This systematic review and meta-analysis (2013, n=629) analyzed data from all trials investigating the antidepressant efficacy of ketamine up to publication date, and provides a systematic overview of its neurobiological and pharmacodynamic profile. The vast majority of the studies showed that ketamine infusion rapid antidepressant response, and an independent rapid antisuicidal effect.
Abstract
“The burden of depressive disorders and the frequent inadequacy of their current pharmacological treatments are well established. The anaesthetic and hallucinogenic drug ketamine has provoked much interest over the past decade or so as an extremely rapidly acting antidepressant that does not modify ‘classical’ monoaminergic receptors. Current evidence has shown several ways through which it might exert therapeutic antidepressant actions: blockade of glutamatergic NMDA receptors and relative upregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtypes may alter cortical connectivity patterns; through intracellular changes in protein expression, including the proteins mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF); and alteration of intracellular signalling cascades. The clinical evidence demonstrates rapid improvements in mood and suicidal thinking in most participants, although study numbers have generally been small and many trials are unblinded and methodologically weak. There is a small body of work to suggest ketamine might also augment electroconvulsive therapy and potentially have a role as a surgical anaesthetic in depressed patients. A major problem is that the effects of ketamine appear temporary, disappearing after days to weeks (although longer benefits have been sustained in some), and attempts to circumvent this through pharmacological augmentation have been disappointing thus far. These exciting data are providing new insights into neurobiological models of depression, and potentially opening up a new class of antidepressants, but there are significant practical and ethical issues about any future mainstream clinical role it might have.”
Authors: Caroline Caddy, Giovanni Giaroli, Thomas P. White, Sukhwinder S. Shergill & Derek K. Tracy
Summary
Psychotomimetic effects
The prefrontal cortex homeostatically limits its own input via a cortico-striatal-thalamic-cortical loop. Ketamine produces its psychotomimetic effects through a parallel disinhibitory process, acting as a noncompetitive and nonselective high-affinity NMDA antagonist on the GABAergic interneurons, increasing PFC input.
Modulation of cortical networks
Linking the well-established actions of antidepressants with a mechanism to explain putative antidepressant effects has proven more difficult. However, data from healthy subjects has demonstrated the concept of two large anticorrelated cortical networks.
The dominant model of depression focuses on serotonin and noradrenaline, and to a lesser extent dopamine. Current antidepressants alter neuronal gene transcription. Glu is a ubiquitous excitatory neurotransmitter that is tightly controlled by glial support cells. Proton magnetic resonance spectroscopy work has shown that glu levels are low in depressive disorders, and that this may be therapeutically facilitated by ketamine administration.
Effects on intracellular protein expression and function
Antagonism of inhibitory GABA interneuron NMDA receptors results in increased Glu release and subsequent activation of other glutamatergic receptors, including -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which are associated with neuronal growth, differentiation, synaptogenesis, and general functioning of the neuron.
A recent rat study showed that ketamine increased mTOR activation and phosphorylation, and increased prefrontal pyramidal neuron spine density. This study also showed that blocking mTOR signalling inhibited ketamine-induced synaptogenesis and behavioural improvement.
Ketamine reduced depression-like behaviour in mouse controls, but not in BDNF knockout mice. It also reduced the circadian transcription of genes driven by the key CLOCK:BMAL-1 heterodimeric complex, but the therapeutic role of modulating this pathway by ketamine remains uncertain.
Endoplasmic reticulae 1 receptors are involved in regulation of intracellular calcium signalling, neuronal plasticity, neurite growth and synaptogenesis, and antioxidant responses. Ifenprodil, a NMDA GluN2B subunit antagonist, potentiates concentration-dependent nerve growth factor-induced neurite outgrowth in cell cultures.
Epidemiological studies have linked obesity and depressive disorders through psychosocial factors, but the role of neuroendocrinologically active adipokines secreted by adipose tissue is also being investigated. Leptin levels are reduced in rodents subjected to chronic stress, and administration of leptin has been shown to have antidepressant effects.
Materials and methods
The following databases were searched: PSYCINFO, MEDLINE, EMBASE. The search criteria were: hallucinogen, lysergic acid diethylamide, ketamine, mescaline, psilocybin, magic mushroom, phenethylamine, phencyclidine, depression, mood disorder, bipolar, depressive-order, unipolar.
A meta-analysis of five studies with control groups found that ketamine had rapid antidepressive effects within 240 minutes, with mean scores falling from a baseline MADRS score of 40.4 to 11.5 (standard error of the mean [SEM] = 2.2).
There is a high rate of comorbidity between depressive disorders and substance misuse. Those with a family history of alcohol dependency showed a statistically significant improvement in MADRS, HDRS and BDI scores within 230 minutes of ketamine administration.
Three open-label studies evaluated multiple-dosing ketamine. The first study included 10 participants who responded to a single ketamine infusion without significant side effects, and the second study included 24 participants.
After a wash-out period from their antidepressants, participants received thrice weekly injections of ketamine over 12 days. A total of 80% of participants demonstrated response to ketamine, and 50% met remission, with 2 still meeting remission criteria at the 4-week follow up.
Two studies looked at the effects of ketamine on suicidal ideation. Both studies reported positive results, although the results were difficult to truly blind participants due to the short-term dissociative effects of ketamine.
Regarding the two studies only assessing effects on MDD, Zarate and colleagues found that ketamine demonstrated a significant improvement over placebo at 24 hours and at 1 week, and that ketamine reduced HAMD scores by 48% at 72 hours.
Two studies investigating the effect of ketamine in bipolar depression yielded similar positive results, with the largest effect size recorded at 2 days post-infusion. Three studies reported significant reductions in depression scores between 60 and 80 minutes, whilst two studies reported no change.
The disparity between baseline depression scores in the placebo and ketamine condition was not statistically significant, but the effect of ketamine on depression was statistically significant.
Ketamine and a second drug
There have been three studies evaluating ketamine augmentation with an anticonvulsant, but unfortunately their results have been disappointing.
Ibrahim and colleagues found no difference in time to relapse between 42 participants with MDD randomized to either riluzole or placebo after an initial ketamine infusion days post-infusion. However, no significant effect was reported for drug (p = 0.93).
Ketamine had antidepressant effects and a significant mean reduction in MADRS and QIDS-SR scores at 24 hours. Riluzole had no effect on post-ketamine relapse and the two treatment groups did not differ in MADRS scores at any point.
Ketamine as an antidepressant in ECT or surgery
Ketamine has been used as an anaesthetic for decades, and some studies have explored the use of ketamine in combination with ECT. The results show promising potential for ketamine, although most work shows additional, albeit brief, benefits.
Three papers explored the use of ketamine as an anaesthetic in ECT compared with a common anaesthesia. All demonstrated significantly improved depression scores in the ketamine groups, although benefits were short-lived.
In a single session ECT study, 48 patients with MDD were randomized into three equal-sized groups, each receiving a differing ECT anaesthesia protocol. The combined ketamine and propofol anaesthesia group showed fewer physical and psychological adverse effects than the ketamine-alone group.
In a prospective study, patients with TRD who received ketamine or propofol before ECT showed statistically significant improvements in HDRS scores after the second and fourth sessions, but not after the sixth or eighth sessions.
Kranaster and colleagues evaluated 42 patients with TRD who had ECT anaesthetised with either. They observed a considerable response rate to be observed at this early time point.
Ketamine is used as an anaesthetic in surgery and as a second-line drug for depression. Some studies have shown positive results, but most have lost their effects within days to weeks.
Most studies reported dissociative and psychotomimetic effects following ketamine infusion, with the effects returning to normal around 80 minutes post-infusion. There was no significant correlation between change in depression scores and dissociative and psychotomimetic effects.
Methodologically, many of the studies discussed in this review are severely limited in regard to their sample size, and none of the preparations increase risks of misappropriation of the medication.
Suicidal ideation is common in crisis presentations, many of which are not depressive disorders. Ketamine has been shown to lessen suicidal thinking independent of effects on depressive symptoms.
The counter-argument is that ketamine is acutely effective in severely unwell populations, and there is an uncalculated opportunity cost for admissions to psychiatric hospitals, the use of crisis teams, and compulsory detention under the Mental Health Act.
class of antidepressant?
Ketamine may be used to treat depression, but longer-term data on relapse prevention and tolerability are lacking. Most studies utilized participants with treatment-resistant MDDs.
Study details
Participants
629