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Evening Chronotype & Lower Efficacy of SSRI Antidepressants (2024 Study)

Recent research in the Australian Genetics of Depression Study reveals a fascinating connection between an individual’s chronotype and the efficacy of antidepressants.

A study, focusing on selective-serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), suggests that evening chronotypes may experience poorer responses to these medications.


  • Chronotype Impact: Individuals with an evening chronotype reported lower efficacy with certain SSRIs and SNRIs.
  • Comprehensive Study: The study analyzed responses from over 15,000 participants, examining their experiences with 10 common antidepressants.
  • Genetic and Self-Rated Chronotypes: Both genetic and self-rated measures of chronotype were used, offering a multifaceted view of chronotype’s role in antidepressant efficacy.
  • Broader Implications: These findings suggest the need for further exploration of circadian mechanisms in depressive disorders and antidepressant treatments.

Source: Biological Psychiatry (2024)

The Link Between Chronotype & Depression

Chronotype refers to an individual’s inherent preference for activities in the morning or evening, influenced by circadian rhythms.

This internal clock dictates various physiological processes, including sleep-wake cycles, hormone release, and mood fluctuations.

Recent studies indicate a compelling correlation between chronotype and depression.

Predominantly, individuals with an evening chronotype, who are more active and alert during the latter part of the day, are found to be at a higher risk of developing depression.

This association can be attributed to several factors:

  • Social Jetlag: Evening-type individuals often experience a mismatch between their biological clocks and societal expectations, leading to ‘social jetlag’. This misalignment can cause sleep deprivation, disrupt daily routines, and aggravate stress, all of which are risk factors for depression.
  • Exposure to Light: Evening chronotypes tend to have less exposure to morning light, which is crucial for synchronizing circadian rhythms. Reduced exposure can lead to disturbances in mood-regulating mechanisms.
  • Lifestyle Factors: Evening types often engage in behaviors such as late-night eating or screen time, which can negatively impact sleep quality and mood.

The misalignment in circadian rhythm seen in evening chronotypes can exacerbate the symptoms of depression, making it more severe and persistent.

This relationship between chronotype and depression highlights the importance of considering circadian factors in mental health assessments and treatments.

Effect of Chronotype on Antidepressant Efficacy

Chronotype appears to significantly impact the efficacy of antidepressants, especially SSRIs and SNRIs.

This variation can be attributed to several possible mechanisms:

  • Circadian Misalignment: Since SSRIs and SNRIs target neurotransmitter systems that are intricately linked with the circadian system, individuals with a misaligned circadian rhythm (like evening types) may respond differently to these medications. If the core issue in their depression is circadian disruption, SSRIs and SNRIs might not adequately address these underlying circadian issues.
  • Variations in Drug Metabolism: Chronotype may influence the body’s metabolism of drugs. Evening types may metabolize and eliminate antidepressants differently than morning types, affecting drug efficacy and the occurrence of side effects.
  • Impact on Sleep Patterns: SSRIs and SNRIs can influence sleep architecture. Given that evening types are more prone to sleep disturbances, they might be more sensitive to these effects, which could, in turn, impact the overall effectiveness of the treatment.
  • Neurotransmitter Dynamics: Serotonin, a key neurotransmitter targeted by SSRIs and SNRIs, has a complex relationship with the circadian system. The misalignment of circadian rhythms in evening types may alter serotonin pathways, affecting how these individuals respond to serotonergic medications.

Understanding the role of chronotype could lead to more personalized antidepressant therapy.

For instance, evening types might benefit from treatments that directly address circadian misalignments, such as light therapy or medications like agomelatine, which target melatonin receptors and have a more direct effect on the circadian system.

Chronotypes & SSRI Efficacy for Depression (2024 Study)

Crouse et al. investigated the relationship between chronotype and the efficacy of antidepressants.

The study sought to determine whether individuals with a certain chronotype (morningness or eveningness) experienced differing levels of effectiveness when treated with selective-serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).



The study encompassed a large sample size of 15,108 participants, with a majority being female (75%), aged between 18 to 90 years.

Importantly, 68% of participants had at least one other lifetime diagnosis besides depression.

Survey Data

Participants completed a survey assessing their experiences with 10 different antidepressants.

Additionally, the reduced Morningness-Eveningness Questionnaire was used to self-rate their chronotype.

A chronotype polygenic score (PGS) was calculated for each participant, adding a genetic perspective to the self-rated chronotype data.

Statistical Analysis

Age- and sex-adjusted regression models were used to analyze the data.

The study focused on various antidepressant variables such as efficacy, duration of symptom improvement, side effects, and discontinuation due to side effects, in relation to both self-rated and genetic chronotypes.


  • Chronotype-PGS & Variance: The chronotype-PGS accounted for about 4% of the variance in self-rated chronotype.
  • Association with Antidepressant Efficacy: Higher self-rated eveningness was associated with poorer efficacy of certain SSRIs and SNRIs, including escitalopram, fluoxetine, sertraline, and desvenlafaxine. The study also found a significant profile of increased side effects, particularly sleep difficulties, among those with higher eveningness.
  • Genetic Chronotype Associations: The chronotype-PGS was specifically associated with suicidal thoughts and attempts but did not show a direct correlation with antidepressant efficacy.


  • Self-Reported Data: One of the main limitations of the study is the reliance on self-reported data, which can be subject to biases and inaccuracies.
  • Generalizability: The demographic skew towards a predominantly female sample may limit the generalizability of the findings across different genders.
  • Scope of Antidepressants: The study focused on SSRIs and SNRIs, potentially overlooking the impact of chronotype on other classes of antidepressants.
  • Chronotype Measurement: The use of the reduced Morningness-Eveningness Questionnaire and chronotype-PGS for measuring chronotype may not capture the full complexity of an individual’s circadian preferences.
  • Causal Relationships: The study’s design does not allow for the establishment of causal relationships between chronotype and antidepressant efficacy.

Details of the Study Results: Chronotype & Antidepressant Efficacy (2024)

The Australian Genetics of Depression Study’s exploration into the nuanced relationship between chronotype and antidepressant efficacy provides critical insights.

Notably, a higher self-rated eveningness, indicative of an inclination towards later activities and sleep times, showed significant correlations with diminished efficacy of key SSRIs and SNRIs, specifically escitalopram, fluoxetine, sertraline, and desvenlafaxine.

This reduction in effectiveness is profound, as these medications are among the most commonly prescribed for depression.

The connection between evening chronotype and increased side effects is particularly striking.

The study noted an 80% rise in various side effects in individuals with a higher evening chronotype, with sleep difficulties standing out.

This correlation suggests that individuals’ circadian preferences might substantially influence not just the effectiveness of antidepressants but also their tolerability, potentially impacting adherence to medication and overall treatment outcomes.

Further, the chronotype polygenic score (PGS) added a genetic dimension to these findings.

While it accounted for a relatively small percentage (4%) of the variance in self-rated chronotype, it was significantly associated with increased reports of suicidal thoughts and attempts.

This absence of a direct link between the chronotype-PGS and the efficacy of antidepressants is intriguing, suggesting a complex interplay between genetic predispositions, circadian rhythms, and mental health.

The associations maintained statistical significance after adjustments for multiple comparisons using the rigorous Bonferroni correction method.

The odds ratio (OR) for the efficacy of escitalopram was particularly noteworthy at 1.04 (95% CI 1.02-1.06).

This statistic conveys a meaningful impact of chronotype on antidepressant response, indicating that even slight variations in circadian preferences can significantly affect treatment outcomes.

What are the implications of the findings? (Chronotype & Antidepressants)


The clear association between chronotype and antidepressant efficacy suggests that adjusting medication choices and dosing schedules to align with an individual’s circadian rhythm could markedly enhance treatment efficacy and minimize adverse effects.

This personalized approach could revolutionize treatment plans, moving away from the one-size-fits-all model currently prevalent in psychiatric medication management.


The study highlights the potential of chronotherapeutics, an emerging field focusing on the timing of treatment interventions in sync with biological rhythms.

Strategies like light therapy, which can shift and stabilize circadian rhythms, or lifestyle modifications that align daily activities with natural circadian preferences, could be particularly beneficial for evening types.

These approaches, in tandem with pharmacotherapy, could offer a more holistic and effective treatment for depression, especially for those who struggle with traditional medication regimens.

Broader Clinical Evaluation

From a clinical perspective, these results advocate for a more comprehensive assessment in psychiatric evaluations.

Incorporating chronotype assessment into routine evaluations could provide clinicians with crucial information for developing more informed and effective treatment strategies, potentially improving outcomes for patients with depression.

Considering Correlation: Genetics & Lifestyle Factors

Genetic Contributions

The intricate relationship between chronotype and antidepressant efficacy might be partially influenced by genetic factors.

The link between chronotype-PGS and increased suicidal thoughts hints at a complex genetic framework that could modulate how individuals respond to antidepressant treatments.

This finding raises the possibility that genetic predispositions related to circadian rhythms could play a significant role in treatment outcomes.

Lifestyle & Behavioral Factors

Lifestyle behaviors, including caffeine intake, substance use, and physical activity, have known impacts on both chronotype and depression.

These factors could act as confounding variables in the observed relationships, as they may independently influence both the severity of depression and the response to SSRIs.

For instance, higher caffeine intake commonly associated with evening types could exacerbate anxiety symptoms, complicating the effectiveness of antidepressant medications.

Bidirectional Limitations

The bidirectional nature of these relationships adds to the complexity of understanding the interplay between chronotype, lifestyle behaviors, and antidepressant efficacy.

Evening chronotypes might engage more in behaviors like increased caffeine or alcohol consumption to cope with the mismatch between their natural rhythms and societal expectations.

This adaptation can potentially worsen depressive symptoms and reduce the effectiveness of SSRIs, creating a challenging cycle to break.

Modulating Chronotype: Potential Strategies & Impact on Antidepressant Efficacy

Chronotype, a person’s inherent preference for activity and sleep times, significantly influences their daily functioning and mental health.

Modulating chronotype, especially in individuals with a pronounced evening preference, can be beneficial in managing depressive symptoms and enhancing the efficacy of antidepressants.

Various strategies, including lifestyle changes, dietary adjustments, and controlled substance use, can effectively shift one’s chronotype towards a more balanced circadian rhythm.

Lifestyle changes

  • Morning Light: Exposure to natural light in the morning helps reset the internal clock, promoting an earlier chronotype. This can be achieved by spending time outdoors in the morning or using light therapy boxes.
  • Reducing Evening Light: Minimizing exposure to artificial light, especially blue light from screens, in the evening can prevent delays in the sleep-wake cycle.
  • Consistent Sleep Schedule: Establishing a regular sleep-wake schedule, even on weekends, helps regulate the body’s internal clock and encourages a more morning-oriented chronotype.
  • Bedroom Environment: Optimizing the sleep environment to be conducive to rest, such as maintaining a cool, dark, and quiet bedroom, can improve sleep quality, thereby influencing chronotype.

Dietary Adjustments

  • Meal Timing: Eating meals around the same time every day, especially having breakfast shortly after waking, can signal the body to adopt a more morning-aligned chronotype.
  • Caffeine & Alcohol: Limiting caffeine intake to the morning hours and avoiding alcohol close to bedtime can reduce sleep disturbances and help in advancing the sleep phase.
  • Supplements: Melatonin supplements, taken in the evening under medical supervision, can assist in advancing the sleep-wake cycle in evening types.

Exercise & Physical Activity

  • Morning Exercise: Engaging in physical activity in the morning can strengthen the body’s natural circadian rhythms, promoting an earlier sleep onset.
  • Avoiding Evening Workouts: Avoiding high-intensity workouts in the evening can prevent the stimulation that delays sleep onset.

Substance Use & Medication

  • Controlled Caffeine Use: Restricting caffeine consumption to the early part of the day can prevent it from affecting sleep timing and quality.
  • Medication Timing: Consulting with healthcare providers about the timing of medication, including antidepressants, can optimize their effectiveness in line with the individual’s chronotype.

Potential Impact on Antidepressant Efficacy

Improving Sleep Quality: Better alignment of the sleep-wake cycle and improved sleep quality can enhance the overall mood and augment the effectiveness of antidepressants.

Regulating Neurotransmitters: Regularizing the circadian rhythm can stabilize neurotransmitter levels, potentially increasing the responsiveness to antidepressants.

Enhanced Compliance & Reduced Side Effects: A more synchronized circadian rhythm can lead to better medication adherence and reduced side effects, as the body is more in tune with the natural rhythm.

Holistic Improvement: A combined approach of lifestyle changes and appropriate medication can lead to a more holistic improvement in mental health and well-being.

Takeaway: Chronotype & SSRI Antidepressant Efficacy

The Australian Genetics of Depression Study offers valuable insights into the relationship between chronotype and antidepressant efficacy.

It underscores the potential of integrating chronotype assessment into depression treatment, suggesting a step towards more personalized medicine.

However, the findings also caution us to consider the intricate interplay of genetic and lifestyle factors that might influence this relationship.

Lifestyle habits such as caffeine consumption, alcohol use, and physical activity levels could both shape and be shaped by an individual’s chronotype, affecting mental health and medication responses.

This study, therefore, opens a door to a more nuanced understanding of depression treatment but also highlights the complexity and multifactorial nature of mental health disorders.

Ultimately, these findings pave the way for more research to disentangle these interactions and optimize treatment strategies for depression.


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