Circadian genes, rhythms and the biology of mood disorders

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Abstract

For many years, researchers have suggested that abnormalities in circadian rhythms may underlie the development of mood disorders such as bipolar disorder (BPD), major depression and seasonal affective disorder (SAD). Furthermore, some of the treatments that are currently employed to treat mood disorders are thought to act by shifting or “resetting” the circadian clock, including total sleep deprivation (TSD) and bright light therapy. There is also reason to suspect that many of the mood stabilizers and antidepressants used to treat these disorders may derive at least some of their therapeutic efficacy by affecting the circadian clock. Recent genetic, molecular and behavioral studies implicate individual genes that make up the clock in mood regulation. As well, important functions of these genes in brain regions and neurotransmitter systems associated with mood regulation are becoming apparent. In this review, the evidence linking circadian rhythms and mood disorders, and what is known about the underlying biology of this association, is presented.

Introduction

Daily rhythms are prominent in everything from sleep/wake cycles, body temperature, hormone levels, and even cognition, attention and mood (Bunney and Bunney, 2000, Reppert and Weaver, 2001). Disruptions in biological rhythms are known to be strongly associated with mood disorders. Indeed some of the major hallmarks of diseases like major depressive disorder (MDD) and bipolar disorder (BPD) are abnormal sleep/wake, appetite, and social rhythms (Boivin, 2000, Bunney and Bunney, 2000, Lenox et al., 2002, Grandin et al., 2006). Depression symptoms are also diurnal with the most severe symptoms occurring typically in the morning (Rusting & Larsen, 1998), and depression is more prevalent in areas of the world that receive little sunlight for extended periods of time (Booker et al., 1991). In addition, one of the most common mood disorders, affecting some 2–5% of the population in temperate climates, is seasonal affective disorder (SAD), a syndrome where depressive symptoms occur only in the winter months when there are shorter days and a later dawn (Lam and Levitan, 2000, Magnusson and Boivin, 2003). Thus, it has long been hypothesized that abnormalities in the molecular clock underlie the development of these disorders. In addition, nearly all of the successful treatments for mood disorders seem to affect circadian rhythms, and it appears that the shifts, resetting and stabilization of these rhythms produced by these treatments are important for therapeutic efficacy. Though these associations have been known for many years, we are only now starting to understand the biology that underlies this connection. With the cloning and characterization of the individual genes that make up the molecular clock, researchers now have the opportunity to explore the molecular mechanisms that underlie this association, and determine the importance of circadian rhythms in mood disorders.

Section snippets

The molecular clock

The primary molecular clock is located in the suprachiasmatic nucleus (SCN) in the hypothalamus, and consists of a transcriptional feedback loop which cycles over the course of ∼ 24 hr in the absence of environmental input (Reppert and Weaver, 2001, Ko and Takahashi, 2006). The major transcriptional activator consists of a dimer between the circadian locomotor output cycles kaput protein (CLOCK) and brain and muscle ARNT-like protein 1 (BMAL1, also known as ARNTL or MOP3). This complex binds to

A generally disrupted clock

Mood disorders such as MDD and BPD may be more prevalent in individuals that are born with an abnormally shifted or arrhythmic clock. Indeed, blunted or abnormal circadian rhythms in a variety of bodily functions including body temperature, plasma cortisol, norepinephrine, thyroid stimulating hormone, blood pressure, pulse, and melatonin have been found in depressed and bipolar patients (Atkinson et al., 1975, Kripke et al., 1978, Souetre et al., 1989). Interestingly, these rhythms seem to

Sleep deprivation therapy

Total sleep deprivation (TSD) is a rapid and effective short-term treatment for depression. It improves depressive symptoms in some 40–60% of patients (Wirz-Justice and Van den Hoofdakker, 1999, Giedke and Schwarzler, 2002). Partial sleep deprivation (through the second half of the night) can also be effective, though usually not to the same degree as TSD (Wirz-Justice et al., 2005). Sleep following treatment can lead to a relapse in symptoms, however, in some patients this is delayed for

Human genetic studies

Several human genetic studies have implicated specific genes that make up the molecular clock in the manifestation of mood disorders. For example, an amino acid substitution in Npas2 (471 Leu/Ser) has been found to associate with the development of SAD (Johansson et al., 2003). Furthermore, in bipolar patients, a single nucleotide polymorphism (SNP) in the 3′ flanking region of the Clock gene (3111 T to C) associates with a higher recurrence rate of bipolar episodes (Benedetti et al., 2003).

Summary and conclusions

The connection between mood disorders and circadian rhythms is becoming increasingly clear. With the cloning and identification of individual members of the molecular clock, studies examining the biology behind this association and the clock's influence on mood are now being conducted. These studies should provide valuable information in terms of our overall understanding of the development of mood disorders and the most appropriate ways to treat them. Treatments like TSD and light therapy are

Acknowledgments

I would like to thank Eric Nestler, John Enwright, Shibani Mukherjee, Joseph Peevey and Addie Dickson for their helpful comments on this manuscript. Results included from our laboratory were funded by NIDA, NIMH and NARSAD.

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