Symposium
Session Room: Alsh
Session Room: Alsh
Sunday, June 28, 10:50 AM – 12:05 PM
Symposium 12:
Back to the Future-clozapine, the cholinergic system and non-dopaminergic antipsychotics
Back to the Future-clozapine, the cholinergic system and non-dopaminergic antipsychotics
The mechanism of action of clozapine in treatment-resistant schizophrenia remains one of the most beguiling questions in psychopharmacology, almost 70 years after its synthesis.
In a 2025 commentary, Morrison proposes that clozapine’s unique profile owes much to muscarinic acetylcholine receptor activation (particularly M1/M4), a similar review published in Biological Psychiatry around the same time (by one of the proposers) coming to similar conclusions.
This work suggests a reconceptualisation of antipsychotic pharmacology: understanding clozapine as a prototype of a class of non-(or less) D2-centric treatments. The seminar will begin by summarising Morrison’s argument: how the drug’s peripheral pharmacology pointed to cholinergic engagement, and how this dovetails with central muscarinic signalling that may normalise striatal and cortical dysfunction in psychosis. This will focus on basic tenets of psychopharmacology and the cholinergic system.
Building on this, the second half will incorporate insights from recent developments in both muscarinic and trace-amine compounds led by Grazia Rutigliano, who is a psychiatrist who has developed preclinical models, and examined TAAR agonists (an additional non D2 compound) as a model for treatment in schizophrenia.)
. TAAR1 is ideally placed to modulate dopaminergic, serotonergic and glutamatergic circuits, thereby offering a fundamentally different mechanistic approach. Although results from Phase 3 trials have been mixed-and the FDA and EMA have requested more data, their mechanism of action, especially on dopamine synthesis, may hhave a role in other disorder, such as bipolar disorder.
Preclinical models examining muscarinic agonists will also be discussed.
Finally, Dr Jauhar, a clinical academic specialising in psychosis, who has reviewed Kar XT trials will examine the current data on muscarinic agonists and clinical utility of these drugs.
Thus, this seminar will explore three interconnected themes:
Cholinergic modulation as non-dopamine antipsychotic mechanism – We will examine how muscarinic M1/M4 activation (as proposed) may underpin clozapine’s efficacy: influencing cortical and subcortical networks, improving cognitive/negative symptoms, and reducing EPS/DA-dependency.Trace-amine/TAAR1 agonists as next generation antipsychotics – Leveraging Rutigliano’s and others’ work, we will map the biology of TAAR1 (expression, monoamine/ glutamate modulation), review pre-clinical and early clinical data, and contrast their mechanism (dopamine‐modulation via TAAR1) with both classical D2 antagonists and muscarinic cholinergic agents.
Translational and clinical implications – We will integrate both lines of research (cholinergic & TAAR1) into a forward‐looking framework: how might we stratify patients for cholinergic vs TAAR1 vs D2-targeting treatments? What are the implications for treatment-resistant schizophrenia, cognitive/negative symptoms, metabolic burden and tolerability? Are we on the cusp of a mechanistic shift away from dopamine-solely therapies?
In summary, this seminar proposes to bridge mechanistic reinterpretation of clozapine with the emergent TAAR1 agonist paradigm (via Rutigliano et al.), thereby providing attendees with both deep mechanistic insight and a roadmap for next-generation non-dopamine antipsychotic strategies. Participants will take away: (a) a refined understanding of clozapine’s cholinergic mechanism; (b) the pharmacology and clinical potential of TAAR1 agonists; and (c) a translationally-oriented framework for repositioning antipsychotic design beyond dopamine.
In a 2025 commentary, Morrison proposes that clozapine’s unique profile owes much to muscarinic acetylcholine receptor activation (particularly M1/M4), a similar review published in Biological Psychiatry around the same time (by one of the proposers) coming to similar conclusions.
This work suggests a reconceptualisation of antipsychotic pharmacology: understanding clozapine as a prototype of a class of non-(or less) D2-centric treatments. The seminar will begin by summarising Morrison’s argument: how the drug’s peripheral pharmacology pointed to cholinergic engagement, and how this dovetails with central muscarinic signalling that may normalise striatal and cortical dysfunction in psychosis. This will focus on basic tenets of psychopharmacology and the cholinergic system.
Building on this, the second half will incorporate insights from recent developments in both muscarinic and trace-amine compounds led by Grazia Rutigliano, who is a psychiatrist who has developed preclinical models, and examined TAAR agonists (an additional non D2 compound) as a model for treatment in schizophrenia.)
. TAAR1 is ideally placed to modulate dopaminergic, serotonergic and glutamatergic circuits, thereby offering a fundamentally different mechanistic approach. Although results from Phase 3 trials have been mixed-and the FDA and EMA have requested more data, their mechanism of action, especially on dopamine synthesis, may hhave a role in other disorder, such as bipolar disorder.
Preclinical models examining muscarinic agonists will also be discussed.
Finally, Dr Jauhar, a clinical academic specialising in psychosis, who has reviewed Kar XT trials will examine the current data on muscarinic agonists and clinical utility of these drugs.
Thus, this seminar will explore three interconnected themes:
Cholinergic modulation as non-dopamine antipsychotic mechanism – We will examine how muscarinic M1/M4 activation (as proposed) may underpin clozapine’s efficacy: influencing cortical and subcortical networks, improving cognitive/negative symptoms, and reducing EPS/DA-dependency.Trace-amine/TAAR1 agonists as next generation antipsychotics – Leveraging Rutigliano’s and others’ work, we will map the biology of TAAR1 (expression, monoamine/ glutamate modulation), review pre-clinical and early clinical data, and contrast their mechanism (dopamine‐modulation via TAAR1) with both classical D2 antagonists and muscarinic cholinergic agents.
Translational and clinical implications – We will integrate both lines of research (cholinergic & TAAR1) into a forward‐looking framework: how might we stratify patients for cholinergic vs TAAR1 vs D2-targeting treatments? What are the implications for treatment-resistant schizophrenia, cognitive/negative symptoms, metabolic burden and tolerability? Are we on the cusp of a mechanistic shift away from dopamine-solely therapies?
In summary, this seminar proposes to bridge mechanistic reinterpretation of clozapine with the emergent TAAR1 agonist paradigm (via Rutigliano et al.), thereby providing attendees with both deep mechanistic insight and a roadmap for next-generation non-dopamine antipsychotic strategies. Participants will take away: (a) a refined understanding of clozapine’s cholinergic mechanism; (b) the pharmacology and clinical potential of TAAR1 agonists; and (c) a translationally-oriented framework for repositioning antipsychotic design beyond dopamine.