Lacosamide intake during pregnancy increases the incidence of foetal malformations and symptoms associated with schizophrenia in the offspring of mice

Abstract

The use of first and second generation antiepileptic drugs during pregnancy doubles the risk of major congenital malformations and other teratogenic defects. Lacosamide (LCM) is a third-generation antiepileptic drug that interacts with collapsing response mediator protein 2, a protein that has been associated with neurodevelopmental diseases like schizophrenia. The aim of this study was to test the potential teratogenic effects of LCM on developing embryos and its effects on behavioural/histological alterations in adult mice. We administered LCM to pregnant mice, assessing its presence, and that of related compounds, in the mothers’ serum and in embryonic tissues using liquid chromatography coupled to quadrupole/time of flight mass spectrometry detection. Embryo morphology was evaluated, and immunohistochemistry was performed on adult offspring. Behavioural studies were carried out during the first two postnatal weeks and on adult mice. We found a high incidence of embryonic lethality and malformations in mice exposed to LCM during embryonic development. Neonatal mice born to dams treated with LCM during gestation displayed clear psychomotor delay and behavioural and morphological alterations in the prefrontal cortex, hippocampus and amygdala that were associated with behaviours associated with schizophrenia spectrum disorders in adulthood. We conclude that LCM and its metabolites may have teratogenic effects on the developing embryos, reflected in embryonic lethality and malformations, as well as behavioural and histological alterations in adult mice that resemble those presented by patients with schizophrenia.

Treatment and care of women with epilepsy before, during, and after pregnancy: a practical guide

“… 102 , 103 Data from preclinical studies found a high incidence of embryonic lethality and malformations. 104 In mice, morphological alterations in the prefrontal cortex, hippocampus, and amygdala were associated with behaviors associated with schizophrenia spectrum disorders. 104 The number of human lacosamide–exposed fetuses is very low (1–10) but without MCMs.…”

“… 104 In mice, morphological alterations in the prefrontal cortex, hippocampus, and amygdala were associated with behaviors associated with schizophrenia spectrum disorders. 104 The number of human lacosamide–exposed fetuses is very low (1–10) but without MCMs. 92 , 105 More recent data from NAAPR quote no MCM risk (0.0%, 95% CI = 0.28–13.6).…”

Antiseizure medication in early nervous system development. Ion channels and synaptic proteins as principal targets

“…Despite the development of new ASM, investigations of third generation ASM can generate nervous system malformations in vitro. LCM and its metabolites may have teratogenic effects on the developing mice embryos, reflected in embryonic lethality and malformations, as well as behavioral and histological alterations (López-escobar et al, 2020). Then, LCM generates growth retardation and major malformations increased in a dose-dependent manner and observed mostly in the supratherapeutic group (Mete et al, 2016).…”

Клінічні Особливості Лікування Фокальної Резистентної Епілепсії

“…Новонароджені миші, народжені від самок, які отримували лакосамід під час вагітності, демонстрували чітку психомоторну затримку і поведінкові й морфологічні зміни в префронтальній корі, гіпокампі й мигдалині, які пов'язані з поведінковими розладами шизофренічного спектра в дорослому віці. Авторами зроблено висновок, що лакосамід і його метаболіти можуть мати тератогенний вплив на ембріони, що проявляється в ембріональній летальності та вадах розвитку, а також у поведінкових і гістологічних змінах у дорослих мишей, які нагадують ті, що спостерігаються в пацієнтів з шизофренією [34]. Відповідно до рекомендацій FDA у США при вагітності не призначається [35].…”