Synaptic Regeneration: A New Frontier in Schizophrenia Treatment
The approval of muscarinic-targeting drugs such as Cobenfy has catalyzed the schizophrenia drug discovery industry.
Our approach to treating schizophrenia has changed little for more than half a century. But a shift may be underway, emphasizing novel approaches to the disease and its underlying pathology. This potential transition – from symptom management to functional recovery – is sparking new hope among patients, families and providers.
Gaps exist in schizophrenia treatment
The introduction of dopamine blockers in the 1950s represented the first major – and arguably only significant – advance in schizophrenia treatment until atypical antipsychotics entered the market in earnest in the 1990s. By helping reduce patients’ “positive symptoms” of hallucinations and delusions, dopamine-blocking drugs like haloperidol and fluphenazine quickly rose to dominate the treatment market.
Despite their impact, these medications left significant gaps. They often involved damaging side effects, including extrapyramidal (motor control) issues, metabolic disorders and cardiovascular complications, while having little impact on the negative and cognitive symptoms of the disease. The introduction of atypical antipsychotics like risperidone and olanzapine reduced some of the more severe side motor effects but often incurred more metabolic issues. While they helped to expand treatment options, by also relying on modulating dopamine, the underlying paradigm of treatment did not change.
The winds of change
The US Food & Drug Administration’s recent approval of xanomeline/trospium chloride (CobenfyTM) marks a turning point in the battle against schizophrenia. Instead of targeting dopamine, it targets cholinergic receptors and stimulates the muscarinic system, bypassing dopamine receptors entirely to activate the specific receptors in the brain that influence cognition and psychosis.
This opens new possibilities for patients and physicians in a field where alternative options have been limited for far too long. Clinical trials have shown the efficacy of Cobenfy to be comparable to or better than current antipsychotics. Early indications suggest it may have some pro-cognitive benefits as well, without the movement disorders that typically accompany dopamine antagonists.
The approval of Cobenfy shows that the schizophrenia treatment landscape is ripe for change and opens the door for innovators to explore alternative approaches that may break our longstanding overreliance on dopamine therapies.
While muscarinic drugs are understandably gaining significant attention, they are only part of a larger wave of innovation. Other molecular mechanisms are under investigation as drug developers recognize the commercial opportunity for new medications that may be even more effective while having fewer side effects. Digital therapies are also starting to make inroads, with Click Therapeutics and Boehringer Ingelheim reporting promising results in a recent trial of CT-155 addressing negative symptoms.
Despite these significant advances, several pressing needs remain. Patients often only partially respond to these therapies, particularly when it comes to cognition and motivation. Stigma towards schizophrenia patients also persists, driven by an outdated cultural narrative and sensationalist depictions that continue to portray them as dangerous. This is despite the reality that, when treated properly, schizophrenia patients are more likely to be the victims of crime than perpetrators.
These challenges highlight the need for continued innovation in schizophrenia treatment; in particular, the development of solutions that, beyond managing symptoms, can change the long-term trajectory of the disease.
The promise of synaptic regeneration
Increasing evidence has emerged showing synapse loss to be a critical pathology in schizophrenia. Postmortem tissue and brain imaging studies from individuals with schizophrenia have revealed significant reductions in neural connections in brain regions like the prefrontal cortex and hippocampus, which are fundamental for cognition and emotion.
This anomaly in synaptic connectivity reveals an opportunity for therapeutic intervention beyond symptom relief. Restoring synapses could “rewire” the neural circuits disrupted by schizophrenia, enabling the development of new connections to help mitigate some of the underlying pathology of the disease.
Studies of other neurodegenerative disorders suggest this is possible. Experimental therapies to enhance synaptic density in Alzheimer's and ALS patients have shown functional improvement, suggesting that synaptic regeneration in schizophrenia could promote broader functional recovery.
This approach could mitigate the negative and cognitive symptoms that are often resistant to current therapies. The potential benefits are substantial in helping reduce the risk of relapse and hospitalization. Meanwhile, the possibility to improve cognition, motivation and social engagement would be a paradigm shift from mere symptom management to long-term functional recovery.
Looking ahead: Wider implications of synaptic regeneration
The prospect of synaptic regeneration will require us to start rethinking treatment strategies. As each psychotic episode is thought to contribute to cumulative damage to the brain, early intervention may become even more critical. Thus, the ability to preserve or restore synapses may change the course of the disease, if applied before extensive deterioration can set in.
The approval of muscarinic-targeting drugs like Cobenfy has already catalyzed the industry, signaling to stakeholders that the schizophrenia market is no longer static and encouraging more players to enter the space. Synaptic regeneration could serve as a similar turning point, resulting in greater investment in new treatment approaches.
Schizophrenia remains a complex and challenging illness, placing a heavy burden on patients, their families and caregivers. With the introduction of muscarinic drugs and digital therapies demonstrating that new treatment mechanisms can succeed, the field is finally beginning to shift.
Building on these achievements, synaptic regeneration has the potential to further redefine treatment, from controlling psychosis to restoring the neuronal networks fundamental to cognition and motivation to improve patients’ quality of life. Finally, schizophrenia research is moving beyond dopamine, toward strategies that could alter the course of the disease itself.
