Why Some Patients Respond Better to Ketamine

One of the most common questions patients ask before starting ketamine therapy is straightforward: will it work for me? The honest answer is that while ketamine has strong overall efficacy for treatment-resistant depression — and Isha Health's published data shows an 88.8% improvement rate — individual responses vary. Some patients experience profound and rapid improvement. Others respond more modestly or not at all. A 2026 pilot study by Krivosova and colleagues, published in Frontiers in Pharmacology, begins to illuminate why.

The pharmacogenetics question

Pharmacogenetics is the study of how genetic variation influences an individual's response to medications. It is already clinically relevant in fields like oncology and cardiology, where genetic testing can predict whether a patient will benefit from a specific drug or experience adverse effects. For ketamine and esketamine, pharmacogenetic research is still in its early stages — but the Krivosova study represents an important step forward.

The study examined genetic, clinical, and demographic variables in patients receiving intranasal esketamine (Spravato) for treatment-resistant depression, with the goal of identifying factors that predict treatment response.

Genetic factors: NMDA receptors and drug metabolism

Ketamine's primary mechanism of action involves blocking NMDA receptors in the brain, which triggers a cascade of downstream effects including increased BDNF release, enhanced synaptic plasticity, and modulation of glutamate signaling. But NMDA receptors are not identical across individuals. Genetic variations — known as polymorphisms — in the genes encoding NMDA receptor subunits (particularly GRIN2A and GRIN2B) can alter receptor structure and function, potentially influencing how effectively ketamine engages its primary target.

The Krivosova study also examined polymorphisms in genes encoding drug-metabolizing enzymes, particularly cytochrome P450 enzymes (CYP2B6 and CYP3A4) that are involved in ketamine's hepatic metabolism. Patients who metabolize ketamine more rapidly may achieve lower effective brain concentrations at standard doses, while slow metabolizers may experience stronger or more prolonged effects. These differences in metabolic rate could explain why the same dose produces very different clinical outcomes in different patients.

Additionally, variations in genes related to BDNF signaling — the neuroplasticity pathway that ketamine activates — were examined as potential modulators of treatment response. The well-studied BDNF Val66Met polymorphism, which affects activity-dependent BDNF secretion, has been implicated in antidepressant response more broadly and may be relevant to ketamine specifically.

Clinical factors: who responds best?

Beyond genetics, the study identified several clinical variables associated with treatment response:

Severity of depression. Patients with more severe baseline depression (as measured by standardized scales) tended to show larger absolute improvements, though this partly reflects a statistical ceiling effect — there is simply more room for improvement when starting from a more severe baseline.

Treatment history. The number of prior failed antidepressant trials influenced response patterns. Interestingly, the relationship was not linear — patients who had failed two to three prior medications often showed the strongest responses, while those who had failed five or more had somewhat attenuated responses. This suggests that treatment resistance exists on a spectrum and that earlier intervention with ketamine may yield better outcomes.

Comorbidities. The presence of comorbid anxiety appeared to modestly influence esketamine response, as did the presence of chronic pain conditions — consistent with research on ketamine's dual pain and mood mechanisms.

Demographic factors: age and sex

The study found that age and biological sex were both associated with response patterns. Younger patients tended to show somewhat faster initial response, while older patients sometimes required additional sessions to achieve comparable outcomes. Sex-based differences in ketamine metabolism — women generally have higher CYP3A4 activity — may contribute to differential dosing needs, though the study was not powered to make definitive claims on this point.

What this means for personalized ketamine therapy

The Krivosova study is a pilot — its sample size is modest and its findings require replication in larger cohorts. But its central message is clinically significant: ketamine response is not random. It is influenced by identifiable biological and clinical variables, which means that treatment can, in principle, be personalized to optimize outcomes.

This aligns directly with Isha Health's clinical approach. Rather than applying a one-size-fits-all protocol, our physicians tailor treatment based on individual patient characteristics — including symptom severity, treatment history, comorbid conditions, and observed response to initial sessions. Understanding the different forms of ketamine — racemic ketamine, S-ketamine, and R-ketamine — is part of this equation, as each may have distinct pharmacological profiles that interact differently with individual patient biology.

As pharmacogenetic research matures, it is plausible that genetic testing will eventually become a standard part of pre-treatment assessment for ketamine therapy — similar to how HER2 testing guides breast cancer treatment selection. We are not there yet, but studies like this one bring that possibility closer.

The bottom line

The question of why some patients respond better to ketamine than others is not a mystery — it is a research problem with identifiable variables. Genetic differences in NMDA receptors and drug-metabolizing enzymes, clinical factors like depression severity and treatment history, and demographic variables all contribute. For patients considering ketamine therapy, the practical takeaway is that working with a physician-led program that can adjust protocols based on individual response — rather than a fixed, one-size-fits-all approach — is likely to produce the best outcomes.

Reference: Krivosova M, et al. "Pharmacogenetic predictors of esketamine treatment response in treatment-resistant depression: a pilot study." Frontiers in Pharmacology. 2026.

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