Ketamine Research

Depression is a mental illness characterized by episodes of a sad, despondent mood and/or a loss of interest or pleasure (1). This pathology affects nearly 20% of the population in the United States (2), and treatments are limited. Indeed, in the 5 years following remission, 80% of patients will endure relapse and more than 30% of patients suffer from treatment-resistant depression. Recently, the U.S. Food and Drug Administration (FDA) approved the clinical use of esketamine nasal spray for depression that is resistant to other treatments (3). Esketamine is an enantiomer of ketamine, a drug with antidepressant properties, although its mechanism of action remains unclear. Brain imaging studies suggest that neuronal circuitry in the medial prefrontal cortex (mPFC) is involved in the physiopathology of this disorder (4). On page 147 of this issue, Moda-Sava et al. (5) report that ketamine induces plasticity of dendritic spines on mPFC neurons and restores microcircuit activity and behavior in animal models of depression. This may expand therapeutic strategies for treating major depression.

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Two new studies suggest the psychiatric benefits of ketamine treatment may extend beyond just the targeting of depression. The research demonstrates ketamine may be helpful in targeting both anxiety- and substance abuse-related depression.

Although ketamine is a relatively old drug, originally developed in the 1950s as an anesthetic, over the last decade a growing body of research has affirmed its unique, and rapid, antidepressant effects. The anecdotal effects of the drug on depression have raced ahead of scientific research so quickly that ketamine clinics have popped up all across the United States, where the drug can be administered for up to US$1,000 a dose.

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Ketamine infusions elicit different responses among 3 distinct subgroups of individuals dealing with depression and suicidal ideation. One group, remitters, had no suicidal ideation by day 2, and another group, responders, showed improvement independent of depressed mood, according to a study published in the Journal of Affective Disorders.

Researchers pooled data from 5 clinical trials involving treatment-resistant individuals with major depressive disorder or bipolar depression (N=128). All participants received a ketamine infusion and were evaluated at baseline and days 1 through 3. Evaluations included plasma markers to monitor neurotrophic factors, kynurenine pathway analytes, inflammatory cytokines, cortisol, and suicidal ideation composite scores to monitor depressed mood, hopelessness, sadness, and suicidal thoughts.

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Ketamine, a widely used anesthetic that’s also an illicit party drug, has taken on a new role in recent years: treating severe depression in people who have not responded to standard treatment. Researchers have called it the most exciting breakthrough in the field of depression research in the past half-century.

One form of the drug, being developed as a nasal spray called esketamine, is in the final stages of testing needed before it can go to the FDA for approval.

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A low dose of ketamine infusion can provide a rapid and sustained antidepressant effect in patients with treatment-resistant depression, according to a study published in the Journal of Affective Disorders. In addition, a subanesthetic dose of ketamine was shown to improve functional impairment traditionally associated with treatment-resistant depression.

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Average scores on the Children's Depression Rating Scale dropped by 42.5% following low-dose IV ketamine infusions among 13 teenagers with treatment-resistant depression, findings published in Journal of Child and Adolescent Psychopharmacology showed.

“Adult [treatment-resistant depression] research has begun to explore repeated administrations of ketamine, which may have promise for greater effectiveness and longer remission periods than single doses,” Kathryn R. Cullen, MD, division of child and adolescent psychiatry, University of Minnesota Medical School, and colleagues wrote.

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Adolescents treated with intravenous ketamine for treatment-resistant depression showed a significant average decrease— 42.5%—in Children’s Depression Rating Scale scores, according to a small, open-label study published online in the Journal of Child and Adolescent Psychopharmacology.

“Novel interventions for treatment-resistant depression (TRD) in adolescents are urgently needed,” wrote researchers. “Ketamine has been studied in adults with TRD, but little information is available for adolescents.”

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A new study has shown a significant average decrease in the Children's Depression Rating Scale (42.5%) among adolescents with treatment-resistant depression (TRD) who were treated with intravenous ketamine. The study, which demonstrated the tolerability and potential role of ketamine as a treatment option for adolescents with TRD, is published in Journal of Child and Adolescent Psychopharmacology.

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While depression is a treatable condition, some individuals do not respond to conventional prescription medications or talk therapies.

It can be a long and frustrating road for those with treatment-resistant depression who seek help, but Dr. Pierre Blier, Director of Mood Disorder Research at The Royal’s Institute of Mental Health Research (IMHR), has been able to offer hope to some of these individuals, via a cutting-edge treatment that uses an old drug in a new and effective way.

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Results of a recent study indicate that response to ketamine treatment in mood disorders may be better predicted based on existing baseline metabolic-inflammatory alterations, most notably cognitive impairment.

Researchers aimed to identify mood disorder subpopulations that were more, or less, likely to respond to treatment with ketamine. Current literature indicates that ketamine has a quick antidepressant effect on treatment-resistant depression symptoms in patients with both major depressive disorder (MDD) and bipolar disorder. The authors focused their study on predictive pretreatment elements in these disorders.

They searched PubMed/MEDLINE, ClinicalTrials.gov, and Scopus for relevant literature and bibliographies that included terms such as major depressive disorder, depression, bipolar disorder, remission.

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Depression is common in the hospice and palliative care population,withprevalence estimates ranging from 17% in the palliative care population to up to 40% in hospice patients. Depressive disorders such as major depression frequently go unrecognized or undertreated, and are associated with significant disability, impaired quality of life, and increased healthcare utilization.

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Recent studies demonstrating a rapid, robust improvement in treatment resistant depression (TRD) following a single sub-anesthetic infusion of ketamine have generated much excitement. However, these studies are limited in their generalizability to the broader TRD population due to their subject exclusion criteria which typically limit psychiatric comorbidity, concurrent medication, and level of suicide risk. This paper describes the safety and efficacy of sub-anesthetic ketamine infusions in a naturalistic TRD patient sample participating in a real-world TRD treatment program within a major university health system.

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A decade has now passed since research into the antidepressant effects of ketamine began in earnest, after the clinical trial reported by Zarate et al. in 2006 (1). In that proof-of-concept study, 18 medication-free patients with treatment-resistant major depressive disorder (TRD) showed a large reduction in core depressive symptoms within hours of receiving a single low-dose 0.5 mg/kg intravenous infusion of ketamine as measured by the 21-item Hamilton Depression Rating Scale compared with saline placebo.

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Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms.

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Ketamine, an N-methyl-D-aspartate glutamate receptor antagonist, has demonstrated a rapid-onset antidepressant effect in patients with treatment-resistant depression. This study evaluated the efficacy of twice- and thrice-weekly intravenous administration of ketamine in sustaining initial antidepressant effects in patients with treatment-resistant depression.

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Ketamine has demonstrated rapid antidepressant effects in patients with treatment-resistant depression (TRD); however, the safety and tolerability of ketamine in this population have not been fully described. Herein we report the largest study to date of the safety, tolerability, and acceptability of ketamine in TRD.

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The primary outcome measure was change in PTSD symptom severity, measured using the Impact of Event Scale–Revised. Secondary outcome measures included the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impression–Severity and –Improvement scales, and adverse effect measures, including the Clinician-Administered Dissociative States Scale, the Brief Psychiatric Rating Scale, and the Young Mania Rating Scale.

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One of the most novel and exciting findings in major depressive disorder research over the last decade is the discovery of the fast-acting and long-lasting antidepressant effects of ketamine. Indeed, the therapeutic effects of classic antidepressants, such as selective serotonin reuptake inhibitors, require a month or longer to be expressed, with about a third of major depressive disorder patients resistant to treatment. Clinical studies have shown that a low dose of ketamine exhibits fast-acting relatively sustained antidepressant action, even in treatment-resistant patients. However, the mechanisms of ketamine action at a systems level remain unclear.

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One of the most novel and exciting findings in major depressive disorder research over the last decade is the discovery of the fast-acting and long-lasting antidepressant effects of ketamine. Indeed, the therapeutic effects of classic antidepressants, such as selective serotonin reuptake inhibitors, require a month or longer to be expressed, with about a third of major depressive disorder patients resistant to treatment. Clinical studies have shown that a low dose of ketamine exhibits fast-acting relatively sustained antidepressant action, even in treatment-resistant patients. However, the mechanisms of ketamine action at a systems level remain unclear.

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Preliminary evidence suggests intravenous ketamine has rapid effects on suicidal cognition, making it an attractive candidate for depressed patients at imminent risk of suicide. In the first randomized controlled trial of ketamine using an anesthetic control condition, we tested ketamine’s acute effects on explicit suicidal cognition and a performance-based index of implicit suicidal cognition (Implicit Association Test; IAT) previously linked to suicidal behavior

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Serotonin reuptake inhibitors (SRIs), the first-line pharmacological treatment for obsessive-compulsive disorder (OCD), have two limitations: incomplete symptom relief and 2-3 months lag time before clinically meaningful improvement. New medications with faster onset are needed. As converging evidence suggests a role for the glutamate system in the pathophysiology of OCD, we tested whether a single dose of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, could achieve rapid anti-obsessional effects.

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Ketamine, a glutamate Nmethyl-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.

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Treatment-resistant depression is a significant clinical problem with great morbidity and mortality (1). The report by Murrough et al. (2), published concurrently with this editorial, of their two-site randomized controlled clinical trial of ketamine in patients with treatment-resistant depression is an exciting and important step in evaluating a new and promising approach for these patients. Should our desire as clinicians to help these often desperate patients propel us to adopt ketamine now, or do we need to know more before proceeding? More studies, or change practice now? Let’s take a look.

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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.

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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.

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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.

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—Existing therapies for bipolar depression have a considerable lag of onset of action. Pharmacological strategies that produce rapid antidepressant effects—for instance, within a few hours or days—would have an enormous impact on patient care and public health.

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Patients not responding to conventional treatment for depression are classified as having treatment-resistant depression (TRD). Electroconvulsive therapy is effective in ~50% of the patients diagnosed with TRD. Recent reports of rapid antidepressant effect with a single dose of ketamine suggest a potential benefit for TRD patients. However, there are no studies characterizing optimal dosing parameters (eg, frequency and inter-dose interval). The following case describes the effects of two ketamine administration regimens in a patient with a 15-year history of depression.

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A single subanesthetic (intravenous) IV dose of ketamine might have rapid but transient antidepressant effects in patients with treatment-resistant depression (TRD). Here we tested the tolerability, safety, and efficacy of repeated-dose open-label IV ketamine (six infusions over 12 days) in 10 medication-free symptomatic patients with TRD who had previously shown a meaningful antidepressant response to a single dose.

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Seventy detoxified heroin-addicted patients were randomly assigned to one of two groups receiving ketamine psychotherapy (KPT)
involving two different doses of ketamine. The patients of the experimental group received existentially oriented psychotherapy in
combination with a hallucinogenic (‘‘psychedelic’’) dose of ketamine (2.0 mg/kg im).

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