Ketamine vs. Spravato: Which is Better for Treatment-Resistant Depression?

At PsychAtlanta, one of the Southeast's largest treatment-resistant depression (TRD) practices, the people we treat have often failed multiple antidepressant trials, counseling, and even combinations of supplements, diets, and lifestyle changes. They come to us for something different and often ketamine and the intranasal ketamine -like drug Spravato comes up as treatment options. Naturally the question we frequently get from not just patients and their families but also healthcare providers (HCPs) who refer to us is “Which is better -ketamine or Spravato?” ?Like most answers in medicine, it isn’t that simple – it depends. Let's break down what you need to know about both options. This is what we do with our patients when we discuss both treatments and then decide together what is the best approach for that patient at this particular time.

Understanding the Basics

Many patients and even HCPs when asking about ketamine and Spravato use the terms interchangeably, but they are very distinct treatments. Here's how they differ:

Ketamine is a general anesthetic medication used in lower doses to treat depression, typically given through intravenous (IV) infusion. While some HCPs prescribe ketamine in other forms and may even allow patients to administer it at home (another controversial topic for another article), we will focus on in office IV administration since that is the most studied. The standard ketamine used is a racemic mixture, meaning it contains equal amounts of two mirror-image forms (isomers) of the molecule called R-ketamine and S-ketamine.

Spravato (esketamine) is a nasal spray that contains only the S-ketamine isomer and is FDA-approved specifically for treatment-resistant depression. While ketamine and Spravato work similarly in the brain, Spravato is more standardized and regulated as to how it is given and the dosing since it's an FDA-approved prescription. This has advantages and disadvantages.

Why No Clear Winner?

These two treatments have never been directly compared head-to-head in a rigorous clinical trial to see if one is better or safer. Such a study would be expensive and complex. And may not even give us the answer, if there is one since studies can have bias too. Many clinics like ours generally see better results with ketamine than Spravato but this is not universally the case. We have had patients do equally well on both and have had plenty of patients do better on Spravato. We even have reported these findings in this following study: https://pubmed.ncbi.nlm.nih.gov/34411009/

Several factors might explain this “unscientific observation”:

1. The presence of R-ketamine in traditional ketamine might offer additional benefits
2. IV delivery may provide more reliable absorption than nasal spray
3. Flexible IV dosing allows for personalized dosing
4. The more intense experience with IV ketamine might have therapeutic value or give patient’s the perception they are getting something stronger and therefore better
5. Provider and patient expectations and treatment bias may influence outcomes
6. Ketamine doesn’t require insurance authorization and reduced insurance reimbursement which could impact clinics treatment preference

Comparing the Options

Spravato Advantages

• Less invasive nasal spray delivery
• Standardized dosing and monitoring
• FDA approval with established safety data
• Potential insurance coverage

Spravato Challenges

• Higher cost without insurance
• Limited dosing flexibility
• Must be taken with an antidepressant, at least for now
• Insurance approval can take time
• Not approved for other conditions like bipolar depression, anxiety or PTSD

Ketamine Advantages

• Long safety record in medicine
• Predictable IV administration
• Quick treatment initiation
• Flexible dosing
• Can be used without antidepressants
• May help with multiple conditions

Ketamine Challenges

• Usually not covered by insurance
• Less standardized protocols
• More intense dissociative effects
• Limited long-term safety data
• Potential for abuse

What Research Shows: A? 2020 Review and Meta-Analysis of esketamine and Ketamine https://pubmed.ncbi.nlm.nih.gov/33022440/

Treatment Response

• Ketamine: 60-70% of patients improve
• Spravato: 50-60% improve when combined with antidepressants

Speed of Action

Both work quickly, but ketamine may act faster:

• Ketamine: Peak effect in 24-72 hours
• Spravato: Significant improvement within 24 hours, but may be slightly slower

Duration

• Ketamine: Effects last 7-14 days per treatment
• Spravato: Maintained through structured twice-weekly treatments, then weekly/bi-weekly maintenance

Making Your Choice

When discussing options with patients, we emphasize that there's no wrong choice – you can always switch treatments if needed. Some important things to consider beyond just the cost and access of one treatment over another. There are additional risks when using a non -FDA approved treatment over one that is FDA approved. There is more scientific rigor, standardization delivery of treatment, and safety oversight with FDA approved therapies. When receiving ketamine at a clinic, you are more dependent on the style and expertise of those clinicians. ?However, for urgent cases, many patients may start with ketamine since getting Spravato insurance approval and be a drawn-out process. Often our patients who get ketamine as an urgent treatment will transition to Spravato once approved. Some patients opt for ketamine first line since they like the dosing flexibility and the ability to slow down or stop the infusion if desired. Others like the fact that ketamine has a long safety track record as an anesthetic medicine or have heard about positive experiences from others which may influence their decision. Since there is enough of a benefit and side effect difference in the two therapies, both should be considered as treatment alternatives Which one to try first really will depend on your individual needs and concerns. Hopefully, you will be so successful with what you try first you won’t need the other.

The Keys to Success

A good TRD clinic should:

• Offer individualized treatment plans and be able to provide a variety of interventions to give you more options based you’re your clinical needs and side effect concerns
• Stay current with the latest research on new treatments
• Maintain strict safety protocols and a safe, therapeutic environment during the dissociative experience
• Provide ongoing comprehensive care that includes medication management, counseling, and lifestyle recommendations to augment the ketamine/Spravato effect
• Adjust or change treatments based on response and side effects

Looking Forward

Treatment-resistant depression has more options than ever before. While choosing between treatments may feel overwhelming, remember that both ketamine and Spravato offer paths to recovery. The key is finding an experienced clinic that offers diverse treatment options and will guide you with as little bias as possible adjusting your care as needed along the way.

This article is based on clinical experience at PsychAtlanta and current research in the field of treatment-resistant depression. Always consult with healthcare providers about your specific situation.

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