We’ve moved far beyond the monoamine hypothesis. Modern neuroscience reframes depression as a disorder of impaired neuroplasticity and dysregulated network connectivity—particularly in the hippocampus, prefrontal cortex, and anterior cingulate cortex (Campbell et al., 2004; Bora et al., 2012).
TMS and Spravato don’t just alter neurotransmitter levels; they catalyze neuroplasticity.
Both treatments can rapidly elevate BDNF (Chen et al., 2001; Duman & Monteggia, 2006), enhancing synaptogenesis, dendritic branching, and functional connectivity. These effects are often particularly robust in circuits implicated in emotional regulation, memory encoding, and salience processing.
Per the REBUS model (Carhart-Harris & Friston, 2020), these interventions can relax high-level priors in the default mode network—loosening rigid self-referential patterns and maladaptive predictive coding. Clinically, this can be experienced as a momentary break from depressive identity formation—creating fertile ground for new learning.
TMS and Spravato can create a transient period of increased cortical malleability. If leveraged with targeted psychotherapeutic intervention (CBT, DBT, ACT, mindfulness), the patient is more likely to consolidate adaptive neural circuits.
This could be the psychophysiological equivalent of “lifting weights on steroids”—the combination of synaptic rewiring and behavioral reinforcement often both accelerates and sustains recovery.
Programs that integrate interventional psychiatry, psychotherapy, and psychopharmacology are uniquely positioned to deliver long-term remission. Clinicians who recognize the neurobiological window that can be opened by TMS and Spravato—and pair it with structured therapy—are driving the next evolution of psychiatric care.
This isn’t just a treatment shift. It’s a paradigm shift.
Chen, G., Rajkowska, G., Du, F., Seraji-Bozorgzad, N., & Manji, H. K. (2000). Enhancement of hippocampal neurogenesis by lithium. Journal of Neurochemistry, 75(4), 1729–1734. https://doi.org/10.1046/j.1471-4159.2000.0751729.x
Duman, R. S., & Monteggia, L. M. (2006). A neurotrophic model for stress-related mood disorders. Biological Psychiatry, 59(12), 1116–1127. https://doi.org/10.1016/j.biopsych.2006.02.013
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