Unpacking Negative Symptoms, Medication Adverse Effects, and Emerging Schizophrenia Treatments

Psych Congress Steering Committee Member Jonathan Meyer, MD, voluntary clinical professor of psychiatry at the University of California San Diego, discusses the challenges in managing schizophrenia, particularly focusing on the persistence of negative cognitive symptoms despite current antipsychotic treatments. He unpacks how the adverse effects of current antipsychotic medications contribute to high non-adherence rates and the strategies that can be implemented to mitigate those issues. Dr Meyer also sheds light on muscarinic receptor activators and their potential benefits compared to traditional antipsychotic treatments, offering insights into the revolutionary treatment approaches for schizophrenia.

Visit the Schizophrenia Learning Library for more schizophrenia rapid refreshers, clinical pearls, and perspectives from Dr Meyer and other experts in the field.

Jonathan Meyer, MD, is a voluntary clinical professor of psychiatry at University of California, San Diego, and a Distinguished Life Fellow of the American Psychiatric Association. Dr Meyer also has teaching duties at UC San Diego and the Balboa Naval Medical Center in San Diego, is a consultant to the first episode psychosis program at Balboa NMC, and is a Senior Academic Advisor to the California Department of State Hospitals. Dr Meyer has lectured and published extensively on psychopharmacology, and is the sole author of the chapter on the Pharmacotherapy of Psychosis and Mania for the last 3 editions of Goodman & Gilman's The Pharmacological Basis of Therapeutics. Along with Dr Stephen Stahl he is co-author of The Clozapine Handbook published in 2019, The Clinical Use of Antipsychotic Plasma Levels published in 2021, and The Lithium Handbook published in 2023.

Read the transcript:

Dr Jonathan Meyer: Hi out there in Radioland, I'm Dr Jonathan Meyer, voluntary clinical professor of psychiatry at the University of California San Diego, and a member of the Steering Committee of Psych Congress.

Meagan Thistle, Psych Congress NP Institute Online Learning Hub (PCNPI): Can you elaborate on the primary challenges in managing schizophrenia, particularly the persistence of negative symptoms despite current antipsychotic treatments?

Dr Meyer: One thing we've come to recognize is that while dopamine D2 receptor blockade or modulation has proven helpful in a significant proportion of people to manage their positive symptoms, it often does not address the other aspects of the illness, namely negative symptoms and cognitive deficits. Also, sadly, our D2 blockade agents go everywhere. We have a lot of off target effects. So even among those people who are responders, sometimes therapy can be intolerable or unacceptable due to motor adverse effects or endocrine adverse effects.

Thistle, PCNPI: How do adverse effects of current antipsychotic medications contribute to nonadherence rates, and what strategies can be implemented to mitigate these issues?

Dr Meyer: The reason we focus on the adverse effects of medications is that for people who have to take these medications, literally for the rest of their life, almost any type of adverse effect manifests itself as a decreased likelihood of taking the medication. This has been shown in surveys studies which have demonstrated that regardless of the type of adverse effect, whether it's motor, endocrine, sedation... people don't like it and it's associated with lower rates of treatment adherence. How we manage this in the present age is try to find a molecule which is a better fit for that particular person and will give them the efficacy that they need while eliminating or minimizing the adverse effect which they find unpleasant. Sometimes that can be challenging and it may be a reason why many patients on average do not persist with any antipsychotic for long periods of time.

Thistle, PCNPI: What are muscarinic acetylcholine receptor activators, and how do they differ from traditional antipsychotic treatments in terms of mechanism and potential benefits?

Dr Meyer: The revolution, which is going to be coming soon for the treatment of symptoms of schizophrenia, relates to the fact that we have come to appreciate that the positive symptoms of schizophrenia, in particular, are related to too much presynaptic dopamine release. In the animal model we call the mesolimbic pathway. In humans, it's a slightly different part of the striatum. We have managed this with postsynaptic D2 blockers, but the problem is largely a presynaptic one. There's too much presynaptic dopamine release, or it turns out that presynaptic dopamine release in this tract, which comes from the VTA neuron, specifically in the animal model, is controlled by pathways where we can modulate the activity using a muscarinic agonist. There's a couple of ways this can happen. This VTA dopamine neuron receives cholinergic input from a midbrain pathway, which is a cholinergic pathway.

If we give a drug which decreases the cholinergic activity, we get less presynaptic release of dopamine from the VTA, and most importantly, it happens selectively. Meaning, if I give an M4 specific activating drug, I get less release of acetylcholine from this LDT pathway and therefore less release of dopamine from the VTA. But this only happens in the area of the striatum associated with the positive symptoms of psychosis. The motor area actually has another cholenergic pathway, but there its activity is largely governed by the M2 auto receptor. So giving an M4 agonist does not give motor side effects.

There's also another pathway which comes down from the prefrontal cortex. We can modulate its input into VTA using M1 agonist strategy. So, through a combination of stimulating M1 or M4 receptors or both, we decreased presynaptic dopamine release in the area of the striatum associated with the positive symptoms of psychosis