Olanzapine is a widely used atypical
antipsychotic with significant
weight gain and other metabolic side effects. The locus of the
transcription factor 7-like 2 (TCF7L2) gene is strongly associated with
type 2 diabetes (T2D). The goal of this study was to determine whether polymorphic TCF7L2 is involved in the susceptibility to the metabolic changes associated with the atypical
antipsychotic agents (AAPs). In this study, a parallel clinical study with 3-day consecutive administration of
olanzapine (10 mg/day) was conducted in 17 healthy subjects with a genotype of TCF7L2 rs7903146 CC (N = 10) or CT (N = 7).
Olanzapine caused rapid metabolic changes including
body-weight gain, increased
triglycerides level and reduced
HDL-cholesterol level in the healthy subjects. rs7093146 T carriers (CT) were found to have greater AUC0-2 hr of
insulin during OGTT compared to those (CC) bearing only reference alleles before and after
olanzapine treatment. However, the
triglyceride level in the subjects with the CT genotype was found to be significantly lower than that in the subjects with CC genotype. Moreover, a significant interaction between the effect by genotype and that by
olanzapine treatment on
triglyceride level was identified. Acute
olanzapine treatment also significantly caused total
protein,
albumin and haemoglobin decrease and
uric acid increase in the healthy subjects. In conclusion, even acute
olanzapine treatment induces significant and rapid metabolic changes, and TCF7L2 polymorphism is a genetic risk factor of
olanzapine-associated metabolic side effects.