As a psychiatrist, it doesn’t take a long career to recognize that our current treatments often fall short of the mark when it comes to treating depression. The traditional serotonergic agents have been readily prescribed since the 1950’s with MAOIs through to the boom of SSRIs in the 1980s. If you were to judge a medication’s efficacy by the amount of prescriptions filled, you would think Zoloft and Lexapro were the best antidepressants on the market as they commonly find themselves in the top 10 most filled prescriptions in the US. 

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But real-world, day-to-day practice tells a much different story. No matter how you feel about the term “treatment resistant,” even the most conservative estimates report at minimum 1/3rd of patients do not respond to traditional serotonergic medications. Where to go from here often depends on many factors: insurance coverage, logistics, symptoms, etc. Options include ECT, TMS, Spravato (esketamine nasal spray), vagus nerve stimulation, or ketamine. 

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I started my career as an inpatient psychiatrist, where I was confronted with the obvious limitations of our current medication options. On a daily basis I had cared for patients at the lowest points of their lives who had come to the hospital feeling both hopelessness and a sense that they were out of options. Without resources for inpatient TMS or Spravato, the only real alternative was ECT. While I strongly believe in ECT and think it is one of the best treatments we have in all of psychiatry, this is often a tough sell to patients, given the stigma portrayed in movies & television. 

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This is where my story leads to IV ketamine. During my residency training, I had the privilege of learning under faculty who had established one of the largest IV ketamine clinics in the Midwest. I had also started reading about the work being done by Dr. John Krystal at Yale in Connecticut.

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Interest in the field of psychedelic psychiatry led me to co-found an academic journal called The Journal of Psychedelic Psychiatry and speak with leaders in the field on a podcast I also helped develop, “The New Perception Podcast.” I saw firsthand how transformative this treatment could be and knew that one day, I wanted to open my own practice. 

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Navigating the field of ketamine treatment in 2024 can feel daunting. Many clinics are popping up across the US, and knowing who to trust and where to send patients is difficult. To make it more confusing, there has also been an upswell of “at home” oral ketamine companies that offer oral ketamine delivered to patients’ doorsteps. Sure, it’s all technically racemic ketamine but what’s the best route to successful treatment response while maintaining patient safety?

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The best summary of this discussion was just recently published by Dr. Owen Muir, MD and colleagues in the American Journal of Therapeutics. This article provides an in-depth analysis regarding the history of ketamine and its use in psychiatry. 

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Ketamine as a chemical compound works in several different ways. At a molecular level, ketamine is an NMDA antagonist at gabaergic interneurons. Binding at this receptor leads to a downstream cascade of effects, including increased glutamate release in the medial prefrontal cortex (mPFC), activation of AMPA receptors, increased release of BDNF, activation of the mTOR pathway and ultimately increased synaptogenesis. 

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On a more digestible level, studies using functional MRI imaging have shown that IV ketamine treatments can normalize the activity in the Default Mode Network, an area of the brain commonly considered our mind’s “autopilot.” In patients who are suffering from severe depression, this area becomes overactive, leading to negative ruminating thoughts that often become overwhelming. Treatment with IV ketamine is thought to essentially “turn the volume down” of these obstructive auto-pilot thoughts and allow patients to break from this rigid line of thinking.

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In my clinic, my partner, Dr. Simon Chamakalayil and I chose to utilize IV ketamine over the other formulations of ketamine. This decision was multifaceted but ultimately came down to efficacy and safety profile. Our most commonly received question is, “How well does it work?” While this is a perfectly reasonable starting point, context is important. If you are considering sending a referral for IV ketamine treatment, the patient has likely already failed at least two full antidepressant trials. In my experience, most referrals have already failed 4+ medication trials. 

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Traditionally, trying a 3rd or 4th medication next step because the original STAR-D trial had claimed that after the 4th step in their algorithm, 67% of patients reached remission. However, a recent reanalysis of this data suggests that “the [remission] rate was only 35.0% when using the protocol-stipulated HRSD and inclusion in data analysis criteria.” So you must ask yourself, “How likely is the 5th, 6th, 7th medication going to work?” And at what cost? When we get to this level of treatment, the side effect burden starts to add up: increased risk of metabolic changes, movement disorders, sexual side effects, weight gain, and more. 

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If you were to search Pubmed, you’d find a large list of studies with varying response and remission rates using IV ketamine treatment. As with most medications, real-world evidence often tells a different story. L. Alison McInnes, MD, Vice President of Scientific Affairs at Osmind, recently published the largest summary of real-world clinical efficacy. This summary describes replicated real-world studies eliciting a 50 % response rate (Cohen's d = 1.5) and a 30 % remission rate in patients with depression.

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They also showed that 80% of responders retained response status at 1 month and 60% at 2 months, even without maintenance infusions. Increases in symptoms were minimal even up to a year after the end of their induction series (6 infusions), suggesting that tachyphylaxis was not an issue for these patients.  This is magnitudes higher than any available evidence to support a third or more antidepressant trial in patients who have already failed 2 previous treatments. 

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Another key importance of ketamine in the treatment-resistant depression algorithm is safety and side effect profile. Based on available data, the most common side effects of ketamine are generally transient, mild, and self-limited. These include nausea, drowsiness, headache, elevated heart rate (~9 beats per min average), and a transient increase in blood pressure (average ~ 20mmHg systolic / 13mmHg diastolic).

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Bladder pathology has not been consistently reported in patients receiving therapeutic doses (0.5mg/kg) of IV ketamine in line with prescribing guidelines for depression. This is much more commonly seen in patients undergoing at-home oral ketamine and is thought to be due to the difference in ketamine metabolism with oral vs. IV routes of administration. 

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The last part of this discussion leads to which formulation of ketamine is best. In my opinion, and the opinion of many within this space, the largest amount of evidence supports IV ketamine over oral at-home ketamine. The treatment protocol has been in place since Dr. Robert Berman first published his landmark trial showing the antidepressant effects of IV ketamine in humans in 2000. Most clinics have adopted a similar protocol, with weight-based dosing of ketamine at 0.5mg/kg infused over 40 minutes. This allows for precision dosing because when delivered IV, ketamine is 100% bioavailable. 

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At-home ketamine comes with more risk of diversion, abuse and adverse outcomes. As with the unfortunate case of actor Matthew Perry, tragedy can occur when there is no one to monitor patients during treatment. At our clinic, patients are under close supervision by our team of physicians and nurses. Their vital signs are monitored, and the infusion can be stopped immediately if an unforeseen event occurs. With at-home ketamine, there is no way to “turn off” the treatment and no clinical staff to help intervene if needed. In addition, dosing is also much more difficult to establish because of the variable bioavailability of oral ketamine. Estimates suggest 8-30% bioavailability of oral ketamine formulations (oral and sublingual). 

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In conclusion, IV ketamine represents a step in the right direction in the treatment of depression. It offers hope when traditional medications have either failed or carried too much of a side effect burden to bear. Its proven efficacy, alongside its favorable tolerability profile and supervised administration, distinguishes it as a valuable option for patients suffering from treatment-resistant depression. But with this optimism, we must remember it is a treatment, not a cure. It is a tool in our diverse toolbox, not the all-in-one multi-tool it is sometimes marketed to be. 

Written by Osmind Community Advisory Board Member, Joe Pullara, MD. Learn more about Dr. Pullara by reading his full bio here.