Ignite Creation Date:
2024-05-05 @ 11:32 AM
Last Modification Date:
2024-10-26 @ 9:09 AM
Study NCT ID:
NCT00078715
Status:
COMPLETED
Last Update Posted:
2019-08-29
First Post:
2004-03-04
Brief Title:
Rapid Antidepressant Effects of Yohimbine in Major Depression
Sponsor:
National Institute of Mental Health NIMH
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
An Investigation of a Pharmacologic Strategy to Bring About Rapid Next Day Antidepressant Effects
Status:
COMPLETED
Status Verified Date:
2019-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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 antidepressantPatients 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 patients 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
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 antidepressantPatients 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 patients 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
Detailed Description:
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 ie 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 alpha2 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 0125 mgkg 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 alpha2 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
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 0125 mgkg 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 alpha2 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 04-M-0091 | OTHER | CNS-IRB NIH | None |