Ketamine for Treatment-Resistant Depression: Comparing Routes of Administration

Ketamine routes of administration

For those living with treatment-resistant depression (TRD), ketamine offers a unique and promising pathway to relief—especially when traditional medications have failed. But not all ketamine treatments are the same. At Anodyne, we’re often asked about the differences between the various ways ketamine can be administered, and which might be the most effective or suitable for a given patient.

In this blog, we explore and compare the four main routes used in clinical practice:

• Intravenous (IV)
• Intranasal (Spravato®)
• Oral/Sublingual/Buccal (Lozenges or Troches)
• Intramuscular (IM) or Subcutaneous (SC)

Intravenous (IV) Ketamine

Most researched and evidence base

How it works: Delivered directly into the bloodstream through a slow infusion. This is the most studied and widely used form of ketamine for TRD in clinical settings.

Pros:

• Backed by the strongest clinical evidence. IV ketamine has the strongest evidence base, with multiple randomized controlled trials demonstrating rapid antidepressant effects.
• Precise and adjustable dosing. IV allows for fine control over dose and titration, ensuring optimal and consistent plasma levels.
• Fast onset. Effects can be felt within hours

Considerations:

• Requires a clinical setting. Must be administered under medical supervision, typically in a specialized clinic or hospital setting
• Higher cost due to staffing, equipment, and facility requirements

Intranasal Esketamine (Spravato®)

TGA-approved and clinic-based

How it works: Self-administered under supervision as a nasal spray (Spravato® contains esketamine, the S-enantiomer of ketamine).

Pros:

• Regulatory approval. Spravato is approved for TRD in Australia, offering a recognized option
• Less invasive than IV and quicker to administer

Considerations:

• Absorption can vary depending on nasal congestion, mucosal variability, and technique
• Slower response for some. While effective, it may not match the rapid and robust outcomes seen with IV ketamine.
• May take multiple doses over weeks to reach full effect
• Must still be supervised in specialised clinic setting

Oral/Sublingual/Buccal (Lozenges or Troches)

How it works: These are swallowed (oral) or dissolvable (sublingual/buccal) formulations that are placed under the tongue or in the cheek, where ketamine is absorbed through mucous membranes.

Pros:

• Easy to use. No needles or sprays.
• Convenient and less invasive

Considerations:

• Lower and less predictable absorption due to liver metabolism, which may reduce effectiveness.
• Limited research. Far less clinical evidence compared to IV or intranasal forms.
• Risk of misuse or diversion. Especially without supervision.
• Greater potential risk of longer term liver, bladder and cognitive problems due to daily dose requirement
• Slower onset and reduced potency means it is not ideal for induction treatment phase or severe cases

Intramuscular (IM) or Subcutaneous (SC) Injection

How it works: IM ketamine involves a single injection into a muscle (often the thigh or deltoid). SC ketamine involves a single injection under the skin in the subcutaneous tissue (often the abdomen).

Pros:

• Rapid onset. Faster than oral and sometimes comparable to IV.
• Easier logistics. Simpler than setting up an IV line.

Considerations:

• Less flexibility. Once administered, dose cannot be adjusted.
• Absorption may vary. Depends on muscle and subcutaneous mass, blood flow, and other factors.

So, Which Route Is Best?

There’s no one-size-fits-all answer. At Anodyne, we tailor ketamine therapy to the individual. For many patients, IV ketamine remains the gold standard, particularly during the induction phase due to its rapid onset and proven efficacy. However, intranasal and other injectable forms can be excellent options for maintenance treatment or for patients seeking less invasive approaches.

Ultimately, the best route depends on a range of factors, including:

• Clinical history and treatment response
• Comorbid conditions
• Accessibility and supervision needs
• Personal preferences
• Cost and availability

Conclusion

Choosing the right delivery method is a key part of optimizing ketamine therapy. IV ketamine remains the most evidence-backed and effective for acute symptoms, while intranasal route may suit those in maintenance or seeking more convenience.

Is Ketamine Therapy Right for You?

If you have tried multiple antidepressants without success, or if you are experiencing severe depression, PTSD, chronic pain, or suicidal thoughts, ketamine therapy may be an option worth exploring.

Disclaimer

Anodyne is a specialised health service focused on patient centred and novel approaches for pain management and mental health treatments.

Any advice posted on our blog, website, or app is of a general nature and for informational purposes only. It is not intended to replace or substitute for any medical or other advice.

Anodyne makes no representations or warranties and expressly disclaim any and all liability concerning any treatment, action by, or effect on any person following the general information offered or provided within or through the blog, website, or app. If you have specific concerns or a situation arises in which you require medical advice, you should consult with an appropriately trained and qualified medical practitioner.

Want to know more?

For more information on ketamine, please go to our comprehensive guide Ketamine Infusion Unveiled: A Comprehensive Guide or our Ketamine Resource: Opens in new window - Opens in new tab and Ketamine Therapy pages. If you think ketamine may be a treatment for you, please contact Anodyne to book a consultation with one of our doctors.