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Lithium and valproate serum level fluctuations within the menstrual cycle

a systematic review

Carmassi, Claudiaa; Del Grande, Claudiaa; Masci, Isabellaa; Caruso, Danilaa; Musetti, Lauraa; Fagiolini, Andreab; Dell’Osso, Lilianaa

International Clinical Psychopharmacology: May 2019 - Volume 34 - Issue 3 - p 143–150
doi: 10.1097/YIC.0000000000000253

Some women affected by mood disorders experience mood instability during the premenstrual phase. Assuming that fluctuations in drug serum levels may contribute to the worsening of mood symptoms, we carried out a systematic review of available studies that investigated changes in lithium and valproate levels in relation to menstrual phases. We selected five studies; four of which assessed menstrual fluctuations in lithium serum levels and one in valproate levels. Study samples included women in their fertile age affected by bipolar disorder, epilepsy as well as healthy ones. Preliminary results showed a close relationship between cyclic premenstrual exacerbation of affective symptoms and a significant decrease in lithium levels during the luteal phase, despite stable oral doses, in bipolar women. In healthy women, lithium levels were influenced by neither menstrual cycle phases nor oral contraceptives use. Valproate serum levels in epileptic women showed a small, nonsignificant decline during the mid-luteal phase. Pharmacokinetic sex differences in adsorption, volume distribution, hepatic metabolism, and renal excretion of mood stabilizers have been supposed to partly explain such menstrual serum level fluctuations. A better understanding in this field could help to counteract the distress related to premenstrual phase, improving therapeutic management of mood disorders in women.

aDepartment of Clinical and Experimental Medicine, Division of Psychiatry, University of Pisa, Pisa

bDepartment of Molecular and Developmental Medicine, Division of Psychiatry, University of Siena, Siena, Italy

Received 30 October 2018 Accepted 31 January 2019

Correspondence to Claudia Del Grande, MD, Department of Clinical and Experimental Medicine, Division of Psychiatry, University of Pisa, Via Roma 67, 56126 Pisa, Italy Tel: +39 050 221 9760; fax: +39 050 221 9787; e-mail:

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