Early Life Stress and Chronobiological Rhythms Desynchronization: Possible Impact on Mood Symptoms and Suicidal Ideation in Bipolar Disorder.

ABSTRACT: The study aimed at investigating the potential impact of early stressful events on the clinical manifestations of bipolar disorder (BD). A sample of 162 adult individuals with BD was assessed using the Structural Clinical Interview for DSM-5, the Beck Depression Inventory-II, the Young Mania Rating Scale, the Early Trauma Inventory Self Report-Short Form, the Biological Rhythms Interview of Assessment in Neuropsychiatry, the Insomnia Severity Index, and the Scale for Suicide Ideation. A significant path coefficient indicated a direct effect of early life stressors on biological rhythms (coeff. = 0.26; p < 0.001) and of biological rhythms on depressive symptoms (coeff. = 0.5; p < 0.001), suicidal risk (coeff. = 0.3; p < 0.001), and insomnia (coeff. = 0.34; p < 0.001). Data suggested that the desynchronization of chronobiological rhythms might be one mediator of the association between early life stress and the severity of mood symptoms/suicidal ideation in BD. Addressing circadian rhythm alterations in subjects exposed to early stressors would help in preventing consequences of those stressors on BD.

Predictors of Suicidal Ideation and Preparatory Behaviors in Individuals With Bipolar Disorder: The Contribution of Chronobiological Dysrhythmicity and Its Association With Hopelessness.

OBJECTIVE: To examine the role of chronobiological dysrhythmicity in suicidal ideation and behaviors and its relation with hopelessness. METHODS: One hundred twenty-seven patients (77 females, mean age of 47.4 ± 12.5 years) with a major depressive episode and bipolar disorder (BD) type I or II (according to Structured Clinical Interview for DSM-5 assessment) were recruited in 2019 and assessed for depressive and manic symptoms (Beck Depression Inventory-II, Young Mania Rating Scale) and with the Biological Rhythms Interview of Assessment in Neuropsychiatry, Beck Hopelessness Scale, and Scale for Suicide Ideation. Univariate regression and mediation analyses were performed. RESULTS: Forty-one patients (32.3%) showed clinically significant suicidal ideation and were more frequently affected by BD type I (P = .029) with mixed features (P = .022). Compared to nonsuicidal individuals, they had significantly more depressive symptoms (P = .019), higher emotional component of hopelessness (P = .037), and higher dysrhythmicity of sleep (P = .009), activities (P = .048), and social life (P = .019). Passive and active suicidal ideation and suicidal plans were best predicted by dysrhythmicity of sleep and social life. Dysrhythmicity of sleep and social life mediated the direct effect of depressive symptoms on passive and active suicidal ideation and also of active ideation on suicidal plans. The emotional component of hopelessness was related to dysrhythmicity of social life and mediated its effect on suicidal plans (P = .010). CONCLUSIONS: Chronobiological alterations directly contributed to passive and active suicidal ideation and to suicidal preparation, with a key role of dysrhythmicity of sleep, activities, and social life. Chronobiological alterations also impacted the emotional component of hopelessness, hence indirectly contributing to suicidal ideations and plans. These findings call for the systematic screening of these dysrhythmicity dimensions when considering suicidal risk in individuals with BD.

Post-traumatic stress disorder in train crash survivors in Italy: the role of mood spectrum dysregulations and intrusiveness.

BACKGROUND: To explore relationships among post-traumatic stress disorder (PTSD), depressive spectrum symptoms, and intrusiveness in subjects who survived the crash of a train derailed carrying liquefied petroleum gas and exploded causing a fire. METHODS: A sample of 111 subjects was enrolled in Viareggio, Italy. AMOS version 21 (IBM Corp, 2012) was utilized for a structural equation model-path analysis to model the direct and indirect links between the exposure to the traumatic event, the occurrence of depressive symptoms, and intrusiveness. Subjects were administered with the SCID-IV (Structured Clinical Interview for DSM-IV), the Questionnaire for Mood Spectrum (MOODS-SR)-Last Month version, the Trauma and Loss Spectrum Questionnaire (TALS-SR), and the Impact of Event Scale-Revised version (IES-R). RESULTS: Sixty-six (66/111; 59.4%) subjects met SCID-IV criteria for PTSD. Indices of goodness of fit were as followed: χ2/df = 0.2 P = .6; comparative fit index = 1 and root mean square error of approximation = 0.0001. A significant path coefficient for direct effect of potential traumatic events on depressive symptoms (ß = 0.25; P < .04) and from depressive symptoms to intrusiveness (ß = 0.34; P < .003) was found. An indirect effect was also observed: standardized value of potential traumatic events on intrusiveness was 0.86. The mediating factor of this indirect effect path was represented by depressive symptoms. Potential traumatic events explained 6.2% of the variance of depressive symptoms; 11.8% of the variance of intrusiveness was accounted for traumatic event and depressive symptoms. CONCLUSIONS: Path analysis led us to speculate that depression symptoms might have mediated the relationship between the exposure to potential traumatic events and intrusiveness for the onset of PTSD.

Association between affective temperaments and mood features in bipolar disorder II: The role of insomnia and chronobiological rhythms desynchronization.

BACKGROUND: Bipolar disorders are complex disorders involving the interaction of multiple factors. Affective temperaments, insomnia, and chronobiological rhythms desynchronization may all contribute to bipolar disorder. Since there is a paucity of research examining this topic we aimed to study how they are interrelated and collectively associated with clinical features of bipolar disorder. METHOD: One-hundred patients with Bipolar Disorder type II depressive episode with and without mixed features were recruited and compared. Subjects were evaluated with SCID -5, the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN), the Insomnia Severity Index (ISI), and the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Auto-questionnaire (TEMPS-A) while evaluating depressive (Beck Depression Inventory-BDI-II) and manic (Young Mania Rating Scale-YMRS) symptoms. Logistic regression and mediation analyses were conducted. RESULTS: Subjects with mixed features showed a higher scores in both insomnia and chronobiological rhythms scores. When considering affective temperaments not only depressive, cyclothymic and irritable temperaments predicted mood symptoms but also insomnia (depressive symptoms O.R. 4.17, p = 0.043) and chronobiological sleep de-synchronization (manic symptoms O.R. 8.69, p = 0.001). Insomnia symptoms and chronobiological alterations mediated the association between affective temperaments and mood symptoms. LIMITATIONS: the cross-sectional design limited any causal interpretation. CONCLUSION: Subjects with mixed features showed a greater severity of insomnia and chronobiological rhythm de-synchronization compared to subjects without. Insomnia and chronobiological alterations may contribute to mood disorders together with affective temperaments in a complex interplay also mediating their effect on mood. Preventive strategies for bipolars should also act on the dysregulation of sleep and circadian rhythms.

Stress & sleep: A relationship lasting a lifetime.

Stress is an adaptative response aimed at restoring body homeostasis. The classical neuroendocrine stress response involving the activation of the hypothalamic-pituitary-adrenal (HPA) axis modulates many physiological aspects, such as the wake-sleep cycle. In the present review, we will first report a series of human and rodent studies showing that each actor of the HPA axis has the potential to interfere with sleep homeostasis and, then, we will highlight how acute or chronic stress differently modulates the wake-sleep cycle. Moreover, we will present new and interesting studies dealing with the relationship between sleep and stress on a different (longer) time scale. Particularly, we will discuss how the exposure to perinatal stress, probably through epigenetic modulations, is sufficient to cause persistent sleep derangements during adult life. In light of this evidence, the main message of the present review is that the complex relationship between sleep and stress changes dramatically on the basis of the time scale considered and, consequently, "time" should be considered as a critical factor when facing this topic.

Eveningness and poor sleep quality contribute to depressive residual symptoms and behavioral inhibition in patients with bipolar disorder.

Eveningness and sleep disturbances are considered as markers of Bipolar Disorder (BD) and influence mood and emotional or behavioral states. This study investigates the associations between circadian markers and sleep quality on residual depressive symptoms and inhibition/activation dimensions during the euthymic phase. A sample of 89 euthymic adult individuals with BD was assessed for circadian preference and typology using the Composite Scale of Morningness (CSM) and the Circadian Type Inventory (CTI) and for sleep quality using the Pittsburgh Sleep Quality Index (PSQI). The Montgomery and Asberg Depression Rating Scale (MADRS) and the Multidimensional Assessment of Thymic States (MAThyS) were used to measure residual depressive symptoms and the inhibition/activation dimensions. We examined any associations between these parameters using correlations and path analyses. We identified significant associations between eveningness and poorer sleep quality that correlated to higher depressive residual symptoms and a global inhibition. The use of path analyses led us to conclude that poor sleep quality mediated the relationship between eveningness and either residual mood symptoms or behavioral inhibition (motivation, sensory perception, interpersonal interaction, and cognition). These factors should be considered in the clinical evaluation of individuals with BD, with a specific attention during the euthymic phase, in order to achieve the best functional outcome possible.

Systematic Review of Sleep Disturbances and Circadian Sleep Desynchronization in Autism Spectrum Disorder: Toward an Integrative Model of a Self-Reinforcing Loop.

Background: A compelling number of studies, conducted in both children and adults, have reported an association between sleep disturbances/circadian sleep alterations and autism spectrum disorder (ASD); however, the data are sparse and the nature of this link is still unclear. The present review aimed to systematically collect the literature data relevant on sleep disturbances and circadian sleep dysrhythmicity related to ASD across all ages and to provide an integrative theoretical framework of their association. Methods: A systematic review of the MEDLINE, PubMed, and Cochrane databases was conducted from November 2018 to February 2019. The search strategies used were MeSH headings and keywords for "sleep-wake circadian rhythms" OR "circadian sleep disorders" OR "sleep-wake pattern" OR "sleep disorders" OR "melatonin" AND "autism spectrum disorder" OR "autism". Results: One hundred and three studies were identified, 15 regarded circadian sleep dysrhythmicity, 74 regarded sleep disturbances, and 17 regarded melatonin alterations in children and adults with ASD. Our findings suggested that autistic subjects frequently present sleep disturbances in particular short sleep duration, low sleep quality/efficiency, and circadian sleep desynchronization such as delayed phases and/or eveningness. Sleep disturbances and circadian sleep alterations have been related to the severity of autistic symptoms. Genetic studies have shown polymorphisms in circadian CLOCK genes and in genes involved in melatonin pathways in subjects with ASD. Conclusions: Sleep disturbances and circadian sleep alterations are frequent in subjects with autistic symptoms. These subjects have shown polymorphisms in clock genes expression and in genes involved in melatonin production. The impairment of circadian sleep regulation may increase the individual's vulnerability to develop symptoms of ASD by altering the sleep regulation in toto, which plays a key role in normal brain development. Even though controversies and "research gaps" are present in literature at this point, we may hypothesize a bidirectional relation between circadian sleep dysfunction and ASD. In particular, circadian sleep dysrhythmicity may predispose to develop ASD symptoms and vice versa within a self-reinforcing feedback loop. By targeting sleep disturbances and circadian sleep dysrhythmicity, we may improve treatment strategies for both children and adults with ASD.

Insomnia and depressive symptoms during the menopausal transition: theoretical and therapeutic implications of a self-reinforcing feedback loop.

Insomnia is a common and recurring condition during the menopausal transition that negatively affects both quality of life and health. Peri-menopausal insomnia has a multifactorial etiology; previous depression, hormonal changes and age/hormone-related irregularity in circadian rhythms can contribute to menopausal insomnia. Age-related poor health, pain and stress may favor the development of insomnia, while vasomotor symptoms, in particular hot flashes, may contribute to chronic forms of insomnia by activating a vicious cycle. Insomnia increases two- to threefold the risk of developing depressive symptoms during the peri-menopause. In fact, the menopausal transition is a window of vulnerability for the development of depressive symptoms, in which the risk of a major depressive disorder is 2-4 times greater than in the premenopausal period. Depression naturally has a negative impact on daily functioning, quality of life and health. Since the relationship between insomnia and depressive symptoms has been shown to be bidirectional, the aim of this review is to provide a brief overview of their association in the context of the menopausal transition. By exploring the potential pathways of their bidirectional relationship, this overview should be useful for preventive and therapeutic purposes. By treating insomnia we may be able to interrupt the self-reinforcing feedback loop with depressive symptoms, and thereby improve affective symptoms and women's wellbeing in this period of their life.

Lithium and valproate serum level fluctuations within the menstrual cycle: a systematic review.

Some women affected by mood disorders experience mood instability during the premenstrual phase. Assuming that fluctuations in drug serum levels may contribute to the worsening of mood symptoms, we carried out a systematic review of available studies that investigated changes in lithium and valproate levels in relation to menstrual phases. We selected five studies; four of which assessed menstrual fluctuations in lithium serum levels and one in valproate levels. Study samples included women in their fertile age affected by bipolar disorder, epilepsy as well as healthy ones. Preliminary results showed a close relationship between cyclic premenstrual exacerbation of affective symptoms and a significant decrease in lithium levels during the luteal phase, despite stable oral doses, in bipolar women. In healthy women, lithium levels were influenced by neither menstrual cycle phases nor oral contraceptives use. Valproate serum levels in epileptic women showed a small, nonsignificant decline during the mid-luteal phase. Pharmacokinetic sex differences in adsorption, volume distribution, hepatic metabolism, and renal excretion of mood stabilizers have been supposed to partly explain such menstrual serum level fluctuations. A better understanding in this field could help to counteract the distress related to premenstrual phase, improving therapeutic management of mood disorders in women.

Stress-related sleep reactivity is associated with insomnia, psychopathology and suicidality in pregnant women: preliminary results.

INTRODUCTION: Depression and anxiety symptoms are commonly experienced by women during pregnancy and may have negative consequences on mothers and newborns. Deterioration of sleep quality throughout pregnancy increases insomnia, which may lead to adverse outcomes including increased psychopathology in the perinatal period. Thus, identifying women at high risk of developing insomnia may have important clinical implications on maternal-fetal outcomes. Stress-related sleep reactivity is a well-established risk factor for future insomnia, depression, and anxiety in general adult samples. However, little is known of sleep reactivity and its relations to sleep and mood pathology in pregnancy. Therefore, we explored sleep reactivity in pregnant women and its relations to prenatal symptoms of insomnia, depression, anxiety, and suicidality. METHOD: Sixty-two pregnant women (mean age 33.6 ± 3 years, 20.6 ± 0.6 weeks of pregnancy) were evaluated during their routine visit at the Gynecological Unit of the University of Pisa, Italy, using the Insomnia Severity Index (ISI) for insomnia symptoms, the Ford Insomnia Response to Stress Test for sleep reactivity (FIRST), Edinburgh Postnatal Depression Scale (EPDS) for depressive symptoms, and the Zung Self Rating Anxiety Scale (SAS) for anxiety symptoms. Item #10 of the EPDS was used to assess for suicidality. Differences in means between women with high vs low stress-related sleep reactivity were calculated using t-test or Mann-Whitney U/Wilcoxon test. Linear/multiple regression analyses have been performed to study associations between variables. RESULTS: Pregnant women with high stress-related sleep reactivity, relative to those with low reactivity, reported greater symptoms of insomnia (t = 6.5, 0.004) as well as higher rates of depression (62.0% vs 6.1%, p < 0.001), anxiety (55.1% vs 15.1%, p = 0.030), and suicidality (17.2% vs 3.0%, p = 0.025). Multivariate models revealed sleep reactivity to correlate independently with symptoms of insomnia, depression, and anxiety, when controlling for comorbid symptoms. CONCLUSIONS: In mid-pregnancy, women with high sleep reactivity report elevated symptoms of insomnia, depression, and anxiety, and are more likely to endorse suicidal ideation. As a prognostic marker of future insomnia and psychiatric illness, early detection of high prenatal sleep reactivity holds potential to prevent the development of sleep and mood pathology during pregnancy, thereby potentially improving maternal and child outcomes.

Chronobiological dis-rhythmicity is related to emotion dysregulation and suicidality in depressive bipolar II disorder with mixed features.

In Bipolar Disorder, chronobiological rhythm alterations play a key role by negatively influencing its entire trajectory. Our aim was to assess their potential association with emotion dysregulation and suicidality in subjects with Bipolar Disorder. Eighty-five patients with Bipolar Disorder - II depressive episode with mixed features were recruited and 35 as healthy controls. Subjects were evaluated with SCID-DSM-5, the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN), the DERS: Difficulties in Emotion Regulation Scale, the Beck Depression Inventory-II (BDI-II), the Young Mania Rating Scale (YMRS) and the Scale for Suicide Ideation (SSI). When compared to healthy controls, subjects with bipolar disorder showed significantly higher scores in the BRIAN, the DERS, the BDI-II, the YMRS and the SSI total scores. Chronobiological dis-rhythmicity was significantly related to the severity of depressive symptoms, emotion dysregulation, and suicidality in bipolar individuals. In particular, the dis-rythmicity of the sleep/wake pattern showed a significant correlation with manic symptoms, the dis-rythmicity of daily activities with depressive symptoms and emotion dysregulation and that of social life with suicidality. Emotion dysregulation played as a mediator for the association between chronobiological dis-rhythmicity and depressive symptoms (mediated effect = 3.25, p = 0.001) and for social life dis-rhythmicity and suicidality (mediated effect = 2.52, p = 0.011) as well. Therefore, our findings showed that chronobiological dis-rhythmicity in bipolar individuals was related to the severity of mood swings, emotion dysregulation and suicidality. The assessment of potential alteration in chronobiological rhythms should be investigated in the clinical setting in subjects with bipolar disorder to identify those who may benefit from early chronobiological intervention.

Insomnia symptoms predict emotional dysregulation, impulsivity and suicidality in depressive bipolar II patients with mixed features.

INTRODUCTION: Insomnia symptoms are very common in Bipolar Disorder. Our aim was to assess the potential association between insomnia, emotion dysregulation and suicidality in subjects with Bipolar Disorder. METHODS: Seventy-seven subjects with Bipolar Disorder type II with a depressive episode with mixed features were recruited. Patients were assessed with SCID-DSM-5, the Insomnia Severity Index (ISI), the Difficulties in Emotion Regulation Scale (DERS), the Scale for Suicide Ideation (SSI) while evaluating manic and depressive symptoms. RESULTS: Subjects with insomnia symptoms compared to those without showed higher scores in the DERS scale and subscales, including impulsivity, and in the SSI scale. Insomnia symptoms significantly predicted the severity of depressive symptoms, emotion dysregulation, and suicidality in subjects with bipolar disorder. In particular, insomnia was related to difficulties in some areas of emotion regulation including impulsivity. Emotion dysregulation significantly mediated the association between insomnia and depressive symptoms (Z = 2.9, p = 0.004). Furthermore, emotional impulsivity mediated the association between insomnia symptoms and suicidality (Z = 2.2, p = 0.03). CONCLUSION: In our study, subjects with bipolar disorder suffering from insomnia experienced a greater severity of depressive symptoms and suicidality compared to subjects without insomnia. Insomnia was associated with emotion dysregulation, impulsivity and suicidality. Further research is necessary to investigate if these latter features may benefit from early insomnia treatment in subjects with bipolar disorder.

Lack of Resilience Is Related to Stress-Related Sleep Reactivity, Hyperarousal, and Emotion Dysregulation in Insomnia Disorder.

STUDY OBJECTIVES: According to the diathesis-stress model of insomnia, insomnia may develop in vulnerable individuals in response to stress. Resilience is a psychobiological factor that determines an individual's capacity to adapt successfully to stressful events and low resilience increases vulnerability for development of mental disorders. The aim was to explore resilience in subjects with insomnia and its relationship with the factors that contribute to its development and perpetuation. METHODS: The study consisted of 58 subjects with Insomnia Disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition and 38 good sleepers. Resilience Scale for Adults (RSA), Ford Insomnia Response to Stress Test (FIRST), Pre-sleep Arousal Scale (PSAS), and Difficulties in Emotion Regulation Scale (DERS) were administered while taking into account psychiatric symptoms. Differences in means between groups were assessed using t test or Mann-Whitney U/Wilcoxon test. Linear/multivariable regression analyses and mediation analyses were performed. RESULTS: Subjects with insomnia (24 females, mean age 49 ± 2.1 years) had lower RSA and higher FIRST, DERS, and PSAS scores than good sleepers (22 females, mean age 47.2 ± 1.2 years). After controlling for anxiety/depressive symptoms, low resilience correlated with high stress-related sleep reactivity (P = .004), pre-sleep cognitive hyperarousal (P = .01) and emotion dysregulation (P = .01). Emotion dysregulation mediated the relationship between low resilience and cognitive hyperarousal (Z = 2.06, P = .03). CONCLUSIONS: Subjects with insomnia showed low resilience, which was related to high stress-related sleep reactivity, emotional dysregulation, and hyperarousal. If resilience helps to minimize the extent of pathogenesis in the developmental process, an early identification of vulnerable candidates should be useful for preventing insomnia development and maintenance. COMMENTARY: A commentary on this article appears in this issue on page 709.

Adult insecure attachment plays a role in hyperarousal and emotion dysregulation in Insomnia Disorder.

Studies show that unhelpful cognitive processes play a role in insomnia, whereas interpersonal factors have been less studied in insomnia. Attachment theory can be used as a cognitive-interpersonal framework for understanding insomnia. Because attachment insecurity (vs security) is related to psychiatric disorders the objective was to study the attachment style in insomnia. To this aim sixty-four subjects with Insomnia Disorder (DSM-5) and 38 good sleepers were evaluate in a cross-sectional study with: Attachment Style Questionnaire (ASQ), Arousal Predisposition Scale (APS), Pre-Sleep Arousal Scale (PSAS) and Difficulties in Emotion Regulation Scale (DERS). Differences in means between groups were assessed using t-test or Mann-Whitney U/Wilcoxon test. Linear/multiple regression analyses were performed. Subjects with insomnia (mean age 47.1 + 13 yrs) presented an insecure attachment style and higher scores in all the scales (ASQ, APS, PSAS, DERS p < 0.0001) than good sleepers (mean age 48.2 + 14 yrs). After taking into account anxiety/depressive symptoms, insecure attachment was related to hyperarousal trait (p = 0.02), pre-sleep hyperarousal (p = 0.04) and emotion dysregulation (p = 0.002). In conclusion subjects with insomnia showed an insecure attachment which was related to hyperarousal trait, pre-sleep hyperarousal and emotion dysregulation. It may intervene in the trajectory of insomnia starting from predisposition to perpetuation. Clinical implications are discussed.