Transcript:

Hello, I’m Dr Leslie Citrome, Clinical Professor of Psychiatry and Behavioral Sciences at New York Medical College in Valhalla, New York. Welcome to our program on schizophrenia.  

Current treatments for schizophrenia predominantly focus on symptom management and are limited in terms of efficacy and tolerability.

This approach has led to high rates of nonadherence to antipsychotic medications, with estimates suggesting that about 50% of patients do not consistently take their prescribed medications.

The reliance on traditional antipsychotics has resulted in significant unmet needs, particularly in targeting cognitive deficits, negative symptoms, and treatment-resistant schizophrenia.

Traditional therapies primarily targeted dopamine receptors for symptom management via postsynaptic receptor blockade in the part of the brain responsible for the production of hallucinations and delusions. These first- and second-generation antipsychotics had extensive side effects related to blockade of dopamine receptors elsewhere in the brain with resultant motor abnormalities and elevation in prolactin blood levels. Moreover, multiple pharmacodynamic properties of traditional antipsychotics cause weight gain, metabolic abnormalities, sedation, and prolongation of the electrocardiogram (ECG) QT interval.

Rather than postsynaptic dopamine receptor blockade, other approaches to the treatment of schizophrenia have been developed. This has involved regulation of presynaptic dopamine release. This approach has already been demonstrated to be successful in the treatment of people with schizophrenia via muscarinic receptor agonism in the specific circuits of the brain that control dopamine release related to psychosis.

Xanomeline-Trospium combination (or Cobenfy), is the first truly novel US Food and Drug Administration (FDA)-approved treatment for schizophrenia in decades. It is an oral fixed-dose combination of xanomeline, a muscarinic agonist, and trospium chloride, a peripheral muscarinic antagonist. This represents a significant advancement, as it is the first modern treatment for schizophrenia in the United States that does not directly block dopamine receptors, focusing instead on modulating central nervous system cholinergic circuitry to address symptoms associated with schizophrenia. The three 5-week placebo-controlled randomized clinical trials of xanomeline-trospium demonstrated robust reduction of symptoms without the common side effects linked to traditional dopamine antagonists, such as motor symptoms and metabolic disturbances. It also does not contain the bolded boxed warning associated with previous antipsychotics.

Remaining as works in progress, and that have not yet resulted in a commercially available product for the treatment of schizophrenia, are agents that are direct glutamatergic modulators, including NMDA receptor antagonists and metabotropic glutamate receptor agents. Although initially considered promising, glycine transport inhibitors, which target NMDA receptors, have failed late-stage clinical development efforts across 2 different agents (bitopertin and iclepertin).

Trace Amine-Associated Receptor Type 1 agonism has shown preclinical evidence in modulating dopaminergic and glutamatergic systems, potentially alleviating symptoms associated with hyperdopaminergic activity. Trace Amine-Associated Receptor Type 1 selectively reduces spontaneous glutamatergic activity while enhancing evoked responses, suggesting a state-dependent modulation of glutamatergic tone that may contribute to its antipsychotic-like effects. Unfortunately, recently completed late-stage clinical trials have been unsuccessful.

The integration of technology into schizophrenia treatment is rapidly evolving, with digital therapeutics emerging as a promising adjunct to traditional care. Smartphone applications and artificial intelligence-driven platforms, as well as immersive virtual reality platforms, are being developed to monitor symptoms and support medication adherence, providing patients with tools to manage their condition more effectively.

Biomarker-based diagnostics are also gaining traction, allowing for the identification of personalized treatment pathways through advanced imaging and genomics. This approach aims to tailor interventions based on individual patient profiles, potentially improving treatment outcomes.  

Ongoing clinical trials are exploring the efficacy of these innovative approaches, with many studies listed on ClinicalTrials.gov for virtual reality interventions, technological support, and lifestyle interventions for treating schizophrenia.

In summary, the landscape of schizophrenia treatment is evolving, with emerging therapies and technological innovations offering new hope for patients. As research continues to advance, it is crucial to remain up to date in understanding these approaches to ensure that individuals living with schizophrenia receive the comprehensive care they need.  

I hope this has been helpful to you in better understanding schizophrenia and the challenges that our patients and caregivers face.  

For more information, please listen to the other podcasts in this series:


References:  

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