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Depression is the leading cause of disability globally (1, 2). One-third to one-half of patients suffering from major depressive disorder (MDD) do not achieve remission even after multiple antidepressant trials (3). Ketamine is a commonly-used FDA-approved anesthetic medication that at subanesthetic doses leads to rapid antidepressant and anti-suicidal ideation effects in hours, rather than weeks, following administration. Despite these promising findings, a key limitation of ketamine treatment is that it only yields an antidepressant response in approximately 50% of those treated. The goal of this project is to A) elucidate ketamine's mechanism of action and B) identify biomarkers predicting treatment outcome to ketamine which could be used to match patients to treatment based on the likelihood of effectiveness at the individual level. Data from animal models suggests that ketamine acts by enhancing the connections between neurons through a process known as synaptic plasticity (4-7), and that these biological changes are responsible for the sustained behavioral effects of ketamine (8). A newly available tool allows us to image the density of these synaptic connections in the living brain using PET (positron emission tomography) imaging with a radiotracer called [11C]UCB-J, which is a marker of synaptic density. We propose to directly quantify synaptic density in depressed patients before and after a course of ketamine, to examine changes in density following treatment. In exploratory analyses, we will examine synaptic density as a mediator of the sustained antidepressant effects of ketamine and as a predictor of treatment outcome. To study these questions, we will quantify synaptic density using PET imaging before and after a course of 4 sequential intravenous infusions of ketamine administered over a two week period.
Depression is the leading cause of disability globally (1, 2). One-third to one-half of patients suffering from major depressive disorder (MDD) do not achieve remission even after multiple antidepressant trials (3). Ketamine is a commonly-used FDA-approved anesthetic and non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist. Recent randomized trials demonstrate that subanesthetic doses of ketamine lead to rapid antidepressant and antisuicidal ideation effects in individuals with MDD and bipolar depression (reviewed in (9)). In contrast to current FDA-approved antidepressants, ketamine exerts antidepressant effects in hours, rather than weeks, following administration. Despite these promising findings, a key limitation of ketamine treatment is that it only yields an antidepressant response in approximately 50% of those treated. In addition, ketamine's clinical utility is limited by its acute dissociative side effects, a one to two-week duration of action as monotherapy, its addictive potential, and long term safety concerns related to cognition and interstitial cystitis (9-11). Given the profound benefit of ketamine for some individuals yet these key limitations, developing a precision medicine research strategy for ketamine's antidepressant effects could be of tremendous scientific and clinical benefit, in order to A) elucidate ketamine's mechanism of action, to advance the development of safer alternative agents and B) identify biomarkers predicting treatment outcome to ketamine, which could be used to match patients to treatment based on the likelihood of effectiveness at the individual level.
There is evidence of brain atrophy in depression: gray matter volume is reduced in the prefrontal cortex (PFC) and in the hippocampus (HC) in depressed individuals (12). Postmortem studies in depression show low expression of several genes related to synaptic function and decreased synapse number in the dorsolateral PFC (13). Chronic stress, a risk factor for depression, precipitates neuronal atrophy and dendritic spine loss in HC and PFC (14, 15). Preclinical work in rodents suggests that ketamine may exert antidepressant effects by reversing neuronal atrophy, specifically through the formation of new dendritic spine synapses in the brain. In rodents, ketamine induces rapid synaptogenesis via stimulation of mechanistic target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF), leading to a reversal of chronic, stress-induced neuronal atrophy (4-7).
A recently developed research tool enables examination of synaptic density in vivo in humans. [11C]UCB-J is a PET radiotracer that is specific for synaptic vesicle glycoprotein 2A (SV2A) (16, 17), providing a quantitative measure of synaptic density in vivo in the brain in humans. A recent PET imaging pilot study identified low [11C]UCB-J binding in the PFC of individuals with current MDD as compared to healthy volunteers, providing early evidence that this synaptic density biomarker may quantify a disease-relevant process in depression (18). Furthermore, PET imaging with [11C]UCB-J displays outstanding test-retest reliability, with absolute test-retest variability of only 4-5% in brain regions of interest in this study (19), making it an outstanding tool for longitudinal studies of the effects of treatment interventions. We therefore propose to directly quantify synaptic density in depressed patients to investigate whether it is increased by treatment with ketamine in a regionally-specific manner. Moreover, we will examine synaptic density as a mediator of the sustained antidepressant effects of ketamine and as a predictor of treatment outcome. We will quantify synaptic density using PET imaging before and after a course of 4 sequential intravenous infusions of ketamine administered over a two-week period.
Major Depressive Disorder
Not yet recruiting
New York State Psychiatric Institute
Published on BioPortfolio: 2019-09-23T04:51:49-0400
The purpose of this study is to measure the amount of ketamine in blood over time in subjects diagnosed with Major Depressive Disorder (MDD) and explore the anti-depressive effects of keta...
Medically healthy Veterans ages 21-75 that have been diagnosed with Depression will get up to 6 treatments of Ketamine infusions, weekly. After treatment is completed, follow up will occur...
The purpose of this study is to test the antidepressant effect of ketamine when given repeatedly over a period of 1 week, as well as the use of Lithium as a relapse-prevention strategy for...
his study is examining the safety and effectiveness of two medications, ketamine and riluzole, in treating patients with treatment resistant major depressive disorder. This study will also...
To evaluate if naltrexone plus ketamine is effective in reducing depression and alcohol consumption.
This study aimed to investigate the efficacy and safety of intermittent low-dose ketamine on improving the efficacy of ECT. Patients diagnosed with Major Depressive Disorder (MDD) (n = 134) were r...
Major depressive disorder is a complex multifactorial condition with a so far poorly characterized underlying pathophysiology. Consequently, the available treatments are far from satisfactory as it is...
The purpose of this article is to provide psychiatrists and other health care professionals who treat patients with major depressive disorder and bipolar disorder a set of best practices, tools, and o...
The antidepressant effect of ketamine is associated with increased activity in the reward circuitry of the brain and a suppression of circuitry that mediates perceptual processing of negative emotions...
Major depressive disorder (MDD) is one of the most common psychiatric disorders characterized by major depressive episodes. Although great efforts have been made to develop antidepressant drugs that t...
A major affective disorder marked by severe mood swings (manic or major depressive episodes) and a tendency to remission and recurrence.
Marked depression appearing in the involution period and characterized by hallucinations, delusions, paranoia, and agitation.
A serotonin uptake inhibitor that is used as an antidepressive agent. It has been shown to be effective in patients with major depressive disorders and other subsets of depressive disorders. It is generally more useful in depressive disorders associated with insomnia and anxiety. This drug does not aggravate psychotic symptoms in patients with schizophrenia or schizoaffective disorders. (From AMA Drug Evaluations Annual, 1994, p309)
Inability to experience pleasure due to impairment or dysfunction of normal psychological and neurobiological mechanisms. It is a symptom of many PSYCHOTIC DISORDERS (e.g., DEPRESSIVE DISORDER, MAJOR; and SCHIZOPHRENIA).
A cyclohexanone derivative used for induction of anesthesia. Its mechanism of action is not well understood, but ketamine can block NMDA receptors (RECEPTORS, N-METHYL-D-ASPARTATE) and may interact with sigma receptors.
Adhd Anorexia Depression Dyslexia Mental Health Psychiatry Schizophrenia Stress Mental health, although not being as obvious as physical health, is very important, causing great unhappiness to those affected, causing add...
In order to become availible to pateints, drugs need to undergo a number of phases of clinical trials to test their efficacy and safty and to then be authorised by the drug approval organistion in each respective country. This is the FDA in the USA and N...
Anesthesia is the loss of feeling or sensation in all or part of the body. It may result from damage to nerves or can be induced by an anesthetist (a medical professional) using anesthetics such as thiopental or propofol or sevoflurane during a surgical ...