Depression depressive disorder
Conditions
Interventions
S-ketamine 0.2 mg/kg oral solution in single dose
S-ketamine 0.45 mg/kg oral solution in single dose
S-ketamine 0.4 mg/kg IV over 40 min
placebo: intravenous saline, oral matching solution (double-dum
Sponsors
Centre for Human Drug Research
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: 1. Healthy female or male subjects, 18 to 45 years of age, inclusive. Healthy status is defined by absence of evidence of any active or chronic disease following a detailed medical, surgical and psychiatric history, a complete physical examination including vital signs, 12-lead electrocardiogram (ECG), haematology, blood chemistry, and urinalysis. 2. Able to participate and willing to give written informed consent and to comply with the study restrictions. 3. Use of any form of birth control is required for heterosexual subjects of childbearing potential who are sexually active during the study, either used by the subject or their sexual partner. 4. Able to read and understand English at a sufficient level in order to participate in the ETB.
Exclusion criteria
Exclusion criteria: 1. Positive test for drugs of abuse at screening or pre-dose. 2. The subject has a positive pregnancy test. 3. History (within 3 months of screening) of alcohol consumption exceeding 2 standard drinks per day on average. 4. History or symptoms of any significant disease including (but not limited to), neurological, endocrine, cardiovascular, respiratory, gastrointestinal, hepatic, or renal disorder. 5. The subject has a previous or current, or a family history of, a clinically significant psychiatric disorder, including substance use disorder. 6. A history or family history of epilepsy, seizures or convulsions. 7. Having metal objects in brain or skull. 8. The subject has a history of intracranial mass lesion, hydrocephalus and/or head injury or trauma. 8. Having a cochlear implant or implanted deep brain stimulator. 9. Abnormal sleeping pattern (e.g. working night shifts). 10. Resting motor threshold (rMT) of more than 75% of the maximum stimulator output, measured using TMS-EMG during screening. 11. Systolic blood pressure (SBP) greater than 140 mmHg during screening. The measurement may be repeated before randomization to confirm eligibility or judged to be clinically irrelevant for healthy subjects. 12. Use of any medications within 14 days of study drug administration, or less than 5 half-lives (whichever is longer). 13. Use of more than 5 cigarettes (or other tobacco or nicotine products with equivalent nicotine dose) daily within the previous month before the first dose administration, and/or unable or unwilling to not smoke during the in-house periods. 15. Regular recreational use of illicit drugs (notably ketamine) within 12 months of screening.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Tolerability / safety endpoints - treatment-emergent adverse events (AEs) and serious adverse events (SAEs) - adverse events leading to premature discontinuation of study drug - epileptic seizures as a result of TMS - laboratory safety, vital signs and ECG Pharmacokinetic endpoints Pharmacokinetic variables (including but not limited to Cmax, AUC0-*, clearance (CL), Vss, terminal half-life (t*)) for the different compounds and metabolites will be evaluated if deemed appropriate. For analysis concentrations of S-ketamine, S-norketamine, and S-hydroxynorketamine will be obtained in plasma, according to the schedule specified in table 1. Data may be used for PK or PK-PD modelling. Pharmacodynamic endpoints NeuroCart * Saccadic eye movements * Smooth pursuit eye movements * Body sway * Adaptive tracking * Visual Analog Scales (VAS) Bond and Lader * Visual Analog Scale (VAS) Bowdle * Digit Symbol Substitution Test (DSST) TMS-EMG * rMT measured with single pulse TMS * Peak-to-peak amplitude of the motor evoked potential (MEP) measured with single pulse TMS (stimulation intensity: 120% rMT) * Short intracortical inhibition (SICI) measured with paired pulse TMS at an interstimulus * interval (ISI) of 2 ms (stimulation intensity: conditioning pulse 80% rMT, test pulse: 120% rMT) * Long intracortical inhibition (LICI) measured with paired pulse TMS at ISIs 50, 100 and 300 ms (stimulation intensity: conditioning and test pulse 120% rMT). TMS-EEG * Amplitude of the TMS evoked potential (TEP) measured with single pulse TMS and paired pulse TMS at ISIs 2, 50, 100 and 300 ms EEG * Resting state EEG * P300/ active auditory oddball * 40Hz Auditory Steady State Response (ASSR) * Auditory Sensory Gating (ASG) | — |
Secondary
| Measure | Time frame |
|---|---|
| Oxford ETB * Facial Expression Recognition Task (FERT) - perception of social cues * Emotional Categorisation Task (ECAT) - attention to affective information * Faces Dot Probe Task (FDOT) - attention to affective information * Emotional Recall Task (EREC) - memory for affective information * Emotional Recognition Memory Task (EMEM) - memory for affective information MEQ30 * scores on *mystical* (subdomain) * scores on *positive mood* (subdomain) * scores on *space/time* (subdomain) * scores on *ineffability* (subdomain) | — |
Countries
Netherlands
Outcome results
None listed