Trial Summary
What is the purpose of this trial?
This research study is designed to look at the involvement of the glutamate system in depression. Each subject will undergo a screening appointment to determine study eligibility. Thereafter, the study will take 2 or 3 visits depending on schedule availability and will consist of one MRI scan, and PET scan. Subjects will also participate in cognitive testing. Depending on camera time, staff availability and subject schedule, total study participation may last 1-2 months.
Do I need to stop my current medications to join the trial?
The trial requires participants to be medication-free for at least 2 weeks or to be on a permissible medication. The protocol does not specify which medications are permissible, so you may need to discuss your current medications with the study team.
What data supports the idea that Glutamate Imaging and Cognitive Testing for Depression is an effective drug?
The available research shows that ketamine, a drug used in Glutamate Imaging and Cognitive Testing for Depression, can rapidly reduce symptoms in people with severe depression who haven't responded to other treatments. Studies have found that ketamine can quickly improve mood and decrease suicidal thoughts. For example, one study showed that ketamine led to changes in brain areas related to mood and reward, which are important for feeling better. Another study found that ketamine increased certain brain chemicals linked to feeling less depressed. These findings suggest that ketamine can be an effective option for people with treatment-resistant depression.12345
What safety data exists for ketamine treatment in depression?
Ketamine has been shown to be safe in short-term use for depression, with rapid antidepressant effects demonstrated in several studies. However, its long-term safety profile is not well-established. Known side effects include psychiatric, cardiovascular, neurologic, and genitourinary effects, as well as potential for abuse. While ketamine is safe in sub-anesthetic doses administered once or a few times, prolonged use safety data is lacking.35678
Is the drug Ketamine, used with MRI and PET scans, a promising treatment for depression?
Yes, Ketamine is a promising drug for treating depression, especially for those who don't respond to traditional treatments. It works quickly and can help understand how depression affects the brain. MRI and PET scans can help doctors see how Ketamine changes brain activity, which can improve treatment strategies.19101112
Eligibility Criteria
This trial is for adults aged 18-65 with certain psychiatric conditions like depression, bipolar disorder, or PTSD. It's also open to healthy individuals without any DSM-5 diagnosis. Participants must be English-speaking and medication-free or on approved meds for at least two weeks.Inclusion Criteria
I haven't taken any medication for the last 2 weeks or only allowed medications for depression.
I haven't taken any medication in the last 2 weeks or only allowed medications for PTSD.
Subjects must be English speaking
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Exclusion Criteria
Have given a blood donation within eight weeks of the start of the study
I have a bleeding disorder or am on blood thinners like Coumadin.
Have history of prior radiation exposure for research purposes within the past year such that participation in this study would place them over FDA limits for annual radiation exposure. This guideline is an effective dose of 5 rem received per year
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Treatment Details
Interventions
- Cognitive Testing (Behavioral Intervention)
- MRI (Other)
- PET (Other)
Trial OverviewThe study examines the glutamate system in mental health by using PET scans, MRI imaging, and cognitive tests over 1-2 months. The goal is to understand how this system differs among those with psychiatric disorders compared to healthy controls.
Participant Groups
3Treatment groups
Experimental Treatment
Active Control
Group I: Cognitive TestingExperimental Treatment1 Intervention
Cognitive assessments
Group II: Magnetic Resonance ImagingActive Control1 Intervention
All subjects will have one MRI with a possibility of one functional MRI (fmri).
Group III: Positron Emission TomographyActive Control1 Intervention
All subjects will have PET scan using FPEB or ABP688.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
PET CenterNew Haven, CT
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Who Is Running the Clinical Trial?
Yale UniversityLead Sponsor
VA Office of Research and DevelopmentCollaborator
References
Ketamine-Associated Brain Changes: A Review of the Neuroimaging Literature. [2023]Major depressive disorder (MDD) is one of the most prevalent conditions in psychiatry. Patients who do not respond to traditional monoaminergic antidepressant treatments have an especially difficult-to-treat type of MDD termed treatment-resistant depression. Subanesthetic doses of ketamine-a glutamatergic modulator-have shown great promise for rapidly treating patients with the most severe forms of depression. As such, ketamine represents a promising probe for understanding the pathophysiology of depression and treatment response. Through neuroimaging, ketamine's mechanism may be elucidated in humans. Here, we review 47 articles of ketamine's effects as revealed by neuroimaging studies. Some important brain areas emerge, especially the subgenual anterior cingulate cortex. Furthermore, ketamine may decrease the ability to self-monitor, may increase emotional blunting, and may increase activity in reward processing. Further studies are needed, however, to elucidate ketamine's mechanism of antidepressant action.
A preliminary study of the association of increased anterior cingulate gamma-aminobutyric acid with remission of depression after ketamine administration. [2021]Gamma-aminobutyric acid (GABA) and glutamate neurotransmission have been implicated in the pathophysiology of depression and mechanistically linked to ketamine's antidepressant response. Seven patients with treatment-resistant depression enrolled in an open-label, feasibility trial of a single IV 40-min ketamine infusion during a functional MR spectroscopy (fMRS) scan utilizing a novel frequency adjusting MEGA-PRESS sequence. Next-day treatment remission and reduction in the MADRS scores correlated with anterior cingulate cortex peak GABA levels. These novel findings provide further insights into the underlying neurobiological mechanisms of ketamine and, if confirmed in larger studies, would be encouraging for further development of GABAergic biomarker associated with ketamine response.
Rapid neuroplasticity changes and response to intravenous ketamine: a randomized controlled trial in treatment-resistant depression. [2023]Intravenous ketamine is posited to rapidly reverse depression by rapidly enhancing neuroplasticity. In human patients, we quantified gray matter microstructural changes on a rapid (24-h) timescale within key regions where neuroplasticity enhancements post-ketamine have been implicated in animal models. In this study, 98 unipolar depressed adults who failed at least one antidepressant medication were randomized 2:1 to a single infusion of intravenous ketamine (0.5 mg/kg) or vehicle (saline) and completed diffusion tensor imaging (DTI) assessments at pre-infusion baseline and 24-h post-infusion. DTI mean diffusivity (DTI-MD), a putative marker of microstructural neuroplasticity in gray matter, was calculated for 7 regions of interest (left and right BA10, amygdala, and hippocampus; and ventral Anterior Cingulate Cortex) and compared to clinical response measured with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptoms-Self-Report (QIDS-SR). Individual differences in DTI-MD change (greater decrease from baseline to 24-h post-infusion, indicative of more neuroplasticity enhancement) were associated with larger improvements in depression scores across several regions. In the left BA10 and left amygdala, these relationships were driven primarily by the ketamine group (group * DTI-MD interaction effects: p = 0.016-0.082). In the right BA10, these associations generalized to both infusion arms (p = 0.007). In the left and right hippocampus, on the MADRS only, interaction effects were observed in the opposite direction, such that DTI-MD change was inversely associated with depression change in the ketamine arm specifically (group * DTI-MD interaction effects: p = 0.032-0.06). The acute effects of ketamine on depression may be mediated, in part, by acute changes in neuroplasticity quantifiable with DTI.
Neuroimaging-Derived Biomarkers of the Antidepressant Effects of Ketamine. [2023]Major depressive disorder is a highly prevalent psychiatric disorder. Despite an extensive range of treatment options, about a third of patients still struggle to respond to available therapies. In the last 20 years, ketamine has gained considerable attention in the psychiatric field as a promising treatment of depression, particularly in patients who are treatment resistant or at high risk for suicide. At a subanesthetic dose, ketamine produces a rapid and pronounced reduction in depressive symptoms and suicidal ideation, and serial treatment appears to produce a greater and more sustained therapeutic response. However, the mechanism driving ketamine's antidepressant effects is not yet well understood. Biomarker discovery may advance knowledge of ketamine's antidepressant action, which could in turn translate to more personalized and effective treatment strategies. At the brain systems level, neuroimaging can be used to identify functional pathways and networks contributing to ketamine's therapeutic effects by studying how it alters brain structure, function, connectivity, and metabolism. In this review, we summarize and appraise recent work in this area, including 51 articles that use resting-state and task-based functional magnetic resonance imaging, arterial spin labeling, positron emission tomography, structural magnetic resonance imaging, diffusion magnetic resonance imaging, or magnetic resonance spectroscopy to study brain and clinical changes 24 hours or longer after ketamine treatment in populations with unipolar or bipolar depression. Though individual studies have included relatively small samples, used different methodological approaches, and reported disparate regional findings, converging evidence supports that ketamine leads to neuroplasticity in structural and functional brain networks that contribute to or are relevant to its antidepressant effects.
Structural connectivity and response to ketamine therapy in major depression: A preliminary study. [2018]Ketamine elicits an acute antidepressant effect in patients with major depressive disorder (MDD). Here, we used diffusion imaging to explore whether regional differences in white matter microstructure prior to treatment may predict clinical response 24h following ketamine infusion in 10 MDD patients.
Ketamine for the treatment of depression. [2022]Ketamine (Ketalar®) is an anesthetic agent derived from the hallucinogenic drug phencyclidine (PCP). It is a high-affinity antagonist at N-methyl-D-aspartate receptors and also binds to opioid mu and sigma receptors. Ketamine is being intensively investigated as an antidepressant therapy. To date, five short-term controlled studies and other open-label studies in patients with unipolar or bipolar depression have demonstrated that intravenous ketamine is safe and has a rapid and profound short-term effect on depressive symptoms, including suicidal thoughts, even among patients considered treatment-resistant to standard medications or electroconvulsive therapy. Before ketamine can be incorporated into clinical practice, however, its long-term safety and effectiveness need to be evaluated. Although the effectiveness of alternative routes of ketamine administration (i.e., oral, intranasal, or intramuscular) needs to be determined, intravenous ketamine could be conceptualized as a clinic-based procedural therapy for treatment resistant forms of depression.
Pharmacotherapy: Ketamine and Esketamine. [2023]Ketamine and esketamine have rapid-onset antidepressant effects and may be considered for the management of treatment-resistant depression. Intranasal esketamine has regulatory approval in the United States and European Union. Intravenous ketamine is often administered off-label as an antidepressant, though no standard operating procedures exist. Repeated administrations and the use of a concurrent standard antidepressant may maintain antidepressant effects of ketamine/esketamine. Possible adverse effects of ketamine and esketamine include psychiatric, cardiovascular, neurologic and genitourinary effects, and the potential for abuse. The long-term safety and efficacy of ketamine/esketamine as antidepressants require further study.
Has psychiatry tamed the "ketamine tiger?" Considerations on its use for depression and anxiety. [2015]Ketamine has been available for approximately 50 years as an anesthetic agent. It is known to have potent effects on the central nervous system glutamatergic system, in particular blockade of N-methyl-D-aspartate (NMDA) receptors. Based upon pre-clinical evidence of involvement of the glutamatergic system in mood disorders, studies have been undertaken to test the antidepressant properties of ketamine. Several well-controlled studies, along with open-label case series, have established that ketamine can have rapid antidepressant effects. Additionally, data exist showing benefits of ketamine in post-traumatic stress disorder as well as obsessive compulsive disorder. However, improvements in these conditions tend to be short-lived with single infusions of ketamine. Of concern, ketamine has been associated with neurotoxicity in pre-clinical rodent models and is well-known to cause psychotomimetic effects and addiction in humans. While ketamine has been proven safe for use in sub-anesthetic doses administered once or a few times, the safety profile of prolonged use has not been established. Aspects of safety, possible mechanisms of action, and future directions of ketamine research are discussed in addition to the clinical literature on its use in psychiatric conditions.
Neuropsychological and neuroimaging evidence for the involvement of the frontal lobes in depression. [2022]The onset and reversibility of major depression is likely to be explained by diffuse neuromodulatory mechanisms rather than permanent abnormalities of connectivity and neurotransmission. However, the expression of mood state appears to involve fronto-striatal mechanisms. Lesions of the ventral frontal cortex give rise to profound modification of affect and behaviour not explained by effects on current intellectual function. These may represent the most extreme possible disturbances of emotional experience. Neuropsychological testing in major depression shows evidence of slowing in motor and cognitive domains with additional prominent effects on mnemonic function most marked in the elderly. Structural imaging with X-ray computed tomography or magnetic resonance imaging in older patients with major depression shows evidence of structural abnormality compared with controls. These findings are not highly localizing but they tend to confirm the role of cognitive impairment as an important age-related risk factor for major depression. Perfusion or metabolic imaging reflects both reversible changes in function and permanent loss of active neurones. The usual finding has been reductions in anterior brain structures in major depression. Hypoperfusion tends to be greatest in frontal, temporal and parietal areas and most extensive in older (male) patients; high Hamilton scores tend to be associated with reduced uptake. There have also been correlations in the cingulate cortex between increased perfusion and other aspects of the mental state. In general, reductions in frontal areas may be more likely in patients with impoverished mental states. The more prominent impairments of memory are likely to be associated with the finding of impaired temporal function or with a more diffuse failure of neuromodulation.
Brain structural and functional changes in patients with major depressive disorder: a literature review. [2020]Depression is a mental disorder characterized by low mood and anhedonia that involves abnormalities in multiple brain regions and networks. Epidemiological studies demonstrated that depression has become one of the most important diseases affecting human health and longevity. The pathogenesis of the disease has not been fully elucidated. The clinical effect of treatment is not satisfactory in many cases. Neuroimaging studies have provided rich and valuable evidence that psychological symptoms and behavioral deficits in patients with depression are closely related to structural and functional abnormalities in specific areas of the brain. There were morphological differences in several brain regions, including the frontal lobe, temporal lobe, and limbic system, in people with depression compared to healthy people. In addition, people with depression also had abnormal functional connectivity to the default mode network, the central executive network, and the salience network. These findings provide an opportunity to re-understand the biological mechanisms of depression. In the future, magnetic resonance imaging (MRI) may serve as an important auxiliary tool for psychiatrists in the process of early and accurate diagnosis of depression and finding the appropriate treatment target for each patient to optimize clinical response.
Glutamatergic Dysfunction and Glutamatergic Compounds for Major Psychiatric Disorders: Evidence From Clinical Neuroimaging Studies. [2020]Excessive glutamate release has been linked to stress and many neurodegenerative diseases. Evidence indicates abnormalities of glutamatergic neurotransmission or glutamatergic dysfunction as playing an important role in the development of many major psychiatric disorders (e.g., schizophrenia, bipolar disorder, and major depressive disorder). Recently, ketamine, an N-methyl-d-aspartate antagonist, has been demonstrated to have promisingly rapid antidepressant efficacy for treatment-resistant depression. Many compounds that target the glutamate system have also become available that possess potential in the treatment of major psychiatric disorders. In this review, we update evidence from recent human studies that directly or indirectly measured glutamatergic neurotransmission and function in major psychiatric disorders using modalities such as magnetic resonance spectroscopy, positron emission tomography/single-photon emission computed tomography, and paired-pulse transcranial magnetic stimulation. The newer generation of antidepressants that target the glutamatergic system developed in human clinical studies is also reviewed.
[The anatomy of depression in light of evidence from neuroimaging studies]. [2009]The introduction of structural and functional neuroimaging methods has significantly improved our knowledge ofneurobiological basis of psychiatric disorders. The aim of this review is to present the results of studies using magnetic resonance imagining and positron emission tomography in affective disorders. The most consistently reported structural abnormalities in major depressive disorder include a reduced volume of the prefrontal lobe, (orbitofrontal, dorsolateral and anterior cingulate cortex) hippopocampus and amygdala. In bipolar disorder, smaller prefrontal lobes, subgenual prefrontal cortex as well as enlarged amygdala and striatum volume were found. Several mechanisms explaining the structural abnormalities including the neurotoxic effect of hipercortisolemia, and disturbances ofneurogenesis have been postulated. Results of studies using functional imaging showed a common pattern of decreased activation in the dorsolateral prefrontal cortex (part of the dorsal system) and increased regional cerebral blood flow and metabolism in the subgenual cingulate, amygdala, anterior insula and ventral striatum (parts of ventral system) during the depressive episode. In bipolar depression, a reduced metabolism in the dorsolateral prefrontal cortex and increased metabolism in amygdala and thalamus were reported. Successful therapy normalized these abnormalities. According to the proposed models, structural and functional abnormalities in the ventral and dorsal systems, responsible for emotion regulation, are associated with symptoms of depression.