Ketamine and its role in treatment-resistant depression

By Sarah Handzel, BSN, RN | Medically reviewed by Amanda Zeglis, DO, MBA
Published June 23, 2022

Key Takeaways

  • Ketamine is an NMDA receptor antagonist that could significantly change treatment possibilities for treatment-resistant depression.

  • Several newer studies demonstrate ketamine’s efficacy in addition to its use as an adjunct to other treatments.

  • Potential adverse effects, such as blood pressure changes and visual hallucinations, are possible.

Ketamine, an N-methyl-D aspartate (NMDA) receptor antagonist commonly used as an analgesic and anesthetic, has also found application in treatment of a variety of mental health disorders.

First demonstrated in a randomized, double-blind clinical trial in the year 2000, ketamine has significant, rapid antidepressant action for many patients affected by major depressive disorder (MDD).

Furthermore, more information is surfacing regarding ketamine's potential effects on treatment-resistant depression.

As many as one-third of patients with MDD are thought to experience treatment-resistant depression (TRD), defined as an inadequate response to at least two adequate trials of antidepressant medications.

Ketamine’s rapid action, combined with its powerful antidepressant properties, could be key to successfully treating this specific patient population moving forward.

Ketamine’s mechanism of action

There are multiple pathways of functioning that have been indicated with ketamine.

Research has demonstrated ketamine’s effect against NMDA receptors in the brain. The drug blocks these receptors, which quickly helps control depressive symptoms.

Ketamine is also thought to increase glutamate levels, which play a role in multiple metabolic pathways as an excitatory neurotransmitter.[]

Finally, research indicates ketamine may increase levels of brain-derived neurotrophic factor and the number of synapses between nerve cells. Its effects, which are typically long-lasting, may be mediated by this increase in synaptic activity.[]

Ketamine and TRD

The use of ketamine on mental health disorders including post-traumatic stress disorder, bipolar disorder, obsessive-compulsive disorder, and generalized anxiety disorder has been documented.

The drug is also effective in reducing suicidal ideation; among participants of one study, 85% reported no further instances of this within a week after ketamine administration.

Recent studies show promise

Several recent studies have examined ketamine’s effects on TRD.

A 2022 study examined the response of individuals with TRD to ketamine infusion therapy lasting eight to 10 treatments.[] A total of 22 participants completed the entire treatment and follow-up process.

Of those participants, all took antidepressants while receiving ketamine infusions.

Each participant completed two questionnaires—the 16-item Quick Inventory of Depressive Symptomatology-Self Report scale (QIDS-SR16) and the Montreal Cognitive Assessment (MoCA), which help determine the severity of depression and level of cognitive functioning, respectively.

There was a 47.17% reduction in QIDS-SR16 scores demonstrated by those in the study, alongside six patients with QIDS-SR16 scores low enough to indicate no further depressive symptoms. Furthermore, there was no significant change in MoCA scores, indicating a lack of cognitive impairment with the ketamine infusion protocol.

A 2020 study compared the effects of ketamine infusions and intravenous midazolam.[]

Depression symptoms showed greater improvement after repeated doses of ketamine compared to midazolam.

Ketamine as adjunct to conventional therapies

A comprehensive systematic review published in 2021 discussed three double-blind randomized controlled trials in which ketamine boosted the effectiveness of ECT compared to other anesthetics.[] Ketamine was associated with a variety of benefits, including:.

  • Better overall improvement

  • Fewer required ECT sessions

  • Higher remission rate

  • Earlier symptom improvement in depression 

  • Reduced cognitive impairment

  • Longer seizure duration

Contraindications to ketamine therapy

Ketamine is associated with several adverse effects, and therefore may not be appropriate for all patients.

High doses have been associated with serious neurocognitive problems. Research indicates that adverse effects may include transient blood pressure increases, tachycardia, bradycardia, intermittent atrial fibrillation, visual hallucinations, conceptual disorganization, and unusual thought content. 

What this means for you

Ketamine shows promise as an effective treatment for a variety of mental health conditions, including treatment-resistant depression. However, due to its potential adverse effects, clinicians should use cautious judgment when initiating this therapy.

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