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Ketamine Therapy for Depression Treatment: Key Scientific Studies Over the Past Two Decades (Updated 2024)

Ketamine has attracted significant attention in recent years for its potential as a rapid-acting antidepressant, especially in the context of treatment-resistant depression (TRD). Numerous clinical trials have demonstrated that intravenous (IV) administration of ketamine leads to a significant improvement in depressive symptoms within hours of an infusion. These positive effects have been shown to endure, particularly when ketamine is administered as a series of infusions rather than just a single dose. Various mechanisms of action have been proposed for ketamine therapy, including NMDA receptor blockade and the promotion of neuroplasticity.

While the majority of studies have focused on adults, preliminary research involving adolescents with TRD has shown promising results, with ketamine therapy significantly reducing depressive symptoms. Further investigation is necessary to fully assess ketamine's efficacy and safety in adolescents with TRD.

It's worth noting that, although alternative routes of administration such as intramuscular, oral, and nasal have been explored, current evidence suggests that subanesthetic-dose IV ketamine is the safest and most effective route.

Today, we will succinctly review some important studies and findings spanning over two decades regarding ketamine therapy for the treatment of depression. Additionally, we will explore a few key topics, such as how ketamine therapy can help alleviate suicidal thoughts, reasons why IV ketamine is superior, how ketamine affects specific parts of the brain (prefrontal cortex and amygdala), and how, when combined with psychotherapy (as is our approach at Innerbloom) it may increase response rates and lead to more enduring effects.

Ketamine's Rapid Antidepressant Effects

Antidepressant effects of ketamine in depressed patients (Berman · 2000)

This pioneering study was among the first to demonstrate the rapid antidepressant effects of ketamine. The randomized controlled trial found that a single subanesthetic dose of ketamine produced rapid and robust antidepressant effects in patients with treatment-resistant major depression. This study provided preliminary evidence for the potential of ketamine as a novel and rapid-acting treatment for depression, sparking further research in this area.

A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression (Zarate · 2006)

In this study, researchers examined the antidepressant effects of ketamine in patients with treatment-resistant major depression. The results revealed a significant improvement in depressive symptoms within hours of ketamine administration. These findings suggest that ketamine could present a novel and effective treatment for depression, especially in refractory cases. Moreover, the study contributes to our understanding of the potential of NMDA receptor antagonists as a new class of antidepressants, fostering hope for enhanced patient outcomes and reduced morbidity linked to traditional antidepressant medications.

Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression (Murrough · 2013)

Participants in this study with treatment-resistant depression underwent a washout of antidepressant medication followed by a series of up to six IV infusions of ketamine (0.5 mg/kg), administered three times weekly over a twelve day period. The overall response rate at the end of the study was 70.8%, with a significant mean decrease in Montgomery-Åsberg Depression Rating Scale score observed at two hours after the first ketamine infusion.

colorful illustration of a nerve synapse
How and where does ketamine work?

Understanding the Mechanism and Formulations of Ketamine

R (-)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine (Zhang · 2014)

Intravenous ketamine, also known as generic or racemic ketamine, contains both the R and S forms of ketamine, while esketamine, administered in nasal form, only contains S-ketamine. In this study, R-ketamine demonstrated prolonged antidepressant effects whereas S-ketamine did not. This suggests that R-ketamine may offer greater potency and longer-lasting antidepressant effects compared to S-ketamine, highlighting the importance of both molecules rather than just one and emphasizing why IV ketamine is superior to the nasal alternative.

The effects of low‐dose ketamine on the prefrontal cortex and amygdala in treatment‐resistant depression (Li · 2016)

A hypoactive prefrontal cortex and a hyperactive amygdala, the region of the brain that plays a crucial role in processing emotions, particularly fear and other negative emotions, have been suggested to be associated with treatment-resistant depression. This study demonstrated rapid antidepressant effects of low-dose ketamine involving the activation of the prefrontal cortex with downregulation of the amygdala. These findings provide valuable insights into the neurobiological mechanisms underlying ketamine's antidepressant effects.

Expanding Frontiers with Ketamine Therapy

Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression (Grunebaum · 2017)

This study suggests that a single ketamine infusion, adjunctive to ongoing pharmacotherapy, can significantly reduce suicidal ideation in depressed patients. The improvement persisted for at least 6 weeks. Adverse effects were mostly mild to moderate and transient. Follow-up assessments at 3 and 6 months showed no evidence of ketamine abuse.

Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide (Canuso · 2018)

In this trial, researchers evaluated the efficacy and safety of intranasal esketamine (a derivative of ketamine) in patients with treatment-resistant depression. The study found that esketamine produced rapid and significant antidepressant effects compared to placebo, leading to FDA approval of esketamine nasal spray for treatment-resistant depression in 2019.

Ketamine for acute suicidal ideation. An emergency department intervention (Domany · 2019)

In this trial, depressed patients with acute suicidal ideation, requiring hospitalization, were given either intravenous ketamine or a saline placebo. At 90 minutes, 88% of the ketamine group achieved remission of suicidal ideation compared to 33% in the placebo group. No serious adverse events were reported. These findings suggest that ketamine is both safe and effective for rapidly reducing suicidal ideation in highly suicidal patients presenting to the emergency department.

Enduring Antidepressant Effects of Ketamine

Ketamine Enhances Visual Sensory Evoked Potential Long-term Potentiation in Patients With Major Depressive Disorder (Sumnar · 2020)

Researchers investigated the mechanism of ketamine's antidepressant effects in this study. The results showed that 70% of participants experienced a significant reduction in depression symptoms after receiving ketamine, with evidence of changes in neural architecture modulation by ketamine. This study supports the hypothesis that ketamine's antidepressant effects may be mediated by enhancing neuroplasticity.

Efficacy of ketamine for major depressive episodes at 2, 4, and 6-weeks post-treatment (Conley · 2021)

This meta-analysis aimed to assess the efficacy of ketamine in treating major depressive episodes beyond the standard 2-week observation period. The study found significant treatment effects at 2, 4, and 6 weeks post-administration, indicating that ketamine can be an effective pharmacological intervention for major depressive episodes, with effects lasting up to 6 weeks, and possibly longer for some individuals.

back and white photo of a car driving on a long highway
The potential long-lasting effects of ketamine

Improving Efficacy of Ketamine with Combination Therapy While Outperforming Conventional Treatments

Ketamine Assisted Psychotherapy - KAP (Drozdz · 2022)

The systematic review suggest that the combination of ketamine and psychotherapy resulted in significantly greater improvements in depressive symptoms compared to either treatment alone. This suggests that integrating ketamine with psychotherapy could be a promising approach for addressing depression more comprehensively. Higher doses of ketamine, more frequent KAP sessions, and longer periods with psychotherapy appear to increase efficacy and durability of sustained improvements across various disorders. However, there is no one-size-fits-all approach, and tailoring interventions to individuals is essential.

Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression (Anand · 2023)

In a large clinical trial involving 403 patients, researchers from Massachusetts General Brigham compared the effectiveness of subanesthetic intravenous ketamine to electroconvulsive therapy (ECT) for treatment-resistant depression. Ketamine outperformed ECT, the gold standard for treatment-resistant depression, with higher response and remission rates. Published in the New England Journal of Medicine, the study found that 55% of patients treated with ketamine experienced sustained improvement in depressive symptoms, without major side effects. This study, the largest of its kind, also assessed impacts on memory, a concern often associated with ECT. ECT can cause memory loss and other less-than desirable side effects. Ketamine, however, was not associated with significant side effects apart from transient dissociation and potential mild nausea during an infusion.

“People with treatment-resistant depression suffer a great deal, so it is exciting that studies like this are adding new options for them,” said Anand. “With this real-world trial, the results are immediately transferable to the clinical setting.”

Ketamine for the Treatment of Major Depression (Nikolin · 2023)

This systematic review and meta-analysis compared the efficacy of racemic IV ketamine and nasal esketamine in treating depression. They analyzed 49 randomized controlled trials involving 3299 participants. Results showed that racemic ketamine generally had larger effects on depression severity, response, and remission rates compared to esketamine. Higher doses were more effective than lower doses, with differences observed in initial effects, ongoing treatment, and lasting effects after the final dose. The findings suggest that racemic ketamine may be more effective for depression treatment.

Clinical Outcomes of Intravenous Ketamine Treatment for Depression in the VA Health System (Pfeiffer · 2024)

This study published in the Journal of Clinical Psychiatry included 215 Veterans who received six IV ketamine infusions resulting in significant symptom relief. The study suggests those who did experience improvements saw sustained benefits over at least 6 months with decreasing infusion frequency. Lead researcher Paul Pfeiffer underscores that while ketamine isn’t a “silver bullet,” its impact on previously treatment-resistant cases is remarkable.


Ketamine therapy represents a promising avenue for individuals with treatment-resistant depression, offering rapid and significant improvements in mood. While further research is needed to fully understand the optimal dosing and formulation strategies, the findings from studies over the past twenty-four years provide valuable insights into the potential of ketamine as an effective treatment for depression. Just in the second month of the year, there are over ten studies in 2024 further investigating ketamine as a treatment for depression, indicating a significant level of interest, hard work, and collaboration in advancing this field of mental health care. While I am eager for new, larger scale studies to help us understand all the nuances of safe and effective use of ketamine for its antidepressant effects, it is reassuring to know that there is already a solid foundation of evidence.

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