Introduction
In recent years, ketamine, its individual enantiomers, and related compounds have been a major focus of research and clinical development for the treatment of depression. With the United States Food and Drug Administration (USFDA) approval of esketamine for the indication of treatment-resistant depression in 2019, use of the treatment has rapidly increased in clinical settings. As such, it is important for clinicians and researchers to be familiar with the current state of knowledge surrounding efficacy, safety, and proposed mechanisms of action of this treatment modality. It is equally important to be aware of the remaining unanswered questions related to the treatment in order to provide the best possible care to patients and promote meaningful translational research. In this chapter, we briefly review the history of ketamine, explore proposed mechanisms of action, review data pertaining to efficacy and safety, and consider “real-world” usage and the challenges to implementation. Future directions related to the optimization of ketamine and the development of related compounds will also be discussed.
History
Ketamine discovery
Like most meaningful discoveries, the road leading to the development of ketamine as a treatment of mood disorders was long and winding, punctuated by dead ends and fueled by serendipity. In 1956, V. Harold Maddox, a chemist at Parke-Davis, created a new chemical process which resulted in the creation of phencyclidine ( ). Initially used as an anesthetic in animals ( ), phencyclidine was later tried in humans ( ). Although it was generally considered a safe anesthetic, it produced a severe emergence delirium in some patients ( ), and later studies raised concerns that the drug could cause psychotomimetic symptoms similar to schizophrenia ( ). As such, phencyclidine was deemed inappropriate for human use, motivating work to identify related compounds that might be more appropriate for clinical applications. One of these compounds, CI-581, a short-acting agent with favorable anesthetic properties, was synthesized by Calvin Stevens in 1962. Considering the compound contained both a ketone and an amine in its structure, it was named ketamine ( ). Domino and Corssen first reported on the use of ketamine in humans in a study conducted on prisoners at the Jackson Prison in Michigan in 1964 ( ), coining the term “dissociative anesthetic,” that remains in use today.
For over 50 years, ketamine has been used as an anesthetic agent. Originally patented for veterinary use in 1963 and receiving a USFDA indication under the name Ketalar for human use as an anesthetic treatment in 1970 ( ), it rapidly became a favored field anesthetic given its sympathomimetic properties and analgesic effects that outlast its anesthetic effect ( ). Ketamine was first placed on the World Health Organizations Essential Medicines List in 1985 related to its ease of use and safety profile that make it especially appealing in underresourced health systems. In recent years, illicit and recreational use of ketamine in some countries has prompted renewed evaluations of ketamine’s role in the worldwide medical system and the possible need for increased levels of control. However, four reviews of the drug over the past 15 years by the World Health Organization (WHO) consistently recommended that ketamine should not be placed under increased international control that could limit access to the drug ( ).
Rationale for use in depression
A series of evolving hypotheses and discoveries inspired the studies that ultimately demonstrated ketamine’s antidepressant properties. To our knowledge, the first reported study of ketamine’s potential use in the treatment of psychiatric illnesses was done in 1973 in Shiraz, Iran. Khorramzadeh and Lotfy treated 100 patients carrying various psychiatric diagnoses with increasing doses of ketamine. Astonishingly, they reported improvement in psychiatric symptoms in 95% of patients treated with 0.4–0.6 mg/kg or slightly higher (0.7–1.0 mg/kg) doses of ketamine ( ). The rationale behind this trial was based primarily on the psychological effects of ketamine and the potential for it to improve the psychodynamic healing process, as the underlying neurobiological effects of ketamine had not even been well understood at this time.
In the early 1990s, Skolnick and colleagues at the NIH explored the effects of N -methyl- d -aspartate (NMDA) glutamate receptor antagonists on the depression-like behaviors caused by inescapable stress in mice ( ). Based on the knowledge that NMDA receptors are required for long-term potentiation (LTP), which is impaired by inescapable stress, and also by the fact that traditional antidepressants are effective in reversing the depressive-like behaviors caused by inescapable stress, they hypothesized that NMDA receptor antagonists could produce similar antidepressant effects in mice. Using standard rodent behavioral assays they were able to successfully demonstrate antidepressant-like effects with a competitive antagonist, a noncompetitive antagonist, and a partial agonist of the NMDA receptor.
Around the time the findings of the NIH lab were being published, evidence demonstrating notable stress-related effects on glutamatergic neurotransmission was mounting. Studies showing acute stress-related increases the extracellular glutamate levels, especially in hippocampus, amygdala and PFC and dramatic alterations in the membrane trafficking of NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the prefrontal cortex were increasing interest in the potential role of glutamate in the pathogenesis and pathophysiology of mood disorders ( ). Meanwhile, in the chronic stress setting there was evidence of changes in the regulation of glutamate release in PFC following exposure to chronic stressors. In sum, the emerging series of preclinical studies provided increasing supportive evidence to suggest glutamate’s contribution to pathogenic pathways leading to depression and the potential to target the system in the development of novel treatments for mood disorders. This background paired with the recognition that altered function of cortical circuits, that are predominantly glutamatergic in nature, were critical to the pathogenesis and pathophysiology of mood disorders were specifically cited as the driving impetus ( ) for the seminal study by that first demonstrated the antidepressant effects of ketamine in a small controlled clinical trial.
Since the publication of the initial findings suggesting ketamine possessed rapid and robust antidepressant effects there has been a tremendous amount of reverse “bedside to bench” translation providing more information on its mechanisms of antidepressant action. Multiple new mechanisms of action have been proposed in addition to those hypothesized previously, and it is possible, in fact likely, that several mechanisms uniquely contribute to the overall antidepressant effect. At present, evidence of ketamine’s proximal effect as an NMDA receptor antagonist via binding to its phencyclidine site ( ; ) serving as the initial step in antidepressant process remains best supported by the current evidence. The antagonism of NMDA receptors was originally postulated to protect against the excitotoxic effects of elevated levels of extracellular glutamate levels and the associated downstream consequences. However, it was also noted that selective NMDA receptor antagonism can decrease the firing of the inhibitory GABAergic neurons, resulting in transiently increased levels of glutamate release, at times referred to as a glutamate surge. The increased levels of glutamate released into the synaptic space in turn engage other non-NMDA glutamate receptors such as the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. Activation of the AMPA receptor is believed to activate several intracellular signaling cascades and eventually facilitate the process of synaptogenesis ( ; ). Other mechanisms such as effects on opioid receptors ( ), immune function ( ; ), and monoaminergic pathways ( ), among others ( ), have also been reported, but have not been as extensively studied. Beyond the more proximal effects of ketamine’s pharmacology there is also great interest in understanding how the effects are transduced through changes in brain circuitry ( ; ). The range of possible critical mechanisms of antidepressant action and the unique properties of the various forms of ketamine should be considered in review of the efficacy data presented below.
Efficacy
The relation of molecular structure and pharmacology to function and response
When considering the data on efficacy presented below it is important to remember ketamine is a chiral molecule comprised of two enantiomers, S-ketamine (esketamine) and R-ketamine (arketamine). The racemic mixture was initially used for clinical purposes and continues to be the most common form used for anesthetic purposes in North America. However, the S-ketamine enantiomer is also commonly used in Europe for anesthesia based on reports suggesting improved tolerance ( ). R-ketamine is not currently approved for clinical use but remains under development for potential use in neuropsychiatric disorders. The specific properties of the individual enantiomers in relation to the clinical benefits and untoward effects associated with the treatment of mood disorders are currently an area of great interest.
Racemic
The use of racemic ketamine as a therapeutic agent in mood disorders has now been studied for more than two decades and has repeatedly been demonstrated to have efficacy with a generally acceptable safety profile in the treatment of major depressive episodes in numerous small to moderate sized clinical trials. Recent meta-analytic studies ( ; ; ) confirmed the early findings of a ketamine’s significant efficacy advantage over control from 24 h to 7 days post administration of a single dose by both continuous severity measures and binary response and remission rates. The peak response was most commonly reported to be seen over the first 24 h, but while attenuated, the antidepressant effect was still present with small to medium effect sizes 1-week following the administration of a single dose. Typical response rates ranged between studies but were most commonly in the range of 50% for treatment-resistant depressed (TRD) patients and greater for non-TRD patients with odds ratios of response typically approximating five overall compared to placebo for the first week after treatment. There are fewer randomized controlled studies examining repeated dosing with racemic ketamine. However, the limited studies that are available show relatively large advantages of ketamine over placebo for periods of 2–3 weeks with repeated dosing.
S-Ketamine
The use of individual ketamine enantiomers was initially reported by who compared them to the effects of racemic ketamine. They found that S-ketamine produced anesthetic effects with only about half the dose required for racemic ketamine. The quality of anesthesia was similar to the racemic mixture, but the recovery with individual isomers was reported to be persistently shorter. After these findings, S-ketamine was considered as a more potent anesthetic agent, and has been approved and regularly used as an anesthetic in Europe ( ). The fact that S-ketamine has three to four times the affinity compared to R-ketamine for the PCP binding site of the NMDA receptor is believed to explain the increased potency of the enantiomer ( ).
While the use of ketamine in TRD predates esketamine, the most vigorously studied formulation to date for the treatment of TRD is intranasally administered esketamine. Several large multicenter double-blind randomized controlled trials of intranasal esketamine in conjunction with another oral antidepressant were conducted as part of the submission package for USFDA approval in the treatment of TRD ( ). To address a major limitation of ketamine treatment access, the need for intravenous (IN) drug delivery, IN delivery was considered as a possible alternative method of delivery. Nasal insufflation is considered simpler and more comfortable for patients but requires a significant volume of medication to be administered due to issues with delivery and bioavailability. Esketamine, with its higher affinity for the NMDA receptors and consequent greater expected potency ( ; ; ), was reasoned to require lower volumes that could more practically be administered intranasally. In the proof-of-concept phase of development, esketamine’s antidepressant effects were initially studied using IV delivery. This smaller study supported the idea that esketamine could have similar antidepressant responses with reduced doses and plasma levels compared to racemic ketamine ( ).
With the initial data suggest esketamine’s efficacy in MDD, a series of clinical trials were launched to examine the efficacy and safety of intranasal esketamine in the treatment of TRD. These studies consisted of two phase three randomized controlled trials in adults younger than 65 years of age ( ) with another in adults older than 65 ( ). Additionally, a randomized withdrawal study was conducted ( ), along with a long-term 1 year open-label study ( ). Collectively, results from these studies which included over 1000 participants provided adequate efficacy and safety data to lead the USFDA to approve esketamine IN for treatment of TRD alongside an oral antidepressant in March 2019 ( ). It is important to note that as part of the approval, the USFDA required a Risk Evaluation and Mitigation Strategy (REMS) program to monitor the treatment and to ensure it was only conducted in appropriate settings and with adequate monitoring and oversight ( ).
R-Ketamine
As mentioned earlier, in comparison to S-ketamine, R-ketamine has a lower affinity for the PCP site of the NMDA receptor. However, it also weakly interacts with the sigma sites. In addition, R-ketamine produces unique alterations in cerebral metabolic rates of glucose across brain regions, especially in left insula and temporomedial cortex. It also seems not to produce the same quality of psychotomimetic symptoms as racemic or S-ketamine, but rather has been reported to produce a state of relaxation ( ). Interestingly, there have been reports of R-ketamine having superior antidepressant-like responses in rodent models of antidepressant action ( ). Other rodent studies have also suggested that a metabolite of R-ketamine, (2 R ,6 R )-hydroxynorketamine (RR-HNK), is both necessary and sufficient to produce the antidepressant-like response, in part suggesting NMDA receptor activity was not central to the antidepressant response as the metabolite has very little affinity for the receptor ( ). However, contrasting findings have also been reported regarding the efficacy of this metabolite in other preclinical studies ( ). In sum, the combined findings of R-ketamine possibly having reduced negative acute effects on cognition and emotion as well as possible superior antidepressant efficacy in rodent models have been the foundation for the recent interest in R-ketamine as a possible treatment for mood disorders. To date, the limited data available seem promising ( ); however, further investigations are clearly required to assess the true safety and efficacy of this treatment in humans.
In summary, there is now clear evidence demonstrating the efficacy of both racemic and esketamine in the short-term treatment of symptoms in patients with major depressive disorder, especially those considered resistant to standard forms of oral antidepressant medications. Although there are some attempts to compare the relative efficacy of the two formulations (racemic ketamine delivered IV and esketamine delivered IN) ( ) great caution should be used in interpreting these reports as comparisons across trials are notoriously complicated and potentially misleading ( ). At present, only intranasal esketamine spray has been approved for use in the treatment of adults with treatment-resistant depression and for the treatment of depressive symptoms in adults diagnosed with major depressive disorder experiencing suicidal ideation.
Dose
General
Many attempts have been made to assess the effects of ketamine dose on various physiological states in both humans and animals. The findings suggest a clear dose-dependent response to ketamine with an excitatory effect on regional brain function at lower doses and a diffuse inhibitory response with higher, anesthetic doses of ketamine. Preclinical studies done in rats using in vivo microdialysis and magnetic resonance spectroscopy show that ketamine at lower doses increases glutamate efflux and cycling with corresponding cellular and behavioral changes suggestive of antidepressant-like effects ( ; ). However, at higher doses, the opposite is observed, with a decrease in neurotransmitter cycling and a corresponding disappearance of the cellular and behavioral changes suggestive of antidepressant effect ( ; ; ). This preclinical data suggest that ketamine may have a relatively narrow therapeutic window of peak efficacy as an antidepressant.
Another important factor affecting dosage and possibly antidepressant efficacy is the bioavailability of ketamine. Depending on the route of administration, the bioavailability can be significantly affected; the highest bioavailability of is achieved with IV administration (100%), whereas IN administration can have 30%–50% bioavailability ( ). Considering these effects on ketamine bioavailability it is extremely important to not only consider the dose being used but also the route of administration.
Racemic
Remarkably, there is limited high quality clinical data available in humans to assess the dose-response relationship with racemic ketamine doses delivered intravenously. A dose ranging trial of 99 participants across six US academic sites compared the effects of a single 0.1 mg, 0.2 mg, 0.5 mg, and 1 mg/kg dose of ketamine in the treatment of depression. It showed the 0.5 and 1.0 mg doses to be effective compared to midazolam even after appropriate adjustments, but only the 0.5 mg dose was significantly superior to placebo across all secondary outcomes, the 1.0 mg dose was only significant with one of the five secondary outcomes ( ). While this study was not sufficiently powered to detect even moderately sized differences in the antidepressant effect associated with the various doses, and only investigated the response after a single infusion for a relatively short duration of time, it is not inconsistent with the rodent data suggesting the existence of a nonlinear dose-response curve in which the ratio of clinical benefit to adverse events may not favor higher dosing.
S-Ketamine
With regards to esketamine, a double-blind dose-finding study sponsored by Janssen was conducted to assess the optimum dosage of IV esketamine. The results of this multicenter study which compared 0.2 mg/kg versus 0.4 mg/kg IV showed that the lower dosage maintained efficacy while reducing the dose-dependent adverse effects ( ). In the later phase studies with nasal insufflation, there was no clear evidence of superior response between the 56 and 84 mg dosing regimens, but there appeared to be a diminished response to the 28 mg dose. The current recommendation for esketamine dosing in the treatment of TRD consists of starting with the 56 mg dose at the first treatment, which may be adjusted to 84 mg based on clinical response at subsequent sessions. For major depression associated with suicidal ideation (MDSI), which is considered to demand a faster onset of effect, the recommended starting dose is 84 mg, which can be reduced to 56 mg in patients who have difficulty tolerating the higher dose.
Frequency
There are also limited data available to guide the choice of dosing frequency for treatment with ketamine or esketamine at this time. An early study explored the effect of initiating ketamine 0.5 mg/kg IV with different dosing frequencies, comparing treatment twice a week to thrice a week dosing ( ). The study found both regimens to produce a rapid and sustained response to the ketamine treatment compared to placebo over the 2-week treatment period but were not able to detect any meaningful difference between the two dosing frequencies. Although the study was of short duration and not sufficiently powered to determine smaller differences between the two groups the failure to provide evidence suggesting the more frequent dosing was any more beneficial than the twice a week dosing supported the use of lower frequency dosing as the preferable treatment plan. The twice weekly dosing regimen was adopted in the Phase 3 clinical trials for IN esketamine for TRD and for MDSI and continues to serve as the standard recommendation for clinical dosing over the first month of treatment (twice weekly for 4 weeks for both indications) ( ). Interestingly, a survey of providers administering ketamine IV in clinical settings throughout North America performed prior to the approval of esketamine treatment and widespread knowledge of the findings from the dosing frequency study showed that most providers were offering the initial treatments either twice or thrice weekly ( ). This affords some level of experiential evidence that clinicians independently arrived at this dosing frequency. Although the optimal dosing frequency has yet to be established for ketamine or esketamine treatments, it is important to note that there is no high-quality evidence currently available to suggest more frequent dosing is either safe or effective for the treatment of mood disorders. Studies examining alternative dosing frequency strategies are ongoing and will likely provide more information in the near future.
The other major issue regarding the frequency of ketamine and/or esketamine dosing surrounds the continuation/maintenance course treatment following the acute phase. The previously noted survey of ketamine providers showed that the majority of patients treated prior to the esketamine approval were receiving maintenance treatments either on an every 3-week or monthly interval schedule ( ). The long-term continuation ( ; ) and randomized withdrawal studies ( ) completed as part of the esketamine Phase 3 studies used a regimen whereby patients, after completing the 4-week course of twice a week dosing, moved to weekly dosing for 1 month and then dosing at either weekly or every other week dosing based on symptom severity. The currently recommended frequency of esketamine for acute treatment of both indications is twice weekly for 4 weeks. For TRD, the recommendation is for once weekly treatment during weeks 5–8 and every 1–2 weeks beyond that time, individualized to each patient to maintain response or remission ( ). For MDSI, continuation beyond 4 weeks is based on the clinician’s determination, and there are currently no systematic data to guide continuation ( Table 13.1 ).
| Treatment | Indication | Phase | Frequency | Dose | Duration | Goal | Next step |
|---|---|---|---|---|---|---|---|
| Esketamine intranasal | TRD | Induction/acute | Twice weekly | Start at 56 mg, may increase to 84 mg | Eight treatments | Response a | Responder: Go to continuation |
| Nonresponder: Stop | |||||||
| Continuation b | Weekly | 56 mg or 84 mg | Four treatments | Maintain response/achieve remission | Consider maintenance | ||
| Maintenance | Every 1–2 weeks, consider decreasing frequency as tolerated | 56 mg or 84 mg | Varies | Prevent relapse | Consider stopping (individualized) | ||
| MDSI | Induction/acute | Twice weekly | Start at 84 mg, may decrease to 56 mg | Eight treatments | Response | Responder: consider continuation c | |
| Nonresponder: Stop | |||||||
| Continuation | No specific data available for MDSI. May consider similar approach as TRD | 56 mg or 84 mg | Varies | Maintain response/achieve remission | Consider maintenance | ||
| Maintenance | 56 mg or 84 mg | Prevent relapse | Consider stopping (individualized) | ||||
| Ketamine IV d | TRD e | Induction/acute | Twice weekly | 0.5 mg/kg f | —Six to eight treatments | Response | Responder: Go to continuation |
| Nonresponder: Stop | |||||||
| Continuation | Weekly | 0.5 mg/kg | Four treatments | Maintain response/achieve remission | Consider maintenance | ||
| Maintenance | Every 2 weeks, then gradually increase up to every 4–6 weeks | 0.5 mg/kg | Varies | Prevent relapse | Consider stopping (individualized) |
a Usually considered to be a 50% reduction in symptoms.
b Spravato prescribing information does not differentiate between continuation and maintenance phases.
c Spravato prescribing information does not provide any specific recommendation with regards to continuation or maintenance in MDSI; given lack of systematic data, it is advisable for clinicians to consider appropriateness of a similar approach to TRD on a case by case basis.
d Not FDA-indicated for depression. Limited data available for doses other than 0.5 mg/kg, and regarding optimum dosing frequency.
e Also consider a similar approach for other diagnoses on an individualized basis.
f May use ideal body weight instead of weight for patients with a BMI > 30.
Setting
Given concerns surrounding acute adverse events, especially hemodynamic changes and dissociative symptoms, monitoring of ketamine/esketamine treatment is an important factor in providing the safest treatment possible. In a survey of providers administering IV ketamine in the community, most providers reported monitoring heart rate, pulse oximetry and blood pressure with various frequencies during the treatment period.
For esketamine, the recommendation for monitoring during the treatment includes monitoring the patient by a healthcare provider for at least 2 h, followed by an assessment to assure patient is safe to leave. This includes assessment of blood pressure throughout the treatment, especially 40 min after treatment and afterwards as warranted to assure return of blood pressure to baseline.
Considering the above, the treatment setting should be able to support adequate monitoring of vital signs, with a healthcare provider present at all times during treatment. In addition, while data regarding the effects of the environment on the treatment are limited, it is advisable to provide a comfortable environment with minimal distractions considering the dissociative effects of the medication.
Consideration of diagnostic and comorbidity factors
The strongest and most abundant evidence for the use of ketamine and esketamine in psychiatric illnesses relates to its use in the treatment of adults with treatment-resistant major depressive disorder ( ; ). However, limited data are available on the use of ketamine on other disorders such as bipolar depression ( ), mood disorders with psychotic features ( ), PTSD ( ), and OCD ( ; ).
The presence of certain comorbidities has become of specific concern when treating patients with TRD. Extremely limited data available to date suggest that ketamine or esketamine may be used in patients with primary psychotic disorders ( ) or depression with psychotic features ( ; ). However, these data are extremely scant and is imperative to assess risks and benefits when considering treatment options for these patients as no large-scale studies have yet been completed to examine the safety and efficacy of the treatment for these specific depressive subtypes. There is also justifiable concern about using ketamine or esketamine in patients with a history or current substance use disorders. Although a few studies suggest ketamine may actually be used beneficially to reduce the severity of substance use disorders ( ; ; ), these reports should be considered preliminary and caution should be exercised in providing the treatments to patients with histories of significant substance use disorders until more data are available.
Perhaps the most clinically important diagnostic and/or comorbid issue to consider with the use of the treatments is the presence of suicidal ideations and the risk of suicidal behavior. Since ketamine was shown to be effective in rapidly addressing depressive symptoms, and as suicidal ideation and behavior is one of the most severe and urgent presentations of MDD, there was obvious motivation to look into the specific effects of ketamine on addressing these symptoms. Initial data coming from studies of ketamine in depression showed promising potential effects in suicidal ideation ( ; ; ; ; ). A metaanalysis of patient level data from 11 studies of single-dose ketamine use in depression ( ) showed a significant reduction in suicidal ideation with possible independence from the improvement in depressive symptoms ( ; ). Some small studies tried to directly examine the efficacy of ketamine in the treatment of suicidal ideation ( ; ; ; ). The data from these trials suggested that ketamine may be able to rapidly reduce suicidal ideation, though the results were not conclusive.
Given the promising data with racemic ketamine related to suicidal ideation and the evidence of esketamine’s efficacy in TRD patients, a series of trials were initiated to formally assess the effects of intranasal esketamine in the treatment of patients with major depressive disorder experiencing clinically meaningful suicidal ideation or behavior. These consisted of an initial phase 2 randomized controlled trial ( ), which showed greater rapid reduction in depressive symptoms in these patients with esketamine, along with a significant reduction of suicidal ideation at some of the endpoints. Afterwards, two phase 3 trials ( ; ) were conducted to assess these findings at a larger scale. Both studies met their respective primary endpoints, showing statistically significant reduction in depressive symptoms with esketamine plus standard of care treatment over placebo plus standard of care treatment at 4 and 24 h after dosing. However, while a notable and rapid decrease of suicidal ideation was noted in both studies, the difference between the two treatment groups did not reach statistical significance. Though at first glance the failure to find a significant difference in suicidal ideation measures between the two groups may seem concerning, it is important to consider a few major factors that complicate the interpretation of these results. Firstly, every subject in the trial, regardless of study drug assignment, received high-level standard of care treatment that included an inpatient hospital stay. Thus, the trials were unique in nature for antidepressant trials by comparing the study drugs against the background of a newly initiated active treatment rather than placebo; secondly, both groups in these trials achieved rapid reduction in suicidal ideation making it difficult to show one treatment to be superior to another; these facts along with the limited tools available to assess short-term change in suicidal ideation and risk should be considered when interpreting the results.
The USFDA, after review of these findings, concluded that these results in combination demonstrated the benefits of this treatment in patients with major depression and suicidal ideation or behavior and the risks were adequately understood, and approved the use of esketamine in this population in 2020 ( ).
Concomitant treatments
The data on the effects of other medications and treatments on ketamine treatment (whether augmenting or inhibiting) remain limited. However, those most commonly studied in the literature are briefly outlined.
Potential augmenting treatments
Lithium
Both lithium and ketamine are believed to have an inhibitory effect on Glycogen Synthase Kinase 3 ( ; ). Reports from rodent studies suggest that the combination of ketamine with lithium may result in synergistic and enduring antidepressant effects ( ). However, the use of lithium after ketamine treatment in 34 patients with at least partial response to ketamine did not significantly increase the duration of ketamine’s antidepressant effect in the treatment of MDD ( ). A second study conducted 36 patients with bipolar depression ( ) also showed no meaningful difference in effects of ketamine between the valproate and lithium groups. Further studies are needed to better understand the relationship between lithium and ketamine in treatment of depression but at present there is no convincingly supportive clinical evidence.
Riluzole
Based on riluzole’s effects as a glutamatergic modulator it has also been considered to potentially prolong the effects of ketamine treatment. However, a study of 42 subjects comparing riluzole to placebo treatment after a single IV ketamine treatment failed to show any significant improvement in the riluzole group in comparison to placebo ( ). Another similar trial was stopped for futility after enrolling 14 patients ( ).
Transcranial magnetic stimulation
Ketamine has been shown to reduce the resting motor threshold and active motor thresholds in transcranial magnetic stimulation (TMS) and may lead to an increase in the amplitude of EMG response after magnetic stimulation ( ). A few case reports in TRD and bipolar depression have suggested a synergistic effect for ketamine and TMS ( ; ; ). However, the data are insufficient to provide any meaningful guidance on the safety or efficacy of this treatment combination at this time.
CBT psychotherapy
As mentioned previously, some of the early studies exploring ketamine’s use in psychiatric disorders focused on the drug’s potential to facilitate psychotherapeutic interventions. Given ketamine’s effect on neuroplasticity, it is conceivable that it may provide a mechanism to enhance the effectiveness of psychotherapeutic treatments. An open label trial of 16 patients receiving a 4-session course of ketamine treatment suggests that CBT may be able to sustain the improvements achieved with ketamine treatment ( ). Case reports have also shown potential benefits of CBT and ketamine in other disorders such as obsessive compulsive disorder ( ). Several studies examining the effectiveness and possible mechanisms underlying this treatment combination are currently underway.
Inhibiting
Lamotrigine
In preclinical studies, lamotrigine has been shown to decrease the craving for ketamine abuse ( ). In humans, it has been suggested to decrease perceptual changes in healthy subjects ( ), and in patients undergoing surgery ( ), though this findings was not present in another study involving patients with TRD ( ). Given these limited findings, adjustment of lamotrigine dosing in patients receiving ketamine should be considered only after careful assessment of risks and benefits of such modification.
Benzodiazepines
Animal studies have suggested that inhibition of NMDA receptors on GABAergic interneurons may be a critical component in ketamine’s mechanism of antidepressant action. Additionally, glucose utilization increases observed by ketamine in the limbic system may be attenuated or prevented by administration of benzodiazepines such as diazepam ( ), suggesting that concomitant use of benzodiazepines may attenuate or inhibit the antidepressant response to ketamine. In humans, a secondary analysis of the results of two studies involving 47 patients, benzodiazepines were associated with nonresponse and significantly worse outcomes on days 3 and 7 ( ). Another post-hoc analysis of 10 patients with TRD showed a difference in the dose of benzodiazepines in responder versus nonresponder groups ( ), although the same study did not find a significant difference when comparing GABAergic medication users versus nonusers. The larger phase 3 studies with esketamine did not report any specific attenuating effects of benzodiazepines although use in these studies was constrained. Given the theoretical concerns and preliminary findings, it is advisable to use benzodiazepines with caution in patients undergoing ketamine treatment.
Naltrexone
A double-blind cross over study of patients with TRD treated with ketamine and naltrexone/placebo found a significant reduction of antidepressant effects in an interim analysis of 14 participants with no associated change in dissociative effects ( ). Notwithstanding the potential importance of this early finding, other reports have shown no interference in the antidepressant effects of ketamine by naltrexone, buprenorphine or methadone ( ; ). At this point it appears prudent to closely evaluate the potential benefits and risks, including the possibility of reduced response rates, if planning on starting ketamine or esketamine treatments in patients using mu opioid receptor antagonists.
Drug-drug and drug-food pharmacokinetic effects
Ketamine is a substrate of cytochromes CYP2B6 and CYP3A4, and as such can be affected by most inhibitors of these cytochromes such as grapefruit juice and clarithromycin (CYP3A4) and ticlopidine (CYP2B6), and inducers such as rifampin or St. John’s Wart. Of note, due to the first-pass effect, the levels are more significantly affected if ketamine is administered orally ( ).
Given these factors, it is important to consider the effects of inhibitors or inducers of these cytochrome (e.g., thioridazine (CYP2B6 inhibitor), carbamazepine (CYP3A4 and CYP2B6 inducer), and nefazodone (CYP3A4 inhibitor)) when administering ketamine.
Overall, given the limited data currently available in this area, it is best to make decisions on treatment augmentation or discontinuation of ongoing medications with care and by considering all factors relevant for each individual patient.
Safety
Personal
As noted, concerns over ketamine use in several countries had previously prompted several reviews of the drug by the WHO. Although the organization consistently recommended that ketamine should not be placed under increased international control which could limit access to the drug ( ), several issues related to the broader use of ketamine remain of concern. These concerns can be considered at the more basic physiological level or at the psychological level. Issues surrounding the broader use of the treatment could also be deliberated at the individual and societal levels.
Physiological
One of the more easily tractable and manageable side effects of ketamine and esketamine are effects on hemodynamic measures. Ketamine can cause an increase in pulse rate and blood pressure, which in the latter case seems to be dose-dependent ( ; ). A recent report of 66 patients receiving 684 total ketamine infusions at 0.5 mg/kg over 40 min at Emory University found the greatest increases in blood pressure were measured at 30 min, averaging 3.28 mmHg systolic and 3.17 mmHg diastolic. Blood pressures returned to baseline during postinfusion monitoring. Of note, hypertensive patients at baseline exhibited higher blood pressure peaks during the infusions ( ). A second study of 135 patients with unipolar and bipolar depression who received a total of 741 infusions under similar dosing conditions also reported maximum blood pressure and pulse values 30–40 min after initiating infusions. In this case, the largest mean systolic/diastolic blood pressure increases were 7.4/6.0 mmHg, and the largest mean pulse increase was 1.9 beats per min ( ). In pooled data from 97 patients receiving 205 doses of ketamine IV from three different studies, a substantial increase in blood pressure 19.6 systolic and 13.4 mm/Hg diastolic was observed ( ). These findings, while quite variable, are generally in line with those reported in the dose testing study noted previously where blood pressure values were higher in the ketamine 0.5 and 1.0 mg/kg groups compared to the active placebo midazolam ( ).
Much more comprehensive hemodynamic data have been collected with esketamine IN spray, including data from 1708 esketamine-treated adults with TRD in six trials initiating the treatment along with a new oral antidepressant medication ( ). In the two randomized studies of adults aged 18–65, each 4 weeks in duration with two treatments per week, the largest mean maximum systolic/diastolic postdose BP increases were 13.3 systolic and 6.1 diastolic with esketamine compared to 8.7 and 4.9 mmHg for placebo, and in a short-term study of adults ≥ 65 years of age the increase was 16.0 systolic and 11.1 diastolic for esketamine compared to 9.5 systolic and 6.8 mmHg diastolic for placebo. Most importantly, cardiovascular adverse events were relatively rare and only three cardiovascular adverse events related to BP increase were reported as serious and severe. Similar to racemic ketamine infusions hemodynamic increases reached the maximum postdose value within ~ 40 min of esketamine dosing and returned to the predose range by ~ 1.5 h of dosing. Also similar to the ketamine studies, patients with underlying hypertension appeared to be at greatest risk of having significantly elevated blood pressures with treatment. No clinically relevant effect on ECG parameters was observed.
Based on these findings, vital sign monitoring before, during, and for a short period of time after dosing is highly recommended to assure a safe treatment and a return to baseline values before discharge. It is important to note that the large majority of the studies contained in the literature carefully screened and excluded patients from participation if they had underlying medical conditions. In light of this, it is especially important to complete a thorough evaluation process that includes screening for cardiovascular risk factors prior to initiating treatment with either ketamine or esketamine.
Another physiological side effect reported mainly with long-term use or misuse of ketamine is ulcerative or interstitial cystitis. In the longer-term clinical studies with esketamine, no cases of interstitial cystitis were reported, including in patients followed up for a year after initiating treatment ( ). There are not enough prospectively collected data related to interstitial cystitis with racemic ketamine to comment on its safety at this point; however, there is no clearly defined reason to believe that treatment at similar frequencies and resulting in similar plasma levels as reported in the esketamine studies should produce dramatically different effects.
The brain is the other major organ believed to be at risk with ongoing ketamine exposure ( ), and concerns of persistent cognitive impairment are warranted with repeated ketamine use. The limited data currently available with short- and extended-term racemic ketamine treatment of mood disorders suggest either no change or possibly even marginal improvement, but has not provided any evidence meaningful declines in cognitive processes ( ; ; ). Again, much more extensive and comprehensive data have been collected with regards to esketamine IN spray’s effects on cognition. Similar to the existing data with racemic IV administration, the data suggest either no change or possibly even marginal improvement in most measures without any meaningful concerns, although there was note of a decline in reaction time in patients over the age of 65 ( ). In short, dosing with either racemic ketamine 0.5 mg/kg IV delivered over 40 min or esketamine IN at either 56 mg or 84 mg according to the published dosing regimens of up to thrice weekly for initiation with no more than weekly for extended time periods does not appear to be associated with any meaningful decline in cognitive function at this time. However, there are little or no data to suggest safety for more frequent dosing or higher doses, or for longer-term treatments. It is important to continue to maintain some level of surveillance to ensure safety.
Psychological
The acute effects of ketamine on cognition and perception are well documented ( ). Dissociation is one of the most common effects of ketamine provided at doses used for the treatment of depression ( ). Some level of dissociation is reported by the majority of patients receiving either ketamine or esketamine for the first time. However, the effect is usually mild to moderate and not distressing if the patient is appropriately prepared. The presence and severity of dissociation is usually assessed with a psychometric scale, most commonly the Clinician-Administered Dissociative States Scale (CADSS) and typically decreases with repeated treatments. Given the frequency of this side effect, specifically monitoring for resolution of any dissociative symptoms after treatment is advisable. The question of whether the dissociative effects are associated with the antidepressant properties of ketamine and esketamine treatment remains in debate ( ). However, the dissociation does not appear to be highly correlated with the clinical improvement and especially not beyond the first treatment ( ).
The acute anxiogenic or dysphoric effects of ketamine also remain an issue of concern. Ketamine use as an anesthetic has been somewhat limited by patients reporting anxiety and dysphoria on awakening, sometimes considered part of an emergence delirium. It is not uncommon that patients can experience elevated levels of anxiety with the initial treatments with either ketamine or esketamine. However, experience suggests that education prior to the first treatment session, and having trained staff readily available to assure patients during the treatment markedly lowers the number of patients who terminate treatment due to this adverse event.
Yet another important concern surrounding ketamine and esketamine treatment relates to its effects on cognition and alertness is the impact it can have on patients’ ability to drive or operate machinery. Two studies assessed the ability of patients to drive after receiving nasal esketamine. In one study, driving performance of subjects after single-dose and multidose treatment was similar to placebo after 18 and 6 h, respectively. In another study, the driving performance of subjects after a single 84 mg dose of esketamine was similar to placebo at 8 h, but two subjects discontinued the driving test after receiving nasal esketamine. Given these findings and until more information is available patients are recommended to avoid driving or operating heavy machinery until after a restful night of sleep ( ).
Addiction
Raising concerns at both the individual and societal levels is the fact that ketamine is a known drug of abuse. Ketamine has been used as a recreational drug, mostly in “rave” settings, for several decades ( ). It has also been shown to reinforce self-administration in preclinical studies ( ). It is considered a controlled substance in many countries, and is classified as schedule III in the United States ( ) and as class B in United Kingdom ( ). Given these facts, the risks of abuse should always be considered when contemplating the use of ketamine for the treatment of TRD. At the same time, the clinical data to date including an open label 1-year safety study of nasal esketamine have not indicated any increase in substance use to be associated with the treatment under controlled conditions ( ).
Societal
At the societal level, drug diversion becomes a potential concern for the expansion of ketamine treatment. Due to its use as a recreational substance, ketamine has an underground market with a street value of between $20 and $25 per dose ( ). While esketamine treatment is closely monitored by a REMS program, and the majority of ketamine providers only administer the treatment in clinic, thus it is necessary to consider the risk of diversion in the use of ketamine or esketamine, and to monitor as appropriate for this phenomenon.
Implementation
Considering the various safety and societal concerns surrounding the use of the drug the USFDA approval for esketamine included a Risk Evaluation and Mitigation Strategy (REMS) program ( ). This program has specific requirements for healthcare settings and pharmacies providing nasal esketamine. Healthcare settings need to be certified by the program to ensure that esketamine is only dispensed and administered in the healthcare setting, that patients are enrolled in the REMS program, and that treatment is done under direct observation of a healthcare provider and patients are monitored for at least 2 h after treatment. Pharmacies require certification and must ensure that nasal esketamine is only made available to healthcare settings certified to provide this treatment ( ). By extension, it would appear similar mitigation strategies should be used for racemic ketamine treatment until further data are presented.
The complexity and costs associated with the unique demands of ketamine/esketamine delivery and compliance with the risk mitigation strategies have dramatically limited access to the treatment. At present, third-party payer coverage for the treatments remains somewhat limited and can vary regionally. This has led to a situation whereby specialty clinics offering ketamine/esketamine and related services have appeared in a variety of unique settings, offering treatment predominantly to self-paying individuals ( ). The specific issues related to this development have stirred controversy and led to some division in the field. However, along with other developments such as the use of Brexanolone treatment for postpartum depression and a growing number of neurostimulation therapeutics, the increasing use of ketamine and esketamine treatments in psychiatry signals a possible evolution within the field and the need for specialized training in these developing areas within psychiatry.
Interventional psychiatry is an emerging subspecialty of psychiatry that focuses on advanced diagnostic and treatment modalities to help patients with psychiatric disorders that have been resistant to “traditional” treatments such as oral medications and psychotherapy. With advancements in various technological and more medically based psychiatric treatment modalities in the past two decades, the need for clinicians with training and experience in implementing these treatments is rapidly becoming a necessity in the field of psychiatry. The modalities under this umbrella are generally treatments that require higher levels of care for diagnosis, administration or monitoring of treatment. Neuromodulation modalities such as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), deep brain stimulation (DBS) and vagal nerve stimulation (VNS) among others are the treatments most commonly considered to be in this category. However, other modalities such as ketamine, esketamine, and psychedelic treatments also seem appropriate, not only because they require a specialized setting for their administration, but also because they require further training and experience to be appropriately implemented. Interventional psychiatrists are not only able to offer these treatments, but perhaps more importantly are able to provide consultation and advice to patients and their primary psychiatric providers about the most appropriate modality for their needs.
Conclusion
As seen in the paragraphs above, it is difficult to draw a direct line neatly connecting the discovery process leading to the development of ketamine as an antidepressant, and ultimately the USFDA indication of esketamine for treatment-resistant depression and major depressive disorder associated with suicidal ideation. The hypotheses related to the treatment’s mechanisms of action have evolved over time and continue to be refined. The initial focus on the use of ketamine as an antidepressant had a heavier focus on its dissociative and acute psychological effects, suggesting a capacity by ketamine to render the patient more open to psychological change. The later efforts, which are most closely associated with the final stages of clinical development, focused more on the underlying neurobiological mechanisms including ketamine’s effects on glutamate neurotransmission, neuroplasticity, and neurocircuitry. While the exact mechanisms of ketamine’s antidepressant action remain unknown and are probably multifactorial, there is a growing consensus related to its primary effects on glutamate neurotransmission contributing to these effects.
There is now overwhelming evidence of the short-term clinical benefits of treatment with both ketamine and esketamine. Large, longer-termed controlled studies examining the safety and efficacy of the treatment remains limited to esketamine IN treatment. Balancing the optimism generated by this new class of antidepressants offering rapid onset of action to previously treatment-resistant patients, and to patients experiencing suicidal ideation, are the unique complexities associated with the delivery of the treatment. Results of several ongoing studies will soon provide information regarding the efficacy and safety of other formulations and variants of ketamine and related compounds.
References
Related posts:
Clinical and epidemiological predictors of treatment-resistant depression
The economic burden of treatment-resistant depression: Cost-of-illness perspective
The neurobiology of treatment-resistant depression
Monoamine oxidase inhibitors for treatment-resistant depression
Switching antidepressants in patients with treatment-resistant depression
Adjunctive strategies for treatment-resistant depression
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