Bipolar Disorder
Conditions
Keywords
Bipolar Disorder
Brief summary
The purpose of this study is to test whether ketamine and D-cycloserine can be safely and effectively used for the treatment of depression. The investigators hypothesize that ketamine will serve as a rapid acting and safe antidepressant in patients with bipolar depression, and furthermore, that D-cycloserine will serve as an effective therapy following ketamine treatment.
Detailed description
Bipolar disorder affects 2% of the population in the United States and the depressive phase contributes disproportionally to morbidity and mortality. At present, few approved treatments for bipolar depression are available, and have primarily depended on manipulations of brain monoaminergic systems. In contrast, recent studies suggest that the N-methyl-D-aspartate glutamate-receptor (NMDAR) antagonist, ketamine, may provide near-immediate relief for treatment resistant depression. Its utility during long-term treatment, however, is limited by its psychotomimetic potency and the need for repeated IV infusions. D-cycloserine (DCS) is an approved oral antibiotic for tuberculosis drug and a well-studied mixed agonist/antagonist at the NMDAR/glycine binding site. DCS showed preliminary evidence of efficacy in a pilot study. DCS would thus be practical from both a safety and route of administration perspective. The present study will explore the feasibility and safety of DCS for maintenance treatments, as measured by magnetic resonance spectroscopy (MRS).
Interventions
DRUGStandard of Care
Quetiapine, olanzapine-fluoxetine, and lurasidone are approved treatments for bipolar depression. Quetiapine dosing will follow the product label(Anon), and will be titrated over the first 4 days to the target dose of 300 mg. Olanzapine-fluoxetine dosing will also follow standard guidelines. Lurasidone will be started at 20 mg, and titrated up to 60 mg daily as clinically indicated. Study physicians will use clinical judgment to choose between standard-of care treatments, and have the option to titrate standard-of-care within approved ranges, and to prescribe adjunctive benztropine and benzodiazepines if clinically indicated.
DRUGKetamine
Ketamine administration will be carried out according to the methods as described by previous studies. Subjects will receive ketamine hydrochloride (0.5 mg/kg) intravenously during 40 minutes. This dosage was selected based on previous trials of ketamine for the treatment of refractory depression and bipolar depression. Vital signs (blood pressure, heart rate) will be closely monitored throughout the time of infusion. Subjects will be evaluated for 2 consecutive days during this phase; i.e. treatment days (day 1) and rating days (day 2). Non-responders to ketamine will not proceed into the DCS phase. Response will be a 25% improvement on the Hamilton Depression Rating Scale (HDRS).
DRUGD-cycloserine
Immediately after the ketamine infusion, subjects will begin an eight-week treatment of DCS adjunctive to standard of care. DCS dosing will begin at 250 mg for three days→500mg (2 capsules)/day for 1 week → 750 mg (3 capsules)/day for 1 week → and 1000 mg (4 capsules)/day for the remainder of the study.
Sponsors
New York State Psychiatric Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Male and female patients with Diagnostic and Statistical Manual, Version 4 (DSM-IV) diagnosis of bipolar disorder I or II, current major depressive episode without psychotic features, 18-60 * Insufficient therapeutic response during the current episode * Medically stable for study participation * Judged clinically not to be at significant suicide or violence risk * Subject is off all psychotropic and other types of drugs likely to interact with glutamate for at least 14 days before starting the study. One exception is chloral hydrate or short acting benzodiazepines for distressing anxiety or insomnia (up to 72 hours prior to each MRI scan). In addition, subjects will be off antipsychotics for 1 month and off fluoxetine for 6 weeks prior to the study. * Subject is likely to be able to tolerate a medication washout. Only subjects who have failed their current medication regiment will be washed off medications.
Exclusion criteria
* History of chronic psychosis or drug induced psychosis of any kind * Current DSM-IV diagnosis of drug abuse/dependence in the last six months. Subjects must have a negative drug screen at baseline. * Women will be excluded if they are pregnant lactating, or not either surgically-sterile or using appropriate methods of birth control. Women must agree to continue using applicable birth control throughout the trial. All women of child-bearing potential must have a negative urine pregnancy test * Taking any medication contraindicated with ketamine or DCS (ethionamide, isoniazid) * History of seizures, renal insufficiency or congestive heart failure * History of clinically significant violence * History of ketamine abuse/dependence or prior clinically significant adverse reaction to ketamine * Current alcohol abuse or dependence * Untreated hypertension * Clinically abnormal liver function tests (LFTs), thyroid, renal function or anemia * Metal implants, pacemaker, other metal (e.g. shrapnel or surgical prostheses) or paramagnetic objects contained within the body which may present a risk to the subject or interfere with the MR scan. * Medicinal patch, unless removed prior to the MR scan
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hamilton Depression Rating Scale (HAM-D) | 8 weeks | Depression rating scale: Range 0-53, higher scores indicate worse depression. 0-7 = Normal 8-13 = Mild Depression 14-18 = Moderate Depression 19-22 = Severe Depression ≥ 23 = Very Severe Depression |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Loss of Motivated Behavior HAM-D Factor | 8 weeks | includes the total of four HAM-D items: (Item 7: Work and activities, Item 12. Somatic symptoms (appetite), Item 14. Genital symptoms (libido), and Item 16. Weight loss). Range 0-11, higher scores indicate worse symptoms |
| HAM-D Suicide Item | 8 weeks | Ham-D suicide item: range 0-4, higher scores indicate worse symptoms |
| Hamilton Anxiety Scale | 8 weeks | Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where \<17 indi- cates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. |
| Beck's Depression Inventory | 8 weeks | Range 0-63, with higher scores worse. Total score of 0-13 is considered minimal range, 14-19 is mild, 20-28 is moderate, and 29-63 is severe. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ketamine and DCS Treatment Standard of Care: Subjects will receive treatment with either quetiapine, olanzapine-fluoxetine, or lurasidone. If after about 2 week, subjects are symptomatic, subjects will receive infusion of ketamine hydrochloride (0.5 mg/kg). After the ketamine phase, subject who show improvement will begin an 8-week treatment of oral D-cycloserine. | 8 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lack of Efficacy | 1 |
Baseline characteristics
| Characteristic | Ketamine and DCS Treatment |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Age, Continuous | 37 years STANDARD_DEVIATION 16 |
| Beck's depression inventory | 31.4 units on a scale STANDARD_DEVIATION 10.4 |
| Hamilton Anxiety Rating Scale (HAM-A) | 12.6 units on a scale STANDARD_DEVIATION 4.2 |
| Hamilton Depression Rating Scale (HAM-D) | 18.8 units on a scale STANDARD_DEVIATION 6.7 |
| Hamilton Depression Rating Scale (HAM-D) suicide item | 1.25 units on a scale STANDARD_DEVIATION 0.9 |
| Loss of Motivated Behavior HAM-D Factor | 5 units on a scale STANDARD_DEVIATION 1.6 |
| Montgomery Asberg Depression Rating scale | 29 units on a scale STANDARD_DEVIATION 6 |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 3 Participants |
| Time of treatment resistance | 3.3 Months STANDARD_DEVIATION 4 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 4 / 8 |
| serious Total, serious adverse events | 0 / 8 |
Outcome results
Primary
Hamilton Depression Rating Scale (HAM-D)
Depression rating scale: Range 0-53, higher scores indicate worse depression. 0-7 = Normal 8-13 = Mild Depression 14-18 = Moderate Depression 19-22 = Severe Depression ≥ 23 = Very Severe Depression
Time frame: 8 weeks
Population: bipolar depression
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine and DCS Treatment | Hamilton Depression Rating Scale (HAM-D) | 9.5 units on a scale (final score) | Standard Deviation 7 |
p-value: <0.001linear mixed model
Secondary
Beck's Depression Inventory
Range 0-63, with higher scores worse. Total score of 0-13 is considered minimal range, 14-19 is mild, 20-28 is moderate, and 29-63 is severe.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine and DCS Treatment | Beck's Depression Inventory | 10.8 units on a scale (final score) | Standard Deviation 9.2 |
p-value: <0.001Mixed Models Analysis
Secondary
HAM-D Suicide Item
Ham-D suicide item: range 0-4, higher scores indicate worse symptoms
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine and DCS Treatment | HAM-D Suicide Item | 0.3 units on a scale (final) | Standard Deviation 0.5 |
p-value: 0.026ANOVA
Secondary
Hamilton Anxiety Scale
Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where \<17 indi- cates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine and DCS Treatment | Hamilton Anxiety Scale | 6.4 units on a scale (final score) | Standard Deviation 5 |
p-value: 0.011ANOVA
Secondary
Loss of Motivated Behavior HAM-D Factor
includes the total of four HAM-D items: (Item 7: Work and activities, Item 12. Somatic symptoms (appetite), Item 14. Genital symptoms (libido), and Item 16. Weight loss). Range 0-11, higher scores indicate worse symptoms
Time frame: 8 weeks
Population: bipolar depression
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine and DCS Treatment | Loss of Motivated Behavior HAM-D Factor | 1.6 units on a scale (final score) | Standard Deviation 1.9 |
p-value: <0.001Mixed Models Analysis