clinical topic updates

Differing Mechanisms of Action in the Treatment of Schizophrenia

by Leslie Citrome, MD, MPH

Overview

No patient or medication can be reduced to a set of neural circuits or receptor binding affinities; however, there can be clinically relevant distinctions among the second-generation antipsychotics that may stem from mechanistic differences.

Expert Commentary

Leslie Citrome, MD, MPH

Clinical Professor
Department of Psychiatry and Behavioral Sciences
New York Medical College
Valhalla, NY

“Antipsychotic agents do have different ‘fingerprints,’ and each can be quite distinctive. It is fortunate that a variety of agents with distinct binding affinities are currently available so that we can try different therapies until the best option for the individual patient is identified.”

Leslie Citrome, MD, MPH

Second-generation antipsychotics differ in their affinities for individual receptors, and patients differ in their individual neurocircuitry. We can hypothesize about how a particular antipsychotic agent will perform, but no one really knows about efficacy until a clinical trial is performed, and, even then, we cannot be certain of an individual patient’s response (ie, whether a given drug will be the best agent for them) until they try it. 

However, antipsychotic agents do have different “fingerprints,” and each can be quite distinctive. Side effects tend to be a bit more predictable, as borne out by the clinical data. For example, α1-adrenergic receptor antagonism may cause postural hypotension and H1 receptor antagonism may cause sedation; still, individuals differ in the extent to which they experience these side effects. We know that there are some second-generation antipsychotics that are more likely to be associated with metabolic dysregulation, such as olanzapine and clozapine, but there are also agents that are not specifically linked to this, such as lumateperone, cariprazine, and lurasidone, just to name a few. 

A patient’s medical history can be very helpful in guiding the path forward. If an individual has had a good clinical response to a particular medication but poor tolerability, it is reasonable to consider a drug with similar binding affinities related to efficacy but different binding affinities related to tolerability. It is fortunate that a variety of agents with distinct binding affinities are currently available so that we can try different therapies until the best option for the individual patient is identified.

At present, all US Food and Drug Administration–approved antipsychotics have at least some degree of postsynaptic Dreceptor binding affinity. Of note, there are new agents in clinical development with unique mechanisms that do not involve postsynaptic Dreceptor binding. A trace amine-associated receptor 1 (TAAR1) agonist that is in development (SEP-363856) modulates neurotransmission in monoaminergic neurons. Eventually, it modulates dopamine without directly blocking postsynaptic dopamine receptors. This interesting profile reduces the symptoms of schizophrenia with a low occurrence of extrapyramidal motor side effects, metabolic dysregulation, or weight gain. 

A second agent in clinical development combines a muscarinic M1/Magonist with a nonspecific muscarinic receptor antagonist that has minimal to no penetration across the blood-brain barrier. The agonist acts centrally to control symptoms while the nonspecific antagonist protects against peripheral side effects. This agonist ultimately modulates dopamine, but, similar to the TAAR1 agonist, does so without binding to the postsynaptic D2 receptor. Although all roads continue to lead to dopamine in the end, these new agents with unique binding profiles have the potential to greatly expand the options for controlling symptoms and improving tolerability of treatment in patients with schizophrenia.

References

Brannan SK, Sawchak S, Miller AC, Lieberman JA, Paul SM, Breier A. Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia. N Engl J Med. 2021;384(8):717-726. doi:10.1056/NEJMoa2017015

Correll CU. Current treatment options and emerging agents for schizophrenia. J Clin Psychiatry. 2020;81(3):MS19053BR3C. doi:10.4088/JCP.MS19053BR3C

Koblan KS, Kent J, Hopkins SC, et al. A non-D2-receptor-binding drug for the treatment of schizophrenia. N Engl J Med. 2020;382(16):1497-1506. doi:10.1056/NEJMoa1911772

Pillinger T, McCutcheon RA, Vano L, et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis. Lancet Psychiatry. 2020;7(1):64-77. doi:10.1016/S2215-0366(19)30416-X

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