Antidepressants are cytotoxic to rat primary blood brain barrier endothelial cells at high therapeutic concentrations

Abstract

Antidepressants are commonly employed for the treatment of major depressive disorders and other psychiatric conditions. We investigated the relatively acute cytotoxic effects of three commonly prescribed antidepressants: fluoxetine, sertraline, and clomipramine on rat primary blood brain barrier endothelial cells over a concentration range of 0.1-100μM. At therapeutic concentrations (0.1μM) no significant cytotoxicity was observed after 4, 24, or 48h. At high therapeutic to overdose concentrations (1-100μM), antidepressants reduced cell viability in proportion to their concentration and exposure duration. At 1μM, antidepressants significantly reduced mitochondrial membrane potential. At drug concentrations producing ~50% inhibition of cell viability, all drugs significantly reduced cellular oxygen consumption rates, activities of mitochondrial complexes I and III, and triggered a significant increase of lactate production. Fluoxetine (6.5μM) and clomipramine (5.5μM) also significantly lowered transcellular transport of albumin. The mechanism of cellular cytotoxicity was evaluated and at high concentrations all drugs significantly increased the production of reactive oxygen species, and significantly increased the activity of the pro-apoptotic caspases-3, 8, and 9. Comet assays revealed that all drugs were genotoxic. Pre-incubation of cells with glutathione significantly ameliorated antidepressant-induced cytotoxicity, indicating the potential benefit of treatment of overdosed patients with antioxidants.

Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis

“…Antipsychotic medication has been found to increase BBB permeability in animal studies [103] and affect immune cells in the CNS [23, 104–106], highlighting the importance of evaluating the effect of psychotropic medication when analyzing CSF; however, the evidence for antidepressants is conflicting [107, 108]. Cross-sectional studies mostly found no association between CSF parameters and psychotropic medication apart from a correlation between a higher albumin ratio [88], higher IL-1alpha [78], and IL-8 [86] with antipsychotic treatment, and none of the studies investigating this aspect longitudinally.…”

Neuronal life or death linked to depression treatment: the interplay between drugs and their stress-related outcomes relate to single or combined drug therapies

“…Elmorsy et al presented that fluoxetine, sertaline and clomipramine treatment reduces cellular oxygen consumption rates, activities of the mitochondrial complexes I and II and triggers an increase of lactate production. Moreover, higher concentrations of antidepressants were linked with upregulation of pro-apoptotic caspases-3, 8 and 9 in response to global reactive oxygen species-mediated DNA damage in rat primary blood barrier endothelial cells [19]. Further detailed studies revealed that structural chromosomal abnormalities [20], as well as telomeres shortening, may be involved in antidepressants-induced neurotoxicity [21].…”

Rapid Ascending Sensorimotor Paralysis, Hearing Loss, and Fatal Arrhythmia in a Multimorbid Patient due to an Accidental Overdose of Fluoxetine

“…Multiple experimental studies have showed that at hypertherapeutic and overdose concentrations of fluoxetine, fluoxetine demonstrates evidence of cytotoxicity, antiproliferative effects, and mitochondrial dysfunction. Specifically, these studies noted inhibition of mitochondrial function and depletion of cellular ATP levels with significantly increased lactate production, activation of apoptosis, and evidence of redox stress and DNA damage [ 18 – 22 ].…”

“…To put this into perspective, toxicological analysis on our patient revealed fatal levels of heart blood fluoxetine and norfluoxetine concentrations at 2.3 mcg/mL and 1.1 mcg/mL, respectively, well above the therapeutic limit. It is important to note that, in one study of antidepressant overdose, no correlation between fluoxetine level and mental status was found, while another study of fluvoxamine overdose found no correspondence between drug levels and symptom severity [ 17 , 18 ], suggesting that each patient presenting with an SSRI overdose, despite quantity consumed, can have unique symptomatology.…”