Clinical TrialTreatment-Resistant Depression (TRD)KetamineKetaminePlaceboCompleted

A Study of Brexpiprazole Plus Ketamine in Treatment-Resistant Depression (TRD)

Randomised, double-blind, placebo-controlled five-site trial (n=51) testing oral brexpiprazole (up to 3 mg/day) versus placebo combined with intranasal ketamine (40 mg, six administrations over 4 weeks) added to stable antidepressant therapy for adults with TRD.

Target Enrollment
51 participants
Study Type
Phase IV interventional
Design
Randomized, quadruple Blind

Detailed Description

Five-site, randomised, quadruple-blind, parallel-group study evaluating the acute efficacy of adjunctive oral brexpiprazole versus placebo when combined with intranasal ketamine in adults with treatment-resistant major depressive disorder.

Participants continue stable antidepressant therapy and receive brexpiprazole titrated up to 3 mg/day or matching placebo for four weeks with intranasal ketamine 40 mg administered twice weekly for two weeks then weekly for two weeks (six administrations total); primary outcomes assess depressive symptom change (MADRS) and safety.

Key eligibility includes MADRS >20, documented TRD per MGH ATRQ, BMI 18–35 kg/m2, and medical stability; major exclusions include primary psychotic or bipolar disorders, recent substance use disorder, significant cardiovascular or neurological illness, and pregnancy.

Study Protocol

Preparation

sessions

Dosing

6 sessions

Integration

sessions

Study Arms & Interventions

Ketamine/Brexpiprazole

active comparator

Brexpiprazole up to 3 mg/day for four weeks combined with intranasal ketamine 40 mg: twice-weekly for two weeks then weekly for two weeks (six administrations).

Interventions

  • Compound - 3 mg
    via Oral• daily

    Brexpiprazole titrated up to 3 mg/day for 4 weeks.

  • Ketamine40 mg
    via Inhalation• six administrations over 4 weeks• 6 doses total

    Intranasal ketamine 40 mg: twice weekly for 2 weeks then weekly for 2 weeks.

Ketamine/Placebo

inactive

Placebo matching brexpiprazole for four weeks combined with intranasal ketamine 40 mg administered twice-weekly for two weeks then weekly for two weeks.

Interventions

  • Ketamine40 mg
    via Inhalation• six administrations over 4 weeks• 6 doses total

    Intranasal ketamine 40 mg.

  • Placebo
    via Oral• daily

    Placebo matching brexpiprazole in size and number of tablets per dose for 4 weeks.

Participants

Ages
18 – 65
Sexes
Male & Female

Inclusion Criteria

  • Inclusion Criteria:
  • 1. Male or female, 18 to 65 years of age, inclusive, at screening.
  • 2. Able to read, understand, and provide written, dated informed consent prior to screening. Participants will be deemed likely to comply with study protocol and communicate with study personnel about adverse events and other clinically important information.
  • 3. Diagnosed with MDD, single or recurrent, and currently experiencing a major depressive episode (MDE) of at least eight weeks in duration, prior to screening, according to DSM-5. Diagnosis made by site psychiatrist and supported by the SCID-5; confirmed by remote independent raters with a SAFER interview.
  • 4. History of treatment resistant depression (TRD) during the current MDE, as assessed by investigator and remote centralized rater using the MGH ATRQ. TRD defined as failure to achieve a satisfactory response (e.g., <50% improvement) to at least 2 'treatment courses' during the current episode of therapeutic-dose ADT of at least 8 weeks. Participants must be on a stable (≥4 weeks) and adequate (per MGH ATRQ) dose of ongoing ADT (except MAOIs), total duration at least 8 weeks.
  • 5. MADRS total score >20 at both the screen visit and the baseline visit, confirmed by remote centralized rater.
  • 6. In good general health based on medical history, physical exam, labs, and ECG.
  • 7. If female, non-childbearing potential or use of acceptable birth control; negative pregnancy test at screening and baseline; willing to use contraception during study.
  • 8. Body mass index between 18 and 35 kg/m2.
  • 9. Concurrent psychotherapy allowed if stable for ≥3 months and expected to remain stable.
  • 10. Concurrent hypnotic therapy allowed if stable for ≥4 weeks; benzodiazepines allowed if stable for ≥4 weeks.

Exclusion Criteria

  • Exclusion Criteria:
  • 1. Female of childbearing potential who is not willing to use one of the specified forms of birth control during the study.
  • 2. Female who is pregnant or breastfeeding.
  • 3. Female with a positive pregnancy test at screening or baseline.
  • 4. History during the current MDE of failure to achieve satisfactory response to >7 treatment courses of a therapeutic dose of an antidepressant therapy of at least 8 weeks duration, as confirmed by remote rater.
  • 5. Total MADRS score of <20 at the screen visit or baseline visit, or as assessed by remote rater.
  • 6. Current diagnosis of a substance use disorder (abuse or dependence), with the exception of nicotine dependence, at screening or within 6 months prior to screening.
  • 7. Current Axis I disorder that is the principal focus of treatment and MDD secondary for the past 6 months or more.
  • 8. History of bipolar disorder, schizophrenia or schizoaffective disorder, or any history of psychotic symptoms in current or previous depressive episodes.
  • 9. History of anorexia nervosa, bulimia nervosa, or eating disorder not otherwise specified, within 5 years of screening.
  • 10. Any Axis I or Axis II disorder clinically predominant to MDD at screening or within 6 months prior.
  • 11. Investigator judgment that subject is at significant risk for suicidal behaviour during participation.
  • 12. Failed to respond to ECT during the current depressive episode.
  • 13. Prior VNS treatment.
  • 14. Dementia, delirium, amnestic, or other cognitive disorder.
  • 15. Clinically significant abnormality on screening physical exam that might affect safety or study participation.
  • 16. Participation in any clinical trial with an investigational drug or device within the past month or concurrent participation.
  • 17. Current episode of specified cardiovascular conditions (e.g., hypertension ≥160/100 mmHg at baseline, recent MI within 1 year, syncopal event within past year, CHF >NYHA Stage 2, angina, HR <45 or >110 bpm, QTcF ≥450 msec).
  • 18. Chronic lung disease excluding asthma.
  • 19. Lifetime history of major neurosurgery, encephalitis, meningitis, degenerative CNS disorder, epilepsy, intellectual disability, or significant head trauma within past 2 years.
  • 20. Specified lab abnormalities or requirement for exclusionary concomitant medications.
  • 21. Unstable diabetes or recent hospital admission for diabetes-related illness, or not under physician care for diabetes.
  • 22. History of hypothyroidism on replacement for <2 months prior to screening (unless stable ≥2 months).
  • 23. History of hyperthyroidism treated <6 months prior to screening.
  • 24. Positive urine drug screen for drugs of abuse at screening (exceptions detailed in protocol).
  • 25. Use of exclusionary concomitant psychotropic medications with insufficient washout time per protocol.
  • 26. History of narrow angle glaucoma.
  • 27. Liver or renal function tests meeting exclusion criteria or history of hepatic/renal dysfunction per protocol.

Study Details

Locations

Collaborative Neuroscience Network, LLC. — Garden Grove, California, United States
Pacific Research Partners, LLC — Oakland, California, United States
Rush University Medical Center — Chicago, Illinois, United States
Massachusetts General Hospital, Depression Clinical and Research Program — Boston, Massachusetts, United States
Nathan Kline Institute for Psychiatric Research — Orangeburg, New York, United States
Montefiore Medical Center — The Bronx, New York, United States

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