If you’re considering ketamine therapy at Mindful Infusions in Salt Lake City or trying to understand what your provider is recommending, one of the most empowering things you can do is understand the mechanism. You do not need a neuroscience degree to benefit from treatment, but understanding how and why ketamine works differently from conventional antidepressants can help you make sense of your experience and set realistic expectations. At our clinic, we take time to explain the neuroscience to every patient who wants it, in language that does not require a medical background.
Ketamine has been used as an anesthetic for decades. Its emergence as a psychiatric treatment represents a significant development in mental health medicine, supported by decades of academic research. Here on the Wasatch Front, where Utah continues to face mental health provider shortages, understanding the mechanism can help patients advocate for themselves in conversations with their care teams (Kem C. Gardner Policy Institute, 2024).
The Problem with the Serotonin Model
Most people are familiar with the serotonin hypothesis of depression, the idea that depression results from insufficient serotonin activity and that SSRIs help by increasing serotonin availability at synapses. This model shaped antidepressant development for decades and produced treatments that help many people. But it is incomplete. Many people with depression do not respond adequately to initial antidepressant treatments, and the biological reasons are more complex than serotonin signaling alone.
The glutamate system, long overlooked in psychiatric treatment, is now central to current models of depression, including the role of NMDA, or N-methyl-D-aspartate, receptors. This is where ketamine enters the picture (Duman et al., 2019). If you’re curious about how researchers and clinicians have come to understand these limitations, our overview of how ketamine therapy works in the brain for depression relief offers additional context.
NMDA Receptor Antagonism: Ketamine’s Core Mechanism
Ketamine is an NMDA receptor antagonist. NMDA receptors are a type of glutamate receptor and are important for regulating synaptic strength, learning, memory, and emotional processing. Dysregulation in these systems has been linked with stress- and depression-related synaptic deficits (Duman et al., 2019).
By reducing NMDA receptor signaling, ketamine triggers a downstream cascade that includes increased AMPA receptor activity, BDNF signaling, and mTOR-related synaptic protein synthesis. These changes are thought to contribute to rapid synaptic plasticity (Duman et al., 2019).
Synaptic Plasticity: The Mechanism Behind Rapid Relief
Synaptic plasticity refers to the brain’s ability to strengthen and reorganize connections between neurons. Depression and chronic stress are associated with synaptic deficits, particularly in prefrontal circuits involved in executive function and emotional regulation. Conventional antidepressant effects often take weeks to emerge (Duman et al., 2019; Zarate et al., 2006).
Preclinical research suggests ketamine can rapidly increase synaptic connectivity in prefrontal regions. Clinical studies have separately documented antidepressant effects that can emerge within hours of an infusion. In a landmark 2006 trial, Zarate and colleagues found significant antidepressant improvement within two hours after a single IV ketamine infusion in patients with treatment-resistant major depressive disorder (Zarate et al., 2006).
BDNF and the Neuroplasticity Window
BDNF, or brain-derived neurotrophic factor, supports the growth, maintenance, and differentiation of neurons and synaptic connections. Lower BDNF-related signaling has been implicated in depression, and ketamine’s rapid actions are thought to involve BDNF signaling and synaptic plasticity (Duman et al., 2019).
The idea of a post-infusion neuroplasticity window is promising but remains an area of active study. This is one reason many clinicians recommend engagement with psychotherapy alongside ketamine treatment. The hypothesis is that cognitive and behavioral work may be better supported during a period of enhanced plasticity, though more research is needed to clarify how this works in clinical care (Wilkinson et al., 2019). For patients interested in combining these approaches, our ketamine assisted psychotherapy in Salt Lake City, UT program is designed with this integration in mind. At Mindful Infusions, we discuss this concept with you and help you think about how to use the post-infusion period intentionally.
How This Applies to the Treatments We Offer
At Mindful Infusions, we offer both ketamine therapy for mood disorders and chronic pain for psychiatric conditions, which is used off-label, and SPRAVATO®, an esketamine nasal spray. SPRAVATO® is FDA-approved for treatment-resistant depression in adults and for depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior when used with an oral antidepressant (U.S. Food and Drug Administration [FDA], 2025).
Both treatments act at NMDA receptors, though their delivery routes, bioavailability, and protocols differ. SPRAVATO® uses esketamine, the S-enantiomer of ketamine, while IV ketamine uses racemic ketamine, which contains both S- and R-enantiomers. Research continues into the potential contributions of each enantiomer to antidepressant effects (Duman et al., 2019).
Understanding the neuroscience does not determine whether you’re a candidate. That determination comes from a thorough clinical evaluation. But it can help explain why results vary by individual, why ketamine’s effects can emerge faster than those of conventional antidepressants, and why psychotherapy may be considered alongside treatment. Discuss these details with your provider when determining the right treatment approach for your situation.
Key Takeaways
Ketamine works through NMDA receptor antagonism in the glutamate system, a fundamentally different mechanism than SSRIs, SNRIs, and other monoamine-targeting antidepressants (Duman et al., 2019).
NMDA receptor antagonism is associated with increased AMPA receptor activity, BDNF signaling, mTOR-related protein synthesis, and rapid synaptic plasticity (Duman et al., 2019).
Preclinical research supports rapid synaptic changes, while clinical antidepressant effects from IV ketamine can emerge within hours for some patients (Zarate et al., 2006).
The proposed neuroplasticity window following treatment may support psychotherapy, but this remains an area of active research (Wilkinson et al., 2019).
IV ketamine is used off-label for psychiatric conditions. SPRAVATO® is FDA-approved for specific depressive-disorder indications, and its administration protocols differ from IV ketamine (FDA, 2025).
If you’re trying to understand whether IV ketamine or SPRAVATO® might be right for you, we’re here to explain the neuroscience and help you evaluate your options based on your specific history. We serve patients throughout Salt Lake City and the Wasatch Front. Schedule a consultation to start the conversation.
References
Duman, R. S., Shinohara, R., Fogaça, M. V., & Hare, B. (2019). Neurobiology of rapid-acting antidepressants: Convergent effects on GluA1-synaptic function. Molecular Psychiatry, 24(12), 1816–1832. doi: 10.1038/s41380-019-0400-x. https://pubmed.ncbi.nlm.nih.gov/30894661/
Kem C. Gardner Policy Institute. (2024, March 18). Utah Behavioral Health Assessment & Master Plan. University of Utah. https://gardner.utah.edu/public-policy/health-care-and-life-sciences/utah-behavioral-health-assessment-master-plan/
U.S. Food and Drug Administration. (2025). SPRAVATO® (esketamine) nasal spray: Prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/211243s016lbl.pdf
Wilkinson, S. T., Holtzheimer, P. E., Gao, S., Kirwin, D. S., & Price, R. B. (2019). Leveraging neuroplasticity to enhance adaptive learning: The potential for synergistic somatic-behavioral treatment combinations to improve clinical outcomes in depression. Biological Psychiatry, 85(6), 454–465. doi: 10.1016/j.biopsych.2018.09.004. https://pubmed.ncbi.nlm.nih.gov/30528745/
Zarate, C. A., Jr., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., Charney, D. S., & Manji, H. K. (2006). A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Archives of General Psychiatry, 63(8), 856–864. doi: 10.1001/archpsyc.63.8.856. https://pubmed.ncbi.nlm.nih.gov/16894061/
Medical Disclaimer
The information in this blog is for educational purposes only and does not constitute medical advice. Ketamine infusion therapy and SPRAVATO® should only be pursued under the supervision of a licensed provider familiar with your full medical and psychiatric history. Individual results vary. SPRAVATO® is FDA-approved for specific indications; IV ketamine for psychiatric conditions is used off-label. If you are experiencing a mental health crisis or thoughts of self-harm, please call or text 988 to reach the Suicide and Crisis Lifeline or go to your nearest emergency room.