depression Major depressive disorder
Conditions
Interventions
The glutamatergic NMDAR antagonist ketamine is a racemate of R-(-)-ketamine and
S-(+)-ketamine. It is registered in Europe as an anesthetic agent and it is
frequently applied as an off-label treatme
Sponsors
Sumitomo Dainippon Pharma
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Eligible subjects must meet all of the following inclusion criteria at screening: - Men or women, 18 to 65 years of age, inclusive. - Meet the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnostic criteria for depression, without psychotic features based upon clinical assessment at screening and confirmed by the Mini-International Neuropsychiatric Interview (MINI). Comorbid anxiety disorders with the exception of Post-Traumatic Stress Disorder (PTSD) are allowed, provided these are not the primary psychiatric diagnosis. - Confirmation of the psychiatric diagnosis by the attending general practitioner and/or psychiatrist. - Be medically stable on the basis of physical examination, 12-lead ECG, and vital signs, performed at Screening. If there are abnormalities, they must be consistent with the underlying illness in the study population. - Be medically stable on the basis of clinical laboratory tests performed at screening. - Has a Hamilton questionnaire score of * 18, at screening and randomization - Partial or no response to a first trial with a SSRI or SNRI despite a therapeutic dose for at least 4 weeks of treatment.
Exclusion criteria
Exclusion criteria: - Current DSM-IV-TR diagnosis made by attending GP or psychiatrist, or established with the MINI of a comorbid psychotic disorder or MDD with psychotic features, bipolar or related disorders, obsessive compulsive disorder, intellectual disability, borderline personality disorder, antisocial personality disorder, histrionic personality disorder or narcissistic personality disorder - Patient has a history of drug or alcohol abuse or dependence according to DSM-IV criteria, except nicotine or caffeine, within 6 months before Screening. - Has been involuntarily committed to psychiatric hospital (current episode)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1. Resting state fMRI whole brain analysis: Changes in functional connectivity in the 10 standard template resting state brain networks as described by (Smith et al. 2009), as measured using independent component analysis (ICA) and dual regression. These networks comprise three visual networks (consisting of medial, occipital pole, and lateral visual areas), the default mode network (DMN, medial parietal, bilateral inferior*lateral*parietal and ventromedial frontal cortex), cerebellar network, sensorimotor network (supplementary motor area, sensorimotor cortex, and secondary somatosensory cortex), auditory network (superior temporal gyrus, Heschl's gyrus, and posterior insular), executive control network (medial*frontal areas, including anterior cingulate and paracingulate) and two frontoparietal networks (frontoparietal areas left and right). 2. Altered functional connectivity by a single intravenous dose of ketamine using a seed-based approach: a. functional connectivity from amygdala b. functional connectivity from dorsal nexus (dorsomedial prefrontal cortex) 3. Effects of baseline cerebral blood flow on changes in the MRI signal by performing arterial spin labeling (ASL) 4. Effect on depressive symptoms using the MADRS 5. Dissociative symptoms using the CADSS. 6. Bond-Lader Visual Analogue Scale (VAS) and Bowdle VAS assessment scores. | — |
Secondary
| Measure | Time frame |
|---|---|
| Pharmacokinetic endpoints * Individual and mean Cmax, Tmax, AUC0-t (t to be determined) for plasma ketamine, norketamine and (2S,6S;2R,6R)- hydroxynorketamine * The ratio ketamine: norketamine and (2S,6S;2R,6R)- hydroxynorketamine for Cmax and AUC0-t. * The primary pharmacokinetic parameters for ketamine, norketamine and (2S,6S;2R,6R)- hydroxynorketamine will be estimated by means of compartmental analysis. All pharmacokinetic parameters will be summarized descriptively including mean, geometric mean, median, range, standard deviation and coefficient of variation. Individual plasma concentrations at each sampling point for ketamine and its metabolites will be presented by listing and descriptive summary statistics including means, geometric means, ranges, standard deviation and coefficient of variation. Individual and mean concentration versus time will be plotted on linear or semi- logarithmic scale as appropriate. Tolerability / safety endpoints The safety and tolerability of ketamine will be assessed in patients with MDD, with special attention for: * Suicidal ideation/behaviour as measured with the Columbia Suicide Severity Rating Scale (C-SSRS). * The frequency and severity of adverse events * Questionnaire Psychotic Experiences (QPE) * Laboratory safety, blood pressure, pulse rate, ECG | — |
Countries
Netherlands
Outcome results
None listed