ArticleLiterature Review

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

CNS Neuroscience & Therapeutics

April 2013
19(6)

DOI:10.1111/cns.12103

Source
PubMed

Authors:

Giacomo Salvadore

Janssen Research & Development, LLC

Jaskaran Singh

Johnson & Johnson

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.

Study protocol for SKIPMDD: Subcutaneous ketamine infusion in palliative care patients with advanced life limiting illnesses for major depressive disorder (phase II pilot feasibility study)

Article

Full-text available

Jun 2021

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.

The use of ketamine to cope with depression and post-traumatic stress disorder: A qualitative analysis of the discourses posted on a popular online forum

Article

May 2020

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.

Targeting Inflammatory-Mitochondrial Response in Major Depression: Current Evidence and Further Challenges

Article

Full-text available

Apr 2020
OXID MED CELL LONGEV

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.

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]

Article

Jul 2016

The Effect of Ketamine on Motor Coordination and Thermal Nociception in Ethanol-Withdrawn Mice

Article

May 2014

Jameson Ford

Drug Repurposing for the Management of Depression: Where Do We Stand Currently?

Article

Full-text available

Jul 2021

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.

KetaminKetamin: Einsatz bei chronischen Schmerzen und DepressionKetamine in the therapy of chronic pain and depression

Article

Full-text available

Apr 2019

Zusammenfassung 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.

Cognitive function of patients with treatment-resistant depression after a single low dose of ketamine infusion

Article

Jul 2018
J AFFECT DISORDERS

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.

Ketamine-The Confluence of Old and Recent Concepts

Article

Jan 2017

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.

Ketamine as a treatment of stress-induced maternal depression in mice: effects on offspring behaviour

Article

Full-text available

Jun 2024

Maternal depression during pregnancy adversely affects offspring neurodevelopment and behaviour. Typical antide-pressants like selective serotonin reuptake inhibitors have limitations due to risks of crossing the placenta. Ketamine has emerged as a promising alternative treatment. This research examined ketamine's effects on offspring of mater¬nally stressed mice. Dams were divided into control, maternal adversity, fluoxetine, and ketamine groups. Open field, sucrose preference, elevated plus maze, and forced swim tests assessed offspring anxiety, anhedonia, and despair. Maternal adversity increased anxiety-like behaviours and ketamine or fluoxetine reversed some effects. However, fluoxetine more effectively mitigated despair in forced swim tests. Ketamine moderately alleviated anhedonia versus controls. Further research on dose-response and timing is needed to optimize ketamine treatment. Mitigating maternal depression is crucial for preventing maladaptive offspring neurobehavioral trajectories.

Ketamine: Mechanisms, Applications, and Future Directions

Article

Full-text available

Apr 2024

Ketamine, a versatile anesthetic agent with a complex pharmacological profile, has been utilized in clinical practice for decades 3. This review examines the diverse mechanisms of ketamine's action, ranging from its well-established role as an NMDA receptor antagonist to its modulation of other neurotransmitter systems and inflammatory pathways 22. Ketamine's efficacy extends beyond its traditional use in anesthesia, with emerging applications in acute and chronic pain management, depression, and neuroprotection 31,52. The review highlights ketamine's potential as a first-line treatment for refractory depression and suicidal ideation, as well as its utility in pediatric pain management and emergency department settings 31. While evidence supports ketamine's acute analgesic effects in chronic pain, further research is needed to establish its long-term efficacy and safety in this context. Moreover, ketamine's anti-inflammatory properties warrant exploration for their therapeutic implications 26,43. Overall, ketamine represents a prime example of drug repurposing and holds promise for addressing diverse clinical needs, but continued research is essential to optimize its clinical use and fully elucidate its mechanisms of action. Introduction:

Instant and Lasting Down-Regulation of NR1 Expression in the Hippocampus is Associated Temporally with Antidepressant Activity After Acute Yueju

Article

Full-text available

Jan 2016
CELL MOL NEUROBIOL

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 antide-pressant 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.

Post-Partum Depression Lactating Rat Model for Evaluating Ketamine’s Safety as a Pharmacotherapeutic Treatment: Roles in Cardiac and Urinary Function

Article

Full-text available

Sep 2022

Depression is one of the world’s most common and mentally disabling illnesses. Post-partum depression is a subtype of depression that affects one in seven women worldwide. Successful pharmacological treatment must consider the consequences for both, since the mother–child bond is fundamental for the well-being of both mother and infant as well as the general development of the newborn. Changes in maternal physiology and/or behavior can significantly influence the development of breastfed infants. Ketamine has been extensively studied for use as an antidepressant due to its mixed mechanisms of action. Safety and efficacy studies in the cardiovascular and urinary systems of a lactating postpartum depression animal model are essential for contributing toward ketamine’s clinical use in the respective patient population. Thus, this project aimed to study the implications of postpartum maternal exposure to ketamine during lactation on the cardiovascular system of female rats submitted to the depression induction model by maternal separation. This model promotes depressive effects through stress caused by the interruption of mother–infant bond early in the offspring’s life. To achieve depression, each dam was separated from her offspring for 3 h per day, from post-natal day 2 (PND2) to PND12. Experimental groups received daily treatment with either 5, 10, or 20 mg/kg of ketamine intraperitoneally during the lactation period, from PND2 to PND21. Behavioral tests consisted of the maternal and aggressive maternal behavior tests, the olfactory preference test, and the forced swim test. A technique for the detection of catecholamines and indoleamines in the heart muscle was developed for the experimental model groups. The histopathological evaluation was performed on these animals’ cardiac muscles and urinary bladders. Our findings suggest that ketamine is safe for use in postpartum depression and does not induce cardiovascular and/or urinary systems toxicity.

A hidden Markov model reliably characterizes ketamine-induced spectral dynamics in macaque local field potentials and human electroencephalograms

Article

Full-text available

Aug 2021
PLOS COMPUT BIOL

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.

Comeback of Ketamine: Resurfacing facts and dispelling myths

Article

Full-text available

Jan 2021

Initially known as CI-581, ketamine was first synthesized in 1962 as a replacement from phencyclidine. It has since been used as an anesthetic and analgesic. In addition, it has bronchodilating, sedative, and amnestic properties, preserving airway reflexes and sympathetic nervous system tone. Since the discovery of ketamine, it has been a major topic of discussion due to controversies regarding its usage in particular sets of patients. In the past 50 years, despite its potential benefits, it is not commonly used because of concerns of “emergence phenomenon,” its use as a substance of abuse, and its systemic side effects. Since 2012, three World Health Organization reviews on ketamine have addressed its international control. Researchers have been studying this wonder drug for a decade worldwide. Many myths of ketamine regarding emergence phenomenon and its use in traumatic brain injury and open eye injury have been disproved in recent times. It is becoming popular in pre-hospital settings, critical care, emergency medicine, low-dose acute pain services, and adjuvant in regional anesthesia techniques. This review highlights the current consensus on the various applications of ketamine in the literature.

Localized Prediction of Glutamate from Whole-Brain Functional Connectivity of the Pregenual Anterior Cingulate Cortex

Article

Nov 2020

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.

A review on the recent application of ketamine in management of anesthesia, pain, and health care

Article

Full-text available

Mar 2020

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.

Localized prediction of glutamate from whole-brain functional connectivity of the pregenual anterior cingulate cortex

Preprint

Full-text available

Feb 2020

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.

The ketamine crisis: Does South Africa have a plan B?

Article

Full-text available

Nov 2019

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.

Comparing the Effects of Ketamine and Lidocaine on Mood, Subjective Drug Effects, and Pain

Conference Paper

Oct 2018

Matt Knox

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.

Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial

Article

Full-text available

Dec 2017

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

Visceral Inflammation and Immune Activation Stress the Brain

Article

Full-text available

Nov 2017

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.

Ketamine in Clinical Use

Data

Full-text available

Nov 2017

Hong Liu

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.

Drug repurposing may generate novel approaches to treating depression

Article

Sep 2017

Mohamed Elsaed Ebada

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.

Pathogen-mediated NMDA receptor autoimmunity and cellular barrier dysfunction in schizophrenia

Article

Full-text available

Aug 2017

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.

Ketamine for the Treatment of Depression

Article

Jul 2017

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.

Administration of ketamine for unipolar and bipolar depression

Article

Full-text available

Jan 2017
INT J PSYCHIAT CLIN

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.

Chronic Kappa opioid receptor activation modulates NR2B: Implication in treatment resistant depression

Article

Full-text available

Sep 2016

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.

Temporal Dynamics of Antidepressant Ketamine Effects on Glutamine Cycling Follow Regional Fingerprints of AMPA and NMDA Receptor Densities

Article

Sep 2016

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.

Rapid and sustained antidepressant properties of an NMDA antagonist/monoamine reuptake inhibitor identified via transporter-based virtual screening

Article

Aug 2016

The Recent History of Seasonal Affective Disorder (SAD)

Book

Full-text available

Nov 2014

Ketamine use in current clinical practice

Article

Full-text available

Mar 2016
ACTA PHARMACOL SIN

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.

Instant and Lasting Down-Regulation of NR1 Expression in the Hippocampus is Associated Temporally with Antidepressant Activity After Acute Yueju

Article

Full-text available

Oct 2016
CELL MOL NEUROBIOL

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.

Ketamine and Esketamine

Chapter

Full-text available

Jul 2024

Ketamine role in the treatment of Maternal depression: effects on offspring behaviour

Preprint

Full-text available

Feb 2024

Maternal depression during pregnancy adversely affects offspring neurodevelopment and behaviour. Typical antidepressants like selective serotonin reuptake inhibitors have limitations due to risks of crossing the placenta. Ketamine has emerged as a promising alternative treatment. This research examined ketamine's effects on offspring of maternally stressed mice. Dams were divided into control, maternal adversity, fluoxetine, and ketamine groups. Open field, sucrose preference, elevated plus maze, and forced swim tests assessed offspring anxiety, anhedonia, and despair. Maternal adversity increased anxiety-like behaviours and ketamine or fluoxetine reversed some effects. However, fluoxetine more effectively mitigated despair in forced swim tests. Ketamine moderately alleviated anhedonia versus controls. Further research on dose-response and timing is needed to optimize ketamine treatment. Mitigating maternal depression is crucial for preventing maladaptive offspring neurobehavioral trajectories.

Astro & Ciencias Revista de Divulgación Científica - Enero 2024

Article

Full-text available

Jan 2024

AstroCiencias Ecuador les anuncia la publicación de la quinta edición de la Revista digital de divulgación científica Astro&Ciencias – Enero 2024 Estos son los contenidos más destacados. El Cometa con Cuernos y Cola - Evolución Estelar - Qué pasa con Betelgeuse - Perspectivas y desafíos evaluación de limitaciones en el uso de Coordenadas Selenográficas para la Cartografía Lunar - Europa Clipper, Explorando nuevos Mundos - Una visión general de la propuesta del Telescopio Espacial Espectroscópico y de Imágenes de la India - Misiones Espaciales del 2023 - Ecuación de Drake - La Psicología ¿Una rama objetiva y experimental de las Ciencias Naturales? - Neuroplasticidad y Depresión - Vida Extraterrestre - Steam como Enfoque Disruptivo en la Enseñanza - Para saber más - La Astrofotografía de la edición Les invitamos a leer y descarga.

Subcutaneous ketamine infusion in palliative patients for major depressive disorder (SKIPMDD)—Phase II single-arm open-label feasibility study

Article

Full-text available

Nov 2023
PLOS ONE

Background Ketamine at subanaesthetic dosages (≤0.5mg/kg) exhibits rapid onset (over hours to days) antidepressant effects against major depressive disorder in people who are otherwise well. However, its safety, tolerability and efficacy are not known for major depressive disorder in people with advanced life-limiting illnesses. Objective To determine the feasibility, safety, tolerability, acceptability and any antidepressant signal/activity to justify and inform a fully powered study of subcutaneous ketamine infusions for major depressive disorder in the palliative setting. Methods This was a single arm, open-label, phase II feasibility study (Australian New Zealand Clinical Trial Registry Number—ACTRN12618001586202). We recruited adults (≥ 18-years-old) with advanced life-limiting illnesses referred to four palliative care services in Sydney, Australia, diagnosed with major depressive disorder from any care setting. Participants received weekly subcutaneous ketamine infusion (0.1–0.4mg/kg) over two hours using individual dose-titration design. Outcomes assessed were feasibility, safety, tolerability and antidepressant activity. Results Out of ninety-nine referrals, ten participants received ketamine and were analysed for responses. Accrual rate was 0.54 participants/month across sites with 50% of treated participants achieving ≥ 50% reduction in baseline Montgomery-Åsberg Depression Rating Scale, meeting feasibility criteria set a priori. There were no clinically relevant harms encountered. Conclusions A future definitive trial exploring the effectiveness of subcutaneous infusion of ketamine for major depressive disorder in the palliative care setting may be feasible by addressing identified study barriers. Individual dose-titration of subcutaneous ketamine infusions over two hours from 0.1mg/kg can be well-tolerated and appears to produce transient antidepressant signals over hours to days.

Effect of Repeated Intravenous Esketamine on Adolescents With Major Depressive Disorder and Suicidal Ideation: A Randomized Active-Placebo-Controlled Trial

Article

Jul 2023
J AM ACAD CHILD PSY

Objective: Suicide is a major cause of death in adolescents with limited treatment options. Ketamine and its enantiomers have shown rapid antisuicidal effects in adults with major depressive disorder (MDD), but their efficacy in adolescents is unknown. We conducted an active, placebo-controlled trial of intravenous esketamine's safety and efficacy in this population. Method: A total of 54 adolescents (aged 13-18) with MDD and suicidal ideation were included from an inpatient setting and randomly assigned (1:1) to receive three infusions of esketamine (0.25 mg/kg) or midazolam (0.045 mg/kg) over 5 days, with routine inpatient care and treatment. Changes from baseline to 24 hours after the final infusion (Day 6) in the scores of the Columbia Suicide Severity Rating Scale (C-SSRS) Ideation and Intensity (primary outcome) and Montgomery-Åsberg Depression Rating Scale (MADRS, key secondary outcome) were analyzed using linear mixed models. Additionally, the 4-week clinical treatment response was a key secondary outcome. Results: The mean changes in C-SSRS Ideation and Intensity scores from baseline to Day 6 were significantly greater in the esketamine group than in the midazolam group (Ideation, -2.6 [SD=2.0] vs. -1.7 [SD=2.2], P=0.007; Intensity, -10.6 [SD=8.4] vs. -5.0 [SD=7.4], P=0.002), and the changes in MADRS scores from baseline to Day 6 were significantly greater in the esketamine group than in the midazolam group (-15.3 [SD=11.2] vs. -8.8 [SD=9.4], P=0.004). The rates of antisuicidal and antidepressant responses at 4 weeks posttreatment were 69.2% and 61.5% after esketamine, and 52.5% and 52.5% after midazolam, respectively. The most common adverse events in the esketamine group were nausea, dissociation, dry mouth, sedation, headache and dizziness. Conclusion: These preliminary findings indicate that three-dose intravenous esketamine, added to routine inpatient care and treatment, was an effective and well-tolerated therapy for treating adolescents with MDD and suicidal ideation.

CB1 Receptor Silencing Attenuates Ketamine-Induced Hyperlocomotion Without Compromising Its Antidepressant-Like Effects

Article

Sep 2022

Introduction: The antidepressant properties of ketamine have been extensively demonstrated in experimental and clinical settings. However, the psychotomimetic side effects still limit its wider use as an antidepressant. It was recently observed that endocannabinoids are inolved in ketamine induced reward properties. As an increase in endocannabinoid signaling induces antidepressant effects, this study aimed to investigate the involvement of cannabinoid type 1 receptors (CB1R) in the antidepressant and psychostimulant effects induced by ketamine. Methods: We tested the effects of genetic and pharmacological inhibition of CB1R in the hyperlocomotion and antidepressant-like properties of ketamine. The effects of ketamine (10-20 mg/kg) were assessed in the open-field and the forced swim tests (FSTs) in CB1R knockout (KO) and wild-type (WT) mice (male and female), and mice pre-treated with rimonabant (CB1R antagonist, 3-10 mg/kg). Results: We found that the motor hyperactivity elicited by ketamine was impaired in CB1R male and female KO mice. A similar effect was observed upon pharmacological blockade of CB1R in WT mice. However, genetic CB1R deletion did not modify the antidepressant effect of ketamine in male mice submitted to the FST. Surprisingly, pharmacological blockade of CB1R induced an antidepressant-like effect in both male and female mice, which was not further potentiated by ketamine. Conclusions: Our results support the hypothesis that CB1R mediate the psychostimulant side effects induced by ketamine, but not its antidepressant properties.

Efficacy and Safety of Subcutaneous Esketamine in the Treatment of Suicidality in Major Depressive Disorder and Bipolar Depression

Article

Aug 2022
CLIN DRUG INVEST

Background and Objective Affective disorders account for most cases of suicide. The pharmacological arsenal to treat suicidality is limited and available agents take too long to take effect. A large body of evidence shows optimal results of ketamine for treating depression, but the evidence concerning suicidality has not been fully described. We report the first real-world study of severely depressed patients presenting with suicide ideation who were treated with repeated administration of subcutaneous esketamine.Methods We analyzed data from 70 acutely depressed subjects diagnosed with resistant major depressive disorder or bipolar depression. Subjects were administered subcutaneous esketamine once a week for 6 weeks. The primary efficacy endpoint, the change from baseline to 24-h post-administration 6 in the item 10 Montgomery–Åsberg Depression Rating Scale score, was analyzed using a mixed-effects repeated-measures model.ResultsThere were significant effects for time on item 10 Montgomery–Åsberg Depression Rating Scale scores (p < 0.0001) but not for a time × diagnosis interaction (p = 0.164) from baseline to the end of the study. Efficacy of esketamine did not differ between groups (major depressive disorder vs bipolar depression) at any timepoint. Statistical significance on suicidality scores was observed from 24 h after the first administration (p < 0.001), and a further reduction was observed with repeated administrations. Esketamine was safe and well tolerated. Mean heart rate remained stable during the administrations and the blood pressure increase was self-limited.Conclusions Repeated subcutaneous esketamine administration had significant anti-suicidality effects in both major depressive disorder and bipolar groups, with a rapid onset of action and a good tolerability profile. Large randomized controlled trials are warranted to confirm these preliminary findings.

A hidden Markov model reliably characterizes ketamine-induced spectral dynamics in macaque LFP and human EEG

Preprint

Nov 2020

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.

Comparability of blinded remote and site-based assessments of response to esketamine or placebo nasal spray in patients with treatment resistant depression

Article

Apr 2019
J PSYCHIATR RES

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.

Treatment Resistance in Psychiatry Risk Factors, Biology, and Management: Risk Factors, Biology, and Management

Book

Jan 2019

Yong-Ku Kim

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.

Developing Therapies for Treatment-Resistant Depressive Disorder in Animal Models: Risk Factors, Biology, and Management

Chapter

Full-text available

Jan 2019

Michel Sylvain Bourin

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.

The effects of a combination of intravenous dexamethasone and ketamine on postoperative mood in patients undergoing laparoscopically assisted-gynecologic surgery

Article

Full-text available

Aug 2018
PSYCHOPHARMACOLOGY

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.

Ketamine and other glutamate agents

Chapter

Full-text available

May 2017

Clinical Effects and Applications of Ketamine

Chapter

Mar 2017

Mark G. Roback

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.

Investigation of antidepressant-like and anxiolytic-like actions and cognitive and motor side effects of four N-methyl-D-aspartate receptor antagonists in mice

Article

Oct 2016
BEHAV PHARMACOL

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.

Ketamine as a rapid antidepressant: The debate and implications

Article

Jul 2016

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.

Ethical Considerations for Clinical Research and Off-label Use of Ketamine to Treat Mood Disorders: The Balance Between Risks and Benefits

Article

May 2016

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.

Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial

Article

Full-text available

Aug 2013
AM J PSYCHIAT

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.

Synaptic Mechanisms Underlying Rapid Antidepressant Action of Ketamine

Article

Full-text available

Nov 2012
AM J PSYCHIAT

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.

Multi-locus genome-wide association analysis supports the role of glutamatergic synaptic transmission in the etiology of major depressive disorder

Article

Full-text available

Nov 2012

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.

Ketamine Decreases Resting State Functional Network Connectivity in Healthy Subjects: Implications for Antidepressant Drug Action

Article

Full-text available

Sep 2012
PLOS ONE

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.

Synaptic Dysfunction in Depression: Potential Therapeutic Targets

Article

Full-text available

Oct 2012
SCIENCE

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.

Brain-Derived Neurotrophic Factor Val66Met Polymorphism and Antidepressant Efficacy of Ketamine in Depressed Patients

Article

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Jul 2012

Psychiatric safety of ketamine in psychopharmacology research

Article

Full-text available

Apr 2007

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.

Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder

Article

Full-text available

Jun 2012

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.

Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder

Article

Full-text available

Jun 2012
INT J NEUROPSYCHOPH

Synaptic Potentiation Is Critical for Rapid Antidepressant Response to Ketamine in Treatment-Resistant Major Depression

Article

Full-text available

Apr 2012

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.

Course of Improvement in Depressive Symptoms to a Single Intravenous Infusion of Ketamine vs Add-on Riluzole: Results from a 4-Week, Double-Blind, Placebo-Controlled Study

Article

Full-text available

Feb 2012
NEUROPSYCHOPHARMACOL

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.

Ketamine effects on brain GABA and glutamate levels with 1H-MRS: Relationship to ketamine-induced psychopathology

Article

Full-text available

Jan 2012

Molecular Psychiatry publishes work aimed at elucidating biological mechanisms underlying psychiatric disorders and their treatment

Predictive performance of the Domino, Hijazi, and Clements models during low-dose target-controlled ketamine infusions in healthy volunteers

Article

Full-text available

May 2007

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.

NMDA Receptor Blockade at Rest Triggers Rapid Behavioural Antidepressant Responses

Article

Full-text available

Jun 2011
NATURE

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.

Lack of effect of ketamine on cortical glutamate and glutamine in healthy volunteers: A proton magnetic resonance spectroscopy study

Article

Full-text available

May 2011

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.

Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice

Article

Full-text available

Apr 2011

Molecular Psychiatry publishes work aimed at elucidating biological mechanisms underlying psychiatric disorders and their treatment

Short Term Antidepressant Administration Reduces Negative Self-referential Processing in the Medial Prefrontal Cortex in Subjects at Risk for Depression

Article

Full-text available

Mar 2011

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.

mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists

Article

Full-text available

Aug 2010
SCIENCE

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.

Sheline YI, Price JL, Yan Z, Mintun MA. Resting-state functional MRI in depression unmasks increased connectivity between networks via the dorsal nexus. Proc Natl Acad Sci USA 107: 11020-11025

Article

Full-text available

Jun 2010
P NATL ACAD SCI USA

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.

Targeted Electrode-Based Modulation of Neural Circuits for Depression

Article

Full-text available

May 2009
J CLIN INVEST

Helen Mayberg

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.

Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex

Article

Full-text available

May 1997

Subanesthetic doses of ketamine, a noncompetitive NMDA receptor antagonist, impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in schizophrenia and dissociative states, including impaired performance of frontal lobe-sensitive tests. Several lines of evidence suggest that ketamine may impair PFC function in part by interacting with dopamine neurotransmission in this region. This study sought to determine the mechanism by which ketamine may disrupt dopaminergic neurotransmission in, and cognitive functions associated with, the PFC. A thorough dose-response study using microdialysis in conscious rats indicated that low doses of ketamine (10, 20, and 30 mg/kg) increase glutamate outflow in the PFC, suggesting that at these doses ketamine may increase glutamatergic neurotransmission in the PFC at non-NMDA glutamate receptors. An anesthetic dose of ketamine (200 mg/kg) decreased, and an intermediate dose of 50 mg/kg did not affect, glutamate levels. Ketamine, at 30 mg/kg, also increased the release of dopamine in the PFC. This increase was blocked by intra-PFC application of the AMPA/kainate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione CNQX. Furthermore, ketamine-induced activation of dopamine release and impairment of spatial delayed alternation in the rodent, a PFC-sensitive cognitive task, was ameliorated by systemic pretreatment with AMPA/kainate receptor antagonist LY293558. These findings suggest that ketamine may disrupt dopaminergic neurotransmission in the PFC as well as cognitive functions associated with this region, in part, by increasing the release of glutamate, thereby stimulating postsynaptic non-NMDA glutamate receptors.

Two views of brain functioning

Chapter

Jan 2013

M.E. Raichle

Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders

Conference Paper

Jan 2010

G. Sanacora

Cellular mechanisms forming the basis of the antidepressant effects of ketamine: Role of alpha-amino-3-hydroxymethylisoxazol-4-propionic acid receptors

Article

Oct 2009

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.

Suppression of Regional Cerebral Blood during Emotional versus Higher Cognitive Implications for Interactions between Emotion and Cognition

Article

Aug 2010

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.

Sleep and Synaptic Homeostasis

Article

Feb 2005
BEHAV BRAIN SCI

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.

Capturing the Angel in "Angel Dust": Twenty Years of Translational Neuroscience Studies of NMDA Receptor Antagonists in Animals and Humans

Article

Aug 2012

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.

Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression

Article

Jul 2012

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.

Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects

Article

Apr 2005

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.

Neural Circuits Underlying the Pathophysiology of Mood Disorders

Article

Dec 2011

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.

H-1-[C-13]-Nuclear Magnetic Resonance Spectroscopy Measures of Ketamine's Effect on Amino Acid Neurotransmitter Metabolism

Article

Dec 2011

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.

An investigation of amino-acid neurotransmitters as potential predictors of clinical improvement to ketamine in depression

Article

Nov 2011
INT J NEUROPSYCHOPH

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.

Liu RJ, Lee FS, Li XY, Bambico F, Duman RS, Aghajanian GK. Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry 71: 996-1005

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

Abstract

No full-text available