Dopaminergic dysfunction is a hallmark of schizophrenia, but other neurotransmitter imbalances are also involved in psychosis and may be particularly prominent in patients with schizophrenia who do not respond to dopamine modulators. Dr. Jonathan Meyer, Clinical Professor at the University of California San Diego School of Medicine, discussed the evolution in our understanding of the complex neurobiology of schizophrenia and novel treatments that affect presynaptic dopamine signaling pathways during a virtual educational webinar called “Improving the Lives of Patients with Schizophrenia” offered by the Neuroscience Education Institute (NEI).
Dopamine dysfunction and the mesolimbic hypothesis
Pharmacologic treatments for schizophrenia have been dominated by agents that directly target dopaminergic dysfunction,1,2 which is a hallmark of psychosis. Positive symptoms are associated with excessive dopaminergic signaling in the mesolimbic tract.1,2 While blockade of dopamine D2 receptors in this brain region can improve symptoms of psychosis, blocking D2 receptors also has peripheral and central off-target effects including the inhibition of prolactin release in the hypothalamo-hypophyseal tract and stimulation of spiny neurons in the nigrostriatal tract that can induce parkinsonism.1,3
Traditional D2 blockers can improve positive symptoms of schizophrenia but may be associated with off-target side effects
Beyond dopamine: The role of other neurotransmitter imbalances
Although dopaminergic dysfunction is common in schizophrenia, other neurotransmitter imbalances have been implicated in the disease pathology including glutamate hypofunction. Agents that modulate glutamate signaling in the striatum have been shown to improve positive and negative symptoms in patients with schizophrenia who do not respond to dopamine D2 modulators.4
Novel treatments that target the glutamate system are in development
Evidence supports a genetic link between polymorphisms modulating N-methyl-D-aspartate (NMDA) function and an increased risk of schizophrenia,5 and NMDA hypofunction has been associated with psychosis.6
Finally, serotonergic dysfunction involving 5HT2A and 5HT1A receptors in the prefrontal cortex has been linked with disturbances in cognition, mood, reality perception, and response to stressors in patients with schizophrenia.2,7
A more recent model of schizophrenia suggests that disturbances in these neurotransmitter pathways are interconnected and could lead to presynaptic dopaminergic overactivity.1 Dr. Meyer concluded that from a pharmacologic perspective, this suggests that there could be indirect pathways to reduce excessive presynaptic dopaminergic activity without relying on non-selective D2 blockers.
Indirect pathways resulting in presynaptic dopaminergic overactivity are potential pharmacologic targets for schizophrenia
Muscarinic agonism: A new presynaptic antipsychotic mechanism
Several lines of evidence point to a reduced density of cortical muscarinic M1 receptors in patients with schizophrenia, and this is associated with cognitive dysfunction and more severe negative symptoms.2 Moreover, neurons in the striatum that release presynaptic dopamine have inhibitory muscarinic M4 autoreceptors. Therefore, stimulation of M4 receptors could reduce dopamine release in the striatum and down-tune presynaptic dopamine signaling. Muscarinic agonists therefore represent a promising strategy for addressing the negative symptoms of schizophrenia, which are poorly responsive to traditional antipsychotics that block D2 receptors. Agonists at M1/M4 receptors have been shown to improve cognition and symptoms of schizophrenia;2 however, despite being devoid of adverse motor and endocrine effects that are associated with D2 blockade, they are limited by relatively high rates of peripheral side effects associated with M1 agonism, notably gastrointestinal side effects.8
Muscarinic agonists have shown promising effects on positive, negative and cognitive symptoms of schizophrenia
Blocking the peripheral actions of muscarinic M1 agonism could be a solution to overcome the treatment-limiting side effects of this class.9 Dr. Meyer described studies of a novel muscarinic M1/M4 agonist combined with a nonselective muscarinic peripheral M1 antagonist in patients with schizophrenia that have shown a promising efficacy and safety/tolerability profile.9,10
NMDA modulators: Glycine transporter type 1 inhibitors
The glutamate hypothesis of psychosis posits that hypofunctional NMDA and glutamate hyperactivity is associated with positive, negative and cognitive symptoms in schizophrenia, mediated in part by interactions with dopamine neurons in the mesocortical pathway.2 There are three different subunits of the NMDA receptor, two of which have a glycine binding site. Glycine is an amino acid that has poor CNS penetration, but stimulation of the glycine binding site on NMDA receptors is possible by inhibiting the reuptake of glycine type 1 transporters (Gly1).11,12 Several inhibitors of Gly1 transporters are being investigated for their potential ability to target cognitive symptoms of schizophrenia.11,12
Inhibiting the glycine type 1 transporter is a novel glutamate-based strategy to improve cognitive symptoms in schizophrenia
In conclusion, Dr. Meyer shared his vision that the future of schizophrenia treatment is bright with several novel agents in various stages of development. Some of these act on presynaptic dopamine, which could impart therapeutic benefits on multiple symptom domains without the adverse effects of peripheral and central D2 blockade. “There is hope in these new strategies that work presynaptically, which is where we always wanted to be, with modes of action that do not result in the motor or endocrine effects associated with D2 receptor binding.”
Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.
