Pharmacotherapeutic management of insomnia and effects on sleep processes, neural plasticity, and brain systems modulating stress: A narrative review

IntroductionInsomnia is a stress-related sleep disorder, may favor a state of allostatic overload impairing brain neuroplasticity, stress immune and endocrine pathways, and may contribute to mental and physical disorders. In this framework, assessing and targeting insomnia is of importance.AimSince maladaptive neuroplasticity and allostatic overload are hypothesized to be related to GABAergic alterations, compounds targeting GABA may play a key role. Accordingly, the aim of this review was to discuss the effect of GABAA receptor agonists, short-medium acting hypnotic benzodiazepines and the so called Z-drugs, at a molecular level.MethodLiterature searches were done according to PRISMA guidelines. Several combinations of terms were used such as “hypnotic benzodiazepines” or “brotizolam,” or “lormetazepam” or “temazepam” or “triazolam” or “zolpidem” or “zopiclone” or “zaleplon” or “eszopiclone” and “insomnia” and “effects on sleep” and “effect on brain plasticity” and “effect on stress system”. Given the complexity and heterogeneity of existing literature, we ended up with a narrative review.ResultsAmong short-medium acting compounds, triazolam has been the most studied and may regulate the stress system at central and peripheral levels. Among Z-drugs eszopiclone may regulate the stress system. Some compounds may produce more “physiological” sleep such as brotizolam, triazolam, and eszopiclone and probably may not impair sleep processes and related neural plasticity. In particular, triazolam, eszopiclone, and zaleplon studied in vivo in animal models did not alter neuroplasticity.ConclusionCurrent models of insomnia may lead us to revise the way in which we use hypnotic compounds in clinical practice. Specifically, compounds should target sleep processes, the stress system, and sustain neural plasticity. In this framework, among the short/medium acting hypnotic benzodiazepines, triazolam has been the most studied compound while among the Z-drugs eszopiclone has demonstrated interesting effects. Both offer potential new insight for treating insomnia

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

Abstract 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

Melatonin and pro-hypnotic effectiveness of the antidepressant Trazodone: A preliminary evaluation in insomniac mood-disorder patients

Objective To preliminary investigate the link between the darkness hormone melatonin (MLT) and the pro-hypnotic effectiveness of the atypical antidepressant Trazodone (TRZ) in a group of mood disorder patients suffering of insomnia. Design and methods The study's design comprised: i) the enrolment of insomniac outpatients, ii) baseline (t0) psychiatric and biochemical examinations; iii) the subsequent patients' introduction into a treatment with TRZ for 3–4 weeks, followed by post-therapy re-evaluations (t1). The MLT function was investigated by t0/t1 ELISA determinations of 6-hydroxy-MLT sulfate (6-OH-MLTs) levels in early-morning urines and HPLC analysis of morning MLT serum amount. Concomitantly, TRZ and its metabolite m-chloro-phenylpiperazine (m-CPP) were measured by HPLC in serum to monitor patients' compliance/metabolism. Results Seventeen insomniac outpatients, displaying mild symptoms of depression/anxiety resistant to antidepressants, completed TRZ therapy (dose:10–20 mg/day, bedtime). Serum TRZ levels (127 ± 57 ng ml− 1, mean ± SD) confirmed patients' compliance, while the anxiogenic metabolite m-CPP resulting almost undetectable. Moreover, the 6-OH-MLTs output was found increased at t1 vs. baseline values (t1: 58.4 ± 45.02 ng ml− 1; t0: 28.6 ± 15.8 ng ml− 1; mean ± SD, P < 0.05) in 9 patients who recovered both insomnia and depression/anxiety (P < 0.01). Unresponsive subjects showed instead no post-therapy 6-OH-MLTs variation (t1: 48.53 ± 50.70 ng ml− 1; t0: 49.80 ± 66.53 ng ml− 1). Morning MLT in serum slightly diminished at t1 without reaching the statistical significance, not allowing therefore to define the patients' outcome. Conclusions This initial investigation encourages to explore MLT networks as possible correlates of TRZ pro-hypnotic responses

Association between Type-D Personality and Affective (Anxiety, Depression, Post-traumatic Stress) Symptoms and Maladaptive Coping in Breast Cancer Patients: A Longitudinal Study

Background: Type-D (distressed) personality has not been prospectively explored for its association with psychosocial distress symptoms in breast cancer patients. Objective: The objective of the study was to test the hypothesis that Type-D personality can be associated with psychosocial distress variables in cancer over a 2-point period (6 month-follow-up). Aims: The aim of the study was to analyze the role of Type-D personality in relation to anxiety, depression, post-traumatic stress symptoms, general distress, and maladaptive coping among cancer patients. Methods: 145 breast cancer patients were assessed within 6 months from diagnosis (T0) and again 6 months later (T1). The Type-D personality Scale, the Hospital Anxiety and Depression Scale, Depression subscale (HAD-D), the Brief Symptom Inventory (BSI-18) Anxiety subscale, the Distress Thermometer (DT), the Post-traumatic Symptoms (PTS) Impact of Event Scale (IES), and the Mini Mental Adjustment to Cancer (Mini-MAC) Anxious Preoccupation and Hopelessness scales were individually administered at T0 and T1. Results: One-quarter of cancer patients met the criteria for Type-D personality, which was stable over the follow-up time. The two main constructs of TypeD personality, namely social inhibition (SI) and negative affectivity (NA), were related to anxiety, depression, PTS, BSI-general distress and maladaptive coping (Mini-MAC anxious preoccupation and hopelessness). In regression analysis, Type-D SI was the most significant factor associated with the above-mentioned psychosocial variables, both at T0 and T1. Conclusion: Likewise other medical disorders (especially cardiology), Type-D personality has been confirmed to be a construct significantly related to psychosocial distress conditions and maladaptive coping that are usually part of assessment and intervention in cancer care. More attention to personality issues is important in oncology

Insomnia evaluation and treatment during peripartum: a joint position paper from the European Insomnia Network task force “Sleep and Women,” the Italian Marcè Society and international experts task force for perinatal mental health

Insomnia symptoms are frequent during peripartum and are considered risk factors for peripartum psychopathology. Assessing and treating insomnia and related conditions of sleep loss during peripartum should be a priority in the clinical practice. The aim of this paper was to conduct a systematic review on insomnia evaluation and treatment during peripartum which may be useful for clinicians. The literature review was carried out between January 2000 and May 2021 on the evaluation and treatment of insomnia during the peripartum period. The PubMed, PsycINFO, and Embase electronic databases were searched for literature published according to the PRISMA guidance with several combinations of search terms “insomnia” and “perinatal period” or “pregnancy” or “post partum” or “lactation” or “breastfeeding” and “evaluation” and “treatment.” Based on this search, 136 articles about insomnia evaluation and 335 articles on insomnia treatment were found and we conducted at the end a narrative review. According to the inclusion/exclusion criteria, 41 articles were selected for the evaluation part and 22 on the treatment part, including the most recent meta-analyses and systematic reviews. Evaluation of insomnia during peripartum, as for insomnia patients, may be conducted at least throughout a clinical interview, but specific rating scales are available and may be useful for assessment. Cognitive behavioral therapy for insomnia (CBT-I), as for insomnia patients, should be the preferred treatment choice during peripartum, and it may be useful to also improve mood, anxiety symptoms, and fatigue. Pharmacological treatment may be considered when women who present with severe forms of insomnia symptoms do not respond to nonpharmacologic therapy

Chronic insomnia, REM sleep instability and emotional dysregulation: A pathway to anxiety and depression?

Summary: The world‐wide prevalence of insomnia disorder reaches up to 10% of the adult population. Women are more often afflicted than men, and insomnia disorder is a risk factor for somatic and mental illness, especially depression and anxiety disorders. Persistent hyperarousals at the cognitive, emotional, cortical and/or physiological levels are central to most theories regarding the pathophysiology of insomnia. Of the defining features of insomnia disorder, the discrepancy between minor objective polysomnographic alterations of sleep continuity and substantive subjective impairment in insomnia disorder remains enigmatic. Microstructural alterations, especially in rapid eye movement sleep (“rapid eye movement sleep instability”), might explain this mismatch between subjective and objective findings. As rapid eye movement sleep represents the most highly aroused brain state during sleep, it might be particularly prone to fragmentation in individuals with persistent hyperarousal. In consequence, mentation during rapid eye movement sleep may be toned more as conscious‐like wake experience, reflecting pre‐sleep concerns. It is suggested that this instability of rapid eye movement sleep is involved in the mismatch between subjective and objective measures of sleep in insomnia disorder. Furthermore, as rapid eye movement sleep has been linked in previous works to emotional processing, rapid eye movement sleep instability could play a central role in the close association between insomnia and depressive and anxiety disorders

Poor Sleep Quality and Its Consequences on Mental Health During the COVID-19 Lockdown in Italy

Background: Coronavirus disease 2019 (COVID-19) seriously affected the whole of Italy. The extreme virulence and the speed of propagation resulted in restrictions and home confinement. This change was immediately perceived by people who found themselves exposed to feelings of uncertainty, fear, anger, stress, and a drastic change in the diurnal but above all nocturnal lifestyle. For these reasons, we aimed to study the quality of sleep and its connection to distress levels and to evaluate how lifestyle changed in the Italian population during the lockdown. Methods: By means of an Internet survey we recruited 6,519 adults during the whole of the COVID-19 lockdown (from March 10–1st phase to May 4–2nd phase). We investigated the sociodemographic and COVID-19-related information and assessed sleep quality using the Medical Outcomes Study–sleep scale (MOS-SS) and mental health with the short form of Depression, Anxiety, and Stress Scales–21 Items (DASS- 21). Multiple logistic regression model was used to evaluate the multivariate association between the dependent variable (good sleeper vs. poor sleeper) and all the variables that were significant in the univariate analysis. Results: A total of 3,562 (55.32%) participants reported poor sleep quality according to the MOS-Sleep Index II score. The multiple binary logistic regression results of poor sleepers revealed several risk factors during the outbreak restrictions: female gender, living in Central Italy, having someone close who died because of COVID-19, markedly changed sleep–wake rhythms characterized by earlier or postponed habitual bedtime, earlier habitual awakening time and reduced number of afternoon naps, and extremely severe levels of stress, anxiety, and depression. Conclusion: This is the first study designed to understand sleep quality and sleep habits during the whole of the lockdown period in the Italian population that provides more than 6,000 participants in a survey developed specifically for the health emergency related to COVID-19. Our study found that more than half of the Italian population had impaired sleep quality and sleep habits due to elevated psychological distress during the COVID- 19 lockdown containment measures. A multidisciplinary action should be undertaken in order to plan appropriate responses to the current crisis caused by the lockdown for the COVID-19 outbreak

Characteristics of psychiatric comorbidities in emergency medicine setting and impact on length of hospitalization: A retrospective study

This study aims to evaluate clinical correlates of psychiatric comorbidity and length of hospitalization in patients admitted in a general hospital emergency medicine setting. Overall, 160 patients hospitalized for different acute medical pathologies were selected consecutively over 12 months. All subjects were evaluated with proper forms to collect data on medical and psychiatric diagnoses. Levels of C-reactive protein were also measured in all patients. Statistical analyses were conducted with univariate, logistic, and multiple linear regressions. Patients with psychiatric comorbidity had significantly longer hospitalization than did patients with no psychiatric diagnoses (days 10.9±9.5 vs. 6.9±4.5, p<0.005). Agitation and delirium were more frequent in the psychiatry comorbidity study group (p<0.05), as was cognitive impairment (p=0.001). These variables predicted longer hospitalisation (respectively: t=-3.27, p=0.002; t=-2.64, p=0.009; t=-2.85, p=0.006). Psychiatric comorbidity acts as an adjunct factor in determining clinical severity and predicting a more difficult recovery in patients hospitalized in an emergency medicine setting

Insomnia evaluation and treatment during peripartum : a joint position paper from the European Insomnia Network task force “Sleep and Women,” the Italian Marcè Society and international experts task force for perinatal mental health

Insomnia symptoms are frequent during peripartum and are considered risk factors for peripartum psychopathology. Assessing and treating insomnia and related conditions of sleep loss during peripartum should be a priority in the clinical practice. The aim of this paper was to conduct a systematic review on insomnia evaluation and treatment during peripartum which may be useful for clinicians. The literature review was carried out between January 2000 and May 2021 on the evaluation and treatment of insomnia during the peripartum period. The PubMed, PsycINFO, and Embase electronic databases were searched for literature published according to the PRISMA guidance with several combinations of search terms “insomnia” and “perinatal period” or “pregnancy” or “post partum” or “lactation” or “breastfeeding” and “evaluation” and “treatment.” Based on this search, 136 articles about insomnia evaluation and 335 articles on insomnia treatment were found and we conducted at the end a narrative review. According to the inclusion/exclusion criteria, 41 articles were selected for the evaluation part and 22 on the treatment part, including the most recent meta-analyses and systematic reviews. Evaluation of insomnia during peripartum, as for insomnia patients, may be conducted at least throughout a clinical interview, but specific rating scales are available and may be useful for assessment. Cognitive behavioral therapy for insomnia (CBT-I), as for insomnia patients, should be the preferred treatment choice during peripartum, and it may be useful to also improve mood, anxiety symptoms, and fatigue. Pharmacological treatment may be considered when women who present with severe forms of insomnia symptoms do not respond to nonpharmacologic therapy