Antidepressants and Circadian Rhythm: History
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Subjects: Neurosciences
Contributor:
Tânia Soraia Vieira da Silva

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. There is 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. 

  • antidepressant
  • circadian rhythm
  • chronopharmacokinetics
  • chrono-pharmacodynamics

1. Introduction

All organisms display biological processes with rhythmic oscillations of 24 h periodicity defined as circadian rhythms. Among them is the sleep–wake cycle associated with the sleep hormone melatonin, which has a 24 h-variation [1]. In a process regulated by noradrenergic and neuropeptidergic signaling, the pineal gland converts serotonin (5-hydroxytryptamine; 5-HT) to melatonin, which is then released into the systemic circulation [2]. Melatonin secretion is enhanced by darkness and inhibited by light, achieving plasma peak levels between 2h00 and 4h00 in the morning [2]. Other biological processes are repeated throughout the 24 h (i.e., ultradian rhythms) such as blood circulation, respiration, heart rate, and thermoregulation [3]. If repeated for periods longer than 24 h, rhythms are known as infradian, such as the menstrual cycle or seasonal rhythms [4].
At a molecular level, circadian rhythms are controlled by positive and negative feedback loops that dictate the transcription and translation of clock-genes [5]. The transcription factors, brain and muscle ARNT-like 1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK), dimerize and bind to E-box or E-box-like elements of the promotor region of clock-genes, inducing the transcription of rhythmic clock genes Period 1 and 2 (PER1 and PER2) and cryptochrome (CRY) [6]. In the nucleus, the corresponding expressed proteins PER and CRY inhibit BMAL1:CLOCK heterodimerization in a negative feedback loop. The PER and CRY display peak levels at the end of the day and decrease during the night, in opposition to BMAL1:CLOCK activity [6]. Simultaneously, a secondary mechanism mediated by retinoid-related orphan receptors (RORs) and reverse erythroblastosis virus α (REV-ERBα) induce and inhibit BMAL1 transcription, respectively [5][7].
In mammals, the central clock is found in the suprachiasmatic nucleus (SCN) located in the medio-frontal hypothalamus. The SCN is responsible for maintaining all body cells synchronized by directly or indirectly adjusting peripheral clocks through the synthesis of hormones, such as melatonin or cortisol [5][8]. For instance, neuronal and hormonal clock outputs regulate cell growth, renal filtration, cognition, nutrient metabolism, and immune function [9]. Sunlight, temperature, or food intake are known time-givers (zeitgebers in German), i.e., external factors that modulate circadian rhythms [10]. Light signals are received by visual photoreceptors and retinal photosensitive ganglion cells, and the nerve impulse is then transmitted to the SCN by demyelinated axons via retinohypothalamic tract [5].
A deficient stimulation of post-synaptic neurons by norepinephrine (NE) and 5-HT is one of the principal factors underlying the physiopathology of depression [11]. The mechanism of action of most antidepressant drugs relies on slowing the reuptake and thus raising the concentration of those neurotransmitters in the synaptic cleft, increasing neurotransmission and the relief of depressive symptoms [12]. The classification of antidepressant drugs is associated with their respective mechanism of action: selective 5-HT reuptake inhibitors (SSRIs), 5-HT and NE reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and atypical antidepressants [13]. New classifications have been proposed by regional and international organizations, including European, Asian, American, and International Colleges of Neuropsychopharmacology and International Union of Basic and Clinical Pharmacology. These classifications rely on a pharmacologically-driven nomenclature focusing on approved indications, efficacy, side effects, and neurobiology, but until today, none have been unanimously accepted [14][15]. Antidepressants are usually applied in chronic treatments for long periods of time, despite revealing several side effects. In particular, TCAs exhibit poor tolerability and adverse effects, such as dry mouth, tremors, blurred vision, body weight gain, memory disorders, postural hypotension, and gastrointestinal disturbances and sedation, which ultimately undermine adherence to treatment [16][17]. Since depression is usually worse in the morning, antidepressants can be administered in this period, although their side effects may shift dosing to bedtime [18]. Even so, less than 50% of depressed patients achieve remission following several pharmacological interventions.
Based on the aforementioned bidirectional interactions between circadian rhythms and depression, interest in chronotherapy with antidepressants has increased exponentially [19]. Pharmacokinetic processes, specifically, absorption, distribution, metabolism, and excretion (ADME), present time-dependent oscillations that can lead to different concentrations in the plasma and tissues and, therefore, distinct therapeutic effects [20]. Complementarily, pharmacodynamic studies describe the association between drug concentrations and their effects [21]. The role of clock genes on antidepressant targets seem to influence antidepressant efficacy and side effects during the day [22][23].
Chronopharmacokinetics, chrono-pharmacodynamics, and chronotoxicology are hence defined by differences in pharmacokinetics and pharmacodynamics due to biological rhythms in ADME or in therapeutic and toxic effects, respectively [24][25]. Variations with clinical impact must be considered to adjust the dosing-time of an antidepressant, in order to improve its benefits [26].

2. Pharmacokinetics of Antidepressants

2.1. Circadian Rhythm Effect on Pharmacokinetic Stages

2.1.1. Absorption

Chronopharmacological studies with antidepressants are often performed in vivo. Light is a strong zeitgeber in rodents, which display an active phase during the night. For this reason, studies are usually performed under a 12h00 light–12h00 dark cycle, during which drugs are administered at different zeitgeber times (ZT). The ZT0 corresponds to the moment that lights are turned on and ZT12 when lights are turned off [27]. In contrast, chronotherapy in humans needs to consider zeitgeber factors other than light, namely mealtime, oxygen levels, temperature, and exercise [27]. Pharmacokinetic alterations at different drug dosing times are associated with intrinsic circadian rhythms in several tissues that are also involved in physiological ADME (Figure 1).

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Figure 1. Physiological processes regulated by circadian rhythms with strong effect on the pharmacokinetics of antidepressants. BBB, blood–brain barrier.

Since antidepressants are orally administered, their bioavailability depends not only on their physicochemical properties, such as lipophilicity, but also on physiological processes of the digestive system modulated by circadian rhythms that may be disrupted in depressed patients [28].

Although the mechanism of action of trimipramine is not fully characterized, it is known to be a TCA that differs from others, particularly because it does not directly inhibit reuptake transporters, namely the 5-HT transporter (SERT) or NE reuptake transporter (NET) [29]. Chronopharmacokinetic studies in humans treated with two oral formulations of the trimipramine (solution and tablet) showed that tablets seem to be less affected by dosing-time (Table 1) [30]. Importantly, drug absorption remains faster after solution administration than tablets administration. Solutions demonstrated significantly higher maximum concentration (Cmax), lower time to reach Cmax (tmax), and lower mean residence time (MRT) in the morning (under fasting conditions) than at night (after a meal).

Table 1. Chronopharmacokinetic parameters of antidepressants in human studies.
Antidepressant or Active Metabolite Subjects Study Design Daily Dose (mg) Duration (Days) Formulation Time of Administration Plasma Pharmacokinetic Parameters Ref.
tmax (h) Cmax (mg/L) AUC (mg.h/L) t1/2β
(h)		 kel
(h−1)		 ka (h−1) MRT (h)
Amitriptyline 10 healthy subjects (♂), 22–31 years old. Crossover 50 21 Injectable solution 9h00 3.2 * 96.1 1270 15.7 - 0.36 * - [23]
21h00 4.4 * 72.8 1224 17.2 - 0.25 * -
Nortriptyline 10 healthy subjects (♂), 22–30 years old. Crossover 100 14 Oral formulation: 25 mg capsules 9h00 6.2 32 730 15.0 - - - [31]
21h00 8.8 31 730 16.0 - - -
Trimipramine 12 healthy subjects (6 ♀, 6 ♂), 22–37 years old. Crossover 100 15 Oral formulation: 100 mg tablet 8h00 2.5 37.8 362 10.9 - - 10.8 [30]
20h00 2.8 39.2 376 9.9 - - 11.5
Oral formulation: solution 8h00 1.5 * 48.2 * 372 9.9 - - 9.8 *
20h00 2.5 * 28.8 * 322 11.1 - - 11.8 *
Sertraline 10 healthy subjects (♂), 18–45 years old. Crossover 100 1 Oral formulation: 100 mg tablet Morning 7.0 24.5 0.664 20.0 0.0347 - - [32]
Evening 7.3 24.4 0.705 20.8 0.0333 - -
Note: Only average values are presented for pharmacokinetic parameters, and some were converted to uniform units. Abbreviations: AUC, area under the curve; Cmax, maximum concentration; ka, constant absorption rate; kel, constant elimination rate; MRT, mean residence time; t1/2β, elimination half-life time; tmax, time to reach the maximum concentration. * Statistically significant values (* p < 0.05).

Intestinal permeability shows daily rhythms due to variations of expression of tight junction proteins that regulate the epithelial paracellular pathway [33]. In the small intestine, mRNA levels of occludin and claudin-3 were higher during the late dark phase than the late light phase and inversely associated with paracellular permeability data [34].

From another point of view, it is important to bear in mind that several antidepressant drugs are known as substrates of efflux transmembrane ATP-binding cassette (ABC) proteins, including P-glycoprotein (P-gp; ABCB1; MDR1) [35][36][37][38][39] and Breast Cancer Resistant Protein (BCRP; ABCG2) [40]. These transporters are expressed in several tissues, namely the intestine, kidney, liver, and blood–brain barrier (BBB). They reduce the bioavailability, facilitate the elimination, and hamper the access of compounds to the brain, including antidepressant drugs [41]. The expression of P-gp in the intestine is modulated by proline- and acid-rich basic leucine zipper (PAR bZIP) proteins, particularly hepatic leukemia factor (HLF), whose expression is regulated by core oscillator components [42]. The HLF and E4 promoter binding protein-4 (E4BP4), a putative antagonist of PAR bZIP proteins, respectively, increase and decrease the mRNA levels and expression of P-gp [43]. In the mouse intestine, Mdr1a mRNA levels exhibit a significant 24 h daily variation, increasing during the light phase with a peak at ZT12, when the lights go off [43][44]. Similarly, in the rat jejunum, P-gp mRNA varies 5.4-fold with the circadian time [45]. Consistent with the daily rhythmicity observed in total protein with a peak level at ZT8, the P-gp function in the intestine is significantly higher at ZT12 than ZT0 [44]. Additionally, feeding patterns and gender also influence the expression and activities of the ABC transporters during the day, since circadian amplitudes of mRNA and protein levels of P-gp in the ileum are larger in female mice than in male mice [46].

2.1.2. Distribution

The cardiovascular system is susceptible to circadian rhythmicity since blood pressure, heart rate, and plasma protein levels display daily oscillations [47][48]. The blood pressure of mammals has a 24 h cycle, with a peak during their active phase and a 10–20% slope at rest phase, along with a 17% daily fluctuation of total plasma proteins [49][50]. Particularly for antidepressant drugs that are highly protein-bound, distribution is strongly affected by the presence of plasma proteins, mainly albumin and α1-acid glycoprotein [51][52]. A study performed in rats demonstrated that plasma protein levels are higher in the active phase [50]. Furthermore, in healthy humans, α1-acid glycoprotein plasma levels are also increased during the active phase [53]. Hence, these protein fluctuations may be important to adjust the dosing-time of highly protein-bound antidepressants since differences of unbound fraction and tissue exposure can affect drug efficacy and toxicity [54]. A single intragastric administration of amitriptyline in rats (64 mg/kg) at six different time-points revealed highest bioavailability at the end of the active phase (ZT22) [54]. In fact, the total drug exposure was higher in the beginning of the rest phase, even though the ka after intragastric administration was unaltered during the light–dark cycle [54]. Exposure in liver and lung, given by area under the concentration–time curve (AUC), showed a 24 h oscillation (peak at ZT4). Moreover, multi-dosing for 10 days demonstrated significantly higher AUC values in liver, lung, and kidney tissues in the light than in the dark phase [54]. These results may be linked to the reduction of plasma protein levels during the light phase, since amitriptyline is a highly protein-bound drug (95%) [55].

The therapeutic targets of antidepressant drugs are located in the central nervous system (CNS), whose access is limited by blood-CNS barriers, including the BBB and the blood-cerebrospinal fluid (CSF) barrier. Circadian rhythms have an important role in BBB homeostasis and integrity, since the deletion of the clock component BMAL1 leads to BBB hyperpermeability [56]. Additionally, a strong circadian gene expression of Per2 in the choroid plexus is responsible for the adjustment of the SCN clock and brain homeostasis through the CSF [57].

One of the main causes behind antidepressant inefficacy is the overexpression of P-gp and BCRP by the endothelial cells of BBB of depressed patients [41] and the efflux of xenobiotics across the BBB of mammals is known to be regulated by circadian rhythms [58]. Nonetheless, there is not much data concerning diurnal variations in the transcript and protein levels of efflux transporters in the brain and the studies performed until today are conflicting. Pulido et al. observed an inverse association between P-gp activity and the active phase of wild-type mice [59]. The authors reported a diurnal oscillation of P-gp transcription (peak at ZT12) in the brain, which increased during the light phase and decreased during the dark phase. It was modulated by PAR bZip transcription factors, specifically albumin D box-binding protein (DBP), thyrotroph embryonic factor (TEF), and HLF [59]. Accordingly, the accumulation of a P-gp substrate (rhodamine-123) in the brain was higher in the beginning of the light phase [59]. In opposition, Zhang et al. did not find circadian alterations of mRNA or protein levels of P-gp in the BBB of mice or humans [58]. However, its activity was modulated by clock genes. In mice, higher efflux activity was observed during the active phase, but transcription levels and protein expression were unaffected. The magnesium transporter transient receptor potential cation channel, subfamily M, member 7 (TRPM7) contributed to efflux rhythms in human cultured brain endothelial cells [58]. The BMAL1 modulates transcript and protein expression of TRPM7 during active periods, which enhances intracellular magnesium levels and promotes efflux activity. It was observed that BBB permeability in Drosophila is regulated by 24 h cyclically expressed gap junctions [60].

Transcript levels of BCRP in the BBB display circadian oscillations with peak levels at ZT14, independent of BMAL1 [58]. To the best of our knowledge, data on daily oscillations of the BCRP protein and function on the BBB remain scarce. Additional studies would assist our current understanding of the impact of circadian rhythms on the xenobiotic efflux in the BBB.

2.1.3. Metabolism and Excretion

Liver enzyme activity and hepatic blood flow are two time-dependent processes that drive hepatic drug metabolism [61]. Lipophilic drugs, such as antidepressants, are metabolized in the liver into more hydrophilic polar metabolites in three phases [62]. Phase I functionalization reactions are mostly performed by the cytochrome P450 (CYP) enzyme superfamily, specifically the isoforms CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 [62]. After phase II conjugation reactions, metabolites may be excreted into the bile or transported into the systemic circulation by efflux transporters (phase III). The PAR bZip and an atypical nuclear receptor expressed abundantly in the liver, named as small heterodimer partner (SHP), play a pivotal role in CYP activity 24 h oscillations in mice, controlling daily variations of detoxification and drug metabolism [42][63]. In addition, in mice, Zhang et al. described that the mRNA levels of phase I enzymes increase in the dark phase, while phase II enzymes rise in the light phase [64]. Analyzing serum-shocked cells of a human hepatocellular carcinoma cell line (HepG2), a 24 h oscillation in the expression of CYP3A4 and CYP2D6 was revealed [65][66]. Transcript levels seem to be considerably more affected than protein levels when circadian rhythms are disrupted. The rhythmicity of liver proteins can be explained by rhythmic mRNAs, and translational and post-translational regulation and feeding behavior [67].

Metabolic oscillations appear to have a weaker role in the chronopharmacokinetics of antidepressants. For instance, the elimination half-life time (t1/2β) of sertraline did not change after administration to humans in the morning or evening [30].

The excretion of antidepressants and their metabolites is predominantly renal and involves three processes: glomerular filtration, active tubular secretion, and tubular reabsorption [68]. In a mouse kidney, P-gp mRNA and protein expression do not appear to present 24 h oscillations [44]. Nevertheless, daily variations of blood flow may explain clearance oscillations observed in the excretion of some drugs [69][70]. Single and daily administrations of amitriptyline for 10 days in rats showed significantly higher concentrations at ZT4 in the liver and kidney, compared to administrations at ZT16 [54]. This lower drug exposure was associated with clearance oscillations, since the highest clearance values were obtained between ZT13 and ZT16.
Glomerular filtration rates in rodents are higher during the dark phase, leading to higher urine volume [71]. Therefore, if drug administration is performed in the active phase when clearance is the highest, nephrotoxicity can be reduced [72].

3. Pharmacodynamics of Antidepressants

3.1. Circadian Rhythm Effect on Antidepressant Drug Targets

Different results of chronopharmacodynamic studies with antidepressants can be related with fluctuations of the pharmacokinetic parameters or daily variations of the expression of antidepressant drug targets affected by circadian rhythms (Figure 2). Distinct mechanisms of action of antidepressant drugs may lead to different chronopharmacological profiles, and dosing-time can influence both therapeutic and toxic effects.

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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 [12]. Circadian rhythms are known to affect the expression or activity of NET and SERT [73][74][75], 5-HT1A receptor [75], adrenergic receptors [76], and MAO [77]. 5-HTX, 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.
The monoaminergic hypothesis, established in 1965, postulates that depression is linked with noradrenergic and serotoninergic dysfunction in the CNS [78]. Hence, the development of antidepressants aimed towards the direct inhibition of SERT occurs, a member of the Na+/Cl−-dependent transporter family, or the blockade of both SERT and NET. The first is mediated by SSRIs, SNRIs, and TCAs and the second by SNRIs and TCAs. Notwithstanding, antidepressants exhibit different inhibitory potencies on reuptake transporters. The fact that inhibition is not equal among all drugs that prevent SERT and NET activity leads to different pharmacodynamic results in the same antidepressant classes [79].
Serotonergic and noradrenergic systems from the prefrontal cortex and hippocampus are very important to reduce depressive symptoms. Both systems have a 30% amplitude of mean content levels in the rat brain during a light–dark cycle [73]. The SERT transcription levels and activity revealed significant time-dependent changes in the mouse mid-brain, with higher levels during the active phase [74]. The 5-HT peak levels in the synaptic cleft occur at the end of the dark phase and are higher throughout the light phase than the dark phase. In the rat hippocampus, 5-HT turnover shows a peak during the ZT18–ZT22 and a trough at ZT10-14, while the NE turnover peaks between ZT22 and ZT2. Base levels were detected at ZT14-ZT18 [73]. Discrepancies of peak activity times in serotonergic and noradrenergic systems may be responsible for differences in the chronopharmacological profiles of antidepressants. In humans, positron emission tomography was applied to examine changes of the 5-HT1A receptor and SERT in the brain of 40–56 healthy volunteers [75]. This study showed an increase and decrease of the 5-HT1A receptor and SERT, respectively, in the midbrain during the day [75]. The increase of the 5-HT1A receptor is directly correlated with the duration of daylight, leading to seasonal differences [75]. Indeed, potential binding values to SERT in the brain were significantly higher in the fall and winter, compared to the spring and summer, revealing a negative correlation with the daily amount of sunshine [80].
The TCAs are potent inhibitors of 5-HT and NE reuptake by binding to sodium-dependent transporters. They also block histamine H1 receptors, α1-adrenergic receptors, and muscarinic receptors causing sedative, hypotensive, and anticholinergic effects (e.g., blurred vision, dry mouth, constipation, urinary retention), respectively [81]. These receptors have been described to be modulated by circadian rhythm in rodents with higher expression during the day [76][82].
Overall, several antidepressant targets are known to be regulated by circadian rhythms, which may have important implications regarding their efficacy at different dosing times. Nevertheless, much is yet unknown about this relationship. Further research in this field would benefit the design of future therapeutic approaches and improve the efficacy of currently available options.

3.1.1. Animal Studies

Before chronopharmacological studies, it is important to ensure the entrainment of circadian rhythms in healthy mice to a standard light/dark cycle. Phenotyping circadian rhythms in mice requires measurements of their activity in free running conditions [83], quantifying circadian clock or clock-related genes [84], or monitoring sleep behavior [85].

The most common behavioral tests in rodents to evaluate antidepressant effects are the forced swimming test (FST) and the tail suspension test (TST). Both present high predictive reliability and validity but different sensitivity [86][87].

Specifically, NET inhibition increases climbing, whereas inhibition of SERT selectively increases swimming [88]. However, for a reliable comparison with clinical data, it is advisable to investigate therapeutic effects following chronic treatment in rodents [89]. It is important to refer that reduction of immobility is interpreted as an antidepressant effect, if it does not increase general locomotor activity, which could be interpreted as a false positive result [86]. This is related with the fact that antidepressants and psychostimulants, respectively, reduce and increase the locomotor activity of rodents in new environments [86]. Moreover, behavioral experiments at different times of the day strongly affect the obtained results [90]. The FST experiments display different results if performed during the dark or light phase, since rodents are more active during the dark phase [91]. Kelliher et al. noticed that rats were more agitated or worsened when taken from the swim apparatus during light phase [91].

Seasonal variations seem to influence the efficacy of antidepressants. In rats, FST revealed significant seasonal fluctuations of the antidepressant effect for TCAs, namely amineptine, amitriptyline, desipramine, imipramine, and mianserin [92]. Maximal reduction of immobility in FST was observed in March for all aforementioned antidepressants. The desipramine and mianserin anti-immobility effect was also evaluated in a light–dark cycle and was not circadian-dependent (Table 2) [92]. Nomifensine, a NE-dopamine reuptake inhibitor, was equally effective throughout the year with no seasonal variations, but it revealed a circadian-dependent effect, more pronounced during the light phase (peak at ZT7) (Table 2) [92]. The interpretation of these results is complicated by the low number of experimental replicates (n = 1 or 2). Furthermore, the controlled conditions of rats excluded the influence off the light–dark cycle, humidity and temperature variations that occur during the seasons. Therefore, the observed seasonal effect may be linked with internal mechanisms, namely the daily amplitude of subtype receptor 5-HT1A binding in the rat brain, which is higher in March than December [93].

Table 2. Chronopharmacodynamic studies of antidepressant drugs in rodents.
Antidepressant Species (Gender) Dose (mg/Kg) Initial of Experiment after Administration (h) Route Zeitgeber
Time (ZT) Administrations		 Pharmacodynamic Drug Concentration Ref.
Test 24 h Rhythm Variation Observations
Amitriptyline ICR mice (male) 15 0.5 Intraperitoneal ZT2, ZT6, ZT10, ZT14, ZT18, ZT22 FST Yes Lowest immobility at ZT14. - [74]
Bupropion C57BL/6 mice (male) 20 1 Intraperitoneal ZT1, ZT7, ZT13, ZT19 TST No, but significantly different between ZT Lowest immobility at ZT1. No significant differences between dosing times in plasma and brain. [94]
Locomotor activity No Increased
Desipramine CD-COBS rats (male) 20 24, 5 and 1 Intraperitoneal ZT3, ZT7, ZT11, ZT15, ZT19, ZT23 FST No - - [92]
Fluoxetine C57BL/6 mice (male) 30 1 Intraperitoneal ZT1, ZT7, ZT13, ZT19 TST Yes Lowest immobility at ZT1. No significant differences between dosing times in plasma and brain. [94]
Locomotor activity Yes Lowest locomotion activity at ZT1
Fluvoxamine ICR mice (male) 30 0.5 Intraperitoneal ZT2, ZT6, ZT10, ZT14, ZT18, ZT22 FST Yes Lowest immobility at ZT14. ZT2 > ZT14 in plasma, significantly different after 1h of drug injection. No differences in brain. [74]
ZT2, ZT14 Locomotor activity No No effect
Imipramine C57BL/6 mice (male) 30 1 Intraperitoneal ZT1, ZT7, ZT13, ZT19 TST Yes Lowest immobility at ZT13. No significant differences between dosing times in plasma and brain [94]
Locomotor activity No Reduced
Wistar Hannover rats (male) 30 1 Intraperitoneal ZT1, ZT13 FST Yes Lowest immobility and highest climbing at ZT1. ZT1 > ZT13 for imipramine and desipramine in plasma but not significantly different [22]
10 for 2 weeks 1 Intraperitoneal ZT1, ZT13 FST Yes Lowest immobility and highest climbing at ZT1. -
30 for 2 weeks 1 Intraperitoneal ZT1, ZT13 FST No - -
Mianserin CD-COBS rats (male) 15 24, 5 and 1 Intraperitoneal ZT3, ZT7, ZT11, ZT15, ZT19, ZT23 FST No - - [92]
Milnacipran Wistar Hannover rats (male) 60 1 Oral ZT1, ZT13 FST Yes Lowest immobility and highest swimming at ZT1. No significant differences between dosing times in plasma and brain [73]
Nomifensine CD-COBS rats (male) 5 24, 5 and 1 Intraperitoneal ZT3, ZT7, ZT11, ZT15, ZT19, ZT23 FST Yes Lowest immobility at ZT7 - [92]
Venlafaxine C57BL/6 mice (male) 30 1 Intraperitoneal ZT1, ZT7, ZT13, ZT19 TST Yes Lowest immobility at ZT7. No significant differences between dosing times in plasma and brain [94]
Locomotor activity Yes Lowest locomotion activity at ZT7.
FST, Forced swimming test; TST, tail suspension test.

The effect of light–dark cycles on pharmacodynamic studies with antidepressants has also been investigated. In the modified FST, the immobility time of mice treated with SSRI fluvoxamine showed a significant 24 h rhythm, with the lowest immobility at the beginning of the dark phase (ZT14) (Figure 3) without increasing locomotor activity (Table 2) [74].

Dual-action antidepressants may also have different chronopharmacological profiles. In FST, the immobility time of mice treated with TCA amitriptyline exhibited a 24 h rhythm variation with a peak of antidepressant effect at ZT14 (Table 2 and Figure 3), identical to the previously mentioned results for fluvoxamine [74].

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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 [22][73][74] or tail suspension [94] tests. ZT0 represents lights on and ZT12 indicates lights off.

In general, data from the animal studies herein discussed demonstrate that antidepressants display distinct chronopharmacodynamic outcomes (Figure 3) which should be specifically evaluated. Other behavioral experiments (sucrose preference test or elevated plus maze) could be additionally performed to increase result reliability [95]. Moreover, the use of depressive mice and the monitorization of circadian rhythms could facilitate the implementation of clinical studies in humans. Transferability of data from mice to humans regarding circadian rhythms is challenging. For instance, although mice are nocturnally active and humans are diurnally active, both secrete melatonin during the nighttime [96]. Therefore, the translation of chronopharmacological results of antidepressants from mice to humans needs particular care.

3.1.2. Human Data

Despite having yielded interesting and helpful results, chronopharmacodynamic studies in humans have not been performed in recent years. Side effects of TCAs are the principal focus of these types of studies and experiments showed diverse results for different TCAs (Figure 4).
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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 [23] and higher antidepressant effects for clomipramine [97] and lofepramine [98].
The side effects of amitriptyline seem to be higher after morning administrations. Its antimuscarinic effect, measured through the mean percent decrease from the pre-drug level in salivary flow, demonstrated to be higher if the drug is administered in the morning than in the evening, at 2 h (78 ± 3% vs 59 ± 7%) and 3 h (76 ± 4% and 65 ± 5%) post-administration [23]. Identically, amitriptyline-induced sedative effects, such as drowsiness, confusion, and mental slowness, measured by self-rating scales, were higher with morning than evening doses (Table 3) [23].
Table 3. Chrono-pharmacodynamics of orally administered antidepressant drugs in humans.
Antidepressant Subjects Study Design Daily Dose (mg) Duration (Days) Time Administrations Pharmacodynamic Ref.
Test 24 h Rhythm Variation Observations
Amitriptyline 10 healthy (♂) subjects. Range age: 22–31 years old. Crossover 50 21 9h00
21h00		 Antimuscarinic action (saliva flow) and sedation effect by self-rating scales Yes Highest salivary flow and lowest sedative effect at 21h00 [23]
Clomipramine 40 patients with MDD (15 ♀, 25 ♂). Range age: 18–65 years old. Crossover 150 28 8h20
12h20
20h30		 HRSD and BDRS Yes Lowest depressive symptoms at 12h20 [97]
Lofepramine 30 patients with MDD (22 ♀, 8 ♂). Range age: 25–60 years old. Parallel 210 21 8h00
16h00
24h00		 HRSD and CSRS Yes Lowest depressive symptoms at 24h00 [98]
Beck Depression Rating Scale (BDRS); Clinical Self-Rating Scales (CSRS); HRSD, 17-item Hamilton Rating Scale for Depression; MDD, major depressive disorder.

3.2. Antidepressant Effects on Circadian Rhythms

Circadian gene polymorphisms have been associated with affective disorders, including depression, through the modulation of MAO-A and dopamine neurotransmission [99]. Moreover, pineal abnormalities lead to altered melatonin secretion and circadian disruptions, which are related with clinical subtypes of MDD and its symptomatology [100]. Therefore, the evaluation of circadian rhythm differences in depressed-like mice before and after antidepressant treatments is of utmost importance. Depressed patients experience a wide range of circadian rhythms and sleep-cycle disruptions, and chronotherapy has proved to reduce their depressive symptoms [101]. Therefore, drugs targeted to normalize circadian rhythms could be of interest for the treatment of depression. The main implications of antidepressants on circadian rhythms in pre-clinical and clinical studies are depicted in Table 4.
Table 4. Main findings of pre-clinical and clinical studies reporting the influence of different classes of antidepressants on circadian rhythms.
Antidepressant Pre-Clinical Studies Clinical Studies References
SSRI
Citalopram/escitalopram
‑
Modulates Per1 oscillation in vitro.
‑
Restores daily rhythms of PER2 and BMAL1 and baseline levels of serum melatonin;
‑
Increases melatonin suppression and delays the internal clock rhythm.
 [102][103][104]
Fluoxetine
‑
Modulates Per1 oscillation in vitro;
‑
Induces non-photic effects in light–dark cycle in mice;
‑
Induces light-phase advances of SCN firing;
‑
Normalizes disrupted circadian locomotor activity and clock gene expression in depressive-like mice;
‑
Decreases the response of mice to light-induced phase-delays.
‑
Increases 6-sulfatoxymelatonin in urine.
 [102][105][106][107][108]
Fluvoxamine
‑
Modulates Per1 oscillation in vitro.
‑
Increases plasma levels of melatonin and cortisol;
‑
Improves sleep parameters and reduces insomnia.
 [102][109][110][111]
Paroxetine
‑
Modulates Per1 oscillation in vitro.
‑
Delays REM onset and reduces REM time sleep;
‑
Increases the changeover time of wakefulness to sleep;
‑
May induce “hypersomnia”.
 [102][112][113]
Sertraline
‑
Modulates Per1 oscillation in vitro.
   [102]
SNRI
Duloxetine  
‑
Increases 6-sulfatoxymelatonin in urine.
 [105]
TCA
Desipramine
‑
Restores photic entrainment of activity after exposure to glucocorticoids.
‑
Increases melatonin plasma levels.
 [114][115][116]
Imipramine
‑
Does not restore photic entrainment after light shifting.
‑
Increases melatonin plasma levels.
 [114][115][117]
Atypical
Agomelatine
‑
Modulates daily rhythm of melatonin secretion;
‑
Induces circadian effects on locomotor activity and body temperature;
‑
Restores resynchronization of light–dark cycle advances;
‑
Improves sleep parameters (only if taken at night);
‑
Restores circadian rhythm activity in depressive-like rodents.
‑
Induces circadian alterations of cortisol and melatonin levels, core body temperature and heart rate;
‑
Improves sleep parameters;
‑
Resynchronizes the circadian rhythms and sleep parameters of depressed patients.
 [118][119][120][121][122][123][124][125][126][127][128][129][130]
Ketamine
‑
Alters the entrainment of clock genes;
‑
Resets main clock in the SNC.
‑
Increases neuroplasticity;
‑
Improves sleep quality.
 [131][132]
Mirtazapine  
‑
Improves sleep continuity;
‑
Increases slow-wave sleep;
‑
Increase melatonin plasma levels;
‑
Reduces cortisol plasma levels.
 [133]
Vortioxetine  
‑
Delays REM onset and reduces REM time sleep;
‑
Increases the changeover time of wakefulness to sleep
 [113]
SCN, suprachiasmatic nucleus; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.
Several antidepressants enhance plasma melatonin levels, restoring circadian rhythmicity in depression [105][109][110][114][115]. Fluvoxamine increased the plasma levels of melatonin and cortisol in healthy men [109][110], while SSRI fluoxetine and SNRI duloxetine increased 6-sulfatoxymelatonin in depressed patients [105]. Chronic treatment with imipramine or desipramine also resulted in higher peak levels of melatonin in depressed patients [114][115].
Sleep–wake states can also be modulated by agomelatine [123][124][125]. Acute administration of melatonin or agomelatine (5 mg) 5 h before bedtime increased rapid eye movement (REM) sleep and advanced sleep–wake cycles in healthy men [123]. Interestingly, when rats were orally treated with agomelatine (10 and 40 mg/kg) before the light phase, no relevant sleep–wake alterations were found [124].
In vitro studies indicated that ketamine inhibits the CLOCK:BMAL1 function by altering the entrainment of clock genes and reducing the daily amplitude of transcription of several clock genes (Bmal1, Per2, Cry1) [131]. Single intravenous treatment of 0.5 mg/kg ketamine hydrochloride in depressed patients increased neuroplasticity and improved their mood and sleep quality [132]. Acute ketamine altered circadian timekeeping (amplitude and timing) leading to an initial weak interaction between sleep homeostasis and circadian processes [132]. However, patients in continuous treatment who develop a strong sleep-circadian interaction are associated with fewer relapses and a better ketamine response [132].
In conclusion, commercially available antidepressants have demonstrated to play a critical role on circadian entrainment. Nevertheless, the links behind the modulation of circadian rhythms by antidepressants still require more investigation. New insights may help the design of better chronopharmacological strategies for the treatment of depression.

4. Conclusions

Chronotherapy is known to improve drug efficacy and reduce toxicity. The choice of an appropriate dosing-time for antidepressants is a possible factor of variation in pharmacokinetics and may promote therapeutic effects, while reducing adverse effects. Several factors that can affect the pharmacokinetics and pharmacodynamics of antidepressants are modulated by circadian rhythms, which undermine the comprehension of in vivo and human findings. In spite of increasing scientific evidence emerging in this field, further studies in animals and humans remain necessary to determine pharmacokinetic and pharmacodynamic parameters and understand the best time of administration for different antidepressants.
Exploring the chronopharmacological profiles of each antidepressant is expected to provide a more effective pharmacotherapy. Depressed patients can require different dosing-times for the same antidepressant, indicating that individual chronopharmacological therapy should be the primary tool for effective treatment. Moreover, the readjustment of circadian rhythms by some antidepressants is partially responsible for their effectiveness. Thus, restoring circadian rhythmicity is a valid mechanism to promote the development of rapid and sustained treatments in MDD, as it has been discovered in the recent years.

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics13111975

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