title: Glutamatergic gene variants impact the clinical profile of efficacy and side effects of haloperidol.
abstract: BACKGROUND
  The glutamatergic system may be relevant to the pathophysiology of psychosis and to the effects of antipsychotic treatments.
  
  
  OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  This result further stresses the relevance of the glutamatergic system in modulating the effects of haloperidol treatment, especially with regards to motor side effects.
authors.affiliation: Department of Psychiatry, Ludwig Maximilians University, Munich, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Giegling
authors.forename: Antonio
authors.initials: A
authors.lastname: Drago
authors.forename: Vita
authors.initials: V
authors.lastname: Dolžan
authors.forename: Blanka Kores
authors.initials: BK
authors.lastname: Plesničar
authors.forename: Martin
authors.initials: M
authors.lastname: Schäfer
authors.forename: Annette M
authors.initials: AM
authors.lastname: Hartmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Sander
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Toliat
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Möller
authors.forename: Hans H
authors.initials: HH
authors.lastname: Stassen
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.forename: Alessandro
authors.initials: A
authors.lastname: Serretti
mesh_terms: D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D014644:Genetic Variation; D005838:Genotype; D006220:Haloperidol / Q000009:adverse effects* / Q000627:therapeutic use; D006239:Haplotypes; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D017470:Receptors, Glutamate / Q000235:genetics*; D017524:Slovenia
chemical_list: D014150:Antipsychotic Agents; D017470:Receptors, Glutamate; D006220:Haloperidol