[Antipsychotics with no dopamine receptor blockade; promise or hype?]

Over twenty different antipsychotics are available in the treatment of schizophrenia. All antipsychotics are generally effective, although differences exist in terms of efficacy but also in side effect profile. So far, all antipsychotics block the dopamine-2 (D2) receptor in the brain, including recently available antipsychotics such as lurasidone, cariprazine and brexpiprazole. However large differences exist in binding strength to the D2 receptor that influence dosage ranges. Thus, there seems to be a rock-solid law of antipsychotics: D2 receptor blockade is necessary for an antipsychotic to be effective. Hitherto, the effects of molecules that do not block the D2 receptor for the treatment of psychotic disorders are either disappointing or equivocal, e.g. glutamate system modulators as the metabotropic mGLu2/3 agonist LY2140023. This is disappointing because there is a great need for antipsychotics with novel mechanisms of action. This is pivotal as a proportion of patients with schizophrenia do not sufficiently benefit from currently available dopamine-blocking antipsychotics with limited effects on negative and cognitive symptoms of schizophrenia. In addition, side effects of antipsychotics sometimes prevent its long-term use. Recently, a randomized controlled trial evaluated SEP-363856 for the treatment of acute schizophrenia, a molecule that does not bind to the D2 receptor but binds to trace amine-associated (TAAR) receptors and 5-HT1A receptors. SEP-363856 was more effective compared to placebo after 4 weeks of treatment (effect size 0.45). This is encouraging, although the duration of the RCT and relatively selected group of patients preclude firm conclusions on its efficacy. We may be hopeful that antipsychotics with a novel mechanism of action are investigated, but only the future will learn whether SEP-363856 will have true added value to improve the life of patients suffering from psychotic disorders.