Major Depressive Disorder
Conditions
Keywords
Major Depressive Disorder, Ketamine, Evoked potentials, Somatosensory evoked potentials, Motor evoked potentials, Cortical plasticity
Brief summary
To evaluate if somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) obtained with electroencephalography (EEG) and electromyography (EMG) can be used to detect changes in cortical plasticity in responders to a single IV infusion of ketamine as compared to non-responders.
Detailed description
This study will be conducted in patients with Major Depressive Disorder (MDD) and divided into 2 sequential cohorts. Cohort 1 will be conducted in 12 patients at a single center. For each patient, there will be up to 4 sequential phases: a screening phase of up to 6 weeks, an open-label treatment phase of up to 4 weeks, an optional open-label treatment phase of up to 1 week, and a follow-up phase of up to 1 week (if applicable). Cohort 2 will be conducted in 20 patients and will be a multicenter, double-blind (neither physician nor patient knows the treatment that the patient receives), randomized (the study drug is assigned by chance), placebo-controlled (an inactive substance that is compared with a drug to test whether the drug has a real effect in a clinical trial) design. For each patient, there will be up to 4 sequential phases: a screening phase of up to 6 weeks, a double-blind treatment phase of up to 4 weeks, an optional open-label treatment phase of up to 1 week, and a follow-up phase of up to 1 week (if applicable). The total study duration for each patient will be maximally about 12 weeks. Participant safety will be monitored throughout the study.
Interventions
DRUGKetamine
During Cohorts 1 and 2, a single ketamine 0.5 mg/kg dose will be given as a continuous IV infusion over 40 minutes by use of an electronic syringe infusion pump. The predefined dose and infusion rate/duration should not be adjusted. If a patient is unable to tolerate the study medication, the infusion should be stopped. Within 1 week of completion of the open-label treatment phase, participants can receive a single dose of ketamine 0.5 mg/kg administered as an IV infusion over 40 minutes during an optional open-label treatment phase.
DRUGPlacebo
During Cohort 2, a single placebo dose will be given as a continuous IV infusion over 40 minutes by use of an electronic syringe infusion pump. Within 1 week of completion of the double-blind treatment phase, participants can receive a single dose of ketamine 0.5 mg/kg administered as an IV infusion over 40 minutes during an optional open-label treatment phase.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
* Patient must be medically stable * Patient must meet Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) diagnostic criteria for Major Depressive Disorder (MDD), without psychotic features, based upon clinical assessment and confirmed by the Mini International Psychiatric Interview (MINI) * Patient must have had an inadequate response to at least 2 antidepressants, one of which is in the current episode of depression * Patient must have an Inventory of Depressive Symptomatology 30-item Clinician-rated (IDS-C30) total score ≥ 34 at Screening and Day -1 * Women must be postmenopausal, surgically sterile, or, if heterosexually active, practicing a highly effective method of birth control * Men who are heterosexually active with a woman of childbearing potential must agree to use a double barrier method of birth control and to not donate sperm during the study and for 3 months after receiving the last dose of study drug
Exclusion criteria
* Patient has current signs and/or symptoms of liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, or metabolic disturbances * Patient has a primary DSM-IV diagnosis of current (active) generalized anxiety disorder (GAD), panic disorder, obsessive compulsive disorder (OCD), posttraumatic stress disorder (PTSD), anorexia nervosa, or bulimia nervosa * Patient has a current diagnosis of bipolar disorder, mental retardation, or cluster b personality disorder (e.g., borderline personality disorders, antisocial personality disorder, etc) * Patient has a current or prior diagnosis of a psychotic disorder or MDD with psychosis * Patient has not responded to treatment with electroconvulsive therapy (ECT) in the current episode of depression * Patient has suicidal ideation with intent to act, or has homicidal ideation/intent, during Screening phase per Investigator's clinical judgment * Patient has any significant primary sleep disorder
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Ketamine Responders and Ketamine Non-responders in the Change From Baseline in Somatosensory Evoked Potential (SEPs) Amplitudes at 4 Hours Postdose on Day 1 | Baseline and Day 1 (4 hours postdose) | SEPs are the electrical signals generated by the nervous system in response to somatosensory stimuli - typically through electrical stimulation of the median nerve. SEPs are read on the skull with electroencephalography (EEG). SEPs was recorded using a 64-channel EEG system at baseline (predose) and regularly after study drug administration. The change from baseline was calculated as post-baseline value minus baseline value for each participant. Since the number of participants at baseline differ from the number of participants at post-baseline measure (that is \[i.e.\] not all baseline values are paired), the mean change is not equal to the difference between the means at the two time points. |
| Comparison of Ketamine Responders and Ketamine Non-responders in the Change From Baseline in Motor Evoked Potential (MEPs) Amplitudes at 4 Hours Postdose on Day 1 | Baseline and Day 1 (4 hours postdose) | MEPs are generated when stimulation of the brain on the motor cortex (with Transcranial Magnetic Stimulation \[TMS\]) causes the spinal cord and peripheral muscles to produce neuroelectrical signals. MEPs are typically measured in the hand muscles. The Motor Evoked Response to Transcranial Magnetic Stimulation (TMS MEPs) was evaluated at baseline and regularly after study drug administration. Intracortical inhibition and facilitation was also evaluated using TMS. A figure-of-eight coil with external loop diameters of 9 cm was used to elicit motor responses in the contralateral first dorsal interosseus. |
Countries
United States
Participant flow
Recruitment details
A total of 13 participants were enrolled, treated and completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Ketamine IV 0.5mg/kg Participants received a single ketamine 0.5 milligram per kilogram (mg/kg) dose as a continuous Intravenous (IV) infusion over 40 minutes by use of an electronic syringe infusion pump on Day 1. Participants who responded continued the open-label treatment phase through Day 28 or until relapse, whichever occurred first. An additional single IV dose of ketamine 0.5 mg/kg was available during an optional open label treatment phase. | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | Ketamine IV 0.5mg/kg |
|---|---|
| Age, Continuous | 40.9 years STANDARD_DEVIATION 11.45 |
| Gender Female | 9 Participants |
| Gender Male | 4 Participants |
| Region of Enrollment USA | 13 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 10 / 13 |
| serious Total, serious adverse events | 0 / 13 |
Outcome results
Primary
Comparison of Ketamine Responders and Ketamine Non-responders in the Change From Baseline in Motor Evoked Potential (MEPs) Amplitudes at 4 Hours Postdose on Day 1
MEPs are generated when stimulation of the brain on the motor cortex (with Transcranial Magnetic Stimulation \[TMS\]) causes the spinal cord and peripheral muscles to produce neuroelectrical signals. MEPs are typically measured in the hand muscles. The Motor Evoked Response to Transcranial Magnetic Stimulation (TMS MEPs) was evaluated at baseline and regularly after study drug administration. Intracortical inhibition and facilitation was also evaluated using TMS. A figure-of-eight coil with external loop diameters of 9 cm was used to elicit motor responses in the contralateral first dorsal interosseus.
Time frame: Baseline and Day 1 (4 hours postdose)
Population: Efficacy analysis set included all participants who received a dose of ketamine and who had at least 1 postbaseline value of MEP.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketamine IV 0.5mg/kg | Comparison of Ketamine Responders and Ketamine Non-responders in the Change From Baseline in Motor Evoked Potential (MEPs) Amplitudes at 4 Hours Postdose on Day 1 | Responders: Change from Baseline (n=9) | 0.179 mV | Standard Deviation 0.765 |
| Ketamine IV 0.5mg/kg | Comparison of Ketamine Responders and Ketamine Non-responders in the Change From Baseline in Motor Evoked Potential (MEPs) Amplitudes at 4 Hours Postdose on Day 1 | Responders: Baseline (n=9) | 0.874 mV | Standard Deviation 0.71 |
| Ketamine IV 0.5mg/kg | Comparison of Ketamine Responders and Ketamine Non-responders in the Change From Baseline in Motor Evoked Potential (MEPs) Amplitudes at 4 Hours Postdose on Day 1 | Responders: Day 1, 4 hour (H) (n=9) | 1.052 mV | Standard Deviation 0.867 |
| Ketamine IV 0.5mg/kg | Comparison of Ketamine Responders and Ketamine Non-responders in the Change From Baseline in Motor Evoked Potential (MEPs) Amplitudes at 4 Hours Postdose on Day 1 | Non-Responders: Baseline (n=4) | 1.257 mV | Standard Deviation 1.055 |
| Ketamine IV 0.5mg/kg | Comparison of Ketamine Responders and Ketamine Non-responders in the Change From Baseline in Motor Evoked Potential (MEPs) Amplitudes at 4 Hours Postdose on Day 1 | Non-Responders: Day 1, 4H (n=4) | 1.197 mV | Standard Deviation 1.067 |
| Ketamine IV 0.5mg/kg | Comparison of Ketamine Responders and Ketamine Non-responders in the Change From Baseline in Motor Evoked Potential (MEPs) Amplitudes at 4 Hours Postdose on Day 1 | Non-Responders: Change from Baseline (n=4) | -0.060 mV | Standard Deviation 0.088 |
Primary
Comparison of Ketamine Responders and Ketamine Non-responders in the Change From Baseline in Somatosensory Evoked Potential (SEPs) Amplitudes at 4 Hours Postdose on Day 1
SEPs are the electrical signals generated by the nervous system in response to somatosensory stimuli - typically through electrical stimulation of the median nerve. SEPs are read on the skull with electroencephalography (EEG). SEPs was recorded using a 64-channel EEG system at baseline (predose) and regularly after study drug administration. The change from baseline was calculated as post-baseline value minus baseline value for each participant. Since the number of participants at baseline differ from the number of participants at post-baseline measure (that is \[i.e.\] not all baseline values are paired), the mean change is not equal to the difference between the means at the two time points.
Time frame: Baseline and Day 1 (4 hours postdose)
Population: Efficacy analysis set included all participants who received a dose of ketamine and who had at least 1 postbaseline value of SEP (P40).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketamine IV 0.5mg/kg | Comparison of Ketamine Responders and Ketamine Non-responders in the Change From Baseline in Somatosensory Evoked Potential (SEPs) Amplitudes at 4 Hours Postdose on Day 1 | Responders: Baseline (n=9) | 1.83 millivolts (mV) | Standard Deviation 1.13 |
| Ketamine IV 0.5mg/kg | Comparison of Ketamine Responders and Ketamine Non-responders in the Change From Baseline in Somatosensory Evoked Potential (SEPs) Amplitudes at 4 Hours Postdose on Day 1 | Responders: Day 1, 4 Hours (n=6) | 2.58 millivolts (mV) | Standard Deviation 1.24 |
| Ketamine IV 0.5mg/kg | Comparison of Ketamine Responders and Ketamine Non-responders in the Change From Baseline in Somatosensory Evoked Potential (SEPs) Amplitudes at 4 Hours Postdose on Day 1 | Responders: Change from Baseline (n=6) | 0.47 millivolts (mV) | Standard Deviation 1.68 |
| Ketamine IV 0.5mg/kg | Comparison of Ketamine Responders and Ketamine Non-responders in the Change From Baseline in Somatosensory Evoked Potential (SEPs) Amplitudes at 4 Hours Postdose on Day 1 | Non-Responders: Baseline (n=4) | 1.70 millivolts (mV) | Standard Deviation 1.1 |
| Ketamine IV 0.5mg/kg | Comparison of Ketamine Responders and Ketamine Non-responders in the Change From Baseline in Somatosensory Evoked Potential (SEPs) Amplitudes at 4 Hours Postdose on Day 1 | Non-Responders: Day 1, 4 Hours (n=3) | 1.84 millivolts (mV) | Standard Deviation 1.48 |
| Ketamine IV 0.5mg/kg | Comparison of Ketamine Responders and Ketamine Non-responders in the Change From Baseline in Somatosensory Evoked Potential (SEPs) Amplitudes at 4 Hours Postdose on Day 1 | Non-Responders: Change from Baseline (n=3) | 0.47 millivolts (mV) | Standard Deviation 0.43 |