Muscarinic Approaches to Schizophrenia, Mechanism, EMERGENT Data, and Open Questions

In this video webinar, Ilan Melnick, MD, a psychiatrist in Miami, discusses muscarinic approaches to schizophrenia and reviews mechanism, long-term data, and open questions about how these agents may be used in treatment. He begins with a broad description of the classical dopamine model of schizophrenia, contrasting mesolimbic positive symptoms with mesocortical negative and cognitive symptoms, and noting limitations of postsynaptic D2 blockade across multiple pathways.

Melnick then describes why acetylcholine and muscarinic receptors may play a role in schizophrenia. He states that high-dose antimuscarinic exposure can cause psychosis, that decreased muscarinic receptor density has been seen in regions of the brain in patients with schizophrenia, and that mutations in genes encoding muscarinic receptors are associated with schizophrenia. He reviews nicotinic versus muscarinic signaling, the five muscarinic receptor subtypes, and the distribution of M1 and M4 in central nervous system regions involved in schizophrenia, including the prefrontal cortex, striatum, hippocampus, and ventral tegmental area. He describes 2 proposed presynaptic mechanisms, M4 autoreceptor effects in the ventral tegmental area and M1-mediated effects through GABA and glutamate in the prefrontal cortex, that may lower dopamine release in the striatum while hopefully not affecting negative symptoms in the way traditional D2 blockers do.

He then reviews the EMERGENT program and the xanomeline and trospium chloride combination. He describes EMERGENT-1, -2, and -3 as identical 5-week randomized, double-blind, placebo-controlled trials in hospitalized adults with acute exacerbation of psychosis, and EMERGENT-5 as a 52-week open-label single-arm trial in psychiatrically stable adults switched from prior antipsychotics. He reports that in the acute trials, with almost 640 patients, total PANSS score decreased by almost 19.4 points versus 9.6 points with placebo, with separation as early as week 2, and that positive and negative symptoms each showed close to twice the improvement. In the longer-term trial of about 558 patients, he reports continued improvement from a PANSS score of 66 to about 60, positive symptoms from 16.5 to 14.7, and negative symptoms from 17.7 to 16.7. In the discussion, he says negative symptoms may be a major barrier to reintegration, describes his clinical experience in a forensic program with patients asking to return to school, earning GEDs, and working, and states that the goal of treatment is to improve and maintain functionality. He closes by raising interest in ongoing trials in bipolar disorder and in psychosis or agitation in patients with Alzheimer’s disease.

Financial support was provided by Bristol Myers Squibb. Psychiatrist.com independently selected the topic and speaker and produced and edited the video. The views expressed are Dr. Melnick’s own and do not necessarily reflect those of Psychiatrist.com or Bristol Myers Squibb. This content is for educational purposes only and is not a substitute for independent clinical judgment; clinicians should consult full prescribing information and evaluate each patient individually before making treatment decisions. Dr. Melnick was compensated by Psychiatrist.com for his participation. Dr. Melnick discloses the following relevant financial relationships: Advisor, Consultant, Speaker, Honoraria Recipient: AbbVie, Alkermes, Axsome, Bristol Myers Squibb, Eisai, Idorsia, Indivior, Intra-Cellular Therapies, Janssen, Lilly, Lundbeck, Merck, Neurocrine Biosciences, Noven, Otsuka, Sage, Sunovion, Takeda, Teva, Vanda.