There is an ongoing need to develop new therapeutic options to treat schizophrenia using agents targeting novel receptor systems. The present treatments have multiple limitations including neurological and metabolic side-effects. Besides, current strategies have not treated negative symptoms which are enduring and responsible for long-term debilitation due to this disease state. Our current treatments do not put patients with schizophrenia back to work.
The limitations include a small number of sites (12), and lack of ethnic diversity (70% black population) as the trial was conducted in urban centers. The entire study was done as an inpatient which does not simulate the real world and compliance issues are managed in the inpatient setting. There were only two groups, as the trial which did not include an assay drug group for trial validity. Nevertheless, this trial brings hope to clinicians and patients.
- Xanomeline targets novel receptors M1 and M4 which are implicated in schizophrenia, and its cholinergic side-effects are mitigated by trospium a peripherally restricted muscarinic receptor antagonist. Xanomeline lacks action on the dopamine receptor and hence lacks neurological side-effects.
- The discontinuation rate from adverse events was similar in the active drug and placebo group suggesting good tolerability.
- Common adverse events were constipation, nausea, dry mouth, dyspepsia, and vomiting both cholinergic and anticholinergic.
- Extrapyramidal side-effects, weight gain, QTc prolongation, and metabolic issues were no different than placebo which important from the clinical perspective.
- The improvement in negative symptoms is an important finding as this group of symptoms is responsible for long-term debilitation in schizophrenia which persists after treating the positive symptoms with the currently available antipsychotics (do not treat negative symptoms).
- It is a concept of using two drugs xanomeline for acute symptom treatment and trospium for managing the peripheral anticholinergic-side effects. This feels like using a first-generation antipsychotic with benztropine to manage tremors or a second-generation antipsychotic with metformin to manage weight and hyperglycemia issues. In psychiatry, we are familiar with these concepts. The question is how far ahead are patients with this combination in the domain of day-to-day functioning, relationships, quality of life, and gainful employment (functional integration). The answer to this issue will only be known once there is FDA approval and we have had a chance to try the drug in the real world.
I suggest that the readership stay tuned to more research-related news regarding this novel compound a potential treatment for schizophrenia. This trial shows efficacy not only against positive but also negative symptoms. The negative symptoms have been enduring, tough to treat, and responsible for the significant dysfunction caused by this illness. The side effect profile is also highly favorable in regard to metabolic issues, weight, and cardiac issues such as QTc (no different than placebo).