeat polymorphism within the first intron of the D4 gene in 50 schizophrenia patients refractory to traditional antipsychotics. These patients were prospectively followed for antipsychotic response during clozapine treatment. Analysis of variance found significant differences in antipsychotic response as demonstrated by mean change in Brief Psychiatric Rating Scale scores among the genotype panels for this polymorphism F[3,49]=4.1 (P=0.01). Future studies investigating the mechanistic basis of variability in response to clozapine should focus on both pharmacokinetic and pharmacodynamic factors.

Original languageEnglish (US)
Pages (from-to)30-56
Number of pages27
JournalCNS spectrums
Volume4
Issue number6
StatePublished - Jun 30 1999

Fingerprint

Dopamine D4 Receptors
Cytochrome P-450 CYP1A2
Clozapine
Antipsychotic Agents
Genes
Schizophrenia
Caffeine
Cytochrome P-450 Enzyme System
Brief Psychiatric Rating Scale
Introns
Analysis of Variance

ASJC Scopus subject areas

  • Clinical Neurology
  • Psychiatry and Mental health

Cite this

Ozdemir, V., Masellis, M., Basile, V. S., Kalow, W., Meltzer, H. Y., Lieberman, J. A., & Kennedy, J. L. (1999). Variability in response to clozapine: Potential role of cytochrome P450 1A2 and the dopamine D4 receptor gene. CNS spectrums, 4(6), 30-56.
Ozdemir, Vural ; Masellis, Mario ; Basile, Vincenzo S. ; Kalow, Werner ; Meltzer, Herbert Y. ; Lieberman, Jeffrey A. ; Kennedy, James L. / Variability in response to clozapine : Potential role of cytochrome P450 1A2 and the dopamine D4 receptor gene. In: CNS spectrums. 1999 ; Vol. 4, No. 6. pp. 30-56.
@article{b9737a88a7a443beaf0e8f9b7e4bf148,
title = "Variability in response to clozapine: Potential role of cytochrome P450 1A2 and the dopamine D4 receptor gene",
abstract = "Clozapine is a prototype atypical antipsychotic drug and displays efficacy in 30{\%} to 60{\%} of schizophrenia patients who do not respond to traditional antipsychotics. There is considerable evidence supporting a concentration-response relationship for clozapine. A plasma clozapine concentration >200 to 420 ng/mL increases the probability of antipsychotic effects. Approximately 70{\%} to 80{\%} of variability in clozapine plasma concentration can be attributed to variability in cytochrome P450 1A2 activity. Measurement of caffeine metabolites in plasma or urine can be used as an in vivo index of cytochrome P450 1A2 activity, since caffeine is primarily eliminated by oxidative metabolism through this cytochrome P450 enzyme. Caffeine-based tests may contribute to individualization of clozapine dosages and optimization of its antipsychotic effects in schizophrenia patients. There are several lines of evidence suggesting the potential involvement of the dopamine D4 receptor in pharmacodynamic effects of clozapine. Clozapine has a 10-fold higher affinity for the dopamine D4 receptor in comparison to the D2 and the D3 receptors. Moreover, the flee plasma fluid concentration of clozapine is comparable to its binding affinity for the D4 receptor in vitro. Blockade of the D4 receptor in the mesocorticolimbic region, a brain area implicated in the pathogenesis of schizophrenia, may contribute to efficacy of clozapine in negative symptoms. Moreover, the dopamine D4 receptor gene (DRD4) displays an unusual degree of genetic variation (polymorphism). In a recent preliminary study, we investigated the (G)(n) mononucleotide repeat polymorphism within the first intron of the D4 gene in 50 schizophrenia patients refractory to traditional antipsychotics. These patients were prospectively followed for antipsychotic response during clozapine treatment. Analysis of variance found significant differences in antipsychotic response as demonstrated by mean change in Brief Psychiatric Rating Scale scores among the genotype panels for this polymorphism F[3,49]=4.1 (P=0.01). Future studies investigating the mechanistic basis of variability in response to clozapine should focus on both pharmacokinetic and pharmacodynamic factors.",
author = "Vural Ozdemir and Mario Masellis and Basile, {Vincenzo S.} and Werner Kalow and Meltzer, {Herbert Y.} and Lieberman, {Jeffrey A.} and Kennedy, {James L.}",
year = "1999",
month = "6",
day = "30",
language = "English (US)",
volume = "4",
pages = "30--56",
journal = "CNS Spectrums",
issn = "1092-8529",
publisher = "MBL Communications",
number = "6",

}

Ozdemir, V, Masellis, M, Basile, VS, Kalow, W, Meltzer, HY, Lieberman, JA & Kennedy, JL 1999, 'Variability in response to clozapine: Potential role of cytochrome P450 1A2 and the dopamine D4 receptor gene', CNS spectrums, vol. 4, no. 6, pp. 30-56.

Variability in response to clozapine : Potential role of cytochrome P450 1A2 and the dopamine D4 receptor gene. / Ozdemir, Vural; Masellis, Mario; Basile, Vincenzo S.; Kalow, Werner; Meltzer, Herbert Y.; Lieberman, Jeffrey A.; Kennedy, James L.

In: CNS spectrums, Vol. 4, No. 6, 30.06.1999, p. 30-56.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Variability in response to clozapine

T2 - Potential role of cytochrome P450 1A2 and the dopamine D4 receptor gene

AU - Ozdemir, Vural

AU - Masellis, Mario

AU - Basile, Vincenzo S.

AU - Kalow, Werner

AU - Meltzer, Herbert Y.

AU - Lieberman, Jeffrey A.

AU - Kennedy, James L.

PY - 1999/6/30

Y1 - 1999/6/30

N2 - Clozapine is a prototype atypical antipsychotic drug and displays efficacy in 30% to 60% of schizophrenia patients who do not respond to traditional antipsychotics. There is considerable evidence supporting a concentration-response relationship for clozapine. A plasma clozapine concentration >200 to 420 ng/mL increases the probability of antipsychotic effects. Approximately 70% to 80% of variability in clozapine plasma concentration can be attributed to variability in cytochrome P450 1A2 activity. Measurement of caffeine metabolites in plasma or urine can be used as an in vivo index of cytochrome P450 1A2 activity, since caffeine is primarily eliminated by oxidative metabolism through this cytochrome P450 enzyme. Caffeine-based tests may contribute to individualization of clozapine dosages and optimization of its antipsychotic effects in schizophrenia patients. There are several lines of evidence suggesting the potential involvement of the dopamine D4 receptor in pharmacodynamic effects of clozapine. Clozapine has a 10-fold higher affinity for the dopamine D4 receptor in comparison to the D2 and the D3 receptors. Moreover, the flee plasma fluid concentration of clozapine is comparable to its binding affinity for the D4 receptor in vitro. Blockade of the D4 receptor in the mesocorticolimbic region, a brain area implicated in the pathogenesis of schizophrenia, may contribute to efficacy of clozapine in negative symptoms. Moreover, the dopamine D4 receptor gene (DRD4) displays an unusual degree of genetic variation (polymorphism). In a recent preliminary study, we investigated the (G)(n) mononucleotide repeat polymorphism within the first intron of the D4 gene in 50 schizophrenia patients refractory to traditional antipsychotics. These patients were prospectively followed for antipsychotic response during clozapine treatment. Analysis of variance found significant differences in antipsychotic response as demonstrated by mean change in Brief Psychiatric Rating Scale scores among the genotype panels for this polymorphism F[3,49]=4.1 (P=0.01). Future studies investigating the mechanistic basis of variability in response to clozapine should focus on both pharmacokinetic and pharmacodynamic factors.

AB - Clozapine is a prototype atypical antipsychotic drug and displays efficacy in 30% to 60% of schizophrenia patients who do not respond to traditional antipsychotics. There is considerable evidence supporting a concentration-response relationship for clozapine. A plasma clozapine concentration >200 to 420 ng/mL increases the probability of antipsychotic effects. Approximately 70% to 80% of variability in clozapine plasma concentration can be attributed to variability in cytochrome P450 1A2 activity. Measurement of caffeine metabolites in plasma or urine can be used as an in vivo index of cytochrome P450 1A2 activity, since caffeine is primarily eliminated by oxidative metabolism through this cytochrome P450 enzyme. Caffeine-based tests may contribute to individualization of clozapine dosages and optimization of its antipsychotic effects in schizophrenia patients. There are several lines of evidence suggesting the potential involvement of the dopamine D4 receptor in pharmacodynamic effects of clozapine. Clozapine has a 10-fold higher affinity for the dopamine D4 receptor in comparison to the D2 and the D3 receptors. Moreover, the flee plasma fluid concentration of clozapine is comparable to its binding affinity for the D4 receptor in vitro. Blockade of the D4 receptor in the mesocorticolimbic region, a brain area implicated in the pathogenesis of schizophrenia, may contribute to efficacy of clozapine in negative symptoms. Moreover, the dopamine D4 receptor gene (DRD4) displays an unusual degree of genetic variation (polymorphism). In a recent preliminary study, we investigated the (G)(n) mononucleotide repeat polymorphism within the first intron of the D4 gene in 50 schizophrenia patients refractory to traditional antipsychotics. These patients were prospectively followed for antipsychotic response during clozapine treatment. Analysis of variance found significant differences in antipsychotic response as demonstrated by mean change in Brief Psychiatric Rating Scale scores among the genotype panels for this polymorphism F[3,49]=4.1 (P=0.01). Future studies investigating the mechanistic basis of variability in response to clozapine should focus on both pharmacokinetic and pharmacodynamic factors.

UR - http://www.scopus.com/inward/record.url?scp=0033022950&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033022950&partnerID=8YFLogxK

M3 - Review article

AN - SCOPUS:0033022950

VL - 4

SP - 30

EP - 56

JO - CNS Spectrums

JF - CNS Spectrums

SN - 1092-8529

IS - 6

ER -

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. CNS spectrums. 1999 Jun 30;4(6):30-56.