Why does ketamine have a rapid effect on depression that is difficult to treat?


The anesthetic drug ketamine has been shown, in low doses, to have a rapid effect on difficult-to-treat depression.

Researchers at Karolinska Institutet now report that they have identified a key target for the drug: specific serotonin receptors in the brain. Their findings, which are published in Translational Psychiatry, give hope of new, effective antidepressants.

Depression is the most common psychiatric diagnosis in Sweden, affecting one in ten men and one in five women at some point during their lives. Between 15 and 30 percent of patients are not helped by the first two attempts at therapy, in which case the depression is designated difficult to treat.

Studies have shown that low doses of the anesthetic drug ketamine are rapid-acting on certain sufferers, but exactly how it works is unknown.

A nasal spray containing ketamine has recently been approved in the USA and EU for patients with treatment-resistant depression.

Researchers at Karolinska Institutet in Sweden have now imaged the brains of study participants using a PET (positron emission tomography) camera in connection with ketamine treatment.

“In this, the largest PET study of its kind in the world, we wanted to look at not only the magnitude of the effect but also if ketamine acts via serotonin 1B receptors,” says the study’s first author Mikael Tiger, a researcher at the Department of Clinical Neuroscience, Karolinska Institutet.

“We and another research team were previously able to show a low density of serotonin 1B receptors in the brains of people with depression.”

In the first phase of the study, 30 people with difficult-to-treat depression were randomly assigned to either a ketamine-infusion group (20 individuals) or a placebo (saline) group. It was a randomized double-blind study, so neither patient nor doctor initially knew who received the active substance.

The participants’ brains were imaged with a PET camera before the infusion and 24-72 hours afterward.

In the next phase, those who so wished (29 individuals) received ketamine twice a week for two weeks. The result was that over 70 percent of those treated with ketamine responded to the drug according to a rating scale for depression.

Serotonin plays a key role in depression and low levels are thought to be linked to more serious disease. There are 14 different kinds of receptors for this neurotransmitter on the surface of neurons.

For their PET imaging, the researchers used a radioactive marker that binds specifically to serotonin 1B receptors. They found that the ketamine operated via these receptors in a formerly unknown mechanism of action.

Binding to this receptor reduces the release of serotonin but increases that of another neurotransmitter called dopamine. Dopamine is part of the brain’s reward system and helps people to experience positive feelings about life, something that is often lacking in depression.

“We show for the first time that ketamine treatment increases the number of serotonin 1B receptors,” says the study’s last author Johan Lundberg, research group leader at the Department of Clinical Neuroscience, Karolinska Institutet.

Ketamine has the advantage of being very rapid-acting, but at the same time, it is a narcotic-classed drug that can lead to addiction.

So it’ll be interesting to examine in future studies if this receptor can be a target for new, effective drugs that don’t have the adverse effects of ketamine.”


NMDA receptor blockade paradigm

Neurochemical antidepressant mechanism by blockade of NMDA receptor

NMDA receptors are glutamatergic and heterotetrameric ligand- gated ion channel receptors that are activated by concurrent binding of L-glutamate and glycine or D-serine to the GluN2 and GluN1 subunits or via flow of calcium ions when a depolarization repels the Mg2+ block from the ion channel pore in a voltage-dependent manner.

In a forced swim test in mice, it was demonstrated that a non-competitive NMDA receptor antagonist and a competitive NMDA receptor antagonist have an antidepressant effect of reducing the duration of immobility in these mice [26]. In the same experiment, long-term administration of antidepressants reduced the binding of a radioactive ligand to the NMDA receptors, which was believed to be an adaptive change of the receptor.

Therefore, the researchers suggested that rapid-acting antidepressant actions were caused by direct blockade of NMDA receptors.

Ketamine blocks excitatory glutamate signaling and increases the overall activity of the prefrontal cortex [27] by preferentially inhibiting NMDA receptors expressed in GABA neurons [28,29].

This mechanism is supported by a preclinical study, which found that a non-competitive NMDA receptor antagonist, dizocilpine, inhibited the firing of GABA interneurons but increased the firing of pyramidal neurons. Ketamine has a high affinity for the GluN2D subunit of the GluN2D-NMDA receptors that are highly expressed in the inhibitory interneurons of the forebrain [30].

It is predicted that inhibition of NMDA receptors in GABAergic interneurons induces a general decrease in inhibition, which will then disinhibit pyramidal neurons and strengthen excitatory glutamate signaling in the medial prefrontal cortex [28]. When a subanesthetic dose of ketamine is administered to mice, the extracellular glutamate concentration and glutamate cycling in the prefrontal cortex are increased [28,31].

Ketamine may induce antidepressant actions through direct inhibition of extrasynaptic NMDA receptors. The presence of extrasynaptic NMDA receptors has been demonstrated through immunohistochemical and electrophysiological studies [32].

GluN2B-containing extrasynaptic NMDA receptors located in dendrites near glial cells are not activated by transient synaptic glutamate release but are chronically activated by low levels of glutamate in the extracellular space [33,34].

This tonic glutamate level is regulated by the glutamate transporter, EAAT2, which is expressed in glial cells. Ketamine inhibits glutamateinduced tonic actions through specific inhibition of extrasynaptic GluN2B-NMDA receptors, and this is presumed to induce excitation of pyramidal neurons [35].

Activation of extrasyna ptic GluN2B-selective NMDA receptors occurs through the mTOR signaling pathway associated with inhibition of protein synthesis for homeostatic synaptic scaling [35-37], and, as such, blockade of the above receptors may induce antidepressant actions via disinhibition of protein synthesis and an mTOR-dependent mechanism.

Although selective antagonism of GluN2B-containing NMDA receptors produces antidepressant actions, it is not as rapid-acting as the antidepressant effects of ketamine through other mechanisms. GluN2B-NMDA receptor antagonists, traxoprodil and MK-0657, elicited significant antidepressant actions approximately five days after their infusion [38,39].

The lateral habenula is an epithalamic structure that plays a mediating role between the monoaminergic systems and the forebrain and midbrain [40]. Activation of the lateral habenula neurons is associated with depression-like phenotypes in depressed animals and humans.

In mice, depression and fatigue were associated with increased activity burst in the lateral habenula neurons [41]. Direct application of ketamine to the lateral habenula neurons decreased the abnormally high levels of NMDA receptor-dependent firing bursts and induced immediate antidepressant effects [41].

Further studies are needed to investigate whether other types of rapid-acting antidepressants share the same mechanism of action, whether these effects converge with other antidepressant actions of ketamine, and if the same results can be obtained in humans.

The mechanism of enhancing synaptic plasticity by blockade of NMDA receptor

The mechanism underlying the action of rapid-acting antidepressants comes from rapid changes in synaptic functions and neural plasticity. Ketamine increases the mTORC1 signaling through Akt and ERK activation and increases the number and function of synapses in the prefrontal cortex [35,42,43].

This leads to increased synthesis of proteins required for the formation and maturation of synapses, which may be blocked by pre-infusion with a selective mTORC1 inhibitor rapamycin [35,42,44]. The rapid activation of mTORC1 and dendritic mRNA translation of synaptic proteins by ketamine triggers continuous synapse formation and behavioral changes.

Ketamine-mediated mTORC1 activation, synapse formation, and antidepressant actions are determined by glutamate signaling and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation.

Animal and clinical studies found that blockade of NMDA receptors on GABAergic interneurons increased glutamate signaling [28,29,45]. In addition, activation of the AMPA receptor induced the release of BDNF in neurons and mTORC1 signaling through Akt and ERK signaling [46,47].

In contrast to ketamine’s activity-dependent BDNF release, monoamine antidepressants do not induce the release of BDNF but increase BDNF expression through complex intracellular signaling cascades [48]. This process is relatively slower than the antidepressant action of ketamine [11].

The rapid induction of mTORC1 signaling and synaptogenesis recovers the synaptic loss between neurons in patients with depression and restores the ability to adequately control emotions in the prefrontal lobe and amygdala.

This has been demonstrated by a chronic stress-depression rat model exposed to stress for several weeks [49]. The rats in this study exhibited prefrontal neuron atrophy and anhedonia, which are characteristic of depression; however, a single dose of ketamine rapidly improved the aforementioned structural deficit and behavioral problems.

This has also been demonstrated with brain imaging studies in animals and in clinical studies showing that ketamine increased the connectivity of the prefrontal lobe with the limbic system in species with depression [50,51].

Independent synaptic vesicle glutamate release via independent fusion of synaptic vesicles at presynaptic terminals induces miniature excitatory postsynaptic currents (mEPSCs), which regulate synaptic strength and protein synthesis [52-54]. mEPSCs inhibit protein synthesis while blocking NMDA receptor-mediated neurotransmission, and the resulting selective depletion of vesicles led to synaptic strengthening in the hippocampus [54].

Ketamine blocked resting NMDA receptor-mediated neurotransmission, eliciting disinhibition of protein synthesis leading to the induction of synaptic strengthening in the CA1 regions of the hippocampus and improving depression [54,55].

The inhibition of NMDA receptor-mediated neurotransmission by ketamine occurs in the presence of physiological concentrations of Mg2+ and leads to a rapid-acting antidepressant action [56].

This is different from memantine, which is reduced in NMDA receptor antagonism-mediated mEPSCs at the physiological level of Mg2+ and lacks a rapid-acting antidepressant action [56].

NMDA receptor blockade-independent paradigm

Evidence of NMDA receptor inhibition-independent mechanism of action

After the discovery of the ability of ketamine to produce rapid-acting and long-lasting antidepressant actions, clinical trials were conducted to investigate the antidepressant potential of other NMDA receptor antagonists with similar NMDA inhibition as ketamine.

However, clinical trials showed that these alternative NMDA receptor antagonists lack the rapidacting and long-lasting antidepressant actions of ketamine [57]. In particular, memantine, a prescription drug for the treatment of moderate to severe dementia related to Alzheimer’s disease, repeatedly failed to produce antidepressant actions in patients with MDD [58,59].

In addition, a non-selective NMDA receptor antagonist, lanicemine, did not reproduce the longlasting antidepressant effect of ketamine in MDD patients [60], and in the follow-up clinical trial, no significant difference was found between adjunctive lanicemine treatment and placebo treatment [61]. This suggests an antidepressant mechanism of ketamine that is independent of NMDA receptor inhibition.

Antidepressant action of metabolites of ketamine

(2S,6S;2R,6R)-hydroxynorketamine (HNK) is a key metabolite of ketamine found in the plasma and brain in humans [62]. (2S,6S;2R,6R)-HNK has been considered inactive since it does not affect anesthetic action.

An animal study found evidence that the metabolism of ketamine to (2S,6S;2R,6R)-HNK is needed for its antidepressant actions [63]. Chemical alteration of ketamine by deuteration at the C6 position did not change the binding affinity of ketamine for NMDA receptors but sharply reduced its metabolism to (2S,6S;2R,6R)-HNK.

This alteration blocked the antidepressant actions of ketamine in mice and demonstrated that (2S,6S;2R,6R)-HNK is required for ketamine antidepressant responses. However, in a recent contradictory study, mice were pretreated with cytochrome p450 inhibitors and did not show (2R,6R)-HNK after administration of (R)-ketamine induced an antidepressant action, indicating that (2R,6R)-HNK is not essential for ketamine’s antidepressant action [64]. Therefore, it is still difficult to conclude that ketamine metabolites have antidepressant action, and human data on it are also needed.Go to:


Evidence in support of intravenous injection of ketamine for MDD

In 2000, Berman et al. [23] investigated ketamine as a potential antidepressant for the first time. Using a small number of subjects (n=7), they found that mood symptoms rapidly improved within four hours in response to ketamine (0.5 mg/kg infusion over 40 minutes) infusion, whereas no response was found with placebo (normal saline) infusion.

Ketamine infusion reduced the Hamilton Depression Rating Scale score, a measure of depression severity, by an average of 13 points. This result was reproduced in a subsequent crossover study [65].

Patients who had previously failed at least two antidepressant clinical treatments were treated with ketamine or placebo and then crossed over one week later. Rapid antidepressant effects were observed within 2 hours post-infusion in patients treated with ketamine when compared with placebo-treated individuals.

In a placebo-controlled study, it is difficult for a non-active placebo such as normal saline to produce a dissociative effect that peaks at 15 to 30 minutes after the start of infusion. In order to enhance the effect of blinding, some researchers used midazolam, a short-acting benzodiazepine, in an active control group; 0.045 mg/kg midazolam produces perceptual and cognitive changes with infusion times similar to that of ketamine and may be intravenously administered.

However, it must be taken into consideration that benzodiazepines may also have antidepressant effects [66]. Murrough et al. [67] were the first to conduct a parallel, double-blind, randomized study with ketamine and midazolam for treating TRD. Patients with TRD not undergoing pharmacotherapy were randomly assigned to receive a ketamine or midazolam infusion (2:1 ratio).

In the ketamine group, 30 out of 47 patients showed a response within 24 hours of infusion (50% or greater reduction in symptoms), whereas 7 out of 25 patients in the midazolam group showed a response. The antidepressant effects of ketamine are superior to those of midazolam; however, the effect size for the antidepressant effect of ketamine somewhat decreases when compared to that in studies that used saline solution as a placebo.

Two studies of the same design found antidepressant effects of ketamine on bipolar depression in patients with treatmentresistant bipolar depression [68,69]. The subjects were maintained on lithium or valproate prior to the study protocol.

Using a crossover design with a one-week wash-out period, it was found that ketamine produces a rapid antidepressant effect in bipolar depression. However, the effect started to disappear within one week of infusion in most of the patients.

Sos et al. [70] randomly assigned 30 hospitalized patients to first receive ketamine or a placebo, and then they were crossed over after one week. In this protocol, the ketamine dose was different. Subjects received 0.27 mg/kg over 10 minutes, followed by an additional 0.27 mg/kg for 20 minutes (0.54 mg/kg administered over 30 minutes). Ketamine produced a stronger and superior effect than placebo, as 10 out of 27 patients had a response after ketamine infusion, while only 1 out of 19 patients had a response after placebo infusion.

Hu et al. [71] investigated the efficacy of single-dose ketamine augmentation of standard antidepressants. In this parallel study, 30 patients with severe major depressive disorder were randomly assigned to ketamine [0.5 mg/kg intravenous (IV) infusion over 40 minutes] or a placebo group. All patients were started on escitalopram on the same day of ketamine infusion. At week 4 of treatment, the response and remission rates of the ketamine group were greater when compared to those of the placebo group. The time until the response of the ketamine group was shorter than that of the placebo group.

Based on the fact that patients with chronic pain sometimes receive prolonged ketamine infusion [72], Lenze et al. [73] applied a similar protocol in their study of depression. Twenty participants were randomly assigned to two groups that received a continuous infusion of 0.6 mg/kg/h ketamine for 96 hours and a standard ketamine infusion (0.5 mg/kg over 40 minutes).

In this protocol, both groups received clonidine in order to prevent dissociative and psychotomimetic effects and minimize the increase in blood pressure. Bipolar symptoms were measured using the Brief Psychiatric Rating Scale, and although the score peaked on day 3 in the 96-ketamine infusion group, the changes of these symptoms were similar to those obtained with the standard protocol. Rapid and sustained improvement in depressive symptoms was found in both protocol groups.

A meta-analysis of the aforementioned seven double-blind RCTs employing an IV infusion and one RCT employing intranasal (IN) ketamine in the treatment of major depressive episodes in patients with bipolar disorder and MDD showed that a single administration of ketamine may have rapid antidepressant effects [74].

All the previous studies, to date, were RCTs with relatively small number of subjects. A large-scale RCT comprising a large number of subjects is being conducted and the results are currently being reported (Table 1). In order to establish evidence on the optimal ketamine dose, an RCT compared 0.1 (n=18), 0.2 (n=20), 0.5 (n=22), and 1.0 mg (n=20) ketamine with an active placebo (midazolam 0.45 mg/kg, n=19) in TRD.

This comparison showed that, although the effect of a low dose (0.1 and 0.2 mg/kg) ketamine was ambiguous, a ketamine dose of 0.5 mg/kg or greater was clearly more efficacious than the active placebo [75]. Other studies in which repeated infusions following a single dose infusion were employed and the analyses of the efficacy of this infusion regimen at different times are discussed in the following section.

Table 1.

RCTs published since 2018 (N>40 for each RCT)

StudyMain purposeTarget diagnosisDesignRoute of administrationSample sizePrimary outcomeMain result
Singh et al. [78]To assess dosefrequency in IV ketamine therapyTRDDouble-blind, randomized, placebo-controlled trialIV67MADRSTwice-weekly and thrice-weekly administrations of ketamine similarly maintained antidepressant efficacy over 15 days
IV ketamine vs. IV placebo, either two or three times weekly, for up to 4 weeks
Fava et al. [75]To assess doseranging in IV ketamine therapyTRDDouble-blind, randomized, placebo-controlled trialIV99HAMD-6, MADRSConfirm the efficacy of the 0.5 mg/kg and 1.0 mg/kg doses of IV ketamine
IV dose of ketamine 0.1 mg/kg, 0.2 mg/kg, 0.5 mg/kg, 1.0 mg/kg, and midazolam 0.045 mg/kgNo clinically meaningful efficacy of lower doses of IV ketamine
Daly et al. [84]To assess doseresponse of in esketamineTRDDouble-blind, randomized, placebo-controlled trialIN60MADRSAD effect of IN ketamine was rapid in onset and was dose related
IN dose of ketamine 28 mg, 56 mg, 84 mg, and placeboResponse appeared to persist for more than 2 months with a lower dosing frequency
Grunebaum et al. [93]To assess rapid relieve of suicidal ideation by ketamineMDD with suicidal ideationDouble-blind, randomized, placebo-controlled trialIV80Scale for Suicidal Ideation scoreAdjunctive ketamine demonstrated rapid and greater reduction of suicidal ideation in depressed patients compared with midazolam
AD+adjunctive IV ketamine on suicidal ideation in MDD (vs. AD+adjunctive IV placebo)
Phillips et al. [79]To evaluate the AD effects of a single, repeated, and maintenance infusion of ketamineTRDDouble-blind, randomized comparison of single infusions of IN ketamine and placeboIV41MADRSRepeated ketamine infusions have cumulative and sustained antidepressant effects
6 ketamine infusions thrice weekly over 2 weeks (after relapse of depressive symptoms)Reductions in depressive symptoms were maintained among responders through once-weekly infusions
Responders received four additional infusions once weekly (maintenance)
Daly et al. [85]To assess the efficacy of delaying depressive symptoms relapse in TRD in stable remissionTRD patients in remission and stable TRD patients who have responded to treatmentDouble-blind, randomized withdrawal study Continue IN esketamine vs. discontinue IN esketamine (converted to placebo) with oral antidepressant treatment in both groupsIN297Time to relapseKetamine+AD group had fewer relapses than the placebo+AD group in both stable remission and stable response
Popova et al. [86]To assess the efficacy of switching patients with TRD from an ineffective AD to flexibly dosed IN ketamine plus a newly initiated ADTRDDouble-blind, randomized, placebo-controlled trialIN197MADRSKetamine+newly initiated AD reduced more depressive symptoms than placebo+newly initiated AD
IN flexible dose of ketamine (28 mg, 56 mg, or 84 mg) vs. placebo
Twice weekly, for up to 4 weeks

IV: intravenous, TRD: treatment-resistant depression, MADRS: Montgomery-Åsberg Depression Rating Scale, HAMD-6: the 6-item Hamilton Depression Rating Scale, IN: intranasal, MDD: major depressive disorder, AD: antidepressant

A single dose IV ketamine administration produced consistent antidepressant effects only for a maximum of seven days; therefore, there is a need to investigate whether repeated ketamine infusion produces a better response rate and better maintenance of antidepressant effects.

In the first open-label study that investigated the effect of six IV ketamine infusions over two weeks, 70.8% of patients with TRD showed a response, and the median relapse time was 18 days. Treatment results were strongly predicted by the response at four hours after the first infusion.

In contrast, a study, in which 28 participants with unipolar and bipolar TRD received IV ketamine infusion three or six times a week over three weeks, showed that 29% of the patients responded to the ketamine treatment [76]. In this study, 11% of the patients showed a response within six hours after a single dose infusion, and in all responders, a response was seen before the third infusion. Further, following the last infusion, the treatment effect lasted for 25 to 168 days.

However, in an RCT of 26 patients with severe TRD and chronic suicidal ideation who received six IV ketamine augmentation doses or placebo for over three weeks, the ketamine infusion group did not show a higher treatment effect when compared to the placebo infusion group. The authors suggested that a standard 0.5 mg/kg dose or administration period may be insufficient for patients with severe TRD and chronic suicidal ideation [77].

According to the first multicenter RCT (n=67) in which a twice-weekly or thrice-weekly IV ketamine (0.5 mg/kg administered over 40 minutes for four weeks) group was compared with a twice-weekly or thrice-weekly IV placebo group, both ketamine doses were similarly effective in reducing depressive symptoms in contrast to the placebo [78]. In this study, all responders also responded before the third administration. The adverse effect profiles were similar between the twiceweekly and thrice-weekly groups.

A recent repeated ketamine infusion study evaluated the cumulative and sustained therapeutic effects of repeated ketamine infusion after confirming the efficacy of a single dose infusion. Phillips et al. [79] found that, in 46 patients with TRD, a single IV infusion of ketamine produced a greater reduction in depressive symptoms when compared to that with the active control, midazolam.

The patients then received six ketamine infusions administered thrice weekly over two weeks, and 59% of the patients had a 50% or greater decrease in their Montgomery-Åsberg Depression Rating Scale score (MADRS). These patients then received a maintenance treatment once a week for four weeks, and their MADRS score was maintained without relapse.

Evidence in support of intranasal injection of ketamine for MDD

Ketamine has been administered intranasally as an analgesic, and this form of administration is known to be less invasive and well-tolerated than IV infusion [80,81]. Intranasal ketamine has been shown to be effective within minutes, which has been hypothetically suggested due to blockage of the NMDA receptor circuits that generate the emotional representations of pain [82]. Lapidus et al. [83] firstly investigated whether IN ketamine administration produces an antidepressant effect in patients with MDD. Eighteen patients with TRD were randomized to receive 50 mg of IN racemic ketamine or placebo before the end of a one-week drug-free period. At 24 hours following administration, 8 out of 18 patients showed a response to ketamine treatment and only 1 out of 18 showed a response to placebo treatment.

In a recently published study, participants were randomized into a placebo and s-ketamine 28, 56, or 84 mg twice weekly groups at a 3:1:1:1 ratio, and patients in the placebo group who had moderate to severe symptoms were randomly assigned again to the three ketamine groups [84].

The participants then received infusion twice weekly for two weeks, followed by an open-label treatment with administration once weekly for three weeks followed by a maintenance infusion once every two weeks for up to 10 weeks. In this study, all the ketamine groups demonstrated superior antidepressant effects than the placebo group. In addition, it was concluded that the antidepressant effect was sustained even with reduced dosing frequency.

A placebo-controlled study designed to investigate the maintenance effect of ketamine treatment was recently reported. In this RCT, patients with MDD (n=121) who achieved remission or stable response (50% or greater reduction in MADRS score for two weeks or longer) after IN s-ketamine treatment, received additional administration of 56 or 84 mg esketamine as an adjunctive therapy plus an oral antidepressant during the maintenance phase. Relapse was significantly delayed in the ketamine group [85].

In a recent study, IN ketamine flexible doses (28, 56, or 84 mg) twice weekly for 4 weeks with oral antidepressants significantly reduced the depressive symptoms in TRD patients [86]. In contrast, an abstract of an unpublished study using the same design showed that IN ketamine plus oral antidepressant did not significantly reduce the depressive symptoms in TRD patients >65 years of age in all the study regions except in the United States [87].


Suicidal ideation is the most serious symptom of depression and is one of the leading causes of death [88]. Suicidal ideation has been suggested as a symptom caused by cognitive dysfunction, especially associated with dysregulation of glutaminergic neurotransmission in the prefrontal cortex in patients with MDD with suicidal ideation.

The antidepressant effects of ketamine through the glutamate pathway has been reported to exert anti-suicidal effect by preclinical studies [89]. Although most pharmacological studies on depression exclude individuals with imminent risk of suicide, several ketamine studies have included patients with a moderate level of suicidal ideation.

In many case series and open-label studies, ketamine infusion consistently reduced suicidal ideation [90]. A review of an RCT on the effects of ketamine on suicidality showed that a single infusion of ketamine reduced suicidal ideation in patients with TRD [91].

A study involving suicidal psychiatric inpatients with various mood and anxiety spectrum disorders (n=24) showed that, when compared with midazolam, IV ketamine produced a significant reduction in suicidal ideation at post-infusion day 2, although the significance was lost at day 7 [92].

In an RCT of 80 MDD patients with suicidal ideation, suicidal ideation was significantly reduced in the single adjunctive subanesthetic IV ketamine infusion group (n=40) when compared with the midazolam control group (n=40) and the observed decrease in suicidal ideation was maintained following infusion [93].

In an RCT to determine the effect of IN esketamine on depressive symptoms and suicidal thoughts in MDD patients at risk for suicide, repeated infusion of 84 mg of IN esketamine (twice weekly through day 25, once weekly through day 52, and once every other week through day 81) significantly decreased the MADRS total score and MADRS suicidal ideation item scores when compared with IN-placebo infusion [94].

In a recent RCT, ketamine administration in MDD patients reduced the functional connectivity of the left dorsolateral prefrontal cortex and the left dorsal anterior cingulate cortex [95]. This seems to correlate with the antidepressant and anti-suicidal effects of ketamine infusion. Rapid improvement of suicidal ideation suggests that ketamine may be administered first in a clinical setting when urgent treatment is needed, as in patients with suicidal ideation or behavior.


It has been demonstrated that healthy volunteers experience psychotomimetic symptoms, perceptual impairment, dissociative symptoms, or reduced cognitive function during ketamine infusion using the standard protocol (0.5 mg/kg over 40 minutes or longer intravenously) [96,97].

These side effects were resolved within approximately 40 to 80 minutes of infusion completion. Patients with a mood disorder have shown, with repeated dosing, some resistance to the acute dissociative and psychotic symptoms induced by ketamine. Moreover, subjects with TRD who received low dose IV ketamine showed improvement in cognitive function [98].

A meta-analysis of depression reported that a single use of ketamine for the treatment of depression can cause adverse symptoms including dizziness, blurred vision, headache, nausea, vomiting, and dry mouth as other mild side effects, but these were generally not serious and resolved after dose administration [99].

It has also been proposed that, although the side effect of blood pressure elevation during and shortly after a 40-minute ketamine infusion is transient, careful monitoring is required for patients with a history of cardiovascular disease as transient blood pressure elevations may be problematic in such patients [100]. A recent systemic review reported that it is still difficult to conclude that repeated dosing of ketamine has a cumulative effect and long-term risk because of insufficient data [101].

Lamotrigine, and other glutamate release-inhibiting drugs may reduce hyper-glutamatergic consequences presented as perceptual abnormalities [102]. Thus, glutamatergic inhibition of lamotrigine could prevent hyperglutamatergic activation due to ketamine abuse, with potential benefit identified in some case reports [103]. This property of lamotrigine may cause downregulation of ketamine’s antidepressant action.

The interaction of ketamine and opioid receptors, including mu, delta, and kappa, have been considered to have an antinociceptive role in acute and chronic pain. Interestingly, in human studies, pretreatment with naltrexone, an opioid receptor antagonist, decreased the antidepressant action of ketamine but did not alter its dissociative effects [104]. This suggests that the opioid system may play an important role in the antidepressant action of ketamine, but may not be involved in the development of adverse effects (dissociative symptoms).

Whether repeated use of ketamine can result in prolonged cognitive and perceptual changes or psychosis-like symptoms is an important issue. This is especially important because a method for maintaining the antidepressant effects of ketamine without repeated ketamine exposure is unclear.

The most useful evidence for the long-term effects of ketamine comes from a study involving ketamine abusers. Although it is evident that reduced cognitive function, thought disorder, or neuropsychiatric abnormality, including depression, may arise from ketamine abuse, this is dose-dependent and limited to frequent users who use ketamine almost every day [105].

Because ketamine has been used as a recreational drug, there is a potential for patients to abuse its use or to develop a use disorder [106]. Ketamine abuse is a common global problem, and, although the prevalence of its abuse in Korea has not been studied, 1.7% of adolescents in the United States abuse it one or more times a year [107].

Ketamine abuse is also common in the Asian regions of Hong Kong and Taiwan, with a prevalence of 1.1% to 1.8% [108]. However, many aspects of ketamine abuse are not yet well known, including risk factors that increase ketamine abuse. A long-term study is needed to investigate whether ketamine use in patients with depression leads to its abuse.

Karolinska Institute

Funding: The study was conducted in association with North Stockholm Psychiatry and was financed by the Swedish Research Council, the Söderström König Foundation, the Centre for Psychiatry Research, Region Stockholm, the Swedish Psychiatric Foundation and Karolinska Institutet.

26. Trullas R, Skolnick P. Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol. 1990;185:1–10. [PubMed] [Google Scholar]

27. Breier A, Malhotra AK, Pinals DA, Weisenfeld NI, Pickar D. Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am J Psychiatry. 1997;154:805–811. [PubMed] [Google Scholar]

28. Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci. 1997;17:2921–2927. [PMC free article] [PubMed] [Google Scholar]

29. Homayoun H, Moghaddam B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci. 2007;27:11496–11500. [PMC free article] [PubMed] [Google Scholar]

30. Khlestova E, Johnson JW, Krystal JH, Lisman J. The Role of GluN2CContaining NMDA Receptors in Ketamine’s Psychotogenic Action and in Schizophrenia Models. J Neurosci. 2016;36:11151–11157. [PMC free article] [PubMed] [Google Scholar]

31. Chowdhury GM, Zhang J, Thomas M, Banasr M, Ma X, Pittman B, et al. Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects. Mol Psychiatry. 2017;22:120–126. [PMC free article] [PubMed] [Google Scholar]

32. Hardingham GE, Bading H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci. 2010;11:682–696. [PMC free article] [PubMed] [Google Scholar]

33. Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron. 1996;16:675–686. [PubMed] [Google Scholar]

34. Guo H, Lai L, Butchbach ME, Stockinger MP, Shan X, Bishop GA, et al. Increased expression of the glial glutamate transporter EAAT2 modulates excitotoxicity and delays the onset but not the outcome of ALS in mice. Hum Mol Genet. 2003;12:2519–2532. [PubMed] [Google Scholar]

35. Miller OH, Yang L, Wang CC, Hargroder EA, Zhang Y, Delpire E, et al. GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine. Elife. 2014;3:e03581. [PMC free article] [PubMed] [Google Scholar]

36. Gray JA, Shi Y, Usui H, During MJ, Sakimura K, Nicoll RA. Distinct modes of AMPA receptor suppression at developing synapses by GluN2A and GluN2B: single-cell NMDA receptor subunit deletion in vivo. Neuron. 2011;71:1085–1101. [PMC free article] [PubMed] [Google Scholar]

37. Wang CC, Held RG, Hall BJ. SynGAP regulates protein synthesis and homeostatic synaptic plasticity in developing cortical networks. PLoS One. 2013;8:e83941. [PMC free article] [PubMed] [Google Scholar]

38. Preskorn SH, Baker B, Kolluri S, Menniti FS, Krams M, Landen JW. An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J Clin Psychopharmacol. 2008;28:631–637. [PubMed] [Google Scholar]

39. Ibrahim L, Diaz Granados N, Jolkovsky L, Brutsche N, Luckenbaugh DA, Herring WJ, et al. A Randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder. J Clin Psychopharmacol. 2012;32:551–557. [PMC free article] [PubMed] [Google Scholar]

40. Boulos LJ, Darcq E, Kieffer BL. Translating the Habenula-From Rodents to Humans. Biol Psychiatry. 2017;81:296–305. [PMC free article] [PubMed] [Google Scholar]

41. Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature. 2018;554:317–322. [PubMed] [Google Scholar]

42. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–964. [PMC free article] [PubMed] [Google Scholar]

43. Zhou W, Wang N, Yang C, Li XM, Zhou ZQ, Yang JJ. Ketamine-induced antidepressant effects are associated with AMPA receptorsmediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex. Eur Psychiatry. 2014;29:419–423. [PubMed] [Google Scholar]

44. Liu RJ, Ota KT, Dutheil S, Duman RS, Aghajanian GK. Ketamine strengthens CRF-activated amygdala inputs to basal dendrites in mPFC layer V Pyramidal cells in the prelimbic but not infralimbic subregion, a key suppressor of stress responses. Neuropsychopharmacology. 2015;40:2066–2075. [PMC free article] [PubMed] [Google Scholar]

45. Stone JM, Dietrich C, Edden R, Mehta MA, De Simoni S, Reed LJ, et al. Ketamine effects on brain GABA and glutamate levels with 1HMRS: relationship to ketamine-induced psychopathology. Mol Psychiatry. 2012;17:664–665. [PMC free article] [PubMed] [Google Scholar]

46. Jourdi H, Hsu YT, Zhou M, Qin Q, Bi X, Baudry M. Positive AMPA receptor modulation rapidly stimulates BDNF release and increases dendritic mRNA translation. J Neurosci. 2009;29:8688–8697. [PMC free article] [PubMed] [Google Scholar]

47. Takei N, Inamura N, Kawamura M, Namba H, Hara K, Yonezawa K, et al. Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites. J Neurosci. 2004;24:9760–9769. [PMC free article] [PubMed] [Google Scholar]

48. Bjorkholm C, Monteggia LM. BDNF-a key transducer of antidepressant effects. Neuropharmacology. 2016;102:72–79. [PMC free article] [PubMed] [Google Scholar]

49. Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, et al. Glutamate Nmethyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry. 2011;69:754–761. [PMC free article] [PubMed] [Google Scholar]

50. Gass N, Schwarz AJ, Sartorius A, Schenker E, Risterucci C, Spedding M, et al. Sub-anesthetic ketamine modulates intrinsic BOLD connectivity within the hippocampal-prefrontal circuit in the rat. Neuropsychopharmacology. 2014;39:895–906. [PMC free article] [PubMed] [Google Scholar]

51. Murrough JW, Collins KA, Fields J, DeWilde KE, Phillips ML, Mathew SJ, et al. Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder. Transl Psychiatry. 2015;5:e509. [PMC free article] [PubMed] [Google Scholar]

52. Sutton MA, Wall NR, Aakalu GN, Schuman EM. Regulation of dendritic protein synthesis by miniature synaptic events. Science. 2004;304:1979–1983. [PubMed] [Google Scholar]

53. Sutton MA, Ito HT, Cressy P, Kempf C, Woo JC, Schuman EM. Miniature neurotransmission stabilizes synaptic function via tonic suppression of local dendritic protein synthesis. Cell. 2006;125:785–799. [PubMed] [Google Scholar]

54. Nosyreva E, Szabla K, Autry AE, Ryazanov AG, Monteggia LM, Kavalali ET. Acute suppression of spontaneous neurotransmission drives synaptic potentiation. J Neurosci. 2013;33:6990–7002. [PMC free article] [PubMed] [Google Scholar]

55. Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011;475:91–95. [PMC free article] [PubMed] [Google Scholar]

56. Gideons ES, Kavalali ET, Monteggia LM. Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses. Proc Natl Acad Sci U S A. 2014;111:8649–8654. [PMC free article] [PubMed] [Google Scholar]

57. Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB, et al. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry. 2015;172:950–966. [PubMed] [Google Scholar]

58. Zarate CA, Jr, Singh JB, Quiroz JA, De Jesus G, Denicoff KK, Luckenbaugh DA, et al. A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am J Psychiatry. 2006;163:153–155. [PubMed] [Google Scholar]

59. Lenze EJ, Skidmore ER, Begley AE, Newcomer JW, Butters MA, Whyte EM. Memantine for late-life depression and apathy after a disabling medical event: a 12-week, double-blind placebo-controlled pilot study. Int J Geriatr Psychiatry. 2012;27:974–980. [PMC free article] [PubMed] [Google Scholar]

60. Zarate CA, Jr, Mathews D, Ibrahim L, Chaves JF, Marquardt C, Ukoh I, et al. A randomized trial of a low-trapping nonselective N-methyl- D-aspartate channel blocker in major depression. Biol Psychiatry. 2013;74:257–264. [PMC free article] [PubMed] [Google Scholar]

61. Sanacora G, Johnson MR, Khan A, Atkinson SD, Riesenberg RR, Schronen JP, et al. Adjunctive Lanicemine (AZD6765) in Patients with Major Depressive Disorder and History of Inadequate Response to Antidepressants: A Randomized, Placebo-Controlled Study. Neuropsychopharmacology. 2017;42:844–853. [PMC free article] [PubMed] [Google Scholar]

62. Zarate CA, Jr, Brutsche N, Laje G, Luckenbaugh DA, Venkata SL, Ramamoorthy A, et al. Relationship of ketamine’s plasma metabolites with response, diagnosis, and side effects in major depression. Biol Psychiatry. 2012;72:331–338. [PMC free article] [PubMed] [Google Scholar]

63. Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533:481–486. [PMC free article] [PubMed] [Google Scholar]

64. Yamaguchi JI, Toki H, Qu Y, Yang C, Koike H, Hashimoto K, et al. (2R,6R)-Hydroxynorketamine is not essential for the antidepressant actions of (R)-ketamine in mice. Neuropsychopharmacology. 2018;43:1900–1907. [PMC free article] [PubMed] [Google Scholar]

65. Zarate CA, Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856–864. [PubMed] [Google Scholar]

66. Petty F, Trivedi MH, Fulton M, Rush AJ. Benzodiazepines as antidepressants: does GABA play a role in depression? Biol Psychiatry. 1995;38:578–591. [PubMed] [Google Scholar]

67. Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170:1134–1142. [PMC free article] [PubMed] [Google Scholar]

68. Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67:793–802. [PMC free article] [PubMed] [Google Scholar]

69. Zarate CA, Jr, Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A, et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 2012;71:939–946. [PMC free article] [PubMed] [Google Scholar]

70. Sos P, Klirova M, Novak T, Kohutova B, Horacek J’ Palenicek T. Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression. Neuro Endocrinol Lett. 2013;34:287–293. [PubMed] [Google Scholar]

71. Hu YD, Xiang YT, Fang JX, Zu S, Sha S, Shi H, et al. Single i.v. ketamine augmentation of newly initiated escitalopram for major depression: results from a randomized, placebo-controlled 4-week study. Psychol Med. 2016;46:623–635. [PubMed] [Google Scholar]

72. Goldberg ME, Domsky R, Scaringe D, Hirsh R, Dotson J, Sharaf I, et al. Multi-day low dose ketamine infusion for the treatment of complex regional pain syndrome. Pain Physician. 2005;8:175–179. [PubMed] [Google Scholar]

73. Lenze EJ, Farber NB, Kharasch E, Schweiger J, Yingling M, Olney J, et al. Ninety-six hour ketamine infusion with co-administered clonidine for treatment-resistant depression: A pilot randomised controlled trial. World J Biol Psychiatry. 2016;17:230–238. [PMC free article] [PubMed] [Google Scholar]

74. McGirr A, Berlim MT, Bond DJ, Fleck MP, Yatham LN, Lam RW. A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol Med. 2015;45:693–704. [PubMed] [Google Scholar]

75. Fava M, Freeman MP, Flynn M, Judge H, Hoeppner BB, Cusin C, et al. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD) Mol Psychiatry. 2018 [Epub ahead of print] [PMC free article] [PubMed] [Google Scholar]

76. Diamond PR, Farmery AD, Atkinson S, Haldar J, Williams N, Cowen PJ, et al. Ketamine infusions for treatment resistant depression: a series of 28 patients treated weekly or twice weekly in an ECT clinic. J Psychopharmacol. 2014;28:536–544. [PubMed] [Google Scholar]

77. Ionescu DF, Bentley KH, Eikermann M, Taylor N, Akeju O, Swee MB, et al. Repeat-dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: A randomized, double blind, placebo controlled trial. J Affect Disord. 2019;243:516–524. [PubMed] [Google Scholar]

78. Singh JB, Fedgchin M, Daly EJ, De Boer P, Cooper K, Lim P, et al. A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression. Am J Psychiatry. 2016;173:816–826. [PubMed] [Google Scholar]

79. Phillips JL, Norris S, Talbot J, Birmingham M, Hatchard T, Ortiz A, et al. Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial. Am J Psychiatry. 2019;176:401–409. [PubMed] [Google Scholar]

80. Weksler N, Ovadia L, Muati G, Stav A. Nasal ketamine for paediatric premedication. Can J Anaesth. 1993;40:119–121. [PubMed] [Google Scholar]

81. Diaz JH. Intranasal ketamine preinduction of paediatric outpatients. Paediatr Anaesth. 1997;7:273–278. [PubMed] [Google Scholar]

82. Opler LA, Opler MG, Arnsten AF. Ameliorating treatment-refractory depression with intranasal ketamine: potential NMDA receptor actions in the pain circuitry representing mental anguish. CNS Spectr. 2016;21:12–22. [PMC free article] [PubMed] [Google Scholar]

83. Lapidus KA, Levitch CF, Perez AM, Brallier JW, Parides MK, Soleimani L, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry. 2014;76:970–976. [PMC free article] [PubMed] [Google Scholar]

84. Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, et al. Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2018;75:139–148. [PMC free article] [PubMed] [Google Scholar]

85. Daly EJ, Trivedi MH, Janik A, Li H, Zhang Y, Li X, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2019 [Epub ahead of print] [PMC free article] [PubMed] [Google Scholar]

86. Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176:428–438. [PubMed] [Google Scholar]

87. Ochs-Ross R, Daly EJ, Zhang Y, Lane R, Lim P, Foster K, et al. Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression. Am J Geriatr Psychiatry. 2019;27:S139–S140. [PubMed] [Google Scholar]

88. Sokero TP, Melartin TK, Rytsala HJ, Leskela US, Lestela-Mielonen PS, Isometsa ET. Suicidal ideation and attempts among psychiatric patients with major depressive disorder. J Clin Psychiatry. 2003;64:1094–1100. [PubMed] [Google Scholar]

89. De Berardis D, Fornaro M, Valchera A, Cavuto M, Perna G, Di Nicola M, et al. Eradicating suicide at its roots: preclinical bases and clinical evidence of the efficacy of ketamine in the treatment of suicidal behaviors. Int J Mol Sci. 2018;19 [PMC free article] [PubMed] [Google Scholar]

90. Price RB, Mathew SJ. Does ketamine have anti-suicidal properties? Current status and future directions. CNS Drugs. 2015;29:181–188. [PMC free article] [PubMed] [Google Scholar]

91. Price RB, Iosifescu DV, Murrough JW, Chang LC, Al Jurdi RK, Iqbal SZ, et al. Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression. Depress Anxiety. 2014;31:335–343. [PMC free article] [PubMed] [Google Scholar]

92. Murrough JW, Soleimani L, DeWilde KE, Collins KA, Lapidus KA, Iacoviello BM, et al. Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial. Psychol Med. 2015;45:3571–3580. [PubMed] [Google Scholar]

93. Grunebaum MF, Galfalvy HC, Choo TH, Keilp JG, Moitra VK, Parris MS, et al. Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial. Am J Psychiatry. 2018;175:327–335. [PMC free article] [PubMed] [Google Scholar]

94. Canuso CM, Singh JB, Fedgchin M, Alphs L, Lane R, Lim P, et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. Am J Psychiatry. 2018;175:620–630. [PubMed] [Google Scholar]

95. Chen MH, Lin WC, Tu PC, Li CT, Bai YM, Tsai SJ, et al. Antidepressant and antisuicidal effects of ketamine on the functional connectivity of prefrontal cortex-related circuits in treatment-resistant depression: A double-blind, placebo-controlled, randomized, longitudinal resting fMRI study. J Affect Disord. 2019;259:15–20. [PubMed] [Google Scholar]

96. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994;51:199–214. [PubMed] [Google Scholar]

97. Morgan CJ, Mofeez A, Brandner B, Bromley L, Curran HV. Acute effects of ketamine on memory systems and psychotic symptoms in healthy volunteers. Neuropsychopharmacology. 2004;29:208–218. [PubMed] [Google Scholar]98. Wan LB, Levitch CF, Perez AM, Brallier JW, Iosifescu DV, Chang LC, et al. Ketamine safety and tolerability in clinical trials for treatmentresistant depression. J Clin Psychiatry. 2015;76:247–252. [PubMed] [Google Scholar]

99. Kishimoto T, Chawla JM, Hagi K, Zarate CA, Kane JM, Bauer M, et al. Single-dose infusion ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med. 2016;46:1459–1472. [PMC free article] [PubMed] [Google Scholar]

100. Fond G, Loundou A, Rabu C, Macgregor A, Lancon C, Brittner M, et al. Ketamine administration in depressive disorders: a systematic review and meta-analysis. Psychopharmacology (Berl) 2014;231:3663–3676. [PubMed] [Google Scholar]

101. Short B, Fong J, Galvez V, Shelker W, Loo CK. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry. 2018;5:65–78. [PubMed] [Google Scholar]

102. Anand A, Charney DS, Oren DA, Berman RM, Hu XS, Cappiello A, et al. Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists. Arch Gen Psychiatry. 2000;57:270–276. [PubMed] [Google Scholar]

103. Huang MC, Chen LY, Chen CK, Lin SK. Potential benefit of lamotrigine in managing ketamine use disorder. Med Hypotheses. 2016;87:97–100. [PubMed] [Google Scholar]

104. Williams NR, Heifets BD, Blasey C, Sudheimer K, Pannu J, Pankow H, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175:1205–1215. [PMC free article] [PubMed] [Google Scholar]

105. Morgan CJ, Muetzelfeldt L, Curran HV. Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study. Addiction. 2010;105:121–133. [PubMed] [Google Scholar]

106. Liu Y, Lin D, Wu B, Zhou W. Ketamine abuse potential and use disorder. Brain Res Bull. 2016;126:68–73. [PubMed] [Google Scholar]

107. Sassano-Higgins S, Baron D, Juarez G, Esmaili N, Gold M. A review of ketamine abuse and diversion. Depress Anxiety. 2016;33:718–727. [PubMed] [Google Scholar]


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