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.
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.
Papers cited by this study that are also in Blossom
Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
Murrough, J. W., Perez, A. M., Pillemer, S. et al. · Biological Psychiatry (2012)
Zarate, C. A., Brutsche, N. E., Ibrahim, L. et al. · Biological Psychiatry (2012)
Papers in Blossom that reference this study
Kopelman, J., Keller, T. A., Panny, B. et al. · Translational Psychiatry (2023)
Major depressive disorder (MDD) and bipolar affective disorder (BPAD) are common, often persistent illnesses for which current monoaminergic antidepressants frequently show limited efficacy, particularly in treatment-resistant depression (TRD). Interest has grown in non-monoaminergic agents, and ketamine — a dissociative anaesthetic and NMDA (N-methyl-D-aspartate) glutamate receptor antagonist — has attracted attention because it appears to produce unusually rapid antidepressant and antisuicidal effects. Understanding ketamine's actions might therefore provide new biological insight into depression and point toward a new class of glutamatergic antidepressants. Caddy and colleagues set out to review mechanistic data on how ketamine might exert antidepressant effects and to systematically collate and meta-analyse clinical trial evidence for its efficacy up to January 2013. The review aimed to summarise pharmacokinetic and pharmacodynamic actions, evaluate clinical trial results (including effects on mood and suicidal ideation), and assess efforts to prolong benefit through augmentation or combination with electroconvulsive therapy (ECT) or surgery anaesthesia.
Caddy and colleagues performed a systematic literature search up to January 2013 across electronic databases (PSYCINFO among them) and by manual reference searching. Search terms included a broad set of hallucinogen- and depression-related keywords (for example, "ketamine", "lsd", "psilocybin", combined with "depression"/"antidepressant"/"bipolar"). The team sought randomized and non-randomized trials of hallucinogens for depression but prioritised ketamine-related studies for detailed synthesis. Pre-specified inclusion criteria required adult participants (≥18 years) with MDD or BPAD diagnosed by structured interview (DSM or ICD). Studies had to assess mood symptoms and/or suicidality using validated rating scales; investigations of addiction or recreational use were excluded. Only journal articles were eligible and case reports with fewer than three participants were excluded. No specific comparator was required for inclusion. Data extraction captured participant characteristics (age, gender, illness duration), diagnostic and trial inclusion/exclusion criteria, details of interventions (route, dose, schedule), response/remission definitions, outcome measures (for example MADRS, HDRS), and follow-up. To aid interpretation the authors grouped studies into three thematic categories: ketamine only, ketamine plus a second drug, and ketamine in combination with ECT or surgery. For quantitative synthesis, Hamilton Depression Rating Scale (HDRS) data from five controlled studies were entered into two cross-study meta-analyses using OpenMeta[Analyst]. The authors assessed differences between ketamine and placebo at baseline, 60–80 minutes post-infusion, and 210–230 minutes post-infusion. Because means and standard deviations were not consistently reported, values were in some cases read from published graphs. The extracted text does not report a formal risk-of-bias assessment approach or detailed search dates beyond the stated 2013 cut-off.
Study identification and overall sample. The extracted text reports that 11,138 records were identified by the search and that, after selection, 26 studies were ultimately reported as fulfilling inclusion criteria with a total of 629 participants. Elsewhere the paper summaries refer to 22 RCTs and non-RCTs totalling 629 participants; the extraction is inconsistent on the exact study count but consistently reports a pooled participant total of 629. Ketamine-only studies. Eleven open-label (no control) studies administering ketamine to all participants were described, enrolling 206 participants with major depressive episodes. Most studies used intravenous ketamine at 0.5 mg/kg (one study used a 0.2 mg/kg bolus). The Montgomery–Åsberg Depression Rating Scale (MADRS) was the common primary outcome, with response defined as ≥50% score reduction and remission typically defined as MADRS <10. Open-label single-dose trials reported rapid and statistically significant mood improvement within hours (for example significant MADRS changes at ~230 minutes post-infusion in several studies). Three open-label multiple-infusion series reported higher sustained response rates through the dosing period: one study delivering six infusions over 12 days reported up to 100% response by study end and 88.9% remission, while another thrice-weekly 12-day protocol reported a 70.8% response rate among completers. Relapse after repeated dosing occurred on average around 19 days (SD 13) following final infusion in one series; in another study median time to relapse was 18 days (IQR 11–27). Effects on suicidal ideation were reported in several open-label and small controlled trials. Some studies found rapid reductions in suicidal thinking that in some cases occurred even in participants who did not meet antidepressant response criteria. Adverse events were generally transient: common effects included short-lived dissociative/psychotomimetic symptoms (measured with scales such as the BPRS or CADSS), transient hypertension and tachycardia, with no long-term adverse-event follow-up reported in the trials. Controlled studies and meta-analysis. Five studies compared IV ketamine (0.5 mg/kg) with saline placebo. As in the open-label work, antidepressant effects were rapid but typically short-lived. For example, one trial reported 79% remission at 24 hours with 35% maintaining remission at one week. Caddy and colleagues meta-analysed HDRS differences between ketamine and placebo: at 60–80 minutes the mean difference was −3.406 (p < 0.001; 95% CI −6.303 to −0.509), and at 210–230 minutes the mean difference was −5.371 (p < 0.001; 95% CI −6.574 to −4.168). Heterogeneity was high at 60–80 minutes (I2 = 79%); at 210–230 minutes the model also showed statistically significant benefit despite some baseline disparities between groups in one study (reported heterogeneity p = 0.531 in the extracted text). The authors note that blinding was likely compromised in many trials because of ketamine's distinctive acute effects. Ketamine plus a second drug. Three studies tested whether anticonvulsant or neuroprotective agents (lamotrigine or riluzole) given alongside ketamine could prolong benefit. Ibrahim et al. randomised 42 participants to riluzole versus placebo following an initial ketamine infusion and found no between-group difference in time to relapse; mean time to relapse across groups was 13.2 days. A Duncan substudy also reported no significant riluzole effect when started 4–6 hours after ketamine. Mathew et al. used a two-stage design (pre-treatment with lamotrigine versus placebo before ketamine, then randomized riluzole versus placebo in responders) and found lamotrigine did not limit side effects or augment efficacy, and riluzole did not prolong time to relapse (mean time to relapse 24.4 days riluzole vs 22.0 days placebo; log-rank p = 0.68). Ketamine in ECT or surgical anaesthesia. Several studies explored ketamine as an adjunct to or anaesthetic for ECT, and one trial examined ketamine as part of general anaesthesia for orthopaedic surgery in depressed patients. Results were mixed but suggested short-lived additional benefit. A randomized trial by Loo et al. (n = 51) found a small early clinical advantage for subanaesthetic ketamine augmentation of ECT in the first week that disappeared by treatment end; Abdallah et al. terminated a trial early for lack of between-group differences. Studies using ketamine as the anaesthetic agent for ECT reported earlier improvement in depressive scores compared with other anaesthetics up to several sessions, but not sustained across longer ECT courses. In a single-surgery cohort, depressed patients receiving ketamine as part of their anaesthetic (combined with propofol and fentanyl) had statistically significant improvement in HDRS scores one day after surgery and reduced postoperative pain compared with those who did not receive ketamine. Overall synthesis. Across the reviewed literature ketamine produced rapid antidepressant and antisuicidal effects in most reported studies. Several RCTs recorded very high early response rates (one cluster of RCTs reported 71–79% response at 24 hours). However, benefit was frequently transient, with relapse typically occurring within days to a few weeks. Methodological limitations were emphasised: small sample sizes, few fully double-blind randomized placebo-controlled trials (six studies reported as adopting that gold standard), and concerns about compromised blinding due to acute drug effects.
Caddy and colleagues interpret the assembled evidence as consistently showing that ketamine can induce rapid and clinically meaningful reductions in depressive symptoms and suicidal ideation, including in treatment-resistant samples. They highlight mechanistic lines of evidence that may underlie these effects: NMDA antagonism on GABA interneurons leading to increased glutamate release and relative AMPA receptor activation; downstream changes in intracellular signalling and expression of proteins implicated in synaptic plasticity (notably mTOR and BDNF); modulation of circadian gene expression; interactions with σ1 receptors; and potential links to adipokine signalling. Animal and cellular studies linking ketamine to rapid synaptogenesis and to BDNF/mTOR signalling are presented as biologically plausible mediators of the clinical effects. At the same time the authors emphasise important limitations and uncertainties. The antidepressant effect of ketamine is often transient, typically lasting days to weeks, and attempts to prolong benefit pharmacologically (for example with riluzole or lamotrigine) have been unsuccessful in the reviewed trials. Practical barriers to clinical implementation include the requirement for IV administration with anaesthetic support in most studies, the potential for dissociative/psychotomimetic effects that compromise blinding and raise safety concerns, and questions about abuse potential if easier formulations (for example oral) were used. They also note that the trials generally excluded people with psychosis or current substance dependence, limiting generalisability, and that long-term adverse effects were not followed up in the reviewed studies; separate MRI data from chronic illicit use suggest possible cortical atrophy, but this was not established in therapeutic settings. The authors position ketamine as a valuable prototype that has advanced understanding of glutamatergic mechanisms in depression and stimulated development of more selective NMDA receptor subunit antagonists (for example NR2B antagonists) that might capture therapeutic benefits without ketamine's liabilities. They conclude that larger, longer-term randomized controlled trials are required to clarify optimal dosing, durability of benefit, safety, and the clinical role ketamine (or next-generation glutamatergic agents) might play in treating depressive disorders. The extracted text emphasises that practical, ethical and longer-term efficacy questions remain unresolved and that ketamine's principal future role may be as a prototype for novel glutamatergic antidepressants rather than as a routine treatment in standard psychiatric practice.
Major depressive disorders (MDDs) and bipolar affective disorders (BPADs) are frequently persistent, disabling psychiatric illnesses]. Lifetime prevalence of MDDs stands at approximately 16%, and BPADs at 1-4%]: although diagnosed by the presence of pathological highs, depressive episodes (so-called bipolar depression) constitute the majority of illness in BPADs. Our recent reviewhighlighted the limited efficacy of traditional antidepressants and the lack of a robust evidence base to guide the management of patients with treatment-resistant depression (TRD). There is a considerable need to develop novel and efficacious antidepressants. Hallucinogenic drugs produce alterations in consciousness, perception, thought and emotion and have been used recreationally and entheogenically for millennia. So-called 'classical' psychedelic drugs such as lysergic acid diethylamide (LSD), psilocybin, dimethyltryptamine (DMT) and mescaline are thought to exert their effects through agonism at the 5-HT 2A receptors. Dissociative hallucinogens including ketamine, phencyclidine (PCP) and dextromethorphan (DXM) act primarily as N-methyl-D-aspartate (NMDA) glutamate (Glu) receptor antagonists]. There has been growing interest in the observation that ketamine has a rapid positive effect on depressive symptoms. Ketamine is used in medicine for inducing and maintaining anaesthesia, and illicitly for its hallucinogenic and dissociative effects. The fact that ketamine does not work through the 'conventional' antidepressant monoaminergic targets of serotonin and noradrenaline has provoked excitement: understanding its effects could provide novel insights into the pathophysiology of depression and open up a new class of medications. In this paper we will consider how ketamine might produce antidepressant effects, systematically review the evidence base for its efficacy and discuss the clinical utility of this novel compound.
Owing to the water and lipid solubility of ketamine, it can be administered by a variety of routes, including intravenous (IV), intramuscular (IM), intranasal (IN) and oral. The bioavailability of ketamine is approximately 90% when given IV or IM, compared with 16% orally, although peak effects occur rapidly with all methods. Whilst oral administration is inevitably more convenient for both patients and staff, to date, the majority of research on the antidepressant effects of ketamine has used IV administration. IN and IM administration of ketamine have been far less explored in the treatment of depression. IN is reasonably easily administered, and has been shown to provide benefit in a trial of analgesic-refractory chronic pain patients]: there are currently two trials underway with IN administration, but as yet no data to support IN use in depression [aan het. To date, two case studies have investigated the efficacy of IM administration with promising results, but with a total number of three participants it is hard to infer efficacy at this time.
The prefrontal cortex (PFC) homeostatically limits its own input via a cortico-striatal-thalamiccortical loop: glutamatergic neurons feedback to GABAergic interneurons that provide a tonic inhibition to ascending thalamic pyramidal neurons. Mesolimbic dopaminergic activity between the ventral tegmental area (VTA) and the striatal nucleus accumbens (NAcc) disinhibits the GABAergic interneurons, increasing stimuli that reach the PFC (Figure). Amongst the accepted neuropathological changes that occur in schizophrenia there is evidence for reduction in the PFC feedback and mesolimbic hyperdopaminergia leading to increased input to the PFC and cortical dysconnectivity. Ketamine appears to produce 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. Ketamine-induced psychosis has thus been shown to be independent of stimulation of mesolimbic dopaminergic D 2 receptors. This model is incomplete insofar as it would predict that benzodiazepines, through facilitation of GABAergic activity, should ameliorate both the effects of ketamine and psychosis more generally. Largely based upon early pharmacological work on ketamine, there is much interest in Glu as a target for a new generation of antipsychotic drugs.
Linking these well-established actions with a mechanism to explain putative antidepressant effects has proven more difficult. At a more global cortical level, data from healthy subjects have demonstrated the concept of two large anticorrelated cortical networks. The so-called default mode network (DMN) is an intrinsic functionally dominant non-goal-orientated resting state, whilst the extrinsic attentional network is involved in goal-driven behaviour, and the connections between these modular hubs can dysfunction in mental illnesses. In depression a so-called 'dorsal nexus' comprising the bilateral dorsal medial PFC has been shown to have marked increased functional connectivity with the DMN. This greater activation of the restingstate non-goal-directed network is associated with In schizophrenia there is evidence for both underactive PFC glutamatergic feedback to GABA interneurons and overactive dopaminergic activity in the mesolimbic system, both of which serve to pathologically dysregulate PFC activity. (B) The effects of ketamine: ketamine is an antagonist at the glutamatergic NMDA receptor, but not the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, increasing the relative activation at the latter. Effects of ketamine binding are dose dependent. At lower doses it appears to alter PFC connectivity from a 'depressive pattern' of excess DMN activation to a more 'normal' pattern. Ketamine can be psychotomimetic: its antagonism at GABA interneurons reduces thalamic inhibition mimicking psychotic pathology without involving the dopaminergic system. (C) Through relative increase in activation, intracellular changes from AMPA receptors are affected. Evidence for several types of change have been discovered, including altering intracellular signalling pathways, binding with endoplasmic reticulum (ER) sigma-one (σ 1 ) receptors, and changing production of cellular proteins such as mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF). introspection and self-reflective processes that can pathologically increase in depression, and the degree of DMN dominance has been demonstrated to be correlated with the degree of depressive rumination. Scheidegger and colleagues showed that in healthy individuals ketamine decreased the connectivity of the DMN to the dorsal nexus and the medial PFC, and the authors argue that the antidepressant effects of ketamine might therefore be due to re-regulating illness-induced dysfunctional connectivity, particularly in the limbic-cortico-striato-pallido-thalamic circuits involved in mood.
The dominant, albeit incomplete, pharmacological model of depression focuses upon the monoaminergic neurotransmitters serotonin and noradrenaline (and to a far lesser extent dopamine). The therapeutic actions of current antidepressants are highly likely to involve complex intracellular enzymatic chains downstream of changes to monoamines, with alterations in neuronal gene transcription. Far less work has explored the role of the ubiquitous excitatory neurotransmitter Glu in depressive disorders: there is reasonably strong evidence to support dysfunction, though not attribute clear causality (for a review, see Sanacora and colleagues). Extracellular levels of Glu are tightly controlled, as in excess in the synapse it is excitotoxic: after neuronal release it is recycled through glial support cells and enzymatically converted by glutamine synthetase to glutamine, which is then reuptaken by neurons and hydrolysed back into Glu. Proton magnetic resonance spectroscopy ([ 1 H]-MRS) work by Salvadore and colleagues administered ketamine to 14 individuals with MDDs and demonstrated an association between a lower pretreatment Glx:Glu ratio (Glx is a composite peak of Glu and glutamine), which is taken as a surrogate marker of glutamine levels, and a greater clinical response to drug treatment. Glutamine is primarily found in glial cells, and these results indirectly implicate such support cells and Glu synthesis as a potential pathological process behind depressive symptomatology, and one possibly therapeutically facilitated by ketamine administration. However, another 1 H-MRS study, by Valentine and colleagues, failed to show any association between ketamine administration in ten participants with MDD and alterations to amino acid neurotransmitter content.
Antagonism of inhibitory GABA interneuron NMDA receptors and subsequent disinhibitory increases in Glu release also increases the relative activation of other glutamatergic receptors, particularly α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Although ionotropic receptors and responsible for the majority of the brain's fast acting excitatory communication, activation of post-synaptic AMPA receptors also results in changes in protein expression in the post-synaptic cell, including brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR). These proteins are associated with neuronal growth, differentiation, synaptogenesis, and general functioning of the neuron: lower serum, hippocampal and cortical levels are associated with depressionand have been shown to return to normal levels with antidepressant treatment]. Ketamine has been demonstrated to increase expression of mTOR, VEGF and BDNF. A recent rat study showed increases in mTOR phosphorylation and activation within half an hour of ketamine administration, followed by rapid increases in the density, maturation and function of prefrontal pyramidal neuron spines. Interestingly this animal depression model study also showed that blockade of mTOR signalling, through a selective AMPA receptor inhibitor, inhibited ketamine-induced synaptogenesis and behavioural improvement, providing further evidence for the importance both of mTOR and functional AMPA receptors. Increased PFC synapse growth has the neurophysiological attraction as a putative model as it could also provide a mechanism to reverse known atrophic brain changes, cell loss and altered glutamatergic neurotransmission from chronic stressdepression paradigms. Autry and colleagues showed that ketamine promptly reduced depression-like behaviour in mouse controls, but not in BDNF knockout mice. Their data further suggest that inhibition of spontaneous miniature NMDA-receptor mediated currents by ketamine leads to deactivation of the kinase eukaryotic elongation factor 2 (eEF2) with subsequent rapid (within half an hour) and transient increases in BDNF translation, and that longerterm effects are due to secondary changes in synaptic plasticity. This work did not detect any changes in mTOR regulation, although analysis of the brain fractionates occurred earlier (30 minutes) than in the studies that showed changes in mTOR. This study also showed that drug effects were due to enhanced plasticity occurring in tonic resting glutamatergic neurons' spontaneous neurotransmission and could not be elicited by evoked neurotransmission. The authors posited that this supports the hypothesis that spontaneous and evoked forms of glutamatergic signalling are segregated. The ubiquitous protein kinase glycogen synthase kinase 3 (GSK-3) has been identified as a regulator of a diverse range of signalling pathways and has a key role in a number of cellular functions including inflammatory responses. Modulation of GSK-3 is held as one of the mechanisms by which lithium exerts its effects. Beurel and colleagues demonstrated that ketamine administration to mice rapidly inhibited GSK-3, and in this study such action was necessary for its rapid antidepressant effects.
Many depressive disorders have established diurnal patterns of mood change and dysregulated sleep. The therapeutic role of ameliorating pathological sleep and circadian patterns has received renewed interest in recent times through evaluation of the novel antidepressant agomelatine. This melatonergic analogue acts as a melatonin MT 1 and MT 2 agonist, as well as a 5-HT 2C antagonist and has been shown to be efficacious as an antidepressant. The melatonergic system has been implicated in depressive disorders] and some of the effects of agomelatine appear to be through the resynchronization of circadian rhythms. Ketamine has been shown in animal studies to change NMDA and AMPA circadian rhythmicity, and inhibit light induction in the suprachiasmatic nucleus], a centre for temporal patterns of gene transcription and neuroendocrine function. Work by Bellet and colleagues showed that ketamine induced a dosedependent reduction in the circadian transcription of genes driven by the key CLOCK:BMAL-1 heterodimeric complex, and that such action was attenuated by administration of the GSK-3B antagonist SB21673. The authors argue that the rapid effects of ketamine might at least in part be accounted for by changes to clock gene expression. However, a study by Ma and colleagues found that whilst single-dose ketamine produced antidepressant effects in mice, sustained up to the 8-day study cut-off, the GSK-3 inhibitor SB216763 did not, challenging the role of GSK-3 as part of the effect of ketamine, and thus the therapeutic role if any for modulation of this pathway by ketamine remains uncertain.
Intracellular σ 1 receptors are primarily located at endoplasmic reticulae (ER) membranes and are involved in regulation of intracellular calcium signalling through interaction with voltage-gated channels. They interact with other signalling pathways and receptors such as inositol-1, 4, 5 triphosphate (IP 3 ), phospholipase C (PLC)gamma, protein kinase C (PKC) and the Ras/Raf/ MAPK pathways. The roles of σ 1 include: promoting correct folding of proteins and facilitating transfer of degraded proteins to proteasomes for lysis to prevent toxic protein accumulation; promoting neuronal plasticity, neurite growth and synaptogenesis; and by activating antioxidant responses]. Reduced levels have been reported in various neurological and psychiatric disorders, and ketamine, fluvoxamine and donepezil, and methylphenidatehave been shown to also be σ1 agonists. There are interesting preliminary data from the NMDA GluN2B subunit antagonist ifenprodil, which has generally been used a cerebral vasodilator. This drug has pharmacological similarities to ketamine, although ex vivo receptor occupancy data in mice hippocampi has demonstrated differential NMDA binding profiles. Work by Ishima and Hashimoto showed that ifenprodil potentiated concentration-dependent nerve growth factor-induced neurite outgrowth in cell cultures, and that such effects were blocked by concomitant administration of a specific σ 1 or IP 3 but not an σ 2 antagonist. Forced swim depression models in mice have been shown to respond to ifenprodil when co-administered with NMDA partial or full antagonists, with ifenprodil's effects blocked by NMDA agonists. Clinically nascent data has shown ifenprodil to be effective in managing so-called emotional incontinence in vascular dementia, and in reducing flashbacks in female sufferers of posttraumatic stress disorder (PTSD). Whether or not ketamine produces some of its antidepressive actions through similar mechanisms remains unclear at this time.
Epidemiological studies have linked obesity and depressive disorders through psychosocial factors, although there is growing interest in the potential role of the neuroendocrinologically active adipokines secreted by adipose tissue such as leptin, adiponectin and resistin. These hormones have roles in homeostatic feedback loops to hypothalamic satiety centres: their expression is stimulated by glucocorticoids, and hence altered in stress states, and they promote cytokine inflammatory responses]. Both excessive and depleted leptin levels have been linked with depressive disorders]. Leptin levels have been shown to be reduced in rodents subjected to chronic stress, and administration of leptin in animal studies has been shown to have antidepressant effects, although the mechanisms of action and clinical implications are unclear. Guo and colleagues showed that mice without the long form of the leptin receptor (Lepr), which are selectively distributed in the PFC and hippocampus, demonstrated normal growth and body weight but depression-like behaviour and NMDA-induced hippocampal long-term synaptic depression]. These mice were very sensitive to antidepressantlike effects of the selective NMDA receptor GluN2B (NR2B) antagonist Ro25-6981 but resistant to leptin. The authors argue that defective Lepr signalling in Glu neurons may play a role in the pathogenesis of depressive disorders and long-term synapse depression mediated through NMDA GluN2B receptors; further, the therapeutic actions of NMDA antagonists might be through facilitation of normal leptin-Glu functioning.
Materials and methods Data acquisition. We attempted to identify all randomized controlled trials (RCTs) and non-RCTs available to review up to January 2013, in which the potential efficacy of hallucinogen drugs in the treatment of depression was analysed. Search strategy. References were retrieved through searching electronic databases and manual searches through reference lists of identified literature. The following data sources were searched: PSYCINFO (1806 to 26 June 2013),. Although the primary aim was to explore the efficacy of ketamine, to ensure the fullest data collection the search criteria were as follows: "hallucinogen" OR "lsd" OR "lysergic acid diethylamide" OR "ketamine" OR "mescaline" OR "psilocybin" OR "magic mushroom" OR "mdma" OR "ecstasy" OR "psychedelic" OR "dissociative" OR "phenethylamine" OR "phencyclidine" combined with AND "antidepressant" OR "depression*" OR "mood disorder" OR "bipolar" OR "depressive-disorder" OR "unipolar". Eligibility criteria. The following inclusion and exclusion criteria were established prior to the literature search. Participants. Studies that looked at adult populations (≥18 years old) with a diagnosis of a MDD or BPAD based on a structured diagnostic interview (DSM or ICD) were included. Interventions. All designs evaluating the effect of ketamine on depressed mood were included. Investigations on addiction, ketamine misuse or specifically looking at psychedelic effects of ketamine were excluded. Comparators. No comparators were required for inclusion in this review. Outcomes. Studies investigating the effect of ketamine on mood symptoms and/or suicidality were included. Studies that failed to use a validated assessment scale for the evaluation of mood changes were excluded. Study design. Only journal articles were included for review, with books, letters, comments, editorial and poster presentations excluded. Case studies documenting fewer than three participants were excluded. Study selection. Using the stated search strategy 11,138 reports were identified. The search and process of identification is summarized in Figure. In total, 26 studies were ultimately identified as fulfilling criteria, with a total of 629 participants.
In order to collate relevant information from each article the following data were extracted from each: characteristics of participants (age, gender, length of illness, length of current episode, method of diagnosis); trial inclusion and exclusion criteria; type of intervention (type, dose, duration, design); response criteria; type of outcome measure (depression scale, response rates, remission rates, follow up). Several different and quite diverse themes emerged during the data extraction and the sample was thus divided into the following three categories to allow better clarification and interpretation of results: ketamine only; ketamine plus a second drug; ketamine and electroconvulsive therapy (ECT) or surgery.
For each of the subcategories of theme identified a table is presented with the characteristics of the included studies. Hamilton depression scale ratings data from the five studies with control groupswere subjected to two cross-study meta-analyses using OpenMeta[Analyst], Brown Education software (see). For the first meta-analysis, the effects of ketamine versus placebo on depressive ratings were assessed at baseline, for the second 60-80 minutes post-infusion, and for the third 210-230 minutes post-infusion. Given that the included studies did not coherently report the means and standard deviations for each group at each time point, values were read off the available graphs in each paper.
Studies with no control group. There were 11 studies that administered ketamine to all participants with no control condition: their characteristics are detailed in Tableand results are given in Table. Six studies evaluated single-dose ketamine administration on depressive symptoms, three multiple-dose schedules and two primarily evaluated changes to suicidal ideation. Trial size varied from 11 to 33 participants, and recorded follow up from 230 minutes to 83 days post-ketamine administration. A total of 206 participants, all with major depressive episodes (MDEs; diagnosed using DSM), completed these trials, and all were undertaken within the past 5 years. Ketamine was administered at 0.5 mg/kg in all trials except one. All studies adopted the Montgomery-Asberg Depression Rating Scale (MADRS) as the primary outcome measure: response was defined as ≥50% reduction in scores throughout, and remission a score of < 10. Outcomes affected by ketamine in these studies were very strong, although this must be contextualized by their open-label and loosely controlled design. Of the six open-label studies assessing response to single-dose ketamine in MDD, two were primarily evaluating postulated drug-induced changes to cortical proteins via 1 H-MRS(n = 14) and serum analysis] (n = 23), and two investigated anterior cingulate cortex activity with regards to drug response(n = 11, 15, respectively), but all also reported clinical responses as secondary measures. These four studies showed statistically significant improvement in mood at 230-minute post-infusion time points (p = 0.005 in; p = 0.001 in; p = 0.006 in; p < 0.001 in). A somewhat different model was undertaken in open-label work by Larkin and Beautrais who trialled the feasibility of undertaking single-dose ketamine administration, administered, somewhat atypically for ketamine studies, as a 0.2mg/kg single bolus over 1-2 minutes, in 14 participants with MDD and suicidal ideation in an emergency department. A primary aim with this work was to evaluate a key conceptual concern about the viability of ketamine use in such 'real-world' scenarios. Fitting with previous data they found rapid antidepressive effects within 240 minutes, with 13 (92.3%) meeting response criteria and mean scores falling from a baseline MADRS score of 40.4 (standard error of the mean [SEM] = 1.8) to 11.5 (SEM = 2.2). There are high rates of comorbidity between depressive disorders and substance misuse. A family history of alcohol dependency has been shown to result in altered responses to ketamine in healthy participants, and changes to the glutamatergic system and NMDA binding has been implicated in both disorders. Phelps and colleagues used linear mixed models to evaluate differential response in 26 MDD participants with and without a (selfreported) family history of alcohol dependency to open-label ketamine administration. Those with positive family histories showed a statistically significant improvement over those who did not in MADRS, Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI) scores within 230 minutes of ketamine infusion. Individual past alcohol dependency and past family history of depression were not correlated with outcome. The authors note that alcohol acts on NMDA receptors (amongst others) and genetic data have shown inheritable variations of these receptors associated with alcohol dependence: they speculate that both clinical histories and genetic markers may in future act as predictors of drug response. Three open-label studies evaluated multiple-dosing ketamine. aan het Rot enrolled 10 participants from an earlier trial of the effects of ketamine on suicidality] who had an initial depressive symptom severity ≥32 on the Inventory for Depressive Symptoms (IDS-C 30 ) and who had demonstrated a clinical response to this single ketamine infusion without significant side effects [aan het. Participants were given 6 infusions over 12 days: 90% of participants responded to the first infusion, and by the end of the trial 100% met response criteria and 88.89% met remission criteria. The same research group undertook a larger studyof 24 individuals, including the 10 participants in the previous work, who, after a wash-out period from their antidepressants, each received thrice weekly injections of ketamine over 12 days. There was a large, statistically significant (p < 0.01) decrease in MADRS scores 2 hours after the initial infusion (mean decrease 18.9, standard deviation [SD] 6.6). A total of 21 participants completed the full 6-infusion schedule and the response rate at the study's conclusion was 70.8% (17 of 24). Response to ketamine 4 hours after the initial infusion was strongly associated with the response by the study's end, with 94% of those responding doing so 4 hours after the first infusion. A more recent study conducted by Rasmussen and colleagues administered 10 participants in a MDE (BPAD II/MDD) with up to 4 ketamine infusions at 0.5 mg/kg over 100 minutes. A total of 80% of the participants demonstrated response to ketamine, defined as at least a 50% reduction in MADRS scores, and furthermore 50% met remission, defined as a MADRS score of 9 and below. Of the 5 participants who met remission, 2 still met remission criteria at the 4-week follow up. Rasmussen and colleagues further documented the effect of ketamine on suicidal ideation, reporting significant improvements in the Scale for Suicide Ideation (SSI; p = 0.007) and the Suicide Status Form (SSF; p = 0.026). In addition, this study reported a significant correlation between SSI/SSF scores and MADRS (p < 0.01), suggesting the observed decrease in suicidality occurred in unison with that of depression scores. Two studies, both single-dosing, looked primarily at the effects of ketamine on suicidal ideation., from a baseline mean MADRS-SI of 3.9 (SEM = 0.4) to a mean of 0.6 (0.1), maintained at day 10 (0.7 (0.2)). Interestingly, the work by Murrough and colleagues demonstrated that even non-responders to the anti-depressant effects showed statistically significant improvements in suicidal ideation]. Most of these trials were designed with only brief follow up of participants, particularly in the single-dose studies. Salvadore and colleagues noted that improvements in MADRS scores remained significant (p = 0.01) at 24 hours, whilst Larkin and Beautrais record that clinical gains were maintained for the 13 participants who completed the study to the end-point at day 10 (mean MADRS 9.2 (SEM = 1.7)). The two multipledosing trials had longer follow ups recorded. Relapse occurred on average 19 (SD 13) days following final infusion, though one participant remained asymptomatic for three months, in the work of aan hen Rot and colleagues [aan hen; whilst in the study by Murrough and colleagues the median time to relapse was 18 days (interquartile range 11-27 days) after the final infusion. Overall ketamine appeared well tolerated though there were frequent reports of mild psychotomimetic symptoms, as measured with the Brief Psychiatric Rating Scale (BPRS) or Clinician Administered Dissociative States Scale (CADSS), primarily an unpleasant dissociative effect, typically occurring and resolving within an hour of administration. Fitting with its known anaesthetic profile transient hypertension and tachycardia were also recorded. In the studies that so-reported, no difference in side-effect profile was noted between depression/suicidal-ideation responders and nonresponders. Studies with a control group. Five studies compared the effect of ketamine (0.5 mg/kg) with a placebo saline infusion treatment: their characteristics are detailed in As with the single-dose studies the effects of ketamine waned after a reasonably short period. Of the 79% who attained remission criteria at 24 hours in the work by Zarate and colleagues], 35% were reported as maintaining this at 1 week, whilst Valentine and colleagues] described the statistically significant improvement of the active treatment over the placebo group was sustained for a week. In the bipolar depression studies the mean time to relapse was reported as 4.5 days by Zarate and colleagues, and although this figure was not documented by DiazGranados and colleagues, comparisons from baseline at days 7, 10 and 14 were no longer significant. The side effects recorded in the controlled studies were similar in nature and frequency to those of the open-label trials, with the active drug generally well tolerated, although distinctive transient dissociative and perceptual disturbances were noted in all trials, and likely to have affected study blinding. Meta-analysis of the double-blind RCTs of ketamine. Meta-analysis of the double-blind RCTs supports the antidepressant efficacy of ketamine. Figureshows the difference between ketamine and placebo at baseline (top), 60-80 minutes (middle) and 210-230 minutes (bottom). At 60-80 minutes the mean difference in depression scores on the HDRS was -3.406 (p < 0.001; 95% CI -6.303 to -0.509) and at 210-230 minutes the mean difference was -5.371 (p < 0.001; 95% CI -6.574 to -4.168). Three studiesreported significant reductions in depression scores between 60 and 80 minutes, whilst the change was not statistically significant in two studies. Four studies report the change in depression scores at the 210-230 minute time point as statistically significant, whilst one studyreports the change in depression scores as not statistically significant. Berman and colleaguesreported a large disparity between baseline depression scores in the placebo and ketamine condition, but this difference was deemed not statistically significant through a paired t test (p = 0.10). Thus, although the Forest plots reveal the mean difference between scores in the placebo and ketamine condition as relatively small, this is owing to the differences recorded at baseline. This disparity led to a heterogeneity p = 0.531 in the meta-analysis for 210-230 minutes, but the model showed a statistically significant effect of p < 0.001. The high heterogeneity evident at 60-80 minutes (I 2 = 79%) is likely due to the figures reported by Berman and colleagues].
There has been work to see whether augmentation of ketamine could support or enhance the initial improvement and avert the rapid relapse seen in the single-drug studies. Three studies have evaluated ketamine (0.5 mg/kg in both) augmentation with an anticonvulsant, either lamotrigine or riluzole, and unfortunately their results have been disappointing: study characteristics are detailed in Tableand results are given in Table. Both of these chosen augmenting drugs are 'neuroprotective', inhibiting Na + channels and glutamate exocytosis, blocking NMDA receptor activation and enhancing AMPA, GluR1 and 2 receptor membrane expression, as well as having demonstrated efficacy in bipolar depression. Ibrahim and colleaguesfound no difference in time to relapse between 42 participants with MDD randomized to either riluzole (100-200 mg/day, n = 21) or placebo (n = 21) after an initial ketamine infusion (0.5mg/kg) in a 4-week follow-up study. A significant improvement over baseline MADRS scores was seen (p < 0.001), with mean time to relapse, across groups, of 13.2 days. Interestingly 27% of responders had not relapsed by the study's 4-week end point. A substudy conducted by Duncan and colleaguesrandomized patients to receive either doubleblind placebo (N = 11) or riluzole (N = 19), 4-6 hours following ketamine infusion (0.5 mg/kg). Results indicated a significant improvement in MADRS scores 230 minutes post-ketamine infusion (p < 0.00001), maintained at 1-day post-infusion (p < 0.00001) and 2 days post-infusion (p < 0.00001). However, no significant effect was reported for drug (p = 0.93), suggesting no difference in depression scores between the riluzole and placebo group. An earlier study by Mathew and colleagues] used a two-stage methodology incorporating both lamotrigine and riluzole with hypothesized differing roles for each drug. In the first stage of this study 26 medication-free participants with TRD received openlabel ketamine and either lamotrigine 300 mg or a placebo 2 hours prior to this to test whether lamotrigine could both limit any psychotomimetic side effects and potentially augment the antidepressive effects of ketamine. Those who met response criteria of a ≥50% decrease in MADRS scores72 hours post-infusion were then entered into a second, double-blind randomized controlled stage, that consisted of a 32-day trial of receiving flexible-dose riluzole (100-200 mg/ day) or a placebo to test whether the active drug, which has some pharmacological similarities to ketamine, would limit post-ketamine relapse. In the first stage of the study the authors found a significant mean reduction in MADRS (60 ± 32%; d = 2.11; 95% CI 1.25-2.97) and Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR; 62 ± 28%) scores at 24 hours, with response rates of 65% (n = 17) and remission rates of 50%; this dropped to 54% (n = 14, who therefore proceeded to stage 2) response rates at 72 hours. Lamotrigine was ineffective in either limiting side effects or augmenting ketamine efficacy and the two treatment groups did not differ in MADRS scores at any point (p = 0.36). In the second stage no difference between the groups (log-rank χ 2 = 0.17, degrees of freedom = 1, p = 0.68) in time to relapse, which for riluzole was a mean of 24.4 days (95% CI 15.9-33.0) and for placebo was 22.0 days (95% CI 14.9-29.1).
There are clear parallels between ketamine and ECT insofar as both have rapid actions and their effects are typically short-lived. In addition ketamine has been used as an anaesthetic, including induction prior to ECT, for decades, although its propensity to raise blood pressure through systemic catecholamine release and to cause aversive dissociative experiences generally makes it a second-line drug. It is thus not surprising that some studies have explored their combined use, especially as ketamine may also, by attenuating Glu release, moderate neurotoxic and cognitive impairment from ECT-induced cortical hyperexcitability. Furthermore, unlike most anaesthetics ketamine is proconvulsive, which might facilitate ECT. Studies have evaluated augmenting ECT with a subanaesthetic dose of ketamine, using ketamine as the anaesthetic agent and one study looked at the use of ketamine as an anaesthetic agent in general orthopaedic surgery in depressed patients. The results shows promising potential for ketamine, with most work showing additional, albeit brief, benefits from its use, although not all research showed positive outcomes. The characteristics of these studies are detailed in Tableand results are given in Table. ECT augmented with subanaesthetic ketamine. Two recent studies have evaluated augmentation of ECT with ketamine, one showing initial, although not sustained, positive results, the otherreporting no benefit. Loo and colleagues undertook a RCT of 51 participants with TRD undergoing a course of ultrabrief pulse-width right unilateral ECT randomized to augmentation with either a subanaesthetic dose of ketamine (0.5 mg/kg) or saline placebo in addition to standard thiopentone anaesthetic. ECT was given three times a week, with ketamine or placebo given after induction of anaesthesia in all sessions. No group differences in neuropsychometric testing, measured on a battery of tests, were observed at any time point, although the study was only powered to detect large changes, and ketamine had no effect on seizure duration. The ketamine group did show a small but statistically significant clinical improvement in depressive symptoms during the first week of treatment and the 1 week follow-up measurement, but this had disappeared by the end of the treatment course (F(1, 40) = 0.921, p = 0.343; η 2 = 0.22). No psychotomimetic problems were noted in the ketamine group, although these typically brief and self-limiting phenomena might be masked by post-anaesthetic recovery. The work by Abdallah and colleagues had a similar design, although it included participants with bipolar depression, and ECT could be unilateral or bilateral for six sessions over 2 weeks]. The number of participants evaluated (n = 18) was smaller than originally planned as the trial was prematurely terminated due to a lack of between-group clinical differences (measured on the HDRS) in improvement of depressive symptoms at 24 or 72 hours after the first ECT session, or after the final (sixth) one. This result is interesting in that the very commonly seen initial positive response to ketamine was not demonstrated. The authors postulate that the known GABAergic potentiation and AMPA blocking effects of the barbiturate anaesthetic might have pharmacologically countered the actions of ketamine. Use of ketamine as an anaesthetic in ECT. Three papers explored the effect of ketamine use as the anaesthetic agent in ECT compared with a common anaesthesia. The methodology was quite different in each, with two prospective studies, one evaluating single-session ECTand the other an eight-session protocol, as well as one retrospective case-note study]. All demonstrated significantly improved depression scores in the ketamine groups, although benefits were short-lived. The single session ECT study by Wang and colleagues had an interesting methodology in that 48 patients with MDD were randomized into three equal-sized (n = 16) groups, each receiving a differing ECT anaesthesia protocol: 'standard' propofol, ketamine (0.8 mg/kg) and a third group that received combined ketamine (0.8 mg/kg) and propofol anaesthesia. This allowed the authors to test dual hypotheses of the clinical superiority of ketamine in treating depressive symptoms as well evaluating whether the combination might result in propofol ameliorating any ketamine-induced cardiovascular excitement. Patients were clinically assessed 1 day before and 1, 2, 3 and 7 days post-single-session bilateral ECT with the HDRS in a double-blinded paradigm. HDRS scores improved earlier (up to and including day 3 post-ECT) in the two ketamine groups compared with the propofol-alone group (p < 0.01), but this difference was lost by day 7 (p > 0.05). The combination anaesthesia group showed fewer physical (hypertension, p = 0.037) and psychological (post-anaesthetic hallucinations, p = 0.33) adverse effects than the ketamine-alone group. The longer prospective study] undertook an open-label trial of 31 inpatients with TRD who were given either ketamine (n = 11) or propofol (n = 20) before each of eight ECT sessions over 4 weeks. Drug allocation was according to patient preference in discussion with the anaesthetist. Those anaesthetized with ketamine showed statistically significantly improvements in HDRS scores compared with those who received propofol after the second (p < 0.001) and fourth sessions (p < 0.001) but not after the sixth (p = 0.086) or eighth (p = 0.360) sessions. The retrospective study by Kranaster and colleagues evaluated the records of 42 patients with TRD who had ECT anaesthetised with either Surgical use of ketamine as an anaesthetic in depressed patients. A single studyevaluated the antidepressant effects of ketamine when used as a general anaesthetic (combined with propofol and fentanyl, n = 35) compared with combined propofol and fentanyl (n = 35) on 70 depressed patients undergoing orthopaedic surgery. A control group of 25 nondepressed patients received the three-drug combination. In the depressed cohort those receiving ketamine as part of their anaesthesia showed statistically significant improvement in their mood measured by the HDRS (p < 0.05) one day after surgery; interestingly the ketamine group also showed a significant reduction in post-operative pain scores (p < 0.05), which the authors highlight is a noted complication of surgery in depressed patients. The control group showed no change in their mental state.
In total, 22 RCTs and non-RCTs were identified that investigated the potential role of ketamine as an antidepressant in MDD and BPAD, totalling 629 participants. Ketamine infusion resulted in a rapid antidepressant effect in the vast majority of the presented studies, either administered alone, with an augmenter, or in combination with ECT. Furthermore, several recent studies demonstrated a rapid antisuicidal effect that was independent of antidepressant response. High response rates were documented in many studies, with three of the included RCTs recording a 71-79% response rate at 24 hours post-ketamine infusion. This is a considerable response rate to be observed at this early time point, certainly when compared with traditional monoaminergic antidepressants wherein response rates of 65% following 6-8 weeks of treatment are notable. The parallels between ketamine and ECT are obvious and there is interesting work in this area, although not all studies showed positive results. The role of ketamine as an anaesthetic is generally as a second-line drug these days due to its sideeffect profile. However, given its mood enhancing effects consideration of its use in both ECT and surgery for depressed patients is an interesting question., indicating psychotomimetic effects were not related to the documented rapid antidepressant effect of ketamine. Adverse effects were not followed up in any of the identified studies, with only short-term effects recorded. Methodologically, many of the discussed studies in this review are severely limited in regard to their sample size, a problem that continues to hinder many pharmacological studies more generally. A sample size of 102, 51 in each group, would be required within RCT methodology to detect a moderate effect size of 0.5, with a power of 80% and 0.05 significance]. However, none of the included studies included a sample size in this region, with the highest sample provided in a non-RCT design of 70. Only six studies adopted the gold standard randomized, double-blind, placebo-controlled design. Caution must therefore be taken in interpreting and applying these results, although several authors identified the difficulties in blinding the administration of ketamine.
The very fast antidepressant effects after single dosing in even treatment-resistant cohorts pose tantalizing possibilities in the treatment of MDD and bipolar depression. Such rapid improvement could have enormous benefits in the care of depressed (and especially acutely suicidal) patients, including allowing time to get other treatments and services in place. It seems selfevident that this could be literally life-saving. The practical issues of IV ketamine administration with anaesthetic support are considerable. This is hardly a common, or even possible, practice for many psychiatric units, and the hurdles in terms of the necessary staff, training equipment, and potentially attitudes are formidable. The work by Larkin and colleagueswas intentionally undertaken in an accident and emergency department to test the viability of emergency care, so there are preliminary results to potentially support this, but the practical challenges are clearly immense. However, in support of the current use of intravenous ketamine it has been arguedthat at this time when the drug's effects and risk are not fully understood, that IV affords a convenient mechanism to: more accurately determine the lowest effective dose; see whether there is a dose-response relationship; evaluate whether or not any higher antidepressant dosing overlaps with significant perceptual or psychotomimetic symptoms; and to rapidly terminate treatment if problematic side effects arise. A further factor influencing the mode of administration is that there is currently less evidence for sustained efficacy from repeated dosing and thus there has been potentially less pressure to devise more patient-tolerable regimens. Finally concerns have been raised about the abuse potential of ketamine and that easier access to the drug (in oral preparations) increase risks of misappropriation of the medication. Suicidal ideation is very common in many crisis presentations, many of which are not depressive disorders. The efficacy of ketamine in such situations is unknown, and ethics challengeable, although ketamine has been shown to lessen suicidal thinking independent of effects on depressive symptoms. Further, such emergency presentations are often outside normal working hours and at times when services are provided by more junior and inexperienced staff. Protocols on who would or should make a decision on the provision of such treatment, and which patients might be excluded, for example those with histories of current or past substance misuse or psychoses, would need defining. The counter-argument is that there is almost overwhelming clinical evidence to support the acute efficacy of ketamine in severely unwell populations; and there is an uncalculated opportunity cost for admissions to psychiatric hospitals, the use of crisis teams, compulsory detention under section of the Mental Health Act, and the sometimes atherapeutic or undesired aspects of hospital admission. This is without consideration of the incalculable costs of suicide in personal and societal terms. An argument can be made that it is unethical to withhold such treatment. The practical, ethical and longer-term efficacy arguments remain unresolved. Hypothetically could a suicidal patient be administered ketamine against their wishes either, in the UK, under the Mental Health Act where their life was in danger from a mental illness, or under the Mental Capacity Act where they lacked the ability to make decisions about their care? The future of ketamine: prototype for a new class of antidepressant? The longer-term role of ketamine in the management of depression is unclear. Optimal dosing and longer-term data on relapse prevention and tolerability are lacking. Although most studies administered ketamine at a dose of 0.5 mg/kg in a saline drip over about 40 minutes, this was not the only schedule, with for example a bolus administration of 0.2 mg/kg over 1-2 minutes. Most studies utilized participants with treatmentresistant MDDs: on the one hand this adds to the clinical appeal of a therapy that works on those who have failed to respond to standard treatment; on the other hand it leaves open the question of the effects of ketamine on mild, moderate or treatment-naïve depressive disorders. There is no current consensus whether those who are treatment refractory and fail to respond to traditional antidepressants have a neurobiologically distinct form of the illness. All studies have methodologically appropriate inclusion and exclusion criteria that nevertheless might hinder the wider generalizability of the data. Whilst used in some individuals with bipolar depression it is not clear if the side effects would differ in those who had previous psychotic episodes as part of their BPAD. Ketamine is well established as a psychotomimetic: occurrences of psychotic symptoms were not common in the trials, but these were shortterm studies in controlled environments, and excluded those with psychotic illnesses and histories of drug dependency. The potential for harm and the broader use of this drug has not been satisfactorily answered, and MRI data on longerterm illicit use of the drug has shown it can cause cortical atrophy. The very strong efficacy data but the practical administration and side-effect problems may terminally limit the use of ketamine in general psychiatric practice, although undoubtedly larger longer follow-up RCTs are needed. Ketamine data have provided new neurobiological evidence to both support aspects of the monoaminergic hypothesis of depression, and also offering novel insights into this illness. There are current trials on selective NMDA receptor subunit 2B (NR2B) antagonists such as Ro 25-6981 to see whether they can elicit the therapeutic responses seen with ketamine without the major potential problems of psychosis and dependency. It currently seems that the primary role of ketamine in depression may turn out to be as a prototype for the development of future glutamatergic antidepressants, and in furthering our understanding of the neuropathology of depression.
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Shamabadi, A., Ahmadzade, A., Hasanzadeh, A. · British Journal of Clinical Pharmacology (2022)
Conley, A. A., Norwood, A. E. Q., Hatvany, T. C. et al. · Psychopharmacology (2021)
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Abdallah, C. G., Averill, L. A., Krystal, J. H. · Annals of the New York Academy of Sciences (2015)