Atypical Antipsychotic Lumateperone Effects on the Adrenal Gland With Possible Beneficial Effect of Quercetin Co-administration

Abstract

Schizophrenia remains one of the most chronic and highly disabling mental disorders. Lumateperone is a recent FDA-approved atypical antipsychotic drug for the treatment of schizophrenia. However, the internal FDA pathologist raised concerns regarding pigment deposition associated with degeneration in different tissue in animal studies with lumateperone treatment. The adrenal gland may be implicated in lumateperone side effects, and quercetin may have the ability to fulfill this treatment gap. To prove this hypothesis, 40 male guinea pigs were used and divided into four groups; control, quercetin-treated, lumateperone-treated, and quercetin/lumateperone cotreated orally for 28 consecutive days. Behavioral forced swim (FST) and open field (OF) tests were done at the end of treatment. Retro-orbital blood samples were taken to assess hormones: adrenocorticotropic hormone (ACTH), cortisol, dehydroepiandrosterone acetate (DHEA), and aldosterone, along with an assessment of oxidative stress parameters: malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD). Adrenal glands were extracted for histopathological assessment with H&E, Mallory trichome staining, immunostaining, and electron microscopy studies. Lumateperone-treated group showed a significant reduction in the activity in FST and OF with histopathological deterioration in adrenal secretory function and structure and increased expression of interleukin-6 (IL-6), CASPASE-3, collagen deposition, and decreased proliferating cell nuclear antigen (PCNA). Cytoplasmic vacuolation, pyknosis of the nuclei, increase in the lysosome, lipofuscin pigment, and cellular infiltration with diminishing in the number of secretory granules could all be observed in lumateperone-treated group. Coadministration of quercetin and lumateperone showed improvement of the previously deteriorated parameters. Quercetin had a prophylactic effect against lumateperone depressive-like effect on animal behavior and its possible adrenal damage.Graphical AbstractConceptual framework for the proposed mechanism of action of coadministration of quercetin and lumateperone.

Antidepressant Potential of Quercetin and its Glycoside Derivatives: A Comprehensive Review and Update

“…Guan et al (2021a) found that the serum levels of iron, copper, and calcium increased, while magnesium, zinc, selenium, and cobalt levels significantly reduced in CUMS rats, and quercetin restored the levels of these elements, demonstrating that it could regulate trace elements in the brain. Moreover, the beneficial effects of quercetin could also be observed in other animal models, such as guinea pigs and zebrafish (El-Haroun et al, 2021;Singh et al, 2022). These studies confirmed that quercetin exerted antidepressant effects by regulating the activity of enzymatic and non-enzymatic antioxidant systems.…”

“…As a flavonol with numerous biological activities, quercetin has different pharmacological effects such as antidepression, anti-cancer, antioxidant, anti-fibrosis, and antiinflammatory (Reyes-Farias and Carrasco-Pozo, 2019;Ou et al, 2020;Alshammari et al, 2021). Many studies have suggested the protection of mature neurons in the hippocampus, improvement of HPA axis dysfunction, anti-inflammatory, and anti-oxidative stress were involved in the antidepressant effects of quercetin (Sun et al, 2007;Bicca et al, 2021;El-Haroun et al, 2021;Han et al, 2021;Li et al, 2021;Sun et al, 2021), which also encompasses hippocampal neurogenesis promotion through direct and indirect effects (Chan et al, 2018;Rahvar et al, 2018;Wang et al, 2021a;Ma et al, 2021). Hence, quercetin has multiple targets and pathways compared to other antidepressants (Figure 3).…”

“…This paradoxical phenomenon reminds us to be more cautious in future. First of all, as numerous studies in vivo have confirmed that quercetin could act on multiple targets in depression treatment (El-Haroun et al, 2021;Han et al, 2021;Li et al, 2021), the top priority of in vitro studies is not to prove whether quercetin has new targets in treating depression, but to reveal the mechanisms of the proved targets through more scientific models and methods. Besides, based on the difficulties to distinguish the non-specifically and therapeutically irrelevant effects (Baell, 2016), it is necessary to review the false positives and related mechanisms of quercetin, in order to guide researchers to select appropriate cells, culture mediums, control groups and evaluation methods.…”

Dopamine, Immunity, and Disease

“…As in schizophrenia, adjunctive treatment with some anti-inflammatory agents seems to alleviate mania and improve depressive symptoms ( Goldsmith et al, 2016 ; Rosenblat, 2019 ). Notably, lumateperone, an antagonist for D1, D2, D4, and serotonin receptor 2A and transporters ( Kumar et al, 2018 ), improved depressive symptoms in bipolar depression patients in the first clinical trials ( Calabrese et al, 2021 ), although it also showed potential inflammatory effects ( El-Haroun et al, 2021 ). Overall, these data suggest a relatively understudied connection between dopaminergic modulation of immune function and bipolar disorder and indicate that the combination of anti-inflammatory and dopaminergic drugs could provide more beneficial alleviation of bipolar symptomatology than individual treatment.…”