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.
* 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.
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