Glucagon-like peptide 1 receptor ( GLP1R ) haplotypes correlate with altered response to multiple antipsychotics in the CATIE trial

• Published in: Schizophrenia research Vol. 160; no. 1; pp. 73 - 79
• Main Authors: Ramsey, Timothy L, Brennan, Mark D
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.12.2014; Elsevier
• Subjects: Adult; Adult and adolescent clinical studies; Antipsychotic Agents - adverse effects; Antipsychotic Agents - therapeutic use; Benzodiazepines - adverse effects; Benzodiazepines - therapeutic use; Biological and medical sciences; Biomarkers, Pharmacological; Dibenzothiazepines - adverse effects; Dibenzothiazepines - therapeutic use; European Continental Ancestry Group - genetics; Female; Genotyping Techniques; Glucagon-Like Peptide-1 Receptor; Haplotypes; Humans; Male; Medical sciences; Models, Genetic; Neuropharmacology; Olanzapine; Perphenazine; Perphenazine - adverse effects; Perphenazine - therapeutic use; Pharmacogenetics; Pharmacology. Drug treatments; Piperazines - adverse effects; Piperazines - therapeutic use; Polymorphism, Single Nucleotide; Psychiatry; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Psychoses; Quetiapine; Quetiapine Fumarate; Receptors, Glucagon - genetics; Regression Analysis; Risperidone; Risperidone - adverse effects; Risperidone - therapeutic use; Schizophrenia; Schizophrenia - drug therapy; Schizophrenia - genetics; Thiazoles - adverse effects; Thiazoles - therapeutic use; Treatment Outcome; Weight Gain - drug effects; Weight Gain - genetics; Ziprasidone; Pharmacogenetics; Olanzapine; Ziprasidone; Schizophrenia; Risperidone; Perphenazine; Quetiapine; Dibenzodiazepine derivatives; Atypical antipsychotic; Neuroleptic; Psychotropic; GLP-1 receptor; Pharmacotherapy; Phenothiazine derivatives; Serotonine receptor; Genetic determinism; Psychosis; Genetics; Dibenzothiazepine derivatives; Haplotype; Benzisoxazole derivatives; Human; Dopamine antagonist; Serotonin antagonist; Hypnotic; Thienobenzodiazepine derivatives; 5-HT2 Serotonine receptor; D2 Dopamine receptor; Treatment; Tranquillizer; Piperazine derivatives
• ISSN: 0920-9964; 1573-2509
• DOI: 10.1016/j.schres.2014.09.038

Abstract Glucagon-like peptide 1 receptor (GLP1R) signaling has been shown to have antipsychotic properties in animal models and to impact glucose-dependent insulin release, satiety, memory, and learning in man. Previous work has shown that two coding mutations (rs6923761 and rs1042044) are associated with altered insulin release and cortisol levels. We identified four frequently occurring haplotypes in Caucasians, haplotype 1 through haplotype 4, spanning exons 4–7 and containing the two coding variants. We analyzed response to antipsychotics, defined as predicted change in PANSS-Total (dPANSS) at 18 months, in Caucasian subjects from the Clinical Antipsychotic Trial of Intervention Effectiveness treated with olanzapine (n = 139), perphenazine (n = 78), quetiapine (n = 14), risperidone (n = 143), and ziprasidone (n = 90). Haplotype trend regression analysis revealed significant associations with dPANSS for olanzapine (best p = 0.002), perphenazine (best p = 0.01), quetiapine (best p = 0.008), risperidone (best p = 0.02), and ziprasidone (best p = 0.007). We also evaluated genetic models for the two most common haplotypes. Haplotype 1 (uniquely including the rs1042044 [Leu260 ] allele) was associated with better response to olanzapine (p = 0.002), and risperidone (p = 0.006), and worse response to perphenazine (p = .03), and ziprasidone (p = 0.003), with a recessive genetic model providing the best fit. Haplotype 2 (uniquely including the rs6923761 [Ser168 ] allele) was associated with better response to perphenazine (p = 0.001) and worse response to olanzapine (p = .02), with a dominant genetic model providing the best fit. However, GLP1R haplotypes were not associated with antipsychotic-induced weight gain. These results link functional genetic variants in GLP1R to antipsychotic response.