Obsessive Compulsive Disorder
Conditions
Keywords
OCD, Obsessive-Compulsive Disorder, ketamine, treatment
Brief summary
Obsessive-Compulsive Disorder (OCD) is a chronic and disabling anxiety disorder and a leading cause of worldwide disability that presents a significant public health problem. Treatment options are limited and many OCD patients fail to respond completely or quickly to standard treatments, including pharmacotherapy and psychotherapy. At this time, patients who fail to respond to treatment with serotonergic drugs, augmenting antipsychotic agents, and behavioral therapy, have few additional treatment options aside from deep brain stimulation. Therefore, despite advances in current pharmacological and behavioral treatments, and the utility of serotonergic drugs, it is likely that other neurotransmitter systems are involved and that targeting these systems may increase treatment efficacy. Despite little evidence for serotonergic dysfunction in OCD, there is significant evidence that glutamatergic dysregulation may contribute to the development and progression of the disorder. Also, preliminary studies suggest that glutamatergic modulators (i.e. riluzole and d-cycloserine), particularly agents acting at the NMDA receptor (i.e. memantine), may be useful in OCD. The NMDA antagonist, ketamine, has demonstrated rapid effects when delivered as a single intravenous (IV) dose in depressed patients. Therefore, the objective of the current study is to investigate the safety and efficacy of a single dose of IV ketamine in treatment-resistant OCD.
Detailed description
This study will test the safety and efficacy of a single intravenous (IV) dose of the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, ketamine, in treatment-resistant OCD.
Interventions
DRUGKetamine
Ketamine hydrochloride is a nonbarbiturate anesthetic. It is formulated as a slight acid (pH 3.5 to 5.5) sterile solution for intravenous or intramuscular injection in concentrations containing the equivalent of either 50 or 100mg ketamine base per milliliter.
DRUGMidazolam
Midazolam is a short-acting benzodiazepine central nervous (CNS) depressant.
Sponsors
Icahn School of Medicine at Mount Sinai
Wayne Goodman MD
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male or female patients, 21-65 years * Women of childbearing potential must agree to use a medically accepted means of contraception for the duration of the study * Primary diagnosis of Obsessive-Compulsive Disorder as assessed by the SCID-P, with symptoms for at least 1 year (Patients who meet criteria for OCD will be required to be medication free or have all psychotropics aside from SSRIs and as needed benzodiazepines tapered. Prior to study entry, proscribed psychotropics are tapered, and subjects must be on the same SSRI for at least 8 weeks with no change in dose for at least 4 weeks and throughout the study. However, subjects will be allowed to use benzodiazepines as needed throughout the study.) * History of a failure to respond to at least two (2) adequate pharmacotherapy trials and CBT for OCD * Subjects must have scored ≥ 21 on the Y-BOCS at Screening, and to not be in remission on Treatment Day #1, and Treatment Day #2 * Each subject must have a level of understanding sufficient to agree to all tests and examinations required by the protocol and must sign an informed consent document * Subjects must be able to identify a family member, physician, or friend who will participate in the Treatment Contract and serve as an emergency contact.
Exclusion criteria
* Women who plan to become pregnant within the next six months, are pregnant or are breast-feeding * Non-English speakers * Any unstable medical illness including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, neurologic, immunologic, or hematologic disease * Clinically significant abnormal findings of laboratory parameters, physical examination, or ECG * Lifetime history of schizophrenia, schizoaffective disorder, bipolar disorder, mental retardation, or pervasive developmental disorders * Current evidence of psychotic or manic symptoms * Drug or alcohol abuse or dependence within the preceding 6 months * Lifetime abuse or dependence on ketamine or phencyclidine * Patients judged by study investigator to be at high risk for suicide * Current use of psychotropics other than SSRIs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Yale-Brown Obsessive Compulsive Scale (Y-BOCCS) Rating OCD Symptom Severity From Baseline to 24-hours After Ketamine Administration | Baseline and 24 Hours | The primary efficacy outcome is change in the Y-BOCCS rating score on a scale from baseline to 24 hrs post-administration of ketamine. The 10 Y-BOCCS items are each scored on a four-point scale from 0 = no symptoms to 4 = extreme symptoms. The sum of the first five items is a severity index for obsessions. The sum of the last five an index for compulsions. A translation of total score into an approximate index of overall severity is: 0-7 - subclinical; 8-15 - mild; 16-23 - moderate; 24-31 - severe; 32-40 - extreme. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Who Meet Response and Remission | up to 14 days | Percentage of patients who meet response (defined as 25% reduction in Y-BOCCS score) and remission (defined as Y-BOCS score ≤10) criteria at 24 hrs post-infusion and durability of efficacy up to two weeks after administration. Assessments will be performed 24, 48 and 72 hrs post-infusion and after 7, 10, and 14 days. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from the Mood and Anxiety Disorders Program (MAPs). In addition, referrals from clinicians in the Mount Sinai Medical Center, community clinics, and affiliated hospitals were also sought.
Pre-assignment details
Eligible participants met treatment-resistant criteria if they failed to respond to ≥ 2 adequate pharmacotherapy trials with SRIs FDA approved medications for OCD with or without adjunctive antipsychotics, as well as cognitive behavioral therapy.
Participants by arm
| Arm | Count |
|---|---|
| Ketamine (Randomized Week 1, Cross Over Midazolam Week 3)) Study participants will receive a one-time intravenous infusion of 0.5 mg/kg racemic ketamine hydrochloride
Ketamine: Ketamine hydrochloride is a nonbarbiturate anesthetic. It is formulated as a slight acid (pH 3.5 to 5.5) sterile solution for intravenous or intramuscular injection in concentrations containing the equivalent of either 50 or 100mg ketamine base per milliliter. | 1 |
| Midazolam (Randomized Wk 1, Cross Over Ketamine Wk 3) Study participants will receive a one-time intravenous infusion of 0.045 mg/kg midazolam
Midazolam: Midazolam is a short-acting benzodiazepine central nervous (CNS) depressant. | 2 |
| Total | 3 |
Baseline characteristics
| Characteristic | Midazolam (Randomized Wk 1, Cross Over Ketamine Wk 3) | Total | Ketamine (Randomized Week 1, Cross Over Midazolam Week 3)) |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 3 Participants | 1 Participants |
| Age, Continuous | 48.5 years | 48.6 years | 49 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 2 Participants | 3 Participants | 1 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 2 |
| other Total, other adverse events | 1 / 1 | 1 / 2 |
| serious Total, serious adverse events | 0 / 1 | 0 / 2 |
Outcome results
Primary
Change in Yale-Brown Obsessive Compulsive Scale (Y-BOCCS) Rating OCD Symptom Severity From Baseline to 24-hours After Ketamine Administration
The primary efficacy outcome is change in the Y-BOCCS rating score on a scale from baseline to 24 hrs post-administration of ketamine. The 10 Y-BOCCS items are each scored on a four-point scale from 0 = no symptoms to 4 = extreme symptoms. The sum of the first five items is a severity index for obsessions. The sum of the last five an index for compulsions. A translation of total score into an approximate index of overall severity is: 0-7 - subclinical; 8-15 - mild; 16-23 - moderate; 24-31 - severe; 32-40 - extreme.
Time frame: Baseline and 24 Hours
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ketamine (Randomized Week 1, Cross Over Midazolam Week 3)) | Change in Yale-Brown Obsessive Compulsive Scale (Y-BOCCS) Rating OCD Symptom Severity From Baseline to 24-hours After Ketamine Administration | -2.98 Units on a scale |
| Midazolam (Randomized Wk 1, Cross Over Ketamine Wk 3) | Change in Yale-Brown Obsessive Compulsive Scale (Y-BOCCS) Rating OCD Symptom Severity From Baseline to 24-hours After Ketamine Administration | -2.185 Units on a scale |
Secondary
Percentage of Patients Who Meet Response and Remission
Percentage of patients who meet response (defined as 25% reduction in Y-BOCCS score) and remission (defined as Y-BOCS score ≤10) criteria at 24 hrs post-infusion and durability of efficacy up to two weeks after administration. Assessments will be performed 24, 48 and 72 hrs post-infusion and after 7, 10, and 14 days.
Time frame: up to 14 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ketamine (Randomized Week 1, Cross Over Midazolam Week 3)) | Percentage of Patients Who Meet Response and Remission | 0 percentage of participants |
| Midazolam (Randomized Wk 1, Cross Over Ketamine Wk 3) | Percentage of Patients Who Meet Response and Remission | 50 percentage of participants |