Rapid Antidepressant Effects of Yohimbine in Major Depression
Condition: Depression, Involutional; Major Depresssion
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 2

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 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.
    

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 (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.
    

Intervention name(s): Yohimbine hydrochloride; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Participants receive yohimbine 0.125 mg/kg administered over 3 minutes during REM sleep.; Participants receive an inactive equivalent of yohimbine 0.125 mg/kg administered over 3 minutes during REM sleep.
Intervention MeSH terms: Yohimbine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Other
Keywords: Yohimbine; Sleep Deprivation; Depression; Mood Disorder; Fast; Affective Disorder; Rapid Onset; Major Depression; MDD