Rapid Antidepressant Effects of Yohimbine in Major Depression
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|ClinicalTrials.gov Identifier: NCT00078715|
Recruitment Status : Completed
First Posted : March 5, 2004
Results First Posted : August 16, 2012
Last Update Posted : August 20, 2012
|First Submitted Date ICMJE||March 4, 2004|
|First Posted Date ICMJE||March 5, 2004|
|Results First Submitted Date||June 7, 2012|
|Results First Posted Date||August 16, 2012|
|Last Update Posted Date||August 20, 2012|
|Study Start Date ICMJE||March 2004|
|Actual Primary Completion Date||August 2009 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Hamilton Depression Rating Scale (6 Items) [ Time Frame: Once per day, where the primary comparison involves an average over the full study after controlling for baseline ]
The 6 item Hamilton Depression Rating Scale is a measurement of the severity of depression with a range of scores from 0 to 24, where 24 indicates the most severe depression.
|Original Primary Outcome Measures ICMJE||Not Provided|
|Change History||Complete list of historical versions of study NCT00078715 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||To Determine Whether Measures Previously Demonstrated to be Predictive of Response to Sleep Deprivation & Noradrenergically Mediated Will be Assoc With Response to Yohimbine When Administered During REM Sleep. [ Time Frame: 2-4 weeks ]|
|Original Secondary Outcome Measures ICMJE||Not Provided|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Rapid Antidepressant Effects of Yohimbine in Major Depression|
|Official Title ICMJE||An Investigation of a Pharmacologic Strategy to Bring About Rapid (Next Day) Antidepressant Effects|
This study examines if Yohimbine, when given during the sleep cycle, will improve symptoms of depression within a matter of hours.
Purpose: This study will examine whether the drug yohimbine, given at a specific time during the sleep cycle, produces chemical changes in the brain similar to those that occur with sleep deprivation. It will also see if yohimbine can induce rapid (next day) antidepressant effects in patients with major depression. Total sleep deprivation for 36 hours improves mood in most patients with major depression in a matter of hours, but the response is usually short-lived. Understanding the chemical changes that occur in the body during sleep deprivation may help in the development of a rapidly acting antidepressant.Patients with major depressive disorder between 18 and 65 years of age may be eligible for this study. Candidates are screened with a medical and psychiatric history, physical examination, electrocardiogram, and blood and urine tests. Participants are hospitalized at the NIH Clinical Center for the study, as follows: Drug-free period: Patients are tapered off their anti-depression medications and remain drug-free for 1 week before beginning study phase 1. Study phase 1: Patients undergo sleep deprivation for 36 hours. Those whose depression improves with sleep deprivation initially and then worsens continue to phase 2. The day after sleep deprivation, patients undergo a lumbar puncture (spinal tap). For this test, a local anesthetic is given and a needle is inserted in the space between the bones in the lower back where the cerebrospinal fluid circulates below the spinal cord. A small amount of fluid is collected through the needle. Study phase 2: Patients spend 1 night in the sleep lab. A catheter (plastic tube) is placed in a vein in each arm-one to give yohimbine and the other to draw blood samples. A small monitor cuff is placed on a finger to measure the patient's blood pressure and blood oxygen levels during the night. While asleep, the patient receives a dose of yohimbine or placebo, given over 3 minutes. A lumbar puncture is done the following morning. Patients receive no medications for 6 days, and then the sleep lab procedure is repeated. Patients who received yohimbine in the previous experiment are switched to placebo, and those who were given placebo are switched to yohimbine.
Sleep deprivation is one of the only interventions that have consistently been demonstrated to produce rapid antidepressant effects. The mechanisms by which sleep deprivation brings about rapid antidepressant effects remain to be elucidated. It is noteworthy, however, that recent genomic and proteomic studies have shown that acute sleep deprivation rapidly brings about an upregulation of several mediators of neuronal plasticity, most notably CREB and BDNF. Intriguingly, these are the very same molecules that are upregulated by chronic antidepressants, and are believed to underlie the delayed therapeutic effects of most antidepressants. Additional investigation of the regulation of CREB and BDNF by sleep deprivation has revealed that these changes are critically dependent upon the activation of the noradrenergic system. This is particularly noteworthy, since the locus coeruleus (LC) noradrenergic projection is quiescent only during rapid eye movement sleep (REM), when the target tissues display their greatest sensitivity; indeed, the temporal dissociation between the firing of the LC noradrenergic neurons, and the sensitivity of its postsynaptic targets in the cortex may have considerable relevance for the antidepressant effects of sleep deprivation. In this context, biological rhythms have the capacity to temporally dissociate biochemical processes, and imposing a temporal coincidence on normally dissociated events can have striking and unexpected effects. Thus, it is our hypothesis that activating the normally quiescent noradrenergic system during REM sleep (i.e. when its postsynaptic target system displays its greatest sensitivity) will robustly upregulate CREB and BDNF, thereby bringing about a rapid antidepressant effect. We propose to activate the noradrenergic system during REM sleep by infusing an alpha(2) antagonist, yohimbine. Since it is our hypothesis that activating the noradrenergic system during REM sleep will bring about an antidepressant effect by a similar mechanism as sleep deprivation, we will "enrich" our sample with sleep deprivation responders in this pilot study.
Patients, ages 18 to 65 with a diagnosis of major depressive disorder, currently depressed without psychotic features will be recruited into this study. This experimental proof-of-concept study has two Study Phases. Study Phase I consists of total sleep deprivation. Responders to total sleep deprivation who subsequently relapse will enter Study Phase II. Study Phase II is a double-blind crossover administration of either intravenous yohimbine or saline solution during REM sleep.
The specific aim of this study is to assess the efficacy of a single dose of intravenous yohimbine hydrochloride (0.125 mg/kg given over 3 minutes) compared with placebo in improving overall depressive symptomatology when administered during REM sleep.
Our primary hypothesis is that the intravenous use of an alpha(2) antagonist in patients with major depression during REM sleep will activate the LC and thus increase noradrenergic activity during a time when the LC is normally quiescent- namely REM sleep. If the hypothesis that it is the timing of the activation of the noradrenergic system that is crucial in the antidepressant effect of sleep deprivation is correct then an acute antidepressant effect should be observed in patients despite minimal to no disruption of sleep.
Assuming that 10% will drop out of the study, then a minimum of 25 patients is necessary in order to obtain a minimum of 8 patients with major depression who will complete the double-blind crossover phase of the study.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 2|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Actual Enrollment ICMJE
|Original Enrollment ICMJE
|Actual Study Completion Date||August 2009|
|Actual Primary Completion Date||August 2009 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
Male or female subjects, 18 to 65 years of age.
Female subjects of childbearing potential must be using a medically accepted means of contraception.
Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.
Subjects must fulfill DSM-IV criteria for Major Depression, based on clinical assessment and confirmed by a structured diagnostic interview, SCID-P.
Subjects must have an initial score of at least 18 on the 21-item HDRS at screen and at baseline of TSD and Study Phase II.
Subjects with a greater than 25% decrease in the 21-item HDRS total scores between screen and baseline of TSD will be dropped from the study.
Subjects with documented uncontrolled hypertension in the 30 days prior to Study Period I, or have a systolic blood pressure greater than or equal to 140 and/or diastolic blood pressure greater than or equal to 90 on 3 or more readings during the drug-free period.
Apnea/hypopnea index is greater than 15 episodes per minute.
Presence of psychotic features or a diagnosis of Schizophrenia or any other psychotic disorder as defined in the DSM-IV.
Subjects with current DSM-IV diagnosis of generalized anxiety disorder, panic disorder, or posttraumatic stress disorder.
Subjects with a history of DSM-IV drug or alcohol dependency or abuse (including for nicotine) within the preceding 3 months.
Female subjects who are either pregnant or nursing.
Serious, unstable illnesses including hepatic, renal gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.
DSM-IV diagnosis of primary sleep disorder.
Subjects with uncorrected hypothyroidism or hyperthyroidism.
Subjects with one or more seizures without a clear and resolved etiology.
Documented history of hypersensitivity or intolerance to yohimbine.
Treatment with a reversible MAOI within 4 weeks prior to Study Phase II.
Treatment with fluoxetine within 3 weeks prior to Study Phase II.
Treatment with any other concomitant medication not allowed 7 days prior to Study Phase II.
Treatment with clozapine or ECT within 3 months prior to Study Phase I.
Judged clinically to be at serious suicide risk.
Previous nonresponse to total sleep deprivation treatment.
STUDY PHASE II:
Same as above plus:
Response to total sleep deprivation (40% decrease in the HAM-D6) followed by:
Depressive relapse (score of at least 18 on the 21-item HDRS and no longer meets response criteria) prior to Study Period II.
YMRS total score of greater than or equal to 12 within 24 hours of yohimbine administration.
|Ages||18 Years to 65 Years (Adult)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT00078715|
|Other Study ID Numbers ICMJE||040091
04-M-0091 ( Other Identifier: CNS-IRB, NIH )
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||Carlos Zarate, M.D., National Institutes of Health Clinical Center (CC)|
|Study Sponsor ICMJE||National Institute of Mental Health (NIMH)|
|Collaborators ICMJE||Not Provided|
|PRS Account||National Institutes of Health Clinical Center (CC)|
|Verification Date||August 2012|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP