Circadian profiles in young people during the early stages of affective disorder

Citation: Transl Psychiatry (2012) 2, e123, doi:10.1038/tp.2012.47 & 2012 Macmillan Publishers Limited All rights reserved 2158-3188/12 www.nature.com/tp Circadian profiles in young people during the early stages of affective disorder SL Naismith1, DF Hermens1, TKC Ip1, S Bolitho1, E Scott1, NL Rogers2,3 and IB Hickie1 Although disturbances of the circadian system are strongly linked to affective disorders, no known studies have examined melatonin profiles in young people in early stages of illness. In this study, 44 patients with an affective disorder underwent clinical and neuropsychological assessments. They were then rated by a psychiatrist according to a clinical staging model and were categorized as having an ‘attenuated syndrome’ or an ‘established disorder’. During the evening, salivary melatonin was sampled under dim light conditions over an 8-h interval and for each patient, the time of melatonin onset, total area under the curve and phase angle (difference between time of melatonin onset and time of habitual sleep onset) were computed. Results showed that there was no difference in the timing of melatonin onset across illness stages. However, area under the curve analyses showed that those patients with ‘established disorders’ had markedly reduced levels of melatonin secretion, and shorter phase angles, relative to those with ‘attenuated syndromes’. These lower levels, in turn, were related to lower subjective sleepiness, and poorer performance on neuropsychological tests of verbal memory. Overall, these results suggest that for patients with established illness, dysfunction of the circadian system relates clearly to functional features and markers of underlying neurobiological change. Although the interpretation of these results would be greatly enhanced by control data, this work has important implications for the early delivery of chronobiological interventions in young people with affective disorders. Translational Psychiatry (2012) 2, e123; doi:10.1038/tp.2012.47; published online 29 May 2012 Introduction Over the last decade, there has been increasing interest in the relationship between the circadian system and affective disorders. Various disruptions of circadian rhythms have been described in depressive disorders, including shifts in the onset and offset of the sleep phase relative to environmental time (phase-advance or delay), as well as disruption to the endogenous release of key hormones such as melatonin and cortisol and changes in core body temperature rhythm.1 Disruption to the rhythmicity of the systems under the control of the circadian system is likely to represent a fundamental disturbance of centrally regulated neurohormonal function, and may well underpin many of the somatic symptoms so often reported by patients with common mental disorders.2 There is evidence to suggest that sleep and/or circadian disturbance may be causally linked to both the emergence and persistence of affective disorders (see review by Harvey et al.3 and Wulff et al.4). Indeed, this notion is well supported by studies conducted in patients with seasonal affective disorder, where circadian misalignment has been linked with the onset, extent and resolution of depressive symptoms.5 Additionally, sleep–wake disturbance has been noted to be a prodromal, inter-episodic and prognostic feature of bipolar disorder (see review by Harvey et al.3). Misalignment of the circadian system relative to environmental time cues has profound affects not only on mood, but also on cognition, and 1 a range of other physiological systems under circadian control, including thermoregulatory, endocrinological, immunological, cardiovascular and metabolic systems.4,6,7 Together, these data suggest that changes in the circadian system may not only represent a potential biomarker for illness onset and progression but may also be associated with adverse health and psychosocial outcomes. The pattern of somatic features, sleep disturbance, daytime fatigue and related anxiety and depressive symptoms that often emerges throughout the adolescent period indicates the need to focus more closely on the underlying physiology of the developing circadian system.8 Developmental changes in the sleep–wake and circadian systems are common in adolescents and young adults, with delayed sleep phase syndrome a common feature of adolescence (see review by Crowley et al.9). It has been postulated that changes to both circadian timing and period are explained largely by intrinsic biological drives, rather than extrinsic environmental or psychosocial factors.9 As altered sleep patterns may precede the onset and persistence of psychological distress in young people,10 better characterization of these features may lead to identification of vulnerability markers that can then underpin better targeting of early interventions.4,11 To date, there has been little attempt to characterize these features in those at high risk or during the onset phases of affective disorders.4 Such objectives can, however, be accomplished by utilizing novel clinical staging Clinical Research Unit, Brain & Mind Research Institute, University of Sydney, Camperdown, NSW, Australia and 2Chronobiology & Sleep, Faculty of Arts, Business, Informatics & Education, School of Management & Marketing, Institute for Health and Social Science Research, Central Queensland University, Mackay, QLD, Australia Correspondence: Associate Professor SL Naismith, Clinical Research Unit, Brain & Mind Research Institute, University of Sydney, Level 4, 94 Mallett Street, Camperdown, NSW 2050, Australia. E-mail: 3 Joint last author. Keywords: affective; circadian; depression; melatonin; sleep; youth Received 6 December 2011; revised 5 April 2012; accepted 10 April 2012 Circadian profiles in young people SL Naismith et al 2 paradigms seeking to identify young people in early stages of major mental disorders.11,12 Within this framework, young people presenting for care with admixtures of anxiety and depressive symptoms are typically categorized as being within early or ‘attenuated syndrome’ phases as compared with those with ‘established disorders’ (that is, first episode of major illness or later relapsing or persisting phases).12,13 Concurrently with the longitudinal evaluation of this model, we are testing whether there are distinct biomarkers evident at the different phases of affective illness. The aim of the present study was to examine circadian parameters, notably the timing, secretion and synchrony of melatonin, according to the clinical stage of affective illness.12 Specifically, we aimed to examine melatonin onset and secretion patterns in those with early ‘attenuated syndromes’ as compared with those with ‘established disorders’. It was hypothesized that those in later stages of illness would exhibit evidence of altered circadian functioning, in comparison with those in early illness phases. Subjects and methods Participants. A total of 44 young indiv (...truncated)