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Examination of efficacy and safety of ketamine treatment and exploration of the neural circuitry basis of its treatment effect on treatment-resistant depression: double-blind randomized placebo-controlled trial and extension open-label single-arm trial

Ketamine administration for treatment-resistant depression

34

Total N=34 Age (year) Mean (SD) 41.4 (9.4) Median 42.5 Min, Max 26, 59 Gender Male (%) 23 (67.6) Female (%) 11 (32.4) Race Mongoloid (%) 34 (100.0) Age at onset (year) Mean (SD) 29.9 (10.4) Median 29 Min, Max 16, 56 History of psychiatric treatment (year) Mean (SD) 11.1 (8.1) Median 8 Min, Max 0.7, 29 Therapeutic Environment Outpatient (%) 34 (100.0) Inpatient (%) 0 Dominant hand Right (%) 34 (100.0) Left (%) 0 (0.0) Ketamine Placebo N=17 N=17 Age (year) Mean (SD) 39.9 (9.5) 42.9 (9.1) Median 41 44 Min, Max 26, 57 29, 59 Gender Male (%) 11 (64.7) 12 (70.6) Female (%) 6 (35.3) 5 (29.4) Age at onset (year) Mean (SD) 29.1 (10.6) 30.8 (10.1) Median 26 30 Min, Max 16, 51 16, 56 History of psychiatric treatment (year) Mean (SD) 10.4 (8.3) 11.7 (7.8) Median 7 15 Min, Max 1, 29 0.7, 21 Total N=34 Height (cm) Mean (SD) 169.2 (8.2) Median 169.9 Min, Max 152.7, 182.0 Weight (kg) Mean (SD) 72.1 (15.4) Median 71.9 Min, Max 41.1, 118.8 SBP (mmHg) Mean (SD) 123.8 (16.0) Median 127.5 Min, Max 95, 147 DBP (mmHg) Mean (SD) 82.1 (11.9) Median 83.5 Min, Max 60, 114 Pulse rate (bpm) Mean (SD) 89.6 (14.8) Median 89.0 Min, Max 63, 125 BT (degree) Mean (SD) 36.5 (0.4) Median 36.6 Min, Max 35.6, 37.5 SpO2 (%) Mean (SD) 97.7 (1.07) Median 99 Min, Max 94, 99 Ketamine Placebo N=17 N=17 Height (cm) Mean (SD) 168.2 (7.3) 170.2 (8.8) Median 168.7 173.0 Min, Max 152.7, 179.7 153.0, 182.0 Weight (kg) Mean (SD) 68.3 (10.2) 75.9 (18.4) Median 70.9 72.3 Min, Max 41.1, 83.7 50.2, 118.8 SBP (mmHg) Mean (SD) 119.1 (15.1) 128.5 (15.5) Median 118 132 Min, Max 95, 146 98, 147 DBP (mmHg) Mean (SD) 77.5 (9.9) 86.6 (12.1) Median 76 86 Min, Max 60, 97 66, 114 Pulse rate (bpm) Mean (SD) 85.2 (11.8) 93.9 (16.2) Median 82 91 Min, Max 65, 117 63, 125 BT (degree) Mean (SD) 36.5 (0.4) 36.5 (0.3) Median 36.5 36.6 Min, Max 35.6, 37.5 35.8, 36.8 SpO2 (%) Mean (SD) 97.9 (0.80) 97.5 (1.24) Median 98 98 Min, Max 96, 99 94, 99 Total N=34 MADRS total Mean (SD) 28.1 (7.6) Median 28 Min, Max 15, 44 HDRS 24items Mean (SD) 16.1 (5.8) Median 17 Min, Max 5, 30 Y-BOCS 1-10 (n=11) Mean (SD) 12.0 (9.6) Median 8 Min, Max 1, 28 RBANS Total Scale Score Mean (SD) 87.7 (20.5) Median 91 Min, Max 46, 122 LNS Total Mean (SD) 13.6 (2.9) Median 13 Min, Max 8, 18 SNST part 3-1(s) Mean (SD) 5.9 (5.3) Median 4.8 Min, Max -2.1, 16.0 TMT part B-A (s) Mean (SD) 12.7 (30.6) Median 3.0 Min, Max -42, 67 PDS Severity (n=9) Mean (SD) 15.9 (9.5) Median 16 Min, Max 1, 31 QIDS-SR Total Mean (SD) 16.0 (5.2) Median 17 Min, Max 6, 26 AQ Total Mean (SD) 25.4 (7.6) Median 27.5 Min, Max 11, 42 JART premorbid IQ Mean (SD) 111.5 (8.6) Median 113 Min, Max 93, 123 BAS 1-3 Total Mean (SD) 0 (0) Median 0 Min, Max 0, 0 AIMS 1-7 Total Mean (SD) 0 (0) Median 0 Min, Max 0, 0 SAS Total Mean (SD) 0 (0) Median 0 Min, Max 0, 0 Ketamine Placebo N=17 N=17 MADRS total Mean (SD) 29.4 (7.9) 26.9 (7.1) Median 29 27 Min, Max 15, 44 15, 43 HDRS 24items Mean (SD) 17.1 (5.6) 15.1 (5.8) Median 17 15 Min, Max 5, 30 5, 24 Y-BOCS 1-10 (n=4, 7) Mean (SD) 7.3 (7.5) 14.7 (9.6) Median 4 10 Min, Max 1, 20 3, 28 RBANS Total Scale Score Mean (SD) 88.7 (23.0) 86.8 (17.5) Median 91 91 Min, Max 32, 122 46, 113 LNS Total Mean (SD) 13.5 (2.9) 13.7 (2.6) Median 14 13 Min, Max 8, 18 8, 21 SNST part 3-1(s) Mean (SD) 4.1 (4.3) 7.8 (5.5) Median 3.1 7 Min, Max -2.1, 15.2 1, 24.1 TMT part B-A (s) Mean (SD) 4.1 (25.9) 21.2 (32.4) Median -5 16 Min, Max -20, 91 -42, 89 PDS Severity (n=7, 2) Mean (SD) 16.1 (10.1) 15.0 (7.0) Median 16 15 Min, Max 1, 31 8, 22 QIDS-SR Total Mean (SD) 17.8 (5.0) 14.2 (4.7) Median 20 14 Min, Max 9, 26 6, 25 AQ Total Mean (SD) 23.1 (8.0) 27.7 (6.4) Median 24 28 Min, Max 11, 38 17, 42 JART premorbid IQ Mean (SD) 109.8 (7.5) 113.2 (9.3) Median 111 115 Min, Max 93, 121 95, 123 BAS 1-3 Total Mean (SD) 0 (0) 0 (0) Median 0 0 Min, Max 0, 0 0, 0 AIMS 1-7 Total Mean (SD) 0 (0) 0 (0) Median 0 0 Min, Max 0, 0 0, 0 SAS Total Mean (SD) 0 (0) 0 (0) Median 0 0 Min, Max 0, 0 0, 0

Enrollment 34 FAS 34 Double-blind SAS 34 Double-blind PPS 31 Open-label SAS 16 Open-label PPS 15

Adverse event, Case, Incidence [%]a, Causality Dissociation 98 76.0 Causally related Increased blood pressure 14 10.9 Causally related Headache 13 10.1 Causally related Dizziness 11 8.5 Causally related Nausea 6 4.7 Causally related Somnolence 5 3.9 Causally related Euphoria 4 3.1 Causally related Dysarthria 3 2.3 Causally related Dysesthesia 3 2.3 Causally related Feeling of drunkenness 2 1.6 Causally related Vomiting 1 0.8 Causally related Skin rash 1 0.8 Causally related Subcutaneous hemorrhage 1 0.8 Causally related a) Incidence = Cases / the total number of times of administration (129).

Primary endpoint 1. Changes in the MADRS total score ITT analysis Ketamine Placebo (n=17) (n=17) delta MADRS (ITT) Mean (SD) -8.1 (10.0) -2.5 (5.2) Median -6 -2 Min, Max -34, 4 -11, 8 PP analysis Ketamine Placebo (n=15) (n=16) delta MADRS (PP) Mean (SD) -9.1 (10.2) -2.7 (5.3) Median -6 -2.5 Min, Max -34, 4 -11, 8 Secondary endpoint 2. Changes in the 17-items HDRS total score ITT analysis Ketamine Placebo (n=17) (n=17) delta HDRS 17 items (ITT) Mean (SD) -4.4 (6.3) -1.4 (4.2) Median -3 0 Min, Max -20, 1 -9, 8 delta QIDS-SR (ITT) Mean (SD) -4.6 (4.9) -2.2 (3.2) Median -3 -1 Min, Max -15, 2 -9, 3 delta Y-BOCS (ITT) (n=5, 7) Mean (SD) 4.0 (6.1) -7.1 (9.0) Median 0 -2 Min, Max -2, 14 -21, 1 delta RBANS (ITT) Mean (SD) -3.5 (16.5) 0.5 (7.8) Median 0 1 Min, Max -45, 23 -16, 17 delta BSS (ITT) Mean (SD) -4.6 (6.1) -2.6 (4.3) Median -3 -1 Min, Max -18, 4 -12, 5 PP analysis Ketamine Placebo (n=15) (n=16) delta HDRS 17 items (PP) Mean (SD) -4.9 (6.5) -1.5 (4.3) Median -4 -0.5 Min, Max -20, 1 -9, 8 delta QIDS-SR (PP) Mean (SD) -5.3 (4.9) -2.4 (3.2) Median -5 -2 Min, Max -15, 2 -9, 3 delta Y-BOCS (PP) (n=3, 6) Mean (SD) 6.7 (6.6) -8.3 (9.2) Median 8 -4 Min, Max -2, 14 -21, 1 delta RBANS (PP) Mean (SD) -3.9 (17.5) 0.6 (8.1) Median -3 1.5 Min, Max -45, 23 -16, 17 delta BSS (PP) Mean (SD) -5.2 (6.3) -2.8 (4.4) Median -5 -1 Min, Max -18, 4 -12, 5 3. Adverse Event Adverse Event, Case, Incidence [%]a, Causality Dissociation 98 76.0 Causally related Increased blood pressure 14 10.9 Causally related Headache 13 10.1 Causally related Dizziness 11 8.5 Causally related Nausea 6 4.7 Causally related Somnolence 5 3.9 Causally related Euphoria 4 3.1 Causally related Dysarthria 3 2.3 Causally related Dysesthesia 3 2.3 Causally related Feeling of drunkenness 2 1.6 Causally related Vomiting 1 0.8 Causally related Skin rash 1 0.8 Causally related Subcutaneous hemorrhage 1 0.8 Causally related a) Incidence = Cases / the total number of times of administration (129).

There was no significant reduction in the MADRS total score between the ketamine and placebo groups on ITT analysis; however, there was a significant reduction in the ketamine group compared to the placebo group on PP analysis. No significant superiority was observed in other outcome measures including HDRS (17-items), QIDS-SR, RBANS, and BSS in the ketamine group compared to the placebo group on both ITT and PP analysis.

Mar. 31, 2025

No

N.A.

https://jrct.mhlw.go.jp/latest-detail/jRCTs031210124

Uchida Hiroyuki

Keio University Hospital

Shinanomachi 35, Shinjuku-ku, Tokyo

hiroyuki_uchida@keio.jp

Uchida Hiroyuki

Keio University Hospital

Shinanomachi 35, Shinjuku-ku, Tokyo

+81-3-3353-3971

hiroyuki_uchida@keio.jp

Complete

May. 31, 2021

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

other

1.Outpatients or inpatients who meet the criteria for depression according to Structured Clinical Interview for DSM-5 Disorders SCID-5-RV (Research Version) Japanese Version
2. Men and women between the ages of 20 and 60 at the time of registration.
3. Inadequate response to 2 or more antidepressants at approved doses for 6 weeks or more for the current depressive episode
4. A Montgomery-Asberg Depression Rating Scale (MADRS) total score of 22 or higher at the time of screening
5. Being capable of providing informed consent confirmed with scores above 70% in the following four items: understanding, appreciation, reasoning, and the ability to express a choice in the MacArthur Competence Assessment Tool (MacCAT)
6. Written consent being provided by study participant

1. Having previously received esketamine or ketamine for the treatment of depression
2. Depression with psychotic features according to the diagnostic criteria of the DSM-5
3. Being pregnant, breastfeeding, or hoping to become pregnant
4. A history of epilepsy or seizures
5. A history of cerebrovascular disease
6. A history of ketamine hypersensitivity
7. High blood pressure (systolic pressure 160 mmHg or more, diastolic pressure 100 mmHg or more)
8. A history of cerebral hypertension
9. A history of severe cardiac compensatory failure
10. A history of glaucoma or ocular trauma
11. Receiving electroconvulsive therapy within 3 months prior to enrollment
12. Substance-related disorders (excluding nicotine and caffeine) within 6 months
13. Positive urine screening for dependent substances (except for those who are positive for drugs taken for treatment)
14. having a metallic substance in the body or having a pacemaker
15. the size of the head, neck and body are not suitable for MRI scanners
16. Having tattoos that are larger than one point (including tattoos and art make-up)
17. A high degree of claustrophobia
18. Significant deformity of brain structure (including congenital and traumatic)
19. At the time of registration, any of the following abnormal laboratory values
Serum creatinine 1.5 mg/dl or more
AST 150 IU/L or more
ALT 150 IU/L or more
20. Participated in another clinical trial within 12 weeks prior to enrollment (limited to those with invasion/intervention)
21. Those deemed unsuitable as research subjects by the principal investigator, etc.

Both

Treatment-resistant depression

Ketamine: Twice a week for 2 weeks (4 times in total), intravenous administration of ketamine hydrochloride (0.5 mg/kg) plus saline solution (total amount 50 mL) will be performed over 40 minutes.
Placebo: Twice a week for 2 weeks (4 times in total), intravenous administration of saline solution (50 mL) will be performed over 40 minutes.

depression

ketamine

D061218

D004358

Severity of mood symptoms assessed with MADRS

- Severity of mood symptoms assessed with HDRS
- Severity of mood symptoms assessed with QIDS-SR
- Severity of obsessive-compulsive symptoms
- Severity of obsessive symptoms assessed with Y-BOCS
- Cognitive function assessed with RBANS
- Degree of suicidal ideation assessed with BSS
- Adverse events associated with ketamine administration

+81-3-5363-3503

May. 25, 2021

none