Curr Psychiatry Rep (2015) 17:68 DOI 10.1007/s11920-015-0606-9
BIPOLAR DISORDERS (W CORYELL, SECTION EDITOR)
Chronobiology of Bipolar Disorder: Therapeutic Implication Sara Dallaspezia 1 & Francesco Benedetti 1
# Springer Science+Business Media New York 2015
Abstract Multiple lines of evidence suggest that psychopathological symptoms of bipolar disorder arise in part from a malfunction of the circadian system, linking the disease with an abnormal internal timing. Alterations in circadian rhythms and sleep are core elements in the disorders, characterizing both mania and depression and having recently been shown during euthymia. Several human genetic studies have implicated specific genes that make up the genesis of circadian rhythms in the manifestation of mood disorders with polymorphisms in molecular clock genes not only showing an association with the disorder but having also been linked to its phenotypic particularities. Many medications used to treat the disorder, such as antidepressant and mood stabilizers, affect the circadian clock. Finally, circadian rhythms and sleep researches have been the starting point of the developing of chronobiological therapies. These interventions are safe, rapid and effective and they should be considered first-line strategies for bipolar depression.
Keywords Chronotherapeutic . Circadian rhythms . Sleep . Clock genes . Sleep deprivation . Lithium salts
This article is part of the Topical Collection on Bipolar Disorders * Sara Dallaspezia [email protected] 1
Department of Clinical Neurosciences, Scientific Institute and University Vita-Salute San Raffaele, Milan, Italy
Introduction Multiple lines of evidence suggest that bipolar disorder (BD) arises in part from a malfunction of the circadian system, linking the disease with an abnormal internal timing [1••, 2]. Altered rhythmicity of circadian functions not only has long been demonstrated before and during mood episodes of illness, both mania and depression but recently it has also been shown during euthymic periods. Thus, sleep and circadian abnormalities have been considered potential biomarkers of the disorder, which may have predictive value for prognosis and treatment response, and they have also been proposed to play a pathogenetic role [3]. In addition, several studies have highlighted the presence of infradian abnormalities in BD, including a seasonal variability of clinical course, called seasonality [4]. Researches exploring seasonal patterns of individual symptom changes showed that patients are more likely to have depressive symptoms in the winter and manic symptoms during the summer [5]. This phenomenon suggests a relationship between bipolar symptomatology and circadian changes of the photoperiod. Several human genetic studies have implicated specific genes that make up the genesis of circadian rhythms in the manifestation of mood disorders [5, 6]. Polymorphisms in molecular clock genes not only show an association with the disorder but they have also been linked to its phenotypic particularities, such as age at onset, recurrence of illness episode, insomnia, rapid cycling and response to treatment. Circadian genes have been suggested to modulate the pattern of recurrences leading to misalignment of circadian rhythms and greater sensitivity to external cues [6]. Finally, both basic and clinical research targeting sleep– wake or circadian systems have focused attention on the potential for development of novel prevention or intervention strategies, and they have led to birth of some of the treatments
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Curr Psychiatry Rep (2015) 17:68
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that are currently used to treat mood disorder, such as total sleep deprivation, light therapy, sleep phase advance. These non-pharmacological treatments are chronobiological interventions that are thought to act by shifting or resetting the circadian clock.
Circadian Rhythms in Bipolar Disorder In mammals, circadian rhythms (that means processes displaying a period around 24 h) are mainly generated by the primary circadian pacemaker which is located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus [7]. The biological molecular clock is controlled by several genes forming autoregulatory transcriptional and translational feedback loops with both negative (PER and CRY proteins) and positive (Clock and Bmal1) elements. Additional positive and negative regulators (RORA/B/C and Rev-Erbα/β, respectively) act influencing rhythmic expression of BMAL1 and other clock components. Also crucial for period determination are posttranslational modifications of clock components by signalling molecules like casein kinases δ/ε and glycogen synthase kinase 3β (GSK3β) [8]. These feedback loop cycles provide a near 24-h timing [9] and is synchronized to external 24-h light–dark cycles by photic inputs through the retino-hypothalamic tract [10]. SNC continually integrates information from the outside world and sends rhythmic temporal cues throughout the organism to peripheral oscillators present in the cells of most tissues using neural, endocrine and metabolic signalling pathways, giving time context to many physiological processes and behaviours including sleep and ensuring proper entrainment of internal rhythms to the daily light/dark cycle [11, 12]. Interestingly, the SCN seems to regulate the timing of rhythms in the periphery via alterations in body temperature [13], and phase-dependent differences in body temperature were found in bipolar patients compared to healthy subjects. Body Temperature A recent study, focusing on the body temperature of bipolar patients during different illness phases, found a shorter circadian period, increased amplitude and similar rates of phase advance and delay during manic episodes compared to measures recorded both in euthymic phase and healthy subjects. Patients during depressive condition showed a phase advance and a reduction in the amplitude of the daily pattern of body temperature, with a remission in symptomatology being paralleled by body temperature cycle normalization [14]. Moreover, while in general populations, body temperature shows an increase during daytime and a decrease during night-time, bipolar depressed patients often show a nocturnal increase of the temperature.
Hypothalamic–Pituitary–Adrenal Axis Cortisol is one of the most studied circadian markers of BD, and an abnormal hypothalamic–pituitary–adrenal axis (HPA) has long been demonstrated during bipolar affective disorder with a persistent HPA dysfunction being found also after clinical remission from episodes [15]. Cortisol secretion over 24 h is significantly higher in bipolar patients than in controls, irrespective of the phase of illness (manic, depressive or euthymic) [16] During euthymia, the history of bipolar illness was shown to influence cortisol secretion and patients with many previous episodes had higher overall cortisol levels, reduced cortisol reactivity to negative daily events and flatter diurnal slopes than patients with fewer episodes [17]. Moreover, a higher and stable over time secretion of cortisol was also found in unaffected offsprings of bipolar patients [18]. The phase cortisol secretion rhythm has been studied in bipolar patients with discordant results. Indeed, both delayed and normal pattern of secretion were found in patients [19].
Melatonin Melatonin is perhaps the best studied circadian endocrine marker of BD and many studies concerning both melatonin serum levels and phase secretion have found alteration in patients. When considering the melatonin profile of secretion, a delayed peak was found in patients during euthymia [20]. In reverse, a phase advance of melatonin levels was observed in patients during mania both compared to healthy subjects [21] and patients during other phases of illness (euthymia and depression) [22]. The change in melatonin profile secretion in manic patients was most apparent during the second part of the day. Indeed, during the afternoon and evening hours, the melatonin levels were elevated to nearly half of the maximal nocturnal [23]. When considering serum levels, melatonin concentrations were found significantly lower in patients irrespective of illness phase (mania, depression or euthymia) when compared to healthy subjects [21, 24, 25]. Thus, a reduction in melatonin production was considered a trait marker of BD [25]. Another phenomena that is not state dependent in bipolar patients but that occurs over every (manic, depressive and euthymic) illness phases is an increased sensitivity of melatonin suppression to light. Patients showed a major percentage reduction in melatonin concentration after exposure to light in comparison to both healthy subjects [26] and patients affected by other affective disorders [27]. This phenomena has been speculated to be a trait marker or endophenotype of the disorder [28], since it also seems to be heritable, having the offspring of affected subjects a greater melatonin sensitivity to light than the offspring of healthy ones [29].
Curr Psychiatry Rep (2015) 17:68
Prolactin and Other Hormones The disorder was shown to influence also the secretion of prolactin (PRL). During depression, PRL circadian rhythm (a daily rhythmic activity cycle, based on 24-h intervals) was found to have a phase-advance and a reduction of its amplitude [30]. Moreover, even though increased levels of PRL were shown to precede a manic or hypomanic attack for a few weeks and to be present in a mixed state of rapid cyclers [31], no alteration in PRL levels was found during depression. Finally, actively symptomatic bipolar patients were found to show disrupted rhythms in the daily profiles of thyrotropin, growth hormone and excretion of various metabolites in the urine [32, 33]. These abnormalities seemed to normalize with patient recovery.
Sleep in Bipolar Disorder Circadian and sleep systems do not overlap but interact closely [2]. Converging lines of evidence suggest the importance of sleep disturbance in bipolar disorder [34]. Not only alteration in sleep are common features of both manic and depressive phases and are considered diagnostic criterions for affective episodes [35], but sleep disturbance is also a prevalent prodrome of episodes of both polarity of illness [36]. A clear temporal relation between sleep and mood has been described, with mood changes occurring on the day following a change in sleep [37]. Recent studies found alteration in sleep also in children of bipolar patients with actigraphic assessment indicating shorter sleep latency and less variable sleep fragmentation (that means the percentage of very brief immobility phases (
BIPOLAR DISORDERS (W CORYELL, SECTION EDITOR)
Chronobiology of Bipolar Disorder: Therapeutic Implication Sara Dallaspezia 1 & Francesco Benedetti 1
# Springer Science+Business Media New York 2015
Abstract Multiple lines of evidence suggest that psychopathological symptoms of bipolar disorder arise in part from a malfunction of the circadian system, linking the disease with an abnormal internal timing. Alterations in circadian rhythms and sleep are core elements in the disorders, characterizing both mania and depression and having recently been shown during euthymia. Several human genetic studies have implicated specific genes that make up the genesis of circadian rhythms in the manifestation of mood disorders with polymorphisms in molecular clock genes not only showing an association with the disorder but having also been linked to its phenotypic particularities. Many medications used to treat the disorder, such as antidepressant and mood stabilizers, affect the circadian clock. Finally, circadian rhythms and sleep researches have been the starting point of the developing of chronobiological therapies. These interventions are safe, rapid and effective and they should be considered first-line strategies for bipolar depression.
Keywords Chronotherapeutic . Circadian rhythms . Sleep . Clock genes . Sleep deprivation . Lithium salts
This article is part of the Topical Collection on Bipolar Disorders * Sara Dallaspezia [email protected] 1
Department of Clinical Neurosciences, Scientific Institute and University Vita-Salute San Raffaele, Milan, Italy
Introduction Multiple lines of evidence suggest that bipolar disorder (BD) arises in part from a malfunction of the circadian system, linking the disease with an abnormal internal timing [1••, 2]. Altered rhythmicity of circadian functions not only has long been demonstrated before and during mood episodes of illness, both mania and depression but recently it has also been shown during euthymic periods. Thus, sleep and circadian abnormalities have been considered potential biomarkers of the disorder, which may have predictive value for prognosis and treatment response, and they have also been proposed to play a pathogenetic role [3]. In addition, several studies have highlighted the presence of infradian abnormalities in BD, including a seasonal variability of clinical course, called seasonality [4]. Researches exploring seasonal patterns of individual symptom changes showed that patients are more likely to have depressive symptoms in the winter and manic symptoms during the summer [5]. This phenomenon suggests a relationship between bipolar symptomatology and circadian changes of the photoperiod. Several human genetic studies have implicated specific genes that make up the genesis of circadian rhythms in the manifestation of mood disorders [5, 6]. Polymorphisms in molecular clock genes not only show an association with the disorder but they have also been linked to its phenotypic particularities, such as age at onset, recurrence of illness episode, insomnia, rapid cycling and response to treatment. Circadian genes have been suggested to modulate the pattern of recurrences leading to misalignment of circadian rhythms and greater sensitivity to external cues [6]. Finally, both basic and clinical research targeting sleep– wake or circadian systems have focused attention on the potential for development of novel prevention or intervention strategies, and they have led to birth of some of the treatments
68
Curr Psychiatry Rep (2015) 17:68
Page 2 of 10
that are currently used to treat mood disorder, such as total sleep deprivation, light therapy, sleep phase advance. These non-pharmacological treatments are chronobiological interventions that are thought to act by shifting or resetting the circadian clock.
Circadian Rhythms in Bipolar Disorder In mammals, circadian rhythms (that means processes displaying a period around 24 h) are mainly generated by the primary circadian pacemaker which is located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus [7]. The biological molecular clock is controlled by several genes forming autoregulatory transcriptional and translational feedback loops with both negative (PER and CRY proteins) and positive (Clock and Bmal1) elements. Additional positive and negative regulators (RORA/B/C and Rev-Erbα/β, respectively) act influencing rhythmic expression of BMAL1 and other clock components. Also crucial for period determination are posttranslational modifications of clock components by signalling molecules like casein kinases δ/ε and glycogen synthase kinase 3β (GSK3β) [8]. These feedback loop cycles provide a near 24-h timing [9] and is synchronized to external 24-h light–dark cycles by photic inputs through the retino-hypothalamic tract [10]. SNC continually integrates information from the outside world and sends rhythmic temporal cues throughout the organism to peripheral oscillators present in the cells of most tissues using neural, endocrine and metabolic signalling pathways, giving time context to many physiological processes and behaviours including sleep and ensuring proper entrainment of internal rhythms to the daily light/dark cycle [11, 12]. Interestingly, the SCN seems to regulate the timing of rhythms in the periphery via alterations in body temperature [13], and phase-dependent differences in body temperature were found in bipolar patients compared to healthy subjects. Body Temperature A recent study, focusing on the body temperature of bipolar patients during different illness phases, found a shorter circadian period, increased amplitude and similar rates of phase advance and delay during manic episodes compared to measures recorded both in euthymic phase and healthy subjects. Patients during depressive condition showed a phase advance and a reduction in the amplitude of the daily pattern of body temperature, with a remission in symptomatology being paralleled by body temperature cycle normalization [14]. Moreover, while in general populations, body temperature shows an increase during daytime and a decrease during night-time, bipolar depressed patients often show a nocturnal increase of the temperature.
Hypothalamic–Pituitary–Adrenal Axis Cortisol is one of the most studied circadian markers of BD, and an abnormal hypothalamic–pituitary–adrenal axis (HPA) has long been demonstrated during bipolar affective disorder with a persistent HPA dysfunction being found also after clinical remission from episodes [15]. Cortisol secretion over 24 h is significantly higher in bipolar patients than in controls, irrespective of the phase of illness (manic, depressive or euthymic) [16] During euthymia, the history of bipolar illness was shown to influence cortisol secretion and patients with many previous episodes had higher overall cortisol levels, reduced cortisol reactivity to negative daily events and flatter diurnal slopes than patients with fewer episodes [17]. Moreover, a higher and stable over time secretion of cortisol was also found in unaffected offsprings of bipolar patients [18]. The phase cortisol secretion rhythm has been studied in bipolar patients with discordant results. Indeed, both delayed and normal pattern of secretion were found in patients [19].
Melatonin Melatonin is perhaps the best studied circadian endocrine marker of BD and many studies concerning both melatonin serum levels and phase secretion have found alteration in patients. When considering the melatonin profile of secretion, a delayed peak was found in patients during euthymia [20]. In reverse, a phase advance of melatonin levels was observed in patients during mania both compared to healthy subjects [21] and patients during other phases of illness (euthymia and depression) [22]. The change in melatonin profile secretion in manic patients was most apparent during the second part of the day. Indeed, during the afternoon and evening hours, the melatonin levels were elevated to nearly half of the maximal nocturnal [23]. When considering serum levels, melatonin concentrations were found significantly lower in patients irrespective of illness phase (mania, depression or euthymia) when compared to healthy subjects [21, 24, 25]. Thus, a reduction in melatonin production was considered a trait marker of BD [25]. Another phenomena that is not state dependent in bipolar patients but that occurs over every (manic, depressive and euthymic) illness phases is an increased sensitivity of melatonin suppression to light. Patients showed a major percentage reduction in melatonin concentration after exposure to light in comparison to both healthy subjects [26] and patients affected by other affective disorders [27]. This phenomena has been speculated to be a trait marker or endophenotype of the disorder [28], since it also seems to be heritable, having the offspring of affected subjects a greater melatonin sensitivity to light than the offspring of healthy ones [29].
Curr Psychiatry Rep (2015) 17:68
Prolactin and Other Hormones The disorder was shown to influence also the secretion of prolactin (PRL). During depression, PRL circadian rhythm (a daily rhythmic activity cycle, based on 24-h intervals) was found to have a phase-advance and a reduction of its amplitude [30]. Moreover, even though increased levels of PRL were shown to precede a manic or hypomanic attack for a few weeks and to be present in a mixed state of rapid cyclers [31], no alteration in PRL levels was found during depression. Finally, actively symptomatic bipolar patients were found to show disrupted rhythms in the daily profiles of thyrotropin, growth hormone and excretion of various metabolites in the urine [32, 33]. These abnormalities seemed to normalize with patient recovery.
Sleep in Bipolar Disorder Circadian and sleep systems do not overlap but interact closely [2]. Converging lines of evidence suggest the importance of sleep disturbance in bipolar disorder [34]. Not only alteration in sleep are common features of both manic and depressive phases and are considered diagnostic criterions for affective episodes [35], but sleep disturbance is also a prevalent prodrome of episodes of both polarity of illness [36]. A clear temporal relation between sleep and mood has been described, with mood changes occurring on the day following a change in sleep [37]. Recent studies found alteration in sleep also in children of bipolar patients with actigraphic assessment indicating shorter sleep latency and less variable sleep fragmentation (that means the percentage of very brief immobility phases (
