Depression is one of humankind’s oldest brain disorders. Major depressive disorder (MDD) is the most common psychiatric disorder in the world, affecting approximately 17% of the population in developed areas at any given time. The World Health Organization ranks depression third among the leading causes of global disease burden.

Ketamine infusion therapy has proven to be rapidly effective in remission of depressive symptoms of MDD, TDD, and BD, sometimes providing temporary relief within hours of the first infusion. It is remarkably effective in aborting suicidal ideations with a single IV infusion. Ketamine is 70% effective in TDD. Although the response to a single infusion is short-lived (a matter of days), repeat administration over a short period of time (typically two weeks) can extend the length of remission, with some patients enjoying improvement for as long as six months. Administering additional “booster” treatments can continually extend the length of remission of symptoms. Ketamine infusions are safe, rapid, and effective. Consequently, ketamine infusion therapy is revolutionizing the treatment of depressive disorders.

Ketamine IV therapy is considered “off-label,” while in 2019, the FDA approved the use of Ketamine for depression via a nasal spray. It is unclear why the FDA approved the nasal spray version. However, research by Bahji and colleagues—from Queen’s University in Canada and the National Institute of Mental Health in the US—suggests racemic Ketamine might be more effective than esketamine (nasal spray). Published in the January 2021 issue of the Journal of Affective Disorders, the article reports the results of the “first systematic review and meta-analysis that has compared the performance of intravenous ketamine to intranasal esketamine for the treatment of unipolar and bipolar depression.”

Sources of Data

The authors sourced electronic databases and found randomized controlled trials using intranasal esketamine or intravenous Ketamine to treat depression. They included studies where the drug was used alone and studies where it was used as an augmenting agent—meaning in addition to another antidepressant medication, such as a selective serotonin reuptake inhibitor (SSRI), like Prozac or Zoloft.

The final list of trials to be included in the meta-analysis and systematic review consisted of 24 randomized controlled trials—1877 participants; 61% females; average age ranging from 36 to 70 years; 98% with major depression and 2% with bipolar depression.

In most of the investigations included in the meta-analysis, the drug had been used as an augmenting agent. In three-quarters of the trials, participants had depressive symptoms that had not responded to previous treatments. In other words, they had treatment-resistant depression. However, depending on the investigation, treatment-resistant depression was defined differently. The most common definition of treatment-resistant depression (used in over 60% of trials) was a lack of response to two or more antidepressants.

Results: IV vs. Nasal Spray 

The results showed that, compared with esketamine, racemic ketamine (IV ketamine) produced a greater response (rate ratio = 3.0 vs. 1.4), remission rate (ratio rate= 3.7 vs. 1.5), and lower dropouts (rate ratio = 0.8 vs. = 1.4).

Thus, compared to “intranasal esketamine, intravenous racemic ketamine demonstrated more significant overall response and remission rates, as well as lower drop-outs due to adverse events” (p. 548).

Their findings also showed a “clear and consistent antidepressive effect of ketamine vs. esketamine treatment, relative to a variety of control conditions, beginning within hours of administration, and lasting up to 7 days after a single dose” (p. 549).

If so, why has the FDA approved only intranasal esketamine (Spravato) for the treatment of depression even though the present review showed a lower drop-out rate due to adverse events in patients treated with IV ketamine compared with Spravato? A likely explanation is that the lack of FDA approval is related to a lack of quality research on the long-term effects (e.g., safety, efficacy) of ketamine infusion.

So How Does It Work?

Ketamine is a dissociative anesthetic with various mechanisms of action and binds to multiple receptors in the brain. Consequently, it is difficult to pin down the precise mode of action, and it appears that there are numerous mechanisms through which Ketamine exerts its action on the brain.

Research suggests that one of Ketamine’s major actions is as an N-methyl-D-aspartate (NMDA) receptor antagonist, which blocks activation of the NMDA receptor. This action leads to increased release of glutamate, which is involved in neuronal plasticity and synaptic growth and repair. These effects through complex pathways lead to the release of Brain-derived neurotrophic factor (BDNF), a substance responsible for maintaining healthy neurons and their connections, known as synapses.

Increased BDNF has been shown to repair, and regrowth damaged synapses and their neuronal connections caused by chronic stress in animal models. Likewise, in humans, Ketamine is thought to lead to the creation of new neuronal circuits and/or repair of the healthy neuronal connections that existed in the brain before the patient suffered from depression, PTSD, OCD, and/or chronic anxiety.