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Which is Better for Depression? Spravato vs. Ketamine

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Patients choosing between Spravato® and ketamine infusions for treatment-resistant depression often face a tough decision. Both treatments activate similar receptors in the brain, promoting neuroplasticity and providing rapid relief. However, differences in administration methods, effects, and costs influence which option is better suited for each individual. 

This article explores Spravato® vs. Intravenous (IV) ketamine research and benefits to help patients make informed decisions about their treatment options.

How are Spravato® and Ketamine Different?

spravato vs ketamine compound

Ketamine is a racemic mixture made up of two mirror-image molecules: R-ketamine (arketamine) and S-ketamine (esketamine), while Spravato® only comprises S-ketamine. 

Preclinical (animal and cell) studies showed that esketamine (S-enantiomer of ketamine) had up to 2- to 3-fold higher affinity for NMDA receptors, linked to a potential increased potency at lower doses than standard ketamine. However, various other preclinical animal studies have now indicated that (R-enantiomer) Rketamine has more potent and longer-lasting antidepressant effects than esketamine, with less psychotomimetic side effects.”

Therefore, racemic IV ketamine used at Avesta, containing both of the above enantiomers in equal parts has a more extensive record of clinical success. And recent research indicates it may have an advantage over Spravato® in treating depression.

What Makes Spravato® and Ketamine Similar?

Ketamine and esketamine work similarly by activating glutamate-related NMDA receptors in the brain. Glutamate is one of the brain’s primary chemical messengers supporting neuroplasticity, or the ability to adapt and change with new experiences. Modulating glutamate helps “rewire” the brain, enhancing cognitive flexibility and emotional resilience. 

Esketamine and ketamine also produce similar dissociative psychedelic effects, meaning they can cause patients to feel detached from their surroundings and experience altered perceptions. These effects, along with their mood-boosting properties, provide rapid relief from depression and other mental health conditions. 

Spravoto® vs. Ketamine Administration and Protocol

Ketamine and Spravato® (esketamine) administration sessions must both occur in monitored clinical settings. However, Spravato® is inhaled as a nasal spray, whereas ketamine is typically administered intravenously (IV) through the veins. 

It is also worth noting that Spravato® is an FDA-approved drug for Major Depressive Disorder (MDD), whereas IV ketamine is FDA-approved as an anesthetic. Thus, using it in the mental health setting is an off-label use of the medication, which occurs frequently with many medications.

Intranasal Spravato®

Spravato nasal spray

Spravato® delivers a low esketamine dose through the nose in a quick burst. Most patients receive two to three doses about five minutes apart, using them twice weekly for the first four weeks and once every week or two in the maintenance phase. Each session requires two hours of monitoring after administration, side effects can last a few hours. 

IV Ketamine 

avesta ketamine therapy patient infusion

IV Ketamine infusions are administered through the vein and directly into the bloodstream under controlled doses via an IV line. Most patients receive six treatments over two to three weeks, with maintenance and booster sessions for those who need them. Sessions last 45 minutes to an hour, and side effects can linger for several hours post-infusion.  

Which Route is Better?

Patients who prefer a non-invasive method might opt for Spravato®, while those who need more precise dose control may favor IV ketamine. Additionally, patients who are diagnosed with MDD and have tried 2 different drug regimens can oftentimes have their insurance cover some or all of the cost of the medication as it is FDA-approved for MDD. Although some clinics like Avesta are in network with insurance carriers, helping offset some of the costs, the cost of the infusions may not be covered or only covered slightly.

Ketamine Infusions in Bethesda, MD, McLean, VA and Washington, DC

Spravoto® vs. Ketamine Side Effects

Spravato® vs IV ketamine exhibit nearly identical side effects, including:

  • Dissociation (feeling detached from reality)
  • Disorientation
  • Fatigue 
  • Nausea and vomiting
  • Headaches
  • Anxiety or panic attacks

Studies indicate that esketamine is less likely to cause drowsiness and impairment. However, IV ketamine typically delivers more pleasant mood-altering effects. 

Which is Better?

Patients might choose Spravato® if they are concerned about the potential for short-term cognitive impairment. Others may prefer ketamine for its potential uplifting effects. 

Cost Differences Between Spravoto® and Ketamine 

Another significant difference between Spravato® vs. IV ketamine is their cost, especially for patients with private insurance plans


Most insurance companies do not cover ketamine infusions because the compound is not FDA-approved for depression. Healthcare credit cards and partial insurance reimbursements help make the treatment accessible. However, the lack of complete coverage options means patients often pay out-of-pocket $400 to $1,000 per infusion


Spravato® is FDA-approved for MDD, so individuals can potentially access it with little out-of-pocket cost. However, gaining esketamine insurance coverage is not easy. Patients must prove that they’ve tried at least two other antidepressants without benefit to be considered qualified.

Uninsured patients and those not eligible for Spravato® coverage will pay up to six times more for esketamine spray than IV ketamine. 

Which is Better?

Patients with insurance might prefer Spravato for the potential cost savings. In contrast, uninsured patients and those who do not meet the FDA’s criteria for coverage may find IV ketamine a more affordable option.

Ketamine Infusions in Bethesda, MD, McLean, VA and Washington, DC

Spravoto® vs. Ketamine for Depression

Comparative studies on the effectiveness of Spravato® (intranasal esketamine) and intravenous ketamine for treating treatment-resistant depression (TRD) offer valuable insights. However, no prospective, randomized, head-to-head trials exist.

 Here are key findings from available research:

Correia-Melo et al. (2020): This randomized, double-blind study involving 63 participants showed that esketamine was non-inferior to ketamine, indicating similar efficacy in treating TRD.

Bahji et al. (2021): This meta-analysis highlighted that intravenous ketamine had slightly higher response rates (57.4% vs. 60.0%) and remission rates (42.6% vs. 26.7%) compared to esketamine. The study concluded that ketamine might be more effective overall.

Singh et al. (2022): This Cambridge study concluded that ketamine and Spravato® showed similar response and remission rates. However, IV ketamine required significantly fewer treatments compared to intranasal esketamine. 

Nikayin et al. (2022): A Yale study indicated ketamine had better secondary outcomes than esketamine, meaning greater improvements in depression symptoms such as mood, sleep, and appetite.

Which is Better?

IV ketamine appears slightly more effective for depression than Spravato® due to its higher response and remission rates and fewer required treatments. However, patients might prefer Spravato® for cost and convenience and still gain significant benefits. 

It’s also worth noting that IV ketamine is a more versatile medicine, with evidence of its efficacy in treating PTSD, OCD, anxiety, eating disorders, and substance use disorder (SUD). On the other hand, Spravato® can only be prescribed to patients with a diagnosis of MDD who demonstrate they are treatment-resistant by failing a two-drug regimen. 

Additionally, Spravato® is only FDA-approved for adults. In contrast, IV ketamine can be used in teenagers, with some recent research showing its promise in this population of mental health patients.

Ultimately, the choice depends on individual patient needs and treatment preferences.

Spravato® vs. Ketamine for Pain

Spravato® is not used as a medicine to prevent or relieve pain, so research on the topic does not exist. However, ketamine clinical trials show that infusions are highly effective for various acute and chronic pain conditions. 

  • A 2019 systematic review of randomized controlled trials concluded that ketamine provides significant short-term pain relief.
  • A 2014 study showed that low-dose ketamine produces potent relief for neuropathic pain states during administration, with some long-term effects lasting up to three months following infusion.
  • The American Society of Hematology reported that ketamine worked well in patients with severe pain not responsive to standard opioid analgesics, such as sickle cell disease and cancer-related pain.

Which is Better?

Spravato® could have pain-relieving properties due to its chemical properties and mechanisms. However, research to date only indicates that ketamine effectively relieves pain. 

The Bottom Line: Ketamine or Spravato® 

Spravato® and ketamine IV infusions are two viable treatment options for depression. Avesta Ketamine and Wellness offers both protocols to patients in its Washington, DC, Bethesda, MD, and McLean, Virginia locations.

Patients interested in learning about treatment options with ketamine or Spravato can contact Avesta’s clinical care team for a free consultation.  

Ketamine Infusions in Bethesda, MD, McLean, VA and Washington, DC

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