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 journalArticle


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. Pharmacogenetics and Genomics 21:206-216.

Original languageEnglish
Pages (from-to)206-216
Number of pages11
JournalPharmacogenetics and Genomics
Issue number4
Publication statusPublished - Apr 2011


  • Antipsychotic
  • Gene
  • Glutamatergic
  • Pharmacogenetics
  • Schizophrenia

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

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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), 206-216.