DepressionPhase 2NCT03102736
Ketamine and Nitroprusside for Depression
A Phase 2 study testing Ketamine and Nitroprusside in people with Depression, run by Icahn School of Medicine at Mount Sinai at 1 site in United States.
Trial summary
The purpose of this study is to test the effects of the medication ketamine and the medication called nitroprusside in patients with major depression. Ketamine has both good and bad effects. Some studies have shown that ketamine improves depression. Read more about this study
- Who is it for?
- Ages 21 to 65 years
- Conditions the study is for
- Depression
- What is being tested?
- Ketamine and Nitroprusside
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 40 participants
- Where
- 1 siteUnited States
- Study dates
- 14 Feb 2017to 12 Jun 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male or female patients, 21-65 years of age;
- Female individuals who are not of childbearing potential (i.e., surgically sterile, postmenopausal for at least one year) or using a medically accepted reliable means of contraception. Women using oral contraceptive medication for birth control must also be using a barrier contraceptive. Women of childbearing potential must also have a negative pregnancy test at screening and at pre-infusion;
- Participants must fulfill current DSM-5 criteria for Major Depression without psychotic features or Persistent Depressive Disorder with specifier of "with persistent major depressive episode";
- Depression is at least moderate severity, defined as a CGI-S score of ≥ 4;
- Current major depressive episode is of at least 4 weeks duration
- Each participant 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
- Each participant must be able to identify a family member, physician, or friend who will act as an emergency contact
Who cannot join
- Lifetime history of psychotic features, diagnosis of schizophrenia or any other psychotic disorder, or diagnosis of bipolar disorder;
- Lifetime histories of autism, mental retardation, pervasive developmental disorders, or Tourette's syndrome;
- Current diagnosis of obsessive compulsive disorder (OCD) or eating disorder (bulimia nervosa or anorexia nervosa);
- Subjects with DSM-V drug or alcohol abuse/dependence within the preceding 2 years;
- Patients with schizotypal or antisocial personality disorder, or any clinically significant axis II disorder that would, in the investigator's judgment, preclude safe study participation;
- Patients judged clinically to be at serious and imminent suicidal or homicidal risk;
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- Women who are either pregnant or nursing;
- Any serious, unstable medical illnesses including hepatic, renal impairment, gastroenterologic, respiratory, cardiovascular, endocrinologic, neurologic, immunologic, or hematologic disease;
- History of congestive heart failure or established coronary artery disease;
- History of cerebrovascular insufficiency
- History of intrapulmonary arteriovenous shunts, co-arctation of the aorta or other conditions where cardiac outflow tract is obstructed;
- Vitamin B12 deficiency;
- Clinically significant abnormal findings of laboratory parameters, physical examination, or ECG;
- Renal impairment, as reflected by a BUN > 20 mg/dL and/or creatinin clearance of >1.3 mg/dL;
- Thyroid impairment, as reflected by a thyroid-stimulating hormone (TSH) > 4.2 mU/L;
- Hepatic injury, as reflected by AST or ALT greater than twice the upper limit of the reference range (AST: >80; ALT >110)
- Patients who have a positive urine toxicology for illicit substances at screening and within 24 hours of the infusion;
- Treatment with an irreversible MAOI within 2 weeks prior to randomization or fluoxetine within 4 weeks prior to randomization;
- Treatment with other antidepressants (classified as SSRIs, SNRIs, Atypical Antidepressants, MAOIs, TCAs) within one week of randomization.
- Previous recreational use of phencyclidine (PCP) or KET;
- Hypertension with systolic BP >160 mm Hg or diastolic BP >90 mm Hg at screening, systolic BP > 165 mm Hg or diastolic BP > 95 mm Hg immediately prior to treatment with study drug or hypotension with systolic BP < 90 or diastolic < 60 at screening or immediately prior to treatment with study drug; heart rate >110 or <60 at either of these time points;
- Treatment with sildenafil (Viagra), tadalafil (Cialis), Avanafil (Stendra), Vardenafil (Levitra) or other drugs in the same category of phosphodiesterase-5 enzyme inhibitors within 2 weeks of infusion.
Trial locations and contacts
1 site in 1 country.
United States1 site
Icahn School of Medicine at Mount Sinai
New York, New York, 10029
About this study
Official title: Pharmacologic Attenuation of Ketamine Using Nitroprusside
The purpose of this study is to test the effects of the medication ketamine and the medication called nitroprusside in patients with major depression. Ketamine has both good and bad effects. Some studies have shown that ketamine improves depression. However, studies have also shown that it causes strange and sometimes unpleasant sensations referred to "psychotic" or "dissociative" symptoms. An example of a psychotic symptom would be hearing or seeing something that in reality is not there. The study team would like to see if nitroprusside can prevent the reported bad effects of ketamine without blocking the reported good effects. This might make ketamine a better treatment for depression.
Read the detailed description
Ketamine is an effective fast-acting therapeutic intervention for patients with treatment refractory depression that is known to have the unwanted effect of inducing temporary psychotomimetic symptoms (i.e., delusions, hallucinations and thought disorganization) in some patients. The precise mechanisms of these psychotropic effects remain to be elucidated, but for several decades the NMDA-type glutamate receptor has been hypothesized to be of central importance. In this vain, recent studies of the antihypertensive agent nitroprusside - which increases the availability of the molecular nitric oxide, a known by-product of NMDA activity - have found evidence for antipsychotic properties both in humans with psychotic illness and healthy subjects given ketamine. Here, the clinical team proposes a study that will build on this work by evaluate the effects of nitroprusside on both the antidepressant and psychotomimetic effects of ketamine given to patients to treat refractory depression. In addition, as an exploratory aim, by collecting serial blood samples from the subjects, as the subjects are administered ketamine and nitroprusside, the clinical team will seek to determine functional markers of therapeutic effect and the mechanisms by which ketamine modulates both mood and psychotic states Research Question: The clinical team will test whether the effects of ketamine (KET) on mood and psychotic states is modified by co-administration with sodium nitroprusside (NP) in patients with depression. Furthermore, the clinical team will evaluate the extent to which the underlying biology of disease states and drug mechanisms can be inferred through analysis of brain-derived molecular material isolated from the peripheral circulation.
Specific Aims:
Aim I. To test whether co-administration with NP has any impact on the efficacy of KET as an antidepressant.
Aim II: To test the ability of NP to prevent the psychotomimetic effects of KET in patients with depression.
Research Hypotheses:
Research Hypothesis I. Patients pre-treated with NP will experience attenuated antidepressant effects (measured by MADRS score) following KET compared to pre-treatment with placebo.
Research Hypothesis II: Patients pre-treated with NP will experience attenuated psychotomimetic effects (e.g., CADSS score) immediately following KET compared to pre-treatment with placebo.
- Conditions
- Depression
- Being tested
- Placebos, Ketamine, Nitroprusside
- Keywords
- depression, ketamine, nitroprusside
- Medical subject headings
- Depression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PlacebosDrug
Placebo saline
KetamineDrug
0.5 mg/kg ketamine
NitroprussideDrug
0.5 mcg/kg nitroprusside
| Study group | Role | What they receive |
|---|---|---|
| Placebo and Ketamine | Placebo comparator | Placebo saline given over 240 minutes + 0.5 mg/kg ketamine given over 40 minutes Receives: Drug: Placebos; Drug: Ketamine |
| Nitroprusside and Ketamine | Experimental | 0.5 mcg/kg/min nitroprusside given over 240 min (4 hours) - 0.5 mg/kg ketamine given over the last 40 min of the nitroprusside infusion (starting at minute 200 the two drugs are given together) Receives: Drug: Ketamine; Drug: Nitroprusside |
What is being measured
The primary outcome is the main question the study is designed to answer.
Montgomery-Asberg Depression Rating Scale
This is a 10-item instrument used for the evaluation of depressive symptoms in adults and for the assessment of any changes to those symptoms. Each of the 10 items is rated on a scale of 0 to 6, with differing descriptors for each item. These individual item scores are added together to form a total score, which can range between 0 (normal) and 60 (severe depression).
Measured: 24 hours after start of infusion
Secondary outcomes (3)
Clinician-Administered Dissociative States Scale
This is used to measure dissociative effects during the infusions. The scale includes 23 clinician administered items scored from 0 (not at all) to 4 (extremely). The CADSS measures impairment in body perception, environmental perception, time perception, memory impairment, and feelings of unreality. Full scale from 0-92, with lower score indicating better health outcomes.
Measured: 240 minutes after start of infusion
Visual Analog Scale
These scales are scored in millimeters from the left-hand side of a 100-mm line to a perpendicular mark made by the patient at a point corresponding to the apparent magnitude of the feeling state. Range: 0 ("not at all") to 100 ("most ever").
Measured: 240 minutes after start of infusion
Brief Psychiatric Rating Scale (BPRS)
BPRS used to assess acute behavioral changes during the infusions. Four key BPRS items for the positive (+) symptoms of psychosis will be used: conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content. Three items representing the negative (-) symptoms of psychosis will also be used: blunted affect, emotional withdrawal, and motor retardation. Each item scored 1-7. Full scale from 7 - 49, with higher score indicating more symptoms.
Measured: +240 minutes (after start of Placebo/Nitroprusside infusion)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Apr 2017
- Study start14 Feb 2017
- Primary completion12 Jun 2019
- Study completion12 Jun 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for DepressionStudies of the same condition, open and under way.
- More trials run by Icahn School of Medicine at Mount SinaiThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- Icahn School of Medicine at Mount Sinai
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, James Murrough, Icahn School of Medicine at Mount Sinai
- Investigators
- James Murrough, MD, PhD, Principal investigator, Icahn School of Medicine at Mount Sinai
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03102736
- Sponsor's protocol ID
- GCO 16-1580
- Status last verified
- Jul 2020
- First submitted
- 31 Mar 2017
- Last updated
- 2 Jul 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Bevilacqua L, Charney A, Pierce CR, Richards SM, Jha MK, Glasgow A, Brallier J, Kirkwood K, Bagiella E, Charney DS, Murrough JW. Role of nitric oxide signaling in the antidepressant mechanism of action of ketamine: A randomized controlled trial. J Psychopharmacol. 2021 Feb;35(2):124-127. doi: 10.1177/0269881120985147.
PubMed 33522376
Study at a glance
From the registry record, last updated by the sponsor on 2 Jul 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacologic Attenuation of Ketamine Using Nitroprusside
- ClinicalTrials.gov ID
- NCT03102736
- Acronym / sponsor ID
- GCO 16-1580
- Conditions
- Depression
- Keywords
- depression, ketamine, nitroprusside
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- Icahn School of Medicine at Mount SinaiUniversity, hospital or other
- Study start
- 14 Feb 2017 (actual)
- Primary completion
- 12 Jun 2019 (actual)
- Study completion
- 12 Jun 2019 (actual)
- First posted
- 6 Apr 2017 (actual)
- Results
- Posted 2 Jul 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to test the effects of the medication ketamine and the medication called nitroprusside in patients with major depression. Ketamine has both good and bad effects. Some studies have shown that ketamine improves depression. However, studies have also shown that it causes strange and sometimes unpleasant sensations referred to "psychotic" or "dissociative" symptoms. An example of a psychotic symptom would be hearing or seeing something that in reality is not there. The study team would like to see if nitroprusside can prevent the reported bad effects of ketamine without blocking the reported good effects. This might make ketamine a better treatment for depression.
Detailed description
Ketamine is an effective fast-acting therapeutic intervention for patients with treatment refractory depression that is known to have the unwanted effect of inducing temporary psychotomimetic symptoms (i.e., delusions, hallucinations and thought disorganization) in some patients. The precise mechanisms of these psychotropic effects remain to be elucidated, but for several decades the NMDA-type glutamate receptor has been hypothesized to be of central importance. In this vain, recent studies of the antihypertensive agent nitroprusside - which increases the availability of the molecular nitric oxide, a known by-product of NMDA activity - have found evidence for antipsychotic properties both in humans with psychotic illness and healthy subjects given ketamine. Here, the clinical team proposes a study that will build on this work by evaluate the effects of nitroprusside on both the antidepressant and psychotomimetic effects of ketamine given to patients to treat refractory depression. In addition, as an exploratory aim, by collecting serial blood samples from the subjects, as the subjects are administered ketamine and nitroprusside, the clinical team will seek to determine functional markers of therapeutic effect and the mechanisms by which ketamine modulates both mood and psychotic states Research Question: The clinical team will test whether the effects of ketamine (KET) on mood and psychotic states is modified by co-administration with sodium nitroprusside (NP) in patients with depression. Furthermore, the clinical team will evaluate the extent to which the underlying biology of disease states and drug mechanisms can be inferred through analysis of brain-derived molecular material isolated from the peripheral circulation.
Specific Aims:
Aim I. To test whether co-administration with NP has any impact on the efficacy of KET as an antidepressant.
Aim II: To test the ability of NP to prevent the psychotomimetic effects of KET in patients with depression.
Research Hypotheses:
Research Hypothesis I. Patients pre-treated with NP will experience attenuated antidepressant effects (measured by MADRS score) following KET compared to pre-treatment with placebo.
Research Hypothesis II: Patients pre-treated with NP will experience attenuated psychotomimetic effects (e.g., CADSS score) immediately following KET compared to pre-treatment with placebo.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Placebo and Ketamine | Placebo comparator | Drug: Placebos, Drug: KetaminePlacebo saline given over 240 minutes + 0.5 mg/kg ketamine given over 40 minutes |
| Nitroprusside and Ketamine | Experimental | Drug: Ketamine, Drug: Nitroprusside0.5 mcg/kg/min nitroprusside given over 240 min (4 hours) - 0.5 mg/kg ketamine given over the last 40 min of the nitroprusside infusion (starting at minute 200 the two drugs are given together) |
Who may qualify
- Ages
- 21 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Male or female patients, 21-65 years of age;
- Female individuals who are not of childbearing potential (i.e., surgically sterile, postmenopausal for at least one year) or using a medically accepted reliable means of contraception. Women using oral contraceptive medication for birth control must also be using a barrier contraceptive. Women of childbearing potential must also have a negative pregnancy test at screening and at pre-infusion;
- Participants must fulfill current DSM-5 criteria for Major Depression without psychotic features or Persistent Depressive Disorder with specifier of "with persistent major depressive episode";
- Depression is at least moderate severity, defined as a CGI-S score of ≥ 4;
- Current major depressive episode is of at least 4 weeks duration
Key exclusion criteria (22 listed)
- Lifetime history of psychotic features, diagnosis of schizophrenia or any other psychotic disorder, or diagnosis of bipolar disorder;
- Lifetime histories of autism, mental retardation, pervasive developmental disorders, or Tourette's syndrome;
- Current diagnosis of obsessive compulsive disorder (OCD) or eating disorder (bulimia nervosa or anorexia nervosa);
- Subjects with DSM-V drug or alcohol abuse/dependence within the preceding 2 years;
- Patients with schizotypal or antisocial personality disorder, or any clinically significant axis II disorder that would, in the investigator's judgment, preclude safe study participation;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PlacebosPlacebo saline | Drug | Placebo and Ketamine |
| Ketamine0.5 mg/kg ketamine | Drug | Nitroprusside and Ketamine, Placebo and Ketamine |
| Nitroprusside0.5 mcg/kg nitroprusside | Drug | Nitroprusside and Ketamine |
Primary outcome
Montgomery-Asberg Depression Rating Scale
Time frame: 24 hours after start of infusion
This is a 10-item instrument used for the evaluation of depressive symptoms in adults and for the assessment of any changes to those symptoms. Each of the 10 items is rated on a scale of 0 to 6, with differing descriptors for each item. These individual item scores are added together to form a total score, which can range between 0 (normal) and 60 (severe depression).
3 secondary outcomes
Clinician-Administered Dissociative States Scale
Time frame: 240 minutes after start of infusion
Visual Analog Scale
Time frame: 240 minutes after start of infusion
Brief Psychiatric Rating Scale (BPRS)
Time frame: +240 minutes (after start of Placebo/Nitroprusside infusion)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jul 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 33522376Bevilacqua L, Charney A, Pierce CR, Richards SM, Jha MK, Glasgow A, Brallier J, Kirkwood K, Bagiella E, Charney DS, Murrough JW. Role of nitric oxide signaling in the antidepressant mechanism of action of ketamine: A randomized controlled trial. J Psychopharmacol. 2021 Feb;35(2):124-127. doi: 10.1177/0269881120985147.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
James Murrough, MD, PhD principal investigator
Icahn School of Medicine at Mount Sinai
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Ketamine and Nitroprusside in people with Depression, run by Icahn School of Medicine at Mount Sinai at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Jul 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 2 Jul 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Montgomery-Asberg Depression Rating Scale (time frame: 24 hours after start of infusion). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03102736, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jul 2020.