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Cited by 666Circadian rhythm and melatoninBipolar Disorder and TreatmentTreatment of Major Depression

Circadian genes, rhythms and the biology of mood disorders

Open access
McClung, Colleen A.·2007·Pharmacology & Therapeutics
DOI 10.1016/j.pharmthera.2007.02.003PMC PMC1925042
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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.

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TL;DR

This review synthesizes evidence that abnormalities in circadian rhythms and the molecular clock underlie mood disorders including bipolar disorder, major depression, and seasonal affective disorder (SAD), and that many effective treatments (sleep deprivation, bright light therapy, lithium, SSRIs, agomelatine) act at least partly by shifting or resetting the circadian clock. It also reviews genetic, gene-expression, and behavioral studies implicating specific clock genes (CLOCK, NPAS2, BMAL1, Per3, GSK3β) in mood regulation.

Key findings

  • Disrupted circadian rhythms in body temperature, plasma cortisol, norepinephrine, TSH, blood pressure, pulse, and melatonin are found in depressed and bipolar patients, and these rhythms normalize with treatment and recovery; genetic sleep disorders (FASPS, DSPS) and "eveningness" preference are highly comorbid with depression and anxiety.
  • SAD affects roughly 2–5% of the population in temperate climates; the melatonin hypothesis and the circadian phase shift hypothesis (later winter dawn delays rhythms) are both supported but remain debated, since some studies find evening light as effective as morning light and others find no therapeutic effect of melatonin.
  • Total sleep deprivation improves depressive symptoms in some 40–60% of patients; bright light therapy (~10,000 lux, 30–90 minutes in the morning) produces a phase shift in body temperature rhythms of ~1 hour and takes 2–4 weeks for mood effects, with blue-spectrum light (446–477 nm) outperforming other wavelengths in melatonin suppression, phase shifting, and antidepressant effects.
  • Human genetic studies link an NPAS2 substitution (471 Leu/Ser) to SAD, a CLOCK 3′ flanking SNP (3111 T to C) to higher bipolar episode recurrence and insomnia, and BMAL1/Per3 haplotypes to bipolar disorder, though most associations are modest and some studies find none; CLOCK mutant mice display a mania-like profile (hyperactivity, reduced depression-like behavior, increased cocaine/sucrose reward, increased VTA dopamine cell firing) that is reversed by lithium.

Methods

This is a narrative review; no primary data or systematic search strategy is reported. It synthesizes human genetic association studies, rodent behavioral and gene-expression studies, and clinical treatment literature (sleep deprivation, light therapy, and pharmacological agents including lithium, valproate, fluoxetine, and agomelatine) to argue for a circadian basis of mood disorders.

Limitations

The paper itself notes that the biology underlying the circadian–mood association is still unknown, that most human genetic associations are modest and sometimes contradictory (with some studies finding no association), that the melatonin–SAD link "is still up for debate," and that the phase shift hypothesis "still remains controversial." Evident from the text: as a narrative review it presents no systematic inclusion criteria or quantitative synthesis, and much of the mechanistic evidence comes from animal models whose translation to human mood disorders is not established.

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Integrity signals

Registry

Crossref · 10.1016/j.pharmthera.2007.02.003

Cites

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Statistics

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Claims the paper makes

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  • Findingcitation

    CLOCK mutant mice display reduced depression-like behavior in the forced swim test and learned helplessness tests.

    “reduced depression-like behavior in the forced swim test and learned helplessness tests”
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  • Findingcitation

    CLOCK mutant mice display hyperactivity in response to novelty and over the light/dark cycle.

    “Their behavioral profile includes hyperactivity in response to novelty and over the light/dark cycle”
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  • Findingcitation

    Treating CLOCK mutant mice with lithium returns the majority of their behavioral responses to wild-type levels.

    “when we treat these mice with the mood stabilizer, lithium, the majority of their behavioral responses return to wild-type levels (Roybal et al., in press).”
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  • Findingcitation

    CLOCK mutant mice display reduced anxiety or increased risk taking behavior in several measures.

    “reduced anxiety or increased risk taking behavior in several measures”
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  • Findingcitation

    CLOCK mutant mice display an increase in the reward value of cocaine, sucrose and intracranial self-stimulation.

    “an increase in the reward value of cocaine, sucrose and intracranial self-stimulation (McClung et al., 2005; Roybal et al, in press).”
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    Premisecitation
    § 2. The molecular clock

    Clock genes are expressed throughout the brain and in other organs where they function as peripheral clocks responding to nonphotic stimuli and likely in other processes unrelated to circadian rhythms.

    “Though the central circadian pacemaker is located in the SCN, all of these genes are expressed throughout the brain and in other organs where they function as peripheral clocks that respond to nonphotic stimuli, and likely in other processes unrelated to circadian rhythms (Abe et al., 2001; Stokkan et al., 2001; Iijima et al., 2002; Granados-Fuentes et al., 2006; McDearmon et al., 2006; Mieda et a”
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    Premisecitation
    § 2. The molecular clock

    NPAS2 may function in place of CLOCK in the SCN if the CLOCK protein is genetically disrupted.

    “NPAS2 may also function in the place of CLOCK in the SCN if the CLOCK protein is genetically disrupted (Debruyne et al., 2006).”
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    Premisecitation
    § 2. The molecular clock

    CLOCK/BMAL1 activates transcription of Rev-erbα and Rorα, and these proteins bind the BMAL1 promoter and both positively and negatively affect its transcription.

    “In addition, there is an adjoining loop in which CLOCK/BMAL1 activates the transcription of Rev-erbα and Rorα (Sato et al., 2004; Guillaumond et al., 2005). Once translated, these proteins can bind to the promoter of the BMAL1 gene and both positively and negatively affect its transcription.”
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    Premisenone given
    § 2. The molecular clock

    The CLOCK/BMAL1 dimer binds E-box sequences in the promoters of many genes including Period and Cryptochrome.

    “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 E-box sequences in the promoters of many genes including the Period (Per) and Cryptochrome (Cry) genes.”
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    Premisecitation
    § 1. Introduction

    Seasonal affective disorder is a syndrome where depressive symptoms occur only in the winter months when there are shorter days and a later dawn.

    “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).”
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    Interpretationnone given
    § 1. Introduction

    Nearly all successful treatments for mood disorders seem to affect circadian rhythms, and the shifts, resetting and stabilization of these rhythms produced by these treatments appear important for therapeutic efficacy.

    “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.”
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    • Rests on an assumption: Abnormalities in circadian rhythms causally contribute to the development of mood disorders, rather than being only associated with them.

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    Premisecitation

    Familial advanced phase sleep syndrome and delayed sleep phase syndrome are both highly co-morbid with depression and anxiety.

    “Furthermore, genetic sleep disorders such as familial advanced phase sleep syndrome (FASPS) in which individuals have shifted circadian rhythms where they fall asleep and wake up much earlier than desired, or delayed sleep phase syndrome (DSPS) which has the opposite phenotype, are both highly co-morbid with depression and anxiety (Shirayama et al., 2003; Xu et al., 2005; Hamet and Tremblay, 2006”
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    Premisecitation
    § 2. The molecular clock

    The primary molecular clock is located in the suprachiasmatic nucleus in the hypothalamus and consists of a transcriptional feedback loop cycling over approximately twenty-four hours in the absence of environmental input.

    “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 approximately twenty-four hours in the absence of environmental input (Reppert and Weaver, 2001; Ko and Takahashi, 2006).”
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    Premisecitation
    § 1. Introduction

    Seasonal affective disorder affects some 2-5% of the population in temperate climates.

    “one of the most common mood disorders, affecting some 2–5% of the population in temperate climates, is seasonal affective disorder (SAD)”
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    Interpretationnone given

    Seasonal affective disorder is perhaps the most common disorder that arises from a failure to properly adapt to changes in the environment.

    “Seasonal affective disorder (SAD) is perhaps the most common disorder that arises from a failure to properly adapt to changes in the environment.”
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    Premisecitation

    Additional abnormalities in melatonin secretion in SAD patients, such as phase delays over twenty-four hours, have been reported; however, other studies have reported no differences in circadian melatonin levels or rhythms in SAD patients.

    “Additional abnormalities in melatonin secretion in SAD patients, such as phase delays over twenty-four hours, have also been reported; however, other studies have reported no differences in circadian melatonin levels or rhythms in SAD patients (Checkley et al., 1993; Srinivasan et al., 2006).”
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    Premisecitation

    In some studies, evening light exposure has an equally strong antidepressant effect as morning exposure, and several studies find no therapeutic effects of melatonin treatment.

    “However, in some studies, evening light exposure has an equally strong antidepressant effect as morning exposure and several studies find no therapeutic effects of melatonin treatment (Wirz-Justice et al., 1990; Wirz-Justice et al., 1993; Terman et al., 2001).”
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    Premisecitation

    Other studies have found significant seasonal alterations in melatonin rhythms in healthy, non-affected individuals, or even melatonin levels that are greater in the summer than the winter.

    “However, other studies have found significant seasonal alterations in melatonin rhythms in healthy, non-affected individuals, or even melatonin levels that are greater in the summer than the winter (Touitou et al., 1984; Kivela et al., 1988; Honma et al., 1992; Morera and Abreu, 2006).”
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    Premisecitation

    Melatonin therapy in the evening can also be effective in producing the same phase advance and may help with the treatment of SAD.

    “In addition, there have been reports that melatonin therapy in the evening can also be effective in producing this same phase advance and may help with the treatment of SAD (Lewy et al., 1998a; Lewy et al., 2006).”
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    Premisecitation

    Melatonin is released primarily by the pineal gland and can bind to the G-protein coupled receptors MT1 and MT2.

    “Melatonin is released primarily by the pineal gland and can bind to the G-protein coupled receptors, MT1 and MT2 (Pandi-Perumal et al., 2006).”
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    Premisecitation

    Melatonin is suppressed by light, participates in sleep, and varies seasonally in many mammals.

    “Melatonin is suppressed by light, participates in sleep, and varies seasonally in many mammals (Pandi-Perumal et al., 2006).”
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    Interpretationreasoning

    Early morning light leads to a phase advance in the circadian system, putting it back on track with the sleep/wake cycle.

    “Therefore, the early morning light is leading to a phase advance in the circadian system putting it back on track with the sleep/wake cycle.”
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    Premisecitation

    Early morning bright light therapy is the most effective in treating SAD while evening light therapy is often not effective.

    “This hypothesis is largely based on research demonstrating that early morning bright light therapy is the most effective in treating SAD while evening light therapy is often not effective (Lewy et al., 1998b; Terman and Terman, 2005).”
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    Premisecitation

    MT1 and MT2 receptors are expressed at high levels in the SCN, and upon stimulation modulate SCN transmission and circadian activity.

    “These receptors are expressed at high levels in the SCN, and upon stimulation, modulate SCN transmission and circadian activity.”
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    Premisecitation

    The social zeitgeber theory proposes that depressive or manic episodes are brought on by life stresses because they disrupt normal social routines and the sleep/wake cycle, leading to changes in biological rhythms and mood.

    “This theory proposes that depressive or manic episodes are brought on by life stresses because they disrupt normal social routines and the sleep/wake cycle, in turn leading to changes in biological rhythms and mood (Grandin et al., 2006).”
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    Interpretationreasoning

    Individuals with these types of mood disorders may have a molecular clock that is not able to properly adapt to certain environmental or other changes.

    “Thus it is possible that individuals that suffer from these types of mood disorders have a molecular clock that is not able to properly adapt to certain types of environmental or other changes.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Abnormalities in circadian rhythms causally contribute to the development of mood disorders, rather than being only associated with them.

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    Premisecitation

    In some studies, SAD sufferers have either a pronounced seasonal melatonin rhythm or more daytime melatonin specifically in the winter, while healthy control subjects have no seasonal alterations in their melatonin rhythms.

    “In some studies, SAD sufferers have been found to have either a pronounced seasonal melatonin rhythm, or more daytime melatonin specifically in the winter, while healthy control subjects have no seasonal alterations in their melatonin rhythms (Danilenko et al., 1994; Wehr et al., 2001).”
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    Premisereasoning

    The same shift in period gene expression does not occur in the SCN with methamphetamine treatment, indicating a disconnect between the SCN, molecular rhythms in the striatum, and locomotor activity rhythms.

    “This same shift in period gene expression does not occur in the SCN with methamphetamine treatment, thus there is a disconnect between the SCN, molecular rhythms in the striatum and locomotor activity rhythms.”
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    Premisecitation

    Partial sleep deprivation through the second half of the night can also be effective, though usually not to the same degree as total sleep deprivation.

    “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).”
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    Premisecitation

    Other theories suggest that SAD patients fall into two categories, some with a phase delay in rhythms and some with a phase advance in rhythms.

    “Other theories suggest that SAD patients actually fall into two categories, some with a phase delay in rhythms and some with a phase advance in rhythms (Boivin, 2000; Lewy et al., 2006).”
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    Interpretationreasoning

    The biology underlying the association between circadian rhythms and mood disorders is still unknown, but may come from the influence of the molecular clock on certain neurotransmitters and their receptors.

    “The biology that underlies the association between circadian rhythms and mood disorders is still unknown, but may come from the influence of the molecular clock on certain neurotransmitters and their receptors.”
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    Premisenone given

    Sleep following total sleep deprivation can lead to a relapse in symptoms, but in some patients this is delayed for several weeks.

    “Sleep following treatment can lead to a relapse in symptoms, however, in some patients this is delayed for several weeks.”
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    Premisecitation

    Total sleep deprivation is a rapid and effective short-term treatment for depression, improving depressive symptoms in some 40-60% of patients.

    “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).”
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    Premisecitation

    There are circadian rhythms in the expression and activity of several receptors that bind these neurotransmitters, suggesting that these entire circuits are under circadian control.

    “There are also circadian rhythms in the expression and activity of several of the receptors that bind these neurotransmitters, suggesting that these entire circuits are under circadian control (Kafka et al., 1983; Wesemann and Weiner, 1990; Witte and Lemmer, 1991; Coon et al., 1997; Akhisaroglu et al., 2005).”
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    Premisereasoning

    Patients who have a shift in rhythms respond positively to lithium treatment in terms of mood stabilization, while those few bipolar patients who begin with an abnormally slow clock do not respond to lithium treatment.

    “Furthermore, patients that have a shift in rhythms respond positively to lithium treatment in terms of mood stabilization, while those few bipolar patients that begin with an abnormally slow clock do not respond to lithium treatment.”
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    Premisecitation

    Total sleep deprivation in hamsters affects serotonin levels in the SCN and other brain regions, and results in a strong phase advance in activity rhythms.

    “It has also been shown in hamsters that TSD affects serotonin levels in the SCN and other brain regions, and results in a strong phase advance in activity rhythms (Asikainen et al., 1995; Grossman et al., 2000).”
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    Premisecitation

    Agomelatine is much more effective than melatonin in reversing depression-like behavioral responses in animal models, suggesting that the therapeutic actions of agomelatine are not exclusively due to its actions at the melatonin receptors.

    “Interestingly, agomelatine is much more effective than melatonin in reversing depression-like behavioral responses in animal models, suggesting that the therapeutic actions of agomelatine are not exclusively due to its actions at the melatonin receptors (Delagrange and Boutin, 2006).”
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    Interpretationcitation

    The kinetics of agomelatine and its actions at the melatonin receptors may differ greatly from those of melatonin, so this action may still underlie at least part of its efficacy as an antidepressant.

    “However, the kinetics of agomelatine, and actions at the melatonin receptors, may differ greatly from those of melatonin, so this action may still underlie at least part of its efficacy as an antidepressant (Hamon and Bourgoin, 2006).”
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    Premisecitation

    Recent studies have found that light in the blue spectrum (446-477) outperforms other wavelengths in melatonin suppression, circadian phase shifting, and antidepressant effects.

    “Recent studies have found that light in the blue spectrum (446–477) outperforms other wavelengths in melatonin suppression, circadian phase shifting, and antidepressant effects (Brainard et al., 2001; Thapan et al., 2001; Lockley et al., 2003; Glickman et al., 2006).”
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    Premisecitation

    Agomelatine, a potent agonist of the melatonin receptors and an antagonist at the serotonin 5-HT2C receptor, has proven to be highly effective in animal models of depression and in several ongoing clinical trials involving patients with major depressive disorder.

    “Recently, agomelatine, a potent agonist of the melatonin receptors and an antagonist at the serotonin 5-HT(2C) receptor, has proven to be highly effective in animal models of depression, and in several on-going clinical trials involving patients with MDD (den Boer et al., 2006; Hamon and Bourgoin, 2006; Zupancic and Guilleminault, 2006).”
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    Premisecitation

    Bright light therapy has been used for more than twenty years to treat SAD with comparable efficacy to antidepressant medications.

    “Bright light therapy has been used for more than twenty years to treat SAD with comparable efficacy to antidepressant medications (Lam et al., 2006).”
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    Premisecitation

    Agomelatine has been shown to resynchronize circadian rhythms in body temperature, cortisol, and other hormones in animal models and in humans, which may underlie some of its therapeutic effects.

    “As expected by its pharmacologic profile, agomelatine has been shown to resynchronize circadian rhythms in body temperature, cortisol, and other hormones in animal models and in humans, which may underlie some of its therapeutic effects (Leproult et al., 2005).”
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    Premisecitation

    Agomelatine seems to produce fewer adverse side effects than some other antidepressant medications, and it alleviates many of the sleep problems associated with depression that are typically exacerbated by SSRI treatment.

    “Agomelatine also seems to produce fewer adverse side effects than some of the other antidepressant medications, and it alleviates many of the sleep problems associated with depression that are typically exacerbated by SSRI treatment, making it a potentially valuable new treatment for depression (Hamon and Bourgoin, 2006).”
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    Premisecitation

    Serotonin neurons from the midbrain raphe nuclei innervate the SCN, and local applications of 5-HT or 5-HT1A and 7 receptor agonists to the SCN produce a phase advance in circadian activity.

    “Indeed, serotonin neurons from the midbrain raphe nuclei innervate the SCN, and local applications of 5-HT or 5-HT 1A and 7 receptor agonists to the SCN will also produce a phase advance in circadian activity (Dudley et al., 1999; Ehlen et al., 2001).”
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    Premisecitation

    Light therapy is thought to work by shifting the circadian clock; morning light produces a phase advance in rhythms while evening light produces a phase delay.

    “It is thought that light therapy works by shifting the circadian clock, and indeed light therapy given in the morning will produce a phase advance in rhythms while light in the evening produces a phase delay (Wirz-Justice et al., 2005).”
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    Premisecitation

    Specific antagonists at the 5-HT2C receptor have potent anxiolytic-like activity in animal models, but they seem to have no effect in models of depression.

    “Interestingly, specific antagonists at the 5-HT(2C) receptor have potent anxiolytic-like activity in animal models, but they seem to have no effect in models of depression (Jenck et al., 1998).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Jenck et al., 1998

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Agomelatine's actions at the 5-HT2C receptors enhance mesolimbic dopaminergic and noradrenergic transmission, an effect also seen with SSRIs.

    “However, its actions at the 5-HT(2C) receptors enhances mesolimbic dopaminergic and noradrenergic transmission, an effect also seen with SSRIs (Millan et al., 2003; Serretti et al., 2004).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Millan et al., 2003

      Not checked in the free run.

    • cites Serretti et al., 2004

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most studies have not found general associations between variants in GSK3β and bipolar disorder or the response to lithium.

    “most studies have not found general associations between variants in this gene and BPD, or the response to lithium”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Michelon et al., 2006

      Not checked in the free run.

    • cites Szczepankiewicz et al., 2006a

      Not checked in the free run.

    • cites Lee et al., 2006

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The therapeutic actions of agomelatine in the treatment of depression are still uncertain, and may involve both the 5-HT2C and melatonin receptors.

    “Therefore, the therapeutic actions of agomelatine in the treatment of depression are still uncertain, and may involve both the 5-HT(2C) and melatonin receptors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Agomelatine seems to have no effect on central serotonin transmission or the density and function of 5-HT1A receptors.

    “Though the latency to action is similar between agomelatine and the SSRIs, agomelatine seems to have no effect on central serotonin transmission or the density and function of 5-HT(1A) receptors (Hanoun et al., 2004; Millan et al., 2005).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Hanoun et al., 2004

      Not checked in the free run.

    • cites Millan et al., 2005

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    GSK3β is a widely expressed kinase that has many functions in the brain.

    “GSK3β is a widely expressed kinase that has many functions in the brain (Jope and Roh, 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Jope and Roh, 2006

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning
    § 6. Summary and conclusions

    The connection between mood disorders and circadian rhythms is becoming increasingly clear.

    “The connection between mood disorders and circadian rhythms is becoming increasingly clear.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    These CLOCK mutant mice have a point mutation in the CLOCK gene caused by ENU mutagenesis that results in a dominant-negative protein.

    “These mice have a point mutation in the CLOCK gene caused by ENU mutagenesis that results in a dominant-negative protein (King et al., 1997).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites King et al., 1997 source

      Not checked in the free run.

48 of 48

  • The paper relies on this without support.

    Abnormalities in circadian rhythms causally contribute to the development of mood disorders, rather than being only associated with them.

    “For many years, researchers have suggested that abnormalities in circadian rhythms may underlie the development of mood disorders such as bipolar disorder, major depression and seasonal affective disorder.”
    “Thus, it has long been hypothesized that abnormalities in the molecular clock underlie the development of these disorders.”

  • The paper relies on this without support.

    Findings from animal models of circadian rhythms and depression are informative about the mechanisms of human mood disorders and their treatments.

    “A few studies using rodent models have begun to look at the mechanism that underlies TSD’s effects on depression.”

  • The paper relies on this without support.

    The molecular clock mechanism is sufficiently conserved across species that findings in Drosophila, non-human primates, rodents, and humans can be treated as evidence about the same circadian process.

    “Interestingly, both of these drugs have been repeatedly shown to alter the circadian period, leading to a long period in Drosophila, non-human primates, rodents and humans”

  • The paper relies on this without support.

    Immobility in the forced swim test is regarded as helpless or depressed behavior and can be reduced with antidepressant treatment.

    “Immobility in this task is regarded as “helpless” or “depressed” behavior, and it can be reduced with antidepressant treatment.”

  • The paper relies on this without support.

    The amygdala is a region of the brain important in anxiety and emotional responses.

    “the amygdala, a region of the brain known to be important in anxiety and emotional responses”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Abnormalities in sleep/wake rhythms, appetite, and social rhythms have been observed in depressive disorders, schizophrenia, bipolar disorder, anxiety disorders, seasonal affective disorder, and a variety of other CNS disorders.

    “Abnormalities in sleep/wake rhythms, appetite and social rhythms have been observed in depressive disorders, schizophrenia, bipolar disorder, anxiety disorders, seasonal affective disorder (SAD), and a variety of other CNS disorders (Lamont et al., 2007; McClung 2007).”

    From Biological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges (2009) · cites this paper as McClung 2007

  • Disruptions of circadian rhythms, especially sleep-wake rhythms, are observed in all major forms of depression.

    “Disruptions of circadian rhythms, especially sleep-wake rhythms, are observed in all major forms of depression (McClung, 2007).”

    From Biological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges (2009) · cites this paper as McClung, 2007

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Herxheimer, 2005, Jet lag, Clin Evid, 2178

Cited by

Sorted by citations

Related

Authors
McClung, C. A.
Affiliations
The University of Texas Southwestern Medical Center (US)
Corresponding author
McClung, Colleen A.
ORCID
McClung, Colleen A.
Venue
Pharmacology & Therapeutics
Publisher
Elsevier BV
Published
2007-05
Volume
114
Issue
2
Pages
222-232
ISSN
0163-7258 (ISSN-L)
DOI
10.1016/j.pharmthera.2007.02.003
PMC
PMC1925042
OpenAlex
W2013987967
Semantic Scholar
9e74947eab39710958aa499d6bfd27dfa2ae4b91
Cited by
666
References
161
Citations by year
2026: 17 · 2025: 16 · 2024: 21 · 2023: 21 · 2022: 26 · 2021: 28 · 2020: 37 · 2019: 28 · 2018: 26 · 2017: 42 · 2016: 43 · 2015: 38 · 2014: 43 · 2013: 34 · 2012: 49
FWCI
5.53
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Pharmacology & Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Mental Health (R01MH082876)
  • National Institute on Drug Abuse (K01DA019541)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
circadian rhythm, clock genes, mood disorders, bipolar disorder, major depressive disorder, seasonal affective disorder, total sleep deprivation, bright light therapy, mood stabilizers, antidepressants, neurotransmitter systems, brain regions
MeSH terms
Biological Clocks, Bipolar Disorder, Circadian Rhythm, Major Depressive Disorder, Genes, Humans, Phototherapy, Sleep Deprivation, Gene Expression, Seasonal Affective Disorder, Mood Disorders

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