Journal of psychopharmacology (Oxford, England) · 2026
Chronopharmacology and implications for the safety and efficacy of anticonvulsants, antipsychotics, and antidepressants: A systematic review.
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Tan Victoria Yue, Wong Sabrina, Le Gia Han, Kwan Angela T H, Zhang Melanie C, Zheng Yang Jing, Teopiz Kayla, Dri Christine E, Ho Roger, Bargiota Stavroula, Cao Bing, McIntyre Roger S
Аннотация
BACKGROUND: Many proteins integral to psychotropic agents' pharmacokinetics (PK) and pharmacodynamics (PD) exhibit circadian variation in expression and function. Chronopharmacology examines the effect of circadian systems on the pharmacology of drugs. Herein, we review the impact of circadian rhythm on drug-metabolizing enzymes and target receptors, with implications for the chronopharmacology of anticonvulsants, antidepressants, and antipsychotics.
METHODS: Systematic searches of MEDLINE, Embase, PsycINFO, AMED, and JBI EBP were conducted from inception to September 2025 using terms related to "circadian rhythm," "chronopharmacology," and "psychotropic agents." Preclinical and clinical studies investigating circadian-aligned dosing effects on anticonvulsant, antidepressant, or antipsychotic PK/PD were included.
RESULTS: Eight preclinical and one clinical study met inclusion criteria. Preliminary evidence suggests that circadian timing may influence the pharmacology of select psychotropic agents. Circadian timing influenced valproic acid PK and antiseizure activity in preclinical seizure models, whereas the single clinical study demonstrated differences in serum valproate concentrations but not seizure outcomes. For antidepressants (i.e., imipramine, milnacipran, fluoxetine, venlafaxine, bupropion), dose-timing altered monoaminergic PD measures in preclinical studies, although the relationship between these findings and antidepressant efficacy remains uncertain. Limited evidence suggests that circadian timing may influence the metabolic effects of quetiapine in mice.
CONCLUSION: Current evidence provides preliminary support that circadian rhythm may differentially affect the pharmacology of select psychotropic agents. Whether the foregoing translates into clinically meaningful differences in efficacy, tolerability, and/or posology of the evaluated agents/classes requires systematic evaluation. Given that evidence is predominantly preclinical, further studies using clinically relevant repeated-dose regimens and disease-relevant animal models are required.
METHODS: Systematic searches of MEDLINE, Embase, PsycINFO, AMED, and JBI EBP were conducted from inception to September 2025 using terms related to "circadian rhythm," "chronopharmacology," and "psychotropic agents." Preclinical and clinical studies investigating circadian-aligned dosing effects on anticonvulsant, antidepressant, or antipsychotic PK/PD were included.
RESULTS: Eight preclinical and one clinical study met inclusion criteria. Preliminary evidence suggests that circadian timing may influence the pharmacology of select psychotropic agents. Circadian timing influenced valproic acid PK and antiseizure activity in preclinical seizure models, whereas the single clinical study demonstrated differences in serum valproate concentrations but not seizure outcomes. For antidepressants (i.e., imipramine, milnacipran, fluoxetine, venlafaxine, bupropion), dose-timing altered monoaminergic PD measures in preclinical studies, although the relationship between these findings and antidepressant efficacy remains uncertain. Limited evidence suggests that circadian timing may influence the metabolic effects of quetiapine in mice.
CONCLUSION: Current evidence provides preliminary support that circadian rhythm may differentially affect the pharmacology of select psychotropic agents. Whether the foregoing translates into clinically meaningful differences in efficacy, tolerability, and/or posology of the evaluated agents/classes requires systematic evaluation. Given that evidence is predominantly preclinical, further studies using clinically relevant repeated-dose regimens and disease-relevant animal models are required.