Glutamatergic gene variants impact the clinical profile of efficacy and side effects of haloperidol

Ina Giegling; Antonio Drago; Vita Dolžan; Blanka Kores Plesničar; Martin Schäfer; Annette M Hartmann; Thomas Sander; Mohammad Reza Toliat; Hans-Jürgen Möller; Hans H Stassen; Dan Rujescu; Alessandro Serretti

doi:10.1097/FPC.0b013e32833efb18

Glutamatergic gene variants impact the clinical profile of efficacy and side effects of haloperidol

Ina Giegling, Antonio Drago, Vita Dolžan, Blanka Kores Plesničar, Martin Schäfer, Annette M Hartmann, Thomas Sander, Mohammad Reza Toliat, Hans-Jürgen Möller, Hans H Stassen, Dan Rujescu, Alessandro Serretti

Research output: Contribution to journal › Journal article › Research › peer-review

21 Citations (Scopus)

Abstract

BACKGROUND: The glutamatergic system may be relevant to the pathophysiology of psychosis and to the effects of antipsychotic treatments.

OBJECTIVES: We investigated a set of 62 SNPs located in genes coding for subunits of glutamatergic receptors (GAD1, GRIA1, GRIA3, GRIA4, GRID2, GRIK1, GRIK2, GRIK3, GRIK4, GRIN2B, GRM1 and GRM4), and the transporter of glycine (SLC6A5), as modulators of the effects of haloperidol.

METHODS AND RESULTS: We studied a sample of 101 acutely ill psychotic patients. We then validated our result in two independent samples from Slovenia (n=71 and n=118) of schizophrenic patients treated with antipsychotics. We both investigated the antipsychotic effect (Positive and Negative Syndrome Scale) and motor side effect (Extrapyramidal Symptom Rating Scale) at baseline and days 3, 7, 14, 21 and 28. SLC6A5 variant (rs2298826) was found to be associated with a rapid rise of motor side effects at the beginning of the treatment (repeated measures of analysis of variance, P=0.0002), followed by a subsequent adaptation, probably dependent on haloperidol doses down titration. A specific effect was noted for dyskinetic symptoms. Haplotype analysis strengthened the relevance of SLC6A5: the C-A-C haplotype (rs1443548, rs883377, rs1945771) was found to be associated with higher Extrapyramidal symptom rating scale scores (overall P=0.01, haplotype P=0.000001). We successfully replicated this finding in the two independent samples from Slovenia.

CONCLUSION: This result further stresses the relevance of the glutamatergic system in modulating the effects of haloperidol treatment, especially with regards to motor side effects.

Original language	English
Journal	Pharmacogenetics and Genomics
Volume	21
Issue number	4
Pages (from-to)	206-16
Number of pages	11
ISSN	1744-6872
DOIs	https://doi.org/10.1097/FPC.0b013e32833efb18
Publication status	Published - Apr 2011
Externally published	Yes

Keywords

Antipsychotic Agents/adverse effects
Genetic Variation
Genotype
Haloperidol/adverse effects
Haplotypes
Humans
Polymorphism, Single Nucleotide
Receptors, Glutamate/genetics
Slovenia

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Giegling, I., Drago, A., Dolžan, V., Plesničar, B. K., Schäfer, M., Hartmann, A. M., Sander, T., Toliat, M. R., Möller, H.-J., Stassen, H. H., Rujescu, D., & Serretti, A. (2011). Glutamatergic gene variants impact the clinical profile of efficacy and side effects of haloperidol. Pharmacogenetics and Genomics, 21(4), 206-16. https://doi.org/10.1097/FPC.0b013e32833efb18

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abstract = "BACKGROUND: The glutamatergic system may be relevant to the pathophysiology of psychosis and to the effects of antipsychotic treatments.OBJECTIVES: We investigated a set of 62 SNPs located in genes coding for subunits of glutamatergic receptors (GAD1, GRIA1, GRIA3, GRIA4, GRID2, GRIK1, GRIK2, GRIK3, GRIK4, GRIN2B, GRM1 and GRM4), and the transporter of glycine (SLC6A5), as modulators of the effects of haloperidol.METHODS AND RESULTS: We studied a sample of 101 acutely ill psychotic patients. We then validated our result in two independent samples from Slovenia (n=71 and n=118) of schizophrenic patients treated with antipsychotics. We both investigated the antipsychotic effect (Positive and Negative Syndrome Scale) and motor side effect (Extrapyramidal Symptom Rating Scale) at baseline and days 3, 7, 14, 21 and 28. SLC6A5 variant (rs2298826) was found to be associated with a rapid rise of motor side effects at the beginning of the treatment (repeated measures of analysis of variance, P=0.0002), followed by a subsequent adaptation, probably dependent on haloperidol doses down titration. A specific effect was noted for dyskinetic symptoms. Haplotype analysis strengthened the relevance of SLC6A5: the C-A-C haplotype (rs1443548, rs883377, rs1945771) was found to be associated with higher Extrapyramidal symptom rating scale scores (overall P=0.01, haplotype P=0.000001). We successfully replicated this finding in the two independent samples from Slovenia.CONCLUSION: This result further stresses the relevance of the glutamatergic system in modulating the effects of haloperidol treatment, especially with regards to motor side effects.",

keywords = "Antipsychotic Agents/adverse effects, Genetic Variation, Genotype, Haloperidol/adverse effects, Haplotypes, Humans, Polymorphism, Single Nucleotide, Receptors, Glutamate/genetics, Slovenia",

author = "Ina Giegling and Antonio Drago and Vita Dol{\v z}an and Plesni{\v c}ar, {Blanka Kores} and Martin Sch{\"a}fer and Hartmann, {Annette M} and Thomas Sander and Toliat, {Mohammad Reza} and Hans-J{\"u}rgen M{\"o}ller and Stassen, {Hans H} and Dan Rujescu and Alessandro Serretti",

year = "2011",

month = apr,

doi = "10.1097/FPC.0b013e32833efb18",

language = "English",

volume = "21",

pages = "206--16",

journal = "Pharmacogenetics and Genomics",

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T1 - Glutamatergic gene variants impact the clinical profile of efficacy and side effects of haloperidol

AU - Giegling, Ina

AU - Drago, Antonio

AU - Dolžan, Vita

AU - Plesničar, Blanka Kores

AU - Schäfer, Martin

AU - Hartmann, Annette M

AU - Sander, Thomas

AU - Toliat, Mohammad Reza

AU - Möller, Hans-Jürgen

AU - Stassen, Hans H

AU - Rujescu, Dan

AU - Serretti, Alessandro

PY - 2011/4

Y1 - 2011/4

N2 - BACKGROUND: The glutamatergic system may be relevant to the pathophysiology of psychosis and to the effects of antipsychotic treatments.OBJECTIVES: We investigated a set of 62 SNPs located in genes coding for subunits of glutamatergic receptors (GAD1, GRIA1, GRIA3, GRIA4, GRID2, GRIK1, GRIK2, GRIK3, GRIK4, GRIN2B, GRM1 and GRM4), and the transporter of glycine (SLC6A5), as modulators of the effects of haloperidol.METHODS AND RESULTS: We studied a sample of 101 acutely ill psychotic patients. We then validated our result in two independent samples from Slovenia (n=71 and n=118) of schizophrenic patients treated with antipsychotics. We both investigated the antipsychotic effect (Positive and Negative Syndrome Scale) and motor side effect (Extrapyramidal Symptom Rating Scale) at baseline and days 3, 7, 14, 21 and 28. SLC6A5 variant (rs2298826) was found to be associated with a rapid rise of motor side effects at the beginning of the treatment (repeated measures of analysis of variance, P=0.0002), followed by a subsequent adaptation, probably dependent on haloperidol doses down titration. A specific effect was noted for dyskinetic symptoms. Haplotype analysis strengthened the relevance of SLC6A5: the C-A-C haplotype (rs1443548, rs883377, rs1945771) was found to be associated with higher Extrapyramidal symptom rating scale scores (overall P=0.01, haplotype P=0.000001). We successfully replicated this finding in the two independent samples from Slovenia.CONCLUSION: This result further stresses the relevance of the glutamatergic system in modulating the effects of haloperidol treatment, especially with regards to motor side effects.

AB - BACKGROUND: The glutamatergic system may be relevant to the pathophysiology of psychosis and to the effects of antipsychotic treatments.OBJECTIVES: We investigated a set of 62 SNPs located in genes coding for subunits of glutamatergic receptors (GAD1, GRIA1, GRIA3, GRIA4, GRID2, GRIK1, GRIK2, GRIK3, GRIK4, GRIN2B, GRM1 and GRM4), and the transporter of glycine (SLC6A5), as modulators of the effects of haloperidol.METHODS AND RESULTS: We studied a sample of 101 acutely ill psychotic patients. We then validated our result in two independent samples from Slovenia (n=71 and n=118) of schizophrenic patients treated with antipsychotics. We both investigated the antipsychotic effect (Positive and Negative Syndrome Scale) and motor side effect (Extrapyramidal Symptom Rating Scale) at baseline and days 3, 7, 14, 21 and 28. SLC6A5 variant (rs2298826) was found to be associated with a rapid rise of motor side effects at the beginning of the treatment (repeated measures of analysis of variance, P=0.0002), followed by a subsequent adaptation, probably dependent on haloperidol doses down titration. A specific effect was noted for dyskinetic symptoms. Haplotype analysis strengthened the relevance of SLC6A5: the C-A-C haplotype (rs1443548, rs883377, rs1945771) was found to be associated with higher Extrapyramidal symptom rating scale scores (overall P=0.01, haplotype P=0.000001). We successfully replicated this finding in the two independent samples from Slovenia.CONCLUSION: This result further stresses the relevance of the glutamatergic system in modulating the effects of haloperidol treatment, especially with regards to motor side effects.

KW - Antipsychotic Agents/adverse effects

KW - Genetic Variation

KW - Genotype

KW - Haloperidol/adverse effects

KW - Haplotypes

KW - Humans

KW - Polymorphism, Single Nucleotide

KW - Receptors, Glutamate/genetics

KW - Slovenia

U2 - 10.1097/FPC.0b013e32833efb18

DO - 10.1097/FPC.0b013e32833efb18

M3 - Journal article

C2 - 20859245

SN - 1744-6872

VL - 21

SP - 206

EP - 216

JO - Pharmacogenetics and Genomics

JF - Pharmacogenetics and Genomics

IS - 4

ER -

Glutamatergic gene variants impact the clinical profile of efficacy and side effects of haloperidol

Abstract

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