Association of variants with treatment-resistant schizophrenia: a genetic association study of dopamine-related genes in schizophrenia.

BACKGROUND

Most genetic analyses that have attempted to identify a locus or loci that can distinguish patients with treatment-resistant schizophrenia (TRS) from those who respond to treatment (non-TRS) have failed. However, evidence from multiple studies suggests that patients with schizophrenia who respond well to antipsychotic medication have a higher dopamine (DA) state in brain synaptic clefts whereas patients with TRS do not show enhanced DA synthesis/release pathways.

PATIENTS AND METHODS

To examine the contribution (if any) of genetics to TRS, we conducted a genetic association analysis of DA-related genes in schizophrenia patients (TRS,  = 435; non-TRS,  = 539) and healthy controls (HC:  = 489).

RESULTS

The distributions of the genotypes of rs3756450 and the 40-bp variable number tandem repeat on differed between the TRS and non-TRS groups. Regarding rs3756450, the TRS group showed a significantly higher ratio of the A allele, whereas the non-TRS group predominantly had the G allele. The analysis of the combination of and yielded a significantly higher ratio of the putative low-DA type (i.e., high COMT activity + high SLC6A3 activity) in the TRS group compared to the two other groups. Patients with the low-DA type accounted for the minority of the non-TRS group and exhibited milder psychopathology.

CONCLUSION

The overall results suggest that () could be involved in responsiveness to antipsychotic medication and () genetic variants modulating brain DA levels may be related to the classification of TRS and non-TRS.