Atypical antipsychotics and metabolic syndrome : from molecular mechanisms to clinical differences

Atypical antipsychotics (AAPs) are commonly prescribed medications to treat schizophre-nia, bipolar disorders and other psychotic disorders. However, they might cause metabolic syndrome (MetS) in terms of weight gain, dyslipidemia, type 2 diabetes (T2D), and high blood pressure, which are responsible for reduced life expectancy and poor adherence. Importantly, there is clear evidence that early metabolic disturbances can precede weight gain, even if the latter still remains the hallmark of AAPs use. In fact, AAPs interfere profoundly with glucose and lipid homeostasis acting mostly on hypothalamus, liver, pancreatic β-cells, adipose tissue, and skeletal muscle. Their ac-tions on hypothalamic centers via dopamine, serotonin, acetylcholine, and histamine receptors affect neuropeptides and 5′ AMP-activated protein kinase (AMPK) activity, thus producing a supra-physiological sympathetic outflow augmenting levels of glucagon and hepatic glucose production. In addition, altered insulin secretion, dyslipidemia, fat deposition in the liver and adipose tissues, and insulin resistance become aggravating factors for MetS. In clinical practice, among AAPs, olan-zapine and clozapine are associated with the highest risk of MetS, whereas quetiapine, risperidone, asenapine and amisulpride cause moderate alterations. The new AAPs such as ziprasidone, lurasi-done and the partial agonist aripiprazole seem more tolerable on the metabolic profile. However, these aspects must be considered together with the differences among AAPs in terms of their efficacy, where clozapine still remains the most effective. Intriguingly, there seems to be a correlation between AAP’s higher clinical efficacy and increase risk of metabolic alterations. Finally, a multidisciplinary approach combining psychoeducation and therapeutic drug monitoring (TDM) is proposed as a first-line strategy to avoid the MetS. In addition, pharmacological treatments are discussed as well.Publisher PDFPeer reviewe

Redox and autonomic responses to acute exercise-post recovery following Opuntia ficus-indica juice intake in physically active women

Background: The aim of this study was to investigate if the supplementation with Opuntia ficus-indica (OFI) juice may affect plasma redox balance and heart rate variability (HRV) parameters following a maximal effort test, in young physically active women. Methods: A randomized, double blind, placebo controlled and crossover study comprising eight women (23.25 ± 2.95 years, 54.13 ± 9.05 kg, 157.75 ± 0.66 cm and BMI of 21.69 ± 0.66 kg/m2) was carried out. A juice containing OFI diluted in water and a Placebo solution were supplied (170 ml; OFI = 50 ml of OFI juice + 120 ml of water; Placebo = 170 ml beverage without Vitamin C and indicaxanthin). Participants consumed the OFI juice or Placebo beverage every day for 3 days, before performing a maximal cycle ergometer test, and for 2 consecutive days after the test. Plasma hydroperoxides and total antioxidant capacity (PAT), Skin Carotenoid Score (SCS) and HRV variables (LF, HF, LF/HF and rMSSD) were recorded at different time points. Results: The OFI group showed significantly lower levels of hydroperoxides compared to the Placebo group in pretest, post-test and 48-h post-test. PAT values of the OFI group significantly increased compared to those of the Placebo group in pre-test and 48-h post-test. SCS did not differ between groups. LF was significantly lower in the OFI group 24-h after the end of the test, whereas rMSSD was significantly higher in the OFI group 48-h post-test. Conclusion: OFI supplementation decreased the oxidative stress induced by intense exercise and improved autonomic balance in physically active women

Supplementation with cactus pear (Opuntia ficus-indica) fruit decreases oxidative stress in healthy humans: A comparative study with vitamin C

Background: Cactus pear (Opuntia ficus-indica) fruit contains vitamin C and characteristic betalain pigments, the radical-scavenging properties and antioxidant activities of which have been shown in vitro. Objective: We investigated the effects of short-term supplementation with cactus pear fruit compared with vitamin C alone on total-body oxidative status in healthy humans. Design: In a randomized, crossover, double-treatment study, 18 healthy volunteers received either 250 g fresh fruit pulp or 75 mg vitamin C twice daily for 2 wk, with a 6-wk washout period between the treatments. Before (baseline) and after each treatment, 8-epiprostaglandin F2α (8-epi-PGF2α) and malondialdehyde in plasma, the ratio of reduced to oxidized glutathione (GSH:GSSG) in erythrocytes, and lipid hydroperoxides in LDL were measured as biomarkers of oxidative stress; plasma Trolox-equivalent antioxidant activity (TEAC) and vitamins A, E, and C were evaluated as indexes of antioxidant status. Results: Both treatments caused comparable increases compared with baseline in plasma concentrations of vitamin E and vitamin C (P < 0.05); vitamin A and TEAC did not change significantly. After supplementation with cactus pear fruit, 8-epi-PGF2α and malondialdehyde decreased by ≈30% and 75%, respectively; GSH:GSSG shifted toward a higher value (P < 0.05); and LDL hydroperoxides were reduced by almost one-half. Supplementation with vitamin C did not significantly affect any marker of oxidative stress. Conclusions: Consumption of cactus pear fruit positively affects the body's redox balance, decreases oxidative damage to lipids, and improves antioxidant status in healthy humans. Supplementation with vitamin C at a comparable dosage enhances overall antioxidant defense but does not significantly affect body oxidative stress. Components of cactus pear fruit other than antioxidant vitamins may play a role in the observed effects. © 2004 American Society for Clinical Nutrition

Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): a multicentre international randomised controlled trial.

BACKGROUND: Pregnant women with type 1 diabetes are a high-risk population who are recommended to strive for optimal glucose control, but neonatal outcomes attributed to maternal hyperglycaemia remain suboptimal. Our aim was to examine the effectiveness of continuous glucose monitoring (CGM) on maternal glucose control and obstetric and neonatal health outcomes. METHODS: In this multicentre, open-label, randomised controlled trial, we recruited women aged 18-40 years with type 1 diabetes for a minimum of 12 months who were receiving intensive insulin therapy. Participants were pregnant (≤13 weeks and 6 days' gestation) or planning pregnancy from 31 hospitals in Canada, England, Scotland, Spain, Italy, Ireland, and the USA. We ran two trials in parallel for pregnant participants and for participants planning pregnancy. In both trials, participants were randomly assigned to either CGM in addition to capillary glucose monitoring or capillary glucose monitoring alone. Randomisation was stratified by insulin delivery (pump or injections) and baseline glycated haemoglobin (HbA1c). The primary outcome was change in HbA1c from randomisation to 34 weeks' gestation in pregnant women and to 24 weeks or conception in women planning pregnancy, and was assessed in all randomised participants with baseline assessments. Secondary outcomes included obstetric and neonatal health outcomes, assessed with all available data without imputation. This trial is registered with ClinicalTrials.gov, number NCT01788527. FINDINGS: Between March 25, 2013, and March 22, 2016, we randomly assigned 325 women (215 pregnant, 110 planning pregnancy) to capillary glucose monitoring with CGM (108 pregnant and 53 planning pregnancy) or without (107 pregnant and 57 planning pregnancy). We found a small difference in HbA1c in pregnant women using CGM (mean difference -0·19%; 95% CI -0·34 to -0·03; p=0·0207). Pregnant CGM users spent more time in target (68% vs 61%; p=0·0034) and less time hyperglycaemic (27% vs 32%; p=0·0279) than did pregnant control participants, with comparable severe hypoglycaemia episodes (18 CGM and 21 control) and time spent hypoglycaemic (3% vs 4%; p=0·10). Neonatal health outcomes were significantly improved, with lower incidence of large for gestational age (odds ratio 0·51, 95% CI 0·28 to 0·90; p=0·0210), fewer neonatal intensive care admissions lasting more than 24 h (0·48; 0·26 to 0·86; p=0·0157), fewer incidences of neonatal hypoglycaemia (0·45; 0·22 to 0·89; p=0·0250), and 1-day shorter length of hospital stay (p=0·0091). We found no apparent benefit of CGM in women planning pregnancy. Adverse events occurred in 51 (48%) of CGM participants and 43 (40%) of control participants in the pregnancy trial, and in 12 (27%) of CGM participants and 21 (37%) of control participants in the planning pregnancy trial. Serious adverse events occurred in 13 (6%) participants in the pregnancy trial (eight [7%] CGM, five [5%] control) and in three (3%) participants in the planning pregnancy trial (two [4%] CGM and one [2%] control). The most common adverse events were skin reactions occurring in 49 (48%) of 103 CGM participants and eight (8%) of 104 control participants during pregnancy and in 23 (44%) of 52 CGM participants and five (9%) of 57 control participants in the planning pregnancy trial. The most common serious adverse events were gastrointestinal (nausea and vomiting in four participants during pregnancy and three participants planning pregnancy). INTERPRETATION: Use of CGM during pregnancy in patients with type 1 diabetes is associated with improved neonatal outcomes, which are likely to be attributed to reduced exposure to maternal hyperglycaemia. CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy. This study is the first to indicate potential for improvements in non-glycaemic health outcomes from CGM use. FUNDING: Juvenile Diabetes Research Foundation, Canadian Clinical Trials Network, and National Institute for Health Research

TRATTAMENTI NEL DISTURBO BIPOLARE: STUDIO DEGLI EFFETTI AVVERSI DI TIPO METABOLICO DA USO DI ANTIPSICOTICI IN SISTEMI CELLULARI IN VITRO

Il disturbo bipolare è una psicopatologia complessa e multicomponenziale. La sua natura cronica e long-life, unitamente all’eterogeneità e all’ingravescenza delle manifestazioni sintomatologiche, cagiona un impatto disabilitante su tutti gli aspetti dell’esistenza. La mutilazione del funzionamento individuale, lavorativo e sociale è accompagnata dalla drastica riduzione della qualità di vita e da un ingente rischio suicidario. Pur riconoscendo il contributo primario ed imprescindibile delle cure farmacologiche, in prima istanza abbiamo esaminato i modelli psicoterapeutici empiricamente più supportati. Essi rispecchiano l’esigenza di un paradigma di cura integrato in grado di appianare il gap esistente tra il recupero sintomatico e la ripresa funzionale, e di facilitare la reintegrazione sociale e lavorativa dopo la remissione sintomatologica. In secondo luogo abbiamo discusso le principali strategie farmacologiche disponibili. La progettazione di un piano di trattamento in grado di indurre la regressione dei sintomi nelle fasi acute di malattia e di promuovere la stabilizzazione umorale negli intervalli inter-episodici, rappresenta una grande sfida e si misura quotidianamente con l’intrinseca tendenza del disturbo a recidivare. Nell’ottica dell’emergente medicina personalizzata, è ribadita l’importanza di un trattamento individualizzato che non consideri unicamente la polarità episodica, ma che sia plasmato sulla scorta delle peculiarità del singolo paziente, delle sue esigenze e delle comorbidità mediche e psichiatriche. Quando la scelta della giusta terapia asseconda questi aspetti e bilancia in modo ottimale costi e benefici, la probabilità che esibisca esiti positivi si eleva. Nel corso della trattazione, infatti, vedremo come la riuscita a lungo-termine della terapia profilattica, dipenda in larga parte dall’adesione alle cure. Non sempre infatti, i pazienti mostrano condotte di aderenza adeguate ed i motivi possono essere diversi. Alla gestione del fenomeno della non aderenza, le psicoterapie per il disturbo bipolare, dedicano un elevato numero di sessioni, che rispecchia l’importanza rivestita dai trattamenti farmacologici. Nell’ambito della farmacoterapia, ci siamo soffermati in modo specifico sul contributo degli antipsicotici atipici (AAPs), poiché nelle ultime due decadi, sono stati la pietra miliare del trattamento del disturbo bipolare nella fase acuta, insieme al litio. Connotati da incisività e rapidità d’azione, sono una manforte soprattutto nella mania acuta e quando la pericolosità dei sintomi richiede un contenimento rapido ed immediato. Tuttavia, talvolta sono inclusi anche nelle terapie a lungo-termine di prevenzione e mantenimento, dando luogo ad effetti avversi di differente portata, tra cui la sindrome metabolica. L’aumento di peso, accresce lo stigma sociale associato alla psicopatologia e concorre alla mancata aderenza farmacologica. In secondo luogo, le anomalie glucidiche e lipidiche, costituiscono un serio rischio per la salute, a causa delle complicanze organiche cardio-metaboliche. L’impiego dei farmaci antipsicotici, pertanto, deve essere accompagnato da adeguate strategie preventive, che attraverso tecniche comportamentali, psicologiche e motivazionali, promuovano uno stile di vita salubre ed equilibrato, contraddistinto dal connubio di attività fisica e dieta alimentare. Talvolta, può rendersi necessaria l’aggiunta di farmaci ipoglicemizzanti e di contenimento del peso. Alla luce di ciò, abbiamo ritenuto importante approfondire i meccanismi fisiopatologici alla base della sindrome metabolica indotta dagli antipsicotici atipici. Esaminando la letteratura, abbiamo riscontato una compromissione estesa su più livelli, spiegata dal complesso profilo farmacodinamico degli AAPs e dalla presenza dei loro target molecolari nel SNC ma anche nei tessuti periferici, con l’attivazione di meccanismi in grado di agire in parallelo e di influenzarsi reciprocamente. A partire da questa considerazione, la presente tesi si è proposta di indagare, nello specifico, il contributo fisiologico ed eziopatologico delle β-cellule pancreatiche nell’insorgenza della sindrome metabolica da AAPs e del diabete mellito di tipo 2. Le β-cellule pancreatiche, infatti, esprimono numerosi recettori, tra cui i recettori alla dopamina e alla serotonina, la cui attività è alterata in presenza degli AAPs. Dunque, abbiamo verificato l’espressione di tali recettori nella linea cellulare INS-1E ricavata da insulinoma di ratto, riscontrandone una quantificazione degna di nota. Successivamente, gli esperimenti condotti si sono proposti di verificare l’effettiva capacità dei farmaci antipsicotici e dopamino-agonisti di influenzare la secrezione d’insulina glucosio-stimolata (GSIS). Come atteso, il trattamento delle cellule INS-1E con ropinirolo e quinpirolo, ha ridotto la GSIS. Al contrario, clozapina ed olanzapina, hanno apportato un incremento significativo della secrezione insulinica, mentre il trattamento con aloperidolo, non è stato in grado di innescare modificazioni di rilievo. Questi risultati, da un lato sono coerenti con la maggiore incidenza di diabete di tipo 2 in seguito all’assunzione degli antipsicotici atipici rispetto ai tipici, dall’altro suggeriscono che l’antagonismo D2 contribuisca solo in parte all’iperinsulinemia. È plausibile, infatti, che altre vie di segnalazione, attivate o inibite dagli AAPs, operino parallelamente al circuito dopaminergico esplicando un contributo addizionale ad esso

Anti-inflammatory effects of sicilian pistachio (pistacia vera l.) Nut in an in vitro model of human intestinal epithelium

Intestinal epithelial cells play an important role in the mucosal inflammatory response. These cells synthesize and secrete inflammatory mediators, and selectively modulate the permeability of the epithelial monolayer thus exposing immune cells to antigens. Although intestinal inflammatory response is crucial to maintain gut structural integrity and function, alteration and dysregulation of inflammatory pathways contribute to tissue damage and ulceration, and are thought to be pivotal factors in the pathogenesis of different inflammatory gut diseases [1]. The limited efficacy of conventional pharmacological therapy in the intestinal inflammatory conditions has fostered research on alternatives and, at the same time, stresses the importance of prevention. In this context, the influence of dietary components, becoming in a physiological close proximity to intestinal cells and then to inflammatory processes within the intestinal mucosa, appears of nutritional and clinical interest [2]. Among natural preventive and complementary approaches to improve inflammatory symptoms, dietary polyphenols represent potential candidates and proanthocyanidins are particularly interesting [3]. For their relatively high concentration in a number of edible plants and their high digestive stability and limited intestinal adsorption [4, 5], proanthocyanidins reach the colon at relatively high concentrations and may have direct effects on the intestinal mucosa through their interaction with the intestinal epithelial cell membranes [6, 7]. The edible pistachio nut has been ranked among the first 50 food products highest in antioxidant potential [8]. A number of data show that the pistachio nut consumption has positive effects in human serum lipid profile and cardiovascular disease (CVD) risk factors [9,10] and significantly improves oxidative status and reduces circulating inflammatory biomarkers [11]. Our previous research provided evidence that a hydrophilic extract from Sicilian pistachio nuts (HPE) contains substantial amounts of polyphenols, including proanthocyanidins, and possesses radical scavenging and antioxidative properties in in vitro models of lipid oxidation [12]. Moreover we also demonstrated that HPE has anti-inflammatory activities in lipopolysaccharide (LPS)-activated macrophages interfering with the NF-kB activation, and that the high molecular weight proanthocyanidin fraction (PF) can play a major role as the bioactive component of HPE [13]. In the present study we investigated the activity of HPE, and of its polymeric proanthocyanidin fraction as well, in an in vitro model of intestinal inflammation, consisting of Caco-2 cells differentiated into epithelial intestinal cells and exposed to the inflammatory actions of interleukin (IL)-1. Our results clearly show that HPE effectively inhibits the inflammatory response in intestinal epithelial cells, and that highly polymeric proanthocyanidin components exhibit qualitative and quantitative effects substantially comparable to those of whole extracts when tested at the same concentration found in the extracts. The protective effects are expressed through a marked decrease in release and expression of inflammatory mediators and occur in parallel with a reduced activation of the nuclear factor-B. Moreover, our results clearly show that HPE can partially prevent the IL-1-induced gap formation with perturbation of the monolayer integrity, as shown by a limited IL-1-induced increase of paracellular permeability. Finally we provide evidence that HPE treatment increases transepithelial electrical resistence of Caco-2 cells monolayer, demonstrating that protective effects of HPE under our conditions occur in parallel with molecular interaction of nut components with the epithelial cells membranes. To assess the physiological relevance of the tested concentration it is worth noting that a single serving of pistachio nut (28.34 g) [USDA National Nutrient Database for Standard Reference] contains around 62,34 mg polymeric proanthocyanidins (cyanidin equivalents). Once diluted in a gastrointestinal volume of 600 mL, this results in a 3,5 M concentration (104 g/ml) (as cyanidin equivalents) of polymeric proanthocyanidins which represent a plausible concentration in the human gut [14]. This concentration is one order higher than the concentrations selected in our cell model and this suggests that our results might be physiologically relevant in the gastrointestinal tract. Data here presented may further remark the potentially beneficial health effects that may arise by daily intake of small quantity of pistachio nut. Widely available, inexpensive and frequently consumed, this nut for its favorable fatty acid profile and high content in bioactive antioxidant compounds, positively influences the plasma lipid parameters and oxidative status, and elicits antinflammatory properties. In this respect, for its high content in large proanthocyanidins, consumption of pistachio nut may exert locally significant beneficial effects to physiology of gastrointestinal tract