Genetic risk for treatment resistant schizophrenia and corresponding variation in dopamine synthesis capacity and D receptor availability in healthy individuals.

Dysfunction of dopamine systems has long been considered a hallmark of schizophrenia, and nearly all current first-line medication treatments block dopamine D receptors. However, approximately a quarter of patients will not adequately respond to these agents and are considered treatment-resistant. Whereas abnormally high striatal presynaptic dopamine synthesis capacity has been observed in people with schizophrenia, studies of treatment-resistant patients have not shown this pattern and have even found the opposite - i.e., reductions in striatal presynaptic dopamine synthesis capacity. Whether such reductions in fact represent clinical epiphenomena such as medication or other treatment effects or whether they rather represent neurobiological differences related to etiology has been unclear. To understand the dopaminergic implications of genetic liability for treatment-resistant schizophrenia without the confound of clinical epiphenomena, we studied a cohort of healthy individuals without neuropsychiatric illness using [F]-FDOPA positron emission tomography (PET) and found that striatal presynaptic dopamine synthesis capacity showed an expected direct association with cumulative genetic risk burden for general schizophrenia but an inverse association with specific polygenic risk for treatment-resistant schizophrenia. Subsequent evaluation of D dopamine receptor availability in an overlapping cohort using [F]-fallypride PET did not identify any effects of genetic risk in the striatum but found an association with treatment-resistant schizophrenia polygenic risk in the thalamus. Overall, these results align with prior PET studies in patients and implicate, at least with respect to the dopamine system, fundamentally distinct molecular mechanisms in the unique genetic liability for treatment-resistant schizophrenia.