There are numerous “antipsychotics” currently approved for the treatment of schizophrenia; all can be categorized as either dopamine antagonists (DAs) or serotonin dopamine antagonists/partial agonists (SDA/PAs) and work to reduce positive symptoms of schizophrenia (i.e., psychosis) primarily via blockade of dopamine D2 receptors. Although blockade of D2 receptors in the nucleus accumbens (NAc) can be quite effective for reducing positive symptoms, indiscriminate blockade of D2 receptors throughout the brain brings about high risk of adverse events, namely, motor side effects such as tardive dyskinesia (Figure 1). The DAs and SDA/PAs also carry risk of metabolic side effects and sedation; such side effects often lead to treatment discontinuation and non-adherence, greatly impacting outcomes. Additionally, for as many as 30% of patients with schizophrenia, DAs and SDA/PAs are not sufficient for reducing positive symptoms and virtually ineffective for negative, affective, and cognitive symptom domains.

Blockade of dopamine D2 receptors in the nucleus accumbens (NAc) mitigates the excess dopaminergic neurotransmission coming from the ventral tegmental area (VTA) (i.e., the mesolimbic A10 psychosis pathway) to reduce symptoms of psychosis. Unfortunately, dopamine D2 receptors are also located in the nigrostriatal (A9 motor pathway) where dopamine levels coming from the substantia nigra (SN) are not in excess. When an antipsychotic indiscriminately blocks D2 receptors in the dorsal striatum (DS) as collateral damage from blocking D2 receptors in the NAc, we end up disrupting dopaminergic neurotransmission, which often results in very troublesome motor side effects such as tardive dyskinesia.

Accumulating data, including those from this study by Kaul et al., indicate that upstream muscarinic modulation of downstream dopamine release may be a novel and effective way to treat schizophrenia without the motor and other side effects commonly associated with DAs and SDA/PAs (Figure 2). One particular muscarinic M1/M4 receptor agonist, xanomeline, is showing great promise. Since xanomeline can bind muscarinic receptors in the periphery as well as the central nervous system (CNS) and thereby cause cholinergic side effects (mostly gastrointestinal), it is combined with trospium, a peripherally acting muscarinic antagonist that does not cross the blood brain barrier.

Muscarinic M1 and M4 receptors modulate dopamine (DA) release upstream in psychosis circuits. In a state of psychosis, low γ-aminobutyric acid (GABA) interneuron activity in the frontal cortex leads to increased neuronal excitability from the ventral tegmental area (VTA), which in turn leads to excess dopamine in the nucleus accumbens (NA) (Figure 2, left). In the frontal cortex, activation of M1 receptors on GABA interneurons (as well as other neurons in the frontal cortex -not shown) leads to a reduction of excitatory glutamate (Glu) release in the VTA. This reduction in Glu decreases the activity of DA neurons via N-methyl-D-aspartate (NMDA) receptors, resulting in a decrease in DA release and a hypothetical decrease in the positive symptoms of psychosis (Figure 2, top right). In addition, M4 receptors on cholinergic projections from the laterodorsal tegmental nucleus (LDT) in the hindbrain act as autoreceptors and turn off acetylcholine (ACh) release from these projections when activated. This reduction in ACh leads to decreased activation of muscarinic M5 receptors located on DA cell bodies, decreased neuronal excitability in the VTA, and hypothetically decreased positive symptoms of psychosis (Figure 2, bottom right).

In this 5-week, phase 3, multicenter, randomized, double-blind, placebo-controlled trial, 256 adult patients with schizophrenia experiencing acute psychosis were treated with xanomeline-trospium (titrated then flexibly dosed to a maximum of 125mg xanomeline/30mg trospium twice daily). At as early as 2-weeks (the first post-baseline rating), significant improvements from baseline were seen in the Positive and Negative Symptom Scale (PANSS) total and positive subscale scores as well as the Clinical Global Impressions (CGI) scale compared to placebo. At 5-weeks, there was a significant and clinically meaningful 8.4 greater reduction in PANSS total score compared to placebo and over 50% of patients were responders (showing at least 30% symptom improvement from baseline) compared to 25.3% of placebo-treated patients. Xanomeline-trospium efficacy in terms of negative symptoms did not quite reach significance compared to placebo (except at 4 weeks). The commonly reported side effects associated with DAs and SDA/PAs (movement disorders, weight gain, and somnolence) were virtually absent in xanomeline-trospium-treated patients; the most prevalent side effects were gastrointestinal in nature, but most were mild to moderate and transient.

This study was short-term in nature (5-weeks); further studies are needed to assess the long-term efficacy, tolerability, and safety of xanomeline-trospium and such studies (52-weeks) are underway. Altogether, combined with previous xanomeline-trospium clinical trial data, these results are very promising for the potential availability of a most-welcomed non-D2 receptor blocking antipsychotic in the near future.

Reference:

Kaul I et al. JAMA Psychiatry 2024; Epub ahead of print. Abstract