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IV Ketamine vs. Nasal Spravato (Esketamine): In-Depth Comparison for Depression Treatment

Let's gain a deeper understanding and conduct a side-by-side comparison of intravenous (IV) generic ketamine, also known as racemic ketamine, versus Esketamine, marketed under the brand name Spravato, which is administered via the nasal route. A thorough comparison of IV ketamine and Spravato for the treatment of depression requires examining various aspects such as their mechanism of action, indications, routes of administration, efficacy, side effects, and cost implications. Both IV ketamine and Spravato are renowned for their rapid-acting antidepressant effects, yet they are utilized in distinct clinical settings and come with differing FDA approvals and usage guidelines.



Ketamine acts as an NMDA receptor antagonist, which is thought to be responsible for its antidepressant effects. This action is believed to increase the amount of glutamate between neurons, leading to improved synapse function and mood improvement.


IV Generic Ketamine:

Originally approved for anesthesia, IV ketamine is used off-label for over two decades for treatment-resistant depression (TRD) chronic pain, and certain psychiatric disorders including anxiety, post traumatic stress disorder (PTSD), substance abuse, obsessive compulsive disorder (OCD) and more. It requires administration in a clinical setting under medical supervision. It includes both the R and K-enantiomers of ketamine (refer to chart for more details).

Spravato (Esketamine Nasal Spray):

Specifically approved by the FDA for treatment-resistant depression (in conjunction with an oral antidepressant) and depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior. It sole contains the S-enantiomer of ketamine.


IV Generic Ketamine:

Administered via IV infusion in a clinical setting, typically over 40-60 minutes. Requires monitoring by healthcare professionals during and after administration. Clinics offering IV ketamine, such as Innerbloom Ketamine Therapy, often recognize the critical importance of creating a holistic approach, with meticulous attention to set and setting. Additionally, many IV ketamine clinics offer and encourage psychotherapy in conjunction with ketamine therapy to maximize therapeutic potential and achieve lasting effects.


Administered as a nasal spray in a certified doctor's office or clinic, the process may lack any sense of preparation, attention to set and setting, or integration of such guidance with psychotherapy support. Patients must be monitored by healthcare professionals for at least 2 hours after administration due to potential sedation and dissociation effects.


IV Generic Ketamine:

Shown to have rapid antidepressant effects, often within hours to days, in individuals with treatment-resistant depression. Regarding efficacy, numerous studies have demonstrated that IV ketamine surpasses other administration routes, including oral and nasal forms, with an expected response rate of 75-80% when used for the treatment of depression.


Clinical trials have demonstrated its efficacy in reduction of depressive symptoms and suicidal thoughts in patients with treatment-resistant depression. The number of treatments administered to achieve remission is greater than IV ketamine. Response rates to be expected for nasal ketamine are between 35-50%.



Can cause dissociation, dizziness, nausea, increased blood pressure, sedation, and euphoria. The intensity and occurrence of these side effects can vary between the IV and nasal administration routes.

IV Generic Ketamine:

Side effects are closely monitored and managed in the clinical setting during and after infusion. 100% absorption (bioavailability) into the circulation allows for the use of lower doses and as such lower potential of side effects when compared to nasal ketamine which has a bioavailability of 40%


Requires a REMS (Risk Evaluation and Mitigation Strategy) program to ensure patient safety due to the risk of sedation and dissociation.


IV Generic Ketamine:

Certain clinics, like Innerbloom, offer patients the opportunity to obtain superbills, which are detailed invoices that patients can submit to their insurance companies in hopes of receiving reimbursement for their treatment expenses. In some cases, patients may be reimbursed for the full cost of their infusion therapy.


Since it is FDA-approved for specific indications, it is more likely to be covered by insurance. However, the cost can still pose a barrier for some patients and represents a substantial burden to the healthcare system, with a single dose costing approximately $800. Due to its Risk Evaluation and Mitigation Strategy (REMS) program, treatment must be administered in a certified medical office or clinic.

Chart comparing nasal esketamine (spravato) to IV ketamine
Key differences between IV ketamine and nasal Spravato


In summary, both IV generic ketamine and Spravato serve as ketamine-based treatments for depression, yet they diverge in aspects such as FDA approval status, modes of administration, monitoring necessities, and potentially in their side effect profiles and costs.

IV ketamine is distinguished by its wider application in off-label uses for various conditions beyond depression, thanks to its precise and controlled administration. This allows medical providers to customize dosages according to the specific needs of each patient. Such precision in dosing is crucial, as it significantly reduces the risk of side effects and enhances therapeutic outcomes—a process that can prove more cumbersome with Spravato due to its variable bioavailability, absorption rates, and restricted dosage options. The immediate and predictable response afforded by IV ketamine presents a distinct advantage in clinical settings, offering healthcare professionals unmatched control and the capacity to modify dosages in real-time based on patient feedback.

What do the experts say? UpToDate, the most widely used and respected medical reference, highlights these distinctions by recommending generic IV ketamine over electroconvulsive therapy (ECT) and nasal Spravato for the treatment of resistant depression. This recommendation is based on IV ketamine's demonstrated effectiveness, safety, and a lower rate of adverse effects, solidifying its status as the preferred treatment approach among healthcare professionals seeking the most efficacious intervention for their patients. This endorsement reflects a growing agreement on IV ketamine's superior clinical potential, making it the preferred treatment approach among healthcare professionals seeking the most efficacious intervention for their patients confronting the challenges of treatment-resistant depression.

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