Sanjay J. Mathew, MD

A Case Built on Current Research Findings

Ketamine has caused quite a stir in psychiatric practice. Sub-anesthetic administrations of ketamine have been shown to markedly improve symptoms of depression and anxiety.

 While the growing off-label use of ketamine speaks to the need for novel approaches to psychiatric care and treatment-resistant illness, it also presents an ethical dilemma, wherein widespread adoption has once again leaped ahead of scientific understanding.

The current literature suggests that therapeutic effects of ketamine involve modulation of glutamate neurotransmission, Î±-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor potentiation, downstream influences on neurotrophic signaling cascades and neuroplasticity, and functional changes in assorted neural networks. Additional work is necessary to clarify the importance and reliability of these biological findings.

Another arc to the ketamine story dates back to a decades-old era of psychedelic research and search for medications with transformative power. Indeed, although primarily conceptualized today as a dissociative anesthetic, ketamine has also been classified more broadly as a hallucinogen. Hallucinogens function by various pharmacological mechanisms of action but exhibit similarities in their ability to occasion temporary but profound alterations of consciousness, involving acute changes in somatic, perceptual, cognitive, and affective processes.

Current biological theories involving ketamine’s antidepressant effect may be inseparable from these non-ordinary experiences of consciousness, but we can only know the answers to questions we ask. Here we examine findings from contemporary research that hint at the unexplored hallucinogenic potential of ketamine and considerations for future investigation.

There has been a resurgence of interest in hallucinogenic psychedelics (eg, psilocybin, lysergic acid diethylamide (LSD), mescaline, N,N-Dimethyltryptamine (DMT)) and entactogens (eg, 3, 4-methylenedioxymethamphetamine [MDMA]) in psychiatric research, which are hypothesized to achieve clinical benefit due to, in part, experiences of altered consciousness and fundamental shifts in mental frameworks.

These drugs have been associated with cognitive states of enduring personal importance and have been compared with mystical experiences that might emerge over the ordinary course of life and carry sacred or spiritual meaning. Furthermore, these experiences may powerfully influence existential concepts of self, including moral values, self-identity, and purpose. There is converging evidence that these psychedelic effects are mediated in part by activity at 5HT-2A receptors. Ketamine may induce alterations in consciousness and personal frameworks similar to those achieved by serotonergic psychedelics while also sharing a common glutamatergic pathway of drug effect.

 However, there has been little investigation into how such changes might mediate the therapeutic potential of ketamine.

Preliminary data suggest that ketamine produces meaningful, transformative experiences that may help patients accept healthier values, behaviors, and beliefs related to abstinence from drugs and alcohol.

 Other evidence suggests that dose-related mystical-type experiences mediate the effects of ketamine on motivation to quit in cocaine-dependent research volunteers.

 Few recent studies have examined whether ketamine’s hallucinogenic properties are implicated in antidepressant effects; however, psychiatric vulnerabilities to depression plausibly involve an existential dimension. This dimension includes depressive symptoms of hopelessness, guilt, and suicidality, which appear to be ketamine-sensitive.

Given the paucity of modern literature exploring the psychedelic and mystical properties of ketamine in depression, more widespread data on psychotomimetic and dissociative effects of ketamine provide some initial groundwork. Berman and collegeagues

 and Zarate and colleagues10 suggested that the antidepressant effects of ketamine (0.5 mg/kg over 40 min) were disconnected from ketamine-induced psychotomimetic symptoms. The antidepressant effects, measured by the Hamilton Depression Rating Scale (HDRS), were significant even after positive symptoms on the Brief Psychiatric Rating Scale (BPRS) returned to baseline. However, it was also noted that initial changes in BPRS positive symptom scales from baseline trended to predict a greater decrease in HDRS scores within a day of treatment with ketamine.

A small study further demonstrated a substantial relationship between psychotomimetic effects 30 minutes after ketamine administration (0.54mg/kg over 30 min) as measured by BPRS and antidepressant effects in the following week.

 A larger study involving 108 patients found that dissociation measured by the Clinician Administered Dissociative States Scale (CADDS) at 40 minutes was associated with HDRS score improvement at 230 minutes and 7 days after infusion.

 Although no relationship between initial BPRS positive subscale scores and antidepressant effect was found, a correlation between CADSS and BPRS scores was found at 40 minutes postinfusion.

In a small study by Valentine and colleagues,

 the proposed correlation between ketamine-induced dissociation and antidepressant efficacy was not observed. However, a larger analysis found that greater intra-infusion dissociation as measured by CADDS was one of the strongest predictors of extended antidepressant response.14 Both of these studies utilized a single 0.5 mg/kg ketamine infusion delivered over 40 minutes.

Further investigation is needed, but there is an emerging rationale for a connection between the psychotomimetic or dissociative effects of ketamine and its antidepressant efficacy. Perhaps the experience of these effects simply un-blinds patients as to whether they are receiving ketamine or placebo in randomized trials; it may also be that such symptoms are only a “side effect” of ketamine’s mechanism of action. However, it is also worth considering that the psychotomimetic or dissociative effects associated with ketamine treatment are markers or mediators of subjective experiences of potential therapeutic value seen with other hallucinogenic agents.

The recommended doses of ketamine for anesthetic induction are typically 1 to 4.5mg/kg IV and 6.5 to 13 mg/kg IM, with alternate, off-label recommendations for 0.5 to 2 mg/kg IV and 4 to 10 mg/kg IM, primarily in the context of adjuvant drug use. For use in depression, ketamine is most commonly administered at a sub-anesthetic dose of 0.5mg/kg IV across 40 minutes.

Interestingly, in a study of electroconvulsive therapy (ECT) and anesthetic induction with either a near-anesthetic dose of IV ketamine (0.8mg/kg) alone, sub-anesthetic ketamine (0.5mg/kg) plus propofol (0.8mg/kg), or propofol alone (0.8mg/kg), predicted a more rapid antidepressant effect and a higher remission rate than propofol use. The near-anesthetic dose of ketamine was associated with superior antidepressant effects than the mixed, sub-anesthetic dose.

In a study of ketamine alongside psychotherapy for heroin addiction, Krupitsky and colleagues

 compared the effects of 2 doses of ketamine (0.2 and 2.0 mg/kg IM) and found that only the higher dose was associated with a “full psychedelic experience” as measured by the Hallucinogen Rating Scale (HRS). The lower dose was considered a “sub-psychedelic” active placebo, but was nonetheless associated with some positive drug effects: patients were still affected by their experiences and considered them useful and therapeutic. The high dose group ultimately experienced higher rates of abstinence, greater effect on emotional attitudes related to abstinence, and lower rates of relapse and drug craving than the low dose group. Both doses resulted in post-treatment reductions in measures of depression and anxiety; there were no significant differences between the groups.

 compared the effects of 0.41 mg/kg and 0.71 mg/kg doses of IV ketamine given to cocaine-dependent patients. Dose-dependent mystical-type effects as measured by Hood’s Mysticism Scale (HMS) were seen as well as a relationship between HMS scores and the motivation to quit cocaine 24 hours post-infusion.

A different study involving a lower dose of intramuscular (IM) ketamine did not generate the same mystical-type phenomena.

 Perhaps these results highlight the importance of calibrating dosing and delivery. Clements and colleagues

 demonstrated that ketamine had reduced bioavailability with IM administration compared with IV administration. Taken together, these findings support the idea that positive treatment outcomes for ketamine may be dose-dependent and its psychoactive effects are based on delivery parameters.

One criticism of ketamine has been its short duration of antidepressant effect, with benefits peaking at 24 hours post-infusion and generally subsiding by 72 hours. The most promising approach to this challenge thus far seems to be the strategy of repeated-dose ketamine infusions, which have observed extended time-to-relapse and increased rates of antidepressant response.

If ketamine’s therapeutic effect is indeed mediated by psychoactive experience, it may be that repeated dosing of ketamine improves outcomes by increasing opportunities for personally meaningful events to occur. One caveat is that some studies have shown repeated dosing to be associated with fewer dissociative symptoms over time-at first glance this suggests that the antidepressant value of serial ketamine administration might be independent of hallucinogenic effects.

While this requires further investigation, it is also important to consider other interpretations of that evidence: that acclimation to altered states of consciousness may contribute to recall bias, that experimental protocols that frame dissociative symptoms as a “side effect” or “adverse event” may lead to underreporting if overall patient experiences of ketamine are positive, or even that the benefit of repeated dosing may be less related to cumulative drug effect than other factors, such as repeated interactions with care providers or increased opportunities for reflection and synthesis.

One study of repeated infusions demonstrated that antidepressant response very early in the course of treatment strongly predicted subsequent response; conversely, a lack of rapid response was a poor prognostic indicator for improvement after additional infusions. Whether positive early responses to ketamine are mediated by psychological factors, biological susceptibility, or both: it is necessary to clarify these factors in shaping sustainable strategies for treatment.

A cautious approach also seems imperative given evidence that ketamine demonstrates agonist activity at Î¼-opioid receptors and dopaminergic effects that may confer acute relief of depressive symptoms but also greater risk for positive drug reinforcement and dependence. With further insight into psychological responses mediated by ketamine, it may be that a therapy-based framework for ketamine administration optimizes treatment efficacy and sustainability, while also minimizing unnecessary drug exposure, adverse effects of chronic use, and dependency risk.

In one study, long-term abstinence in persons who were substance dependent was achieved with Ketamine Psychedelic Therapy (KPT), which incorporates 1 or 2 sessions of ketamine-facilitated existential reappraisal into an existential psychotherapy.

 Additional exploration would be needed to determine which therapeutic approaches most beneficially augment ketamine treatment and minimize risks for harm. Nevertheless, a more holistic approach to ketamine as a treatment modality may be better suited to recreate the marked, persistent effects of MDMA in patients with PTSD. For example, in one study sustained symptom reductions were achieved with 12 weeks of psychotherapy but with limited MDMA exposures of only three 8-hour sessions.

Another area that requires further investigation is how a patient’s past history might shape psychoactive responses. These personal and quite variable histories have been explored for some hallucinogenic agents but minimally for ketamine. The expectations and personal experiences of the individual user along with the external environment of use have been identified as critical factors in influencing subjective drug effects-coined “set” and “setting,” respectively-and are now considered well-established elements of human hallucinogen research.

Therapies aimed at the pharmacological production of a transformative experience may depend on factors such as patient personality structure, preparation for treatment, emotional activation before drug intake, treatment context, and perceived quality of the experience. Given the unique psychological risks of hallucinogen administration, it is recommended that clinicians screen for personal or family histories of psychotic or other severe psychiatric disorders prior to treatment. Clinicians are also encouraged to facilitate careful patient preparation for sessions, provide a safe physical environment for treatment administration, and allow for interpersonal support during sessions. These and other insights from hallucinogenic research might valuably inform treatment protocols for ketamine administration.

Ketamine is uniquely poised to make a tremendous impact on psychiatric care, even redefining boundaries for patients with variations in depressive disorders that were once thought to be “treatment resistant.” Our synthesis of this emerging and old literature points to the unexplored hallucinogenic potential of ketamine. By further understanding the desirable psychoactive effects of ketamine, clinicians can build on initial treatment successes and maximize patient successes.

  • Further investigating the relationship between ketamine-induced psychotomimetic and dissociative effects and treatment efficacy

  • Clarifying the connection between these effects and potentially desirable hallucinogenic experiences

  • Exploring the therapeutic value of such elicited experiences

  • Revisiting dosing strategies that account for existential phenomena and looking beyond dissociation as simply being an “adverse event”

  • Incorporating psychotherapy-based frameworks into ongoing investigation

  • Assessing set and setting factors that may shape treatment responses

Some answers and clues are likely to be found in the forgotten works of older psychedelic research. Agents like ketamine can exert their greatest therapeutic effect in the afterglow of profound alterations of consciousness, revealing a propensity for growth and healing that has not been evident to the suffering, depressed patient. Wherever the journey takes us, it is exactly the right time to bring together all the strands-brain and mind, old and new, caution and thrill-in assembling the unfinished story of ketamine.

Dr. Mathai is PGY 1 Psychiatry Resident, Dr. Mathew is Professor of Psychiatry, Dr. Storch is Professor of Psychiatry, and Dr. Kosten is Professor of Psychiatry, Baylor College of Medicine, Houston, TX.

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Articles

An exploration of findings from contemporary research that hint at the unexplored hallucinogenic potential of ketamine and considerations for future investigation.

Revisiting the Hallucinogenic Potential of Ketamine

The World Health Organization projects that by 2020, MDD will be the second leading cause of disability worldwide, trailing only cardiovascular diseases.

 Despite decades of research, the response to conventional antidepressant treatments is suboptimal. Based on Sequenced Treatment Alternatives to Relieve Depression (STAR*D) data, one-third of patients achieved remission after 12 weeks of treatment with a first-line antidepressant; one-third never achieved remission, even after 4 consecutive levels of treatments.

There is growing evidence for the role of ketamine, an 

-methyl-D-aspartate (NMDA) receptor antagonist used for many years as an anesthetic, in rapidly alleviating depressive symptoms in patients who have treatment-resistant depression (TRD). The mechanism of action through which ketamine exerts its antidepressant effects is not fully understood. However, the direct modulation of glutamatergic pathways is unique compared with currently approved antidepressant medications that mostly target mono-aminergic systems. As such, the discovery that a single intravenous infusion of low-dose (subanesthetic) ketamine exerts rapid antidepressant effects constitutes an expansion in the understanding of the neurobiology of depression and provides new avenues for drug development.

Ketamine has a very complex pharmacological profile with a variable affinity for numerous receptors. Besides being an open-channel nonselective NMDA receptor antagonist, ketamine interacts with several receptors, including the intracellular Ï receptors, the opioid Î¼ receptors, serotonin-3 receptors, and muscarinic receptors, as well as the serotonin, norepinephrine, and dopamine transporters.

 Research on the molecular signaling pathways associated with the antidepressant effects of ketamine has only recently begun in preclinical models.

In rodent models of depression, a single dose of ketamine was found to increase the number and function of new spine synapses in the prefrontal cortex and reverse the loss of spine density in animals exposed to chronic unpredictable stress.

 The antidepressant effects of ketamine were replicated using a selective antagonist of the NMDA receptor (NR2B subunit).

 These effects were blocked by adding a mammalian target of rapamycin (mTOR) inhibitor and were not observed in brain-derived neurotrophic factor (BDNF)-mutant mice.

 The findings suggest a role for specific neurotrophic signaling cascades in the therapeutic mechanism of ketamine.

Our study team published a preliminary finding that BDNF levels were significantly increased (

 < .05) at 240 minutes postinfusion in patients who responded to ketamine, and BDNF levels were highly correlated with Montgomery-Ãsberg Depression Rating Scale (MADRS) scores at 240 min (

 = −0.700; P = .007).12 Similar results were seen by kavalali and Monteggia

 These results form the basis of our understanding of ketamine’s possible antidepressant mechanism of action.

Several studies suggest that by blocking the excitatory NMDA receptors on Î³-aminobutyric acid inhibitory interneurons, ketamine leads to activation of downstream glutamatergic neurons. This results in an increase in extracellular glutamate levels and activation of the Î±-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. AMPA receptors regulate synaptic function through the activation of voltage-dependent calcium channels and the release of BDNF, which stimulates mTOR and spine formation.

These studies have identified new targets for understanding the neural basis of the antidepressant properties of ketamine that extend beyond the NMDA receptor channel and glutamate. But most important, these data are consistent with hypotheses that link the antidepressant effects of NMDA receptor antagonists to enhancement of neurotrophic and neuroplasticity-related factors and fit more broadly within neurotrophic theories of depression.

 provides a detailed illustration of the link in the induction of mTOR signaling and BDNF release through ketamine and novel glutamatergic modulators.

There is rapidly growing literature on the quick antidepressant effect of ketamine since the first published report by Berman and colleagues

 in 2000. In this early study, 4 of 8 patients demonstrated a 50% or greater reduction in Hamilton Depression Rating Scale (HDRS) scores at 72 hours postinfusion. A subsequent larger study by Zarate and colleagues

 using a cross-over design found that of the 17 participants who received ketamine, 12 (71%), 8 (47%), 6 (35%), and 2 (12%) met response criteria at 24 hours, 72 hours, 1 week, and 2 weeks postinfusion, respectively. Despite the encouraging results of these two studies, they included a fairly small number of patients and used a cross-over design with an inert placebo-control condition.

Our group recently published a parallel-arm, randomized controlled trial (RCT) of ketamine in 72 patients with TRD in whom 3 or more trials of an antidepressant have failed. Patients were randomized to ketamine (0.5 mg/kg over 40 minutes) or midazolam under triple-masked conditions (patient, rater, anesthesiologist).

 Patients in the ketamine group had significantly greater improvement in the MADRS score at 24 hours compared with the midazolam group (t [68] = 3.34; 

 < .001]. After adjusting for baseline scores and site, the MADRS score was 7.95 points lower in the ketamine group than in the midazolam group (95% confidence interval [CI], 3.20 to 12.71), corresponding to a large effect size (Cohen’s 

 = 0.81). ketamine also increased the likelihood of response at 24 hours compared with midazolam (odds ratio, 2.18; 95% CI, 1.21 to 4.14; 

 < .006). Our results provided further evidence that supports the use of ketamine as a novel option for patients with TRD.

A main advantage of ketamine over currently FDA-approved antidepressants is the robustness and rapidity of its effect. Based on the STAR*D study, fewer than half of depressed patients will respond to first-line treatment, about two-thirds of whom achieve response criteria after 6 weeks of treatment. A meta-analysis of ketamine double-blind RCTs showed a statistically significant difference on HDRS as early as 80 minutes after the start of treatment.

 Of note, the clinical effects of ketamine were not mediated by nonspecific mood-elevating effects, but rather by targeting core depressive symptoms, such as sad mood, helplessness, and worthlessness, as well as suicidality.

Ketamine’s effects on suicidal ideation seems independent of its antidepressant effect.

 A post hoc analysis of 2 trials in TRD found that open-label intravenous ketamine was associated with rapid reductions in explicit and implicit suicidal cognition within the first 24 hours. This effect persisted for patients who received up to 5 additional infusions over 2 weeks.

The rapid antisuicidal effects of a single administration of ketamine were recently replicated in an RCT.

 saw decreases in the Scale for Suicidal Ideation scores within 40 minutes of ketamine infusion (0.5 mg/kg over 40 minutes). These results further support the possibility of ketamine’s rapid antisuicidal effects.

 reported complete resolution of suicidal ideation in 14 actively suicidal patients following an intravenous bolus of ketamine (0.2 mg/kg) over 1 to 2 minutes in the emergency department (ED). MADRS item 10 (suicidality) score decreased significantly, from 3.9 at baseline to 0.6 within 40 minutes of treatment; this improvement was maintained for 10 days postinfusion.

Feasibility of using ketamine in clinical practice

There has been some skepticism regarding the practicality of administering intravenous ketamine infusions in clinical practice.

 However, one of the most important features of the Larkin and Beautrais study is that it took place in the ED, which suggests the feasibility of using ketamine in a busy ED setting. ketamine is available in oral, subcutaneous, intranasal, intramuscular, and intravenous formulations. This is a significant advantage over current antidepressants.

Intramuscular formulation could be considered for acutely suicidal patients when access to intravenous lines are limited.

 An intranasal formulation with a controlled delivery system may address concerns of ketamine abuse if prescribed in outpatient settings. Indeed, a recent report found that a single administration of intranasal ketamine was effective for patients with depression.

 Studies of intranasal esketamine (the S-isomer of racemic ketamine) for acute suicidal depression have been initiated (ClinicalTrials.gov Identifier NCT02133001).

Another advantage of ketamine is the potential use of BDNF, a peripheral biomarker, to predict antidepressant response to ketamine.

 Thus, within 24 hours of the first ketamine dose, clinicians are able to make informed decisions on whether to continue ketamine or use a different therapeutic modality.

ketamine is classified as a schedule class III agent by the FDA, with potential for abuse liability. However, ketamine’s safety and utility in specific clinical populations is well characterized based on years of use in anesthesiology and emergency medicine. Perry and colleagues

 reviewed the safety of ketamine in a psychiatric research setting and concluded that ketamine was safe in healthy volunteers. The emerging evidence of patients with TRD who receive subanesthetic doses of ketamine further cements its safety and tolerability.

Because of its sympathomimetic effects, ketamine may produce increases in blood pressure, heart rate, and cardiac output, and it can provoke ischemia in patients with underlying coronary artery disease.

 Although frequently mild and self-limited, ketamine-induced perceptual disturbances have been reported in up to 30% of study samples.

 Psychotomimetic disturbances may manifest as vivid dreams, visualization of psychedelic color, suspension in space, kaleidoscopic floating, and out-of-body experiences. Some patients describe these psychic experiences as bizarre or frightening, while other patients find them pleasurable, joyful, and fascinating.

 Finally, repetitive high anesthetic doses of ketamine have been linked to apoptosis and increased brain cell death in rodents and nonhuman primates.

 The available data support a favorable risk to benefit profile of subanesthetic low-dose ketamine; however, the long-term effects in humans have not been explored.

The clinical use of ketamine in the treatment of TRD is still unsettled. The optimal dose of ketamine has not been established, which is the focus of a new NIMH-sponsored trial (ClinicalTrials.gov Identifier NCT01920555). Most of the studies thus far have used a slow infusion over 40 minutes of 0.5 mg/kg, but the study by Larkin and Beautrais

 showed antisuicidal effectiveness at a lower dose given as a bolus. Moreover, higher anesthetic doses of ketamine (2 to 3 mg/kg) seem to lack effect on mTOR signaling.

While the ketamine antidepressant effect is fast, it is short-lived. Most patients relapse within 2 weeks of a single infusion.

 Repeated ketamine infusions have not led to substantial prolongation of the antidepressant effects. Two studies piloted a 2-week course of ketamine (0.5 mg/kg) administered 3 times weekly on a Monday-Wednesday-Friday schedule in patients with TRD.

 The response rate after the sixth infusion was 71% in the report by Murrough and colleagues.

 However, the median to relapse was 18 days. The augmentation of a single ketamine infusion with the glutamate modulator riluzole showed no difference from placebo in preventing relapse post-ketamine.

 Using ketamine in combination with electroconvulsive therapy (ECT) did not improve outcomes whether at anesthetic or subanesthetic dose. While earlier response was noted in the groups receiving ketamine, no difference was noted between the study groups at the end of the ECT course.spe

It is important to recognize that RCTs for ketamine as treatment for MDD are still in their early stages, and the evidence is limited. Several treatment modalities have been recommended for patients who have inadequate responses to repeated antidepressant trials, including augmentation with lithium, triiodothyronine, or second-generation anti- psychotics, and neuromodulatory techniques, such as repetitive transcranial magnetic stimulation. Although, its use is curtailed by cognitive adverse effects and the public’s opinion about “shock therapy,” ECT remains the most effective therapy for patients with TRD.

While there is understandable enthusiasm regarding ketamine’s potential, there are insufficient data to support its integration in clinical care at this time. The broader effectiveness of ketamine in varied clinical settings has not been systematically examined. More studies are needed on critical issues, such as dose optimization, alternative drug delivery routes, methods to prevent relapse following resolution of depressive symptoms, and understanding neurobiological mechanisms underlying the putative antidepressant actions of ketamine.

-This article is the result of work supported with resources from and the use of facilities at the Michael E. DeBakey Veterans Affairs Medical Center in Houston.

Drs Al Jurdi and Mathew are Associate Professors at the Mental Care Line at the Michael E. DeBakey Veterans Affairs Medical Center and the Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston. Dr Al Jurdi reports no conflicts of interest concerning the subject matter of this article. Dr Mathew reports that he has received research support from Janssen Research and Development, AstraZeneca, and the NIMH; he is a consultant to Bristol-Myers Squibb, Genentech, and Naurex.

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 Loo CK, katalinic N, Garfield JB, et al. Neuropsychological and mood effects of ketamine in electroconvulsive therapy: a randomised controlled trial. 

 Okamoto N, Nakai T, Sakamoto k, et al. Rapid antidepressant effect of ketamine anesthesia during electroconvulsive therapy of treatment-resistant depression: comparing ketamine and propofol anesthesia. 

The discovery that a single IV infusion of low-dose (subanesthetic) ketamine exerts rapid antidepressant effects constitutes an expansion in our understanding of the neurobiology of depression and provides new avenues for drug development. 

Sanjay J. Mathew, MD

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