臨床研究等提出・公開システム

Efficacy and Safety study of the therapeutic approach using ketamine in refractory depression.

Study of the therapy using ketamine in refractory depression

10

In this clinical study, subjects were not assigned, and the study was conducted in the same drug administration format as in all cases. Background information on the subject is provided below. *Main inclusion criteria: The MADRS score is higher than or equal to 17 and BDI-II score is higher than or equal to 14. An inadequate response to at least 1 antidepressant, administered at an adequate dose and duration in the current episode of depression, or intolerant to more than one antidepressant. *Age: 18-61 years old, average 46.4 years old *Age at onset of depression: 14 to 49 years old, average 33.6 years old *Gender: 3 males, 7 females

*Consent acquisition : Consent was obtained from 1 to 2 subjects per month during the study period. Specific acquisition times are listed below. 2022 March-1 case, May-1 case, June-1 case, July-2 cases, September-2 cases, October-1 case, November-1 case, December-1 case *Treatment initiation : Treatment periods were initiated approximately once a month during the study period. The specific implementation timing is described below. 2022 May-1 case, June-2 cases, July-1 case, August-1 case, September-1 case, October-1 case, November-1 case, December-1 case *Completion of treatment : Of the 9 cases in which treatment was started, 8 cases completed the treatment period in 16 days as planned. In one case, the treatment was discontinued at the request of the subject.

Occurrence of serious adverse events : None Cases of non-serious adverse events that may have a causal relationship with this treatment : *Vascular pain at the site of intravenous injection 1 case: Outcome (recovery) was confirmed on the day of onset *Photophobia 1 case: Outcome (recovery) was confirmed at the end of the treatment period *Headache 4 cases: Outcomes (remission) were confirmed on the day of onset in all cases *Vomiting 1 case: Due to strong nausea and vomiting, the study was discontinued after the first treatment at the request of the subject, and the outcome (recovery) was confirmed 11 days later *Anxiety attack 3 cases: Outcome (remission) was confirmed on the day of onset in all cases

Main analysis results are described below. *Primary endpoint: CADSS The CADSS score, the primary endpoint, was compared between before the start of treatment on each administration day and at 40 minutes after administration of ketamine using Wilcoxon signed-rank test (paired). And the presence or absence of a statistically significant increase in the CADSS score was determined for each combination pattern. As a result, when combined with placebo, ketamine 3 mg, and brexpiprazole 2 mg, there was a tendency for the CADSS total score to increase after administration compared to before administration of ketamine (p<0.1). On the other hand, no increase in CADSS total score was observed when co-administered with aripiprazole 12 mg (p=0.25). *Secondary endpoints (ketamine side effect assessment): BPRS-P, MOAA/S, VAS In addition to dissociative symptoms, a study was conducted to determine whether the combined use of aripiprazole and brexpiprazole also has a suppressive effect on ketamine-induced side effects such as positive symptoms, sedation, dizziness, and headache. Wilcoxon signed-rank test (paired) was used to analyze the comparison of concomitant use and no pretreatment. And no significant changes were observed in the changes before and after ketamine administration when aripiprazole and brexpiprazole were combined, compared to the changes before and after ketamine administration when combined with placebo. *Secondary endpoint (ketamine antidepressant effect): MADRS The improvement effect of depressive symptoms was verified using MADRS, which can evaluate the severity of depressive symptoms. Friedman's test was used to compare the baseline and each measurement time point, and Dunn's test was used as a post hoc multiple test. As a result, a significant decrease in the MADRS total score was observed after Day 9, the day after the administration of aripiprazole 12 mg compared to before the start of Day 1 treatment.

Regarding safety, we obtained results suggesting that concomitant use of aripiprazole reduces ketamine-induced dissociative symptoms. Although it should be noted that the antidepressant efficacy was evaluated in an open-label manner, an improvement effect of depressive symptoms was shown by MADRS evaluation. Considering the findings on efficacy and safety obtained in this study above, the clinical usefulness of concomitant use of aripiprazole with ketamine is considered to outweigh the risk.

Mar. 31, 2024

No

No plans to share.

https://jrct.mhlw.go.jp/latest-detail/jRCTs051210192

Murai Toshiya

Kyoto University Hospital

54 Shogoinkawahara-cho, Sakyo-ku,Kyoto-shi,Kyoto

murai@kuhp.kyoto-u.ac.jp

Suwa Taro

Kyoto University Hospital

54 Shogoinkawahara-cho, Sakyo-ku,Kyoto-shi,Kyoto

+81-75-751-3373

tarosuwa@kuhp.kyoto-u.ac.jp

Complete

Mar. 11, 2022

Interventional

single arm study

double blind

placebo control

single assignment

treatment purpose

1) Men or women over 18 years (inclusive).
2) Having provided voluntary written consent for participation in this study. If younger than 20 years, Legal representative also has to aggree with the consent.
3) Meet Diagnostic and Statistical Manual of Mental Disorders-5th Edition (DSM-5) diagnostic criteria for major depressive disorder (MDD), based upon the Mini-International Neuropsychiatric Interview, M.I.N.I. The length of the current depressive episode must be longer than or equal to (>=)4 weeks.
4) The MADRS score is higher than or equal to 17, and BDI-II score is higher than or equal to 14.
5) Have had an inadequate response to at least 1 antidepressant, administered at an adequate dose and duration in the current episode of depression, or intolerant to more than one antidepressant.

1) Patient has complications such as serious hepatic disorder, renal disorder, heart disease,
lung disease, hematological disease, and metabolic disease.
2) Non-responder to esketamine or ketamine in the depressive episode.
3) Patient has had complications such as neurodevelopmental disorders, schizophrenic disorders, PTSD, Disruptive, impulse-control, and conduct disorders.
4) Patient has complictions such as obsessive-complusivity disorders, anorexia nervosa, bulimia nervosa,
binge eating disorder, neurocognitive disorders, disruptive mood dysregulation disorder.
5) Patient has complication such as epilepsy (including medical history), sleep apnea syndrome, COPD.
6) Patient experienced gastric bypass surgery, gastric sleeve or lap band surgery, or treatment inhibiting gastrointestinal transit.
7) Corrected QT interval >450 msec on an electrocardiogram.
8) Patient with hypertension, systolic and diastolic blood pressures are >140mmHg and >90mmHg, respectively. For patients older than or equal to 65 years, systolic blood pressure is >150mmHg.
9) Significant observation in the Interview, clinical test or 12-lead electrocardiogram.
10) Patient with sucidal tendency and ideation judged with C-SSRS (yes in Q4, Q5 or questions about actual sucidal behaviors except for the item about non-intentional self-injuring behavior)
11) Patient violating the rules of adjunctive medications.
12) Patient has medical history of substance use disorders.
13) Positive in a urine drug screen (except for the case positive because of antidepressant therapy)
14) Pregnant or attempting to be pregnant during the study, and lactating.
15) Difficult to complete the study, having the potential to have disadvantages, difficult to ensure the safety, inappropriate to evaluate the safety and efficacy of the medicines used in this study, or inappropriate judged by principal investigator or subinvestigators.
16)Patients with a history of seizures or hypersensitivity to the components of KETALAR, and patients with cerebrovascular disorders, intracranial hypertension and severe cardiac decompensation.

Both

refractory depressive disorder

Oral administration of placebo, aripiprazole 3mg/12mg or brexpiprazole 2mg, 4 hours prior to ketamine intravenous injection over 40min at 0.5mg/kg.

depression, anxiety, anhedonea

ketamine, aripiprazole, brexpiprazole

D003865

D000068180, C000591922, D007649

CADSS

Efficacy:BPRS-P, MADRS, PHQ-9, CGI-I, CGI-S, VAS, MOAA/S, anhedonia (MADRS anhedonia factor, PHQ9 anhedonia factor), correlation between scores before treatments and effects of treatments, correlation analysis between each endpoint and plasma drug concentration
Safety: vital signs, Electrocardiogram, Clinical test, Adverse events

+81-75-753-4680

Feb. 14, 2022

none