A single and multiple dose safety and tolerability study of oral ketamine in healthy volunteer and patients with a history of depression or anxiety.

INTERVENTION: Participants will be confined at the clinical site for the duration of the dosing and sampling periods. Cohort 1‐3: Study days 0 to 4 and study days 6 to 10 Cohort 4: Study days 0 to 5 Cohort 5: Study days 0 to 2 and study days 6 to 9 Planned doses as follows: Dose level 1 (Cohort 1 ‐ 8 healthy volunteers): single capsule containing 60 mg oral ketamine or methylcellulose placebo on day 1, then twice daily day 7‐9 Dose level 2 (Cohort 2 ‐ 8 healthy volunteers): 2 x capsules containing 60 mg oral ketamine or methylcellulose placebo on day 1, then twice daily day 7‐9 Dose level 3 (Cohort 3 ‐ 8 healthy volunteers): 4 x capsules containing 60 mg oral ketamine or methylcellulose placebo on day 1, then twice daily day 7‐9 Dose level 4 (Cohort 4 ‐ 6 patients with depression and 6 patients with anxiety): single capsule containing 60 mg oral ketamine once daily in the morning and then 1‐2x (dependant on whether or not depression or anxiety has improved along with assessments of safety and tolerability assessed by the Principal Investigator/Head of Department Psychological Medicine) 60 mg oral ketamine once daily 12 hours after the morning dose on day 1 and then 1‐4x 60 mg (dependant on whether or not depression or anxiety has improved along with assessments of safety and tolerability assessed by the Principal Investigator/Head of Department Psychological Medicine) twice daily on days 2‐4 Dose Level 5 (Cohort 5 ‐ 12 healthy volunteers): Dose will be the highest single dose of oral ketamine from the results of Cohort 1 to 3 in fasted state on day 1 and fed state on day 8. Volunteers are not required water for 1 hour prior to dosing until 1 hour after dosing (except for the water consumed with each dose). For cohort 5 volunteers are required not to eat for 10 hours before dosing on day 1 and the a standardised high fat content meal on day 8 and to fast for approximately 4 hours after each dose. CONDITION: Anxiety Depression PRIMARY OUTCOME: To evaluate the pharmacokinetics (as summarised by Cmax and AUC). All plasma samples will be assayed for ketamine and norketamine using one fully validated LC/MS/MS method. Validation will be conducted to comply with FDA guidelines. To evaluate the pharmadynamics (as summarised by BDNF). All serum samples will be assayed using a fully validated ELISA method. Validation will be conducted to comply with FDA guidelines. To evaluate the safety (as summarised by adverse events, vital signs and ECG). SECONDARY OUTCOME: Additional Primary Outcome: To evaluate efficacy (as summarised by questionnaires and rating scores (CADSS and C‐SSRS)). Time to maximum peak concentration (Tmax) will be determined by plasma sample analysis. Tmax will be the time where the maximum concentration occurred in the sample points. INCLUSION CRITERIA: Subjects will be eligible for enrolment for Cohorts 1, 2, 3 and 5: on the basis of: a) Provide written informed consent b) Male or non‐pregnant females c) Aged 18 to 55 years on the day of consent d) Body Mass Index greater than 18 and less than 30kg/m2 on day of consent e) Healthy individuals as determined by medical history, physical examination, ECG, vital signs and laboratory tests f) HIV and Hepatitis B and C negative g) Non‐smoker (for at least 6 months prior to the date of consent). h) Drug free as determined by urine drug testing Subjects will be eligible for enrolment for Cohort 4 on the basis of: a) Provide written informed consent b) Male or non‐pregnant females c) Aged 18 to 60 years on the day of consent d) Body Mass Index greater than 18 and less than 35 kg/m2 on day of consent e) Healthy individuals as determined by medical history, physical examination, ECG, vital signs and laboratory test