The Role of Circadian Rhythmicity and CLOCK Genes in Psychiatry.

Circadian rhythms are biological oscillations, that perpetuate themselves even in the absence of "zeitgebers" (external time cues), with a period of approximately 24 hours. The master pacemaker is the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN is entrained by environmental factors, particularly light, to the 24-hour light-dark cycle by the Earth's rotation. Peripheral circadian oscillators, located in multiple cell types and tissues, are controlled by signals arising from the SCN and from the environment, particularly food intake, hormonal signals and body-temperature fluctuations. Circadian rhythmicity is observable in almost every cell of living organisms including humans and, for example in cell cultures, these rhythms persist even without the SCN 1 2.

Circadian Clocks in the Regulation of Neurotransmitter Systems.

To anticipate and adapt to daily recurring events defined by the earth's rotation such as light-dark and temperature cycles, most species have developed internal, so-called circadian clocks. These clocks are involved in the regulation of behaviors such as the sleep-wake cycle and the secretion of hormones and neurotransmitters. Disruptions of the circadian system affect cognitive functions and are associated with various diseases that are characterized by altered neurotransmitter signaling. In this review, we summarize the current knowledge about the interplay of the circadian clock and the regulation of psychiatric health and disease.

Synchronization of Fibroblasts Ex Vivo in Psychopharmacology.

The central oscillator for the inner clock is the suprachiasmatic nuclei of the hypothalamus. Furthermore, many peripheral oscillators are present in tissues such as skin. Human derived fibroblasts provide an advantageous model to study circadian rhythmicity as well as the influence of pharmacological drugs on circadian gene expression. Importantly, the synchronization of the circadian system of fibroblasts can be done by different methods. The review presents an overview of the current knowledge of different synchronization methods mostly used in mice or rat fibroblasts. Furthermore, the review sums up and discusses the role of norepinephrine as a possible synchronizer agent.

Human Derived Dermal Fibroblasts as in Vitro Research Tool to Study Circadian Rhythmicity in Psychiatric Disorders.

A number of psychiatric disorders are defined by persistent or recurrent sleep-wake disturbances alongside disruptions in circadian rhythm and altered clock gene expression. Circadian rhythms are present not only in the hypothalamic suprachiasmatic nucleus but also in peripheral tissues. In this respect, cultures of human derived dermal fibroblasts may serve as a promising new tool to investigate cellular and molecular mechanisms underlying the pathophysiology of mental illness. In this article, we discuss the advantages of fibroblast cultures to study psychiatric disease. More specifically, we provide an update on recent advances in modeling circadian rhythm disorders using human fibroblasts.

The impact of COVID-19 on psychiatric and mental health services in Europe: suffering experienced by professionals.

BACKGROUND: The COVID-19 pandemic has not only impacted intensive care units, but all healthcare services generally. This PsyGipo2C project specifically investigates how psychiatry and mental health professionals have been affected by the reorganizations and constraints imposed, which have reshaped their often already difficult working conditions. METHODS: Our research combined quantitative and qualitative methods, surveying and interviewing health professionals of all occupations working in psychiatric and mental health services. A questionnaire was completed by 1241 professionals from 10 European countries, and 13 group interviews were conducted across 5 countries. In addition to this, 31 individual interviews were conducted in Belgium and France. RESULTS: Among the questionnaire respondents, 70.2% felt that their workload had increased, particularly due to their tasks being diversified and due to increased complexity in the provision of care. 48.9% felt that finding a work-life balance had become more difficult, and 59.5% felt their health had been affected by the crisis. The impact of the health crisis nevertheless varied across professions: our data provides insight into how the health measures have had a differential impact on professional tasks and roles across the various categories of occupations, obliging professionals to make various adaptations. The distress incurred has been linked not only to these new constraints in their work, but also to the combination of these with other pressures in their personal lives, which has consequently compromised their well-being and their ability to cope with multiple demands. DISCUSSION: The COVID-19 health crisis has had varying impacts depending on the profession and access to remote work, sometimes leading to conflicts within the teams. The suffering expressed by the professionals was tied to their values and patterns of investment in work. Our research also highlights how these professionals made little use of the psychological supports offered, probably due to a reluctance to acknowledge that their mental health was affected.

Norepinephrine influences the circadian clock in human dermal fibroblasts from study participants with a diagnosis of attention-deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder (ADHD) is characterized by changes to the circadian process. Many medications used to treat the condition, influence norepinephrine levels. Several studies have, in addition, reported that norepinephrine itself has an effect on circadian function. The aim of this study was to investigate the circadian gene expression in primary human-derived dermal fibroblast cultures (HDF) after norepinephrine exposure. We analyzed circadian preference, behavioral circadian and sleep parameters as well as the circadian gene expression in a cohort of healthy controls and participants with an ADHD diagnosis. Circadian preference was evaluated with German Morningness-Eveningness Questionnaire (D-MEQ) and rhythms of sleep/wake behavior were assessed via actigraphy. After ex vivo exposure to different norepinephrine concentrations in HDF cultures, the rhythmicity of circadian gene expression was analyzed via qRT-PCR. The exposure of 1 µM norepinephrine to confluent cultures of human dermal fibroblasts from participants with a diagnosis of ADHD, was shown to dampen Per1 rhythmicity. The expression of Bmal1, Per1 and Per3 in control subjects was also influenced by incubation with 1 µM norepinephrine. Cultures from the ADHD group revealed no statistically significant overall differences in circadian gene expression, between cultures with and without norepinephrine incubation. Per3 expression showed a significant ZT × group interaction via mixed ANOVA. Per3 expression at ZT4 was significant higher in the group of control samples incubated with 1 µM norepinephrine, compared to the control group without norepinephrine. This effect was also shown in the control samples incubated with 1 µM norepinephrine and cultures from subjects with ADHD without norepinephrine incubation. Per3 expression differed between the healthy control group and the ADHD group without norepinephrine incubation at ZT28. The results of the present study illustrate that norepinephrine impacts on circadian function. In both groups, control group and cultures taken from subjects with ADHD, the expression of the periodic genes (Per1-3) was significantly influenced by incubation with norepinephrine.

Atomoxetine and circadian gene expression in human dermal fibroblasts from study participants with a diagnosis of attention-deficit hyperactivity disorder.

Atomoxetine (ATO) is a second line medication for attention-deficit hyperactivity disorder (ADHD). We proposed that part of the therapeutic profile of ATO may be through circadian rhythm modulation. Thus, the aim of this study was to investigate the circadian gene expression in primary human-derived dermal fibroblast cultures (HDF) after ATO exposure. We analyzed circadian preference, behavioral circadian and sleep parameters as well as the circadian gene expression in a cohort of healthy controls and participants with a diagnosis of ADHD. Circadian preference was evaluated with German Morningness-Eveningness-Questionnaire (D-MEQ) and rhythms of sleep/wake behavior were assessed via actigraphy. After ex vivo exposure to different ATO concentrations in HDF cultures, the rhythmicity of circadian gene expression was analyzed via qRT-PCR. No statistical significant effect of both groups (healthy controls, ADHD group) for mid-sleep on weekend days, mid-sleep on weekdays, social jetlag, sleep WASO and total number of wake bouts was observed. D-MEQ scores indicated that healthy controls had no evening preference, whereas subjects with ADHD displayed both definitive and moderate evening preferences. ATO induced the rhythmicity of Clock in the ADHD group. This effect, however, was not observed in HDF cultures of healthy controls. Bmal1 and Per2 expression showed a significant ZT × group interaction via mixed ANOVA. Strong positive correlations for chronotype and circadian genes were observed for Bmal1, Cry1 and Per3 among the study participants. Statistical significant different Clock, Bmal1 and Per3 expressions were observed in HDFs exposed to ATO collected from ADHD participants exhibiting neutral and moderate evening preference, as well as healthy participants with morning preferences. The results of the present study illustrate that ATO impacts on circadian function, particularly on Clock, Bmal1 and Per2 gene expression.

Feigning ADHD and stimulant misuse among Dutch university students.

The increasing number of university students seeking diagnosis of attention-deficit/hyperactivity disorder (ADHD), and findings of an increased stimulant misuse among university students, has raised concerns regarding the credibility of the symptoms of those students. However, most of our current knowledge refers to university students in North America and less is known about this issue on European campuses. The present survey aimed to collect opinions on feigning ADHD and to estimate the prevalence of stimulant misuse among 1071 university students in the Netherlands. The majority of students expressed liberal attitudes towards feigning ADHD. Also, a substantial number of respondents considered feigning ADHD themselves or know someone who feigns ADHD. Furthermore, 68% of students assumed benefits of taking stimulants without prescription and 16% have indeed already taken stimulants without prescription. Feigning ADHD and misuse of prescription medication are prevalent issues among Dutch students. The results underline the need for a careful diagnostic evaluation of individuals for ADHD. Furthermore, efforts are required in order to prevent stimulant drug trafficking and misuse among university students.

Dopamine adjusts the circadian gene expression of Per2 and Per3 in human dermal fibroblasts from ADHD patients.

A link between dopamine levels, circadian gene expression, and attention deficit hyperactivity disorder (ADHD) has already been demonstrated. The aim of this study was to investigate the extent of these relationships by measuring circadian gene expression in primary human-derived dermal fibroblast cultures (HDF) after dopamine exposure. We analyzed circadian preference, behavioral circadian and sleep parameters as well as the circadian gene expression in a cohort of healthy controls and participants with ADHD. Circadian preference was evaluated with German Morningness-Eveningness-Questionnaire (D-MEQ) and rhythms of sleep/wake behavior were assessed via actigraphy. After ex vivo exposure to different dopamine concentrations in human dermal fibroblast (HDF) cultures, the rhythmicity of circadian gene expression (Clock, Bmal1, Per1-3, Cry1) was analyzed via qRT-PCR. We found no statistical significant effect in the actigraphy of both groups (healthy controls, ADHD group) for mid-sleep on weekend days, mid-sleep on weekdays, social jetlag, wake after sleep onset, and total number of wake bouts. D-MEQ scores indicated that healthy controls had no evening preference, whereas subjects with ADHD displayed both definitive and moderate evening preferences. Dopamine has no effect on Per3 expression in healthy controls, but produces a significant difference in the ADHD group at ZT24 and ZT28. In the ADHD group, incubation with dopamine, either 1 µM or 10 µM, resulted in an adjustment of Per3 expression to control levels. A similar effect also was found in the expression of Per2. Statistical significant differences in the expression of Per2 (ZT4) in the control group compared to the ADHD group were found, following incubation with dopamine. The present study illustrates that dopamine impacts on circadian function. The results lead to the suggestion that dopamine may improve the sleep quality as well as ADHD symptoms by adjustment of the circadian gene expression, especially for Per2 and Per3.

Remdesivir shifts circadian rhythmicity to eveningness; similar to the most prevalent chronotype in ADHD.

Circadian clocks control immunity and virus replication, as well as pharmacokinetics and efficacy therapeutics. The aim of this study was to investigate the extent of these relationships by measuring circadian gene expression in primary human-derived dermal fibroblast cultures (HDF) after remdesivir exposure. In the current study, we analysed circadian gene expression in a cohort of participants without a neuropsychiatric diagnosis. After ex vivo exposure to remdesivir to human dermal fibroblast (HDF) cultures and dexamethasone synchronization, the rhythmicity of circadian gene expression (Clock, Bmal1, Per1-3, Cry1) was analysed via qRT-PCR. In this study, D-MEQ scores indicated that participants without a neuropsychiatric diagnosis had no evening preference. Remdesivir leads to a slight phase-shift in Clock, Per1 and Per2. Significant different expressions of Bmal1 and Per3 were detected after remdesivir exposure: Bmal1 at ZT8 (t(22) = 3.26, p = 0.004), ZT24 (t(22) = - 2.66, p = 0.015), ZT28 (t(20) = - 2.14, p = 0.045) and Per3 at ZT8 (t(22) = - 4.27, p < 0.001) and ZT12 (t(22) = - 2.61, p = 0.016). A significant difference between chronotype and circadian gene expression for Bmal1, Cry1 and Per3 was observed. The present study shows that remdesivir has an impact on circadian function. It is well known that the circadian rhythm effects sleep and, moreover, sleep quality. The results suggest that remdesivir medication may alter sleep quality in participants without a neuropsychiatric diagnosis and shifts chronotype to eveningness; similar as prevalent in ADHD.

The impact of social jetlag and chronotype on attention, inhibition and decision making in healthy adults.

Sleep and circadian clock disruption are associated with neuropsychiatric disorders, such as attention deficit hyperactivity disorder, but the impact on neurocognitive performance is unclear. We assessed whether chronotype and everyday circadian misalignment manifested as social jetlag were associated with inter-individual neurocognitive performance across domains of attention, inhibitory control and decision making. One hundred and eighty-eight healthy young adults were assessed for sleep and circadian properties and performed two neurocognitive tasks, the Continuous Performance Test and the Iowa Gambling Task. Social jetlag was associated with significantly faster and less variable reaction times and commission errors on the Continuous Performance Test. Poorer subjective sleep quality was associated with poorer decision making on the Iowa Gambling Task. No effects were present for polymorphisms in the circadian clock genes CLOCK and PER3. We conclude that circadian disruption shaped by everyday environmental factors may impact on attentional/inhibitory performance but not on a measure of risky decision making.

Current source density analysis of resting state EEG in depression: a review.

Electroencephalography (EEG) has been widely used in the neurophysiological investigation of major depressive disorder (MDD) during past decades. An approach that has attracted particular interest over the past 20 years is current source density (CSD) that assesses current source in extracellular spaces, which are the local generators of the field potentials caused by the activation of neurones. Our aim was to review the current literature regarding resting state CSD analysis in MDD patients. To date, the most prominent aspects in such studies comprise the identification of clinical endophenotypes on the basis of resting state CSD, and the investigation of CSD with respect to treatment outcome prediction. Increased alpha band resting state CSD in frontal regions is typical for MDD, while increased theta band activity in the rostral anterior cingulate gyrus (rACC) has been found to be a good predictor of better antidepressant response. However, differences in the methods used in different studies could be responsible for some contradictions in reported findings. Further research is needed for better distinction of depressive patients from patients with other psychiatric disorders, as well as from healthy subjects.

Effects of prefrontal rTMS on autonomic reactions to affective pictures.

Repetitive transcranial magnetic stimulation (rTMS) can modulate the excitability of stimulated cortical areas, such as prefrontal areas involved in emotion regulation. Low frequency (LF) rTMS is expected to have inhibitory effects on prefrontal regions, and thereby should disinhibit limbic activity, resulting in enhanced emotional and autonomic reactions. For high frequency (HF) rTMS, the opposite pattern might be assumed. The objective of this study was to determine the effects of different rTMS frequencies applied to the right dlPFC on autonomic functions and on emotional perception. In a crossover design, two groups of 20 healthy young women were either stimulated with one session of LF rTMS (1 Hz) or one session of HF rTMS (10 Hz), compared to sham stimulation. We assessed phasic cardiac responses (PCR), skin conductance reactions (SCR), and emotional appraisal of emotional pictures as well as recognition memory after each rTMS application. After LF rTMS, PCR (heart rate deceleration) during presentation of pictures with negative and neutral valence was significantly increased compared to the presentation of positive pictures. In contrast, the modulatory effect of picture valence and arousal on the cardiac orienting response was absent after HF rTMS. Our results suggest that frontal LF rTMS indirectly activates the ANS via inhibition of the right dlPFC activity, likely by enhancing the sensory processing or attention to aversive and neutral stimuli.

The role of sleep problems and circadian clock genes in attention-deficit hyperactivity disorder and mood disorders during childhood and adolescence: an update.

A more recent branch of research describes the importance of sleep problems in the development and treatment of mental disorders in children and adolescents, such as attention-deficit hyperactivity disorder (ADHD) and mood disorders (MD). Research about clock genes has continued since 2012 with a focus on metabolic processes within all parts of the mammalian body, but particularly within different cerebral regions. Research has focused on complex regulatory circuits involving clock genes themselves and their influence on circadian rhythms of diverse body functions. Current publications on basic research in human and animal models indicate directions for the treatment of mental disorders targeting circadian rhythms and mechanisms. The most significant lines of research are described in this paper.

How does healthy aging impact on the circadian clock?

Circadian rhythms are recurring patterns in a host of physiological and other parameters that recur with periods of near 24 h. These rhythms reflect the temporal organization of an organism's homeostatic control systems and as such are key processes in ensuring optimal physiological performance. Dysfunction of circadian processes is linked with adverse health conditions. In this review we highlight the evidence that normal, healthy aging is associated with changes in the circadian system; we examine the molecular mechanisms through which such changes may arise, discuss whether more robust circadian function is a predictor of longevity and highlight the role of circadian rhythms in age-related diseases. Overall, the literature shows that aging is associated with marked changes in circadian processes, both at the behavioral and molecular levels, and the molecular mechanisms through which such changes arise remain to be elucidated, but may involve inflammatory process, redox homeostasis and epigenetic modifications. Understanding the nature of age-related circadian dysfunction will allow for the design of chronotherapeutic intervention strategies to attenuate circadian dysfunction and thus improve health and quality of life.

Insomnia complaints and substance use in German adolescents: did we underestimate the role of coffee consumption? Results of the KiGGS study.

The purpose of the study was to study the associations of tobacco, alcohol, marijuana, and coffee use and insomnia complaints (IC) in adolescents with special consideration of the influence of coffee consumption on these relationships. 7698 Subjects aged 11-17 years were investigated in a cross-sectional study within the German Health Interview and Examination Survey for Children and Adolescents. Self-report questionnaires were distributed to the participants. Hierarchical regression analyses were performed to assess possible effects of coffee consumption on the association of tobacco, alcohol, and marijuana use with IC. Common risk factors for insomnia were included in the adjusted analyses. Tobacco, alcohol, marijuana and coffee use displayed significant bivariate associations with IC. After adjusting the first three substances for coffee consumption, their associations with IC were reduced considerably. After additionally adjusting for other potential confounders (age, gender, socio-economic status, externalizing and internalizing psychiatric problems, media use, bodyweight, medical condition), frequent coffee consumption, high alcohol intake and frequent smoking contributed to the prediction of IC in male subjects while frequent coffee consumption and high alcohol intake predicted the occurrence of IC in females. Coffee consumption could be an important risk factor for IC in adolescents and it significantly affects the association of smoking, alcohol, and marijuana with IC. Future research that includes long-term studies about psychoactive substance use (PSU) and sleep should also consider coffee consumption. Parents, educators, clinicians, and researchers should be aware of the potentially hazardous influence of PSU, especially coffee, alcohol and tobacco, on sleep in young individuals.

Driving and attention deficit hyperactivity disorder.

Adults with attention deficit hyperactivity disorder (ADHD) suffer from various impairments of cognitive, emotional and social functioning, which can have considerable consequences for many areas of daily living. One of those areas is driving a vehicle. Driving is an important activity of everyday life and requires an efficient interplay between multiple cognitive, perceptual, and motor skills. In the present study, a selective review of the literature on driving-related difficulties associated with ADHD is performed, seeking to answer whether individuals with ADHD show increased levels of unsafe driving behaviours, which cognitive (dys)functions of individuals with ADHD are related to driving difficulty, and whether pharmacological treatment significantly improves the driving behaviour of individuals with ADHD. The available research provides convincing evidence that individuals with ADHD have different and more adverse driving outcomes than individuals without the condition. However, it appears that not all individuals with ADHD are affected uniformly. Despite various cognitive functions being related with driving difficulties, these functions do not appear helpful in detecting high risk drivers with ADHD, nor in predicting driving outcomes in individuals with ADHD, since impairments in these functions are defining criteria for the diagnoses of ADHD (e.g., inattention and impulsivity). Pharmacological treatment of ADHD, in particular stimulant drug treatment, appears to be beneficial to the driving difficulties experienced by individuals with ADHD. However, additional research is needed, in particular further studies that address the numerous methodological weaknesses of many of the previous studies.

Sustained attention in adult ADHD: time-on-task effects of various measures of attention.

Neuropsychological research on adults with ADHD showed deficits in various aspects of attention. However, the majority of studies failed to explore the change of performance over time, so-called time-on-task effects. As a consequence, little is known about sustained attention performance of adults with ADHD. The aim of the present study was therefore to test the hypothesis of sustained attention deficits of adults with ADHD. Twenty-nine adults with ADHD and 30 healthy individuals were assessed on four 20-min tests of sustained attention, measuring alertness, selective attention, divided attention and flexibility. The deterioration of performance over time (time-on-task effects) was compared between patients with ADHD and healthy individuals to conclude on sustained attention performance. Compared to healthy individuals, patients with ADHD showed significant deficits of medium size in selective attention and divided attention. Furthermore, medium sustained attention deficits was observed in measures of alertness, selective attention and divided attention. This study supports the notion of sustained attention deficits of adults with ADHD.

Sweat it out? The effects of physical exercise on cognition and behavior in children and adults with ADHD: a systematic literature review.

As attention-deficit/hyperactivity disorder (ADHD) is one of the most frequently diagnosed developmental disorders in childhood, effective yet safe treatment options are highly important. Recent research introduced physical exercise as a potential treatment option, particularly for children with ADHD. The aim of this review was to systematically analyze potential acute and chronic effects of cardio and non-cardio exercise on a broad range of functions in children with ADHD and to explore this in adults as well. Literature on physical exercise in patients with ADHD was systematically reviewed based on categorizations for exercise type (cardio versus non-cardio), effect type (acute versus chronic), and outcome measure (cognitive, behavioral/socio-emotional, and physical/(neuro)physiological). Furthermore, the methodological quality of the reviewed papers was addressed. Cardio exercise seems acutely beneficial regarding various executive functions (e.g., impulsivity), response time and several physical measures. Beneficial chronic effects of cardio exercise were found on various functions as well, including executive functions, attention and behavior. The acute and chronic effects of non-cardio exercise remain more questionable but seem predominantly positive too. Research provides evidence that physical exercise represents a promising alternative or additional treatment option for patients with ADHD. Acute and chronic beneficial effects of especially cardio exercise were reported with regard to several cognitive, behavioral, and socio-emotional functions. Although physical exercise may therefore represent an effective treatment option that could be combined with other treatment approaches of ADHD, more well-controlled studies on this topic, in both children and adults, are needed.

EUDOR-A multi-centre research program: A naturalistic, European Multi-centre Clinical study of EDOR Test in adult patients with primary depression.

BACKGROUND: Electrodermal reactivity has been successfully used as indicator of interest, curiosity as well as depressive states. The measured reactivity depends on the quantity of sweat secreted by those eccrine sweat glands that are located in the hypodermis of palmar and plantar regions. Electrodermal hyporeactive individuals are those who show an unusual rapid habituation to identical non-significant stimuli. Previous findings suggested that electrodermal hyporeactivity has a high sensitivity and a high specificity for suicide. The aims of the present study are to test the effectiveness and the usefulness of the EDOR (ElectroDermal Orienting Reactivity) Test as a support in the suicide risk assessment of depressed patients and to assess the predictive value of electrodermal hyporeactivity, measured through the EDOR Test, for suicide and suicide attempt in adult patients with a primary diagnosis of depression. METHODS AND DESIGN: 1573 patients with a primary diagnosis of depression, whether currently depressed or in remission, have been recruited at 15 centres in 9 different European countries. Depressive symptomatology was evaluated through the Montgomery-Asberg Depression Scale. Previous suicide attempts were registered and the suicide intent of the worst attempt was rated according to the first eight items of the Beck Suicide Intent Scale. The suicide risk was also assessed according to rules and traditions at the centre. The EDOR Test was finally performed. During the EDOR Test, two fingers are put on gold electrodes and direct current of 0.5 V is passed through the epidermis of the fingers according to standards. A moderately strong tone is presented through headphones now and then during the test. The electrodermal responses to the stimuli represent an increase in the conductance due to the increased number of filled sweat ducts that act as conductors through the electrically highly resistant epidermis. Each patient is followed up for one year in order to assess the occurrence of intentional self-harm. DISCUSSION: Based on previous studies, expected results would be that patients realizing a suicide attempt with a strong intent or committing suicide should be electrodermally hyporeactive in most cases and non-hyporeactive patients should show only few indications of death intent or suicides. TRIAL REGISTRATION: The German Clinical Trials Register, DRKS00010082 . Registered May 31st, 2016. Retrospectively registered.