Clarity for Schizophrenia: The Latest in Drug Treatment

Imagine your life cut short by 15-20 years, that’s the reality for many patients with schizophrenia. While antipsychotics have been effective in managing many positive symptoms, they have been less effective on negative symptoms and cognitive defects and come with a whole host of side effects. The practice guideline for treating patients with schizophrenia from the American Psychiatric Association was last approved in 2019. However, much has changed since.  

A recent publication by Kantrowitz et. al., discusses new therapeutics with novel mechanisms of action (MOA) for schizophrenia. In the publication, titled “New Developments in the Treatment of Schizophrenia: An Expert Roundtable,” four experts in the treatment of schizophrenia present the current treatment landscape and approaches and challenge us to consider rethinking the paradigm of emerging therapies. 

Current Treatment Landscape and Approaches 

• First-generation (typical) antipsychotics have been the mainstay of treatment since the 1950’s with the primary actions as dopamine D₂ antagonists. 
• Clozapine is unique compared to other antipsychotics as it works through several different pathways in serotonin, muscarinic, histamine, and alpha-adrenergic antagonism and trace amine-associated receptor 1 (TAAR1) agonism. Even though its non-specific drug action leads to many adverse effects, clozapine remains a widely used treatment for schizophrenia. 
• Long-acting injectables (LAIs) have the advantage over other treatments in reducing relapses and increasing medication adherence with their effects lasting weeks to months. Integration of LAIs in regular practice have been challenging due to a lack of clinician education, costs, and data on the clear and consistent advantages over typical antipsychotics.  

Challenging the Treatment Paradigm 
Promising novel MOAs that have shown potential in Phase 2 and 3 clinical trials include muscarinic receptor agonists, trace amine-associated receptor 1 (TAAR1) agonists, serotonin receptor antagonists/inverse agonists, and glutamine modulators. The characteristics of these MOA’s include: 

• Muscarinic receptor agonists module M₄ muscarinic auto-receptors, reduces acetylcholine, and thus reduced dopamine transmission 
• TAAR1 agonists pre-synaptically reduce dopamine release due to heterodimerization with D2 receptors leading to receptor internalization  
• Serotonin receptor antagonists/inverse agonists with potential specificity for 5-HT_2A and 5-HT_2C receptors leading to reduced dopamine release through indirect reduction of glutamate in cortical pyramidal cells 
• Glutamatergic modulators that can reduce glycine reuptake or inhibit D-amino acid oxidase to increase D-serine 

Results from early clinical trials of agents with novel MOAs are encouraging, particularly for muscarinic and TAAR1 agonists. These agents offer renewed hope for meaningful improvement in the management of patients with schizophrenia. 

Despite advancements and the availability of treatments to improve outcomes for patients with schizophrenia, a significant unmet need for more effective and better-tolerated therapies exists. While LAIs can improve medication adherence and desirable outcomes while reducing the risk of relapses, clear advantages of their safety and efficacy are variable when compared to typical antipsychotics.  

Further research and development of agents with novel MOAs are needed to address the full range of symptoms in schizophrenia and provide personalized care for patients. Individualizing patient care plans based on patient preferences, medication efficacy, and adverse effects cannot be emphasized enough. 

REFERENCES 
Kantrowitz, Joshua T, Christoph U Correll, Rakesh Jain, and Andrew J Cutler. 2023. “New Developments in the Treatment of Schizophrenia: An Expert Roundtable.” The International Journal of Neuropsychopharmacology 26 (5): 322–30. https://doi.org/10.1093/ijnp/pyad011. 

Keepers, George A., Laura J. Fochtmann, Joan M. Anzia, Sheldon Benjamin, Jeffrey M. Lyness, Ramin Mojtabai, Mark Servis, et al. 2020. “The American Psychiatric Association Practice Guideline for the Treatment of Patients with Schizophrenia.” American Journal of Psychiatry 177 (9): 868–72. https://doi.org/10.1176/APPI.AJP.2020.177901.