ArticleLiterature Review

Ketamine as a Fast Acting Antidepressant: Current Knowledge and Open Questions

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Several recent studies have shown that a single intravenous subanesthetic dose of ketamine, a NMDA receptor antagonist, exerts rapid antidepressant effects in patients with treatment refractory mood disorders and reduces suicidal ideation. Those insights have fueled tremendous excitement in the efforts to elucidate the mechanism underlying ketamine's antidepressant properties in animal models of depression, as well as in humans through the use of brain imaging as well as peripheral blood measurements. For example, there is emerging evidence that ketamine's antidepressant properties rely on increasing AMPA signaling and rapidly inducing synaptogenesis. While pilot clinical studies are promising, a number of critical questions still remain unanswered. They relate to the safe and effective use of ketamine in patients with mood disorders regarding the optimal dose range, modality and method of administration for acute and long-term maintenance of effect, and the biomarkers associated with response/nonresponse. In this review article, we first summarize the clinical evidence about the use of ketamine in mood disorders, as well as preclinical and humans studies which investigated the mechanisms of action of ketamine, and predictors of antidepressant response in clinical populations. We then provide a critical overview of the knowledge gaps about the use of ketamine in depression and suggest some future research directions for the investigation of ketamine as a promising tool to develop novel more effective and fast acting antidepressants.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... [26][27][28][29][30][31][32][33][34][35] The proposed mechanism of action has involved increasing synaptogenesis and neural plasticity secondary to the rapid rise in the brain extracellular glutamate level. 36 Additionally, it may induce alphaamino-3-hydroxy-5-methyl-4isoxazeolepropionic acid receptor activation and brain-derived neurotrophic factor in the prefrontal cortex and hippocampus. 36 The onset of its antidepressant effect may be as rapid as 2 hours after administration and can potentially last for up to 1 week after a single bolus dose. ...
... 36 Additionally, it may induce alphaamino-3-hydroxy-5-methyl-4isoxazeolepropionic acid receptor activation and brain-derived neurotrophic factor in the prefrontal cortex and hippocampus. 36 The onset of its antidepressant effect may be as rapid as 2 hours after administration and can potentially last for up to 1 week after a single bolus dose. 37 With repeated boluses, the effects may last up to 12 weeks. ...
... 65 The exclusion of ketamine use in the last 4 weeks has also been chosen as ketamine's antidepressant effect might last up to this time. 36 ...
Article
Full-text available
Introduction Major depressive disorder (MDD) in people with advanced life-limiting illnesses can have significant impact on the quality-of-life of those affected. The management of MDD in the palliative care setting can be challenging as typical antidepressants may not work in time nor be tolerated due to coexisting organ dysfunctions, symptom burden and frailty. Parenteral ketamine was found to exhibit effective and rapid-onset antidepressant effect even against treatment-resistant depression in the psychiatric population. However, there is currently neither feasibility study nor available prospective study available to inform of the safety, tolerability and efficacy of such for MDD in the palliative setting. Methods and analysis This is an open-labelled, single arm, phase II pilot feasibility study involving adult patients with advanced life-limiting illnesses and MDD across four palliative care services in Australia. It has an individual dose-titration design (0.1–0.4 mg/kg) with weekly treatments of subcutaneous ketamine infusion over 2 hours. The primary outcome is feasibility. The secondary outcomes are related to the safety, tolerability and antidepressant efficacy of ketamine, participants’ satisfaction in relation to the trial process and the reasons for not completing the study at various stages. The feasibility data will be reported using descriptive statistics. Meanwhile, side effects, tolerability and efficacy data will be analysed using change of assessment scores from baseline. Ethics and dissemination Ethics approval was acquired (South Western Sydney Local Health District: HREC/18/LPOOL/466). The results of this study will be submitted for publication in peer-reviewed journals and presented at relevant conferences. Trial registration number Australian New Zealand Clinical Trial Registry Number: ACTRN12618001586202; Pre-results.
... Non ci sono evidenze che suggeriscano come l'infusione ripetuta di ketamina a dosi subanestetiche non provochi dipendenza. Il potenziale della ketamina come antidepressivo è stato affrontato di recente da diverse review (Salvadore 2013;DeWild 2015), che tuttavia presentano tra gli autori dipendenti e consulenti della casa farmaceutica produttrice della ketamina intra-nasale. Queste review offrono inoltre poche informazioni riguardo all'abuso di ketamina e alle potenziali complicanze relative all'uso cronico; potrebbero quindi sottostimare i rischi della somministrazione ripetuta per mantenere l'effetto antidepressivo (Salvadore 2013). ...
... Il potenziale della ketamina come antidepressivo è stato affrontato di recente da diverse review (Salvadore 2013;DeWild 2015), che tuttavia presentano tra gli autori dipendenti e consulenti della casa farmaceutica produttrice della ketamina intra-nasale. Queste review offrono inoltre poche informazioni riguardo all'abuso di ketamina e alle potenziali complicanze relative all'uso cronico; potrebbero quindi sottostimare i rischi della somministrazione ripetuta per mantenere l'effetto antidepressivo (Salvadore 2013). ...
... Tale dosaggio non è tuttavia senza rischi e una singola dose sub-anestetica e.v. di ketamina causa effetti collaterali nel 2% dei casi (Salvadore 2013). ...
Article
La ketamina come antidepressivo ad azione rapida: controversia e implicazioni [translation of “Ketamine as a rapid antidepressant: the debate and implications” by Dr. Giacomo Galli and Dr. Serena Saraceni] - Volume 22 Issue 4 - Roger C. M. Ho, Melvyn W. Zhang
... Ketamine, an NMDA receptor antagonist, has been used as an intramuscular and intravenous anesthetic in both human and veterinary medicine since the 1970s (Salvadore & Singh, 2013). Beginning in the early 2000s with a study by Berman et al., 2000, the possible role of ketamine in the treatment of major depression began to be explored, with a number of other studies being conducted from that time to present day. ...
... At anesthetic doses, ketamine blocks the function of NMDA glutamate receptors (Salvadore & Singh, 2013). However, at low, sub-anesthetic doses, we see a very different phenomenon occur, in that ketamine dramatically increases glutamate release for an acute period (around 2 hours) (Salvadore & Singh, 2013). ...
... At anesthetic doses, ketamine blocks the function of NMDA glutamate receptors (Salvadore & Singh, 2013). However, at low, sub-anesthetic doses, we see a very different phenomenon occur, in that ketamine dramatically increases glutamate release for an acute period (around 2 hours) (Salvadore & Singh, 2013). One hypothesis suggests that low-dose ketamine may block NMDA receptors on GABAergic interneurons, thus disinhibiting glutamatergic pyramidal cells and increasing glutamate release in the prefrontal cortex (Duman et al., 2012). ...
... Several studies have demonstrated that intravenous (IV) ketamine can induce an antidepressant effect in patients with depression who were previously resistant to standard treatment with oral antidepressants as well as ECT (17,21,(25)(26)(27)(28)(29)(30)(31). Ketamine's possible antidepressant effect has been described to last from three days to a few months, with a median relapse time of eighteen days (25,32). ...
... Several studies have demonstrated that intravenous (IV) ketamine can induce an antidepressant effect in patients with depression who were previously resistant to standard treatment with oral antidepressants as well as ECT (17,21,(25)(26)(27)(28)(29)(30)(31). Ketamine's possible antidepressant effect has been described to last from three days to a few months, with a median relapse time of eighteen days (25,32). However, the study that showed the highest inter-individual variability in duration of response (32) applied an open-label design. ...
... Despite having several negative effects, the examined discourses considered the use of ketamine to elevate mood both efficient and worthwhile among individuals dealing with self-reported depressive symptoms. The positive results obtained with ketamine for coping with depressive symptoms, as described by the analyzed reports on Bluelight, are corroborated by a vast scientific literature (4,9,10,13,16,17,21,(25)(26)(27)(28)(29)(30)(31)57,58). ...
Article
Background Because of the shortcomings of traditional pharmacotherapy for major depressive disorder and post-traumatic stress disorder (PTSD), there has been growing interest in the rapid mood-enhancing effect of ketamine. Objectives To analyze what has been posted about ketamine use for dealing with self-reported depression and/or PTSD on one of the biggest international message boards on the internet. Methods Qualitative study with online observation of threaded discussions on Bluelight. In-depth online searches were conducted in 2018. Twenty-nine threads, with a total of 708 units of analysis, were selected and subjected to content analysis, where, via a coding process, the units of analysis were organized into nodes. Results Despite having several negative effects (e.g. dizziness, nausea and inability to talk), the examined discourses suggested that the use of ketamine to elevate mood was both efficient and worthwhile. Intranasal use was the most common route of administration mentioned. We traced how the mood enhancement caused by ketamine is perceived: the loss of pleasure disappears, as well as the depressed mood; the markedly diminished interest in activities vanishes and motivation comes back. From all the posts analyzed, only two reported negative outcomes (i.e. no mood-enhancing effect). The most mentioned adverse event was damage to the urinary bladder and the kidneys in cases of misuse. Conclusion Although online research of user-generated content has its limitations in terms of reliability and validity, the present study adds relevant information on the use of ketamine for managing depression and PTSD, whether this use is done legally or not.
... Interest in using ketamine to treat TRD has increased in the last decade. The long-term beneficial actions of ketamine on the central nervous system are very evident; however, there are not enough studies to discuss the long-term effects of a single ketamine administration on the functioning of neural circuits in MDD [103]. Previous evidence demonstrates that ketamine may increase the expression and synthesis of BDNF [103,104]. ...
... The long-term beneficial actions of ketamine on the central nervous system are very evident; however, there are not enough studies to discuss the long-term effects of a single ketamine administration on the functioning of neural circuits in MDD [103]. Previous evidence demonstrates that ketamine may increase the expression and synthesis of BDNF [103,104]. The antidepressant effects of ketamine were inhibited in mice with BDNF deletion as well as after infusion of an anti-BDNF antibody into the prefrontal cortex [105]. ...
... The antidepressant effects of ketamine were inhibited in mice with BDNF deletion as well as after infusion of an anti-BDNF antibody into the prefrontal cortex [105]. Furthermore, preclinical studies show that ketamine exerts its antidepressant effects by increasing the expression of mammalian rapamycin target protein (mTOR), which modulates cell growth, proliferation, motility, survival, and protein synthesis [103,106]. These observations provide insight into why the decreased levels of BDNF associated with depressive symptoms could be reversed through the rapid actions of ketamine. ...
Article
Full-text available
The prevalence of psychiatric disorders has increased in recent years. Among existing mental disorders, major depressive disorder (MDD) has emerged as one of the leading causes of disability worldwide, affecting individuals throughout their lives. Currently, MDD affects 15% of adults in the Americas. Over the past 50 years, pharmacotherapy, psychotherapy, and brain stimulation have been used to treat MDD. The most common approach is still pharmacotherapy; however, studies show that about 40% of patients are refractory to existing treatments. Although the monoamine hypothesis has been widely accepted as a molecular mechanism to explain the etiology of depression, its relationship with other biochemical phenomena remains only partially understood. This is the case of the link between MDD and inflammation, mitochondrial dysfunction, and oxidative stress. Studies have found that depressive patients usually exhibit altered inflammatory markers, mitochondrial membrane depolarization, oxidized mitochondrial DNA, and thus high levels of both central and peripheral reactive oxygen species (ROS). The effect of antidepressants on these events remains unclear. Nevertheless, the effects of ROS on the brain are well known, including lipid peroxidation of neuronal membranes, accumulation of peroxidation products in neurons, protein and DNA damage, reduced antioxidant defenses, apoptosis induction, and neuroinflammation. Antioxidants such as ascorbic acid, tocopherols, and coenzyme Q have shown promise in some depressive patients, but without consensus on their efficacy. Hence, this paper provides a review of MDD and its association with inflammation, mitochondrial dysfunction, and oxidative stress and is aimed at thoroughly discussing the putative links between these events, which may contribute to the design and development of new therapeutic approaches for patients.
... YH-200 exhibited an anti-immobility effect without the influence of locomotor activity As shown in Figure 2, YH-200 (60 mg/kg, ig) significantly decreased the immobility time of mice in the FST (F (4,45) =9.94, P<0.0001; Figure 2A) and TST (F (4,30) =9.07, P<0.0001; Figure 2B). The OFT showed that YH-200 (15-60 mg/kg, ig) did not influence the locomotor activity of mice (total distance: F (3,36) =0.11, P=0.9560; distance in peripheral area: F (3,36) =0.08, P=0.9721; distance in central area: F (3,36) =0.17, P=0.9140; mean movement speed: F (3,36) =0.11, P=0.9560; Figures 2C and 2D). In the comparison test, YH-200 (60 mg/kg, ig) showed the same potency by prolonging the latency to immobility (F (4,45) =8.75, P<0.0001; Figure 3A) and shortening the immobility time (F (4,45) =22.96, ...
... YH-200 exhibited an anti-immobility effect without the influence of locomotor activity As shown in Figure 2, YH-200 (60 mg/kg, ig) significantly decreased the immobility time of mice in the FST (F (4,45) =9.94, P<0.0001; Figure 2A) and TST (F (4,30) =9.07, P<0.0001; Figure 2B). The OFT showed that YH-200 (15-60 mg/kg, ig) did not influence the locomotor activity of mice (total distance: F (3,36) =0.11, P=0.9560; distance in peripheral area: F (3,36) =0.08, P=0.9721; distance in central area: F (3,36) =0.17, P=0.9140; mean movement speed: F (3,36) =0.11, P=0.9560; Figures 2C and 2D). In the comparison test, YH-200 (60 mg/kg, ig) showed the same potency by prolonging the latency to immobility (F (4,45) =8.75, P<0.0001; Figure 3A) and shortening the immobility time (F (4,45) =22.96, ...
... YH-200 exhibited an anti-immobility effect without the influence of locomotor activity As shown in Figure 2, YH-200 (60 mg/kg, ig) significantly decreased the immobility time of mice in the FST (F (4,45) =9.94, P<0.0001; Figure 2A) and TST (F (4,30) =9.07, P<0.0001; Figure 2B). The OFT showed that YH-200 (15-60 mg/kg, ig) did not influence the locomotor activity of mice (total distance: F (3,36) =0.11, P=0.9560; distance in peripheral area: F (3,36) =0.08, P=0.9721; distance in central area: F (3,36) =0.17, P=0.9140; mean movement speed: F (3,36) =0.11, P=0.9560; Figures 2C and 2D). In the comparison test, YH-200 (60 mg/kg, ig) showed the same potency by prolonging the latency to immobility (F (4,45) =8.75, P<0.0001; Figure 3A) and shortening the immobility time (F (4,45) =22.96, ...
Article
Full-text available
7-O-ethylfangchinoline (YH-200) is a bisbenzylisoquinoline derivative. The aim of this study was to investigate the antidepressant-like action and underlying mechanisms of YH-200 in mice. Mice were treated with YH-200 (15, 30, and 60 mg/kg, ig) or tetrandrine (30 and 60 mg/kg, ig) before conducting forced swimming test (FST), tail suspension test (TST), or open field test (OFT). YH-200 (60 mg/kg) significantly decreased the immobility time in both FST and TST, and prolonged the latency to immobility in FST. YH-200 (60 mg/kg) was more potent than the natural bisbenzylisoquinoline alkaloid tetrandrine (60 mg/kg) in FST. Pretreatment with α1-adrenoceptor antagonist prazosin (1 mg/kg), β-adrenoceptor antagonist propranolol (2 mg/kg), dopamine D1/D5 receptor antagonist SCH23390 (0.05 mg/kg), dopamine D2/D3 receptor antagonist haloperidol (0.2 mg/kg) or AMPA receptor antagonist NBQX (10 mg/kg) prevented the antidepressant-like action of YH-200 (60 mg/kg) in FST. In contrast, pretreatment with α2 adrenoceptor antagonist yohimbine (1 mg/kg) augmented the antidepressant-like action of YH-200 (30 mg/kg) in FST. Chronic administration of YH-200 (30 and 60 mg/kg for 14 d) did not produce drug tolerance; instead its antidepressant-like action was strengthened. Chronic administration of YH-200 did not affect the body weight of mice compared to control mice. YH-200 exerts its antidepressant-like action in mice via acting at multi-targets, including α1, α2 and β-adrenoceptors, D1/D5 and D2 /D3 receptors, as well as AMPA receptors.
... Retrospective clinical analysis (PM surveillances and CD) [13] MDD, BP1 depressive episodes (FA) [8] Aripiprazole NA MDD (FA) [9] Brexpiprazole NA MDD (FA) [35] Mecamylamine Computational molecular docking [23] Depression (SA) [23], MDD (INV) [17,19,20,36,37] Cyproheptadine Computational molecular docking [26] NA Dextromethorphan Computational molecular docking [13] MDD (INV) [38][39][40][41] Pregabalin GWAS [23] MDD (SA) [23] ...
... Gabapentin GWAS [23] MDD (SA) [23] Cycloserine GWAS [23] BP depression (INV) [42], MDD (SA, INV) [23,36] Risperidone GWAS [23] Extrapyramidal symptoms, suicidal ideation (INV) [43] Cannabidiol Pathway or network mapping [21] MDD (SA) [21] N-acetyl-l-cysteine Pathway or network mapping [21] MDD (SA) [21] Sho-saiko-to Pathway or network mapping [21] NA Spermine Pathway or network mapping [21] TRD (SA) [21] Nimodipine Pathway or network mapping [21] Vascular depression in old patients (SA) [ MDD and bipolar depression, Depressive symptoms in adults with MDD with acute suicidal ideation or behavior (FA) [52] Pioglitazone Signature matching (transcriptomic) [13] MDD, a major depressive episode in bipolar disorder (SA) [13] BP ...
Article
Full-text available
A slow rate of new drug discovery and higher costs of new drug development attracted the attention of scientists and physicians for the repurposing and repositioning of old medications. Experimental studies and off-label use of drugs have helped drive data for further studies of approving these medications. A deeper understanding of the pathogenesis of depression encourages novel discoveries through drug repurposing and drug repositioning to treat depression. In addition to reducing neurotransmitters like epinephrine and serotonin, other mechanisms such as inflammation, insufficient blood supply, and neurotoxicants are now considered as the possible involved mechanisms. Considering the mentioned mechanisms has resulted in repurposed medications to treat treatment-resistant depression (TRD) as alternative approaches. This review aims to discuss the available treatments and their progress way during repositioning. Neurotransmitters' antagonists, atypical antipsychotics, and CNS stimulants have been studied for the repurposing aims. However, they need proper studies in terms of formulation, matching with regulatory standards, and efficacy.
... Ketamin verbindet Analgesie und rasche Sedierung in einer Substanz, wobei bei niedriger Dosierung die Analgesie im Vordergrund steht [1,3]. Niedrige Dosis ist in der Literatur häufig definiert mit einem Bolus von weniger als 2 mg/kg intramuskulär oder 1 mg/kg intravenös [10]. Bezogen auf S-(+)-Ketamin ist als Niedrigdosierung maximal die Hälfte der dieser Werte zu empfehlen. ...
... Ungeachtet der dokumentierten Erfolge bleiben noch zahlreiche offene Fragen. Dies betrifft insbesondere die Dosierung sowie Strategien, die eine langfristige antidepressive Behandlung mit Ketamin möglich machen [10,52]. ...
Article
Full-text available
Obwohl Ketamin seit langem bekannt und im klinischen Einsatz ist, bleiben nach wie vor Fragen rund um die vielfältigen möglichen Anwendungsfelder als Anästhetikum und Analgetikum offen. Diese betreffen nicht das klassische Einsatzgebiet in der Notfallmedizin und Anästhesie, sondern auch potentielle, neue Indikationen, in denen Ketamin in niedrigen, subanästhetischen Dosierungen zum Einsatz kommt. Der Wirkmechanismus am NMDA-Rezeptor unterscheidet Ketamin deutlich von allen anderen Analgetika. Mögliche Einsatzgebiete sind Prävention chronischer postoperativer Schmerzen sowie die Behandlung neuropathischer Schmerzen. Mit der Behandlung der refraktären Depression könnte sich Ketamin auch in einem gänzlich neuen Feld etablieren.
... The dose of ketamine can be the major factor responsible for the beneficial or harmful effects of ketamine infusion on cognitive and affective function (Li et al., 2010;Browne and Lucki, 2013;Salvadore and Singh, 2013). Animal studies have shown that only a subanesthetic dose (10 mg/kg), but not an anesthetic dose (80 mg/kg), of intraperitoneal ketamine infusion in rats activated the mTOR pathway and increased hippocampal brain-derived neurotrophic factor (BDNF) levels and synaptogenesis, which contributed to an antidepressant effect (Li et al., 2010;Browne and Lucki, 2013;Salvadore and Singh, 2013). ...
... The dose of ketamine can be the major factor responsible for the beneficial or harmful effects of ketamine infusion on cognitive and affective function (Li et al., 2010;Browne and Lucki, 2013;Salvadore and Singh, 2013). Animal studies have shown that only a subanesthetic dose (10 mg/kg), but not an anesthetic dose (80 mg/kg), of intraperitoneal ketamine infusion in rats activated the mTOR pathway and increased hippocampal brain-derived neurotrophic factor (BDNF) levels and synaptogenesis, which contributed to an antidepressant effect (Li et al., 2010;Browne and Lucki, 2013;Salvadore and Singh, 2013). Studies have supported that BDNF and hippocampal synaptic plasticity play vital roles in cognitive function and memory (Leal et al., 2017;Lu et al., 2014). ...
Article
Background: Clinical and animal studies have reported conflicting results regarding the effect of ketamine on cognitive function, although increasing evidence supports a rapid and sustained antidepressant effect of a subanesthetic dose of ketamine infusion for patients with treatment-resistant depression (TRD). However, the cognitive function before and after ketamine infusion was rarely investigated in patients with TRD. Methods: A total of 71 adult patients with TRD were enrolled and randomized to 0.5-mg/kg ketamine, 0.2-mg/kg ketamine, or normal saline infusion groups. Depressive symptoms were measured using the Hamilton Depression Rating Scale at baseline and at different time points post ketamine infusion. Cognitive function was evaluated using working memory and go/no-go tasks at baseline, Day 3, and Day 14 post ketamine infusion. Results: A single low dose of ketamine infusion did not impair the cognitive function of patients with TRD. The paired t test revealed that patients with TRD receiving 0.5 mg/kg of ketamine infusion exhibited a slight improvement in sustained attention and response control measured using the go/no-go task at Day 14 post ketamine infusion. A significant association was also observed between depressive symptoms and cognitive function changes at Day 3 in the 0.5-mg/kg ketamine infusion group. Discussion: A 0.5 mg/kg dose of ketamine infusion was not harmful, but slightly beneficial, for the cognitive function of patients with TRD. Additional studies are necessary to elucidate the effects of repeated ketamine infusion on cognitive function.
... Although termed as dissociative anesthetic agent, but it has not dissociated itself from the anesthesiologist's shelf. It has been recommended as a core drug (a minimum medical need for a basic health system) by World Health Organization (WHO) on the basis of clinical trials, research statistics, various case reports and also from opinions of experts [2]. The current narrative review aims to highlight these aspects through a short journey from its pharmacological profile to its older and recent indications. ...
... Recently ketamine has re-emerged as an off-label rapid-acting antidepressant in case of severe depression, resistant to other therapies [2]. It has been considered as one of the most exciting developments among antidepressant agents, which has been seen effective in bipolar affective disorders and suicidal ideation etc. ...
Article
Not many drugs in anaesthesiology have gained so much attention as ketamine got for so many years. It has been used worldwide for the last five decades through various routes and for various indications. In its early year of its manufacture, it was considered a wonder or magic drug though the popularity declined with observation of so many side effects coming to the fore through various clinical trials. However, recently its non-anaesthetic properties and anaesthetic profile has re-kindled a newer interest in its pharmacological profile. Here we stand at a new juncture where a possible confluence of its old and recent utilities can make it a drug for future thus revolutionizing its clinical usage in many scenarios. The current narrative review aims to highlight these aspects through a short journey from its pharmacological profile to its older and recent indications.
... Additionally ketamine exhibits weak agonism at the l-opioid and j-opioid receptors, agonism at the D 2 -receptor, antagonism at the mACh receptor, as well as reuptake inhibition of serotonin, dopamine and norepinephrine (Kohrs & Durieux 1998;Bergman 1999). The substance has a blocking effect on voltage-gated sodium channels and L-type calcium channels, NO-synthetase inhibition and is agonist at r receptors 1 and 2, while the importance of additional pharmacologic mechanisms in its antidepressant action is not well understood (Salvadore & Singh 2013). The half-life of ketamine is between 80 and 180 min with predominantly renal elimination, and hepatic conjugation by the CYP3A4-enzyme to it s active but less potent metabolite norketamine (Domino et al. 1982;Hijazi & Boulieu 2002). ...
Article
To the Editor We congratulate Sanacora et al¹ for the publication of their consensus statement in JAMA Psychiatry. The growing amount of literature on this topic has generated interest among patients and physicians, which called for such an important document as the basis for decision-making societies, health care professionals, and regulatory authorities. Until official approval of depression as an indication, off-label uses by medical experts assuming legal, scientific, and medical hazards will increase. On the other hand, ketamine clinics or ketamine wellness centers already offer ketamine as outpatient treatment with unscientific and dangerous methods. To overcome the lack of regulation, consensus statements and their dissemination are of utmost importance.
... The duration and interval statistics of the alternating gamma and slow-delta activities that we estimated for NHP LFP can serve as quantitative constraints in the design of rhythm-generating neuronal microcircuit models that would mimic the neurophysiological dynamics caused by ketamine, similar to ones previously done for other anesthetics [23,24,26,69,70]. Furthermore, since ketamine is also used in treatment of depression [71,72], in pharmacologic models for schizophrenia [20,73,74], and in studies of altered states of consciousness [75], insights into ketamine's effects on brain state dynamics will provide neuroscientific insight beyond the field of anesthesia. ...
Article
Full-text available
Ketamine is an NMDA receptor antagonist commonly used to maintain general anesthesia. At anesthetic doses, ketamine causes high power gamma (25-50 Hz) oscillations alternating with slow-delta (0.1-4 Hz) oscillations. These dynamics are readily observed in local field potentials (LFPs) of non-human primates (NHPs) and electroencephalogram (EEG) recordings from human subjects. However, a detailed statistical analysis of these dynamics has not been reported. We characterize ketamine’s neural dynamics using a hidden Markov model (HMM). The HMM observations are sequences of spectral power in seven canonical frequency bands between 0 to 50 Hz, where power is averaged within each band and scaled between 0 and 1. We model the observations as realizations of multivariate beta probability distributions that depend on a discrete-valued latent state process whose state transitions obey Markov dynamics. Using an expectation-maximization algorithm, we fit this beta-HMM to LFP recordings from 2 NHPs, and separately, to EEG recordings from 9 human subjects who received anesthetic doses of ketamine. Our beta-HMM framework provides a useful tool for experimental data analysis. Together, the estimated beta-HMM parameters and optimal state trajectory revealed an alternating pattern of states characterized primarily by gamma and slow-delta activities. The mean duration of the gamma activity was 2.2s([1.7,2.8]s) and 1.2s([0.9,1.5]s) for the two NHPs, and 2.5s([1.7,3.6]s) for the human subjects. The mean duration of the slow-delta activity was 1.6s([1.2,2.0]s) and 1.0s([0.8,1.2]s) for the two NHPs, and 1.8s([1.3,2.4]s) for the human subjects. Our characterizations of the alternating gamma slow-delta activities revealed five sub-states that show regular sequential transitions. These quantitative insights can inform the development of rhythm-generating neuronal circuit models that give mechanistic insights into this phenomenon and how ketamine produces altered states of arousal.
... The importance of the glutamatergic system in the pathophysiology and therapy of mood disorders (Krystal et al, 2002;Sanacora et al, 2008) has been recently supported by rapid antidepressant effects following a single intravenous subanesthetic dose of ketamine, a non-selective N-methyl-Daspartate (NMDA) receptor antagonist (Berman et al, 2000;Salvadore and Singh, 2013;Zarate et al, 2006). Initial evidence suggests that ketamine acutely increases glutamate release, which leads to enhanced glutamatergic transmission (Maeng et al, 2008) and ultimately results in increased synaptic plasticity and synaptogenesis (Duman and Li, 2012). ...
Article
The anterior cingulate cortex (ACC) has shown decreased glutamate levels in patients with major depressive disorder (MDD). Subanesthetic doses of ketamine were repeatedly shown to improve depressive symptoms within 24 h after infusion and this antidepressant effect was attributed to increased AMPA throughput. To elucidate ketamine's mechanism of action, we tested if the clinical time course of the improvement is mirrored by the change of glutamine/glutamate ratio and if such effects show a regional and temporal specificity in two distinct subdivisions of ACC with different AMPA/NMDA receptor profiles. In a double-blind, placebo-controlled intravenous infusion study of ketamine, we measured glutamate and glutamine in the pregenual ACC (pgACC) and the anterior midcingulate cortex (aMCC) at 1 and 24 h post-infusion with magnetic resonance spectroscopy at 7 Tesla. A significant interaction of time, region, and treatment was found for the glutamine/glutamate ratios (placebo, n=14; ketamine, n=12). Post-hoc analyses revealed that the glutamine/glutamate ratio increased significantly in the ketamine group, compared to placebo specifically in the pgACC after 24 h. The glutamine/glutamate increase in the pgACC caused by ketamine at 24 h post-infusion was reproduced in an enlarged sample (placebo, n=24; ketamine, n=20). Our results support a significant temporal and regional response in glutamine/glutamate ratios to a single subanesthetic dose of ketamine, which mirrors the time-course of the antidepressant response and reversal of the molecular deficits in patients and which may be associated with the histoarchitectonical receptor fingerprints of the ACC subregions.Neuropsychopharmacology accepted article preview online, 08 September 2016. doi:10.1038/npp.2016.184.
... Additionally ketamine exhibits weak agonism at the l-opioid and j-opioid receptors, agonism at the D 2 -receptor, antagonism at the mACh receptor, as well as reuptake inhibition of serotonin, dopamine and norepinephrine (Kohrs & Durieux 1998;Bergman 1999). The substance has a blocking effect on voltage-gated sodium channels and L-type calcium channels, NO-synthetase inhibition and is agonist at r receptors 1 and 2, while the importance of additional pharmacologic mechanisms in its antidepressant action is not well understood (Salvadore & Singh 2013). The half-life of ketamine is between 80 and 180 min with predominantly renal elimination, and hepatic conjugation by the CYP3A4-enzyme to it s active but less potent metabolite norketamine (Domino et al. 1982;Hijazi & Boulieu 2002). ...
Article
Full-text available
Objective: Clinical trials demonstrated that ketamine exhibits rapid antidepressant efficacy when administered in subanaesthetic dosages. We reviewed currently available literature investigating efficacy, response rates and safety profile. Methods: Twelve studies investigating unipolar, seven on bipolar depression were included after search in medline, scopus and web of science. Results: Randomized, placebo-controlled or open-label trials reported antidepressant response rates after 24 h on primary outcome measures at 61%. The average reduction of Hamilton Depression Rating Scale (HAM-D) was 10.9 points, Beck Depression Inventory (BDI) 15.7 points and Montgomery-Asberg Depression Rating Scale (MADRS) 20.8 points. Ketamine was always superior to placebo. Most common side effects were dizziness, blurred vision, restlessness, nausea/vomiting and headache, which were all reversible. Relapse rates ranged between 60% and 92%. To provide best practice-based information to patients, a consent-form for application and modification in local language is included. Conclusions: Ketamine constitutes a novel, rapid and efficacious treatment option for patients suffering from treatment resistant depression and exhibits rapid and significant anti-suicidal effects. New administration routes might serve as alternative to intravenous regimes for potential usage in outpatient settings. However, long-term side effects are not known and short duration of antidepressant response need ways to prolong ketamine's efficacy.
... Scientific RepoRts | 6:33401 | DOI: 10.1038/srep33401 whereas conventional antidepressants take several weeks for the therapeutic onset 11 . However, antidepressant effects of ketamine have been found to be short-lived 12 and psychotomimetic properties associated with pan NMDA antagonism have been a major concern for long term clinical use of ketamine. ...
Article
Full-text available
Psychotomimetic and prodepressive effect by kappa opioid receptor (KOR) activation in rodents and human is widely known. Significantly, recent clinical investigations demonstrated the salutary effects of KOR antagonists in patients with treatment resistant depression, indicating essential role of KOR signaling in refractory depression. This study was undertaken to reveal the molecular determinant of KOR mediated depression and antidepressant response of KOR antagonist. We observed that chronic KOR activation by U50488, a selective KOR agonist, significantly increased depression like symptoms (behavioral despair, anhedonia and sociability) in C57BL/6J mice, which were blocked by KOR antagonist norBNI and antidepressant imipramine, but not by fluoxetine or citalopram. Further, chronic KOR activation increased phosphorylation of NR2B subunit of NMDA at tyrosine 1472 (pNR2B NMDA) in the hippocampus, but not in the cortex. Similar to behavioral effects norBNI and imipramine, but not SSRIs, blocked NR2B phosphorylation. Moreover, KOR induced depression like behaviors were reversed by NR2B selective inhibitor Ro 25-6981. Mechanistic studies in primary cultured neurons and brain tissues using genetic and pharmacological approaches revealed that stimulation of KOR modulates several molecular correlates of depression. Thus, these findings elucidate molecular mechanism of KOR signaling in treatment resistant depression like behaviors in mice.
... [65,66] Ketamine at low doses has been found to act rapidly and therefore especially useful for treating resistant depression. [67] Ketamine exerts its anaesthetic actions through non-competitive blockade of N-methyl-D-aspartate glutamate receptors. [68] On the other hand, ketamine metabolites hydroxynorketamines per se were found to mediate its antidepressant effects through activation of a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, [69] paying attention to glutamate receptors as a promising drug target for developing novel rapidly acting antidepressant drugs. ...
Article
Objectives: The breakthrough advancements in scientific medical research have greatly improved our understanding of the pathogenesis of depression, encouraging drug discoverers to take a shorter path than ever through drug repurposing to generate new antidepressant medications. In addition to reduced noradrenergic and serotonergic neurotransmission in the brain, other coincidence features such as glutamate neurotoxicity, inflammation and/or cerebrovascular insufficiency are implicated in the pathogenesis of major depressive disorder and late-life depression. This short review discusses the progress made in repurposing drugs for antidepressant actions. Key findings: Drugs being repurposed as antidepressants act on novel drug targets, thereby treating resistant depression and improving remission rate. Drugs such as ketamine, dextromethorphan/quinidine and scopolamine are rapidly acting antidepressants targeting glutamate receptors. Nimodipine and quetiapine are efficient add-on therapy for late-life depression. Anti-inflammatory drugs, statins, insulin sensitizers, minocycline could remarkably contribute to treating refractory depression. Summary: Drug repurposing represents an alternative approach to cope with major obstacles, including financial insufficiency and unavoidable long lag evaluation time, undermining the classical pathway of developing new hit compounds into clinically approved antidepressants.
... While ketamine has emerged as a prototypical glutamatergic antidepressant, its utility as a viable long-term antidepressant agent is less clear. The drug's adverse effect profile, oral bioavailability, and duration of antidepressant action are less than ideal, and it has potential for abuse (Salvadore and Singh, 2013). However, its rapid antidepressant effects and potential for efficacy in treatment-refractory disease have led to intense investigation of drugs with ketamine-like pharmacology. ...
... The other thing I want to mention just getting back to the DSM-V criteria is that they require you to have SAD only if there's complete remission or hypomania in the summer whereas many, many people with SAD do not completely return to a normal mood in the summer time. You can comment on this maybe, Jennifer, but a lot of people 119 See, for example, Salvadore and Singh (2013); Browne and Lucki (2013). 120 See, for example, Parry et al. (1987). ...
... (Berman et al. 2000). With this standard protocol, the dissociative effects of ketamine typically persist until 80 minutes post-infusion and are thought to arise during the slow dissociation of ketamine from the NMDA channel (Pochwat et al. 2014 Several other studies have documented the dissociative and/or mild psychotomimetic effects of ketamine under this protocol as measured by changes in the CADSS and BPRS scores (Zarate et al. 2006a, Salvadore and Singh 2013, Diazgranados et al. 2010, Murrough et al. 2013a, Murrough et al. 2013b, Loo et al. 2012, Carlson et al. 2013, Sos et al. 2013, Lapidus et al. 2014. For example, Zarate et al. (2006a) observed a significant increase in BPRS scores (p=0.04) after an IV infusion of 0.5mg/kg ketamine over 40 minutes between ketamine and placebo groups at 40 minutes in 18 subjects with TRD. ...
Article
OBJECTIVES: Replicated evidence has demonstrated that ketamine exerts rapid-acting and potent antidepressant effects. Notwithstanding, its promise to mitigate depressive symptoms and suicidality in antidepressant-resistant populations, several limitations and safety concerns accompany ketamine including, but not limited to, the potential for abuse and psychotomimetic/dissociative experiences. The focus of the current narrative review is to synthesize available evidence of strategies that may mitigate and fully prevent treatment emergent psychotomimetic and dissociative effects associated with ketamine administration. METHODS: PubMed, Google Scholar and ClinicalTrials.gov were searched for relevant articles. RESULTS: Potential avenues investigated to minimize psychotomimetic effects associated with ketamine administration include the following: 1) altering dosing and infusion rates; 2) route of administration; 3) enantiomer choice; 4) co-administration with mood stabilizers of antipsychotics; and 5) use of alternative NMDA modulating agents. Emerging evidence indicates that dissociative experiences can be significantly mitigated by using an intranasal route of administration, lower dosages, or use of alternative NMDA modulating agents, namely lanicemine (AZD6765) and GLYX-13. CONCLUSIONS: Currently, intranasal administration presents as the most promising strategy to mitigate dissociative and psychotomimetic effects; however, studies of strategies to mitigate the adverse events of ketamine are limited in number and quality and thus further investigation is still needed.
... However, a debate is ongoing as to whether it is the direct actions of ketamine at the phencyclidine site on the NMDA receptor that account for its actions, or the downstream stimulation of AMPA receptors [8] . Ketamine works incredibly fast, lifting depres sion in as little as two hours, which is unlike conven tional anti-depressants that generally take weeks to start working [84,85] . npg tomography (PET) on 21 subjects with bipolar disorder in a depressed state showed a distinct change in metabolism in the subgenual anterior cingulate cortex, which may explain the anti-depressant response to ketamine [86] . ...
Article
Full-text available
After nearly half a century on the market, ketamine still occupies a unique corner in the medical armamentarium of anesthesiologists or clinicians treating pain. Over the last two decades, much research has been conducted highlighting the drug's mechanisms of action, specifically those of its enantiomers. Nowadays, ketamine is also being utilized for pediatric pain control in emergency department, with its anti-hyperalgesic and anti-inflammatory effects being revealed in acute and chronic pain management. Recently, new insights have been gained on ketamine's potential anti-depressive and antisuicidal effects. This article provides an overview of the drug's pharmacokinetics and pharmacodynamics while also discussing the potential benefits and risks of ketamine administration in various clinical settings.
... It is believed to improve glutamatergic transmission through the increased release of glutamate. 66,67 Hypofunction of the NMDAR in schizophrenia could involve a range of insufficiencies including that of the primary ligand glutamate, its binding partner glycine or D-serine or it may be that densities of actual functional receptors in this disorder are unusually sparse. In order for the correct pharmacological treatment to be clinically tested and developed, however, the appropriate patient population afflicted by an NMDAR pathology needs to be identified. ...
Article
Full-text available
Autoantibodies that bind the N-methyl-D-aspartate receptor (NMDAR) may underlie glutamate receptor hypofunction and related cognitive impairment found in schizophrenia. Exposure to neurotropic pathogens can foster an autoimmune-prone environment and drive systemic inflammation leading to endothelial barrier defects. In mouse model cohorts, we demonstrate that infection with the protozoan parasite, Toxoplasma gondii, caused sustained elevations of IgG class antibodies to the NMDAR in conjunction with compromised blood–gut and blood–brain barriers. In human cohorts, NMDAR IgG and markers of barrier permeability were significantly associated with T. gondii exposure in schizophrenia compared with controls and independently of antipsychotic medication. Combined T. gondii and NMDAR antibody seropositivity in schizophrenia resulted in higher degrees of cognitive impairment as measured by tests of delayed memory. These data underscore the necessity of disentangling the heterogeneous pathophysiology of schizophrenia so that relevant subsets eligible for NMDAR-related treatment can be identified. Our data aid to reconcile conflicting reports regarding a role of pathological NMDAR autoantibodies in this disorder.
... 11 Several studies have shown antidepressant efficacy with the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine. [12][13][14][15][16][17] One limitation of ketamine for treating depression is that it may require intravenous administration, reducing its applicability in outpatient settings. ...
Article
Full-text available
Importance Approximately one-third of patients with major depressive disorder (MDD) do not respond to available antidepressants. Objective To assess the efficacy, safety, and dose-response of intranasal esketamine hydrochloride in patients with treatment-resistant depression (TRD). Design, Setting, and Participants This phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study was conducted in multiple outpatient referral centers from January 28, 2014, to September 25, 2015. The study consisted of 4 phases: (1) screening, (2) double-blind treatment (days 1-15), composed of two 1-week periods, (3) optional open-label treatment (days 15-74), and (4) posttreatment follow-up (8 weeks). One hundred twenty-six adults with a DSM-IV-TR diagnosis of MDD and history of inadequate response to 2 or more antidepressants (ie, TRD) were screened, 67 were randomized, and 60 completed both double-blind periods. Intent-to-treat analysis was used in evaluation of the findings. Interventions In period 1, participants were randomized (3:1:1:1) to placebo (n = 33), esketamine 28 mg (n = 11), 56 mg (n = 11), or 84 mg (n = 12) twice weekly. In period 2, 28 placebo-treated participants with moderate-to-severe symptoms were rerandomized (1:1:1:1) to 1 of the 4 treatment arms; those with mild symptoms continued receiving placebo. Participants continued their existing antidepressant treatment during the study. During the open-label phase, dosing frequency was reduced from twice weekly to weekly, and then to every 2 weeks. Main Outcomes and Measures The primary efficacy end point was change from baseline to day 8 (each period) in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Results Sixty-seven participants (38 women, mean [SD] age, 44.7 [10.0] years) were included in the efficacy and safety analyses. Change (least squares mean [SE] difference vs placebo) in MADRS total score (both periods combined) in all 3 esketamine groups was superior to placebo (esketamine 28 mg: −4.2 [2.09], P = .02; 56 mg: −6.3 [2.07], P = .001; 84 mg: −9.0 [2.13], P < .001), with a significant ascending dose-response relationship (P < .001). Improvement in depressive symptoms appeared to be sustained (−7.2 [1.84]) despite reduced dosing frequency in the open-label phase. Three of 56 (5%) esketamine-treated participants during the double-blind phase vs none receiving placebo and 1 of 57 participants (2%) during the open-label phase had adverse events that led to study discontinuation (1 event each of syncope, headache, dissociative syndrome, and ectopic pregnancy). Conclusions and Relevance In this first clinical study to date of intranasal esketamine for TRD, antidepressant effect was rapid in onset and dose related. Response appeared to persist for more than 2 months with a lower dosing frequency. Results support further investigation in larger trials. Trial Registration clinicaltrials.gov identifier: NCT01998958
... However, a debate is ongoing as to whether it is the direct actions of ketamine at the phencyclidine site on the NMDA receptor that account for its actions, or the downstream stimulation of AMPA receptors [8] . Ketamine works incredibly fast, lifting depres sion in as little as two hours, which is unlike conven tional anti-depressants that generally take weeks to start working [84,85] . npg tomography (PET) on 21 subjects with bipolar disorder in a depressed state showed a distinct change in metabolism in the subgenual anterior cingulate cortex, which may explain the anti-depressant response to ketamine [86] . ...
Data
Full-text available
After nearly half a century on the market, ketamine still occupies a unique corner in the medical armamentarium of anesthesiologists or clinicians treating pain. Over the last two decades, much research has been conducted highlighting the drug’s mechanisms of action, specifically those of its enantiomers. Nowadays, ketamine is also being utilized for pediatric pain control in emergency department, with its anti-hyperalgesic and anti-inflammatory effects being revealed in acute and chronic pain management. Recently, new insights have been gained on ketamine’s potential anti-depressive and antisuicidal effects.
... In a similar vein, the NMDA receptor antagonist ketamine abrogates LPS-induced depression-like behavior without affecting the sickness response (192). Ketamine is able to induce rapid antidepressant effects in patients with treatment-refractory depression, highlighting the potential of targeting glutamatergic neurotransmission as a treatment option for depressive disorders (193). The sickness behavior evoked by immune stimulation comprises anorexia, a response in which IL-18 plays a role through inhibition of type III GABAergic neurons in the bed nucleus of the stria terminalis (194). ...
Article
Full-text available
Stress refers to a dynamic process in which the homeostasis of an organism is challenged, the outcome depending on the type, severity, and duration of stressors involved, the stress responses triggered, and the stress resilience of the organism. Importantly, the relationship between stress and the immune system is bidirectional, as not only stressors have an impact on immune function, but alterations in immune function themselves can elicit stress responses. Such bidirectional interactions have been prominently identified to occur in the gastrointestinal tract in which there is a close cross-talk between the gut microbiota and the local immune system, governed by the permeability of the intestinal mucosa. External stressors disturb the homeostasis between microbiota and gut, these disturbances being signaled to the brain via multiple communication pathways constituting the gut–brain axis, ultimately eliciting stress responses and perturbations of brain function. In view of these relationships, the present article sets out to highlight some of the interactions between peripheral immune activation, especially in the visceral system, and brain function, behavior, and stress coping. These issues are exemplified by the way through which the intestinal microbiota as well as microbe-associated molecular patterns including lipopolysaccharide communicate with the immune system and brain, and the mechanisms whereby overt inflammation in the GI tract impacts on emotional-affective behavior, pain sensitivity, and stress coping. The interactions between the peripheral immune system and the brain take place along the gut–brain axis, the major communication pathways of which comprise microbial metabolites, gut hormones, immune mediators, and sensory neurons. Through these signaling systems, several transmitter and neuropeptide systems within the brain are altered under conditions of peripheral immune stress, enabling adaptive processes related to stress coping and resilience to take place. These aspects of the impact of immune stress on molecular and behavioral processes in the brain have a bearing on several disturbances of mental health and highlight novel opportunities of therapeutic intervention.
... The slow onset and moderate degrees of receptor occupancy could largely be used to avoid the anesthesia effect, dissociation and psychotomimetic reactions [38]. Ketamine works incredibly fast, lifting depression in less than two hours, which is unlike conventional antidepressants that generally take weeks to work [39,40]. A systematic review also showed ketamine to be a rapid and effective treatment option for depression, as well as reducing suicidal ideation, with minimal short-term side effects [41]. ...
Article
Initially known as CI-581, ketamine was first synthesized in 1962 as a replacement for phencyclidine (PCP). It is being used since then as a profound anesthetic and analgesic, in addition has bronchodilating, sedative and amnestic properties with the preservation of airway reflexes and sympathetic nervous system tone. Ketamine is always a stimulating topic of discussion since its discovery as the controversies regarding its usage in certain set of patients mostly overpowers its boon. In past 50 years, despite of potential benefits it has not gained acceptable popularity because of concerns of "emergence phenomenon", its use as substance of abuse and systemic side effects. Since 2012, ketamine has been subject to three World Health Organization (WHO) reviews addressing its international control. Researchers are widely studying this wonder drug since a decade worldwide. Many myths of ketamine regarding emergence phenomenon, its use in traumatic brain injury, open eye injury is getting busted in recent times. It's again getting popular in pre-hospital settings, critical care, emergency medicine, low dose acute pain services & adjuvant in regional anesthesia techniques. This review will highlight the current consensus on the various applications of ketamine in the light of available evidence in the literature.
... Thus far, these studies have not accounted for the considerable cytoarchitectonic and functional variation between areas that comprise this region. The pgACC is part of the default mode network (DMN) of the human brain and has been implicated in the pathophysiology of depression (Salvadore and Singh, 2013). Previous work suggests altered glutamatergic metabolism in the pgACC in patients with major depressive disorder (MDD; Walter et al., 2009;Horn et al., 2010;Colic et al., 2019) and pgACC levels of a marker of glutamatergic metabolism (glutamate 1 glutamine) were correlated with FC between pgACC and insula in patients but not in healthy control subjects (Horn et al., 2010). ...
Article
Local measures of neurotransmitters provide crucial insights into neurobiological changes underlying altered functional con-nectivity in psychiatric disorders. However, noninvasive neuroimaging techniques such as magnetic resonance spectroscopy (MRS) may cover anatomically and functionally distinct areas, such as p32 and p24 of the pregenual anterior cingulate cortex (pgACC). Here, we aimed to overcome this low spatial specificity of MRS by predicting local glutamate and GABA based on functional characteristics and neuroanatomy in a sample of 88 human participants (35 females), using complementary machine learning approaches. Functional connectivity profiles of pgACC area p32 predicted pgACC glutamate better than chance (R 2 = 0.324) and explained more variance compared with area p24 using both elastic net and partial least-squares regression. In contrast, GABA could not be robustly predicted. To summarize, machine learning helps exploit the high resolution of fMRI to improve the interpretation of local neurometabolism. Our augmented multimodal imaging analysis can deliver novel insights into neurobiology by using complementary information. Magnetic resonance spectroscopy (MRS) measures local glutamate and GABA noninvasively. However, conventional MRS requires large voxels compared with fMRI, because of its inherently low signal-to-noise ratio. Consequently, a single MRS voxel may cover areas with distinct cytoarchitecture. In the largest multimodal 7 tesla machine learning study to date, we overcome this limitation by capitalizing on the spatial resolution of fMRI to predict local neurotransmitters in the PFC. Critically, we found that prefrontal glutamate could be robustly and exclusively predicted from the functional connectivity fingerprint of one of two anatomically and functionally defined areas that form the pregenual anterior cingulate cortex. Our approach provides greater spatial specificity on neurotransmitter levels, potentially improving the understanding of altered functional connectivity in mental disorders.
... [75] Ketamine quickly effects, reducing depression within 2 h, while other conventional antidepressants require weeks to effect. [76,77] Several case studies also found similar results, stating that the intravenous administration of subanesthetic ketamine resulted in antidepressant effects about a few hours, and remained for 4 to 7 days after administration. [78,79] Ketamine has a great potential to be used for treatment-resistant depression; however, additional studies are needed on its mechanism of action, of action, long-term and the adverse effects. ...
Article
Full-text available
Ketamine is considered as a promising drug for many clinical applications even after five decades since its discovery. Ketamine is a dissociative anesthetic agent with a variety of pharmacological effects from anesthetic induction and maintenance to analgesic and sedative depending on the consuming dose. It can be used solely or in combination with other co-adjuvant drugs, increasing their efficacy. Many therapeutic properties of ketamine have been attributed to its antagonism mechanism to N-Methyl-D-aspartate receptor. Identifying new properties of ketamine such as neuroprotective, antiinflammatory, and antitumor effects, on one hand, and taking advantage of subanesthetic regimens of ketamine, on the other hand, have resulted in a widespread use of ketamine in various clinical applications. Ketamine is solvable in aqueous and lipid solutions, providing convenient administration via multiple routes, including oral, nasal, rectal, intravenous, intramuscular, subcutaneous, transdermal, sublingual, and intraosseous administration. Application of ketamine has some advantages over other sedative and anesthetic agents. It produces bronchodilation status, allowing for most secure induction of anesthesia in patients with life-threatening asthma and intense acute bronchial constriction. Ketamine has an excellent hemodynamic profile, makes it the agent of choice for patients with unstable hemodynamics, such as shocked or hypotensive patients. Ketamine usage has been associated with a lower risk of respiratory depression and relatively more conserved airway reflexes. Although being an anesthetic agent, ketamine has been increasingly used in subanesthetic doses for acute and chronic pain as well as depression. Using ketamine in pre and postoperative pain management is well established. However, the studies on ketamine performance in pain management demonstrated contradicting results. On the other hand, various side effects along with no confirmatory data on long-term treatment demand great caution when using ketamine for treating complex chronic pains. The present study aimed to provide a general review on the recent applications of ketamine in anesthesia, pain management, and critical care.
... It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.02.26.966259 doi: bioRxiv preprint 4 brain and has been implicated in the pathophysiology of depression (Salvadore & Singh, 2013). ...
Preprint
Full-text available
Local measures of neurotransmitters provide crucial insights into neurobiological changes underlying altered functional connectivity in psychiatric disorders. However, non-invasive neuroimaging techniques such as magnetic resonance spectroscopy (MRS) may cover anatomically and functionally distinct areas, such as p32 and p24 of the pregenual anterior cingulate cortex (pgACC). Here, we aimed to overcome this low spatial specificity of MRS by predicting local glutamate and GABA based on functional characteristics and neuroanatomy, using complementary machine learning approaches. Functional connectivity profiles of pgACC area p32 predicted pgACC glutamate better than chance (R ² = .324) and explained more variance compared to area p24 using both elastic net and partial least squares regression. In contrast, GABA could not be robustly predicted. To summarize, machine learning helps exploit the high resolution of fMRI to improve the interpretation of local neurometabolism. Our augmented multimodal imaging analysis can deliver novel insights into neurobiology by using complementary information.
... [7] Over the past two decades, several studies have investigated the additional antidepressant and anti-inflammatory effects of ketamine. [7][8][9] The appeal of ketamine in the clinical setting is its versatility as a result of its unique ability to induce three clinical outcomes, i.e. narcosis, analgesia and amnesia. There is currently no other medicine used in clinical practice that can provide these three effects simultaneously. ...
Article
Full-text available
South Africa (SA) has a high incidence of deaths from trauma and injuries. Trauma has been identified as one part of the quadruple burden of disease afflicting the country. This article is concerned with the management of burns, which 3% of the population suffer from annually. Ketamine, acknowledged for its versatility and safety profile, remains a critical component in the medical arsenal of anaesthesiologists and clinicians treating both acute and chronic pain. In the management of burn-injured patients in particular, ketamine is the cornerstone of many analgesia protocols. However, issues pertaining to shortages of this medicine in SA warrant concern and discussion, particularly in view of the high reliance of doctors on ketamine for first-line procedural analgesia in the management of burns in both adult and paediatric patients. This article attempts to highlight the issues related to ketamine shortages, which often have significant clinical, safety, operational and research implications.
... Furthermore, ketamine, at sub-anaesthetic doses, has also been shown to produce good analgesia in patients experiencing neuropathic pain (Lynch et al., 2005), a condition that is particularly hard to treat effectively with other agents. In addition to this, recent evidence has shown intravenous and intranasal ketamine administration to produce rapid antidepressant effects in populations of depressed patients that have not responded to other treatments for depression (Krystal 2007;Salvadore and Singh, 2013;Young, 2013). ...
Conference Paper
Aim: To explore the effects of sub-anaesthetic intravenous infusions of ketamine compared to lidocaine in chronic neuropathic pain patients. The study examined the effects of ketamine treatment on mood, subjective drug effects and pain. The association between pain and mood was also evaluated. Method: A between subject’s design was used to compare patients receiving ketamine treatment (n=24) with a control group receiving lidocaine treatment (n=34) over four-time points (baseline, mid-infusion, post-infusion and one-week follow-up). Mood was assessed using the Hospital Anxiety and Depression Scale (HADS), Patient Health Questionnaire-2 (PHQ-2) and an 11-point Numerical Rating Scale (NRS). Pain was assessed over three indices (intensity, distress and interference) using 11-point NRS and similar scales were used for patient ratings of subjective drug effects. Results: Both ketamine and lidocaine treatments yielded similar reductions in pain intensity at the one-week follow-up. Ketamine provided a greater reduction in pain intensity during the infusion. Subjective drug effect scales indicated that the ketamine treatment group felt significantly higher, felt a stronger sensation of drug effect, and liked the drug effect more than the lidocaine group. Data from mood measures were inconclusive. PHQ-2 and depression NRS showed reductions in scores of depression at the one-week follow-up for both treatment groups. However, HADS depression scores showed no significant differences. HADS anxiety data indicated that both ketamine and lidocaine groups showed significant reductions in anxiety at one-week follow-up. Further correlational analysis indicated a relationship between a reduction in both pain intensity and interference scores (baseline and one-week follow-up) with a reduction in HADS anxiety scores for the ketamine treatment group. Conclusion: The findings support previous literature showing the efficacy of ketamine treatment for chronic neuropathic pain. Results indicated that participants experienced the acute reinforcing effects of ketamine (feeling high and liking the drug effect) but did not want more of the drug. This may indicate a reduced abuse potential in the chronic pain population. Findings also indicated that ketamine did not produce anti-depressant effects in patients with chronic neuropathic pain. Therefore, that the rapid-acting anti-depressant effects found in populations of treatment-resistant depressed patients may not extend to those with chronic pain.
... This agent is being used increasingly for the treatment of refractory chronic CRPS, where several day infusions are a common method of administration [5][6][7][8] ; however, neither the basis for the drug's effects in CRPS nor its efficacy at different stages of the syndrome is clearly defined at this point. Ketamine has been shown to have antidepressive effects in rodents 9 and is increasingly being used in patients with refractory depression and anxiety, 10,11 symptoms commonly co-occurring with CRPS. Furthermore, in a clinical setting, chronic ketamine treatment in patients with CRPS has been associated with improvement in motor function 12 and the reversal of the "pain brain" state, compared with that in control subjects, suggesting central sites of action. ...
Article
Full-text available
Background: Complex regional pain syndrome (CRPS) is a painful, disabling, and often chronic condition, where many patients transition from an acute phase with prominent peripheral neurogenic inflammation to a chronic phase with evident central nervous system changes. Ketamine is a centrally acting agent believed to work through blockade of N-methyl-D-aspartate receptors and is being increasingly used for the treatment of refractory CRPS, although the basis for the drug's effects and efficacy at different stages of the syndrome remains unclear. Methods: The authors used a mouse model of CRPS (n = 8 to 12/group) involving tibia fracture/cast immobilization to test the efficacy of ketamine (2 mg kg day; 7 days) or vehicle infusion during acute (3 weeks after fracture) and chronic (7 weeks after fracture) stages. Results: Acute-phase fracture mice displayed increased limb temperature, edema, and nociceptive sensitization that were not reduced by ketamine. Fracture mice treated with ketamine during the chronic phase showed reduced nociceptive sensitization that persisted beyond completion of the infusion. During this chronic phase, ketamine also reduced latent nociceptive sensitization and improved motor function at 18 weeks after fracture. No side effects of the infusions were identified. These behavioral changes were associated with altered spinal astrocyte activation and expression of pain-related proteins including N-methyl-D-aspartate receptor 2b, Ca/calmodulin-dependent protein kinase II, and brain-derived neurotrophic factor. Conclusions: Collectively, these results demonstrate that ketamine is efficacious in the chronic, but not acute, stage of CRPS, suggesting that the centrally acting drug is relatively ineffective in early CRPS when peripheral mechanisms are more critical for supporting nociceptive sensitization.
... To see how addiction could develop, consider the properties of ketamine. Ketamine has high first past metabolism [46] and a short half-life (3 h) [47]. Ketamine does not maintain acute mood elevations, therefore, patients can crash into depressive states shortly after stopping use [39]. ...
Article
Full-text available
Depressive disorders are a common form of psychiatric illness and cause significant disability. Regulation authorities, the medical profession and the public require high safety standards for antidepressants to protect vulnerable psychiatric patients. Ketamine is a dissociative anaesthetic and a derivative of a hallucinogen (phencyclidine). Its abuse is a major worldwide public health problem. Ketamine is a scheduled drug and its usage is restricted due to its abuse liability. Recent clinical trials have reported that ketamine use led to rapid antidepressant effects in patients suffering from treatment-resistant depression. However, various flaws in study designs, and possible biased reporting of results, may have influenced those findings. Further analyses of ketamine use are needed to ensure patient safety. The use of ketamine in research and treatment of depressive disorders is controversial. Recently, mental health professionals raised ethical concerns about an ongoing ketamine trial in the UK. Also, a Canadian agency reviewed the existing evidence and did not recommend prescribing ketamine to treat depressive disorders. Findings obtained from tightly controlled research settings cannot be easily translated to clinical practice as substance abuse is commonly comorbid with depressive disorders. An effective antidepressant should reduce severity of depressive symptoms without liability problems. Although the US FDA has not approved the use of ketamine to treat depressive disorders, some psychiatrists offer off-label repeat prescription of ketamine. Prescribing ketamine for treating depressive disorders requires substantial empirical evidence. Clinicians should also consider research findings on ketamine abuse. Depressive disorders can be chronic conditions and the current evidence does not rule out the risk of substance abuse after repeat prescription of ketamine. Off-label ketamine use in treating depressive disorders may breach ethical and moral standards, especially in countries seriously affected by ketamine abuse. This article presents two real-world clinical vignettes which highlight ethical principles and theories, including autonomy, nonmaleficience, fidelity and consequentialism, as related to off-label ketamine use. We urge clinicians to minimise the risk of harming patients by considering the empirical evidence on ketamine properties and attempting all standard antidepressant therapies before considering the off-label use of ketamine.
... These findings suggest that factors suppressing NMDA neurotransmission may play a key role in inducing rapid antidepressant efficacy. On the other hand, amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) signaling was found to be required for the fast antidepressant effect of ketamine (Salvadore and Singh 2013). Instant and lasting up-regulated expressions of GluA1 (GluR1) as well as other synaptic proteins in prefrontal cortex have been suggested crucial for the rapid and lasting antidepressant effects of ketamine (Li et al. 2010). ...
Article
Full-text available
Accumulating evidence indicated that N-methyl-d-aspartate (NMDA) receptors are involved in the pathophysiology of depression and implicated in therapeutic targets. NMDA antagonists, such as ketamine, displayed fast-onset and long-lasting antidepressant activity in preclinical and clinical studies. Previous studies showed that Yueju pill exerts antidepressant effects similar to ketamine. Here, we focused on investigating the association of acute and lasting antidepressant responses of Yueju with time course changes of NMDA receptor subunits NR1, NR2A, and NR2B expressions in the hippocampus, a key region regulating depression response. As a result, Yueju reduced immobility time in the forced swimming test from 30 min to 5 days post a single administration. Yueju acutely decreased NR1 and NR2B protein expression in the hippocampus, with NR2A expression unaltered. NR1 expression remained down-regulated 5 days post Yueju administration, whereas NR2B returned to normal level in 24 h. Yueju and ketamine similarly ameliorated the depression-like symptoms at least for 72 h in learned helplessness test. They both reversed the up-regulated expression of NR1 in the learned helpless mice 1 or 3 days post administration. Different from ketamine, the antidepressant effects of Yueju were not influenced by blockade of amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor. These findings served as preclinical evidence that Yueju may confer acute and long-lasting antidepressant effects by favorably modulating NMDA function in the hippocampus.
Article
The concept of psychiatric diagnosis is discussed with a historical perspective, leading to a modern final common pathway model. In this model, gene x meme x brain x environment interaction through development results in multiple pathways to psychiatric syndromes. Evaluation and management of such final common pathways syndromes are discussed.
Article
Antidepressant drugs remain poorly understood, especially with respect to pharmacological mechanisms of action. This lack of knowledge results from the extreme complexity inherent to psychopharmacology, as well as to a corresponding lack of knowledge regarding depressive disorder pathophysiology. While the final analysis is likely to be multifactorial and heterogeneous, compelling evidence exists for upregulation of brain α2 adrenergic receptors (ARs) in depressed patients. This evidence has sparked a line of research into actions of a particular antidepressant drug class, the tricyclic antidepressants (TCAs), as direct ligands at α2AARs. Our findings, as outlined herein, demonstrate that TCAs function as arrestin-biased ligands at α2AARs. Importantly, TCA-induced α2AAR/arrestin recruitment leads to receptor endocytosis and downregulation of α2AAR expression with prolonged exposure. These findings represent a novel mechanism linking α2AR trafficking with antidepressant pharmacology. © 2015 Elsevier Inc. All rights reserved.
Article
Mood is a continuum, with one end representing feeling down, blue, sad, miserable, depressed, or down in the dumps; the middle representing euthymia; and the other end representing feeling happy, high, joyous, euphoric, elated, exulted, ecstatic, or manic. All of us experience varying gradations of moods, and they are necessary and adaptive experiences for survival and emotional maturation. The extremes of moods, the depressive syndrome and the manic syndrome, are final common pathway brain dysfunctions. The diagnosis and treatment of mood disorders are discussed in this chapter.
Article
Tishler & Gordon (1999) highlighted ethical concerns behind challenge studies inducing psychosis with ketamine and made recommendations to enhance ethical standards. Recently, there is a plethora of clinical trials evaluating the efficacy of ketamine to treat mood disorders which lead to complex ethical issues. Pharmaceutical companies and researchers hope to profit by developing patentable variations on ketamine for treating depression. Media has labelled ketamine as a “miracle” antidepressant. Some clinics offer expensive off-label use of ketamine to treat mood disorders. This article examines the ecological validity of ketamine trials, measures to protect patients, informed consent procedures, financial inducements to participants and conflict of interest of researchers, therapeutic misconception, concealment and deception. Further recommendations are purposed to improve ethical standard of clinical research involving ketamine.
Article
Ketamine, a synthetic derivative of phencyclidine, is a commonly misused par ty drug that is restricted in high-income countries because of its addictive potential. Ketamine is also used as an anaesthetic in human and veterinary medicine. In the 1990s, research using ketamine to study the pathophysiology of schizophrenia was terminated owing to ethical concerns. Recently, controversy surrounding the drug has returned, as researchers have demonstrated that intravenous ketamine infusion has a rapid antidepressant effect and have therefore proposed ketamine as a novel antidepressant. This article debates the question of ketamine as an antidepressant, considering the drug’s addictive potential, ethical concerns about prescribing a hallucinogen, the evidence base and motives behind ketamine trials.
Article
Evidence suggests that N-methyl-D-aspartate receptor (NMDAR) antagonists could be efficacious in treating depression and anxiety, but side effects constitute a challenge. This study evaluated the antidepressant-like and anxiolytic-like actions, and cognitive and motor side effects of four NMDAR antagonists. MK-801, ketamine, S-ketamine, RO 25-6981 and the positive control, citalopram, were tested for antidepressant-like and anxiolytic-like effects in mice using the forced-swim test, the elevated zero maze and the novelty-induced hypophagia test. Side effects were assessed using a locomotor activity test, the modified Y-maze and the rotarod test. All compounds increased swim distance in the forced-swim test. In the elevated zero maze, the GluN2B subtype-selective RO 25-6981 affected none of the measured parameters, whereas all other compounds showed anxiolytic-like effects. In the novelty-induced hypophagia test, citalopram and MK-801 showed anxiogenic-like action. All NMDAR antagonists induced hyperactivity. The high doses of ketamine and MK-801 impaired performance in the modified Y-maze test, whereas S-ketamine and RO 25-6891 showed no effects in this test. Only MK-801 impaired rotarod performance. The study supports that NMDARs could be a possible therapeutic target for treating depression and anxiety. However, selective antagonism of GluN2B subunit-containing NMDARs showed no effect on anxiety-like behaviours in this study.
Chapter
Ketamine was originally developed as a potent but safe intravenous anesthetic drug which has subsequently been used for premedication, sedation, induction, and maintenance of general anesthesia (Sinner and Graf, Handb Exp Pharmacol 182:313–333, 2008). It is currently widely administered to children for dissociative sedation for painful procedures performed outside the operating room (Green et al., Ann Emerg Med 54:158–168, 2009; Green et al., Ann Emerg Med 54(2):171–80.e1–4, 2009). Due to its unique and diverse properties, a large number of additional indications for ketamine have developed since it was derived from phencyclidine in 1963. This chapter will review the history, pharmacology, clinical effects, and applications of ketamine. The evidence for and against traditional and expanding indications for ketamine administration will be examined.
Article
Full-text available
Background: It has been known that anesthetic adjuvants such as dexamethasone or ketamine might change mood. This study aimed to investigate the effects of a single dose of each drug individually along with their combined usage on postoperative mood changes in patients undergoing gynecologic surgery. Methods: Two hundred ninety-seven patients randomly allocated were divided into three groups. Group K (n = 99) received a single dose of ketamine (0.5 mg/kg iv); group D (n = 99) received a single dose of dexamethasone (0.1 mg/kg iv), and group KD (n = 99) received both ketamine (0.5 mg/kg iv) and dexamethasone (0.1 mg/kg iv) at 5 min after the induction of anesthesia. A change in the patient health questionnaire (PHQ)-9 scores on the first and third day after surgery, the duration of anesthesia, the postoperative visual analog scale (VAS) for pain, and the patient controlled analgesia (PCA) consumption were evaluated. Results: Groups K and KD showed a significant reduction in PHQ-9 score on both the first and third day after surgery compared with those recorded preoperatively and in group D (P < 0.01). There were no differences in the group D PHQ-9 scores pre- and post-operatively. The VAS for pain 24 h after surgery and the PCA consumption in group KD decreased significantly compared to the other two groups (P < 0.05). Conclusions: A single dose of ketamine (0.5 mg/kg) with or without combination with dexamethasone (0.1 mg/kg) give iv 5 min after induction of general anesthetic produced significant improvement in the postoperative mood scores. A single intravenous dose of dexamethasone (0.1 mg/kg) alone did not change postoperative mood scores. The VAS for pain 24 h after surgery and the PCA consumption was significantly lower in patients who received combination of both drugs.
Chapter
Full-text available
Antidepressants regardless of the mechanism of action can cure only 70% of depressed patients. There is therefore a category of depression that is called resistant. The co-administration of antidepressants of a different nature can alleviate this deficit. However, it seems necessary to develop active drugs in the resistant depression to develop animal models or even experimental strategies. The purpose of this chapter is to suggest ways to develop new drugs that may be effective in the treatment of resistant depression. Animal models of depression have been developed with a focus on those likely to demonstrate useful drugs in resistant depression or associations. Genetic or pharmacological leads are also mentioned.
Book
This book reviews all the important aspects of treatment-resistant psychiatric disorders, covering issues such as definitions, clinical aspects, neurobiological correlates, treatment options, and predictors of treatment response. The book is divided into three sections, the first of which examines the most recent thinking on treatment resistance in psychiatry, including definition and epidemiology, paradigm shift in the study of the subjects, individual susceptibility and resilience, abnormal structural or functional connectivity, and insights from animal models. The second section then discusses treatment resistance in each of the major psychiatric disorders, with particular focus on the responsible clinical and biological factors and the available management strategies. Finally, more detailed information is presented on diverse pharmacological and non-pharmacological therapeutic interventions. The book, written by leading experts from across the world, will be of value to all who seek a better understanding of the clinical-neurobiological underpinnings and the development of management for treatment resistance in psychiatric disorders.
Article
Functional unblinding due to treatment emergent adverse events (TEAEs) may occur with any investigational drug and poses a challenge for double-blind, placebo-controlled studies. This pilot study compared site-based Montgomery-Asberg Depression Rating Scale (MADRS) scores to remote, site-independent scores by blinded raters. Audio-digital recordings of site-based MADRS interviews were obtained from a subset of patients during a double-blind, placebo-controlled study of esketamine nasal spray or placebo spray in treatment resistant depression (Clinical Trials Registration: NCT01998958). Fourteen of 67 patients (21%) in the ITT population were randomly selected from 3 clinical trial sites. The site-based MADRS interviews were recorded at the baseline and 2 h post-dose assessments on the first intranasal dosing day. Site-independent raters scored the recordings and were blinded to treatment and all reported TEAEs, including any transient dissociative/perceptual symptoms. None of the 7 placebo-assigned patients achieved a treatment response or remission at the 2-h post-dose assessment. Four of the 7 esketamine-assigned patients (57.1%) achieved a treatment response at 2-h post-dose, and 3 patients (42.9%) achieved remission. Three esketamine-treated patients experienced transient dissociative symptoms. The remote site-independent raters essentially replicated the site-based MADRS scores and yielded a 92.9% predictive value for matching treatment response and remission rates. This small pilot study affirms that blinded remote ratings (without the likelihood of functional unblinding) are comparable to site-based ratings of efficacy of esketamine nasal spray. The audio-digital recording method offers a reasonable strategy for other studies that may also be vulnerable to functional unblinding due to distinctive TEAEs.
Preprint
Ketamine is an NMDA receptor antagonist commonly used to maintain general anesthesia. At anesthetic doses, ketamine causes bursts of 30-50 Hz oscillations alternating with 0.1 to 10 Hz oscillations. These dynamics are readily observed in local field potentials (LFPs) of non-human primates (NHPs) and electroencephalogram (EEG) recordings from human subjects. However, a detailed statistical analysis of these dynamics has not been reported. We characterize ketamine’s neural dynamics using a hidden Markov model (HMM). The HMM observations are sequences of spectral power in 10 Hz frequency bands between 0 to 50 Hz, where power is averaged within each band and scaled between 0 and 1. We model the observations as realizations of multivariate beta probability distributions that depend on a discrete-valued latent state process whose state transitions obey Markov dynamics. Using an expectation-maximization algorithm, we fit this beta-HMM to LFP recordings from 2 NHPs, and separately, to EEG recordings from 9 human subjects who received anesthetic doses of ketamine. Together, the estimated beta-HMM parameters and optimal state trajectory revealed an alternating pattern of states characterized primarily by gamma burst and slow oscillation activity, as well as intermediate states in between. The mean duration of the gamma burst state was 2.5s([1.9,3.4]s) and 1.2s([0.9,1.5]s) for the two NHPs, and 2.7s([1.9,3.8]s) for the human subjects. The mean duration of the slow oscillation state was 1.6s([1.1,2.5]s) and 0.7s([0.6,0.9]s) for the two NHPs, and 2.8s([1.9,4.3]s) for the human subjects. Our beta-HMM framework provides a useful tool for experimental data analysis. Our characterizations of the gamma-burst process offer detailed, quantitative constraints that can inform the development of rhythm-generating neuronal circuit models that give mechanistic insights into this phenomenon and how ketamine produces altered states of arousal.
Article
One of the most fascinating drugs in the anesthesiologist's armament is ketamine, an N-methyl-D-aspartate receptor antagonist with a myriad of uses. The drug is a dissociative anesthetic and has been used more often as an analgesic in numerous hospital units, outpatient pain clinics, and in the prehospital realm. It has been used to treat postoperative pain, chronic pain, complex regional pain syndrome, phantom limb pain, and other neuropathic conditions requiring analgesia. Research has also demonstrated its efficacy as an adjunct in psychotherapy, as a treatment for both depression and posttraumatic stress disorder, as a procedural sedative, and as a treatment for respiratory and neurologic conditions. Ketamine is not without its adverse effects, some of which can be mitigated with certain efforts. Such effects make it necessary for the clinician to use the drug only in situations where it will provide the greatest benefit with the fewest adverse effects. To the best of our knowledge, none of the reviews regarding ketamine have taken a comprehensive look at the drug's uses in all territories of medicine. This review will serve to touch on its chemical data, pharmacokinetics and pharmacodynamics, medical uses, and adverse effects while focusing specifically on the drugs usage in anesthesia and analgesia.
Article
Full-text available
Objective: Ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has shown rapid antidepressant effects, but small study groups and inadequate control conditions in prior studies have precluded a definitive conclusion. The authors evaluated the rapid antidepressant efficacy of ketamine in a large group of patients with treatment-resistant major depression. Method: This was a two-site, parallel-arm, randomized controlled trial of a single infusion of ketamine compared to an active placebo control condition, the anesthetic midazolam. Patients with treatment-resistant major depression experiencing a major depressive episode were randomly assigned under double-blind conditions to receive a single intravenous infusion of ketamine or midazolam in a 2:1 ratio (N=73). The primary outcome was change in depression severity 24 hours after drug administration, as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). Results: The ketamine group had greater improvement in the MADRS score than the midazolam group 24 hours after treatment. After adjustment for baseline scores and site, the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points (95% confidence interval [CI], 3.20 to 12.71). The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18; 95% CI, 1.21 to 4.14), with response rates of 64% and 28%, respectively. Conclusions: Ketamine demonstrated rapid antidepressant effects in an optimized study design, further supporting NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression. More information on response durability and safety is required before implementation in clinical practice.
Article
Full-text available
Recent clinical studies have demonstrated that a single subpsychotomimetic dose of ketamine, an ionotropic glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist, produces a rapid antidepressant response in patients with major depressive disorder, with effects lasting up to 2 weeks. Despite enthusiasm about this unexpected efficacy of ketamine, its widespread use as a fast-acting antidepressant in routine clinical settings is curtailed by its abuse potential as well as possible psychotomimetic effects. However, the ability of ketamine to produce a rapid and long-lasting antidepressant response in patients with depression provides a unique opportunity for investigation of mechanisms that mediate these clinically relevant behavioral effects. From a mechanistic perspective, it is easy to imagine how activation of NMDA receptors may trigger cellular and behavioral responses; it is relatively more difficult, however, to envision how transient blockade of one of the key pathways for neuronal communication produces a persistent beneficial effect. The authors discuss recent work linking ketamine's mechanism of action to homeostatic synaptic plasticity processes activated after suppression of NMDA-mediated glutamatergic neurotransmission. They focus on their recent work demonstrating that ketamine-mediated blockade of NMDA receptors at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase, resulting in reduced eEF2 phosphorylation and desuppression of rapid dendritic protein translation, including BDNF (brain-derived neurotrophic factor), which then contributes to synaptic plasticity mechanisms that mediate longterm effects of the drug. The authors also explore possible molecular strategies to target spontaneous neurotransmitter release selectively to help uncover novel presynaptic avenues for the development of fast-acting antidepressants and possibly psychoactive compounds with effectiveness against other neuropsychiatric disorders.
Article
Full-text available
Major depressive disorder (MDD) is a common psychiatric illness characterized by low mood and loss of interest in pleasurable activities. Despite years of effort, recent genome-wide association studies (GWAS) have identified few susceptibility variants or genes that are robustly associated with MDD. Standard single-SNP (single nucleotide polymorphism)-based GWAS analysis typically has limited power to deal with the extensive heterogeneity and substantial polygenic contribution of individually weak genetic effects underlying the pathogenesis of MDD. Here, we report an alternative, gene-set-based association analysis of MDD in an effort to identify groups of biologically related genetic variants that are involved in the same molecular function or cellular processes and exhibit a significant level of aggregated association with MDD. In particular, we used a text-mining-based data analysis to prioritize candidate gene sets implicated in MDD and conducted a multi-locus association analysis to look for enriched signals of nominally associated MDD susceptibility loci within each of the gene sets. Our primary analysis is based on the meta-analysis of three large MDD GWAS data sets (total N=4346 cases and 4430 controls). After correction for multiple testing, we found that genes involved in glutamatergic synaptic neurotransmission were significantly associated with MDD (set-based association P=6.9 × 10(-4)). This result is consistent with previous studies that support a role of the glutamatergic system in synaptic plasticity and MDD and support the potential utility of targeting glutamatergic neurotransmission in the treatment of MDD.
Article
Full-text available
Increasing preclinical and clinical evidence underscores the strong and rapid antidepressant properties of the glutamate-modulating NMDA receptor antagonist ketamine. Targeting the glutamatergic system might thus provide a novel molecular strategy for antidepressant treatment. Since glutamate is the most abundant and major excitatory neurotransmitter in the brain, pathophysiological changes in glutamatergic signaling are likely to affect neurobehavioral plasticity, information processing and large-scale changes in functional brain connectivity underlying certain symptoms of major depressive disorder. Using resting state functional magnetic resonance imaging (rsfMRI), the "dorsal nexus "(DN) was recently identified as a bilateral dorsal medial prefrontal cortex region showing dramatically increased depression-associated functional connectivity with large portions of a cognitive control network (CCN), the default mode network (DMN), and a rostral affective network (AN). Hence, Sheline and colleagues (2010) proposed that reducing increased connectivity of the DN might play a critical role in reducing depression symptomatology and thus represent a potential therapy target for affective disorders. Here, using a randomized, placebo-controlled, double-blind, crossover rsfMRI challenge in healthy subjects we demonstrate that ketamine decreases functional connectivity of the DMN to the DN and to the pregenual anterior cingulate (PACC) and medioprefrontal cortex (MPFC) via its representative hub, the posterior cingulate cortex (PCC). These findings in healthy subjects may serve as a model to elucidate potential biomechanisms that are addressed by successful treatment of major depression. This notion is further supported by the temporal overlap of our observation of subacute functional network modulation after 24 hours with the peak of efficacy following an intravenous ketamine administration in treatment-resistant depression.
Article
Full-text available
Basic and clinical studies demonstrate that depression is associated with reduced size of brain regions that regulate mood and cognition, including the prefrontal cortex and the hippocampus, and decreased neuronal synapses in these areas. Antidepressants can block or reverse these neuronal deficits, although typical antidepressants have limited efficacy and delayed response times of weeks to months. A notable recent discovery shows that ketamine, a N-methyl-d-aspartate receptor antagonist, produces rapid (within hours) antidepressant responses in patients who are resistant to typical antidepressants. Basic studies show that ketamine rapidly induces synaptogenesis and reverses the synaptic deficits caused by chronic stress. These findings highlight the central importance of homeostatic control of mood circuit connections and form the basis of a synaptogenic hypothesis of depression and treatment response.
Article
Full-text available
Rationale A growing number of investigators are studying ketamine effects in healthy human subjects, but concerns remain about its safety as a research tool. Therefore, it is timely to revisit the safety of subanesthetic doses of ketamine in experimental psychopharmacology studies. Objective To report on the safety of laboratory studies with subanesthetic doses of ketamine in healthy humans using an existing dataset. Materials and methods Medically healthy subjects with no personal or familial Axis I psychotic spectrum disorders were administered subanesthetic doses of ketamine by intravenous infusion in a series of clinical investigations from 1989 to 2005. The safety of ketamine administration was monitored in these subjects. Results Four hundred and fifty subjects received at least one dose of active ketamine. Eight hundred and thirty three active ketamine and 621 placebo infusions were administered. Ten adverse mental status events were documented in nine subjects/infusions that were deemed related to ketamine administration (2% of subjects, 1.45% of infusions). All but one adverse reaction resolved by the end of the test session. The side effects in the remaining individual were no longer clinically significant within 4 days of the test session. No residual sequelae were observed. Conclusion Ketamine administration at subanesthetic doses appears to present an acceptable level of risk for carefully screened populations of healthy human subjects in the context of clinical research programs that intensively monitor subjects throughout their study participation.
Article
Full-text available
The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant major depressive disorder (MDD). In rats, ketamine selectively increased electroencephalogram (EEG) slow wave activity (SWA) during non-rapid eye movement (REM) sleep and altered central brain-derived neurotrophic factor (BDNF) expression. Taken together, these findings suggest that higher SWA and BDNF levels may respectively represent electrophysiological and molecular correlates of mood improvement following ketamine treatment. This study investigated the acute effects of a single ketamine infusion on depressive symptoms, EEG SWA, individual slow wave parameters (surrogate markers of central synaptic plasticity) and plasma BDNF (a peripheral marker of plasticity) in 30 patients with treatment-resistant MDD. Montgomery-Åsberg Depression Rating Scale scores rapidly decreased following ketamine. Compared to baseline, BDNF levels and early sleep SWA (during the first non-REM episode) increased after ketamine. The occurrence of high amplitude waves increased during early sleep, accompanied by an increase in slow wave slope, consistent with increased synaptic strength. Changes in BDNF levels were proportional to changes in EEG parameters. Intriguingly, this link was present only in patients who responded to ketamine treatment, suggesting that enhanced synaptic plasticity - as reflected by increased SWA, individual slow wave parameters and plasma BDNF - is part of the physiological mechanism underlying the rapid antidepressant effects of NMDA antagonists. Further studies are required to confirm the link found here between behavioural and synaptic changes, as well as to test the reliability of these central and peripheral biomarkers of rapid antidepressant response.
Article
Full-text available
The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant major depressive disorder (MDD). In rats, ketamine selectively increased electroencephalogram (EEG) slow wave activity (SWA) during non-rapid eye movement (REM) sleep and altered central brain-derived neurotrophic factor (BDNF) expression. Taken together, these findings suggest that higher SWA and BDNF levels may respectively represent electrophysiological and molecular correlates of mood improvement following ketamine treatment. This study investigated the acute effects of a single ketamine infusion on depressive symptoms, EEG SWA, individual slow wave parameters (surrogate markers of central synaptic plasticity) and plasma BDNF (a peripheral marker of plasticity) in 30 patients with treatment-resistant MDD. Montgomery-Åsberg Depression Rating Scale scores rapidly decreased following ketamine. Compared to baseline, BDNF levels and early sleep SWA (during the first non-REM episode) increased after ketamine. The occurrence of high amplitude waves increased during early sleep, accompanied by an increase in slow wave slope, consistent with increased synaptic strength. Changes in BDNF levels were proportional to changes in EEG parameters. Intriguingly, this link was present only in patients who responded to ketamine treatment, suggesting that enhanced synaptic plasticity - as reflected by increased SWA, individual slow wave parameters and plasma BDNF - is part of the physiological mechanism underlying the rapid antidepressant effects of NMDA antagonists. Further studies are required to confirm the link found here between behavioural and synaptic changes, as well as to test the reliability of these central and peripheral biomarkers of rapid antidepressant response.
Article
Full-text available
Clinical evidence that ketamine, a nonselective N-methyl-D-aspartate receptor (NMDAR) antagonist, has therapeutic effects within hours in people suffering from depression suggests that modulating glutamatergic neurotransmission is a fundamental step in alleviating the debilitating symptoms of mood disorders. Acutely, ketamine increases extracellular glutamate levels, neuronal excitability, and spontaneous γ oscillations, but it is unknown whether these effects are key to the mechanism of antidepressant action of ketamine. Twenty drug-free major depressive disorder patients received a single, open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg). Magnetoencephalographic recordings were made approximately 3 days before and approximately 6.5 hours after the infusion, whereas patients passively received tactile stimulation to the right and left index fingers and also while they rested (eyes-closed). Antidepressant response was assessed by percentage change in Montgomery-Åsberg Depression Rating Scale scores. Patients with robust improvements in depressive symptoms 230 min after infusion (responders) exhibited increased cortical excitability within this antidepressant response window. Specifically, we found that stimulus-evoked somatosensory cortical responses increase after infusion, relative to pretreatment responses in responders but not in treatment nonresponders. Spontaneous somatosensory cortical γ-band activity during rest did not change within the same timeframe after ketamine in either responders or nonresponders. These findings suggest NMDAR antagonism does not lead directly to increased cortical excitability hours later and thus might not be sufficient for therapeutic effects of ketamine to take hold. Rather, increased cortical excitability as depressive symptoms improve is consistent with the hypothesis that enhanced non-NMDAR-mediated glutamatergic neurotransmission via synaptic potentiation is central to the antidepressant effect of ketamine.
Article
Full-text available
The N-methyl-D-aspartate antagonist ketamine has rapid antidepressant effects in patients with treatment-resistant major depression (TRD); these effects have been reported to last for 1 week in some patients. However, the extent and duration of this antidepressant effect over longer periods has not been well characterized under controlled conditions. Riluzole, a glutamatergic modulator with antidepressant and synaptic plasticity-enhancing effects, could conceivably be used to promote the antidepressant effects of ketamine. This study sought to determine the extent and time course of antidepressant improvement to a single-ketamine infusion over 4 weeks, comparing the addition of riluzole vs placebo after the infusion. Forty-two subjects (18-65) with TRD and a Montgomery-Asberg Depression Rating Scale (MADRS) score of ≥ 22 received a single intravenous infusion of ketamine (0.5 mg/kg). Four to six hours post-infusion, subjects were randomized to double-blind treatment with either riluzole (100-200 mg/day; n=21) or placebo (n=21) for 4 weeks. Depressive symptoms were rated daily. A significant improvement (P<0.001) in MADRS scores from baseline was found. The effect size of improvement with ketamine was initially large and remained moderate throughout the 28-day trial. Overall, 27% of ketamine responders had not relapsed by 4 weeks following a single ketamine infusion. The average time to relapse was 13.2 days (SE=2.2). However, the difference between the riluzole and placebo treatment groups was not significant, suggesting that the combination of riluzole with ketamine treatment did not significantly alter the course of antidepressant response to ketamine alone.
Article
Full-text available
Molecular Psychiatry publishes work aimed at elucidating biological mechanisms underlying psychiatric disorders and their treatment
Article
Full-text available
Healthy volunteers received low-dose target-controlled infusions (TCI) of ketamine controlled by the Domino model while cognitive function tests and functional neuroimaging were performed. The aim of the current study was to assess the predictive performance of the Domino model during these studies, and compare it with that of three other ketamine models. Fifty-eight volunteers received ketamine administered by a TCI device on one or more occasions at target concentrations of either 50, 100, or 200 ng ml-1. At each target concentration, two or three venous blood samples were withdrawn during infusion, with a further sample after the infusion ended. Ketamine assays were performed by gas chromatography. The plasma concentration time courses predicted by the Hijazi, Clements 125, and Clements 250 models were calculated retrospectively, and the predictive performance of each of the models was assessed using Varvel methodology. For the Domino model, bias, inaccuracy, wobble, and divergence were - 2.7%, 33.9%, 24.2%, and 0.1463% h-1, respectively. There was a systematic increase in performance error over time. The Clements 250 model performed best by all criteria, whereas the Hijazi model performed least well by all criteria except for bias. Performance of the Domino model during control of low-dose ketamine infusions was sub-optimal. The Clements 250 model may be a better model for controlling low-dose TCI ketamine administration.
Article
Full-text available
Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder, although the underlying mechanism is unclear. Depressed patients report the alleviation of major depressive disorder symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks, unlike traditional antidepressants (serotonin re-uptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current therapies for major depressive disorder and faster-acting antidepressants are needed, particularly for suicide-risk patients. The ability of ketamine to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. Here we show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor. We find that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII), resulting in reduced eEF2 phosphorylation and de-suppression of translation of brain-derived neurotrophic factor. Furthermore, we find that inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings indicate that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants.
Article
Full-text available
Ketamine is a N-methyl-D-aspartic acid (NMDA) antagonist that has been associated with temporary clinical improvement in patients with depression. Studies using magnetic resonance spectroscopy (MRS) have shown that major depression is associated with decreased levels of glutamate and glutamine (Glx) in the anterior cingulate cortex, which normalize with clinical recovery. The present study aimed to test whether a ketamine infusion would increase cortical Glx levels in healthy volunteers. Healthy volunteers received an intravenous infusion of ketamine (0.5 mg kg⁻¹, n = 8) or saline (n = 9) over 40 minutes. MRS measurements were obtained at baseline, during, and at the end of the infusion. The infusion of ketamine had significant effects on mental state but there was no effect of ketamine on the levels of Glx (F (3,39) = 1.70, p = 0.18) or glutamate (F (3,39) = 48, p = 0.70). This study suggests that the gradual infusion of low-dose ketamine in antidepressant doses not cause changes in cortical glutamate or glutamine in healthy volunteers that are visible by proton MRS.
Article
Full-text available
Molecular Psychiatry publishes work aimed at elucidating biological mechanisms underlying psychiatric disorders and their treatment
Article
Full-text available
Depression has been associated with changes in responses within the medial prefrontal cortex (mPFC) during emotional information processing. Antidepressant drug treatment has been shown to modify neural responses in healthy volunteers early in treatment within similar circuitry. It is unclear, however, whether the same early effect occurs in depressed patients, before changes in mood. The current study therefore investigated the effects of 7-days administration of the selective serotonin-uptake inhibitor citalopram vs placebo in volunteers (n=29) at a high risk for the development of depression, using the personality phenotype of high neuroticism in a double-blind, between-groups design. On the last day of treatment, resting haemoperfusion and functional magnetic resonance imaging (MRI) data were acquired during a self-referential words categorisation task. A significant activation in a cluster of mPFC areas, including dorsal anterior cingulate and right orbitofrontal cortex was revealed, driven by decreased responses to the negative self-descriptors following citalopram compared with placebo, in the absence of any mood differences. These findings show a normalisation of neural abnormalities in- and at-risk population early in treatment, supporting the theory that antidepressants may indeed act by modifying specific neural dysfunctions correlated to negative cognitive biases.
Article
Full-text available
The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications. However, the mechanisms underlying this action of ketamine [a glutamate N-methyl-d-aspartic acid (NMDA) receptor antagonist] have not been identified. We observed that ketamine rapidly activated the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats. Moreover, blockade of mTOR signaling completely blocked ketamine induction of synaptogenesis and behavioral responses in models of depression. Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.
Article
Full-text available
To better understand intrinsic brain connections in major depression, we used a neuroimaging technique that measures resting state functional connectivity using functional MRI (fMRI). Three different brain networks--the cognitive control network, default mode network, and affective network--were investigated. Compared with controls, in depressed subjects each of these three networks had increased connectivity to the same bilateral dorsal medial prefrontal cortex region, an area that we term the dorsal nexus. The dorsal nexus demonstrated dramatically increased depression-associated fMRI connectivity with large portions of each of the three networks. The discovery that these regions are linked together through the dorsal nexus provides a potential mechanism to explain how symptoms of major depression thought to arise in distinct networks--decreased ability to focus on cognitive tasks, rumination, excessive self-focus, increased vigilance, and emotional, visceral, and autonomic dysregulation--could occur concurrently and behave synergistically. It suggests that the newly identified dorsal nexus plays a critical role in depressive symptomatology, in effect "hot wiring" networks together; it further suggests that reducing increased connectivity of the dorsal nexus presents a potential therapeutic target.
Article
Full-text available
During the last 20 years of neuroscience research, we have witnessed a fundamental shift in the conceptualization of psychiatric disorders, with the dominant psychological and neurochemical theories of the past now complemented by a growing emphasis on developmental, genetic, molecular, and brain circuit models. Facilitating this evolving paradigm shift has been the growing contribution of functional neuroimaging, which provides a versatile platform to characterize brain circuit dysfunction underlying specific syndromes as well as changes associated with their successful treatment. Discussed here are converging imaging findings that established a rationale for testing a targeted neuromodulation strategy, deep brain stimulation, for treatment-resistant major depression.
Article
BACKGROUND: Ketamine exerts a robust, rapid, and relatively sustained antidepressant effect in patients with major depression. Understanding the mechanisms underlying the intriguing effects of Nmethyl d-aspartate (NMDA) antagonists could lead to novel treatments with a rapid onset of action. METHODS: The learned helplessness, forced swim, and passive avoidance tests were used to investigate ketamine's behavioral effects in mice. Additional biochemical and behavioral experiments were undertaken to determine whether the antidepressant-like properties of ketamine and other NMDA antagonists involve alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor throughput. RESULTS: Subanesthetic doses of ketamine treatment caused acute and sustained antidepressantlike effects. At these doses, ketamine did not impair fear memory retention. MK-801 (dizocilpine) and Ro25-6981, an NR2B selective antagonist, also exerted antidepressant-like effects; these effects, however, were not sustained as long as those of ketamine. Pretreatment with NBQX, an AMPA receptor antagonist, attenuated both ketamine-induced antidepressant-like behavior and regulation of hippocampal phosphorylated GluR1 AMPA receptors. CONCLUSIONS: NMDA antagonists might exert rapid antidepressant-like effects by enhancing AMPA relative to NMDA throughput in critical neuronal circuits.
Article
Brain mapping studies using dynamic imaging methods demonstrate areas regional cerebral blood flow (rCBF) decreases, as well as areas where increases, during performance of various experimental tasks. Task holds for both sets of cerebral blood flow changes (CBF), providing the opportunity to investigate areas that become and “activated” in the experimental condition relative to control state. Such data yield the intriguing observation that in areas in emotional processing, such as the amygdala, the posteromedial cortex, and the ventral anterior cingulate cortex, although flow as expected during specific emotion-related tasks, flow decreases performance of some attentionally demanding, cognitive tasks. Conversely, in some of the areas that appear to subserve cognitive functions, as the dorsal anterior cingulate and the dorsolateral prefrontal cortices, increases while performing attentionally demanding cognitive tasks, but during some experimentally induced and pathological emotional Although the specific nature of such reciprocal patterns of regional remains unclear, they may reflect an important cross-modal interaction during mental operations. The possibility that neural activity is less in areas required in emotional processing during some higher cognitive processes holds implications for the mechanisms underlying interactions cognition and emotion. Furthermore, the possibility that neural in some cognitive-processing areas is suppressed during intense states suggests mechanisms by which extreme fear or severe may interfere with cognitive performance.
Article
This paper discusses the synaptic homeostasis hypothesis of sleep. The main claim of the hypothesis is that plastic processes occurring during wakefulness result in a net increase in synaptic strength in many brain circuits, and that role of sleep is to downscale synaptic strength to a baseline level that is energetically sustainable, makes efficient use of gray matter space, and is beneficial for learning and memory. Thus, sleep is the price we have to pay for plasticity, and its goal is the homeostatic regulation of the total synaptic weight impinging on neurons. In this chapter we review evidence pro and contra the hypothesis, discuss similarities and differences with other hypotheses that focus on the role of sleep in neural plasticity, and mention ongoing and future experiments to test it directly.
Article
Here, we describe our collaborative efforts to use N-methyl-d-aspartate (NMDA) receptor antagonists as a translational tool to advance our understanding of the pathophysiology of schizophrenia and identify potential new targets for treatment of schizophrenia. We began these efforts in the late 1980s with a keen sense that, in both human and animal studies, we needed to move beyond the dopamine hypothesis of schizophrenia; if the dopamine hypothesis were correct, the existing dopamine antagonists should have cured the disease but they have not. We used NMDA receptor antagonists, not to produce schizophrenia, but as a tool to provide insights into effects of disturbances in glutamate synaptic function in schizophrenia. Our work has provided insights into potential mechanisms that may contribute to disrupted cortical function in schizophrenia and has helped identify potential treatment targets for the disorder. The translational nature of this study made the clinical testing of the first of these targets feasible. Advances in systems neuroscience approaches in animals and humans make new types of translational research possible; however, our concern is that the current obstacles facing translational research funding and academia-industry collaborations threaten the future progress in this field.
Article
Background: Ketamine is reported to have rapid antidepressant effects; however, there is limited understanding of the time-course of ketamine effects beyond a single infusion. A previous report including 10 participants with treatment-resistant major depression (TRD) found that six ketamine infusions resulted in a sustained antidepressant effect. In the current report, we examined the pattern and durability of antidepressant effects of repeated ketamine infusions in a larger sample, inclusive of the original. Methods: Participants with TRD (n = 24) underwent a washout of antidepressant medication followed by a series of up to six IV infusions of ketamine (.5 mg/kg) administered open-label three times weekly over a 12-day period. Participants meeting response criteria were monitored for relapse for up to 83 days from the last infusion. Results: The overall response rate at study end was 70.8%. There was a large mean decrease in Montgomery-Åsberg Depression Rating Scale score at 2 hours after the first ketamine infusion (18.9 ± 6.6, p < .001), and this decrease was largely sustained for the duration of the infusion period. Response at study end was strongly predicted by response at 4 hours (94% sensitive, 71% specific). Among responders, median time to relapse after the last ketamine infusion was 18 days. Conclusions: Ketamine was associated with a rapid antidepressant effect in TRD that was predictive of a sustained effect. Future controlled studies will be required to identify strategies to maintain an antidepressant response among patients who benefit from a course of ketamine.
Article
Rationale: Some of the behavioral consequences of deficits in N-methyl-D-aspartate (NMDA) glutamate receptor function are thought to arise from the disinhibition of cortical glutamatergic circuitry. Objective: This study evaluated whether pretreatment with a drug that reduces glutamatergic activation, the group II metabotropic glutamate receptor (mGluR) agonist, LY354740, reduced the cognitive effects of the NMDA glutamate receptor antagonist, ketamine, in healthy human subjects. Methods: Nineteen healthy human subjects completed 3 test days during which LY354740 (matched placebo, 100 mg, 400 mg) was administered under double-blind conditions 4 h prior to the single-blind intravenous administration of saline and 5.7 h prior to ketamine administration (bolus of 0.26 mg/kg over 1 min, infusion of 0.65 mg/kg per hour for 100 min). Thus on each test day each subject received a single dose of LY354740 (or its matched placebo) and both saline and ketamine infusions. Results: Ketamine impaired attention, working memory, and delayed recall. It also produced positive and negative symptoms, perceptual changes, and dysphoric mood. LY354740 did not have a significant effect on working memory on the placebo day; however, it produced a significant dose-related improvement in working memory during ketamine infusion. Conclusions: These data provide preliminary and suggestive evidence that LY354740 or other group II mGluR agonists might play a role in treating working memory impairment related to deficits in NMDA receptor function.
Article
Although mood disorders constitute leading causes of disability, until recently little was known about their pathogenesis. The delineation of anatomical networks that support emotional behavior (mainly derived from animal studies) and the development of neuroimaging technologies that allow in vivo characterization of anatomy, physiology, and neurochemistry in human subjects with mood disorders have enabled significant advances towards elucidating the pathophysiology of major depressive disorder (MDD) and bipolar disorder (BD). In this review, we integrate insights from human and animal studies, which collectively suggest that MDD and BD involve dysfunction within an extended network including the medial prefrontal cortex and anatomically-related limbic, striatal, thalamic and basal forebrain structures.
Article
Ketamine has recently gained significant attention owing to its psychotomimetic and more recently discovered rapid antidepressant-like properties. ¹H-[¹³C]-nuclear magnetic resonance studies were employed to explore potential physiological processes underlying these unique effects. [1-¹³C]glucose and [2-¹³C]acetate-nuclear magnetic resonance ex vivo studies were performed on the medial prefrontal cortex (mPFC) and hippocampus of rats acutely treated with 30 mg/kg or 80 mg/kg ketamine and compared with saline-treated animals to determine the effects of ketamine on amino acid neurotransmitter cycling and glial metabolism. A subanesthetic, but not anesthetic, dose of ketamine significantly increased the percentage of ¹³C-enrichments of glutamate, γ-aminobutyric acid, and glutamine in the mPFC of rats. Subanesthetic doses of ketamine increased mPFC amino acid neurotransmitter cycling, as well as neuronal and glial energy metabolism. These data add to previous reports suggesting increased mPFC levels of glutamate release, following the administration of subanesthetic doses of ketamine, are related to the drug's acute effects on cognition, perception, and mood.
Article
Amino-acid neurotransmitter system dysfunction plays a major role in the pathophysiology of major depressive disorder (MDD). We used proton magnetic resonance spectroscopy (¹H-MRS) to investigate whether prefrontal levels of amino-acid neurotransmitters predict antidepressant response to a single intravenous infusion of the N-methyl-D-aspartate (NMDA) antagonist ketamine in MDD patients. Fourteen drug-free patients with MDD were scanned 1-3 d before receiving a single intravenous infusion of ketamine (0.5 mg/kg). We measured gamma aminobutyric acid (GABA), glutamate, and Glx/glutamate ratio (a surrogate marker of glutamine) in the ventromedial prefrontal cortex (VM-PFC) and the dorsomedial/dorsal anterolateral prefrontal cortex (DM/DA-PFC). Correlation analyses were conducted to determine whether pretreatment GABA, glutamate, or Glx/glutamate ratio predicted change in depressive and anxiety symptoms 230 min after ketamine administration. Pretreatment GABA or glutamate did not correlate with improved depressive symptoms in either of the two regions of interest (p>0.1); pretreatment Glx/glutamate ratio in the DM/DA-PFC was negatively correlated with improvement in depressive symptoms [r s(11)=-0.57, p<0.05]. Pretreatment glutamate levels in the VM-PFC were positively correlated with improvement in anxiety symptoms [r s(11)=0.57, p<0.05]. The findings suggest an association between lower Glx/glutamate ratio and greater improvement in response to ketamine treatment. Because glutamine is mainly contained in glia, the decreased Glx/glutamate ratio observed in this study may reflect the reduction in glial cells found in the same regions in post-mortem studies of individuals with MDD, and suggests that the presence of this neuropathological construct may be associated with antidepressant responsiveness to ketamine.
Article
Knock-in mice with the common human brain-derived neurotrophic factor (BDNF) Val66Met polymorphism have impaired trafficking of BDNF messenger RNA to dendrites. It was hypothesized, given evidence that local synapse formation is dependent on dendritic translation of BDNF messenger RNA, that loss-of-function Met allele mice would show synaptic deficits both at baseline and in response to ketamine, an N-methyl-D-aspartate antagonist that stimulates synaptogenesis in prefrontal cortex (PFC). Whole-cell recordings from layer V medial PFC pyramidal cells in brain slices were combined with two-photon laser scanning for analysis of wildtype, Val/Met, and Met/Met mice both at baseline and in response to a low dose of ketamine. Val/Met and Met/Met mice were found to have constitutive atrophy of distal apical dendrites and decrements in apically targeted excitatory postsynaptic currents in layer V pyramidal cells of PFC. In addition, spine density and diameter were decreased, indicative of impaired synaptic formation/maturation (synaptogenesis). In Met/Met mice the synaptogenic effect of ketamine was markedly impaired, consistent with the idea that synaptogenesis is dependent on dendritic translation/release of BDNF. In parallel behavioral studies, we found that the antidepressant response to ketamine in the forced swim test was blocked in Met/Met mice. The results demonstrate that expression of the BDNF Met allele in mice results in basal synaptic deficits and blocks synaptogenic and antidepressant actions of ketamine in PFC, suggesting that the therapeutic response to this drug might be attenuated or blocked in depressed patients who carry the loss of function Met allele.
Article
Ketamine remains an important medicine in both specialist anaesthesia and aspects of pain management. At the same time, its use as a recreational drug has spread in many parts of the world during the past few years. There are now increasing concerns about the harmful physical and psychological consequences of repeated misuse of this drug. The aim of this review was to survey and integrate the research literature on physical, psychological and social harms of both acute and chronic ketamine use. The literature on ketamine was systematically searched and findings were classified into the matrix of Nutt et al.'s (2007) rational scale for assessing the harms of psychoactive substances. A major physical harm is ketamine induced ulcerative cystitis which, although its aetiology is unclear, seems particularly associated with chronic, frequent use of the drug. Frequent, daily use is also associated with neurocognitive impairment and, most robustly, deficits in working and episodic memory. Recent studies suggest certain neurological abnormalities which may underpin these cognitive effects. Many frequent users are concerned about addiction and report trying but failing to stop using ketamine. The implications of these findings are drawn out for treatment of ketamine-induced ulcerative cystitis in which interventions from urologists and from addiction specialists should be coordinated. Neurocognitive impairment in frequent users can impact negatively upon achievement in education and at work, and also compound addiction problems. Prevention and harm minimization campaigns are needed to alert young people to these harmful and potentially chronic effects of ketamine.