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Melatonin Phases & Circadian Rhythms vs. Depression & Anhedonia Severity (2024 Study)

In the intricate world of mental health, the rhythms of our body’s natural processes play a pivotal role, particularly the circadian rhythm of melatonin, a hormone primarily produced by the pineal gland.

Recent research suggests that variations in melatonin’s circadian rhythm might not only distinguish between depression and bipolar disorder but also correlate with the severity of anhedonia in depression, a symptom characterized by a diminished ability to experience pleasure.


  1. Melatonin’s Circadian Rhythm & Mood Disorders: Research indicates significant differences in the melatonin circadian rhythm between individuals with depression, bipolar disorder, and healthy controls, suggesting a potential biomarker for mood disorders.
  2. Anhedonia & Melatonin: The study reveals a negative correlation between the peak phase of melatonin and the severity of anhedonia in individuals with depression, proposing a link between disrupted melatonin rhythms and reduced pleasure capacity.
  3. Differential Diagnosis: Depression vs. Bipolar Disorder: The findings suggest that the timing and amplitude of melatonin secretion could aid in distinguishing between unipolar depression and bipolar disorder, potentially improving diagnosis and treatment strategies.
  4. Therapeutic Implications: Understanding the relationship between melatonin rhythms and mood disorders could lead to novel treatments targeting the circadian system, offering hope for those with treatment-resistant symptoms of anhedonia.

Source: BMC Psychiatry (2024)

Melatonin Phases & Circadian Rhythms vs. Mood Disorders (Overview)

Melatonin, produced by the pineal gland in response to darkness, plays a pivotal role in regulating the body’s circadian rhythms.

These rhythms are internal cycles that govern numerous physiological processes, including the sleep-wake cycle, hormone release, and mood regulation.

What does “melatonin phase” mean?

Melatonin Phase: The “phase” of melatonin secretion refers to the timing of its peak production within the 24-hour circadian cycle. Normally, melatonin levels begin to rise in the late evening, peak during the night, and decrease towards the morning, aligning with the body’s natural sleep cycle.

Advanced Phase: An “advanced phase” of melatonin secretion means that the peak production of melatonin occurs earlier than usual. For example, if an individual’s melatonin levels peak earlier in the evening instead of the middle of the night, this is considered an advanced phase. It can lead to earlier sleep and wake times, potentially disrupting normal sleep patterns and affecting mood.

Delayed Phase: A “delayed phase” of melatonin secretion refers to the peak production of melatonin occurring later than the typical cycle. In this scenario, melatonin levels might not peak until well into the night or early morning hours, leading to difficulties in falling asleep at conventional times and challenges in waking up early.

Impact on Mood Disorders

Sleep Disturbances: Disruptions in melatonin phases can lead to sleep disturbances, a common feature of mood disorders such as depression and bipolar disorder. Poor sleep can exacerbate symptoms of mood disorders, creating a feedback loop that further disrupts circadian rhythms.

Regulation of Neurotransmitters: Melatonin interacts with neurotransmitter systems, including serotonin and dopamine, which are intimately involved in mood regulation. Abnormal melatonin secretion can thus directly affect mood and contribute to the development or worsening of mood disorders.

Biological Clock Misalignment: Mood disorders are often characterized by a misalignment between the internal biological clock and the external environment. This misalignment, influenced by abnormal melatonin phases, can lead to irregularities in daily routines and social rhythms, further impacting mood and social functioning.

Major Findings: Circadian Rhythms & Melatonin in Mood Disorders (2024)

Li et al. studied circadian rhythms of melatonin among individuals with depression, bipolar disorder, and healthy controls – below were the major findings.

1. Melatonin & Circadian Rhythms in Depression

Phase Advancement in Depression: The peak phase of melatonin secretion was significantly advanced in the depression group compared to both the bipolar disorder group and healthy controls. This phase advancement indicates a potential dysregulation in the internal biological clock of individuals with depression, potentially contributing to sleep disturbances commonly observed in this group.

Comparison with Bipolar Disorder: The distinction between the melatonin peak phase in depression and bipolar disorder patients underscores the heterogeneity in circadian rhythm disruptions across mood disorders. Such differences could reflect distinct underlying pathophysiological mechanisms and might be critical in tailoring chronotherapeutic interventions.

2. Correlation Between Melatonin Rhythm & Anhedonia

A significant negative correlation was observed between the peak phase of melatonin and the severity of anhedonia in depression patients.

This finding suggests that individuals with a more advanced melatonin peak phase experience higher levels of anhedonia, pointing to a potential link between circadian rhythm disturbances and the capacity to experience pleasure.

The relationship between an advanced melatonin peak and increased anhedonia severity may reflect broader disruptions in the reward system and its regulation by the circadian system.

This insight opens new avenues for investigating the neurobiological underpinnings of anhedonia in mood disorders.

3. Differentiation Between Mood Disorders

The advanced peak phase of melatonin in depression, as opposed to its pattern in bipolar disorder and healthy individuals, highlights the potential of melatonin circadian rhythm profiles as biomarkers for differentiating between mood disorders.

This differentiation is crucial, given the clinical challenge of distinguishing between depression and bipolar disorder in the early stages of these conditions.

Melatonin Levels & Circadian Rhythms in Mood Disorders vs. Healthy Adults (2024 Study)

The primary aim of the study was to investigate the differences in melatonin concentrations and circadian rhythm profiles between individuals with depression, bipolar disorder, and healthy controls.

Additionally, the study sought to explore the relationship between anhedonia—a common symptom of affective disorders—and melatonin circadian rhythms.


  • Participants: The study included 34 patients with depression disorder (DP), 20 patients diagnosed with bipolar disorder (BD), and 21 healthy controls (HC).
  • Assessment of Anhedonia: Anhedonia was evaluated using the Revised Physical Anhedonia Scale (RPAS).
  • Saliva Sampling: Saliva samples were collected from all subjects at 14 fixed time points over two consecutive days to measure melatonin concentrations and determine circadian rhythms.
  • Statistical Analysis: The comparison of melatonin circadian rhythms among the three groups utilized ANOVA. Partial correlation analysis and linear regression analysis were employed to examine the correlation between melatonin rhythm variables and anhedonia.


  • Melatonin Circadian Rhythm Variations: The peak phase of melatonin was significantly advanced in the depression group compared to both the control group and the bipolar disorder group.
  • Correlation with Anhedonia: A negative correlation was observed between the peak phase of melatonin and RPAS scores in depression patients, indicating that an advanced melatonin peak phase is associated with more severe anhedonia.
  • Differentiation Between Mood Disorders: These results suggest distinct circadian rhythm profiles of melatonin in depression and bipolar disorder, which could aid in differentiating between these conditions.


  • Medication Use: The study could not entirely control for the potential effects of psychiatric medications on melatonin levels and circadian rhythms, as participants might have been undergoing various treatments.
  • Sample Size: The relatively small sample sizes, especially for the bipolar disorder group, may limit the generalizability of the findings.
  • Objective Light Exposure Data: Lack of objective data on participants’ light exposure prior to and during the study period might have influenced the melatonin profiles.
  • Cross-Sectional Design: The cross-sectional nature of the study precludes drawing causal inferences between melatonin circadian rhythm disturbances and mood disorder symptoms.

Modifying Circadian Rhythms to Treat Mood Disorders?

The findings from the study on melatonin circadian rhythms in individuals with depression, bipolar disorder, and healthy controls may be useful for the development of therapeutic interventions aimed at modifying circadian rhythms to improve mood.

1. Chronotherapy in Depression Treatment

  • Light Therapy: Given the advanced peak phase of melatonin in depression, light therapy, particularly morning light exposure, could be utilized to delay the melatonin onset, thereby potentially correcting the advanced phase shift and improving mood and sleep quality.
  • Sleep Phase Manipulation: Gradually delaying bedtime and wake-up times can help adjust the internal clock to a more typical rhythm, which might be particularly beneficial for patients with advanced melatonin phases.

2. Melatonin Supplementation

  • Tailored Melatonin Administration: For individuals with mood disorders characterized by disrupted melatonin rhythms, carefully timed melatonin supplementation could help realign their circadian cycles with the natural environment, potentially easing symptoms of depression and improving sleep patterns.

3. Strategic Caffeine and/or Stimulants

  • Optimized Caffeine Timing: Advising individuals with mood disorders on the optimal timing for caffeine consumption can significantly impact their circadian rhythms. For those with a delayed phase, morning caffeine intake can help promote earlier wakefulness, indirectly encouraging earlier sleep times and potentially aligning their circadian rhythm more closely with societal norms.
  • Selective Use of Stimulants: In cases where stimulant medication is necessary (e.g., for ADHD or narcolepsy), careful consideration of dosing times can mitigate potential disruptions to circadian rhythms. Early day administration is typically recommended to avoid interference with nighttime sleep.
  • Monitoring Stimulant Effects: Regular review and monitoring of the effects of stimulants on sleep and wakefulness can help in making necessary adjustments to dosage and timing, ensuring that these medications support, rather than hinder, circadian rhythm stabilization.
  • Caffeine as a Chronobiotic Agent: While caffeine is primarily known for its wake-promoting effects, when used judiciously, it can serve as a tool to shift and stabilize circadian rhythms, particularly for individuals experiencing jet lag or shift work disorder.

4. Lifestyle Adjustments for Circadian Rhythm Stabilization

  • Regular Sleep Schedules: Encouraging patients to maintain consistent sleep and wake times can help stabilize circadian rhythms, which may be beneficial in mood regulation.
  • Controlled Light Exposure: Advising patients to increase exposure to natural daylight during the day and reduce exposure to artificial light, especially blue light from screens, in the evening can help correct circadian misalignments.

5. Cognitive Behavioral Therapy for Insomnia (CBT-I)

  • CBT-I & Circadian Rhythms: This therapy, which addresses thoughts and behaviors that affect sleep, can also be adapted to include components focusing on strengthening circadian rhythms, such as establishing a regular bedtime routine and limiting activities that disrupt the sleep-wake cycle.

6. Pharmacotherapy Adjustments

  • Chronopharmacology: The timing of medication administration could be optimized based on individual circadian rhythms to enhance the therapeutic effects and reduce side effects. For instance, medications that have sedative effects might be timed to coincide with the natural onset of the body’s nighttime physiology.

7. Circadian Rhythm Markers in Diagnostics & Treatment

  • Biomarker Utilization: Identifying specific circadian rhythm disruptions through markers like melatonin secretion patterns could aid in the diagnosis of specific mood disorders and the customization of treatment plans to address these disruptions.

8. Wearable Technology for Monitoring

  • Circadian Rhythm Tracking: Wearable devices that monitor sleep, activity levels, and possibly even predict melatonin secretion patterns could be used to provide real-time feedback and interventions tailored to correct circadian misalignments.

What Causes Melatonin Phase Abnormalities?

Melatonin phase abnormalities, including advanced and delayed phases of melatonin secretion, can significantly impact sleep patterns and overall well-being.

Understanding the causes of these abnormalities is crucial for developing effective interventions.

1. Disrupted Circadian Rhythms

  • Internal Clock Misalignment: The body’s internal clock, regulated by the suprachiasmatic nucleus (SCN) in the brain, can become misaligned with external environmental cues, leading to abnormalities in melatonin secretion. This misalignment can result from irregular sleep schedules, jet lag, or shift work.
  • Light Exposure: Light is a crucial regulator of the circadian rhythm. Inadequate exposure to natural daylight or excessive exposure to artificial light, especially in the evening, can shift the timing of melatonin secretion, causing phase abnormalities.

2. Genetic Factors

  • Circadian Gene Variations: Genetic predispositions play a role in circadian rhythm regulation. Variations in genes associated with the circadian clock can lead to intrinsic differences in the timing of melatonin secretion, predisposing individuals to phase abnormalities.

3. Neurotransmitter Dysregulation

  • Serotonin Pathways: Since melatonin is synthesized from serotonin, dysregulation in serotonin pathways can directly affect melatonin production and its timing. Mood disorders, which involve alterations in serotonin levels, can thus influence melatonin phase.
  • Dopamine and Other Neurotransmitters: Interactions between melatonin and neurotransmitters like dopamine, which are involved in regulating sleep and mood, can also contribute to phase abnormalities.

4. Hormonal Imbalances

  • HPA Axis Dysregulation: The hypothalamic-pituitary-adrenal (HPA) axis influences circadian rhythms through cortisol secretion. Dysregulation of the HPA axis, common in stress-related disorders, can indirectly affect melatonin secretion patterns.

5. Lifestyle & Behavioral Factors

  • Irregular Sleep Patterns: Inconsistent sleep and wake times can disrupt the body’s natural circadian rhythm, leading to abnormalities in melatonin secretion.
  • Diet and Exercise: Diet and exercise habits can influence circadian rhythms and melatonin secretion indirectly. For instance, caffeine and alcohol consumption close to bedtime can delay melatonin production.

6. Medication & Substance Use

  • Pharmacological Agents: Certain medications, especially those affecting neurotransmitter systems, can influence melatonin secretion. For example, some antidepressants, beta-blockers, and benzodiazepines have been found to affect melatonin timing.
  • Substance Use: Alcohol and caffeine can alter the sleep-wake cycle and melatonin secretion. Nicotine and illicit drugs may also disrupt circadian rhythms.

7. Environmental Factors

  • Seasonal Changes: Seasonal variations in daylight exposure can lead to seasonal changes in melatonin phase, with potential implications for mood and energy levels.
  • Shift Work & Jet Lag: Exposure to light at unnatural times due to shift work or crossing time zones can cause significant shifts in melatonin secretion patterns.

How Abnormal Melatonin Phases May Exacerbate or Cause Depression

Abnormal melatonin phases, characterized by disruptions in the timing of melatonin secretion, can play a significant role in the development and exacerbation of depressive symptoms.

The intricate relationship between melatonin, a key regulator of the circadian rhythm, and mood regulation provides insight into how disturbances in melatonin phases can impact mental health.

Disruption of Sleep-Wake Cycle

  • Impact on Sleep Quality: Abnormal melatonin phases can lead to difficulties in initiating sleep, maintaining sleep, or experiencing premature awakening. Since restorative sleep is crucial for emotional regulation and cognitive function, disruptions can exacerbate or trigger depressive symptoms.
  • Circadian Misalignment: When melatonin secretion occurs out of sync with the natural environment, it results in a misalignment of the internal circadian clock. This misalignment can lead to a mismatch between an individual’s biological night and the external night, further disrupting sleep patterns and worsening mood.

Alteration of Biological Processes

  • Neurotransmitter Imbalance: Melatonin has regulatory effects on neurotransmitters like serotonin and dopamine, which are directly involved in mood regulation. Abnormal melatonin secretion can therefore disrupt these neurotransmitter systems, potentially leading to depressive symptoms.
  • Stress Response: Abnormal melatonin phases can affect the regulation of the hypothalamic-pituitary-adrenal (HPA) axis, exacerbating the body’s stress response. Chronic stress and elevated cortisol levels are known risk factors for depression.

Psychological and Behavioral Effects

  • Social Rhythm Disruption: Abnormal melatonin phases can disrupt an individual’s social rhythms, including work, social activities, and regular routines. These disruptions can lead to social isolation, a significant risk factor for depression.
  • Reduced Daylight Exposure: Individuals with delayed melatonin phases may experience reduced exposure to natural daylight, especially in the morning. Since daylight exposure has antidepressant effects and is crucial for regulating the circadian rhythm, reduced exposure can contribute to depressive symptoms.

Seasonal Affective Disorder (SAD)

  • Seasonal Variations: Individuals with a predisposition to depression may find their symptoms worsen with seasonal changes, particularly in winter, when daylight hours are shorter. Abnormal melatonin phases, particularly delayed phases, can contribute to the development of Seasonal Affective Disorder (SAD), a type of depression related to changes in seasons.

Potential for a Vicious Cycle

  • Feedback Loop: Depression can lead to changes in sleep patterns and behaviors that further disrupt melatonin secretion, such as irregular sleep schedules and increased indoor activity. This disruption can exacerbate abnormal melatonin phases, creating a feedback loop that perpetuates depressive symptoms.

Conclusion: Melatonin & Circadian Rhythm Abnormalities in Depression

The study’s findings underscore the significant role of melatonin circadian rhythm abnormalities in distinguishing between depression and bipolar disorder, revealing a complex interplay between melatonin secretion patterns and mood disorders.

Specifically, the advanced melatonin phase observed in individuals with depression, compared to those with bipolar disorder and healthy controls, highlights the potential of using melatonin rhythms as biomarkers for more accurate diagnosis and treatment differentiation.

Furthermore, the correlation between an advanced melatonin phase and the severity of anhedonia in depression patients sheds light on the intricate relationship between circadian rhythm disturbances and specific depressive symptoms.

These insights not only enhance our understanding of the pathophysiological mechanisms underlying mood disorders but also open up new avenues for targeted interventions that aim to normalize circadian rhythms.

Addressing melatonin phase abnormalities through chronotherapeutic strategies, lifestyle adjustments, and possibly pharmacological interventions could offer a promising approach to improving outcomes for individuals with mood disorders.

In sum, this study contributes to the growing body of evidence supporting the critical role of circadian biology in mental health, encouraging further research in this domain to develop more effective, personalized treatment modalities.


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