How Ketamine Treatment can Treat Depression

Principium Psychiatry and Ketamine

At Principium Psychiatry, located in New York (Midtown Manhattan near Grand Central Station and downtown Manhattan near Wall Street) and Greenwich, CT, ketamine is offered along with a range of treatments for depression. Principium Psychiatry is a leading center for ketamine therapy in the tristate region, with highly trained professionals on faculty at Mt. Sinai, Cornell, and Columbia as well as New York Presbyterian Hospital. Principium Psychiatry offers IV ketamine therapy as well as Spravato (intranasal ketamine). As the medical director of Principium, I am proud of our work in this area. Below, I discuss the background of ketamine and how it has transformed the treatment of depression.


Depression, a debilitating mental disorder affecting millions worldwide, poses significant challenges in terms of diagnosis and treatment. Traditional antidepressant medications often have delayed onset and limited effectiveness, leaving many patients searching for alternative therapeutic options. Ketamine, an anesthetic agent with dissociative properties, has emerged as a potential breakthrough treatment for depression. Below, I will review the mechanisms, clinical efficacy, safety considerations, and future directions of ketamine as a treatment for depression.


Depression is a complex mental disorder characterized by persistent sadness, loss of interest or pleasure, altered sleep and appetite, fatigue, and impaired cognitive function. Traditional antidepressant medications, such as selective serotonin reuptake inhibitors (SSRIs), often require weeks or even months to exert their therapeutic effects. Moreover, a significant proportion of patients fail to achieve remission with these conventional treatments, something which was famously demonstrated by the STAR*D trial of antidepressants. In recent years, ketamine has gained attention as a rapidly acting and transformative treatment option for depression.



Mechanisms of Action

Ketamine acts on several neurochemical systems implicated in depression, including glutamate, N-methyl-D-aspartate (NMDA) receptors, and the mammalian target of rapamycin (mTOR) pathway. By blocking NMDA receptors and enhancing synaptic plasticity, ketamine promotes the formation of new connections between neurons. This neuroplasticity hypothesis offers a novel perspective on the pathophysiology of depression and the mechanisms underlying ketamine’s antidepressant effects. Neuroplasticity may also underly ketamine’s effectiveness for PTSD (see separate blog on that topic).

Clinical Efficacy

Numerous clinical trials and real-world studies have demonstrated the rapid and robust antidepressant effects of ketamine. Intravenous (IV) ketamine infusion has shown efficacy in treatment-resistant depression, with many patients experiencing significant improvements within hours or days after administration. Additionally, ketamine has demonstrated effectiveness in specific subtypes of depression, such as bipolar depression, postpartum depression, and suicidal thinking.

Safety Considerations

While ketamine has shown remarkable antidepressant properties, safety considerations are paramount. The most common side effects of ketamine administration include transient dissociative symptoms, dizziness, nausea, and increased blood pressure.  Appropriate patient selection is important in rendering ketamine treatment, as well as maintaining monitoring protocols, and discussing with patients potential risks associated with ketamine treatment.

Mechanisms of Resistance and Future Directions

Despite the promising outcomes of ketamine treatment, a significant number of patients do not achieve a sustained response. Mechanisms of resistance may include genetic factors, treatment duration, and heterogeneity of depression subtypes. The emergence of novel ketamine derivatives and alternative routes of administration, such as intranasal and oral formulations, present exciting avenues for future research. The exploration of combination therapies and the integration of ketamine into existing treatment algorithms such as antidepressants and psychotherapy is essential.

Future Research

To maximize the potential of ketamine in treating depression, further research is needed to elucidate the long-term effects and optimal dosing regimens. Longitudinal studies are necessary to assess the durability of ketamine’s antidepressant effects and to monitor potential risks and adverse events associated with prolonged use. Additionally, investigations into the underlying mechanisms of resistance to ketamine treatment can help identify biomarkers or genetic factors that may predict individual response to therapy.

The development of ketamine derivatives and alternative routes of administration holds promise for expanding its accessibility and improving patient experience. Intranasal ketamine formulations, for example, may offer a more convenient and cost-effective approach, allowing for at-home administration and reducing the burden on healthcare facilities. Oral formulations are also being explored, aiming to provide sustained antidepressant effects and enhanced patient compliance.

Combination therapies involving ketamine and other treatment modalities, such as psychotherapy or traditional antidepressant medications, are an area of active investigation. By harnessing the synergistic effects of multiple interventions, clinicians may be able to enhance treatment response rates and promote sustained remission. However, careful consideration must be given to potential drug interactions and safety concerns when combining ketamine with other substances.

Ketamine represents a groundbreaking approach to treating depression, offering rapid and robust antidepressant effects for patients who have failed to respond to traditional therapies. The mechanisms of action involving glutamate and synaptic plasticity provide new insights into the neurobiology of depression. While safety considerations and mechanisms of resistance warrant further exploration, ketamine holds immense promise as a transformative treatment option. By continuing to advance research, refining treatment protocols, and addressing ethical concerns, we can ensure the effective and responsible integration of ketamine into the current landscape of depression treatment.


Ketamine has emerged as a promising and transformative treatment option for depression, offering rapid and robust antidepressant effects. Its unique mechanism of action involving glutamate and synaptic plasticity provides new avenues for understanding the neurobiology of depression. While further research is needed to optimize dosing, address safety considerations, and identify mechanisms of resistance, the potential of ketamine in revolutionizing depression treatment cannot be overlooked. By continuing to advance scientific knowledge, refine treatment protocols, and address ethical concerns, we can harness the full therapeutic potential of ketamine and improve the lives of individuals living with depression.

Principium Psychiatry and Treatment Innovation

Principium Psychiatry is a multidisciplinary, private mental health clinic located in New York City (Grand Central and Downtown Manhattan) as well as Greenwich, CT. Principium offers a range of treatments for depression including IV Ketamine and Spravato. Principium is a REMS certified Spravato treatment center. In addition, Principium has been innovating in the use of Ketamine to treat depression since 2017 under the leadership of Ziv Cohen, MD, clinical assistant professor of psychiatry at Weill Cornell Medicine.

Questions or inquiries may be directed to our office at

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