Novel Approaches to Treating the Full Spectrum of Schizophrenia Symptoms, Modulating Dopamine and Glutamate Neurotransmission

In an interview with Pharmacy Times, Andrew J. Cutler, MD, Clinical Associate Professor of Psychiatry at SUNY Upstate Medical University, Chief Medical Officer of Science Education Institute, discusses his presentation at the 2024 American Association of Psychiatric (AAPP) Conference. Cutler focuses on limitations of current antipsychotics which mainly block dopamine D2 receptors, leading to motor side effects and lack of efficacy for non-positive symptoms. He emphasizes emerging treatments that aim to regulate dopamine presynaptically or target glutamate dysfunction more directly to improve cognitive and negative symptoms. Cutler also discusses novel agents that include muscarinic agonists, glycine transporter inhibitors, and D-amino acid oxidase inhibitors. A variety of promising mechanisms are being explored in developing treatments for the full spectrum of schizophrenia.

Could you elaborate on the neurocircuitry underlying dopaminergic neurotransmission in schizophrenia and how it contributes to the pathophysiology of the disorder?

Historically, the theory that's predominated our understanding of the pathology of schizophrenia has been the dopamine theory. The dopamine theory says essentially, there's too much dopamine in parts of the brain that we call the limbic system. And too much dopamine in the limbic system, we think underlies positive symptoms of schizophrenia, which are principally hallucinations and delusions. Now, at the same time, in a different part of the brain, especially the frontal cortex, we have too little dopamine activity. And we think this leads to the cognitive impairment and negative symptoms of schizophrenia. And those symptoms are the ones that are specially impairing for people with schizophrenia.

Key Takeaways

Current antipsychotics are limited by motor side effects from D2 receptor blockade and inability to treat cognitive/negative symptoms effectively.
Novel treatments aim to modulate dopamine presynaptically or target glutamate dysfunction to improve efficacy across symptom domains.
Promising new classes discussed include muscarinic agonists, glycine transporter inhibitors, and D-amino acid oxidase inhibitors, representing multiple mechanistic approaches.

Can you provide insights into the challenges posed by motor side effects and the lack of efficacy for non-positive symptoms?

All of our currently available FDA approved anti-psychotics work by blocking postsynaptic D2 receptors, in an attempt to try to deal with that overactivity of dopamine in the limbic system— in the ventral striatum, we call it. The problem is D2 receptors live in various parts of the brain. And so, if you just indiscriminately block them, you get what I call collateral damage. And so, you can have side effects such as drug induced motor symptoms, which we sometimes call EPS, but more accurately, there's acute drug induced movement disorders, which are parkinsonism as the most common. Akathisia, which is an uncomfortable sense of restlessness, and dystonia, which is muscle spasm. Now, if somebody continues to take a D2 blocker, you can see tardive dyskinesia, which is a really troubling side effect that can be permanent. We also can have elevation of a hormone called prolactin from blocking D2 receptors in the pituitary axis. Then you can also have wakened, and metabolic dysregulation from these kinds of mechanisms. Now, these drugs are particularly effective at treating the positive symptoms of schizophrenia, which are very troublesome when they happen and can lead to people being hospitalized. But they're not as effective at treating the cognitive impairment. The negative symptoms of schizophrenia, which again, are really the ones that long term is associated with impaired function and quality of life.

What are some of the promising novel agents or strategies for modulating dopamine levels and which avoid the direct blockade of dopamine D2 receptors?

As I mentioned, the currently available FDA approved in a psychotic, we think all essentially worked by blocking postsynaptic, D2 receptors. But it turns out, there's many different ways to regulate dopamine. It turns out that there are presynaptic ways. So, dealing with the increased dopamine release, if we can tone down the synthesis or release of dopamine, that essentially has the same effect as blocking the receptor postsynaptic. Now, there are some drugs in development right now that do that. But what's nice is that they're targeted— they decrease dopamine in the part of the brain that I want to namely the ventral striatum or limbic system, but not in parts of the brain associated with motor side effects or prolactin. And it turns out that some of these drugs also can increase the dopamine into the front part of the brain, which might help with the cognitive impairment and the negative symptoms. So, the mechanism that's closest to the market now is our drugs that stimulate muscarinic cholinergic receptors, acetylcholine receptors are muscarinic or nicotinic. Of the muscarinic receptors, especially, we want to stimulate M1 and M4. By doing that we can influence dopamine. Because acetylcholine dances with dopamine, if you increase acetylcholine, you increase dopamine. But if you decrease acetylcholine, you can decrease dopamine. And again, because these M1 and M4 receptors are targeted and located in only certain parts of the brain that allows me to target these drugs to the efficacy that I want to get, without causing the side effects because we're not influencing dopamine, other parts of the brain.

How do these agents differ in mechanism of action and potential therapeutic benefits compared to traditional antipsychotics?

I've talked now about muscarinic agonism, and these are drugs that we think of as true anti psychotics that may also help cognitive impairment and negative symptoms. However, there are a number of drugs in development that have different mechanisms that are really specifically targeted at cognitive impairment and or negative symptoms. Many of these work on the glutamate system. So, we have a drug that is in phase 3 development called iclepertin, which is a glycine transporter type 1 inhibitor or GlyT1 inhibitor. If you block this transporter, you have more glycine around. Glycine is a co-agonist with glutamate at NMDA glutamate receptors. One of the theories of schizophrenia is that we have dysfunction of these glutamate NMDA receptors on a GABA interneuron, in the prefrontal cortex. And that then causes all kinds of glutamate disturbance, which then ultimately leads to dopamine disturbance. The thinking is if we can fix that NMDA receptor on the GABA neuron — and there's a number of ways of doing that, maybe we can improve these impairments in schizophrenia. So, one is the glycine transporter 1 inhibitor. Another mechanism is an enzyme called D-amino acid oxidase (DAO, DAAO). So, we have DAO inhibitors, and they prevent the degradation of this co-agonist serine. So, if we have more of that co-agonist, again, maybe that helps that glutamate NMDA receptor to work better. We also have a class of drugs called phosphodiesterase inhibitors or PDEs, which also we think indirectly are helping the NMDA receptor to work better. So, there are a number of drugs in development. As far as drugs that truly work on the range though, of symptoms of schizophrenia. We have the class of what we call muscarinic agonist in development, and there's, there's many of them actually in development now. And they bind to either M1 or M4, or both. They are either full agonists, which bind directly to the receptor, where acetylcholine would bind and stimulate it or they can be positive allosteric modulators or PAMs, which don't bind to the orthostatic site, which is the site we're asked to choline binds, they bind to what's called an allosteric site. If you bind there, you change the configuration of the muscarinic receptor to make it more receptive to ask your calling. So, you're enhancing the natural activity of that receptor.