Unmetabolized quetiapine exerts an in vitro effect on innate immune cells by modulating inflammatory response and neutrophil extracellular trap formation.

Quetiapine is an antipsychotic drug that is used to treat psychiatric and neurological disorders. Despite its efficiency and low-toxicity, quetiapine administration has been associated with undesirable side effects such as the development of low-grade inflammatory disorders and neutropenia states. As the liver rapidly metabolizes quetiapine to metabolites, the non-metabolized part of this molecule might play a role in immune alterations. In an in vitro study, this hypothesis was tested by exposing activated and inactivated RAW-264.7 macrophages and human neutrophils to unmetabolized quetiapine (u-QUE). Based on our findings, u-QUE was not cytotoxic to these cells. u-QUE differentially modulates macrophages according to their activation states. In inactivated macrophages, u-QUE induced a proinflammatory state as observed by an increase in cellular proliferation; increased levels of oxidative molecules (nitric oxide and superoxide), protein levels, and gene overexpression of proinflammatory cytokines (IL-1ß, IL-6, and TNF-α); and decreased levels of IL-10, an anti-inflammatory cytokine. Conversely, on phytohemagglutinin (PHA)-activated macrophages, u-QUE exerted an anti-inflammatory effect. u-QUE induced neutrophil extracellular trap (NET) formation and increased the sensitivity of the neutrophils previously activated by exposure to dead yeast cells for NET formation. These results confirm the effect of quetiapine on macrophage and neutrophil function, which may be associated with the side effects of this psychopharmaceutical agent.

Superoxide imbalance triggered by Val16Ala-SOD2 polymorphism increases the risk of depression and self-reported psychological stress in free-living elderly people.

BACKGROUND: Oxidative stress and chronic inflammatory states triggered by a single-nucleotide polymorphism (SNP) in superoxide dismutase manganese-dependent gene (Val16Ala-SOD2) have been associated with the risk of developing several chronic, nontransmissible diseases. However, it is still not clear whether the VV-SOD2 genotype that causes higher basal superoxide anion levels has any impact on the risk for depression and self-reported psychological stress in elderly people. METHODS: In the present study, we tested this hypothesis using a case-control study where depression was detected using the Geriatric Depression Scale-15 (GDS-15). A total of 612 Brazilian free-living elderly subjects with a mean age of 67.1 ± 7.1 years old (number of controls, C = 497, and depressive individuals, D = 115) were included in this study. All participants had similar social, health, and lifestyle variables, with the exception of polypharmacy (≥5 medicines daily intake), which was higher in the D group, compared to C subjects. RESULTS: Our results showed that the VV-SOD2 genotype significantly increased the risk for depression and psychological stress in the elderly subjects, independently of sex/gender, age, and other prior diseases and health indicators (depression risk = 1.842, 1.109-3.061 95% CI, p = .018). VV-subjects also had a higher daily intake of antidepressants, anxiolytics, and anti-inflammatory drugs than A-allele subjects. CONCLUSION: Our findings support the hypothesis that genetically induced oxidative superoxide-hydrogen peroxide imbalance may be involved in an increased risk for developing depression and psychological stress in free-living elderly people without other chronic nontransmissible diseases.

Correction to: The Influence of a Xanthine-Catechin Chemical Matrix on in vitro Macrophage-Activation Triggered by Antipsychotic Ziprasidone.

After publication of our article it came to our attention that it contains a number of errors with regard to the citations. The details are provided below.

Lithium is able to minimize olanzapine oxidative-inflammatory induction on macrophage cells.

BACKGROUND: Olanzapine (OLZ) is a second-generation antipsychotic drug used for treatment of schizophrenia, bipolar disorder, and other neuropsychiatric conditions. Undesirable side effects of OLZ include metabolic alterations associated with chronic oxidative-inflammation events. It is possible that lithium (Li), a mood modulator that exhibits anti-inflammatory properties may attenuate OLZ-induced oxi-inflammatory effects. METHODOLOGY: To test this hypothesis we activated RAW 264.7 immortalized macrophages with OLZ and evaluated oxidation and inflammation at the gene and protein levels. Li and OLZ concentrations were determined using estimated plasma therapeutic concentrations. RESULTS: OLZ triggered a significant increase in macrophage proliferation at 72 h. Higher levels of oxidative markers and proinflammatory cytokines, such as TNF-α, IL-1ß, and IL-6, with a concomitant reduction in IL-10, were observed in OLZ-exposed macrophages. Lithium (Li) exposure triggered a short and attenuated inflammatory response demonstrated by elevation of superoxide anion (SA), reactive oxygen species (ROS), IL-1ß, and cellular proliferation followed by elevation of anti-inflammatory IL-10 levels. Li treatment of OLZ-supplemented macrophages was able to reverse elevation of oxidative and inflammatory markers and increase IL-10 levels. CONCLUSIONS: Despite methodological limitations related to in vitro protocols, results suggested that Li may attenuate OLZ-induced oxidative and inflammatory responses that result from metabolic side effects associated with OLZ.

The Influence of a Xanthine-Catechin Chemical Matrix on in vitro Macrophage-Activation Triggered by Antipsychotic Ziprasidone.

Ziprasidone (ZIP) is an effective antipsychotic with low side effects than other second-generation antipsychotics. Despite this, there are reports of adverse events and previous studies associating the use of ZIP the inflammatory response. It is possible to infer that bioactive molecules present in some foods could attenuate peripheral inflammatory and oxidative stress potentially triggered ZIP. This is the case of guaraná xanthine-catechin chemical matrix (XC-Mix) that presents caffeine, theobromine, and catechin. The in vitro protocols using murine RAW 264.7 cell macrophages were ZIP-exposure in culture medium supplemented with chemical isolated and admixture of Caf, The, and Cat. Main results showed that supplementation with isolated and XC-mix had a lowering effect on 72 h macrophages proliferation. XC-mix with 1:1:1 proportion at 25 µg/mL of each caffeine, theobromine, and catechin, molecules present lowering effect on nitric oxide levels, oxidative stress markers (DNA oxidation quantified by 8-hydroxy-2' -deoxyguanosine), lipoperoxidation, and protein carbonylation. XC-mix also decreased protein levels and downregulated genes of proinflammatory cytokines (IL-1ß, IL-6, TNF-α). At contrary, XC-Mix increased levels and upregulated gene of anti-inflammatory IL-10 cytokine. The results suggest that XC-matrix could present some beneficial action on peripheral proinflammatory effects ZIP-triggered. Complementary in vivo studies could be useful to confirm these in vitro findings described here.

Ziprasidone, a second-generation antipsychotic drug, triggers a macrophage inflammatory response in vitro.

Antipsychotic drugs are used to treat schizophrenia and other psychiatric disorders. However, most of these drugs present side effects causing obesity and other serious metabolic alterations that correlate with grade of chronic inflammation. In contrast, ziprasidone's (ZIP) metabolic side effects are attenuated relative to those of other antipsychotic drugs, but some reports suggest that this drug could cause allergic, hypersensitive reactions in susceptible patients. At present, the mechanism of ZIP's effect on peripheral inflammatory metabolism is not well characterized. We conducted an in vitro study to evaluate the effect of ZIP on a macrophage cell line (RAW 264.1). Our results showed that in non-activated macrophage cells, ZIP exposure initiated macrophage spreading; increased cellular proliferation, as evaluated by MTT and flow cytometry assays; and presented higher levels of oxidant molecules involved in the inflammatory response (nitric oxide, superoxide, reactive oxygen species), and proinflammatory cytokines (IL-1, IL-6, TNFα, INFγ). Levels of IL-10, an anti-inflammatory cytokine were lower in ZIP-exposed cells. These effects were less potent than those caused by the positive control for inflammation induction (phytohemagglutinin), and more intense than the effects of lithium (LI), which was used as an anti-inflammatory molecule. ZIP also modulated cytokine gene expression. Taken together, these data suggest that ZIP can produce a peripheral inflammatory response, and this response may explain the allergen-inflammatory response observed in some patients treated with this antipsychotic drug.

Haloperidol and Risperidone at high concentrations activate an in vitro inflammatory response of RAW 264.7 macrophage cells by induction of apoptosis and modification of cytokine levels.

Antipsychotic drugs, such as haloperidol and risperidone, are used in long-term treatment of psychiatric patients and thus increase the risk of obesity and other metabolic dysfunctions. Available evidence suggests that these drugs have pro-inflammatory effect, which contributes to the establishment of endocrine disturbances. However, results yielded by extant studies are inconsistent. Therefore, in this work, we tested the in vitro effects of different high concentrations of haloperidol and risperidone on the activation of isolated macrophages (RAW 264.7 cell line). The results indicated that macrophages were activated by both drugs. In addition, the activation involved an increase in nitric oxide levels and apoptosis events by modulation of caspases 8 and 3 levels and a decrease of the Bcl-2/BAX gene expression ratio. Cells treated with haloperidol and risperidone also presented higher concentrations of inflammatory cytokines (IL-1ß, IL-6, TNFα) and low levels of IL-6 anti-inflammatory cytokine in a dose-dependent manner. Despite the limitation of cell line studies based solely on macrophages cells, we suggest that antipsychotic drugs could potentially exacerbate inflammatory processes in peripheral tissues (blood and fat). The continued activation of macrophages could contribute to the development of obesity and other endocrine disturbances caused by the use of antipsychotic drugs.