Neuroplasticity, Novel Targets, and the Future of Depression Pharmacotherapy

Jason Kellogg, MD, discussed emerging mechanistic targets and investigational agents in the treatment of major depressive disorder (MDD), with a focus on neuroplasticity, synaptogenesis, and the movement toward precision psychiatry. Kellogg presented on agents in MDD at the 2026 Southern California Psychiatry conference.

Kellogg described a conceptual framework for depression that has evolved substantially beyond monoamine dysregulation. He characterized the depressed brain as undergoing a form of active neurological compromise—one in which synaptic connectivity is impaired, neurons are not communicating optimally, and the downstream consequences manifest as the clinical syndrome of depression. He illustrated this concept with a patient's spontaneous description of his own illness: that his "noodles"—neurons—were not talking to each other the way everyone else's were, a formulation Kellogg offered as an accessible and accurate lay model of the neuroplasticity hypothesis of depression.

Kellogg traced the historical arc of the field's mechanistic understanding—from serotonergic monoamine reuptake inhibition, through dopaminergic and noradrenergic targets, to glutamate receptor antagonism—and described the current frontier as encompassing brain-derived neurotrophic factor signaling, sigma-1 receptor agonism, and mammalian target of rapamycin pathway activation, all of which converge on the shared goal of enhancing synaptogenesis and restoring neural circuit connectivity.¹ He expressed enthusiasm for the direction the field is taking, noting that the diversity of emerging mechanisms reflects a growing recognition that depression is not a single, uniform condition but a heterogeneous syndrome; he noted this is analogous to oncology, where individual tumors vary substantially in their molecular drivers even when grouped under the same diagnostic label.

Kellogg identified the development of validated biomarkers as the critical missing piece preventing the field from fully realizing a precision psychiatry model for depression. He acknowledged that some phenotypic differentiation is already occurring in clinical practice—distinguishing, for example, lethargic from anxious presentations—but noted that no algorithmic or biomarker-guided standard of care currently exists.² He expressed optimism that this gap is recognized and that meaningful progress is underway.

Dr Kellogg is founder and chief executive officer of Progyny Psychiatric Group.

References

1. Pardossi S, Fagiolini A, Cuomo A. Variations in BDNF and their role in the neurotrophic antidepressant mechanisms of ketamine and esketamine: a review. Int J Mol Sci. 2024;25(23):13098.

2. Comai S, Manchia M, Bosia M, et al. Moving toward precision and personalized treatment strategies in psychiatry. Int J Neuropsychopharmacol. 2025;28(5).