Protocol Number: 04-M-0091

Title:

An Investigation of a Pharmacologic Strategy to Bring About Rapid (Next Day) Antidepressant Effects

Number:

04-M-0091

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. A lumbar puncture is done the next morning. The following day, patients have physical and psychiatric examinations, laboratory tests, an electrocardiogram, and are then discharged from the hospital and the study. In addition to the above, participants undergo the following procedures:Daily interviews with psychiatric rating scales to assess the effects of the study medication on mood Measurement of patients' activity and sleep patterns with an actigraph (a small device worn on the wrist) Blood tests to examine how brain chemicals are related to rapid antidepressant response to sleep deprivation Polysomnography (measurement of brain activity and sleep patterns) once during the drug-free period, then twice during phase 1 and twice during phase 2. Electrodes are placed on the skin of the head, chest, arms and legs during the night in the sleep lab. Psychomotor vigilance test to measure reaction time to sleep loss. A device displays numbers very briefly and the patient responds to a certain number by pressing a switch. Participants take the test 14 times during the study.

Atendemos pacientes de habla hispana.

Sponsoring Institute:

National Institute of Mental Health (NIMH)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

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.

EXCLUSION CRITERIA:

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:

INCLUSION CRITERIA

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.

EXCLUSION CRITERIA:

YMRS total score of greater than or equal to 12 within 24 hours of yohimbine administration.

Special Instructions:

Currently Not Provided

Keywords:

Yohimbine

Sleep Deprivation

Depression

Mood Disorder

Fast

Affective Disorder

Rapid Onset

Recruitment Keyword(s):

Major Depression

MDD

Condition(s):

Depression, Involutional

Major Depresssion

Investigational Drug(s):

Yohimbine

Investigational Device(s):

None

Intervention(s):

Drug: Yohimbine hydrochloride

Drug: Yohimbine

Supporting Site:

National Institute of Mental Health

Contact(s):

Nancy Brutsche, R.N.
National Institutes of Health
Building 10
Room 3S242
10 Center Drive
Bethesda, Maryland 20892
Phone: (877) 646-3644
Fax: Not Listed
Electronic Address: moodresearch@mail.nih.gov

Citation(s):

Duman RS. Synaptic plasticity and mood disorders. Mol Psychiatry. 2002;7 Suppl 1:S29-34. Review.

Poo MM. Neurotrophins as synaptic modulators. Nat Rev Neurosci. 2001 Jan;2(1):24-32. Review.

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.

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