Beyond Dopamine: Evaluating the Pipeline for Schizophrenia

Schizophrenia is a burdensome disease that remains challenging to treat – despite several viable pharmaceutical options. Fortunately, multiple companies are working on novel drugs that aim to overcome the limitations of existing treatments.

Limitations of Dopamine Antagonists 

Antipsychotic medications that block dopamine signaling have remained the standard schizophrenia treatment for more than 50 years. It’s prevailed based on the classic dopamine hypothesis that associates D2 receptors with psychotic symptoms.

Unfortunately, blocking D2 receptors can also stir up some troublesome movement-related side effects, such as tardive dyskinesia and akathisia. Second-generation antipsychotics are more tolerable in some ways. But they can include metabolic side effects. This can exacerbate existing nonadherence issues.

As Clione MacSweeney, Neuroscience Program leader at Nxera Pharma, explains, “The weight gain can be really quite significant, and patients don’t like this. So, what happens is that patients don’t want to take the medications.”

Even when a patient maintains compliance, residual symptoms – such as cognitive impairment and anhedonia – frequently persist.

New Directions in the Schizophrenia Pipeline 

Schizophrenia research has now expanded beyond its original focus on dopamine. Now it includes new insights into the cholinergic system, glutamate and NMDA receptors, and the recently discovered trace amine-associated receptors (TAARs). Several drugs that target these non-dopaminergic pathways are in various stages of development.

• The FDA approved KAR-XT (xanomeline-trospium) in September. It’s the first new treatment approach for schizophrenia to receive FDA approval in decades. Xanomeline is an oral, twice-daily muscarinic agonist that targets M1 and M4 receptors. And it works without the typical cholinergic side effects due to its combination with trospium, a peripheral muscarinic antagonist. The EMERGENT clinical trials evaluating KAR-XT showed positive results overall, with significant improvements in both positive and negative symptom scores compared to placebo and continued improvement across the 52-week open-label trials. KAR-XT also earned a favorable metabolic profile and few reported adverse events. “It is promising to see that over one year of treatment, KAR-XT was not associated with burdensome side effects, specifically weight gain and metabolic dysfunction, as well as extrapyramidal symptoms, which underscores its potential to provide a meaningful and differentiated option for people living with schizophrenia,” reported Roland Chen, MD, senior vice president and head, Immunology, Cardiovascular, and Neuroscience development at Bristol Myers Squibb in a press release.
• TerXT is picking up steam, too. It’s a prodrug of xanomeline and trospium in preclinical development. Its once-daily oral and long-acting injectable formulations would offer advantages in both dosing and adherence.
• NBI-1117568 is a compound under development that also targets M4 receptors as a selective orthosteric agent. The manufacturer reported positive phase 2 data for the once-daily oral medication for only the lowest of one of the four doses tested and is planning phase 3 trials for 2025.
• Another oral agent targeting muscarinic M4 receptors, emraclidine, is in phase 2 trials. It showed promise in phase 1 trials for treating both positive and negative symptoms. And its once-daily dosing and minimal GI impact could be an advantage over KAR-XT.
• Ulotaront is in phase 3 trials and is the first schizophrenia medication to target TAAR1. Despite positive phase 2 trial results that led to a Breakthrough Therapy designation from the FDA, top-line results from the phase 3 trials showed symptom scores didn’t improve significantly compared to placebo. This could be due to a “high placebo response,” which Hiroshi Nomura, representative director, president, and CEO of Sumitomo Pharma, explained, “are well documented in psychiatric clinical studies.” Sumitomo and Otsuka plan to continue working with the FDA on their next steps.

Adjunctive Therapies in the Pipeline

Other drugs with non-dopaminergic mechanisms have undergone evaluation as adjunctive therapy to address residual symptoms of schizophrenia, with mixed results.

• Researchers studied Pimavanserin, a 5-HT2A inverse agonist and antagonist approved for Parkinson’s psychosis, as a treatment for the negative symptoms of schizophrenia. Still, it missed the primary endpoint in its phase 3 trial.
• Phase 3 studies of the glycine transporter-1 inhibitor iclepertin as an adjunctive treatment for cognitive impairment in schizophrenia are underway, following promising results from phase 2 studies that showed cognitive improvements at a well-tolerated dose.
• Another compound getting attention as a potential treatment for cognitive impairment in schizophrenia is ALTO-101, which features a unique mechanism as a PDE4 inhibitor and is administered transdermally. Phase 2 trials have just started, with top-line results expected next year.

The schizophrenia pipeline has taken an exciting turn as it now explores new targets beyond dopamine receptors. Researchers, prescribers, patients, and caregivers hope this will soon result in more effective and better-tolerated treatment options.