Antidepressant action of melatonin in the treatment of Delayed Sleep Phase Syndrome

Abstract

Background

Depression is a common problem in patients with Delayed Sleep Phase Syndrome (DSPS). This study used a randomized, double-blind, crossover, placebo-controlled approach to test the hypothesis that exogenous melatonin (5 mg) can attenuate depressive symptomatology in DSPS patients.

Methods

Twenty patients with an established diagnosis of DSPS were dichotomized into DSPS with depressive symptoms (Group I; n = 8) and without depressive symptoms (Group II; n = 12) based on structured clinical interviews and a score greater than 17 on Center for Epidemiologic Studies Depression Scale (CES-D). Both groups received melatonin and placebo treatment for 4 weeks with a 1-week washout period in between. Participants underwent a clinical interview and psychometric evaluation to assess depression, and overnight polysomnographic sleep studies were carried out at baseline and at the end of melatonin and placebo treatments. Furthermore, melatonin secretion rhythm as a circadian phase marker was assessed by measuring urinary 6-sulphatoxymelatonin levels.

Results

Melatonin treatment significantly reduced depression scores in the depressed patients as measured by the CES-D and Hamilton Depression Rating Scale – 17. Melatonin treatment improved sleep continuity in both groups compared to placebo and baseline conditions. Group I individuals showed marked alterations in melatonin rhythms compared to Group II individuals.

Conclusion

Exogenous melatonin treatment may be an effective treatment modality for individuals with circadian rhythm sleep disorders and associated comorbid depressive symptomatology.

Introduction

Depression is often associated with circadian rhythm abnormalities, and many diverse rhythms such as hormone secretion, neurotransmitter secretion and synthesis and behavioral rhythms can be disrupted in depressed patients, suggesting that such disturbances are not unique to a specific rhythm, but instead involve the central circadian pacemaker which regulates the various rhythms [1]. One rhythm that is often disrupted in depression is the sleep-wake cycle, a disruption that, in turn, might lead to other rhythm disturbances [2], [3].

Delayed Sleep Phase Syndrome (DSPS) falls under the group of intrinsic Circadian Rhythm Sleep Disorders (CRSD), amongst which DSPS is most common both in general and clinical populations [4], [5]. DSPS is characterized by the inability to fall asleep and to awake at conventional times. Sleep onset is usually well past midnight, and sleep offset time is typically past noon [5], [6], [7]. When individuals with DSPS are made to conform to earlier retiring times this leads to marked sleep onset insomnia [6], [8], [9], [10]. DSPS often exhibits psychiatric comorbidities including psychological and functional difficulties such as personality disorders and depression [7], [11], [12]. DSPS patients may show marked nervousness and lack of control of emotional expression [13]. These characteristics may worsen social withdrawal, causing a loss of social cues in synchronizing their circadian rhythm and a further exacerbation of the circadian problem.

The neurohormone melatonin regulates the timing of the central circadian pacemaker located in the Suprachiasmatic Nuclei (SCN) [14], [15], [16]. Significant alterations in melatonin secretion in depressed patients during the acute phase of illness have been documented [17], [18], [19], [20], [21]. Stemming from this observation, several strategies have been utilized to manipulate circadian rhythm to alleviate depression [17], [22], [23], [24], [25], [26]. Exogenous melatonin can modulate the timing of the major sleep-wake episode and have beneficial effects on mood [17], [27]. The aim of this study was to investigate the role of exogenous melatonin treatment as a chronobiotic in ameliorating depressive symptomatology in DSPS patients. In addition, we evaluated urinary sulphatoxymelatonin (aMT6s) as a marker of circadian phase and the effects of melatonin on sleep in DSPS patients.