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.
Highlights
All organisms display biological processes with rhythmic oscillations of 24 h periodicity defined as circadian rhythms
Chronopharmacokinetic studies in humans treated with two oral forof the trimipramine showed that tablets seem to be less affected mulations of the trimipramine showed that tablets seem to be less by dosing-time (Table 2) [46]
Different results of chronopharmacodynamic studies with antidepressants can be Different results of chronopharmacodynamic studies with antidepressants can be rerelated with fluctuations of the pharmacokinetic parameters discussed in Section 2.1 or lated with fluctuations of the pharmacokinetic parameters discussed in Section 2.1 or daily daily variations of the expression of antidepressant drug targets affected by circadian variations of the expression of antidepressant drug targets affected by circadian rhythms rhythms (Figure 2)
Summary
All organisms display biological processes with rhythmic oscillations of 24 h periodicity defined as circadian rhythms. Melatonin is associated with sleep–wake rhythms and it is known that bedtime melatonin concentrations have a negative correlation with the severity of depressive symptoms [16] These results emphasize the use of melatonin as clinical biomarker and as a potential marker of treatment response. In plasma of psychiatric patients, increased cortisol levels during inactive hours have been associated with psychotic MDD [20] Depression indicators such as concentration and memory deficit or slow reaction time, vary throughout the day, being more prominent in the morning than evening [21]. Evening-type individuals normally take a higher number of antidepressants with reduced efficacy but similar side effects, compared with morning chronotypes [24] These data emphasize the importance of light–dark cycles in the development of mood disorders, including depression, and the use of individualized therapy for its treatment.
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