Letters to the Editor: Letter to the Editor regarding ‘A challenge to the dopamine orthodoxy in schizophrenia’

It was with great interest that we read the article by Norman and Olver (2023), which argues whether the advent of new non–D2-receptor-binding agents (such as TAAR1/5HT1A agonists) heralds a Kuhnian change in understanding antipsychotic drug action and a paradigm shift away from D2 receptor blockade. The US Food and Drug Administration’s Breakthrough Therapy Designation for ulotaront for schizophrenia treatment has led to increased interest in TAAR1/5HT1A agonist research and drug development in schizophrenia (Nair et al., 2022). The investigational antipsychotic ulotaront demonstrated significant short-term reductions in both positive and negative symptoms and showed persistence of therapeutic benefit in a 6-month open-label extension study. Phase III clinical trials (DIAMOND 1–6; 6–52 weeks randomized controlled trial [RCT]/open-label study) will determine the true clinical benefits of this class of compounds by testing their safety and efficacy over existing antipsychotics and their long-term tolerability. In our opinion, the use of these compounds as antipsychotics may offer greater benefits for patients with schizophrenia, which are beyond the positive, negative and cognitive symptoms of the disease by also possibly addressing the issue of comorbid substance abuse and metabolic syndrome witnessed with current antipsychotics...