Traditional approaches work for many people with major depressive disorder and bipolar depression. However, evidence shows that for around one third of people diagnosed with a depressive disorder, the standard treatments are not effective.

Innovative Therapies for Treatment-Resistant Depression

Mental health professionals describe depressive disorders that don’t respond to traditional therapeutic modes as treatment-resistant depression, also known as TRD.

For individuals diagnosed with treatment-resistant depression, an expanding evidence base shows that treatment with ketamine can help alleviate symptoms. Data indicates that, in some individuals, ketamine can:

  • Reduce depressive symptoms within a short period of time:
    • Patients report positive symptom reduction, compared to placebo, within 40 minutes of treatment
  • Produce positive symptom reduction that persists for:
    • One hour, as reported in three studies
    • 2 hours, as reported in three studies
    • 4 hours, as reported in five studies
    • One day, as reported in six studies
    • 2 days, as reported in 4 studies
    • One week, as reported in 5 studies
    • 2 weeks, as reported in six studies
    • 3 weeks, as reported in one study
    • 4 weeks, as reported in two studies

Please access the source material for the studies mentioned in this list by navigating to the link above, which lands on a journal article called “Ketamine and Depression: A Narrative Review” published in 2019.

We won’t spin this data: several studies found no symptom reduction after the four-week point. With that said, people with treatment-resistant depression – MDD or BD I/BD II – report that four weeks of reduced symptoms is a positive outcome, compared to little or no relief with a traditional, standard course of treatment involving medication, psychotherapy, and education.

How Ketamine Works: Mechanism, Administration and Dosage

Mechanism of Action

Research scientists indicate that ketamine, a medication initially developed as an anesthetic, which many people may recognize as a common veterinary drug, can relieve the symptoms of treatment resistant depression in doses far lower than those used for ketamine as an anesthetic. Whereas typical antidepression medications, called antidepressants, reduce the symptoms of depression by increasing the amount of serotonin in the brain, ketamine works by increasing the number of receptors in brain cells that bind to a chemical called glutamate.

Some studies implicate the opioid receptor system in the human brain in the antidepressant action, but this evidence is new, and the contribution of the opioid system to the positive effects of ketamine on depression are unclear. Current research seeks to clarify this question. To date, though, no studies indicate therapeutic use of ketamine is associated with the misuse or disordered use of opioids.


There are two primary ways to administer ketamine for treatment-resistant depression:

  • Infusion, which means an intravenous (IV) injection which, rather than a brief shot that takes seconds, occurs over the course of around 40 minutes.
    • Ketamine infusion may occur with only one infusion, and achieve positive effects
    • After an initial dose, ketamine infusion may occur once or twice a week for as long as four to six weeks
    • In some cases, patients respond well to a single dose, while in other cases, patients report symptom improvement after six infusions over a month to three weeks

Response to ketamine depends on the patient. Clinicians and patients determine the optimal regimen –dosage, frequency, duration of the infusion session – based on previous treatment history, the results of an intake assessment, and the effect of the initial doses of ketamine on depressive symptoms.

  • Oral administration with liquid ketamine, which is a slightly different form of ketamine called esketamine
    • Oral administration may occur once, daily, every other day, or weekly, depending on clinical evaluation of the effect for each patient
  • Nasal administration – like a decongestant/allergy spray – of esketamine is available in a formulation with the commercial name Spravato®. This method is approved for therapeutic use only under the direct supervision of a healthcare provider
    • Nasal administration of Spravato® most often occurs alongside simultaneous use of oral an oral antidepressant
    • In the first phase of treatment with Spravato®, patients receive the nasal spray twice a week. This phase typically lasts a month
    • In the second phase of treatment with Spravato®, patients receive the nasal spray once a week. This phase typically lasts another month.
    • In the third phase of treatment with Spravato® – typically after 8-9 weeks, patients receive the nasal spray every other week

In all cases, dosage frequency and duration for Spravato® will vary by patient, results, and clinician evaluation.

The Consequences of Untreated Treatment-Resistant Depression (TRD)

People with TRD may lose faith that any type of treatment or standard therapy will help ease their symptoms and allow them to return to a full, fulfilling, and independent life. That’s why we use adjunct therapies like IV ketamine and intranasal Spravato®: while the intranasal formulation is approved by the Food and Drug Administration (FDA) for treatment for TRD, IV ketamine is not.

IV ketamine is used off-label for TRD.

That may give you pause – and it should.  You should understand everything about any treatment you engage in and/or receive, whether for a mental health disorder or any type of medical condition. Therefore, it’s important for you to get a real answer to this question:

Why would a medical team I trust advise the use of a medication off-label?

Here’s the FDA answer:

“From the FDA perspective, once the FDA approves a drug, healthcare providers generally may prescribe the drug for an unapproved use when they judge that it is medically appropriate for their patient.”

Off-label use is common in three circumstances. First, a provider may recommend more than a typical dose, if the typical dose is not effective. Second, there may not be any approved medications for a specific condition.  Third, if you’ve tried all other approved medications for your conditions without success, your physician may recommend an approved medication for off-label use.

That last example is true for TRD treatment with intranasal Spravato®. They symptoms of untreated depression can make life very difficult. If you have TRD, you know this firsthand: depression can impair your relationships, your work life, your family life, your academic pursuits, your desire to participate in hobbies and activities you love – everything you do, serious TRD can interrupt, disrupt, or completely prevent.

That’s why we may recommend Spravato® after discussing all of the information above with you: so you can avoid the negative consequences of untreated TRD. Spravato® has the potential to give you relief from symptoms that may have caused you significant emotional and psychological distress or pain for months, years, or even decades.

In other words, it can work when nothing else has – and when it does work, it can be a lifechanging experience for people with TRD.

Learn More Today

If you or someone in your family has been struggling with acute symptoms of treatment-resistant depression, the IV ketamine or intranasal Spravato® may be an appropriate treatment that can bring relief from severe TRD symptoms quickly.

Contact us today to learn how we can help.