Antidepressants and Circadian Rhythm: Exploring Their Bidirectional Interaction for the Treatment of Depression

Abstract

Scientific evidence that circadian rhythms affect pharmacokinetics and pharmacodynamics has highlighted the importance of drug dosing-time. Circadian oscillations alter drug absorption, distribution, metabolism, and excretion (ADME) as well as intracellular signaling systems, target molecules (e.g., receptors, transporters, and enzymes), and gene transcription. Although several antidepressant drugs are clinically available, less than 50% of depressed patients respond to first-line pharmacological treatments. Chronotherapeutic approaches to enhance the effectiveness of antidepressants are not completely known. Even so, experimental results found until this day suggest a positive influence of drug dosing-time on the efficacy of depression therapy. On the other hand, antidepressants have also demonstrated to modulate circadian rhythmicity and sleep–wake cycles. This review aims to evidence the potential of chronotherapy to improve the efficacy and/or safety of antidepressants. It includes pre-clinical and clinical studies that demonstrate the relevance of determining the most appropriate time of administration for antidepressant drugs. In parallel, their positive influence on the resynchronization of disrupted circadian rhythms is also herein discussed. It is expected that this review will promote the investigation of chronotherapy for the treatment of depression, contribute to a better understanding of the relationship between antidepressants and circadian rhythms, and consequently promote the development of new therapeutics.

Circadian rhythms as modulators of brain health during development and throughout aging

“…Compared to recovered and normal subjects, rhythms of depressed individuals showed reduced amplitude; however, following recovery their rhythms return to normal amplitude ( Souêtre et al, 1989 ). Many current treatments for mood disorders aid in shifting or stabilizing circadian rhythms of the individual ( Kripke et al, 1978 ; Gottlieb et al, 2021 ; Silva et al, 2021 ). However, it is often difficult to distinguish whether the disruption of the circadian clock is a result of the changes in mood or rather the initiator of the mood disorder ( Silva et al, 2021 ).…”

“…Many current treatments for mood disorders aid in shifting or stabilizing circadian rhythms of the individual ( Kripke et al, 1978 ; Gottlieb et al, 2021 ; Silva et al, 2021 ). However, it is often difficult to distinguish whether the disruption of the circadian clock is a result of the changes in mood or rather the initiator of the mood disorder ( Silva et al, 2021 ). The evidence presented here further supports the circadian system as an active participant in crucial brain functions to regulate mood and behavior via plasticity.…”

Circadian dysregulation and Alzheimer’s disease: A comprehensive review

“…SSRIs and antidepressants have received limited study for their effects on restoring a dysregulated circadian rhythm [216]. Although they are not approved for this purpose, they are often prescribed to younger individuals who suffer from insomnia, under the assumption that 247 they are effective at regulating sleep patterns.…”

“…Although they are not approved for this purpose, they are often prescribed to younger individuals who suffer from insomnia, under the assumption that 247 they are effective at regulating sleep patterns. While many antidepressant drugs are effective for regulating circadian rhythms in depressed individuals, it is likely that this is an indirect consequence of the drugs' treatment effects on serotonergic signaling and other physiological symptoms that underlie depression [158,216]. Therefore, while these drugs may indirectly aid in the circadian rhythm restoration of a depressed individual, whether or not they are helpful for circadian regulation in the rest of the population with irregular sleep-wake cycles remains unclear.…”

Development of Nanocrystal Compressed Minitablets for Chronotherapeutic Drug Delivery

“…A high rush of blood pressure at early hours in the morning was noted to have an association with the development of hemorrhagic stroke and sudden cardiac deaths [ 18 , 19 ]. The increased activity of plasma renin and noradrenaline hormones in the morning hours can cause vasoconstriction in the coronary artery, thus leading to greater risk [ 20 ].…”