Psychiatrists have spent decades of man-hours in the attempt to find a cause-and-effect relationship between neurological metrics and the pathology of depression. This causal relationship has alluded the psychiatrist. Markers such as neuroinflammation or reduced activity in the hippocampus are common in depression, yet also existent in diseases like Alzheimer’s and Schizophrenia. This presents the question; what is the biochemical distinction between these disorders? The past decade has seen a flood of mechanistic research, primarily due to the recent introduction of ketamine as a novel rapid-acting antidepressant. The efficacy of ketamine upon Major Depressive Disorder cannot be overstated.

A Brief History of Antidepressant Medication

Drug development and etiological theory proceed in lockstep; each influencing the other and yet requiring the other to be validated. It was not until the discovery of the tricyclic antidepressant (TCA) Imipramine, that the first consensus etiology of depression was formed. Harvard Psychiatrist Dr. Joseph Schildkraut stated in a lecture to his peers, “some depressions, if not all, are associated with an absolute or relative deficit of catecholamines, particularly noradrenaline, in important adrenergic receptors in the brain. Contrariwise elation may be associated with an excess of such amines.” (Schildkraut) The catecholamine hypothesis was the logical conclusion of most psychiatrists, given that the drugs most effective at treating depression acted by increasing the concentration of noradrenaline. The field–having been in its infancy–sought to find a simple mechanism that was not just convenient for explanatory power, but also for profit.

Selective Serotonin Reuptake Inhibitors appeared on the drug market in the 1980 and 90s. These drugs had a separate mechanism of action, but they were similar enough to the catecholaminergic drugs that the theory wasn’t abandoned. All the rise of Prozac did was expand the scope of neurotransmitters that could be released. The catecholamine hypothesis was became the popular monoamine hypothesis, or as advertised to laymen, the ‘chemical imbalance’. Dr. Christopher M. France and Dr. Paul H. Lysaker reviewed the use of this term in a 2007 article stating, “… this chemical imbalance explanation remains unproven and is potentially invalid. The significant limitations of the imbalance explanation, however, have not prevented U.S. laypersons (as well as some treating professionals and other stakeholders) from being urged (e.g., via DTC advertisements) to accept the explanation as a likely fact” (France et. al.). Their claim is that the chemical imbalance theory as advertised misleads the consumer as it posits the cause of depression as a switch that is yet to have been turned on. The switch in this scenario is the increase in concentration of “monoamine” neurotransmitters, including serotonin, norepinephrine, and to a lesser extent at the time — dopamine.

The ‘chemical imbalance’ was widely regarded by academia to be an unlikely explanation, not worth examining to determine pathology or etiology. Researchers consistently found that SSRIs failed to relieve depressive symptoms in nearly a third of the depressed population. In the attempt to compete with Prozac, a second boom of antidepressant drug development began in the late 1980s. Anti-serotonergic drugs such as Nefazodone and Mirtazapine­—introduced to the market in 1994 and ‘96 respectively—had efficacies similar to pro-serotonergic drugs. The success of these new drugs—many of which did not increase serotonin at all—prompted renewed interest in etiological research. It made little sense that both pro-serotonergic and anti-serotonergic agents could contribute to antidepressant effects. In the effort to tease out new pathologies, researchers used non-antidepressant drugs on the depressed patient population, one of which was ketamine.

Initial Uses of Ketamine

Ketamine is an anesthetic derived from the dissociative drug, Phencyclidine (PCP). It was first synthesized by the biochemist Dr. Calvin L. Stevens in 1962. His goal was to modify the PCP molecule to keep its anesthetic properties but eliminate its deleterious side effects: hallucination and paranoia. To this end he succeeded, it began to be used as a form of anesthesia and in the paramedic context, as a chemical restraint. Ketamine was first used in the treatment of depression as an accident. There were numerous case reports observing a pattern of paramedics using ketamine to restrain people attempting to kill or otherwise harm themselves; if the patient had a prior history of depression, they would often report that many of their symptoms were relieved within the week. Eventually, this pattern of ketamine administration and subsequent remission of symptoms was noticed by Dr. John Krystal – now Chair of Psychiatry at Yale.

Krystal and his lab published a series of pilot trials: studies that use designs of clinical trials but on smaller samples. The first trials established the safety of sub-anesthetic doses of the injected drug. A second wave of trials from 2000-2014 performed by other labs sought to establish the efficacy of the drug relative to placebo or other antidepressants. A retrospective published in 2014 by Dr. Alexander McGirr et. al. concluded that, “After 7 days, the pooled OR was 4.00 (95% CI 1.52-10.51, z = 2.81, p < 0.01) for clinical remission and 4.87 (95% CI 2.24–10.55, z = 4.01, p < 0.001) for clinical response, indicating a significant difference in outcome favoring ketamine.” (697) The odds ratio refers to the multiplier by which it is more likely that a patient reached an outcome. For instance, in this study the authors found that only one week after a single dose, patients receiving ketamine had a 400% greater likelihood of remission than patients receiving placebo. This was coupled with a mean effect size of 0.9 after one day, greater than what any other antidepressant had achieved in a randomized trial. While it was well established that ketamine could greatly attenuate suicidality; it was only after this second wave of trials that clinicians began to take the idea of ketamine as an antidepressant seriously.

Etiologies and Enantiomers

The publishing of these trials prompted scrutiny upon the current state of etiological research. While theoretical and mechanistic research accelerated after the introduction of the “atypical” antidepressants, there was little in the way of data verifying these ideas. A growing theory was that of glutamatergic dysfunction, an overexcitation of the NMDA glutamate receptor leading to an inability for cells to communicate. The advent of ketamine – an effective glutamatergic antidepressant – provided researchers with a tool they could use to validate their theories. In demonstrating therapeutic efficacy, the researchers using ketamine shifted the long-standing paradigm of depression away from a disorder of monoamines.

Following successful trials and a preponderance of mechanistic data, the lab of Dr. Kyle Lapidus and his colleagues at Yale published the results of a 2014 trial on a novel means of administering ketamine – via an intranasal spray of ketamine. Two years later, Dr. Ella Daly et. al. performed an identical trial titled, “Intranasal Esketamine in Treatment Resistant Depression - A Double-blind, Randomized, Efficacy and Dose Response Study”. This 2016 study used the “left-handed” isomer of ketamine – esketamine, in order to test the specific mechanism of its antidepressant effects. The trial found that, “[a]t the end of OL phase (day 74; n=34), the majority of remaining patients were responders (n=22/34; 64.7%), and 32.4% patients (n=11/34) met remission criteria.” (Daly et. al.) While not on par with intravenous ketamine, intranasal esketamine was similar in efficacy to—and quicker to activate than—traditional antidepressants. Many scientists maintained that the primary mechanism by which ketamine provided its antidepressant effect was that of NMDAR antagonism. Esketamine, as an enantiopure version of ketamine, was very specific in its targeting of this NMDA receptor. However it as unknown whether or not these effects could be achieved by NMDA-independent mechanisms.

The FDA designated intranasal esketamine as a breakthrough therapy for the indications of depression with suicidal intent. This designation gives a drug preferential treatment for clinical trials. The FDA footed a great portion of the bill by renting hospital space, gathering patients, and other trial related expenses. Within three years, the esketamine molecule was on the market as a nasal spray that could be administered every three days in a licensed clinic. While it was a success for clinicians, researchers reiterated that ketamine had a greater antidepressant effect and even reduced incidence of side-effects. A meta-analysis comparing the two written by the Chief of the NIH Pathophysiology Branch; Dr. Carlos Zarate stated, “… intravenous ketamine demonstrated more significant overall response and remission rates, as well as lower drop-outs due to adverse events. As well, more substantial response and remission rates were observed in crossover trials, while more significant improvements in depression rating scores were observed in parallel trials.” (Zarate et. al) The amount by which ketamine exceeded the performance of esketamine was greater than two-fold measured by rates of remission. Despite being only one-half of the full mixture that is racemic ketamine, esketamine seems to have a far greater likelihood of adverse effects, including those that may increase abuse potential.

Opposition to Therapeutic Ketamine

Opposition to the use of Ketamine as an antidepressant stems from a healthy amount of rational skepticism. There are two primary groups in opposition to the use of ketamine for depression. Many clinicians fear that depressive patients will become addicted to the substance and many researchers dispute the methodological quality of the ketamine trials. Both groups are important to the continuing practice of psychiatric ketamine use. Ethical and efficacious standards of care cannot be created without such critiques.

Ketamine Addiction

Ketamine is not physically addicting in the same sense that amphetamines or opiates are. Despite this, there is a preponderance of evidence showing that ketamine addiction is common phenomena. An article from Dr. Kokane and colleagues entitled, “Overlap in the neural circuitry and molecular mechanisms underlying ketamine abuse and its use as an antidepressant,” reviewed the history of ketamine’s abuse potential. He stated, “Illicit use of ketamine began in the United States in the 1970s [156] and soon spread more widely aided by the emergence of the “rave” culture [67].” (Kokane et. al.) Ketamine was used at raves due to its “psychotomimetic” effects which include scenery slicing, macropsia, and environmental cubism as described in the Effect Index’s catalogue: the “Subjective Effect Index” (Index). Dr. Kokane’s initial research on ketamine was not upon its antidepressant effects, rather he studied its chronic use among addicts. This distinction may seem small as it’s the same drug, however clinical and recreational use differ significantly both in dosage and dose frequency.

Dr. Kokane contends that the use of ketamine as an antidepressant will lead patients to develop dependence and deleterious cognitive side-effects. In his “Overlap” study, he states, “…reports have indicated that a subset TRD patients who were repeatedly treated with ketamine developed ketamine dependence, indicative of ketamine’s abuse potential [12,94,150]” (Kokane et. al.) The evidence he uses to indicate this claim is weak. Of the three citations he provides, two are case reports of depressives self-administering ketamine without clinical approval and the other is a narrative review that speculates upon potential risks using those same two cases. The first report was recorded by Dr. James Liu and colleagues, “Intensive ketamine use for multiple years: A case report.” The report follows up on a chronic abuser of ketamine, who claimed he was using it to cure his depression. It was noted, “… that he did not experience a withdrawal syndrome nor did he have any observable cognitive deficits upon cessation of use” (Liu et. al.) The lack of withdrawal or cognitive deficits after, “… large doses of ketamine (1-3 g) on a daily basis over a period of 5 years” (Liu et. al.) is both astounding and should be of great assurance to those who oppose the use of ketamine in psychiatry. After reading the report I have come to believe that Dr. Kokane either did not read it or he willfully misunderstood it. The lack of withdrawal or cognitive deficit is contrary to the very claims he cites this study to prove. Of importance is the dosage of ketamine used by this patient – over 50x that which is used in psychiatric practice. The report is frankly useless. 

Recreational and psychiatric ketamine have vastly different effects. While both types of administration use the same substance, the dosages are different by multiple orders of magnitude. This was explained by the Dr. Scott Alexander, a psychiatrist initially hesitant to prescribe ketamine due to its deleterious effects on the bladder and brain. Upon reviewing the literature, he found that no patient taking ketamine for depression had experienced these apart from the two case reports cited by Kokane. His position is explained in the 2021 blog “Drug Users Use A Lot Of Drugs.” In which he states, “This Chinese study and this UK study analyze recreational ketamine users, and both find they take about 3g daily, every day. That's 90,000 mg over the course of a month. Again, that's 280 mg for the psych patients and 90,000 mg for the recreational users.” (Alexander) The same pattern is observed between addicts taking 3.5 grams every month and the 90-gram figure above. Alexander paraphrased a review article from Morgan et. al stating, “They find that severe abusers, who are taking an average of 60,000 mg/month, experience cognitive problems. But mild abusers, who take more like 3,500 mg/month, don't.” (Alexander) As of 2024, he prescribes oral ketamine off-label in his practice to great efficacy and is yet to have seen any patient become dependent. Given the lack of evidence for the claim—that patients using psychiatric doses of ketamine will become dependent—and the preponderance of evidence that this is not the case, it is unlikely that this is a concern worth halting approval of ketamine for.

Issues of Methodology

The second argument is that ketamine trials are insufficiently blinded to accurate compare effects between a placebo and a treatment group. Blinding is the practice researchers use to keep secret which group a patient is part of. If a patient is aware they are part of the non-treatment group, they may not experience the placebo effect and would thus be an insufficient control for the patient receiving treatment. This issue was described by Dr. Stuart Ritchie in his essay “Everything you need to know about psychedelics and mental illness.” Dr. Ritchie is a science communicator primarily known for debunking studies regarded as too good to be true, quite a few of which come from the field of psychedelic medicine. In this essay he describes issues with psilocybin trials, but ketamine is hard to blind for the very same reasons, “If you know (or strongly suspect) that you’re in the experimental group, you might be motivated to report stronger results on the questionnaire. … Conversely, if you know you’re in the control group, your mood might slump, since you know that you’re taking a useless inert pill.” (Ritchie) The issue with blinding in ketamine trials is that patients know which group they’re in, 90% of the time. Ketamine at antidepressant doses induces a state in which the patient experiences dissociation and sometimes even visual distortion. In order to truly blind study participants: one would either have to give them an active control — a drug with similar acute effects to ketamine — or would have to anesthetize the patient so they don’t experience any acute effects.

Since the publishing of Dr. Ritchie’s essay, these studies have been done. In 2023 a study was performed in which patients were anesthetized during surgery and given either ketamine or an extra dose of the anesthetic propofol. Dr. Liu and colleague’s study, “Randomized Trial of Ketamine Masked by Surgical Anesthesia in Depressed Patients” reported, “a single dose of intravenous ketamine delivered during surgical anesthesia had no greater effect than placebo in acutely reducing the severity of depressive symptoms.” (Liu et. al.) There was zero significant difference between ketamine and the propofol control group. Despite this conclusion, the study is almost entirely useless. While there were no differences between ketamine and propofol, it was not the case that both were benign; both groups experienced dramatic antidepressant effects, the same sizes as those of ketamine trials. Dr. Scott Alexander reviewed the study in another blog entitled, “Does Anaesthesia Prove Ketamine Placebo?” He presents two main contentions with the study. Quoting an article by PsyPost Founder Dr. Eric Doyle, he claims, “The anaesthetic propofol, used in about 88% of these patients, “may trigger rapid, durable antidepressant effects”, with a purported effect size well above that of SSRIs” (Alexander) Using propofol artificially shrinks the relative effect sizes. To regard ketamine as useless, one must ignore the part where it states that it preformed just as well as another antidepressant drug. Dr. Alexander’s second contention is with the specific scale they used to measure depression, “MADRS asks - for example - about disturbed appetite… But surgery naturally disrupts appetite… MADRS asks about disturbed sleep, but sleep in a hospital ward is also naturally disturbed. MADRS asks about concentration problems, but post-surgical patients are often on lots of painkillers” (Alexander) That the control group was given an antidepressant on par with ketamine, that all subjects were assessed while on opiates, and that they were given a questionnaire not suited to hospital life; these factors confound the results to a degree such that the trial has no bearing on ketamine’s efficacy.

The second proposed way to blind patients is with an active control. These studies have borne more fruit than the anesthetic studies. Midazolam is a dissociative sedative—like ketamine—with little to no antidepressant effects. There have been multiple trials comparing midazolam to ketamine, the largest of which was published in 2023 by Dr. Colleen Lee and thirty-seven other researchers. The study, “Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study)” found that relative to midazolam, “the reduction in mean MADRS score by treatment end differed between groups by 5.5 points (95% CI 2.1–8.7), and response rates (29% v. 4%, P = 0.001) and remission rates (MADRS ≤ 12) (22% v. 4%, P = 0.007) were greater, favouring the ketamine group” (Lee et. al.) Also of note was that both groups didn’t know which treatment they were receiving, only guessing correctly after 4 weeks into the study at which point antidepressant effect had already been noted.

Concluding Remarks

Ketamine is an effective antidepressant regardless of control, whether that be an active one like midazolam or an inert one like saline. Concerns of abuse potential or side-effects are unfounded, as are concerns with long term (>1y) use as studied in recreational users of lower doses. Concerns that insufficient blinding are responsible for ketamine’s antidepressant effects are similarly unfounded. The critiques of ketamine’s use in psychiatry, while rational, stem from misunderstandings about its effects at different doses and unfamiliarity with trials addressing methodological issues.

Of the drugs developed in the wake of the ‘atypical’ antidepressants, none have contributed more than ketamine to the science and treatment of depression. For the first time in decades, researchers and clinicians have been bridging the gap between neurobiology and the psychiatric phenomenology of depression. Without the discoveries about the glutamatergic system made using ketamine, theories of consciousness or perception such as Janina Hesse’s Brain Criticality or Karl Friston’s Free-Energy Principle would have no basis. While this paper focused upon its efficacy in the clinical context, ketamine has been similarly–if not more–influential in the study of how neurobiology gives rise to phenomena.

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