Primary objectiveTo evaluate the CNS effects of a single intravenous dose of ketamine on functional brain networks by performing resting state functional magnetic resonance imaging (fMRI) in major depressive disorder (MDD) patients who fail to…
ID
Source
Brief title
Condition
- Mood disorders and disturbances NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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 outcome
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
Background summary
Ketamine can be conceived of as a pharmacological probe to investigate the role
of glutamatergic system in MDD by modulating central NMDAR*s. Since the
administration of ketamine in untreated MDD patients may raise ethical
concerns, the current study aims to evaluate the effects of a single
intravenous dose of ketamine on functional brain networks in a MDD population
who fails to respond to a first trial with a SSRI or serotonin noradrenaline
reuptake inhibitor (SNRI). To our knowledge this will be the first study to
investigate the CNS PD effects of ketamine by performing resting state
functional magnetic resonance imaging (fMRI) in a non-therapy resistant MDD
population.
Study objective
Primary objective
To evaluate the CNS effects of a single intravenous dose of ketamine on
functional brain networks by performing resting state functional magnetic
resonance imaging (fMRI) in major depressive disorder (MDD) patients who fail
to respond to a selective serotonin reuptake inhibitor (SSRI) or serotonin
noradrenaline reuptake inhibitor (SNRI).
Secondary Objectives
1. To explore altered functional connectivity by administration of a single
intravenous dose of ketamine in patients with SSRI/SNRI-treatment resistant MDD.
2. To explore the changes of functional brain networks and functional
connectivity associated with the pharmacokinetics of ketamine and its
metabolites by PK/PD correlation analysis following a single intravenous dose
of ketamine administration in MDD patients who fail to respond to a SSRI or SNRI
3. To evaluate the effect of single intravenous dose of ketamine on the course
of depressive symptoms using the The Montgomery-Asberg Depression Rating Scale
(MADRS) in MDD patients who fail to respond to a selective serotonin reuptake
inhibitor (SSRI) or serotonin noradrenaline reuptake inhibitor (SNRI).
4. To evaluate the psychomimetic effects of a single intravenous dose of
ketamine) using the The Clinician Administered Dissociative States Scale
(CADSS) and Questionnaire Psychotic Experiences (QPE) in MDD patients who fail
to respond to a selective serotonin reuptake inhibitor (SSRI) or serotonin
noradrenaline reuptake inhibitor (SNRI).
5. To evaluate the safety (ECG, blood and urine analysis, CSSRS) of
administration of a single intravenous dose of ketamine in MDD patients who
fail to respond to a selective serotonin reuptake inhibitor (SSRI) or serotonin
noradrenaline reuptake inhibitor (SNRI).
Study design
A Randomized, Double-Blind, Placebo-Controlled, 2-Period, 2-Treatment
Cross-Over Study
Intervention
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 treatment to help manage chronic pain. In
addition, both single and multiple subanaesthetic intravenous (IV)
administrations of ketamine have demonstrated robust antidepressant effects in
patients suffering from major depressive disorder (MDD).
Study burden and risks
The administration of a subanaesthetic dose of ketamine was generally well
tolerated in previous studies performed at the CHDR (data on file, manuscript
in preparation) and in literature. However, subjects who have no/limited
experiences with the effects of recreational psychoactive substances such as
alcohol may have a higher risk of intolerability to ketamine effects.
Psychotomimetic reactions include anxiety, chest pain, palpitations, agitation,
flashbacks, delirium, dystonia, psychosis and schizophrenia-like symptoms. The
psychomimetic reactions seem related to the infusion of ketamine and disappear
soon after the discontinuation of the infusion. None of the cited studies
reports a rebound effect (increased depressive experience) after termination of
the infusion.
Potential adverse effects of ketamine administration include hypersalivation,
hyperreflexia, muscle hypertonicity, transient clonus, increased intraocular
pressure, emesis, transient rash, agitation dizziness and seizures.
Hypertension, tachycardia, increase pulmonary pressures, increased intra-ocular
pressure and pulmonary edema can also be seen as an effect of sympathomimetic
stimulation by ketamine.
Laryngospasm (during infusion) is frequently cited as an adverse effect of
ketamine, but it is rarely observed. At the dose used during treatment for
treatment resistant depression (TRD) (0.5 mg/kg of ketamine) no laryngospasm
has been observed in literature.
Ketamine has a potential for abuse and abuse may lead to moderate or low
physical dependence or high psychological dependence. Subjects should not drive
a car and should not engage in activities that require operating vehicles or
dangerous machinery following administration of ketamine. Thus, the subjects
will remain in the clinic under supervision and will be discharged by a
physician only if their medical condition allows. No specific antidotes are
available/are necessary. Supportive measures will be used in case of adverse
events. Careful observation and medical management will minimize any associated
risk in this study.
No beneficial effect for the patient is expected from a single subanaesthetic
IV dose of ketamine.
Enoki-cho, Suita 33-94
Osaka 564-0053
JP
Enoki-cho, Suita 33-94
Osaka 564-0053
JP
Listed location countries
Age
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
- 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
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-003999-51-NL |
| CCMO | NL59430.056.16 |