A recent exciting discovery in depression treatment was that low doses of the anesthetic ketamine have antidepressant effects via a novel mechanism of action.1 Such a discovery was much needed, given the scope of the public health impact of untreated depression. Major depressive disorder (MDD) is a leading cause of disability among adults worldwide and is attributed to 386 million disability days per year.2 Greenberg et al.3 estimated that the total cost of MDD, including productivity loss, suicide-related costs, and direct care cost, was $210.5 billion in 2010. Not only is this cost high, but if compared to 2005 data, it is rising.2
Newer antidepressants, such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, have more favorable side-effect profiles relative to their tricyclic antidepressant and monoamine oxidase inhibitor predecessors, but demonstrate only modest additional efficacy. One explanation is that all four classes of antidepressants are based on the monoamine hypothesis of depression.4 This hypothesis may address some portion of the pathophysiology of depression, but there is now consensus that there is more to the story. This necessitated a move beyond monoamine targets, which are only involved in 15% to 20% of synaptic connections, to more prominent systems like the glutamatergic system (eg, glutamate is the primary neurotransmitter in almost 50% of synapses) and beyond neurotransmitter targets more generally to neural pathways and systems.5
Although ketamine is best known as an N-methyl-D-aspartate (NMDA) receptor antagonist, the NMDA receptor is one of three glutamate receptors in the brain. To understand how ketamine works as an antidepressant, we must first understand the function of glutamate in depression.
Ketamine's Mechanism in Depression
Much of the work examining glutamate and its role in synaptic plasticity comes from the chronic stress animal model of depression. After chronic stress, changes seen in glutamatergic neurons include reductions in synapse density, synapse diameter, and dendritic length and branching.6
Glutamate activates NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA), and kainate receptors at the postsynaptic neuron causing depolarization.7 NMDA and AMPA receptors serve multiple functions, but recently have been implicated in the modulation of long-term potentiation and synaptic plasticity in the hippocampus and prefrontal cortex.8
Ketamine is a noncompetitive NMDA receptor antagonist, binding to a site within the NMDA receptor to inhibit depolarization. When ketamine binds to NMDA receptors on inhibitory gamma-aminobutyric acid interneurons, it prevents inhibition of glutamatergic pyramidal neurons, resulting in a glutamate surge in the synaptic cleft. Although glutamate would normally bind to all three above-mentioned receptor types, when ketamine blocks NMDA receptors, it preferentially binds to AMPA receptors (the role of kainate is not as well studied at this time). This postsynaptic activation of AMPA receptors allows for the cascade of intracellular signaling, which eventually activates the mammalian target of rapamycin, increases brain-derived neurotrophic factor translation and secretion, and inhibits glycogen synthase kinase-3.9 The intracellular signaling triggered by ketamine ultimately leads to an increase in synaptic plasticity, which reverses the reductions in synapse density, synapse diameter, and dendrite length and branching caused by chronic stress (Figure 1). In animal models, the result of these physiological changes is an improved result on the forced-swim test or tail suspension test.
Effects of depression and ketamine on synaptic glutamate release and its subsequent binding to AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic) receptors leading to synaptogenesis in the prefrontal cortex. BDNF, brain-derived neurotrophic factor. Adapted from Abdallah et al.30
The exact means by which ketamine ultimately exerts its antidepressant effect are still under examination. Earlier investigation suggested that it was directly related to the strength of NMDA receptor antagonism. Because the S-enantiomer (S-ketamine/esketamine) has a 3- to 4-fold greater affinity for NMDA receptors, it was hypothesized that this would be the stronger antidepressant relative to the R-enantiomer.10 This belief, along with the NMDA receptor antagonism hypothesis, has come into question after a preclinical study by Zanos et al.11 showed that a metabolite of ketamine, [(2R,6R)-hydroxynorketamine], has potential antidepressant effects without antagonizing the NMDA receptor. Another interesting finding from this study was that if AMPA receptors are blocked, the antidepressant effects of ketamine are as well. Therefore, it is clear that it is not just the blockade of NMDA receptors that is important, and perhaps explains why studies of memantine, an NMDA receptor antagonist, as an antidepressant were negative.12 Furthermore, ketamine has a broad and diverse mechanistic reach, affecting monoaminergic and opioid targets, along with anti-inflammatory/immune-modulating properties.
Ketamine for Depression: The Beginnings
Although there had been some prior speculation about ketamine's antidepressant potential among those interested in the properties of psychedelics, formal study was first undertaken by Berman et al.13 in 2000. They tested 0.5 mg/kg of intravenous (IV) ketamine over 40 minutes and found antidepressant effects identifiable at 4 hours and lasting to 72 hours on average. There is little documented rationale for this choice of dose, other than the fact that it is subanesthetic yet still produces dissociation (anesthesia induction occurs at 2–3 mg/kg). This study was not replicated until Zarate et al.14 in 2006 performed a single-dose randomized controlled trial and found that onset of antidepressant effects at 2 hours remained significant for up to 1 week.
Since then, several other studies have confirmed the initial findings and there hasn't been a single negative result study. Results were aggregated in several meta-analyses; one such meta-analysis by Han et al.15 singled out the randomized, double-blind, placebo-controlled studies. These authors included nine studies, pooling 368 patients, and found a beneficial effect from a single infusion of 0.50 mg/kg of ketamine (one study used 0.54 mg/kg) versus placebo at 24 hours, 72 hours, and 7 days postinfusion.15 At 24 hours, there was a 52% response rate with ketamine versus 8% with placebo with an odds ratio of 10 favoring ketamine. The remission rate was 21% for ketamine versus 3% for placebo with an odds ratio of 5, favoring ketamine. At days 3 and 7, odds ratios favored ketamine with response rates of no less than 40% and remission rates no less than 24%. The American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatments also conducted a meta-analysis summarizing seven trials with a total of 147 patients. They found an odds ratio of response to treatment at 24 hours of 9.87 and odds ratio of 14.47 for remission of symptoms at 24 hours.16
Despite these promising results, many thought leaders17 point out that the total number of patients involved in randomized, controlled trials of ketamine for mood disorders is still quite low compared to a US Food and Drug Administration (FDA)-approved clinical study.
Ketamine and Treatment-Resistant Depression
Key ketamine indications in psychiatry include treatment-refractory mood disorders and suicidal ideation. Ketamine has shown rapid and robust antidepressant effects.18 Limitations and risks exist for all treatments. Although FDA-approved treatments exist for MDD and bipolar depression, approximately one-third of patients with MDD fail to respond to currently approved antidepressants.19 Treatment-resistant or treatment-refractory MDD is characterized by patients failing to respond to an adequate dose for an adequate duration of at least two antidepressants from two different pharmacologic classes. Agreement is lacking for such an “exacting” definition of treatment-resistant or refractory bipolar depression; yet, the resistant nature of the depression in a significant proportion of these patients is well known to their treating clinicians. In these refractory-depressive disorders, ketamine presents a potential option.18
Ketamine and Bipolar Depression
Efficacy in bipolar depression has also been documented through meta-analysis, with statistically significant improvement relative to placebo.20 Sixty-nine patients from three randomized, double-blind, placebo-controlled, crossover clinical trials received IV ketamine at 0.5 mg/kg while at therapeutic levels of either lithium or valproate. Pooled analysis revealed that mean primary depression scores showed significant improvement with effects in some patients lasting up to 14 days. No serious side effects were reported, and tolerability were similar between ketamine and placebo groups. Of note, although many antidepressants have been shown not only to be ineffective when used adjunctively in bipolar depression, but may also induce mania, there was no evidence that ketamine induced mania in these trials.21
Ketamine Dose and Delivery
Although the beneficial role of single infusions of ketamine has been established for patients with MDD and bipolar depression, the optimal dosing regimen has not been settled. The dose and delivery of ketamine in most recent clinical trials has been 0.5 mg/kg delivered intravenously over 40 minutes as per the study by Berman et al.13 There is no consensus on dose or time-dependent efficacy as both higher and lower IV concentrations have demonstrated mixed results.18 Currently investigators, as part of the National Institutes of Health-funded RAPID (Rapidly-Acting Treatments for Treatment-Resistant Depression) study, are determining ketamine's antidepressant dose-response in a multisite, psychoactive placebo-controlled trial with ketamine concentrations of 0.1, 0.2, 0.5, and 1 mg/kg.9
Many of the initial ketamine studies were single-dose trials, but in 2013, Murrough et al.22 published results showing a much longer duration of symptom improvement after six ketamine infusions adminstered 3 times weekly. This study included 24 patients and 70.8% responded with an improvement in depressive symptoms. The median time to relapse was 18 days, and those with a duration of response in the 75th percentile had lasting improvements up to 27 days. Despite these positive results, it is unclear if six ketamine infusions administered 3 times weekly is the ideal schedule of administration. A study by Singh et al.23 found similar duration of efficacy when ketamine infusions were given 2 times weekly for 3 weeks versus 3 times weekly for 2 weeks.
Another strategy to increase the durability of antidepressant efficacy may be to add weekly infusions for a short time after this initial series. An open-label study showed that for patients whose unipolar or bipolar depression symptoms remitted after six ketamine infusions given 3 times weekly for 2 weeks, remission continued if given weekly for the subsequent 4 weeks. In the 4-week follow-up period without ketamine, it was found that the patients' symptoms remained decreased from baseline, but their depressive disorder was no longer in remission.24
In addition to routine fixed dosing, both dose escalation25 and concurrent initiation of oral antidepressants26 may be helpful.
Ketamine and Suicidal Ideation
Additionally, in a systematic review of the literature, an IV dose of 0.50 mg/kg over 40 minutes was shown to reduce suicidal ideation among 80 patients within three randomized controlled trials of unipolar and bipolar depressed patients. The average duration of suicidal ideation reduction was 3 days with the earliest significant results at 40 minutes and lasting up to 10 days post a single infusion.27 Furthermore, a posthoc analysis of 133 patients with MDD or bipolar I or II depression, 4 hours after IV ketamine administration at a dose of 0.5 mg/kg over 40 minutes, demonstrated a reduction of suicidal thoughts independent from improvement of depression and anxiety symptoms.28
Ketamine and Electroconvulsive Therapy
Electroconvulsive therapy (ECT) has long been the preferred interventional therapy for severe, treatment-resistant depression. Unfortunately, although efficacious, its utility may be limited by memory loss and anesthesia risk. Although it was hoped that ketamine could improve efficacy of ECT, so far it has not been useful either as augmentation or in lieu of another agent to induce anesthesia in patients undergoing ECT.16 Perhaps the definitive study on ketamine augmentation of ECT was published in 2017; this study examined whether a 0.5 mg/kg IV bolus in addition to the anesthetic would alleviate cognitive adverse effects or improve antidepressant response.29 In both cases, the study was negative.
As the glutamate system becomes a greater emphasis for future drug development, choosing the right glutamate-modulating medication for treatment will remain difficult, given the complexity and ubiquity of glutamate in the brain and a multitude of mechanisms within the glutamate-modulator class of medications.30 Indeed, ketamine is viewed as a “dirty” drug to some so to speak, in that it affects many areas of the brain and affects many different types of receptors, in addition to the new synapses it creates. Fortunately, ketamine, as a glutamate modulator, has an established safety profile as an anesthetic. Concerns remain regarding what treatment(s) should be employed after ketamine and whether ketamine continued for maintenance is indicated without many studies of its longitudinal safety profile. These concerns are being addressed through present and future study. Psychiatrists and other practitioners who wish to understand more about current consensus and future guidelines should review literature released by the American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatments.31
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