Using ketamine to treat bipolar disorder that doesn't respond to other treatments

Repeated Ketamine Infusions for Treatment-Resistant Bipolar Disorder: A Randomized, Double-blind, Midazolam-controlled, Phase II Clinical Trial

This study is testing if repeated ketamine infusions can help people with bipolar disorder who haven't found relief from other treatments feel better during their depressive episodes.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 100 (estimated)
• Ages: 21 Years to 65 Years
• Sex: All
• Sponsor: University Health Network, Toronto (Academic / other)
• Locations: 3 sites (Toronto, Ontario and 2 other locations)
• Trial ID: NCT05004896 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the effects of repeated intravenous ketamine infusions on patients with treatment-resistant bipolar disorder. It aims to assess the acute antidepressant efficacy, safety, and tolerability of four sub-anesthetic doses of ketamine over a two-week period. The study is double-blinded and controlled with midazolam, focusing on a homogenous sample of patients experiencing moderate to severe depressive episodes. Secondary objectives include examining the impact on suicidal ideation, quality of life, and overall functioning.

Who should consider this trial

Good fit: Ideal candidates are adults aged 21 to 65 with a confirmed diagnosis of Bipolar I or II Disorder currently experiencing a major depressive episode that has not responded to previous treatments.

Not a fit: Patients with bipolar disorder who do not have a major depressive episode or those who have not tried adequate first-line treatments may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a rapid and effective option for patients suffering from treatment-resistant bipolar disorder.

How similar studies have performed: While there is growing evidence supporting ketamine's efficacy in treatment-resistant depression, this specific approach for bipolar disorder is novel and has not been extensively tested in previous studies.

Eligibility criteria

Inclusion Criteria

1. Provide written, voluntary informed consent prior to study enrollment. Substitute decision makers will not be allowed to consent to study on a potential patient's behalf.
2. Male or female between the age of 21 to 65, inclusive.
3. Meets DSM-5 criteria for Bipolar I or II Disorder, currently experiencing a Major Depressive Episode without psychotic features. Diagnosis will be confirmed using the Mini-International Neuropsychiatric Interview (MINI) conducted by a delegated physician or trained research study while assessing eligibility.
4. Patient must present with a moderate to severe depressive episode, as determined by the MADRS score greater than 21.
5. Current depressive episode has inadequate response to two or more adequate first-line treatment trials for bipolar depression, as per the 2018 CANMAT Bipolar Disorder Guidelines. First line treatment trials include the use of lithium, valproate, carbamazepine, lamotrigine and/or any antipsychotic medication.
6. Patient must be receiving guideline-concordant pharmacotherapy without changes in the last month, including a therapeutic dose of a guideline-concordant mood stabilizer/antipsychotic.

Exclusion Criteria

1. Currently exhibiting symptoms of mania, hypomania, or mixed state bipolar, as determined by the Young Mania Rating Scale (YMRS) score greater than 12.
2. Current symptoms of psychosis or a substance use disorder within the past 3 months. History of psychotic features during a mood episode will not be excluded.
3. History of neurological disorders (including, but not limited to, uncontrolled seizure disorder, history of stroke within past 12 months, major head injuries, aneurysmal vascular disease \[including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels\], arteriovenous malformation, or intracerebral hemorrhage)
4. Lifetime history of a primary psychotic disorder (including, but not limited to, schizophrenia or schizoaffective disorder)
5. Lifetime history of ketamine use disorder
6. Presence of active suicidality, requiring involuntary inpatient treatment or recent suicide attempts within the past 3 months.
7. Presence of a contraindication to ketamine or midazolam, including a drug allergy, uncontrolled hypertension (baseline systolic blood pressure \> 140 mmHg and/or diastolic blood pressure \> 90 mmHg), low or labile blood pressure, myocardial infarction within past 12 months, cardiac arrhythmia, moderate to severe hepatic impairment (i.e., Child-Pugh score of B or C), moderate or severe renal impairment (glomerular filtration rate (GFR) \< 45 milliliters/min) , heart failure, or coronary artery disease
8. Pregnant or breastfeeding women or women who intend to get pregnant. Patients who are sexually active must agree to use a highly effective contraceptive method (as outlined in section 5.11).
9. Use of prohibited concomitant medications, including other forms of ketamine or esketamine, benzodiazepines, stimulants, alcohol, and medical or recreational cannabis taken during the trial at a specific prohibited time.
10. Use of ketamine in the 30 days leading up to the patient's entry in the trial.
11. Use of monoamine oxidase inhibitors (MAOIs) at least two weeks prior to receiving study treatment.

Where this trial is running

Toronto, Ontario and 2 other locations

• Toronto General Hospital — Toronto, Ontario, Canada (Recruiting)
• Toronto Western Hospital — Toronto, Ontario, Canada (Recruiting)
• Ontario Shores Centre for Mental Health Sciences — Whitby, Ontario, Canada (Recruiting)

Study contacts

• Principal investigator: Joshua Rosenblat, MD, MSc — Toronto Western Hospital, Psychiatry
• Study coordinator: Anesthesia Clinical Trials Unit

Conditions Bipolar Disorder; Bipolar Depression; Bipolar I Disorder; Bipolar II Disorder