Ketamine Therapy Research Articles

Factors Influencing Perceived Helpfulness and Participation in Innovative Research:A Pilot Study of Individuals with and without Mood Symptoms

ABSTRACT Little is known about how individuals with and without mood disorders perceive the inherent risks and helpfulness of participating in innovative psychiatric research, or about the factors that influence their willingness to participate. We conducted an online survey with 80 individuals (self-reported mood disorder [n = 25], self-reported good health [n = 55]) recruited via MTurk. We assessed respondents’ perceptions of risk and helpfulness in study vignettes associated with two innovative research projects (intravenous ketamine therapy and wearable devices), as well as their willingness to participate in these projects. Respondents with and without mood disorders perceived risk similarly across projects. Respondents with no mood disorders viewed both projects as more helpful to society than to research volunteers, while respondents with mood disorders viewed the projects as equally helpful to volunteers and society. Individuals with mood disorders perceived ketamine research, and the two projects on average, as more helpful to research volunteers than did individuals without mood disorders. Our findings add to a limited empirical literature on the perspectives of volunteers in innovative psychiatric research.

Ketamine-Assisted and Culturally Attuned Trauma Informed Psychotherapy as Adjunct to Traditional Indigenous Healing: Effecting Cultural Collaboration in Canadian Mental Health Care.

Ketamine therapy with culturally attuned trauma-informed psychotherapy in a collaborative cross-cultural partnership may provide a critical step in the operationalization and optimization of treatment effectiveness in diverse populations and may provide a foundation for an improved quality of life for Indigenous people. Decolonizing Indigenous health and wellbeing is long overdue, requiring an equal partnership between government and Indigenous communities, built upon an aboriginal culture holistic foundation of balance of mind, body, social and spiritual realms, and within the context of historical and lived experiences of colonialism. Culturally attuned trauma-informed psychotherapy paired with ketamine—a fast-acting antidepressant that typically takes effect within 4 hours, even in cases of acute suicidality—may be uniquely qualified to integrate into an Indigenous based health system, since ketamine’s therapeutic effects engage multiple neuropsychological, physiological, biological, and behavioral systems damaged by intergenerational complex developmental trauma. Ketamine holds the potential to serve as a core treatment modality around which culturally engaged treatment approaches might be organized since its brief alteration of normal waking consciousness is already a familiar and intrinsic element of healing culture in many Indigenous societies. There is great need and desire in Indigenous communities for respectful and sacred partnership in fostering more effective mental health outcomes and improved quality of life.

Ketamine therapy for chronic pain in The Netherlands: a nationwide survey.

Ketamine is used to treat chronic refractory pain. However, there are no scientific guidelines for ketamine use in the Netherlands. The aim of this survey was to provide an overview of the use of ketamine for chronic pain in the Netherlands. All pain clinics in the Netherlands were contacted. A digital survey, available from June 2019 to January 2020, was sent to 68 pain clinics. The survey was completed by one pain physician as a representative of the entire pain department. The survey included questions about ketamine treatment indications, administration, dose, duration, treatment repetition and the inpatient or outpatient setting. The survey was completed by 51 pain clinics (75.0%). Thirty-one clinics used ketamine for chronic pain treatment. The most common indication was Complex Regional Pain Syndrome (83.9%). Pain clinics administered ketamine via intravenous infusions (96.8%), iontophoresis (61.3%), subcutaneous (3.2%) or oral administration (3.2%). Intravenous ketamine treatment was offered in an inpatient setting in 14 pain clinics, in both an inpatient and outpatient setting in 11 pain clinics and in six pain clinics in an outpatient setting. In the outpatient setting, the median starting dose was 5mg/h (IQR=17.5-5). The median maximum dose was 27.5mg/h (IQR=100-11.9). The median infusion duration was 6h (IQR=8-4). In the inpatient setting, the median starting dose was 5mg/h (IQR=5-1.5) and the median maximum dose was 25mg/h (IQR=25-14). Patients were admitted to hospital for a median of 4days (IQR=5-1). The results of this Dutch nationwide survey study show that there are heterogeneous treatment protocols with different indications, treatment setting and dosing regimen for the treatment of chronic pain with ketamine.This study encourages the formulation of a broader consensus and the development of evidence based guidelines for ketamine treatment.

Combining Ketamine and Internet-Based Cognitive Behavioral Therapy for the Treatment of Posttraumatic Stress Disorder: Protocol for a Randomized Controlled Trial.

BackgroundOver one third of patients with posttraumatic stress disorder (PTSD) do not respond to current interventions. Ketamine presents a potential treatment option; however, its effects are temporary. Administering ketamine alongside psychotherapy is one potential means of prolonging its effects; however, only a few studies have investigated this treatment method to date, and none have tested ketamine with internet-based or electronically delivered cognitive behavioral therapy (e-CBT).ObjectiveThis open-label randomized controlled trial aims to assess the efficacy of a combined treatment method of subanesthetic intravenous ketamine and e-CBT for treating patients with PTSD.MethodsIn total, 20 patients with refractory PTSD recruited from a community clinic will be randomly assigned to either an experimental group (n=10), receiving a combination of ketamine and therapist-administered e-CBT over 14 weeks, or a waitlist control group (n=10), receiving the experimental treatment after 14 weeks. Both groups will be assessed for the symptoms of PTSD and comorbid disorders before treatment, at two midway points, and at the end of the experiment.ResultsPTSD symptoms of participants in the experimental group are expected to improve significantly more than those of participants in the waitlist control group (P=.05) with a large effect size (η2=0.14).ConclusionsThis is the first study to assess the relationship between e-CBT and ketamine and their combined ability to treat refractory PTSD. If successful, this study will open web-based, asynchronous therapeutic options for patients with PTSD and will provide new insights into the functional role of glutamate in trauma-related disorders as well as in learning, memory, and fear extinction.Trial RegistrationClinicalTrials.gov NCT04771767; https://clinicaltrials.gov/ct2/show/NCT04771767.International Registered Report Identifier (IRRID)PRR1-10.2196/30334

Stability of 10-mg/mL and 50-mg/mL ketamine oral solutions.

Ketamine is an anesthetic agent commonly used for the induction of anesthesia. Ketamine is also given to control pain, for treatment of posttraumatic stress disorder, and to induce bronchodilation in refractory asthma. Moreover, ketamine therapy is gaining ground as an intervention for patients with treatment-resistant depression and individuals who have depression with serious suicidal ideation. Recently, the drug has been used to disrupt maladaptive reward memories in individuals with harmful alcohol consumption behaviors. The stability of 10-mg/mL and 50-mg/mL ketamine solutions stored at ambient and refrigeration temperatures was assessed over 90 days. Three batches of 10-mg/mL and 50-mg/mL ketamine solutions were stored for 90 days under two temperature conditions (2°C-8°C and 22°C-25°C) in amber plastic bottles. Chemical stability was assessed using a stability-indicating high-performance liquid chromatography assay. At each study time, visual inspection and pH assessments of ketamine concentration and pH were conducted. For all solutions tested at each condition, the ketamine concentration remaining was at least 98% of the initial concentration over 90 days of storage. Throughout the study period, solution pH remained stable and the color and odor of the suspensions remained unchanged. Extemporaneously compounded 10-mg/mL and 50-mg/mL oral solutions of ketamine prepared in a flavored suspending excipient and stored in amber polypropylene plastic bottles were stable for at least 90 days at both ambient and refrigeration temperatures.

Copper Concentrations in Ketamine Therapy for Treatment-Resistant Depression.

Changes in serum copper concentration are observed in patients with depressive symptoms. Unmet needs in contemporary antidepressant treatment have increased interest in non-monoaminergic antidepressants, such as ketamine, an anaesthetic drug that has demonstrated a rapid antidepressant effect in patients with treatment-resistant depression (TRD). The purpose of this study was to examine whether serum copper concentrations change during ketamine treatment and whether there is an association between the copper concentrations and treatment response measured using psychometric scale scores. Moreover, the interlink between somatic comorbidities and copper concentration was studied. Patients with major depressive disorder or bipolar disorder were rated weekly by a clinician using the Montgomery–Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS). Copper level assessments were carried out weekly before the start of ketamine treatment and then after every second infusion and one week after the last ketamine infusion. The serum concentration of copper before ketamine treatment was significantly higher than that after the fifth infusion (p = 0.016), and the serum concentration after the treatment was significantly higher than that after the fifth infusion (p = 0.048). No significant correlations between changes in the copper serum concentrations and MADRS or YMRS were found. The serum copper level was not associated with somatic comorbidities during the course of treatment. This study provides data on the role of copper in short-term intravenous ketamine treatment in TRD, although no clear evidence of a connection between the copper level and treatment response was found.

Modulation of the functional connectome in major depressive disorder by ketamine therapy.

Subanesthetic ketamine infusion therapy can produce fast-acting antidepressant effects in patients with major depression. How single and repeated ketamine treatment modulates the whole-brain functional connectome to affect clinical outcomes remains uncharacterized. Data-driven whole brain functional connectivity (FC) analysis was used to identify the functional connections modified by ketamine treatment in patients with major depressive disorder (MDD). MDD patients (N = 61, mean age = 38, 19 women) completed baseline resting-state (RS) functional magnetic resonance imaging and depression symptom scales. Of these patients, n = 48 and n = 51, completed the same assessments 24 h after receiving one and four 0.5 mg/kg intravenous ketamine infusions. Healthy controls (HC) (n = 40, 24 women) completed baseline assessments with no intervention. Analysis of RS FC addressed effects of diagnosis, time, and remitter status. Significant differences (p < 0.05, corrected) in RS FC were observed between HC and MDD at baseline in the somatomotor network and between association and default mode networks. These disruptions in FC in MDD patients trended toward control patterns with ketamine treatment. Furthermore, following serial ketamine infusions, significant decreases in FC were observed between the cerebellum and salience network (SN) (p < 0.05, corrected). Patient remitters showed increased FC between the cerebellum and the striatum prior to treatment that decreased following treatment, whereas non-remitters showed the opposite pattern. Results support that ketamine treatment leads to neurofunctional plasticity between distinct neural networks that are shown as disrupted in MDD patients. Cortico-striatal-cerebellar loops that encompass the SN could be a potential biomarker for ketamine treatment.

Combining Ketamine, Brain Stimulation (rTMS) and Mindfulness Therapy (TIMBER) for Opioid Addiction.

Opioid addiction in the United States currently presents a national crisis despite availability of different treatments. Prior findings suggest that both repetitive transcranial magnetic stimulation (rTMS) and subanesthetic dose of ketamine are efficacious in patients with opioid use disorders (OUD) when administered in isolation. However, their therapeutic value may be undermined by varying clinical responses that tend to dissipate with treatment cessation. There has been no study to date that has used a combination of both for OUD, and there are still many unanswered questions with respect to both. TIMBER (Trauma Interventions using Mindfulness Based Extinction and Reconsolidation of memories) therapy attempts to alter the expression of emotionally charged memories such as traumatic memories, and has been successfully tried in chronic post-traumatic stress disorder (PTSD) and in combination with memory-altering pharmacotherapy like ketamine infusion. By a combination of extinction and reconsolidation of memory approaches, TIMBER works to not over-flood and/or retraumatize as is seen in other treatment approaches. TIMBER involves a balanced combination of both the memory extinction and memory reconsolidation approaches (rather than extinction-only approaches) which explains its superior efficacy in PTSD and benefit in substance use disorders.

Intraoperative Ketamine and Magnesium Therapy to Control Postoperative Pain After Abdominoplasty and/or Liposuction: A Clinical Randomized Trial.

PurposeThis study aimed to compare the effects of ketamine and ketamine associated with magnesium on opioid consumption and pain scores in patients undergoing abdominoplasty and/or liposuction compared to standard treatment.Patients and MethodsA total of 63 patients were included and randomized as follows: 21 patients in the Control group, 20 patients in the Ketamine group (Ket), and 22 patients in the Ketamine-magnesium group (KetMag). The KetMag group received an IV bolus of 0.3 mg/kg of ketamine and 50 mg/kg magnesium, followed by continuous infusion of ketamine (0.15 mg/kg/h) and magnesium (10 mg/kg/h) until extubation. The Ket group received the same bolus and infusion of ketamine, together with a bolus and continuous infusion of placebo instead of magnesium. The Control group received saline instead of ketamine and magnesium. The groups were compared in morphine consumption during the first 12h, body-postoperative pain and disability scale until the 90th day, the time until the first morphine request on the PCA pump, pain scores, and the adverse effects related to the use of study drugs.ResultsThe KetMag group had a lower morphine consumption by almost 50% during the first 12h than the Control and the Ket groups. In addition, the KetMag group required the first dose of morphine later than the other two groups. There were no differences in the adverse effects of the proposed treatments. Finally, multiple linear regression and a nonlinear approach analysis indicated that the Control group experienced a higher degree of pain and increased morphine consumption per hour than Ket and KetMag groups.ConclusionCo-administration of intraoperative ketamine plus magnesium and ketamine alone are an effective and easy regime for reducing pain and opioid consumption in the postoperative period.

A half-century of participant observation in psychiatry. Part III: psychopharmacology.

The third part of the triptych of my 50-year activity in psychiatry is about psychopharmacology. This way of treatment changed the picture of contemporary psychiatry. The introduction of neuroleptic (antipsychotic) drugs and tricyclic antidepressants in the 1950s resulted in a therapeutic revolution and contributed to the ‛medicalization' of psychiatry and its therapeutic similarity to other non-surgical specialties. Adiscovery of prophylactic lithium activity in the1960s initiated the mood-stabilizing drugs.During the last half-century, the most dynamic was the 1990s when most antipsychotic and antidepressant drugs of the so-called new generation were introduced. The twenty-first century marks a debut of next antidepressant and antipsychotic drugs, some of the latter having long-acting injectable preparations. An interesting event was a demonstration of the antidepressant activity of ketamine. My research domain in psychopharmacology was lithium treatment of affective illnesses. Lithium makes the topic of many papers I authored, more than 150 of them are in the PubMed database. Many clinical and research aspects related to lithium administration have been reported as first in Polish literature and some are pioneering in the world. Recently, I wrote the book Lithium - the amazing drug in psychiatry which has also its English version. I have carried much research on antidepressant drugs, pharmacotherapy of treatment-resistant depression, and mood-stabilizing drugs for which I proposed a modern classification. I participated in European projects EUFEST and OPTIMISE on the optimization of using antipsychotic drugs in schizophrenia. I also performed much research on the antidepressant effect of ketamine and electroconvulsive therapy.

Anxiolytic effects of acute and maintenance ketamine, as assessed by the Fear Questionnaire subscales and the Spielberger State Anxiety Rating Scale.

Ketamine has rapid anxiolytic effects in treatment-resistant obsessive compulsive, post-traumatic stress, generalised anxiety and social anxiety disorders. This study aimed to assess changes following acute and maintenance ketamine therapy on the Fear Questionnaire (FQ) subscales and the Spielberger State Anxiety Inventory (SSAI). This secondary analysis used data from a mixed open-label and double-blinded placebo-controlled study. A total of 24 patients received short-term ascending subcutaneous doses of ketamine and were then eligible to enter a 3-month maintenance phase of 1 mg/kg ketamine dosed once or twice weekly. FQ and SSAI data were analysed using mixed models to identify between-dose differences and to describe trends during maintenance. Acute ketamine dosing showed a rapid dose-related reduction in all three FQ subscales (agoraphobia, social phobia and blood-injury phobia) and in the SSAI. A progressive decrease in pre-dose rating-scale scores was evident during the 3 months of maintenance therapy. Ketamine demonstrated dose-related improvements in all FQ subscales and in the SSAI. Both scales appear to be suitable tools to assess the anxiolytic effects of ketamine in patients with treatment-resistant anxiety. Furthermore, ketamine appears to have broad, dose-related anti-phobic effects. These findings raise the possibility that ketamine may have therapeutic potential in the treatment of other phobic states, such as specific phobia.

Modulation of inhibitory control networks relate to clinical response following ketamine therapy in major depression

Subanesthetic ketamine is found to induce fast-acting and pronounced antidepressant effects, even in treatment resistant depression (TRD). However, it remains unclear how ketamine modulates neural function at the brain systems-level to regulate emotion and behavior. Here, we examined treatment-related changes in the inhibitory control network after single and repeated ketamine therapy in TRD. Forty-seven TRD patients (mean age = 38, 19 women) and 32 healthy controls (mean age = 35, 18 women) performed a functional magnetic resonance imaging (fMRI) response inhibition task at baseline, and 37 patients completed the fMRI task and symptom scales again 24 h after receiving both one and four 0.5 mg/kg intravenous ketamine infusions. Analyses of fMRI data addressed effects of diagnosis, time, and differences between treatment remitters and non-remitters. Significant decreases in brain activation were observed in the inhibitory control network, including in prefrontal and parietal regions, and visual cortex following serial ketamine treatment, p < 0.05 corrected. Remitters were distinguished from non-remitters by having lower functional activation in the supplementary motor area (SMA) prior to treatment, which normalized towards controls following serial ketamine treatment. Results suggest that ketamine treatment leads to neurofunctional plasticity in executive control networks including the SMA during a response-inhibitory task. SMA changes relate to reductions in depressive symptoms, suggesting modulation of this network play an important role in therapeutic response. In addition, early changes in the SMA network during response inhibition appear predictive of overall treatment outcome, and may serve as a biomarker of treatment response.

A comparative study of ketamine vs electroconvulsive therapy in the management of major depressive disorder

Objective The aim was to investigate the efficacy of ketamine vs electroconvulsive therapy (ECT) in hospitalized patients suffering from treatment-resistant major depressive disorder (MDD). Background Both propofol and ketamine are the commonly used anesthetic agents, but recent clinical studies have suggested that ketamine has rapid-acting antidepressant properties, itself, at subanesthetic doses. Patients and methods A clinical comparative randomized cross-sectional study was conducted on 20 patients suffering from treatment-resistant MDD, and receiving ketamine only (group 1) and 20 patients suffering from treatment-resistant MDD receiving ECT only (group 2), who were recruited from inpatients wards of Neuropsychiatry Department, Menoufia University and Met-Khalaf Hospital for Psychiatric Health from December 1, 2018 until March 14, 2019. All participates were subjected to full detailed general medical, neurological, and psychiatric history and examination. Results There was a statistically insignificant differences between the studied patients regarding the types of depression (P = 0.61). Bipolar depression and MDDs were represented in 57 and 54% in the ECT group and 43 and 46% in the Ketamine group, respectively. Also, catatonic depression, melancholic subtype, and seasonal affective disorder were represented by 80, 66.7, and 100% in the Ketamine group vs 20, 33.3, and 0.00% in ECT group, respectively. Conclusion There was statistically significant difference between the ketamine group and ECT, regarding the efficacy of both ketamine and ECT in favor of the ketamine group as ketamine has a more rapid effect in improving depressive symptoms in MDD patients and have more rapid antidepressant effects compared with ECT.

Ketamine as adjunct to midazolam treatment following soman-induced status epilepticus reduces seizure severity, epileptogenesis, and brain pathology in plasma carboxylesterase knockout mice

Delayed treatment of cholinergic seizure results in benzodiazepine-refractory status epilepticus (SE) that is thought, at least in part, to result from maladaptive trafficking of N-methyl-d-aspartate (NMDA) and gamma-aminobutyric acid type A (GABAA) receptors, the effects of which may be ameliorated by combination therapy with the NMDA receptor antagonist ketamine. Our objective was to establish whether ketamine and midazolam dual therapy would improve outcome over midazolam monotherapy following soman (GD) exposure when evaluated in a mouse model that, similar to humans, lacks plasma carboxylesterase, greatly reducing endogenous scavenging of GD. In the current study, continuous cortical electroencephalographic activity was evaluated in male and female plasma carboxylesterase knockout mice exposed to a seizure-inducing dose of GD and treated with midazolam or with midazolam and ketamine combination at 40 min after seizure onset. Ketamine and midazolam combination reduced GD-induced lethality, seizure severity, and the number of mice that developed spontaneous recurrent seizure (SRS) compared with midazolam monotherapy. In addition, ketamine–midazolam combination treatment reduced GD-induced neuronal degeneration and microgliosis. These results support that combination of antiepileptic drug therapies aimed at correcting the maladaptive GABAA and NMDA receptor trafficking reduces the detrimental effects of GD exposure. Ketamine may be a beneficial adjunct to midazolam in reducing the epileptogenesis and neuroanatomical damage that follows nerve agent exposure and pharmacoresistant SE.

A randomized, crossover comparison of ketamine and electroconvulsive therapy for treatment of major depressive episodes: a Canadian biomarker integration network in depression (CAN-BIND) study protocol

BackgroundRecent evidence underscores the utility of rapid-acting antidepressant interventions, such as ketamine, in alleviating symptoms of major depressive episodes (MDE). However, to date, there have been limited head-to-head comparisons of intravenous (IV) ketamine infusions with other antidepressant treatment strategies in large randomized trials. This study protocol describes an ongoing multi-centre, prospective, randomized, crossover, non-inferiority trial comparing acute treatment of individuals meeting diagnostic criteria for a major depressive episode (MDE) with ketamine and electroconvulsive therapy (ECT) on efficacy, speed of therapeutic effects, side effects, and health care resource utilization. A secondary aim is to compare a 6-month maintenance strategy for ketamine responders to standard of care ECT maintenance. Finally, through the measurement of clinical, cognitive, neuroimaging, and molecular markers we aim to establish predictors and moderators of treatment response as well as treatment-elicited effects on these outcomes.MethodsAcross four participating Canadian institutions, 240 patients with major depressive disorder or bipolar disorder experiencing a MDE are randomized (1:1) to a course of ECT or racemic IV ketamine (0.5 mg/kg) administered 3 times/week for 3 or 4 weeks. Non-responders (< 50% improvement in Montgomery-Åsberg Depression Rating Scale [MADRS] scores) crossover to receive the alternate treatment. Responders during the randomization or crossover phases then enter the 6-month maintenance phase during which time they receive clinical assessments at identical intervals regardless of treatment arm. ECT maintenance follows standard of care while ketamine maintenance involves: weekly infusions for 1 month, then bi-weekly infusions for 2 months, and finally monthly infusions for 3 months (returning to bi-weekly in case of relapse). The primary outcome measure is change in MADRS scores after randomized treatment as assessed by raters blind to treatment modality.DiscussionThis multi-centre study will help identify molecular, imaging, and clinical characteristics of patients with treatment-resistant and/or severe MDEs who would benefit most from either type of therapeutic strategy. In addition to informing clinical practice and influencing health care delivery, this trial will add to the robust platform and database of CAN-BIND studies for future research and biomarker discovery.Trial registrationClinicalTrials.gov identifier NCT03674671. Registered September 17, 2018.

Modulation of Inhibitory Control Networks Relate to Clinical Response following Ketamine Therapy in Major Depression

Subanesthetic ketamine is found to induce fast-acting and pronounced antidepressant effects, even in treatment resistant depression (TRD). However, it remains unclear how ketamine modulates neural function at the brain systems-level to regulate emotion and behavior. Here, we examined treatment-related changes in the inhibitory control network after single and repeated ketamine therapy in TRD. Forty-seven TRD patients (mean age = 38, 19 women) and 32 healthy controls (mean age = 35, 18 women) performed a functional magnetic resonance imaging (fMRI) response inhibition task at baseline, and 37 patients completed the fMRI task and symptom scales again 24 h after receiving both one and four 0.5 mg/kg intravenous ketamine infusions. Analyses of fMRI data addressed effects of diagnosis, time, and differences between treatment remitters and non-remitters. Significant decreases in brain activation were observed in the inhibitory control network, including in prefrontal and parietal regions, and visual cortex following serial ketamine treatment, p < 0.05 corrected. Remitters were distinguished from non-remitters by having lower functional activation in the supplementary motor area (SMA) prior to treatment, which normalized towards controls following serial ketamine treatment. Results suggest that ketamine treatment leads to neurofunctional plasticity in executive control networks including the SMA during a response-inhibitory task. SMA changes relate to reductions in depressive symptoms, suggesting modulation of this network play an important role in therapeutic response. In addition, early changes in the SMA network during response inhibition appear predictive of overall treatment outcome, and may serve as a biomarker of treatment response.

Ketamine plus propofol-electroconvulsive therapy (ECT) transiently improves the antidepressant effects and the associated brain functional alterations in patients with propofol-ECT-resistant depression

New methods for using ketamine in patients with propofol-electroconvulsive therapy-resistant depression (ECT-RD) are needed in the clinic. This study aimed to investigate the therapeutic efficacy of ketamine plus ECT in ECT-RD patients, along with the treatment-induced brain alterations. A total of 28 ECT-RD patients were intravenously injected with ketamine six times and treated with propofol-ECT six times alternately within two weeks. The Hamilton Depression Scale was used to assess the treatment effect. Global functional connectivity density (gFCD) and functional connectivity strength (FCS) were used to evaluate functional brain alterations. As compared with the propofol-ECT treatment group, the addition of ketamine could improve the therapeutic outcomes in patients with ECT-RD. The treatment increased gFCD in the left temporal and subgenual anterior cingulated cortex. Simultaneously, the treatment decreased FCS within the default mode network. Although increased functional connectivity could be sustained for 10 days, the clinical effect was only sustained 7 days, indicating that the clinical effect and functional brain alterations were disjointed. Ketamine plus propofol-ECT can obviously improve the effects of propofol-ECT in ECT-RD patients. However, the effect is limited in 7 days, suggesting the benefit is short-term.

Modulation of amygdala reactivity following rapidly acting interventions for major depression.

Electroconvulsive therapy (ECT) and ketamine treatment both induce rapidly acting antidepressant effects in patients with major depressive disorder unresponsive to standard treatments, yet their specific impact on emotion processing is unknown. Here, we examined the neural underpinnings of emotion processing within and across patients (N = 44) receiving either ECT (N = 17, mean age: 36.8, 11.0 SD) or repeated subanesthetic (0.5 mg/kg) intravenous ketamine therapy (N = 27, mean age: 37.3, 10.8 SD) using a naturalistic study design. MRI and clinical data were collected before (TP1) and after treatment (TP2); healthy controls (N = 31, mean age: 34.5, 13.5 SD) completed one MRI session (TP1). An fMRI face‐matching task probed negative‐ and positive‐valence systems. Whole‐brain analysis, comparing neurofunctional changes within and across treatment groups, targeted brain regions involved in emotional facial processing, and included regions‐of‐interest analysis of amygdala responsivity. Main findings revealed a decrease in amygdalar reactivity after both ECT and ketamine for positive and negative emotional face processing (p < .05 family wise‐error (FWE) corrected). Subthreshold changes were observed between treatments within the dorsolateral prefrontal cortex and insula (p < .005, uncorrected). BOLD change for positive faces in the inferior parietal cortex significantly correlated with overall symptom improvement, and BOLD change in frontal regions correlated with anxiety for negative faces, and anhedonia for positive faces (p < .05 FWE corrected). Both serial ketamine and ECT treatment modulate amygdala response, while more subtle treatment‐specific changes occur in the larger functional network. Findings point to both common and differential mechanistic upstream systems‐level effects relating to fast‐acting antidepressant response, and symptoms of anxiety and anhedonia, for the processing of emotionally valenced stimuli.

Comparative Efficacy of Ketamine in Treatment-Resistant Depression

Patients who have not responded to two antidepressant trials in their current depressive episode are usually considered to have treatment-resistant depression (TRD). A detailed search on PubMed was conducted for reported response and remission rates for non-ketamine and ketamine treatments for TRD. From a variety of pharmacological and brain stimulation open-label studies, the treatments were found to have similar response and remission rates of 30% to 70% and 20% to 50%, respectively. For randomized placebo-controlled trials, reported response and remission rates were 15% to 60% and 10% to 40%, respectively. Ketamine and electroconvulsive therapy both have response and remission rates at the higher end of these ranges, and their significant advantage is their fast action in an acute setting. Direct comparative efficacy studies with large sample sizes will be needed to establish any margin of increased benefit of one treatment modality compared to the other. [ Psychiatr Ann . 2020;50(2):62–67.]

Neurobiological biomarkers of response to ketamine.

As a field, psychiatry is undergoing an exciting paradigm shift toward early identification and intervention that will likely minimize both the burden associated with severe mental illnesses as well as their duration. In this context, the rapid-acting antidepressant ketamine has revolutionized our understanding of antidepressant response and greatly expanded the pharmacologic armamentarium for treatment-resistant depression. Efforts to characterize biomarkers of ketamine response support a growing emphasis on early identification, which would allow clinicians to identify biologically enriched subgroups with treatment-resistant depression who are more likely to benefit from ketamine therapy. This chapter presents a broad overview of a range of translational biomarkers, including those drawn from imaging and electrophysiological studies, sleep and circadian rhythms, and HPA axis/endocrine function as well as metabolic, immune, (epi)genetic, and neurotrophic biomarkers related to ketamine response. Ketamine's unique, rapid-acting properties may serve as a model to explore a whole new class of novel rapid-acting treatments with the potential to revolutionize drug development and discovery. However, it should be noted that although several of the biomarkers reviewed here provide promising insights into ketamine's mechanism of action, most studies have focused on acute rather than longer-term antidepressant effects and, at present, none of the biomarkers are ready for clinical use.