quetiapine-fumarate and Inflammation

Knowledge about the neurobiology of psychiatric disorders is increasing in the last decades and evidence from literature suggests a central role for immuno-inflammatory mechanisms in these illnesses. The antipsychotic quetiapine acts on dopamine and serotonin signalling and well-established evidence demonstrates that these neurotransmitters can modulate immune functions in healthy and diseased conditions. Starting from this perspective, in the last few decades, a number of studies attempted to identify quetiapine effects on immune functions in order to highlight a possible additional effect of this drug in psychotic diseases, although no conclusive results were obtained.. We critically reviewed preclinical and clinical studies evaluating quetiapine effects on immune systems, suggesting strategies for future work in this field.. Computerised search, in PubMed and Embase databases, was performed in March 2020: 120 studies were identified but only 29 relevant papers were selected for detailed review.. Despite some interesting preliminary findings about anti-inflammatory effects of quetiapine, mainly supported by preclinical studies, it is possible to conclude further studies are needed to investigate the immunomodulatory effects of this drug and achieve a better understanding of its relevance on clinical outcomes to finally identify new therapeutic approaches in psychiatric treatment. KeypointsMounting evidence points to a role for immuno-inflammatory mechanisms in psychiatric disorders.Quetiapine (QUE) acts on catecholamine (dopamine and norepinephrine) and serotonin signalling.The immunomodulatory effects of catecholamines are well established.Treatment with QUE in psychiatric disorders could leverage immunomodulatory effects.QUE unclear role in immune function modulation suggests future work.

Topics: Antipsychotic Agents; Dibenzothiazepines; Dopamine; Humans; Inflammation; Quetiapine Fumarate; Serotonin

Total white blood cell count (TWBCc), an index of chronic and low-grade inflammation, is associated with clinical symptoms and metabolic alterations in patients with schizophrenia. The effect of antipsychotics on TWBCc, predictive values of TWBCc for drug response, and role of metabolic alterations require further study.. Patients with schizophrenia were randomized to monotherapy with risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, perphenazine or haloperidol in a 6-week pharmacological trial. We repeatedly measured clinical symptoms, TWBCc, and metabolic measures (body mass index, blood pressure, waist circumference, fasting blood lipids and glucose). We used mixed-effect linear regression models to test whether TWBCc can predict drug response. Mediation analysis to investigate metabolic alteration effects on drug response.. At baseline, TWBCc was higher among patients previously medicated. After treatment with risperidone, olanzapine, quetiapine, perphenazine, and haloperidol, TWBCc decreased significantly (. TWBCc is affected by certain antipsychotics among patients with schizophrenia, with decreases observed following short-term, but increases following long-term treatment. TWBCc is predictive of drug response, with lower TWBCc predicting better responses to antipsychotics. It also mediates the effects of certain metabolic measures on improvement of negative symptoms. This indicates that the metabolic state may affect clinical manifestations through inflammation.

Topics: Antipsychotic Agents; Benzodiazepines; Glucose; Haloperidol; Humans; Inflammation; Olanzapine; Perphenazine; Quetiapine Fumarate; Risperidone; Schizophrenia

Major depressive disorder (MDD) etiology is still not completely understood, and many individuals resist the traditional treatments. Chronic exposure to stressful events can contribute to development and progression and be involved in biological changes underlying MDD. Among the biological mechanisms involved, inflammatory changes and oxidative balance are associated with MDD pathophysiology. Quetiapine, a second-generation antipsychotic, induces a better therapeutic response in individuals refractory to traditional treatments. The main objectives of this research were as follows: to evaluate the effect of chronic mild stress (CMS) on depressive-like behaviors, oxidative stress, and inflammation in adult rats; to evaluate the possible antidepressant, antioxidant, and anti-inflammatory effects of quetiapine. The animals were submitted to CMS protocols. At the end of the CMS, the animals were submitted to a chronic treatment for 14 days with the following drugs: quetiapine (20 mg/kg), imipramine (30 mg/kg), and escitalopram (10 mg/kg). At the end of the treatments, the animals were evaluated in the open field tests, anhedonia (splash test), and forced swimming. The animals were euthanized after the behavioral tests, and serum samples were collected. Myeloperoxidase (MPO) activity and interleukin-6 (IL-6) levels were analyzed. CMS induced an increase in depressive-like behaviors, and quetiapine significantly reduced these behaviors. MPO activity and IL-6 levels increased in the serum of animals submitted to CMS. Quetiapine significantly reduced MPO activity and IL-6 levels. These results corroborate other evidence, indicating that chronic stress is a relevant phenomenon in the etiology of depression and suggesting that quetiapine induces an antidepressant effect because it reduces oxidative and inflammatory mechanisms.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Depression; Depressive Disorder, Major; Disease Models, Animal; Inflammation; Interleukin-6; Oxidative Stress; Quetiapine Fumarate; Rats; Stress, Psychological

Torsade de pointes is a potentially lethal polymorphic ventricular tachyarrhythmia that can occur in the setting of long QT syndrome (LQTS). LQTS is multi-hit in nature and multiple factors combine their effects leading to increased arrhythmic risk. While hypokalemia and multiple medications are accounted for in LQTS, the arrhythmogenic role of systemic inflammation is increasingly recognized but often overlooked. We tested the hypothesis that the inflammatory cytokine interleukin(IL)-6 will significantly increase the incidence of arrhythmia when combined with other pro-arrhythmic conditions (hypokalemia and the psychotropic medication, quetiapine).. Guinea pigs were injected intraperitoneally with IL-6/soluble IL-6 receptor and QT changes were measured in vivo. Subsequently, hearts were cannulated via Langendorff perfusion for ex vivo optical mapping measurements of action potential duration (APD. IL-6 prolonged QTc in vivo guinea pigs from 306.74 ± 7.19 ms to 332.60 ± 8.75 ms (n = 8, p = .0021). Optical mapping on isolated hearts demonstrated APD prolongation in IL-6- vs saline groups (3Hz APD. Our experimental observations strongly suggest that controlling inflammation, specifically IL-6, could be a viable and important route for reducing QT prolongation and arrhythmia incidence in the clinical setting.

Topics: Animals; Arrhythmias, Cardiac; Cytokines; Electrocardiography; Guinea Pigs; Hypokalemia; Inflammation; Interleukin-6; Long QT Syndrome; Quetiapine Fumarate; Torsades de Pointes

Chemotherapy is considered a major choice in cancer treatment. Unfortunately, several cognitive deficiencies and psychiatric complications have been reported in patients with cancer during treatment and for the rest of their lives. Doxorubicin (DOX) plays an important role in chemotherapy regimens but affects both the central and peripheral nervous systems. Antipsychotic drugs alleviate the behavioral symptoms of aging-related dementia, and the atypical class, quetiapine (QUET), has been shown to have beneficial effects on various cognitive impairments. The present investigation aimed to determine the possible mechanism underlying the effect of thirty-day administrations of QUET (10 or 20 mg/kg, p.o.) on DOX-induced cognitive deficits (DICDs). DICDs were achieved through four doses of DOX (2 mg/kg, i.p.) at an interval of seven days during drug treatment. Elevated plus maze (EPM), novel object recognition (NOR), and Y-maze tasks were performed to confirm the DICDs and find the impact of QUET on them. The ELISA tests were executed with oxidative [malondialdehyde (MDA), catalase, and reduced glutathione (GSH)], inflammatory [cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), and tumor necrosis factor-alpha (TNF-α)], and apoptosis [B-cell lymphoma 2 (Bcl2), Bcl2 associated X protein (Bax), and Caspase-3] markers were assessed in the brain homogenate to explore the related mechanisms. DICD lengthened the transfer latency time in EPM, shortened the exploration time of the novel object, reduced the discrimination ability of the objects in NOR, and lowered the number of arm entries and time spent in the novel arm. QUET alleviated DICD-related symptoms. In addition, QUET reduced neuronal oxidative stress by reducing MDA and elevating GSH levels in the rat brain. Moreover, it reduced neuronal inflammation by controlling the levels of COX-2, NF-κB, and TNF-α. By improving the Bcl-2 level and reducing both Bax and Caspase-3 levels, it protected against neuronal apoptosis. Collectively, our results supported that QUET may protect against DICD, which could be explained by the inhibition of neuronal inflammation and the attenuation of cellular apoptosis protecting against oxidative stress.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Cognition; Cognitive Dysfunction; Cyclooxygenase 2; Doxorubicin; Inflammation; Neuroinflammatory Diseases; NF-kappa B; Oxidative Stress; Quetiapine Fumarate; Rats; Tumor Necrosis Factor-alpha

Infections can alter drug clearance, but the impact of inflammation-induced changes is still not well known. The aim of the investigation was to examine the effect of pathological C-reactive protein (CRP) values (≥0.5 mg/dL) and leukocyte count on the metabolism of 4 different atypical antipsychotics.. Steady-state serum concentrations of individual patients under therapy with risperidone (n=45), aripiprazole (n=30), olanzapine (n=24), and quetiapine (n=166) were retrospectively analyzed during a period of inflammation by Spearman's Rho correlation analysis. Mann-Whitney U test was applied for comparison of patients with serum concentrations above and below the upper limit of the therapeutic reference range of each target drug with regard to CRP concentration and leukocyte count. Linear regression analysis was applied to correct for confounding parameters age and sex.. Pathological concentrations of CRP were significantly associated with elevated values of C/D of quetiapine (n=166, Spearman's Rho: r=0.269, p<0.001; linear regression: p<0.001). Among patients with quetiapine serum concentrations below 500 ng/mL, CRP concentrations were significantly (p=0.006) lower compared to patients with quetiapine concentrations above 500 ng/mL. A trend for a positive correlation between CRP and serum concentration was found for olanzapine (n=24, Spearman's Rho: r=0.385, p=0.063; linear regression: p=0.086).. During a period of inflammation in patients taking quetiapine, according to our results, attention in dosing strategies is required to prevent toxic plasma concentrations.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antipsychotic Agents; Aripiprazole; C-Reactive Protein; Female; Humans; Inflammation; Leukocyte Count; Male; Middle Aged; Olanzapine; Quetiapine Fumarate; Retrospective Studies; Risperidone; Sex Factors; Young Adult

Quetiapine, an atypical antipsychotic medication has lacked pre-clinical validation for its purported benefits in the treatment of delirium. This laboratory investigation examined the effects of quetiapine on the attentional set shifting task (ASST), a measure of cognitive flexibility and executive functioning, in a rodent model of lipopolysaccharide (LPS) mediated neuroinflammation. 19 Sprague Dawley female rats were randomly selected to receive intraperitoneal placebo (N = 5), LPS and placebo (N = 7) or LPS and quetiapine (n = 7) and performed the ASST. We measured trials to criterion, errors, non-locomotion episodes and latency to criterion, serum cortisol and tumor necrosis factor alpha (TNF-α) levels. TNF-α levels were not different between groups at 24 h. Cortisol levels in the LPS + Quetiapine group were reduced compared to LPS + Placebo (P < 0.001) and did not differ from the placebo group (P = 0.15). Analysis between LPS + Quetiapine and LPS + Placebo treated rats demonstrated improvement in the compound discrimination reversal (CD Rev1) (P = 0.016) and the intra-dimensional reversal (ID Rev2) (P = 0.007) discriminations on trials to criterion. LPS + Quetiapine treated rats had fewer errors than LPS + Placebo treated animals in the compound discrimination (CD) (P = 0.007), CD Rev1 (P = 0.005), ID Rev2 (P < 0.001) discriminations. There was no difference in non-locomotion frequency or latency to criterion between the three groups in all discriminations (P > 0.0167). We demonstrated preserved reversal learning, no effect on attentional set shifting and normalized cortisol levels in quetiapine-treated rats in this neuroinflammatory model of delirium. This suggests that quetiapine's beneficial effects in delirium may be related to the preservation of reversal learning and potential downstream effects related to reduction in cortisol production. Graphical Abstract.

Topics: Animals; Antipsychotic Agents; Appetitive Behavior; Attention; Delirium; Disease Models, Animal; Drug Evaluation, Preclinical; Executive Function; Female; Frontal Lobe; Hydrocortisone; Inflammation; Lipopolysaccharides; Quetiapine Fumarate; Random Allocation; Rats; Rats, Sprague-Dawley; Reversal Learning; Reward; Set, Psychology; Tumor Necrosis Factor-alpha

Previous studies approved the important roles of CD68, as scavenger receptors, in Alzheimer's disease (AD). The aim of this study was to evaluate the effect of treatment with anti-psychotic drugs and vitamin B12 on the expression levels of CD68 in monocytes of psychotic AD patients.. Expression of CD68 on the monocytes was evaluated in the following groups: 1. age and sex matched healthy controls (Group 1), 2. non-psychotic AD patients (Group 2), 3. psychotic AD patients (Group 3), 4. psychotic AD patients treated with Risperidone (Group 4), 5. psychotic AD patients treated with Risperidone plus vitamin B12 (Group 5), 6. psychotic AD patients treated with Quetiapine (Group 6), psychotic AD patients treated with Quetiapine plus vitamin B12 (Group 7). The expression of CD68 has been performed using flow cytometry technique.. The results showed that CD68 levels were significantly increased in AD patients in comparison to healthy controls and in psychotic AD patients in comparison to non-psychotic AD patients. Treatment with anti-psychotic drugs decreased the expression of CD68. Expression of CD68 has a positive correlation with pain, dementia and mental disorders symptoms in psychotic AD patients.. CD68 may play key roles in the pathogenesis of AD and its complications may be via induction of inflammation. Therefore, it may be concluded that CD68 may be considered as a risk factor for development of AD and also psychotic symptoms in the patients.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antipsychotic Agents; Case-Control Studies; Drug Therapy, Combination; Female; Flow Cytometry; Humans; Inflammation; Male; Monocytes; Psychotic Disorders; Quetiapine Fumarate; Risk Factors; Risperidone; Vitamin B 12

In psychiatric clinical practice, there is a need to identify psychotropic drugs whose metabolisms are prone to be altered with increased inflammatory activity in an individual patient.. The aim of this study was to find out whether elevated serum levels (≥5 mg/l) of C-reactive protein (CRP), an established laboratory marker of infection and inflammation, are associated with increased serum concentrations of the atypical antipsychotic drugs clozapine, quetiapine, and risperidone.. Therapeutic drug monitoring request forms of patients whose antipsychotic drug concentrations had been measured under conditions of normal (<5 mg/l) and pathological (>5 mg/l) levels of C-reactive protein were retrospectively screened. The serum concentrations in relation to the daily doses [concentration per dose (C/D) (ng/mL/mg)] and the metabolic ratios [ratio of concentrations (metabolite/drug)] were compared intraindividually by the Wilcoxon signed rank test. To the study effects of the intensity of infections on drug concentrations, C-reactive protein and C/D levels were submitted to Spearman's correlation analysis.. Elevated levels of C-reactive protein were found in 105 patients. They were significantly associated with elevated values in C/D for clozapine (n = 33, P < 0.01) and risperidone (n = 40, P < 0.01). A trend for an increase was found for quetiapine (n = 32, P = 0.05). Median increases were 48.0 % (clozapine), 11.9 % (quetiapine), and 24.2 % (active moiety of risperidone), respectively.. In patients who exhibit signs of inflammation or infection with increased C-reactive protein values during psychopharmacological treatment, especially under clozapine and risperidone, therapeutic drug monitoring is recommendable in order to minimize the risk of intoxications due to elevated drug concentrations.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Biomarkers; C-Reactive Protein; Clozapine; Female; Humans; Inflammation; Male; Psychotic Disorders; Psychotropic Drugs; Quetiapine Fumarate; Risperidone; ROC Curve

Inflammation has been considered important in the pathogenesis of schizophrenia. Increasing evidence reveals that patients with schizophrenia have abnormal expression of cytokines, which are related to development of metabolic abnormalities. Metabolic abnormality has become a critical issue, though its longitudinal relationship with the disorder, such as the antipsychotics influence, is unclear. We aimed to investigate whether abnormalities of metabolic parameters and cytokine levels in acute exacerbated schizophrenic patients existed, and whether intervention of antipsychotic could help. The present study analyzed peripheral cytokines and metabolic/hemodynamic parameters in healthy controls and acute exacerbated schizophrenic patients hospitalized for three weeks under the unique treatment of quetiapine, a well-known second-generation antipsychotic. Our results showed that patients with schizophrenia were predisposed to metabolic abnormalities in acute exacerbation, including body mass index (BMI) and waist circumference (WC). The patients were also prone to dysglycemia, lower high-density lipoprotein cholesterol (HDL-c) levels, and higher blood pressure with concomitant of elevation of interleukin (IL)-2, IL-6 and IL-10 in which IL-6 was associated with BMI. After quetiapine treatment, IL-2, IL-6 and IL-10 remained higher than the controls, but IL-10 was significantly decreased in follow-up comparison. Glycemic-related indexes, HDL-c and IL-10 levels were significantly changed by variance analysis. Results of the present study imply that acute exacerbated schizophrenic patients with metabolism abnormalities may involve disruption of expression of cytokines, and that quetiapine may have therapeutic effects. Nonetheless, metabolism parameters of patients undergoing treatment with quetiapine should be closely monitored.

Topics: Adult; Antipsychotic Agents; Blood Glucose; Blood Pressure; Body Mass Index; Cholesterol, HDL; Cytokines; Female; Humans; Inflammation; Interleukin-10; Male; Middle Aged; Quetiapine Fumarate; Schizophrenia; Waist Circumference

The atypical antipsychotic drug, quetiapine, has recently been suggested to not only show efficacy in schizophrenia, bipolar, major depressive and general anxiety disorders, but to also have a possible anti-inflammatory effect, which could be important in the treatment of the inflammatory aspects of psychiatric diseases. Male C57BL/6 mice were given either quetiapine (i.p. 10mg/kg), its main active metabolite norquetiapine (i.p. 10mg/kg), or saline as a vehicle control, once a day for 14days. On the 14th day, this dose was followed by a single dose of either LPS (i.p. 1mg/kg) or saline. 24h post LPS short-term recognition memory and anhedonia behaviour were measured using the Y-maze and saccharin preference test respectively. Immediately following behavioural testing, mice were culled before serum, prefrontal cortex and hippocampal analysis of cytokine levels was conducted. It was found that LPS challenge led to increased serum and brain cytokine levels as well as anhedonia, with no significant effect on recognition memory. Quetiapine and norquetiapine both increased levels of the anti-inflammatory cytokine IL-10 and decreased levels of the pro-inflammatory cytokine IFN-γ in serum 4h post LPS. Within the brain, a similar pattern was seen in gene expression in the hippocampus at 4h for Il-10 and Ifn-γ, however norquetiapine led to an increase in Il-1β expression in the PFC at 4h, while both drugs attenuated the increased Il-10 in different regions of the brain at 24h. These effects in the serum and brain, however, had no effect on the observed LPS induced changes in behaviour. Both quetiapine and its metabolite norquetiapine appear to have a partial anti-inflammatory effect on IL-10 and IFN-γ following acute LPS challenge in serum and brain, however these effects did not translate into behavioural changes.

Topics: Anhedonia; Animals; Antipsychotic Agents; Behavior, Animal; Brain Chemistry; Cytokines; Dibenzothiazepines; Gene Expression; Hippocampus; Inflammation; Interferon-gamma; Interleukin-10; Lipopolysaccharides; Male; Memory, Short-Term; Mice; Mice, Inbred C57BL; Prefrontal Cortex; Quetiapine Fumarate