Glutamatergic gene variants impact the clinical profile of efficacy and side effects of haloperidol.
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.
Giegling
Ina
I
Department of Psychiatry, Ludwig Maximilians University, Munich, Germany.
Drago
Antonio
A
Dolžan
Vita
V
Plesničar
Blanka Kores
BK
Schäfer
Martin
M
Hartmann
Annette M
AM
Sander
Thomas
T
Toliat
Mohammad Reza
MR
Möller
Hans-Jürgen
HJ
Stassen
Hans H
HH
Rujescu
Dan
D
Serretti
Alessandro
A
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
D014150:Antipsychotic Agents; D017470:Receptors, Glutamate; D006220:Haloperidol