137,147 Further, 5-HT dysfunction due to certain genetic variations in SERT and 5-HT receptor sequences is now detectable by functional neuroimaging.87,150-150 Although not quite completely understood,

these recent data from living human brain imaging support and often greatly extend, previous data obtained by conventional postmortem investigations. Serotonergic circuitries in function Serotonergic circuitries chiefly include 5-HT-producing neurons, 5-HT-autoreceptors (ie, somatodendritic 5HT1 A receptors, 5-HT1B/1D receptors in terminal endings) #DMXAA keyword# and other neurotransmitter or hormone receptors including alpha-adrenoceptors, CRF receptors, tachykinin receptors, estrogen receptor beta and more recently demonstrated, oxytocin receptors151

involved in neuronal firing and 5-HT release. Functionally connected neuronal Inhibitors,research,lifescience,medical elements bearing 5-HT-heteroreceptors (often called postsynaptic or perisynaptic receptors, see below) are obviously another major component of the serotonergic neurotransmission.100,152,153 Additionally, classical neurotransmitters (eg, GABA, glutamate, dopamine, noradrenaline), peptidergic neuromodulators (eg, substance P), and Inhibitors,research,lifescience,medical endocannabinoid coexpression within 5-HT neurons also contribute to the serotonergic function.154,155 Considering that in several Inhibitors,research,lifescience,medical brain areas, including the neocortex

and the hippocampus, 5-HT wired neurotransmission (WT) via true synapses coexists with volume transmission (VT), the terms pre- and postsynaptic should be used with caution. Inhibitors,research,lifescience,medical In fact, distances between release sites and receptors are not of the same magnitude, generally a few nm for WT vs up to 10 µm for VT. Thus, some authors consider that neuropsychoactive drugs act rather as volume transmission signals.156 Due to ethical and methodological limitations, our knowledge on neurotransmitter circuitries and their interconnections in human CNS largely benefits from that described with much detail in nonhuman primates and other species including cat and rodents. In laboratory animal species, the anatomical distribution of brain 5-HT neurons was often completed by other approaches such as transneuronal over retrograde transport, selective lesions, microdialysis, electrophysiology associated with pharmacological manipulations, and more recently developed wireless fast-scan cyclic voltametry, a promising tool for the in vivo monitoring of 5-HT in the brain.157 Therefore, the circuitries of serotonergic neurons in the human brain are mainly based on those known in other mammals.

An open-label, 50-week RLAI study has evaluated remission using the Remission in Schizophrenia Working Group find more criteria in stable patients converted to RLAI [Lasser et al. 2005]. In this

study, all patients were considered clinically stable at baseline; however, 68% were not in remission. After switching to RLAI, 21% of previously nonremitted patients achieved symptom remission for at least 6 months. Remission was also assessed in patients Inhibitors,research,lifescience,medical treated in the Switch to Risperidone Microspheres (StoRMi) open-label study following patients switched to RLAI for up to 18 months [Llorca et al. 2008]. In this sample of 529 patients, 94% of those who achieved or maintained remission at 6 months were in remission at endpoint. Among patients not meeting remission criteria at baseline, 45% were in remission at Inhibitors,research,lifescience,medical endpoint; among patients meeting remission severity criteria at baseline, 85% were in remission at endpoint. In a small long-term study, 50 patients with newly diagnosed schizophrenia or schizophreniform disorder were treated with RLAI for 2 years [Emsley et al. 2008a]. Remission

was achieved by 32 of the 50 patients (64%). The 2-year, RLAI relapse prevention Inhibitors,research,lifescience,medical trial (ConstaTRE) was designed to compare relapse in stable patients with schizophrenia or schizoaffective disorders treated with either RLAI or the oral atypical antipsychotic quetiapine [Gaebel et al. 2010]. The use of nonblinded treatment in this study allows a more real-world evaluation of treatment efficacy as influenced by adherence, rather Inhibitors,research,lifescience,medical than a direct

efficacy analysis of differences between risperidone and quetiapine. In this study, relapse occurred in 16.5% of patients treated with RLAI and 31.3% with quetiapine. The mean ± standard deviation (SD) time to relapse among patients experiencing a relapse was 244.9 ± 208.0 days with RLAI and 207.6 ± 171.0 days with quetiapine. The mean ± SD relapse-free period was 607.1 ± 11.4 days Inhibitors,research,lifescience,medical with RLAI and 532.5 ± 15.6 days with quetiapine. The current report expands on the earlier report by presenting long-term remission results from the ConstaTRE study Terminal deoxynucleotidyl transferase [Gaebel et al. 2010]. Experimental procedures Study design ConstaTRE was a multicentre, open-label, randomized, active-control, 2-year study comparing RLAI and oral quetiapine [ClinicalTrials.gov identifier: NCT00216476]. This study was conducted from October 2004 to November 2007 at 124 sites in 25 countries. Results of a small descriptive arm in which patients could also be randomized to aripiprazole were described in a separate paper [De Arce Cordón et al. 2012]. This trial was conducted in accordance with the guidelines of the International Conference on Harmonization for Good Clinical Practice, and the study protocol and consent were approved by an Institutional Review Board.

Conflict of interest statement: The authors declare that there is no conflict of interest. Contributor Information Giulia Serra, CI 1033 NeSMOS Department (Neurosciences, Mental Health and Sensory Organs), School of Medicine and Psychology, Sapienza University, UOC Psychiatry, Sant’Andrea Hospital, Rome, Italy and Centro Lucio Bini, Rome, Italy.

Lavinia De Chiara, NeSMOS Department (Neurosciences, Mental Health and Sensory Organs), School of Medicine and Psychology, Sapienza University, UOC Psychiatry, Sant’Andrea Hospital, Rome, Italy and Centro Lucio Bini, Rome, Italy. Giovanni Manfredi, NeSMOS Department (Neurosciences, Mental Health and Sensory Inhibitors,research,lifescience,medical Organs), School of Medicine and Psychology, Sapienza University, UOC Psychiatry, Inhibitors,research,lifescience,medical Sant’Andrea Hospital, Rome, Italy and Centro Lucio Bini, Rome, Italy. Alexia E. Koukopoulos, NeSMOS Department (Neurosciences, Mental Health and Sensory Organs), School of Medicine and Psychology, Sapienza University, UOC Psychiatry, Sant’Andrea Hospital, Rome, Italy and Centro Lucio Bini, Rome, Italy. Gabriele Sani, NeSMOS Department (Neurosciences, Mental Health and Sensory Organs), School of Medicine and Psychology, Sapienza University, UOC

Psychiatry, Sant’Andrea Hospital, Rome, Italy and Centro Lucio Bini, Rome, Italy and IRCCS Santa Lucia Foundation, Department Inhibitors,research,lifescience,medical of Clinical and Behavioural Neurology, Neuropsychiatry Laboratory, Rome, Italy. Paolo Inhibitors,research,lifescience,medical Girardi, NeSMOS Department (Neurosciences, Mental Health and Sensory Organs), School of Medicine and Psychology, Sapienza University, UOC Psychiatry, Sant’Andrea

Hospital, Rome, Italy and Centro Lucio Bini, Rome, Italy and IRCCS Santa Lucia Foundation, Department of Clinical and Behavioural Neurology, Neuropsychiatry Laboratory, Rome, Italy. Athanasios Koukopoulos, Centro Lucio Bini, Rome, Italy. Gino Serra, Department of Biomedical Sciences, University of Sassari, Viale San Pietro, Inhibitors,research,lifescience,medical 43/b, 07100 Sassari Italy.
Patients diagnosed with schizophrenia have cognitive deficits compared with their relatives, normal controls and patients diagnosed with other psychiatric disorders, for example, depression and bipolar disorder [Buchanan et al. 2005; Cannon et al. 1994; Caspi et al. 2003; Nielsen, 2011]. The cognitive deficits appear before first psychosis and remain stable over time [Caspi et al. 2003; Szoke et al. unless 2008], although some authors have proposed a more neurodegenerative hypothesis regarding the cognitive function [Levander et al. 2001; Rund, 2009]. Several central nervous system receptors are being investigated as to their effect on cognitive function in general and in patients with schizophrenia [Wallace et al. 2011]. Previous studies have shown some implication of the muscarinergic receptor system on cognitive function in patients with schizophrenia [Fagerlund et al. 2007; Freedman et al. 2008; Keefe et al. 2007; Minzenberg et al. 2004; Shekhar et al.

In vitro, silicon dioxide (SiO2) nanoparticles increased ROS and RNS (reactive nitrogen species) production that, in turn, can induce the intrinsic apoptotic machinery [45]. Furthermore, Wang and collaborators showed that p53 plays a key role in silica-induced apoptosis in vitro (mouse preneoplastic epidermal cells and fibroblasts) and in vivo (p53 wild-type and deficient mice) [46]. TiO2 nanoparticles, sized less than 100nm, triggered apoptotic cell death through

ROS-dependent upregulation of FAS and activation of Bax in normal human lung fibroblast and breast selleck inhibitor epithelial cell lines [47]. Moreover, it was also demonstrated that TiO2 nanoparticles Inhibitors,research,lifescience,medical induced apoptosis through the caspase-8/BID pathway in human bronchial epithelial cells and lymphocytes as well as in mouse preneoplastic epidermal cells [48, 49]. Some reports indicated that TiO2 induced also lipid peroxidation, p53-mediated damage response, and caspase activation [50, 51]. In contrast, there are also reports demonstrating that TiO2 nanoparticles did not induce oxidative stress on mouse macrophages [52] as well as Inhibitors,research,lifescience,medical did not shown cytotoxicity Inhibitors,research,lifescience,medical in human dermal fibroblasts and lung epithelial cells [31]. A number of studies have been published concerning the effects of CNTs on apoptosis. Multiwall carbon nanotubes (MWCNTs) induced an increase of ROS, cell cycle arrest, decrease in mitochondrial membrane potential, determining apoptosis

in different in vitro models [53–56]. In contrast, another study reported that these nanotubes were nontoxic [57]. Accordingly, it has been observed that MWCNTs did not stimulate cell Inhibitors,research,lifescience,medical death in vitro after acute exposure and neither after the continuous presence of their low amounts for 6 months [58]. Instead, apoptotic Inhibitors,research,lifescience,medical macrophages have been observed in the airways of mice after inhalation of SWCNTs (single-walled carbon nanotubes) [6]. Accordingly,

several studies in vivo suggest that the exposure to SWCNTs leads to the activation of specific apoptosis signalling pathways [59, 60]. For more details, recent interesting reviews focus on the nanomaterials toxicity in vivo studies [6, 34]. Nanoparticles are frequently detected in lysosomes upon internalization, and a variety of nanomaterials have been associated with lysosomal dysfunction [61]. It has been established that lysosomal destabilization triggers the mitochondrial pathway of apoptosis [62, 63]. Carbon nanotubes were shown to induce lysosomal membrane permeabilization and much apoptotic cell death in murine macrophages and human fibroblasts [64, 65]. Carbon black nanoparticles elicited intrinsic apoptosis in human bronchial epithelial cells with activation of Bax and release of cytochrome c from mitochondria, whereas TiO2 nanoparticles induced apoptosis through lysosomal membrane destabilization and cathepsin B release, suggesting that the pathway of apoptosis differs depending on the nanomaterials chemical nature [66].

selleck patient B A 30-year-old white man, diagnosed with schizophrenia 11 years previously, had been treated as a refractory patient for 10 years, initially with CLZ during the first 5 years, with good response. However, due to syncope that was attributed to the irregular use of CLZ, this medication was discontinued and olanzapine and then quetiapine were both tried without good results, which led to the reintroduction of CLZ 4 years ago, with the patient showing acceptable symptom

control without any noticeable major side effects with regular use of CLZ 500 mg/day and citalopram 20 mg/day. During one of his evaluations in our outpatient clinic, he complained of 7 days of headache Inhibitors,research,lifescience,medical and bone pain, with high fever in the last 2 days, associated with skin rash and nausea during the Inhibitors,research,lifescience,medical last 24 h. A physical exam revealed a BT of 38.5ºC, BP of 100 × 60 mmHg, PR of 80/min, no signs of dehydration and a disseminated maculopapular rash. A CBC

showed a Hct of 47%, WBC count of 2600 (ANC 1700 and L 500) and a plt count of 114,000. He was rehospitalized to receive supportive care and all medications were immediately discontinued due to fever and neutropenia onset. A day 1 dengue rapid test (IgM) came back positive, confirming the suspicion of classic dengue fever. The third CBC 48 h later came back with better results, namely an Hct of 38%, a WBC count of 3700 and a plt count of 119,000. However, the patient had a worsening Inhibitors,research,lifescience,medical of gastric symptoms, presenting with continuous nausea and episodes of vomiting. At day 5, the CBC was normalized (Hct 40%, WBC count 8000 and plt count 337,000) and the physical complaints were gone, but the psychopathology was much worse, with the patient evolving into a catatonic state. Inhibitors,research,lifescience,medical Aripiprazole 15 mg/day was introduced, along with lorazepam 2 mg three times a day. There was an improvement in the symptoms after 8 days, but this was not sustained, despite increasing the aripiprazole dose to 30 mg. After 1 month, aripiprazole was substituted by ziprasidone, but after 40 days there was not an acceptable response; the patient developed catatonia associated

with tremors due to the antipsychotic. Inhibitors,research,lifescience,medical Because of this poor treatment response, rechallenge with CLZ was carefully tried. Three months later, with a complete improvement of positive symptoms and no hematologic alterations, the patient was discharged on CLZ 500 mg/day, the same dosage used before dengue infection. At 18 months after CLZ else reintroduction, the patient maintained the psychopathology improvement without any new hematologic alterations. Patient C A 26-year-old white man, diagnosed with schizophrenia 6 years previously, was treated as a refractory patient for 10 months after treatment failures with risperidone, olanzapine and ziprasidone. CLZ had been introduced 4 months earlier, and after reaching a dose of 300 mg, with partial improvement (without hallucinations, but still delusional), the patient was transferred to our day hospital to continue his treatment.