Navigating the A to Z of Schizophrenia, Part 3: Novel Treatment Mechanisms

Transcript: 

Hi, I'm Andrew Penn. I'm a psychiatric nurse practitioner and a clinical professor at the University of California San Francisco School of Nursing. I also practice at the San Francisco Veterans Administration Hospital.  

This presentation is going to cover challenges with existing therapies, including gaps in symptom management in schizophrenia, novel treatment mechanisms that target beyond dopamine, nonpharmacologic approaches, including cognitive behavioral therapy and lifestyle modifications, and technology and treatment delivery, including digital tools and virtual reality.

The dopamine hypothesis of schizophrenia was originally proposed in the 1960s by Arvid Carlsson. In the ensuing decades, animal studies and human imaging data substantiated the strong link between dopamine system overactivity and the positive symptoms of schizophrenia.

Antipsychotic treatments approved prior to 2024 possess a common mechanism of action: they decrease postsynaptic dopaminergic activity, and this often correlates with a reduction in the positive symptoms of schizophrenia (such as hallucinations and delusions). However, these agents do not significantly ameliorate the negative or cognitive symptoms of the illness.

First-generation antipsychotics are potent dopamine D2 receptor antagonists and tend to cause high rates of movement disorders, such as parkinsonism, akathisia, dystonia, and tardive dyskinesia, along with endocrine side effects related to prolactin elevation.

Second-generation antipsychotics additionally exhibit 5-HT2A receptor antagonism, which helps to reduce the rates of drug-induced movement disorders. Some of these agents, however, cause other concerns, such as prolactin elevation, weight gain, and metabolic dysregulation.  

Antipsychotics with D2 partial agonist activity have relatively low rates of movement disorders and metabolic adverse effects.

For individuals with treatment-resistant schizophrenia, defined as an insufficient response to at least 2 antipsychotics, the only effective medication is clozapine. However, clozapine has a high risk for weight gain and metabolic disturbance, as well as a unique set of adverse effects, including high rates of neutropenia. The need for regular hematologic monitoring is one of many aspects of clozapine prescribing that poses a significant barrier to patient acceptance and also clinician implementation.

Even for patients who are not treatment-resistant, there is limited benefit for negative and cognitive symptoms, and most do not achieve significant improvements in quality of life. Unfortunately, functional recovery is relatively uncommon.

In September 2024, xanomeline-trospium became the first new US Food and Drug Administration-approved treatment for schizophrenia in decades. It is an oral fixed-dose combination of xanomeline, which is a muscarinic agonist, and trospium chloride, a peripheral muscarinic antagonist. It is the first medication approved in the United States since reserpine in 1955 that is indicated for schizophrenia that doesn’t bind to the dopamine D2 receptors.  

Xanomeline is the active agent in this combination, and it works by activating muscarinic M1 and M4 receptors. By doing so, it reduces dopamine release in the area of the striatum associated with the positive symptoms of psychosis, but it has no biologic effects on motor areas of the striatum, which often leads to side effects.

Clinical trials have shown that xanomeline-trospium effectively reduces symptoms without the side effects linked to traditional dopamine antagonists, such as motor side effects, hyperprolactinemia, weight gain, and other metabolic disturbances. Moreover, stimulating muscarinic receptors, especially M1, was postulated to improve cognitive dysfunction. In clinical trials, the subgroup of patients with extremely low baseline cognitive function saw some improvement.

Muscarinic receptor stimulation is known to produce nausea and vomiting, so trospium was added to reduce rates of these peripheral cholinergic effects. Trospium does not cross the blood-brain barrier to any significant degree, so it doesn’t interfere with xanomeline activity in the brain. The job of trospium is to block the stimulation of muscarinic receptors in the gastrointestinal tract that can lead to things such as nausea and vomiting.

Inflammation is gaining attention as a contributing factor in brain dysfunction broadly, and more specifically, in schizophrenia. Therapies targeting inflammatory pathways, including cytokine inhibitors, are under investigation. These approaches are informed by findings of elevated inflammatory markers in some schizophrenia patients.

The glutamate-targeted agents for cognition have not been successful in clinical trials, including luvadaxistat and iclepertin. There is a paucity of promising mechanisms of action on the horizon for cognition, unfortunately.

Nonpharmacological strategies complement drug therapies by addressing behavioral and functional challenges. Cognitive-behavioral therapy (CBT) can be effective for managing the positive symptoms of psychosis, as it empowers patients to recognize and mitigate distorted thought patterns. Cognitive remediation therapy has also proven effective in multiple studies for reducing the impact of cognitive dysfunction in schizophrenia.

Psychosocial interventions, including supported employment and family education programs, enhance social reintegration and caregiver support. Evidence-based practices such as assertive community treatment (or ACT) have demonstrated improved long-term outcomes by offering coordinated, patient-centered care.

Lifestyle interventions targeting exercise and nutrition also show promise. Regular physical activity can mitigate antipsychotic-induced weight gain and improve mood, as well as promote beneficial structural changes to brain areas associated with cognition and memory. Meta-analyses have demonstrated that exercise and dietary modification are associated with reductions in core schizophrenia symptoms and improvement in mood and quality of life.

New digital tools will hopefully transform how schizophrenia is managed. These tools offer opportunities for symptom monitoring, adherence support, and therapy delivery. Smartphone apps are being created to help patients track their mood, remain adherent to their medication, and recognize warning signs of impending relapse. Some apps include psychoeducational resources to enhance patient understanding and engagement. Digital instruments can potentially provide a method for collecting patient-reported data and empowering patients on their treatment journey. These tools can provide the treating clinician with nuanced insights into treatment response. For example, the heart rate data from a wearable device may possibly alert a clinician to signs of relapse.  

Virtual reality (or VR) therapy is an innovative tool for managing social anxiety. By simulating real-world scenarios, VR helps patients practice coping strategies in a controlled environment. VR has been shown to improve external focus, implicit learning, and task specificity, and it provides real-time feedback. Modular VR treatments are being designed to help young people with psychosis improve their social functioning, with the hope that this method will provide another important treatment option to augment with medications.

So, in review we've talked about how integrative approaches combine pharmacologic and nonpharmacologic treatments to provide personalized care models, precision medicine using genetic and biomarker research to tailor treatments to individual patients and continued research investment, developing therapies targeting novel pathways like neuroinflammation and the gut-brain-axis interactions. Thanks for watching.