Anxiety disorders and circadian rhythms




Philip GORWOOD, MD, PhD
Centre Hospitalier Sainte-Anne (CMME), Paris, and INSERM U894 and University Paris-Descartes, Center of Psychiatry and Neuroscience
Paris, FRANCE

Anxiety disorders and circadian rhythms


by P. Gorwood, France



Anxiety disorders are some of the most common psychiatric disorders, and their risk factors are not fully understood. This review addresses the role of abnormal circadian rhythms in anxiety disorders; these abnormal rhythms may explain some symptoms or highlight the way some risk factors may increase the risk of later anxiety disorders. The presence of apathological sleep-wake cycle in anxiety (due to sleep difficulties in many anxiety disorders), for example, demonstrates that one of the most frequent symptoms is linked to circadian rhythms. As anxiety is often viewed as a developmental disorder, it is interesting that some cohort studies demonstrated that greater regularity in newborns enhances the quality of care provided by the parents, which in turn lowers anxiety symptoms. The synchronicity between child and parent is important, as demonstrated by lower maternal stress reducing stable inhibition temperament, a marker that has been associated with later risk of anxiety disorders. For some of these cohort studies, cortisol levels were also measured, and abnormal cortisol circadian rhythm was proposed as a mediating factor between early stress and later anxiety disorders. Some studies also analyzed different candidate genes in anxiety disorders and found significant association with two interesting clock-related genes. Indeed, the DRD2 gene was shown to be induced by light in the retina and was also strongly associated with anxiety disorders. Although the literature reviewed herein is largely unspecific, it is hoped that the existence of an antidepressive treatment (agomelatine), which acts through melatonergic and 5-HT2C receptors, and which has now demonstrated strong efficacy on anxiety within depression, will enhance this type of study.

Medicographia. 2012;34:289-294 (see French abstract on page 294)



Anxiety disorders are some of the most common psychiatric disorders, with a 12-month prevalence reported to be 18.1%in the US population.1 The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), defines 12 types of anxiety disorders that can be grouped under the following headings according to their symptom profiles: panic disorder (PD) with or without agoraphobia, phobias including specific and social phobias, obsessive-compulsive disorder (OCD), stress disorders including posttraumatic stress disorder and acute stress disorder, generalized anxiety disorder (GAD), anxiety disorders due to known physical causes, and anxiety disorder not otherwise specified. Experience of distress with accompanying disturbances in sleep, concentration, and social or occupational functioning are common symptoms in many of the anxiety disorders. Indeed, anxiety disorder patients often suffer from sleep disturbances constituting diagnostic criteria of posttraumatic stress disorder and GAD. Also, PD has been associated with sleep disorders.

Symptoms of anxiety reflecting abnormal circadian rhythms

The biological clock of mammals (the suprachiasmatic nucleus [SCN]) controls a variety of behavioral rhythmic phenomena, such as locomotor activity and sleep-wakefulness,2 apart from secretion of various hormones. Therefore, sleep complaints are pertinent to circadian rhythms.

Interestingly, sleep complaints may also be considered a risk factor, and among the most robust prodromal symptoms reflecting anxiety disorders.3 Indeed, according to two follow-up studies4,5 presence of sleep disorder at time 1 (with no psychiatric disorder) was associated with a higher risk of anxiety disorder at time 2, from one year4 to three years5 later. More precisely, the epidemiological study based on young adults showed that having pure insomnia at the first visit increased by two the risk of having any anxiety at the second visit (95% confidence interval [CI] of the odds ratio [OR]=1.08-3.60).5

Sleep definitely reflects a core aspect of circadian activities of subjects, but sleep difficulties only represent one facet of circadian activities in patientswith anxiety disorders, and is largely shared with other psychiatric disorders such as mood disorders. Knowing if anxious patients have more abnormal social rhythms than healthy controls is therefore much more interesting. Patients with anxiety might indeed be more sensitive to life changes which result in disruption of daily routine, as these patients were considered as relying more than others on familiarity, predictability, and controllability to manage their lives.6 High levels of anxiety can indeed be disorganizing and disruptive of daily rhythms because of impaired coping and problem solving ability, which might increase the disruptive effects of life events on the regularity of everyday activities. A reduced exposure to zeitgebers (time-giving cues) could be proposed as an alternative explanation, phobic avoidance, for example, being a common strategy in anxiety disorder to lower the level of exposure to stress, but which also reduces exposure to zeitgebers.





Shear et al7 compared 48 patients with an anxiety disorder (and no comorbid depressive episode) with 41 controls, assessing regularity of daily activities according to a two-week daily monitoring with the Social Rhythm Metric (SRM).8 Anxiety disorder patients reported lower rhythmicity of daily life activities and significantly lower frequency of activities than controls. The distinctions between lowered intrinsic rhythmicity in daily activities or heightened vulnerability to stimuli which disrupt social rhythms are difficult to assess in such a study.

Considering abnormal circadian rhythms to be important factors in anxiety disorders does not only require that sleep disorders are both associated with and risk factors for anxiety and that patients with anxiety disorders have abnormal social rhythms. It also requires an explanation of how such abnormalities relate to the onset of anxiety disorders. Therefore, developmental approaches, genetic analyses, and further understanding of the involved biological mechanisms are expected to shed light on such a hypothesis.

Early development: from rhythmicity and inhibition to anxiety

How circadian rhythms might lead to psychiatric disorders such as mood and anxiety disorders, when they are running according to inappropriate timing or in an irregular fashion, is a matter of debate.

Because parents are adults with well-developed daily behavior patterns, an infant’s level of circadian regularity will determine the nature of his or her interaction with them, and may thus affect early attachment relationships and the development of self-regulatory social skills in infancy.8 Greater infant sociability is indeed positively related to maternal contact and responsiveness from 1 to 9 months,9 and secure infant attachment predicts lower levels of child and adolescent anxiety disorders.10 A “virtuous” circle (Figure 1) would take into account that stronger and more regular circadian rhythms in the infant may increase the predictability of infant demands, leading to enhanced parental perception of need cues11 and increased parental confidence12 which might further strengthen caretaking routines. Indeed, mothers and fathers, whose infants exhibited significant increases in regulation and predictability from age 3 to 9 months, displayed increased sensitivity during play and greater caretaking involvement.13

Temperamental rhythmicity in children directly refers to the predictability or unpredictability in timing of the sleep-wake cycle, hunger, feeding, and elimination. Difficult or dysregulated temperament has been associated with greater risk for psychopathology, including symptoms of anxiety.14,15 Children high in effortful control exhibit lower levels of internalizing symptoms, such as anxiety.16 Thus, an infant’s ability to direct attention may represent greater self-regulation, and is perhaps associated with stronger and more regular circadian rhythms.17


Figure 1
Figure 1. How children with more regular rhythms could be at
lower risk of later anxiety disorders.



In order to more specifically test the idea that babies with less predictable rhythms could be at risk of anxiety, Monk et al17 assessed the rhythms of 59 1-month old babies. They were then followed up for up to 13 years, assessing the level of anxiety according to the MacArthur Health and Behavior Questionnaire. The Baby SRM score was significantly correlated with school-age anxiety symptoms, with higher (more regular) SRM scores associated with lower overall levels of anxiety symptoms, across the five separate time points (age 6, 7, 9, 11, and 13 years, r=–0.35, –0.37, –0.24, –0.26, and –0.30, respectively). There was no significant correlation of Baby SRM with child depression. More precisely, the initial Baby SRM explained between 12% and 22% of the total variance of the anxiety level that was observed at up to 13 years old. Thus, daily behavioral regularity in the life of a 1-month old infant appears to be predictive of anxiety levels more than a decade later.

Biological markers of circadian rhythms and their relevance in anxiety

One candidate biological marker of anxiety and circadian rhythms is elevated activity of the limbic system, as testified by elevated cortisol levels, which is associated with the generation of fear in children.18 There are multiple pathways that control the timing and shape of cortisol rhythms, from the SCN to the paraventricular nucleus (PVN)19 as well as direct input from the SCN to the adrenal cortex.20 Imaging studies in monkeys and humans suggest that individual differences in limbic system activity (including the amygdala) are associated with temperamental inhibition and anxiety-related behaviors.21,22 Inhibition is linked with physiological reactivity across systems regulated by the central nucleus of the amygdala, including the neuroendocrine response system.23 Of particular interest are findings suggesting that increased pituitary-adrenal activity, assessed by salivary cortisol levels, is associated with extreme childhood inhibition.18,24

Monkeys exposed to early environmental perturbations and negative maternal behaviors tend to develop increased hypothalamic- pituitary-adrenal reactivity and stable fear-related behaviors.25,26 Studies of young children also suggest that maternal behaviors, including being overly solicitous as well as negative behaviors (eg, low engagement, hostility) associated with maternal depression or distress, might influence the development of elevated cortisol levels27 and early inhibition.28,29

A prospective study was conducted in 1-month old infants to 14- to 15-year-old teenagers to test the role of cortisol release as an intermediate factor between parental distress and their children’s later anxiety disorders. In this cohort, initial level of inhibition (according to a videotaped observation of a 2-hour home visit) and afternoon basal cortisol were compared with later levels of inhibition and presence of DSM-IV diagnoses (with the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version).30 Chronic high levels of inhibition were significantly associated with a lifetime history of social anxiety disorder by grade 9 (Figure 2).30 A “stress pathway” was identified, highlighting that children exposed to greater maternal stress beginning at birth are at greater risk for developing chronic high inhibition, in part because they experience increased afternoon cortisol levels as preschoolers. The role of cortisol as a biological marker of later risk of anxiety disorder is additional proof of the link between anxiety and circadian rhythms.


Figure 2
Figure 2. Longitudinal model of inhibition in 238 children assessed
from grades 1 to 9.

Abbreviation: r, bivariate Spearman correlation coefficient.
After reference 30: Essex et al. Am J Psychiatry. 2010;167(1):40-46. © 2010,
American Psychiatric Association.



Another study attempted to bridge the gap between anxiety traits and daytime cortisol on the one hand and early abuse on the other. Among the array of difficulties exhibited by maltreated children, especially for very young ones, one of the most prevalent and widely documented is indeed an increased risk for internalizing problems, including anxiety disorders.31 In this study, during summer camp, 265 school-aged maltreated children and 288 non-maltreated children were compared with regard tomorning and late afternoon cortisol levels on five consecutive days. Children experiencing early physical and sexual abuse with high internalizing symptoms uniquely exhibited an attenuated diurnal decrease in cortisol, indicative of neuroendocrine dysregulation. Therefore, dysregulation of cortisol could distinguish a subgroup of patients who have a significant risk factor (early sexual abuse) and who already have some anxiety features (high internalizing level), reinforcing the idea that hormones with circadian variability could be involved in the onset and the development of anxiety disorders.

Early exposure to a range of risk factors, such as poor secure relationship with the parents and early sexual abuse, has thus been demonstrated to have an important role in the risk of anxiety disorders. The concept of exposure might be particularly important in the organization of circadian rhythms. Indeed, the perinatal photoperiod has lasting effects on behavior and the circadian rhythms expressed by clock neurons, and it determines the responsiveness of the biological clock to subsequent changes.32

Furthermore, in humans, cortisol (associated with wakefulness) and melatonin (a hormonal signal related to anticipated onset of sleep in diurnal animals) appear to act in opposite manners to each other, both functionally and at the neuroanatomical level. An interesting hypothesis has been put forward, proposing that the interdependence between cortisol and melatonin in relationship to different psychiatric disorders may be more important than either of their independent relationships to the sleep-wake cycle.33 How could such an interaction between melatonin and cortisol occur? Vasopressin (AVP) receptors are located on the SCN;34 their activation by cortisol is thus expected to affect the release of melatonin. Another possibility lies in the effect of melatonin on cortisol as hypertrophy of the rat adrenal and pituitary gland is observed after pinealectomy, which suggests that melatonin may help suppress the hypothalamic-pituitary-adrenal axis.35

Nevertheless, biological markers might be associated with the presence of the disorder, rather than testifying to a specific type of vulnerability. The biological markers protected from this bias are genetic markers.

Genetics

Anxiety disorders are complex diseases; twin and family studies have provided evidence for both genetic and environmental factors affecting predisposition. On the basis of the meta-analyses conducted by Hettema et al,36 the estimated heritability of PD and GAD was assessed as ranging between 30% and 45%. Other anxiety disorders aggregate in families as well. A more recent approach on the heritability of anxiety disorders relied on a latent liability to all anxiety disorders. Such a factor had a higher heritability (54%) than each disorder (23% to 40%), most of the genetic effect being common. Genes contributed over 50% to the covariance between liabilities.37 Therefore, the genetics of anxiety disorders may also help us understand whether anxiety disorders result from an abnormality in circadian rhythms.

Recent isolation of different mammalian homologues of clock genes and their circadian expression in the SCN suggests that molecular components and some mechanisms of the mammalian circadian clock are evolutionarily conserved. Therefore, animal studies on clock genes are informative.

Mice carrying a mutation in the Clock gene were studied for their overall behavioral anxiety profile, according to the open field and elevated plus maze paradigms. Both tests measure the amount of time spent in an anxiety-provoking space, such as the middle of an open field or unprotected arm of a raised platform, and both are sensitive to treatment with anxiolytic drugs. These results showed that the Clock mutants are less anxious or fearful than their wild-type littermates.38 However, as these mice also showed behaviors associated with mania, it is unclear how to best classify this phenotype.39 Another study40 showed that the expression of Per1 mRNA was rapidly reduced in the cerebellum by acute intraperitoneal injection of anxiolytic medications (diazepam, triazolam and tandospirone), but not by clozapine and haloperidol, suggesting that altering circadian-clock–related gene levels could theoretically contribute to the therapeutic action of these drugs.

These two studies provide very indirect evidence for the role of clock genes in anxiety disorders in human. The only study in human we are aware of tested 13 circadian-clock–related genes in a sample of 321 individuals diagnosed with an anxiety disorder and 653 matched healthy controls with a relatively homogeneous ethnic background (all of Finnish origin).41 Evidence for association was detected for three of these genes (BCL2, DRD2, and PAWR) belonging to the signaling pathway connecting circadian rhythmicity and anxiety-like behavior (Table I).41

DRD2 is particularly interesting, as it is also induced by light in the retina42 and was previously associated with neuropsychiatric disorders largely overlapping anxiety disorders, such as alcoholism with comorbid anxiety,43 neuroticism-anxiety personality trait,44 posttraumatic stress disorder,45,46 and social phobia.47 Clock genes constitute a large number of candidate genes to explain abnormal circadian rhythms in anxiety disorders.2

Conclusions

Research directly devoted to the relationship between anxiety disorders and circadian rhythms is surprisingly poor, probably as the circadian variability in anxiety disorders is less obvious than in mood disorders. But restricting to this purely observational assumption might be disadvantageous, as we still lack important insight enabling detection of new pathways explaining anxiety. Furthermore, the recognized role of circadian rhythm abnormalities in major depressive disorder should reinforce the need to assess this domain in anxiety disorders, as anxiety and depression have more shared than specific risk factors.48


Table I
Table I. Association of different
genetic polymorphisms of circadian
clock-related genes with various
phenotypes of anxiety-related
phenotypes.

Abbreviations: ARNTL2, aryl hydrocarbon
receptor nuclear translocator-like 2;
BCL2,
B-cell CLL/lymphoma 2;
DRD2, dopamine
receptor D2; GAD, generalized anxiety disorder;

PAWR, PRKC, apoptosis, WT1, regulator;
SNP, single nucleotide polymorphism.
After reference 41: Siplä et al. Biol Psychiatry.
2010;67(12):1163-1170. © 2010,
Society of Biological Psychiatry.



Although the literature only offers indirect evidence, it is particularly interesting that some of the core risk factors—such as early physical and sexual abuse, insecure attachment, and vulnerability genes—for many anxiety disorders, have the potential to explain abnormal circadian rhythms. For example, and in accordance with the developmental theory of anxiety disorders (ie, that anxiety disorders are acquired early in life), it is particularly interesting that even perinatal variations of the photoperiod have lasting effects on the circadian rhythms expressed by clock genes.32 Aside from this developmental aspect of the disorder, two genes have been associated with anxiety and may also shed light on its circadian aspect. One of these, the DRD2 gene, which might have a key role in the reward process,49 was associated with different anxiety disorders as a clock-related gene.41 Furthermore, an antidepressive treatment (agomelatine) with a mechanism of action involving melatonergic receptors and 5-HT2C has now demonstrated strong efficacy on anxiety in depression50 and will hopefully enhance studies like these. _


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Keywords: anxiety disorder; circadian rhythm; clock-related gene; cortisol; melatonin; rhymicity