Elsevier

Biological Psychiatry

Volume 54, Issue 2, 15 July 2003, Pages 96-104
Biological Psychiatry

Original article
Diurnal variation of cerebrospinal fluid hypocretin-1 (Orexin-A) levels in control and depressed subjects

https://doi.org/10.1016/S0006-3223(02)01740-7Get rights and content

Abstract

Background

Hypocretins, excitatory neuropeptides at monoaminergic synapses, appear to regulate human sleep-wake cycles. Undetectable cerebrospinal fluid hypocretin-1 levels are seen in narcolepsy, which is frequently associated with secondary depression. Shortened rapid eye movement latency is observed in both narcolepsy and depression. Cerebrospinal fluid hypocretin-1 levels have not been reported in mood disorders.

Methods

We examined hypocretin-1 levels in 14 control and 15 depressed subjects. Cerebrospinal fluid was drawn continuously in supine subjects for 24 hours with an indwelling intrathecal catheter under entrained light-dark conditions. Depressed subjects were studied before and after 5 weeks of sertraline (n = 10, three nonresponders) or bupropion (n = 5, two nonresponders).

Results

Hypocretin-1 levels varied slightly (amplitude 10%) but significantly across the diurnal cycle in control subjects, with amplitude significantly reduced in depression (3%). Levels were lowest at midday, surprising for a hypothetically wake-promoting peptide. Mean hypocretin levels trended higher in depressive than in control subjects. Hypocretin-1 levels decreased modestly but significantly after sertraline (−14%) but not bupropion.

Conclusions

Our results are consistent with previous physiologic findings in depression indicating dampened diurnal variations in hypocretin-1. The finding that sertraline but not bupropion slightly decreased cerebrospinal fluid hypocretin-1 indicates a serotoninergic influence on hypocretin tone.

Introduction

Among pathophysiologic findings in depression, relationships with sleep and circadian abnormalities have been emphasized Detre et al 1972, Nowell and Buysse 2001, Reynolds et al 1987, Ringel and Szuba 2001, Winokur et al 2001. Clinically, depressive symptoms early in the course of the disease include sleep disturbances (Nowell and Buysse 2001). Sleep deprivation, and especially rapid eye movement (REM) deprivation have striking antidepressant effects Borbely and Wirz-Justice 1982, Gillin et al 2001, Ringel and Szuba 2001, Wu and Bunney 1990. REM sleep is suppressed by almost all antidepressant medications Duncan et al 1998, Daniels et al 2001, and decreased REM latency in depression is highly replicable Benca et al 1992, Kupfer et al 1991. Decreased amplitudes of behavioral, physiologic, and neuroendocrine circadian measures and disrupted responses of the circadian pacemaker to the light-dark cycle are observed in depression Beersma et al 1983, Healy 1987, Kleitman 1939, Kripke et al 1987, Steiner et al 1987, Van den Hoofdakker 1994, Wirz-Justice 1995. Depression is associated with diurnal changes in hypothalamic-pituitary-adrenal axis activity and other endocrine abnormalities Arborelius et al 1999, Holsboer 2001, Shelton et al 1993, Young et al 1991.

The hypocretin (orexin) neuropeptides Beuckmann and Yanagisawa 2002, Mignot 2001, Willie et al 2001, hypocretin-1 and hypocretin-2, are processed from a prepropeptide encoded by a single gene de Lecea et al 1998, Sakurai et al 1998, Sakurai et al 1999. Hypocretin neurons in the tuberal region of the hypothalamus Peyron et al 1998, Peyron et al 2000 project to the entire neuraxis, including the spinal cord (van den Pol 1999). Extremely dense and almost invariably excitatory projections are noted to aminergic cell groups (e.g., adrenergic locus coeruleus, serotonergic raphé nuclei, histaminergic tuberomammillary nucleus, dopaminergic substantia nigra, and ventral tegmental area; Hungs and Mignot 2001, Peyron et al 1998 and also to cholinergic cell groups Beuckmann and Yanagisawa 2002, Taheri et al 2002. Three decades of hypothesis development links transmitter systems of each of the respective nuclei to the pathophysiology of depression Janowsky and Overstreet 1995, Maes and Meltzer 1995, Schatzberg and Schildkraut 1995, Willner 1995.

Hypocretin deficiency causes human narcolepsy Nishino et al 2000, Peyron et al 2000, Thannickal et al 2000, a disabling disorder characterized by daytime sleepiness, cataplexy, and extremely short REM sleep latency(Mignot 2001). Hypocretin release is higher during the active phase in rats Fujiki et al 2001, Yoshida et al 2001 and may consolidate wakefulness and reduce sleep. Monoaminergic tone, which is high during wakefulness, decreases during sleep and REM sleep and may be driven by hypocretins Hungs and Mignot 2001, Kilduff and Peyron 2000, Mignot 2001. In narcolepsy, low hypocretin would reduce monoaminergic activity, leading to daytime sleepiness and abnormally short REM sleep latency (Mignot 2001).

Narcolepsy is frequently associated with depression (Daniels et al 2001), and both are treated with agents that enhance monoaminergic activity and affect sleep physiology. The hypocretin system is activated by sleep (or REM) deprivation (Yoshida et al 2001) and may mediate its antidepressant effects (Mignot 2001). Finally, hypocretins activate the hypothalamic-pituitary-adrenal axis Jaszberenyi et al 2000, Kuru et al 2000, Russell et al 2001. These relationships led us to study the role of hypocretins in depression. To do so we examined lumbar cerebrospinal fluid (CSF) hypocretin-1 levels in 14 control and 15 depressed subjects (before and after antidepressant therapy) during a 24-hour period.

Section snippets

Subjects

Fourteen control subjects (six of them male, 41 ± 4 years old [all expressions are mean ± SD]) and 15 depressive subjects (five of them male, 39 ± 3 years old) were studied with continuous CSF sampling. Diagnosis was determined by psychiatric interview and confirmed by the Structured Clinical Interview for DSM-IV Axis I Disorders and Structured Clinical Interview for DSM-IV Axis II DisordersFirst et al 1996a, First et al 1996b according to DSM-IV criteria (American Psychiatric Association 1994)

Diurnal variation of hypocretin-1 levels in depressed and control subjects

Overall the concentration of hypocretin-1 obtained from human lumbar CSF did not vary significantly with age or gender (not shown), in agreement with previous reports. In control subjects, hypocretin levels varied very slightly but consistently and significantly across the diurnal cycle (p < .001). Contrary to an expected increasing level gradient across serial samples that is often reported in monoamine metabolite measures, levels of hypocretin declined very gradually during the first few

Discussion

This study presents data from subjects confined to bed rest for 12 hours before the lumbar puncture and also from subjects allowed ad libitum activity until the time of the lumbar puncture. Under condition of constant bed rest, continuously sampled (for 24 hours) CSF hypocretin-1 levels fluctuated moderately but significantly across the 24-hour cycle (<15%; Figure 1). Similar variations were observed in the small number of subjects in the individual tap study (Figure 2), indicating that normal

Acknowledgements

Supported by grants from the National Institutes of Health (Grants NS 23724, NS 33797, and MH40041) to EM, by an investigator-initiated grant from Pfizer, by grants from National Alliance for Research in Schizophrenia and Depression and the Theodore and Vada Stanley Foundation to RMS, and by a General Clinical Research Grant from the National Institutes of Health National Center for Research Resources (Grant MO1RR00095) to Vanderbilt University Medical Center, Nashville, Tennessee.

We thank our

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