Rapid Antidepressant Effects of Yohimbine in Major Depression

NCT00078715 | Completed Phase 2 Results DMC

• 2 other identifiers: 04009104-M-0091
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

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 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.

Conditions

Depression, Involutional; Major Depresssion

Keywords

Yohimbine; Sleep Deprivation; Depression; Mood Disorder; Fast; Affective Disorder; Rapid Onset; Major Depression; MDD

Outcome Measures

Primary Outcomes (1)

• Hamilton Depression Rating Scale (6 Items)

  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.

  Once per day, where the primary comparison involves an average over the full study after controlling for baseline

Study Arms (2)

Yohimbine then Placebo

EXPERIMENTAL

Participants are randomized to receive yohimbine 0.125 mg/kg administered over 3 minutes during REM sleep. After 8 days they receive placebo administered over 3 minutes during REM sleep.

Drug: Yohimbine hydrochloride; Drug: Placebo

Placebo then Yohimbine

EXPERIMENTAL

Participants are randomized to receive placebo administered over 3 minutes during REM sleep. After 8 days they receive yohimbine 0.125 mg/kg administered over 3 minutes during REM sleep.

Drug: Yohimbine hydrochloride; Drug: Placebo

Interventions

Yohimbine hydrochloride DRUG

Participants receive yohimbine 0.125 mg/kg administered over 3 minutes during REM sleep.

Placebo then Yohimbine; Yohimbine then Placebo

Placebo DRUG

Participants receive an inactive equivalent of yohimbine 0.125 mg/kg administered over 3 minutes during REM sleep.

Placebo then Yohimbine; Yohimbine then Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Mental Health (NIMH): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Duman RS. Synaptic plasticity and mood disorders. Mol Psychiatry. 2002;7 Suppl 1:S29-34. doi: 10.1038/sj.mp.4001016.

  PMID: 11986993 BACKGROUND

• Poo MM. Neurotrophins as synaptic modulators. Nat Rev Neurosci. 2001 Jan;2(1):24-32. doi: 10.1038/35049004.

  PMID: 11253356 BACKGROUND

• Cirelli C, Tononi G. Differential expression of plasticity-related genes in waking and sleep and their regulation by the noradrenergic system. J Neurosci. 2000 Dec 15;20(24):9187-94. doi: 10.1523/JNEUROSCI.20-24-09187.2000.

  PMID: 11124996 BACKGROUND

• Ibrahim L, Duncan W, Luckenbaugh DA, Yuan P, Machado-Vieira R, Zarate CA Jr. Rapid antidepressant changes with sleep deprivation in major depressive disorder are associated with changes in vascular endothelial growth factor (VEGF): a pilot study. Brain Res Bull. 2011 Aug 10;86(1-2):129-33. doi: 10.1016/j.brainresbull.2011.06.003. Epub 2011 Jun 16.

  PMID: 21704134 DERIVED

MeSH Terms

Conditions

Depressive Disorder, Major; Sleep Deprivation; Depression; Mood Disorders; Fasting

Interventions

Yohimbine

Condition Hierarchy (Ancestors)

Depressive Disorder; Mental Disorders; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Behavioral Symptoms; Behavior; Feeding Behavior

Intervention Hierarchy (Ancestors)

Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines

Results Point of Contact

• Title: Dr. Carlos A. Zarate, Jr.
• Organization: Experimental Therapeutics and Pathophysiology Branch, DIRP, NIMH

zaratec@mail.nih.gov

301-451-0861

Study Officials

• Carlos A Zarate, M.D.

  Experimental Therapeutics and Pathophysiology Branch, DIRP, NIMH

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief of Experimental Therapeutics and Pathophysiology Branch of NIMH, DIRP

Study Record Dates

• First Submitted: March 4, 2004
• First Posted: March 5, 2004
• Study Start: March 1, 2004
• Primary Completion: August 1, 2009
• Study Completion: August 1, 2009
• Last Updated: August 29, 2019
• Results First Posted: August 16, 2012

Record last verified: 2019-08

Locations

US (1)