Even though ketamine is considered by some to be the biggest antidepressant breakthrough in the past 50 years, an SSRI is almost always tried first. Sadly, SSRI’s work only about half the time on first attempt. Adjusting the dosage or switching to another monoamine antidepressant can sometimes address the problem. However, after failing two or more traditional antidepressant attempts, around 30% of depressed patients are designated “treatment resistant.” Ketamine is most often tried only after a patient receives this designation. (The various monoamine antidepressants are described in a previous post.)
Ketamine not only has an impressive 60-70% success rate in treatment-resistant patients, its antidepressant effect occurs almost immediately (versus 3-4 weeks for monoamine antidepressants)! Ketamine can also provide quick relief to acutely suicidal patients where its effectiveness is comparable to electroconvulsive shock (the gold standard for treating suicidality).
This post examines a number of issues relating to ketamine treatments of both depression and suicidality.
Why is ketamine a second-line antidepressant?
The first rigorous scientific demonstration of ketamine’s antidepressant effectiveness was in 2000. Since then, many studies have verified that ketamine is often effective when monoamine antidepressants are not. However, unlike monoamine antidepressants, ketamine treatment is “off-label.” Off label means that, while legal to use, the Food and Drug Administration (FDA) has not approved ketamine for this purpose.
Two questions that need addressing before proceeding are: 1) Since ketamine is more effective than the first-line SSRI’s, why isn’t ketamine tried first? (2) Since the scientific evidence strongly supports ketamine’s effectiveness, why hasn’t the FDA approved it as an antidepressant?
The major issue that prevents ketamine from being tried first is that ketamine is a DEA schedule-3 drug whose legal administration requires medical supervision. While ketamine is not expensive, its supervised administration is (more about cost below). In addition, these treatments need repeating on a regular basis since the antidepressant effects of ketamine are transitory. On the other hand, SSRI’s are much cheaper (even at full-cost, but often covered by insurance) and can be self-administered safely at home without medical supervision. So, if an SSRI is effective at treating depression and has manageable side effects, it is still considered the best option for most patients.
The reason ketamine is not FDA-approved for depression is that no one has sought approval. FDA approval requires extensive animal and human testing whose costs can sometimes exceed a billion dollars. Since the patent for ketamine expired long ago, it’s not worth the effort to go through this expensive process, only to be undercut by the availability of cheap generics.
Unfortunately, insurance companies often do not provide coverage for off-label drug treatments, particularly if expensive. Definitely a catch 22 for depressed patients who would benefit from, but can’t afford, ketamine treatments! In fact, since there is no commercial advertising for ketamine as an antidepressant, some insurance companies (and physicians) may not even be aware of this use.
Administration of Ketamine for Depression.
Before ketamine is administered, the patient typically is evaluated for suitability. As mentioned, most patients are in the treatment-resistant category. However ketamine is also appropriate for suicidal patients with a past history of depression or if a patient can not tolerate standard monoamine antidepressants. The patient must be judged healthy enough to receive ketamine by the standards of the American Society of Anesthesiologists. Contraindications can also include a past history of psychosis (including schizophrenia, schizoaffective disorder, or mania), hypersensitivity to ketamine, or prior drug abuse/addiction.
Ketamine is most often administered as a 0.5 mg/kg intravenous infusion over 40 minutes, although other routes, dosages, and time frames can also be effective. Administration normally occurs in a medical setting overseen by qualified professionals who monitor administration, acute-symptom recovery, and patient release. For experienced users, ketamine’s effects may be experienced as dreamlike, detached, relaxing, and rewarding. These positive effects also contribute to ketamine’s potential for abuse and addiction when used recreationally.
However, ketamine’s other acute effects can sometimes mimic experiencing a schizophrenic episode. These effects can be very unsettling and should be explained in advance. For example, ketamine can alter time and space perception and cause hallucinations in which you see and hear things that aren’t really there. Ketamine can also cause delusional thinking by impairing short-term memory and cognition. These psychotomimetic effects can sometimes trigger agitation and panic attacks. Since ketamine has analgesic properties, it also decreases the ability to feel pain which puts you at risk for hurting yourself without realizing it. Fortunately, these acute effects typically wear off in an hour or so. However, in psychiatrically predisposed individuals, ketamine can sometimes trigger a longer lasting psychiatric episode. Some patients feel that the most adverse psychological effect is a sense of dissociation, in which they feel strangely disconnected from themselves and the world about them. Paradoxically, in one study, the degree of dissociation was positively correlated with ketamine’s antidepressant effectiveness.
Other transient effects of ketamine can include a rise in blood pressure, nausea, vomiting, drowsiness, and dizziness. Vital signs are monitored throughout treatment and supportive care provided. However, these transient effects are well tolerated by most patients. Once the acute symptoms have worn off and vital signs have returned to normal, the patient can be released, usually within a few hours. However, patients are required not to drive or use heavy machinery for the rest of the day.
As ketamine’s acute effects wear off, most patients begin experiencing relief from depression almost immediately, with maximal effects around 24 hours later. This relief manifests as a reduction in negative thinking and in the obsessive negative spiral of depressive thought characteristic of depression. This relief is also described as an increased clarity of thought and as being different from the emotional smoothing caused by monoamine antidepressants. As with monoamine antidepressants, ketamine’s effectiveness in relation to a placebo is higher the more severe the depression. After a single treatment, ketamine’s antidepressant effect typically lasts about a week in unipolar depressed patients, although there can be substantial individual variation. While ketamine can also treat depression in depressed bipolar (manic/depressive) patients, it does not appear as effective. A single treatment for a bipolar patient usually loses effectiveness by day 3 or 4.
While IV infusion remains the most common method for treating depression, the other methods (subcutaneous, intramuscular, oral, sublingual, and intranasal) have been used successfully as well. Each has its own unique advantages and disadvantages in terms of ease of administration, dosage precision, first-pass metabolism, and absorption into the blood. While oral, nasal, and subcutaneous injections are convenient, these methods result in lesser, and more variable, absorption and also require higher dosages to achieve the desired result. Ketamine can also interact with other drugs that can alter ketamine’s effectiveness. For patients that do not respond initially, increasing the dosage, or administering repeated doses over a week or 2 can sometimes be effective.
In fact, repeated initial dosing is now the norm since it optimizes and prolongs effectiveness. Typical schedules might involve involve 4 treatments over a period of 1 or 2 weeks or 6 treatments over a period of 2 or 3 weeks. Sometimes the patient will be evaluated for their response to the first treatment as a basis for proceeding. However, all ketamine treatments must be administered by a qualified professional in a medical setting, making all treatments expensive. Most clinics charge between $350 – $800 per treatment. A full series of initial treatments can cost between $1000 – $12,000 and generally can be expected to last 2-3 weeks.
Since ketamine’s antidepressant effects are temporary, the patient will almost certainly need re-treatment. Ideally re-treatment should occur before the previous treatment has worn off. Since this time frame can vary from person to person, trial and error may be required. A single re-treatment every week or so is often sufficient to maintain the antidepressant effect and some patients have now been treated successfully for years. The acute side effects of ketamine also seem to diminish with re-treatment, however, there has not been rigorous research on long-term treatment on overall health which provides concerns.
There may be the possibility of unsupervised ketamine self-administration in the future which almost certainly lower costs and increase ketamine’s antidepressant use. Andrade (2019) described 3 studies to examine this possibility that involved drinking a ketamine solution. Once successful dosage and re-treatment schedules were clearly established under professional supervision, patients were able to successfully self-administer and treat their depression at home. The most common side-effects were light-headedness, sedation, and mild dissociative symptoms which typically subsided within an hour. Taking ketamine just before going to bed seemed to minimize these symptoms. In fact, Andrade (2019) makes the argument that, when the ketamine solution was sipped over a 10-15 minute period, the slow absorption into the blood made this method even safer than IV administration. Ketamine does taste very bad, but its taste can be masked by flavoring agents. A company called Mindbloom is attempting to make ketamine self administration at home possible, although expert’s are not in agreement as to whether we know enough for this to be a good idea.
While ketamine can help many treatment-resistant patients, its cost and typical methods of administration prevent it from being ideal. In addition, around 30% of treatment-resistant patients do not respond therapeutically to ketamine. Other strategies are necessary to try to help these patients.
(Since writing this post 3 years ago, it has become possible to get prescriptions for ketamine through telemedicine. While this is definitely helpful to many depressed patients it is also leading to serious misuse/abuse!)
Ketamine’s effects on other correlates of depression.
As with other successful depression treatments, effective ketamine treatment also normalizes other symptoms accompanying depression. For example sleep disturbances and biological rhythms are improved as are cognitive/memory issues. With regard to sleep, ketamine treatment restores the normal levels of slow-wave sleep most prevalent early in the night. One reason this is important is that slow-wave sleep corresponds to the time when the brain is maximally “cleansing itself” by exporting toxic metabolites into general circulation for removal. While the acute effects of ketamine disrupt cognitive processes, it is interesting that the longer term effects are the opposite. Impairments of general health such as metabolic syndrome and enhanced inflammation are also reduced in ketamine-treated patients. And finally, as with other successful antidepressant treatments, ketamine enhances synaptic plasticity and repair of limbic system and cortical abnormalities.
Ketamine treatment of suicidality.
Around 800,000 people worldwide die from suicide each year and many more harm themselves in unsuccessful attempts. Moreover, each unsuccessful attempt increases the likelihood of a subsequent attempt. Effective, accessible treatments are greatly needed.
All suicide treatments have limitations. Traditional monamine antidepressants can reduce suicidal tendencies in some patients. However, since these treatments require 3 or more weeks for effectiveness, they are not very useful for acutely suicidal patients. Electroconvulsive treatment (ECT) historically has been the gold standard for treating suicidally depressed individuals. Compared to monoamine antidepressants, ECT is both quicker acting and more effective. However, because of the specialized equipment and expertise required, access is limited, and wait lists can be long. ECT also has the downsides of being costly and causing some memory loss. And finally it’s mischaracterization in movies and the popular press has created an enduring stigma that, no doubt, reduces its use.
Nowadays, ketamine is being used off label as an alternative to ECT. Ketamine’s effectiveness appears comparable and its speed of action may actually be quicker. And, unlike ECT, virtually all hospitals are equipped to administer ketamine. For some patients a single ketamine treatment may be sufficient although multiple treatments over several days are more typical. Although IV infusion is the most common method of administration, oral, nasal, and IM administration make it even more convenient.
Case studies of suicidal unipolar and bipolar patients have, in many cases, demonstrated rapid and profound effectiveness in reducing the hopelessness that often underlies suicidality. However, some patients require multiple treatments over several days. Experimental support also comes from suicide rating scales administered both before and after ketamine treatment. Whether ketamine would be effective for suicidality associated with other psychiatric disorders such as schizophrenia or obsessive/compulsive disorder has not been conclusively determined.
However, as is the case for depression, ketamine’s anti-suicidal effects are transitory, a single treatment typically lasts about a week. As with depression, daily treatments over several days can prolong effectiveness. Although it seems likely that ketamine maintenance therapy can prevent recurrence, limited evidence is available. Although there are many parallels between ketamine’s effect upon depression and suicidality, there is some disagreement as to whether ketamine’s anti-suicidal effect is the same as its antidepressant effect. This argument seems to hinge, in part, on whether ketamine is effective for non-depressed suicidal patients.
In general, the research on ketamine and suicidality is much less developed than the research on depression. Research is currently underway to compare ketamine and ECT (the two most effective treatments), both separately and in combination, in hopes of optimizing future treatments.
S-ketamine (Esketamine) vs R-ketamine.
As described in the previous post, after synthesis, racemic ketamine is comprised of equal amounts of 2 mirror-image molecules called S-ketamine and R-ketamine. Although complicated, the 2 molecules can be chemically separated. Of the two, S-ketamine is the more potent antagonist of the NMDA receptor, resulting in better anesthesia/analgesia while also causing less drowsiness and cognitive impairment. Randomized, double blind, placebo-controlled research demonstrates that S-ketamine is also an effective antidepressant when administered either IV or intranasally, either by itself or in combination with monoamine antidepressants.
In March of 2019, the S-enantiomer (also called esketamine and patented as Spravato by Janssen Pharmaceuticals), became only the second drug approved by the FDA for treatment-resistant depression. Spravato received a FDA fast-track designation because of the great need for approved treatments for treatment-resistant patients. Spravato also received FDA approval for suicidially depressed patients.
While Spravato treatment is expensive (first month costs are estimated to be between $4000 and $6000), the out-of-pocket costs can be much lower because of insurance coverage (although some insurance companies might be reluctant to cover these costs). To Spravato’s advantage, the only other FDA-approved drug for treatment-resistant depression, Symbyax, is much slower acting, often requiring a month of treatment to be effective. (Symbyax is a combination of fluoxetine, an SSRI; and olanzapine, an atypical antipsychotic used for treating schizophrenia.) While Janssen is predicting blockbuster sales of Spravato, cost and accessibility may be issues for many patients.
To meet FDA requirements, Spravato is administered as a nasal spray and is required to be combined with a traditional oral monoamine antidepressant (typically an SSRI). While nasal administration is more convenient than IV infusion, Spravato’s administration still requires medical supervision. Although Spravato can be used off label for other purposes, it’s not clear that there would be much advantage over standard ketamine treatments.
While S-ketamine is clearly a more potent anesthetic/analgesic than R-ketamine, it’s not clear that S-ketamine is the more effective antidepressant. In fact, in animal models of depression, R-ketamine had longer lasting antidepressant effects with fewer adverse psychotomimetic side effects. R-ketamine also was better at enhancing the neuroplasticity that corrects depression-related neuropathologies. Perception Pharmaceuticals is currently investigating R-ketamine for antidepressant use in humans. However, rigorous comparisons in humans of the antidepressant properties of two enantiomers and the racemic mixture have not been performed.
Other Ketamine-like Drugs?
To displace the SSRI’s as a first-line antidepressant, a new drug would not only have to be more effective, it would also have to be safe enough for self administration without medical supervision. Attempts are underway to develop new antidepressants that have ketamine’s antidepressant property without its acute psychotomimetic side effects. Whether this approach can ultimately produce first-line antidepressants, or just better second-line antidepressants isn’t clear.
Ketamine is thought by some to produce both its antidepressant and its psychedelic effects by completely blocking ion flow through the NMDA ion channel. One strategy for developing new antidepressants would be to only partially block ion flow. The idea is that the reduced ion flow would be sufficient to provide the antidepressant effect, but insufficient to trigger the undesired psychotomimetic side effects.
One approach using this reasoning depends upon the fact that the NMDA receptor has binding sites for other molecules as well. The molecules binding these alternative sites are referred to as allosteric modulators. When bound, these modulators very slightly alter the 3-D shape of the NMDA receptor which, in turn, either increases or decreases the ability of glutamate to open the NMDA ion channel.
As seen in Figure 1, glycine is one such allosteric modulator whose binding is a necessary precondition for glutamate to open the ion channel. To make matters more complicated, there is another binding site, termed the GlyX site, separate from the glycine site, that modulates the ability of glycine to bind the glycine binding site. When a GlyX agonist binds the GlyX binding site, it blocks glycine binding. On the other hand, a partial GlyX agonist only partially blocks glycine binding. Thus a partial agonist should cause the desired partial reduction in glutamate-activated ion flow.
Joseph Moskal of Allergan Pharmaceuticals has, in fact, developed a partial agonist for the GlyX binding site, originally given the code name GlyX13 (and later the brand name of Repastinel). In animal testing, Repastinel had rapid antidepressant effects similar to ketamine, but without ketamine’s pronounced psychotomimetic side effects. As a result the drug was fast tracked through FDA testing. Unfortunately, animal results don’t always translate to humans, and in FDA Phase III human trials in 2019, Repastinel was not better than a placebo as an antidepressant. As a result, further development of Repastinel was discontinued.
However, Allergan has not given up on this approach and currently has another drug in development that also works through the GlyX binding site (code name NRX-1074, also known as Apimostinel) . Apimostinel differs from Repastinel in being a more potent partial agonist and can be administered either IV and orally, in contrast to Repastinel which could only be administered IV. Preliminary animal testing was consistent with antidepressant action without psychotomimetic side effects. Hopefully this drug will succeed in human trials.
Several other pharmaceutical companies have similar drugs under development, targeting both NMDA receptors as well as other types of glutamate receptors in hopes of developing better antidepressants. While one of these antidepressant candidates may prove effective and have fewer side effects than ketamine, most will likely require medical supervision and target mainly treatment-resistant patients unresponsive to monoamine antidepressants. While these new drugs will be expensive, the good news is that with FDA approval, insurance coverage becomes more likely.
A Glutaminergic Model of Depression?
Abnormal glutamate functioning in the etiology of depression is certainly evidenced by excessive glutamate neurosecretion and a decrease in glutamate synapse formation in depressed individuals, as well as by ketamine’s effectiveness in correcting these abnormalities. In addition the brain areas most implicated in depression (the limbic system and cortex) are heavily dependent upon the functioning of glutamate-secreting neurons. In fact, neuroimaging indicates these brain areas are preferentially targeted by ketamine. Consequently there is good reason for thinking that glutamate malfunctioning may be central to understanding depression. However, this post is already too long 🥱 ……… so a post for another day.
The next post will look at another class of psychedelic drugs (including psilocybin, LSD, and ayahuasca), that also appear more effective than than the current first-line SSRI antidepressants.
Some articles for further reading.
The reviews by Andrade cover the full range of issues relevant to ketamine’s antidepressant use and are intended mainly for educating clinicians. The other reviews are written for a more technical scientific audience. Much of the information presented in this post can be found in these reviews.
Andrade, C. (2017a). Ketamine for depression, 1: Clinical summary of issues related to efficacy, adverse effects, and mechanism of action. The Journal of Clinical Psychiatry, 78(4), e415-e419. doi:10.4088/JCP.17f11567 [doi]
Andrade, C. (2017b). Ketamine for depression, 2: Diagnostic and contextual indications. The Journal of Clinical Psychiatry, 78(5), e555-e558. doi:10.4088/JCP.17f11629 [doi]
Andrade, C. (2017c). Ketamine for depression, 3: Does chirality matter? The Journal of Clinical Psychiatry, 78(6), e674-e677. doi:10.4088/JCP.17f11681 [doi]
Andrade, C. (2017d). Ketamine for depression, 4: In what dose, at what rate, by what route, for how long, and at what frequency? The Journal of Clinical Psychiatry, 78(7), e852-e857. doi:10.4088/JCP.17f11738 [doi]
Andrade, C. (2017e). Ketamine for depression, 5: Potential pharmacokinetic and pharmacodynamic drug interactions. The Journal of Clinical Psychiatry, 78(7), e858-e861. doi:10.4088/JCP.17f11802 [doi]
Andrade, C. (2019). Oral ketamine for depression. Journal of Clinical Psychiatry, 80(2), e1-e5.
Corriger, A., & Pickering, G. (2019). Ketamine and depression: A narrative review. Drug Design, Development and Therapy, 13, 3051-3067. doi:10.2147/DDDT.S221437 [doi]
Matveychuk, D., Thomas, R. K., Swainson, J., Khullar, A., MacKay, M. A., Baker, G. B., & Dursun, S. M. (2020). Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers. Therapeutic Advances in Psychopharmacology, 10, 2045125320916657. doi:10.1177/2045125320916657 [doi]
Muller, J., Pentyala, S., Dilger, J., & Pentyala, S. (2016). Ketamine enantiomers in the rapid and sustained antidepressant effects. Therapeutic Advances in Psychopharmacology, 6(3), 185-192. doi:10.1177/2045125316631267 [doi]