Ketamine vs Esketamine (Spravato®) for Depression: What’s the Difference and Which Works Better?

Ketamine and esketamine are two of the most important recent advances in the treatment of treatment-resistant depression (TRD). Both move beyond monoaminergic mechanisms of action and act on the glutamate system in the brain, helping restore connections in areas involved in mood, stress, and emotional regulation.

While they are closely related, they are not the same treatment. Understanding their differences can help patients and clinicians make better treatment decisions.

What are Ketamine and Esketamine?

Ketamine, or racemic ketamine, is a well-established medication that has been used in medicine for decades. It is a racemic compound containing both R- and S-enantiomers. At low (sub-anaesthetic) doses, it has powerful antidepressant effects and can also be used for chronic pain. Ketamine is typically delivered via intravenous (IV) infusion, but can also be delivered subcutaneously (SC), intramuscularly (IM), orally or rectally.

Esketamine is a more recent development. It is a modified version of ketamine (specifically one part of the molecule), containing only one component (the S-enantiomer). It is delivered as a nasal spray (Spravato®) and is currently the only form approved by the TGA for treatment-resistant depression. Esketamine has greater affinity for the NMDA receptor, which initially supported its development as a targeted antidepressant. However, this does not translate directly into superior clinical efficacy and emerging evidence has complicated this assumption.

Which one is more effective?

The key question is whether one is more effective than the other.

Across multiple studies, the answer is nuanced.

Both ketamine and esketamine have been shown to significantly reduce depressive symptoms in people with TRD. Real-world observational data demonstrates that both treatments produce meaningful improvements in depression severity and suicidal ideation, with generally good tolerability profiles.

However, when compared, a consistent pattern emerges. Several studies showing that intravenous ketamine may produce a greater magnitude of symptom reduction, a faster response and more durable effects.

A large retrospective study found that IV ketamine was superior in both speed and magnitude of response, with reduced depression scores by approximately 49% compared to 39% with esketamine over a similar treatment period (Meisner et al., 2025).

Another study showed that while overall response and remission rates were similar, patients receiving ketamine achieved remission significantly faster (Singh et al., 2023).

D’Andrea et al. (2024) showed IV ketamine had higher response rates and larger effect sizes.

Terao et al (2024) found IV ketamine to be more effective than esketamine and aripiprazole and was comparable to lithium, suggesting IV ketamine should be at the top of the augmentation hierarchy.

An early meta-analysis reported higher response rates, higher remission rates and lower dropout rates with ketamine compared to esketamine (Bahji et al., 2021). A later meta-analysis of 49 randomised controlled trials also found that racemic ketamine consistently produced larger effect sizes and more sustained antidepressant effects than esketamine (Nikolin et al., 2023).

Nikolin et al (2023) also showed that esketamine effects were weaker during repeated dosing, suggesting that ketamine may hold a durability advantage over esketamine.

Which works faster?

One of the most important differences is speed of response.

IV ketamine often produces improvement after the first treatment, whereas esketamine may take multiple sessions before significant effects are seen (Meisner et al., 2025).

This is particularly important for patients with:

·        Severe depression

·        High levels of distress

·        Suicidal ideation

In these situations, a faster-acting treatment can be clinically critical.

Are the effects long-lasting?

The durability of antidepressant response is also a critical consideration.

Emerging evidence suggests that ketamine may have more durable antidepressant effects, particularly when delivered as a series of treatments.

Nikolin et al. (2023) meta-analysis found that ketamine maintained significant effects during ongoing treatment and at follow-up, whereas esketamine’s effects were less consistent over time.

However, both treatments typically require maintenance therapy to sustain benefits.

Safety and side effects

Both ketamine and esketamine are generally safe and well tolerated when delivered in a controlled clinical setting.

Studies show:

·        Similar rates of side effects overall (Gutierrez et al., 2024)

·        Mostly mild and transient symptoms (e.g. dizziness, dissociation)

·        No significant difference in treatment discontinuation rates (D’Andrea et al., 2024)

Esketamine may have slightly fewer acute side effects due to lower dosing and its nasal delivery method, but this difference is not large. With no strong evidence from these studies to suggest a meaningful difference in safety when appropriately administered.

Which has stronger scientific evidence?

A key difference between ketamine and esketamine is the strength and history of the evidence base.

Ketamine has been studied for over 20 years in depression, with:

·        Numerous clinical trials

·        Multiple meta-analyses

·        Extensive real-world data

Esketamine is newer and has a more limited evidence base, largely derived from industry-sponsored trials.

Some researchers have raised concerns about esketamine studies. In particular, the difference between esketamine and placebo is often modest, and in some trials the clinical benefit has been questioned despite statistical significance.

In contrast, ketamine studies tend to show larger and more consistent effect sizes across different patient populations (Nikolin et al., 2023; Bahji et al., 2021).

Why might ketamine be more effective?

Both ketamine and esketamine ultimately converge on a shared pathway: NMDA receptor antagonism leading to increased glutamate release, AMPA receptor activation, and synaptic plasticity. Yet their molecular structure, clinical delivery and pharmacokinetics differ substantially, which may all contribute to the observed outcome differences.

First, route of administration may play a significant role. Intravenous delivery results in 100% bioavailability, allowing precise and consistent dosing. In contrast, intranasal esketamine has more variable absorption, which can lead to less predictable drug exposure between patients.

Second, ketamine is a racemic mixture, containing both R- and S-enantiomers (as well as effects on other neurotransmitters). Esketamine contains only the S-enantiomer. Emerging evidence suggests that the R-enantiomer may contribute meaningfully to antidepressant effects and may be associated with longer-lasting benefits and downstream synaptic changes, meaning esketamine may represent only part of the therapeutic potential of ketamine. Ketamine’s action on other neurotransmitters (serotonin, opioid system) may also be influencing the antidepressant effect. This has led to the hypothesis that racemic ketamine’s broader pharmacodynamic profile may underlie its stronger and more sustained clinical effects.

Third, intravenous ketamine allows for individualised dose titration, enabling clinicians to adjust treatment based on response and tolerability. Flexible dosing regimens are an essential part of treatment with ketamine therapy (Loo et al., 2023). Esketamine can only be delivered in fixed doses, which may limit flexibility in clinical practice.

Finally, ketamine’s rapid effects are thought to relate to its robust modulation of glutamatergic signalling and downstream neuroplasticity pathways, including BDNF and mTOR activation. While both ketamine and esketamine act on these systems, differences in pharmacokinetics and receptor engagement may contribute to the observed differences in clinical response.

While all these factors likely work together to explain why ketamine often produces faster and more pronounced antidepressant effects in real-world settings, these differences do not negate esketamine’s efficacy. Careful patient selection remains an essential determinant of outcome. With treatment outcomes depending heavily on individual patient factors, including severity of depression, prior treatment failures, and comorbid conditions (Elmaadawi et al., 2025).

So which is better: ketamine or esketamine?

Both treatments are effective, but they are not identical. And whilst the comparative efficacy of ketamine and esketamine is still under research, when we look at the available studies, a consistent pattern emerges.

1.  Ketamine (IV infusion)

·        Faster onset of action

·        Greater reduction in symptoms

·        Potentially more durable & consistent outcomes

2.  Esketamine (nasal spray)

·        TGA-approved and standardised

·        Slightly simpler delivery

·        Response may be more variable

Importantly, some studies show similar overall remission rates between the two treatments, suggesting that both can ultimately achieve comparable clinical endpoints (Nikayin et al., 2022).

The future of treatment: personalised care

Ketamine and esketamine are closely related treatments with shared mechanisms but distinct clinical profiles. Ketamine offers greater magnitude and speed of response, with more consistent outcomes. Esketamine provides a standardised, regulated treatment pathway, with demonstrated efficacy.

However, the future of mental health care lies in personalised treatment approaches. Optimal care requires matching the treatment to the patient, rather than applying a single approach universally. This means selecting therapies based on:

·        Clinical history

·        Biological factors

·        Treatment response patterns

One of the most important insights comes from Elmaadawi et al. (2025), which examined predictors of response to both ketamine and esketamine. This study highlighted that:

·        Not all patients respond equally to either treatment

·        Clinical factors influence whether a patient responds better to ketamine or esketamine

·        A personalised approach to treatment selection is essential

This supports a shift away from viewing these therapies as interchangeable, toward a precision-based model of care.

Both ketamine and esketamine have a role to play — but the goal is to match the right treatment to the right patient at the right time. As the field evolves, the focus is shifting toward precision medicine, where treatment selection is guided by patient characteristics, response patterns, and clinical context. 

References

Nikayin S, Rhee TG, Cunningham ME, de Fontnouvelle CA, Ostroff RB, Sanacora G, Wilkinson ST. Evaluation of the trajectory of depression severity with ketamine and esketamine treatment in a clinical setting. JAMA Psychiatry. 2022;79(7):736–738.

Singh B, Kung S, Pazdernik V, Schak KM, Geske J, Schulte PJ, Frye MA, Vande Voort JL. Comparative effectiveness of intravenous ketamine and intranasal esketamine in clinical practice among patients with treatment-refractory depression: An observational study. J Clin Psychiatry. 2023;84(2):22m14548.

Meisner R, Li S, Boyle B, Valdivia V, Sedgewick A, Dai D, Miller C, Bolton P, Seiner S. Comparative effects of repeated ketamine infusion versus intranasal esketamine in patients with treatment-resistant depression: A retrospective chart review. J Clin Psychiatry. 2025;86(4):25m15789.

Elmaadawi AZ, Naha I, Prabhudesai S, Eltohamy M. Personalizing ketamine therapy: Real-world predictors of response to IV ketamine and intranasal esketamine in treatment-resistant depression. Psychiatry Res. 2025;354:116821.

Gutierrez G, Swainson J, Ravindran N, Lam RW, Giacobbe P, Karthikeyan G, Kowara A, Do A, Baskaran A, Nestor SM, Kang MJY, Biorac A, Vazquez G. Intravenous ketamine and intranasal esketamine: Results of a multi-site observational study assessing effectiveness and tolerability in treatment-resistant depression. Psychiatry Res. 2024;340:116125.

D’Andrea G, Pettorruso M, Di Lorenzo G, Rhee TG, Chiappini S, Carullo R, Barlati S, Zanardi R, Rosso G, Di Nicola M, Andriola I, Marcatili M, Clerici M, Dell’Osso BM, Sensi SL, Mansur RB, Rosenblat JD, Martinotti G, McIntyre RS. The rapid antidepressant effectiveness of repeated dose intravenous ketamine and intranasal esketamine: A post-hoc analysis of pooled real-world data. J Affect Disord. 2024;348:314–322.

Terao I, Tsuge T, Endo K, Kodama W. Comparative efficacy, tolerability and acceptability of intravenous racemic ketamine with intranasal esketamine, aripiprazole and lithium as augmentative treatments for treatment-resistant unipolar depression: A systematic review and network meta-analysis. J Affect Disord. 2024.

Nikolin S, Rodgers A, Schwaab A, Bahji A, Zarate CA Jr, Vazquez G, Loo C. Ketamine for the treatment of major depression: A systematic review and meta-analysis. eClinicalMedicine. 2023;62:102127.

Bahji A, Vazquez GH, Zarate CA Jr. Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis. J Affect Disord. 2021;278:542–555.

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