The new anti-psychotic lumateperone was developed to treat schizophrenia and bipolar I and II disorder in adults. However, when prescribed patients also showed improved depressive symptoms, hinting that the drug has some unknown tricks up its sleeve.
Released by Intra-Cellular Therapies as Capylta in 2020, research from the company at the close of 2022 suggests that other mental health populations could benefit from the drug’s wide variety of newly uncovered impacts.
Image by Asep Saeful Bahri via Pexel
For a longtime, the fatigue, anhedonia, and depressed mood experienced by sick people were thought to be caused by the disease itself. Now we know that “sickness behavior” is a bodily response to infection. Making cytokines to cause discomfort is a clever and cruel way our bodies make us stay in bed and recover. It’s now theorized the same inflammatory mechanisms that cause behavior changes during infection could contribute to depression symptoms.
Inspired by the growing popularity of the inflammatory hypothesis of depression, researchers at Intra-Cellular Therapies are now discovering just how their drug works.
This backward order of events is far from unusual in mood-disorder drug development. With little understanding of how these disorders affect the brain, it has been impossible to execute more than a scatter-shot approach to drug discovery for centuries. At least now, drug mechanisms of action are being uncovered two years rather than two centuries later.
On top of modulating multiple neurotransmitters, this study discovered new inflammatory-mitigating activities of lumateperone. The anti-psychotic was delivered to acutely stressed or immune-challenged rodents, and it reduced the usual stress-induced proinflammatory cytokine response in a dose-dependent manner. These are the same cytokines that increased in many psychiatric disorders.
While the order of events and mechanisms are unclear, measurable changes in genes and pathways hint at the underlying mechanisms of action. One outcome of treatment was the central nervous system’s personal immune system cells, the microglia, decreased their transcription of proinflammatory genes. The drug treatment also somehow maintained the permeability of the blood-brain barrier in the face of stressful onslaughts.
Perhaps an outcome of these brain changes, treated animals continued to demonstrate interest in pleasurable and engaging experiences (lower rates of anhedonia) including social ones. And finally, lumateperone enhanced the activity of the mTORC1 pathway. A multiprotein complex, mTORC1 is thought to influence synaptic plasticity by regulating the transcription of various neurotropic molecules.
This article from Intra-Cellular Terapies and Dutheil et al. found that lumateperone interacted with immune/inflammatory pathways and improved depression-like behavior in rats and mice (2022). Further research will hopefully provide more insight on the multiple actions of this jack-of-all-trades drug.
Sources: Journal Neuroscience, Psychopharmacology Bulletin, BioMed Central Medicine, International Journal of Molecular Sciences