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.

Keywords: antidepressant; chrono-pharmacodynamics; chronopharmacokinetics; chronotoxicology; circadian rhythm; clinical studies; depression.

Figure 1

Physiological processes regulated by circadian rhythms with strong effect on the pharmacokinetics of antidepressants. BBB, blood–brain barrier.

Figure 2

Summary of the mechanism of action of SSRIs, SNRIs, TCAs, and MAOIs at noradrenergic (left) and serotonergic (right) neurons. The influence of circadian rhythms on antidepressant targets is also depicted. SSRIs, SNRIs, and TCAs increase 5-HT neurotransmission through the direct blockade of SERT at presynaptic terminals. NET is inhibited by SNRIs and TCAs in noradrenergic neurons. MAOIs inhibit MAO enzymes present in mitochondria, responsible for breaking down neurotransmitters, such as 5-HT and NE. These processes increase the levels of 5-HT and NE in the synaptic cleft, leading to an antidepressant effect [26]. Circadian rhythms are known to affect the expression or activity of NET and SERT [104,105,106], 5-HT_1A receptor [106], adrenergic receptors [107], and MAO [108]. 5-HT_X, 5-HT receptor subtypes; α- and β-AR, adrenergic receptors; MAO, monoamine oxidase; MAOI, MAO inhibitors; NET, NE transporter; SERT, 5-HT transporter; SNRI, SERT, and NET inhibitor; SSRI, SERT inhibitor; TCA, tricyclic antidepressant.

Figure 3

Proposed drug dosing-time of antidepressants according to chronopharmacological studies in rodents. This placement was based on studies performed in mice or rats when higher antidepressant effect was observed during forced swimming [36,104,105] or tail suspension [134] tests. ZT0 represents lights on and ZT12 indicates lights off.

Figure 4

Drug dosing-time of antidepressant drugs according to chronopharmacodynamic studies in humans. This figure includes an optimal time for administration based on lower side effects for amitriptyline [37] and higher antidepressant effects for clomipramine [140] and lofepramine [141].