US Pharm. 2016;41(11):HS28-HS32.
ABSTRACT: Ketamine, an antagonist at the N-methyl-d-aspartate (NMDA) receptor, produces rapid antidepressant effects with low, subanesthetic doses of 0.5 mg/kg administered IV over 40 minutes. Response rates range from 25% to 100%, and remission rates range from 8.3% to 89%. Duration of response has been less than 1 week to more than 3 months. Significant hemodynamic and psychiatric adverse effects are seen with the use of ketamine, and its potential for abuse has also raised questions. Research continues to delineate the most effective role for ketamine in depression, and how its use might foster the development of similar agents with a longer duration.
The lifetime prevalence of major depressive disorder (MDD) is nearly 17%, with a 12- month prevalence of 5% to 9%.1 There is an overall 1.4 times greater risk of mortality in people with MDD over that of the general population.2 The World Health Organization ranks depression as a leading cause of disability, and predicts that by 2030, depression will be the leading cause of global disease burden.2,3 The economic burden of depression, including MDD, bipolar disorder, and dysthymia, has also increased from an estimated $83.1 billion in 2000 to $210.5 billion in 2010.4
Pharmacologic management of depression today is based largely on the monoamine hypothesis of depression and the neurotransmitters norepinephrine, serotonin, and dopamine. While the agents in current use help many patients, more than half of those treated fail to achieve remission and are resistant to treatment with a first-line antidepressant.5
The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study was a large, multicenter, effectiveness trial sponsored by the National Institute of Mental Health (NIMH).6 Results demonstrated that only 47% of patients responded to a first-line antidepressant (citalopram), and only 1 in 3 patients remitted. Subjects took an average of nearly 6 weeks to respond, and about 7 weeks to achieve remission from depressive symptoms. In this study, as in most antidepressant trials, response was defined as 50% reduction in score from baseline on the Hamilton Depression Rating Scale (HDRS); remission was defined by achieving a score of 7 on the HDRS. At each step in the study, a significant percentage of patients failed to achieve remission by week 6 or 8, with some remitting at or beyond week 14.6
While there appears to be no definitive, standardized definition for treatment resistant-depression (TRD), it is generally accepted as failure to respond to at least two adequate trials of different classes of antidepressants, an adequate trial being defined as an adequate dose given for an adequate duration (i.e., 6 or 8 weeks).7 For over 40 years, the focus on monoamine neurotransmitters has helped us to better understand the etiology and management of depression; however, this original hypothesis appears to be inadequate for leading to the discovery of newer, faster-acting anti-depressants.8 Ketamine has generated significant interest in the treatment of MDD, bipolar depression, and in depression with suicidal ideation after the publication of a number of studies demonstrating its rapid-acting antidepressant effect following low IV doses.9-11
What Is Ketamine?
Ketamine is a derivative of phencyclidine, with anesthetic, analgesic, and amnestic properties.12 It is approved by the FDA for sedation during procedures and as an adjunct for general anesthesia. Because it causes dissociative effects and has a potential for abuse, the agent is classed as a Schedule III controlled substance. Ketamine is highly lipid soluble, with large volume of distribution and ease of penetration into the central nervous system (CNS).13 The drug has a rapid onset of action (0.5 minutes) and a short duration of action. Its elimination is biphasic, with a rapid initial distribution of drug (t½α ~10 min) and a longer elimination half-life (t½β = 2 to 3 h), representing redistribution from the CNS and hepatic metabolism to an active metabolite, norketamine. The benefit of ketamine in anesthesia is that it does not adversely affect respiratory function.13 The bioavailability of ketamine has been reported to be 100% following IV and intraosseous administration, 93% IM, 16% to 20% oral, 30% sublingual, 45% to 50% intranasal, and 25% to 30% rectal.14
Clinical Use of Ketamine in Depression
In 2000, Berman et al published the first double-blind, placebo-controlled, crossover trial evaluating the use a single dose of 0.5 mg/kg ketamine over 40 minutes in eight patients with recurrent unipolar major depression and one with bipolar disorder, which showed progressive decreases in depressive symptoms within 3 days of treatment.15 Four of eight (50%) ketamine patients responded during the 3 days of follow-up, with significant decreases in individual HDRS items of depressed mood, suicidality, helplessness, and worthlessness. Only one of eight (13%) placebo patients showed a similar response, and three (38%) placebo patients remained above baseline during follow-up. Patients who showed mood improvement on ketamine returned to baseline levels 1 to 2 weeks after infusion. Ketamine infusion also showed significantly greater intoxication “high” scores that returned to baseline by 110 minutes after infusion, as well as significantly greater Brief Psychiatric Rating Scale (BPRS) scores, including profound and transient cognitive deficits and euphoria.15
Six years later, Zarate et al conducted a randomized, placebo-controlled, double-blind crossover study of ketamine 0.5 mg/kg versus saline in 18 patients (12 men and 6 women) with TRD.16 Seventeen (94%) patients receiving ketamine demonstrated significant improvement in depression within 110 minutes of the infusion through 7 days versus the 14 patients who received placebo. Patient ratings on the Beck Depression Inventory (BDI) showed ketamine to improve depression from 40 minutes through 7 days. Twelve of 17 (71%) ketamine patients responded, and five (29%) patients met remission criteria 1 day after infusion versus 0 (0%) of 14 placebo patients for either endpoint. Response was also maintained for at least 1 week in six (35%) and for at least 2 weeks in two (12%) of the 17 patients receiving ketamine. Ketamine patients more commonly experienced disturbances in perception, confusion, increased blood pressure, euphoria, dizziness, and decreases in libido. Most adverse effects had stopped by 80 minutes after infusion, and there were no cases of euphoria or dissociative effects beyond 110 minutes. Notably, the antidepressant effects from ketamine became significant after the BPRS and Young Mania Rating Scale (YMRS) scores had returned to baseline, suggesting no causal relationship between ketamine’s dissociative and antidepressant effects.16
In an attempt to determine the effective dose of ketamine, Lai et al conducted a double-blind, placebo-controlled, crossover pilot, dose-finding study in four patients with TRD, with each patient on stable doses of psychotropics receiving up to four ascending doses of IV ketamine (0.1, 0.2, 0.3, and 0.4 mg/kg) given rapidly over 2 to 5 minutes.17 While three (75%) patients responded, only one responder showed a clear dose-response relationship, achieving remission after only the 0.4 mg/kg dose. All patients relapsed within 1 week. Because there were significant psychotomimetic effects with rapid infusion over 2 minutes, which lasted <20 minutes and returned to pretreatment level within 4 hours for all patients, the authors concluded that the study did not support rapid IV infusion for ketamine dosing.17
Ketamine Effect on Suicidal Ideation
DiazGranados et al evaluated the effect of ketamine on suicidal ideation in 33 patients unmedicated at least 2 weeks prior to infusion.18 Ketamine 0.5 mg/kg was administered over 40 minutes, with assessments up to 230 minutes post infusion. Sixty-one percent of patients had a lifetime history of suicidal ideation, 30% with a previous suicide attempt. There was significant improvement in all suicide scales following infusion, with scores significantly lower at 40 minutes and at 230 minutes. Effect size (d) at 40 minutes was very large (d = 1.05, 95% CI, 0.65-1.45) and moderate at 230 minutes (d = 0.45, 95% CI, 0.12-0.77). There was also a rapid and significant improvement in depression, anxiety, and hopelessness scores.18
Larkin and Beautrais evaluated the effect of a single low-dose bolus of IV ketamine 0.2 mg/kg over 1 to 2 minutes on depression and suicidality in 14 emergency department patients.19 There was a significant decrease in suicidal ideation in all patients at 40, 80, and 120 minutes post infusion, with a sustained response in 13 patients monitored for up to 10 days. Mild psychotomimetic symptoms in two patients resolved within 40 minutes.19
Effect of Ketamine With Repeat/Serial Infusions
The significant reduction in depressive and suicidal symptoms noted with single infusions raised the question of whether multiple, serial doses of ketamine might produce a more prolonged response. In a study of 10 patients who received one dose of ketamine 0.5 mg/kg over 40 minutes, aan het Rot et al reported that nine (90%) responded and went on to receive five additional doses 3 times a week for 2 weeks.20 After the sixth infusion, nine (100%) patients responded, and eight (89%) remitted. Patients who continued to respond after the last dose were followed every 2 weeks for ≥4 weeks or until they relapsed. Of the nine patients receiving repeated infusions, eight relapsed an average of 19 days after the sixth infusion (range 6-45 days); the other patient remained off antidepressants with minimal symptoms for more than 3 months. The authors concluded that patients who respond to an initial dose of IV ketamine will generally respond to additional serial doses, and for 6 days after that.20
In a similar study, Shiroma et al assessed the response to six consecutive ketamine infusions, 0.5 mg/kg over 40 minutes, administered 3 times a week over 12 days in 12 patients maintained on stable doses of anti-depressants.21 Three (25%) patients responded and one (8.3%) remitted after the first infusion. After three or more infusions, seven (58%) responded and six (50%) remitted. Overall, 11 (92%) patients responded and eight (67%) remitted. Response was maintained through 4 weeks in five (45%) of the responders. The mean time to relapse for the remaining six patients was 16 days (range 7-28 days).21
Mechanism of Ketamine’s Antidepressant Effect
Ketamine is a noncompetitive antagonist at the N-methyl-d-aspartate (NMDA) receptor, and it also has agonist activity at opioid, dopamine, norepinephrine, serotonin, and muscarinic cholinergic receptors.12 L-glutamic acid (glutamate) is the principal excitatory neurotransmitter in the CNS, and plays a key role in brain neurogenesis, synaptogenesis, and neuronal migration, differentiation, and survival.22 After release from the presynaptic neuron, it interacts with various glutamate receptors on post-synaptic neurons as well as glial cells, including ionotropic NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainate receptors (KARs), and metabotropic glutamate receptors (mGluRs). Glutamate reuptake into astrocytes is facilitated by excitatory amino acid transporters (EAATs), where it is combined with ammonia to form glutamine. The cycle is completed with the transport of glutamine to presynaptic neurons, where it is deaminated by glutaminase to reform glutamate. Patients with MDD are reported to have higher serum and cerebrospinal fluid glutamate levels; a positive correlation between plasma glutamate levels and depression symptom severity in MDD suggests an abnormality in the glial-neuronal, glutamine-glutamate cycle.22
Prolonged stress and depression are associated with atrophy of neurons and overall synaptic depression in the prefrontal cortex (PFC) and the hippocampus, as well as neuronal hypertrophy and synaptic potentiation in the amygdala and nucleus accumbens.23 These changes likely stem from stress-induced alterations in the release of glutamate and astroglial loss, which lead to deficits in brain-derived neurotrophic factor (BDNF), inhibition of the mammalian target of rapamycin complex 1 (mTOR1) signaling pathway, and sustained increases in extracellular glutamate. Excess glutamate induces excitotoxicity and PFC changes, including alterations in synaptic strength, dendritic spine density loss, retraction of dendrites, and decreased dendritic branching. Effective reversal of depression would thus be supported by enhancing BDNF and mTOR1 signaling, with resultant PFC synaptogenesis and reversal of stress- and depression-induced synaptic disconnectivity and neuronal atrophy. Antidepressants that target monoamine systems have been shown to increase BDNF and synaptogenesis, but only with chronic treatment and a prolonged timeline consistent with response to those antidepressants.23
Ketamine is thought to rapidly restore prefrontal synaptic connectivity through a series of events.23 By blocking NMDA receptors on inhibitory GABAergic interneurons, ketamine disinhibits the release of prefrontal glutamate. This glutamate surge both activates AMPA receptors and blocks extrasynaptic NMDA receptors to increase BDNF and activate mTOR1 signaling, resulting in overall synaptogenesis and synaptic potentiation. It also involves the inhibition of the eukaryotic elongation factor 2 (eEF2), with decreased eEF2 phosphorylation and subsequent increased translation of BDNF. Taken together, these acute ketamine treatment effects rapidly counter the stress-induced prefrontal neuronal atrophy and synaptic disconnectivity.23
Safety and Tolerance
Pooled data from three clinical trials were reviewed to assess the safety and tolerability of ketamine in TRD.24 In general, adverse events were mainly cardiovascular and psychiatric. Dissociative symptoms were relatively common and generally mild, though pronounced in some patients. Common side effects and behavioral changes generally resolved either shortly after or within 4 hours of stopping the infusion. There was a small but significant increase in psychotic symptoms, although psychotomimetic effects were relatively uncommon. There did not appear to be any persistent physical, emotional, or psychological effects, except for one case of anxiety and dysphoria lasting over 1 month. There were also no reports of increased cravings or use of ketamine or other illicit substances. The findings from this study did, however, underscore the need for hemodynamic monitoring. A summary of ketamine’s adverse events are listed in TABLE 1. Other studies have also demonstrated delayed-onset suicidal ideation and dysphoria in patients with obsessive-compulsive disorder (OCD) and isolated cases of mania.24
Potential for Abuse
One of the concerns with the use of ketamine is its potential for abuse with long-term use. With the increased abuse of ketamine as a mainstream club drug, Morgan et al assessed longitudinal changes in neurocognitive function and psychological well-being over 1 year in frequent, infrequent, and abstinent users of ketamine with matched polydrug users and nondrug users.25 They noted significantly greater use of ketamine in the frequent-user group, which was associated with a decreased performance on a number of memory assessments. With regard to psychological well-being, frequent, infrequent, and abstinent users showed mild delusional ideation, though more so in the frequent users. Frequent and abstinent users also demonstrated increased depression scores over the 12 months. In summary, the authors profiled a frequent ketamine user as “an individual with marked, profound cognitive impairments in short- and long-term memory, and someone who is mildly ‘delusional’ and distinctly dissociated in their day-to-day existence.” Conversely, infrequent or recreational users of ketamine appeared not to be cognitively impaired and had only mild delusional symptoms.25
Bonnet reported on a 50-year-old nurse anesthetist successfully treated for MDD with 25 mg IM ketamine.14 After immediate improvement in her pain and depression, she started self-injecting with stock she stole from the hospital, developed tolerance to the beneficial effects of the drug, and escalated her dose and frequency stepwise to 2 g/day, resulting in ketamine addiction, loss of consciousness, dissociative immobility, and amnesia. Inpatient detoxification was remarkable for strong craving for ketamine, and she later developed a severe depressive episode that remitted on venlafaxine. Follow-up after 14 weeks showed a normal condition with no ketamine craving, psychosis, depression, or cognitive abnormalities.14
While many of the studies conducted with ketamine in depression suggest that tolerance, addiction, and abuse of ketamine are minimal, continued research is needed to fully assess the abuse liability of this drug with the use of long-term serial infusions.
Application to Clinical Practice
There may be a number of providers in the United States offering off-label ketamine infusions to treat depression on an outpatient basis.26 With the risk of cardiovascular, psychotomimetic, and other behavioral adverse effects associated with ketamine’s use, precautions are summarized in TABLE 2.26,27
While it is beyond the scope of this article, ketamine has also been studied and shown beneficial antidepressant effects when administered in oral, IM, SC, sublingual, and intranasal dosage forms.9,28,29 The use of ketamine in depression has also fostered research into the development of novel glutamatergic agents with a longer duration of action.30 It is hoped that the outcome of this research will yield faster and more effective agents for the acute and maintenance treatment of depression.
The rapid antidepressant response seen with the use of subanesthetic doses of ketamine has reignited hope for clinicians to find a faster, more effective way to treat MDD. While the data look promising, there are still questions concerning the most effective dose and route of administration; how to address the cardiovascular, psychotomimetic, and possible cognitive adverse effects; and cautious optimism regarding the abuse potential, or lack thereof, with the use of ketamine.
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