A Comparative Analysis of the Pharmacokinetics of Oral and Sublingual Ketamine as Adjunctive Therapies in Major Depressive Disorder
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 10
- 主要终点
- Pharmacokinetic measures
研究概览
简要总结
Major Depressive Disorder (MDD) is one of the most common and severe mental illnesses in the world. Ketamine treatment, especially intravenous ketamine (IVK) and intranasal esketamine (INE), is becoming more popular and is being used more. But these ways of administering aren't perfect. They mostly have problems with cost, accessibility, and the issues of administering. The oral and sublingual routes of ketamine are cheaper alternatives, but they haven't been looked into as much in the medical and academic circles. This is a small pilot feasibility study, involving ten patient participants who will be randomly assigned to take ketamine by oral and sublingual routes as part of a single-blind, crossover design. A local London pharmacy-Ultimate Care Compounding will provide the ketamine formulations.
Ten patients between 18 and 65 years old with Major Depressive Disorder will be recruited from the Mental Health Care Programs at LHSC, Victoria Hospital and SJHC, Parkwood Institute, (that has treatment resistant depression treatment focus). After a screening baseline visit, which will include clinical interviews with medication reconciliation, psychiatric evaluations, routine standard laboratory tests, and an electrocardiogram (ECG).
Due to capacity limitations at the Centre for Clinical Investigation and Therapeutics (CCIT), a maximum of 5 participants will undergo pharmacokinetic sampling simultaneously, enrolment will proceed in two sequential groups with treatment order assigned by group. Group A (n=5): The first 5 eligible participants will receive oral ketamine in Treatment Period 1 and sublingual ketamine in Treatment Period 2. Group B (n=5): The next 5 eligible participants will receive sublingual ketamine in Treatment Period 1 and oral ketamine in Treatment Period 2. Recruitment for Group B will commence once Group A has completed the clinical intervention phase.
During Monday and Thursday of each of Weeks 1 and 2, Group A will receive oral ketamine, while Group B will receive sublingual ketamine. Weeks 3 and 4 are a washout period. In Weeks 5 and 6, on Mondays and Thursdays, groups will switch to the other form of administration [See flowchart of study procedure]. Weeks 7 and 8 are washout periods to ensure consistency with the first half of the study and provide a similar framework for clinical assessments. Blood samples will be collected at 2 time points at the Center for Clinical Investigation and Therapeutics at University Hospital. The study goal is to help define safe and effective oral/SL ketamine doses based on Pharmacokinetic profiles.
详细描述
Background and Rationale:
1.1 Introduction Major Depressive Disorder (MDD) represents one of the most prevalent and debilitating psychiatric disorders, with the WHO stating that it is the most disabling illness worldwide, affecting over 300 million people. Current pharmacotherapies, although effective for some, often fail to provide rapid and lasting relief for many patients, with remission rates of 67% and treatment-resistant depression occurring in approximately 30% of those diagnosed with MDD.
Ketamine has been shown to improve symptoms of treatment-resistant major depressive disorder. The increasing acceptance and use of ketamine, specifically intravenous ketamine (IVK) and intranasal esketamine (INE), have shown promise in bridging this therapeutic gap, particularly given its rapid onset of action.
However, these routes of administration are not without their challenges.
- These challenges include the high cost of IVK and INE preparations compared to oral ketamine. The cost of a single session with IVK can be $400 to $800 CAD due to fees for hospital room and staff. The cost of a single dose of INE is $600 to $1000, not including any hospital costs. On the other hand, the cost of a single dose of compounded oral ketamine (75 mg) is only $5 to $15 CAD.
- The second issue is accessibility. Patients have to be admitted to hospital for IVK administration. Hence, this is done in specialised urban centres, a disadvantage for rural residents.
- The third is administration logistics, like arranging the time of clinical staff to do the IVK and INE treatment.
- Lastly, INE and IVK carry a higher burden of common adverse effects of ketamine, with more dissociation and hypertension occurring compared to oral dosing.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must meet all the following criteria to be eligible for the study. Appendix B is a checklist that will be used by Dr. Hammound for screening, based on the following inclusion and
排除标准
- •Age: Between 18 and 65 years (inclusive) at the time of screening.
- •Weight: Equal to or greater than 50 kg (110 lbs).
- •Diagnosis: A current diagnosis of Major Depressive Disorder (MDD), moderate to severe in intensity, as defined by the DSM-5 criteria.
- •Current Episode: Experiencing a moderate to severe Major Depressive Episode (MDE) at screening.
- •Ongoing Treatment: Actively receiving pharmacological treatment for MDD at the time of enrollment.
- •Treatment Resistance: Documented history of inadequate response to at least two antidepressant medications, each from a different pharmacological class, administered at an adequate dose and duration.
- •Capacity and Consent: Able and willing to provide written informed consent after understanding the nature, risks, and potential benefits of the study.
- •Clinical Oversight: Currently under the regular care of a psychiatrist or general practitioner (GP).
- •Support System: Has a responsible adult (e.g., family member or caregiver) who can accompany them from study visits or ensure safe transportation after ketamine has been used.
- •Able to speak, read and understand English
- •Exclusion Criteria:
- •Participants will be excluded if any of the following criteria apply:
- •Suicidality: Active suicidal ideation with plan or intent, or suicidal behavior, within the past 3 months.
- •Concomitant Medications: Use of medications that may pose a risk of respiratory depression or serious adverse events when combined with ketamine (e.g., benzodiazepines, opioids, barbiturates).
- •Medical Comorbidities: Presence or history of significant or unstable medical conditions that could interfere with study participation or pose a safety risk, including but not limited to cerebrovascular accident, cardiac decompensation, large vessel aneurysms, glaucoma etc.. Participants with clinically significant laboratory abnormalities, as determined by the investigator, will also be excluded.
- •Hypersensitvity to ketamine
- •Uncontrolled hypertension (blood pressure ≥140/90 mmHg at screening, which may be repeated after 30 minutes rest)
- •Psychiatric Comorbidities: Diagnosis of bipolar disorder, psychotic disorders, or history of psychotic symptoms.
- •Substance Use: Clinically significant alcohol or substance use disorder within the last 6 months, as defined by DSM-5 criteria.
- •Cognitive Impairment: Any condition resulting in impaired capacity to understand or consent to participation or to comply with study procedures.
- •Pregnancy and Lactation: Pregnant or breastfeeding individuals.
- •Concurrent Research Participation: Participation in another interventional clinical trial or use of an investigational drug within the 30 days prior to screening.
- •Current or recent (within 90 days) treatment with ketamine (oral, IV or intranasal).
- •ECG demonstrates abnormalities like Qtc interval>470 ms or any arrhythmia reported as clinically significant or abnormal by the interpreting physician. Exclusionary findings would include uncontrolled atrial fibrillation, ventricular arrhythmias, heart block, or other abnormalities that could pose a safety risk with ketamine administration
结局指标
主要结局
Pharmacokinetic measures
时间窗: Plasma samples will be collected at 0, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, and 8 hours of the first day of weeks 1 and 5.
Plasma concentration of ketamine Plasma concentration of norketmaine Area Under Curve from 0 to 8 hours Area Under Curve from 8 hours to infinity Half-life of the log-linear phase Cmax (i.e. peak plasma drug concentration) Tmax (i.e. the time taken to reach the maximum concentration).
次要结局
- Montgomery-Aspberg Depression Rating Scale (MADRS).(This scale will be used at screening and then: Week 1 and Week 2 - biweekly Week 3 and 4 - once a week Week 5 and 6 - biweekly Week 7 and 8 - once a week)
- Hamilton Depression Rating Scale (HAM-D17)(This scale will be used at screening and then: Week 1 and Week 2 - biweekly Week 3 and 4 - once a week Week 5 and 6 - biweekly Week 7 and 8 - once a week)
研究者
Rohit Lodhi
Assistant Professor (Dept of Psychiatry, Schulich School of Medicine and Dentistry)
Western University, Canada