Depression is not a one-size-fits-all disorder. While many people find relief with traditional antidepressant treatments, approximately 30% of patients diagnosed with Major Depressive Disorder (MDD) fall into the category of Treatment-Resistant Depression (TRD). For these individuals, achieving remission can feel nearly impossible. Gaining a greater understanding of the different efficacy and mechanisms of esketamine vs ketamine will push us closer towards developing new MDD and TRD treatment modalities that could change countless lives. A new groundbreaking multi-site observational study, published in Psychiatry Research, explores the effectiveness and tolerability of these two novel therapies for TRD. Explore more about how they offer new hope and resilience to those for whom standard antidepressants have failed.
Understanding Treatment-Resistant Depression (TRD)
TRD is diagnosed when a patient does not respond to at least two adequate trials of antidepressant medications from different classes. For these patients, the traditional approach—targeting serotonin or norepinephrine—may not address the underlying neurobiological roots of their Depression.
The burden of TRD is severe. Individuals living with it generally face:
- Higher rates of suicide: Up to 15% of individuals with untreated TRD attempt suicide.
- Increased healthcare utilization: TRD can cause more frequent hospitalizations and the potential of long-term disability.
- Impaired quality of life: TRD affects relationships, employment, and overall functionality.
Introducing Esketamine vs Ketamine
Traditional antidepressants can take weeks to show noticeable effects, leaving patients vulnerable during that critical waiting period. This is where ketamine and esketamine offer a new, life-saving possibility, with rapid action and a novel mechanism that differs from standard treatments.
Though they are extremely similar, the main difference between esketamine and ketamine lies in their chemical composition; esketamine is a racemic mixture containing two molecules: S-ketamine (esketamine) and R-ketamine. Unlike ketamine, which has long been used as an anesthetic and is administered off-label for Depression, esketamine is FDA-approved specifically for TRD and Depression with suicidal ideation (MDSI).
What is the Difference Between Esketamine and Ketamine?
Since 2019, Mid City TMS has been proud to offer Spravato (esketamine) for patients with TRD. Spravato is the brand name for esketamine, a nasal spray that has proven effective and safe in both short-term and long-term studies.
Ketamine Vs Spravato
The difference between esketamine and ketamine extends beyond their chemical structure. Ketamine, a mixture of R- and S-ketamine, is usually administered intravenously, which can be effective but requires repeated IV insertions—sometimes three times a week—making it costly and inconvenient. Ketamine has not been FDA-approved for Depression, and as such, insurance does not cover it, leaving patients to pay out of pocket.
Esketamine, by contrast, is the isolated S-enantiomer, which is more potent at blocking NMDA receptors, allowing for lower dosing and potentially fewer side effects. Its FDA approval represents one key difference in the Spravato vs ketamine debate—Spravato is almost always covered by insurance, including Medicare.
Esketamine also has unique advantages in safety. It is one of the only drugs besides lithium proven to reduce suicidal thoughts. Unlike other antidepressants, which may temporarily increase suicidal thoughts when first prescribed, esketamine rapidly decreases them.
How Do Ketamine and Esketamine Work?
Both ketamine and esketamine are rapid-acting antidepressants that work through a different mechanism than conventional drugs. Traditional antidepressants increase levels of serotonin, norepinephrine, and dopamine, chemicals that help relay communication between brain cells. In contrast, ketamine and esketamine work primarily through the glutamate system, which plays a key role in synaptic plasticity and mood regulation.
Ketamine and Esketamine affect three main receptors:
- Opioid receptor: some research suggests that activation of opioid receptors is partially involved in ketamine’s and esketamine’s antidepressant effect.
- NMDA (N-methyl-D-asparate) receptor: this receptor manages synaptic plasticity–keeping your synapses pliable and able to retain information. Ketamine and esketamine block NMDA receptors in the brain and thereby increase levels of glutamate, the most abundant chemical messenger in the brain. Blocking NMDA receptors also activates AMPA receptors to release other molecules that help brain cells communicate with each other along new pathways. Known as synaptogenesis, this process likely affects mood, thought patterns, and cognition, including memory.
- AMPA (Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor: this receptor also uses glutamate, similarly to the NMDA receptor. The AMPA receptor manages and mediates fast-acting synaptic activity, such as memory and learning abilities. AMPA receptor abnormalities can contribute to behavioral health disorders, such as ADHD.
What Sets Ketamine and Esketamine Apart from Traditional Antidepressants?
- Speed: Effects can be seen within hours or days, compared to the weeks required for SSRIs or SNRIs.
- Unique Mechanism: By targeting the glutamate system, ketamine therapies provide relief for patients who do not respond to serotonin-based treatments.
- Impact on Suicidal Thoughts: Traditional antidepressants often take weeks to affect suicidal ideation (and come with certain long-term risks), whereas ketamine therapies can reduce such thoughts almost immediately.
Ketamine Vs Spravato – A Groundbreaking Multi-Site Observational Study on Efficacy
This study, published in Psychiatry Research in 2024, explored the effectiveness and tolerability of intravenous (IV) ketamine and intranasal (IN) esketamine. The study aimed to assess real-world outcomes for TRD patients receiving either IV ketamine or IN esketamine. By analyzing data across multiple clinical sites, the researchers sought to answer three key questions:
- How effective are IV ketamine and IN esketamine in reducing depressive symptoms?
- Do these therapies significantly reduce suicidal ideation?
- Are these treatments safe and well-tolerated by patients?
Patient Demographics and Protocols
The study included 53 patients diagnosed with TRD. These participants were divided into two groups:
IV Ketamine Group
- Number: 26 patients
- Gender: 69.23% female
- Age: Average of 52.81 years
IN Esketamine Group
- Number: 27 patients
- Gender: 51.85% female
- Age: Average of 43.93 years
IV ketamine was administered through infusion at specialized centers, while esketamine was delivered as a nasal spray combined with supervised sessions to ensure safety.
Assessment Tools
Researchers used several validated tools to assess outcomes, including the Montgomery and Åsberg Depression Rating Scale (MADRS) to track changes in Depression severity, MADRS item 10 to evaluate suicidal ideation, and the Clinician Administered Dissociative Symptom Scale (CADSS-6) to monitor dissociative side effects and tolerability.
Key Findings in the Difference Between Ketamine and Esketamine
The findings of this study suggest that both IV ketamine and IN esketamine are safe options when administered under medical supervision. Here’s what researchers observed in patients:
Rapid and Significant Reduction in Depressive Symptoms: Patients in both groups showed substantial improvements in their MADRS scores, indicating that both IV ketamine and IN esketamine effectively reduced depressive symptoms. This reduction was observed relatively quickly, aligning with the rapid-acting nature of ketamine-based treatments.
Reduction in Suicidal Ideation: One of the most significant findings was the dramatic decrease in suicidal thoughts reported by patients. Suicidal ideation, often resistant to traditional treatments, was significantly alleviated in both groups. This underscores the potential life-saving role of ketamine-based therapies for high-risk individuals.
Comparable and Favorable Tolerability: Both treatments were well-tolerated, with mild side effects such as dizziness, nausea, and transient dissociation.
No Discontinuations: Importantly, no patients discontinued treatment due to adverse effects.
Dissociation Scores: CADSS-6 assessments revealed no significant differences in dissociative symptoms between the two groups.
Additionally, the safety and efficacy of esketamine (Spravato) is supported by many short-term and long term studies. A 2020 study by Papakostas studied the use of esketamine in 774 people who were involved in 5 trials and showed that patients with MDD or MDSI who received Spravato treatments had a better outcome than those who received placebo. Our clinical experience at Mid City TMS since 2019 confirms these results, with many of our patients responding to Spravato treatment within just one to three sessions.
The Difference Between Spravato vs Ketamine Administration
Importantly, when it comes time to decide between ketamine vs Spravato, esketamine is more potent than ketamine, which allows doctors to give lower doses and potentially see fewer side effects. However, both ketamine and esketamine should be administered by a doctor as these drugs are DEA Schedule III controlled substances and can become highly addictive.
Because esketamine can only be administered by medically trained personnel, patients receive their treatment in a clinic, where they are monitored for about two hours before leaving. Short-term side effects typically peak at 40 minutes and wear off within two hours.
The recommended treatment schedule involves two sessions per week for the first four weeks, followed by weekly sessions, and eventually tapering to maintenance doses once every one to four weeks, and sometimes tapered gradually beyond that period and into discontinuation. However, for ketamine, there is no singular recommended administration schedule as it is still as yet unapproved by the FDA.
Practical Implications for Patients
The safety and efficacy of esketamine have been supported by extensive research, and patients can often see improvements within just a few sessions. These therapies may reduce hospitalization, improve daily functioning, and most importantly, provide rapid hope to those who have struggled with Depression for years.
However, challenges remain in understanding the Spravato vs ketamine paradigm, including questions about the long-term durability of effects, the optimal dosing schedule, and the cost of treatment. While IV ketamine continues to be used off-label, its lack of FDA approval means patients bear the financial burden. Esketamine, on the other hand, benefits from widespread insurance coverage and clear, structured administration guidelines.
Esketamine vs Ketamine: Insurance Coverage
Another difference between esketamine and ketamine lies in their insurance coverage options. Ketamine treatments for Depression are not covered by insurance companies because it’s experimental and not FDA approved. Therefore, patients must pay out of pocket for ketamine therapy.
On the other hand, Esketamine (Spravato) is almost always covered by insurance, including Medicare, because it is FDA-approved and well-studied to be effective and safe. To be considered eligible for insurance coverage for Esketamine (Spravato), a person usually has to have tried at least two other antidepressants without sufficient benefit or with intolerable side effects.
Both Esketamine and Ketamine Are Lifelines for Depression
In the Spravato vs ketamine debate, one thing is certain—both are not merely treatments, but represent lifelines for individuals battling the most severe forms of Depression. Their rapid onset, unique mechanism, and ability to reduce suicidal thoughts set them apart from traditional antidepressants. As research continues and access expands, they are becoming a cornerstone of modern psychiatric care.
For those living with treatment-resistant Depression, options like Spravato and TMS represent not just medical interventions but real hope for recovery. At Mid City TMS, we are proud to continue offering these innovative, research-backed treatments to help patients reclaim their lives.
Exploring Your Treatment Options with Mid City TMS
If you or someone you know is struggling with suicidal ideation or Treatment-Resistant Depression, consult a mental health professional to discuss esketamine vs ketamine and whether Spravato could be an appropriate option to explore within your MDD treatment plan.
At Mid City TMS, Spravato is offered alongside Transcranial Magnetic Stimulation (TMS), another FDA-approved, noninvasive, and highly effective option for MDD. TMS is widely covered by insurance and provides yet another pathway for those who have not found relief with standard medications.
With a team of highly trained professionals and the latest technology at our disposal, Mid City TMS is committed to providing individualized, meaningful, and evidence-based care. Contact us to begin your journey with Spravato treatment today.
Sources
- Vollenweider, F. X., & Kometer, M. (2022). The therapeutic potential of psychedelics: A translational perspective. Frontiers in Psychiatry, 13, 8842481. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8842481/
- Harvard Health Publishing. (2019, May 22). Ketamine for major depression: New tool, new questions. Harvard Health Blog. https://www.health.harvard.edu/blog/ketamine-for-major-depression-new-tool-new-questions-2019052216673
- Wilkinson, S. T., Sanacora, G., & Bloch, M. H. (2020). Ketamine: A potential rapid-acting antidepressant. Journal of Clinical Psychiatry, 81(3), 19f13172. https://pubmed.ncbi.nlm.nih.gov/32459407/
- Johns Hopkins Medicine. (n.d.). Esketamine for treatment-resistant depression. Johns Hopkins Medicine. https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/esketamine-for-treatment-resistant-depression
- Gutierrez, G., Smith, M., Lee, J., & Patel, R. (2024). IN esketamine and IV ketamine: Results of a multi-site randomized controlled trial. Journal of Affective Disorders, 319, 1–8. https://doi.org/10.1016/j.jad.2024.04.010