Re-arrangements of glutamatergic post-synaptic density transcripts after antipsychotics and add-on compounds administration in preclinical settings: translational implications for psychosis therapy and treatment resistance

The possibility to translate real-world practice treatment strategies in psychosis to preclinical settings gives the opportunity to dissect at a molecular level the putative modifications that occur and concur to synaptic plasticity rearrangements. Dopamine-glutamate interplay dysfunctions have been suggested as key factors in psychosis pathophysiology and for the most part, synaptic interactions between dopamine and glutamate signaling pathways take part at the post-synaptic density (PSD). Therefore, the major goal of the present research was to focus on PSD adaptations to pharmacological manipulations mimicking common clinical situations. According to these premises, here we provide a set of preclinical studies whose aim was to investigate: i) the postsynaptic molecular adaptations to prolonged pharmacological treatments with the specific scope of comparing novel multitargeting agents to first and second generation antipsychotics currently used in clinical practice; ii) the comparison of acute versus chronic plasticity-related genes differences in terms of expression as a molecular fingerprint of the two different treatment situations; iii) the molecular effects on key PSD molecules of the combined assumption of voluptuary substances such as caffeine and nicotine plus antipsychotics; iv) the adaptations of PSD transcripts to novel proposed add-on treatment options to antipsychotics, and particularly to the administration of minocycline. With the first set of experiments, particular efforts were made at recreating current pharmacological strategies focusing on newly approved antipsychotic agents that may activate postsynaptic transcripts with a different topographic distribution from that elicited by standard therapies, and that may suggest better clinical efficacy or possibly some new adverse effects. This study was followed by the second set of experiments with the specific aim of providing a direct head-to-head comparison of the synaptic molecular changes caused by acute versus chronic administration of the same compounds focusing on the IEG Homer1a. The third set of experiments, through topographic analyses and a behavioral study, was aimed at providing the differential region-specific brain gene expression changes that may occur when antipsychotics are taken with nicotine and caffeine, whose positive or negative additive effects are still a matter of debate at the clinical level. Finally, since glutamatergic agents have been considered as potentially relevant add-on strategies to antipsychotics in order to reduce negative symptoms and improve cognition, the last set of experiments was aimed at dissecting the molecular effects of the synthetic second-generation tetracycline minocycline that has been recently suggested for the treatment of schizophrenia. Indeed, several lines of evidence suggest that this antibiotic may exert glutamatergic modulatory and anti-inflammatory effects, which are consistent with a potential implication of inflammatory and oxidative pathways in the pathophysiology of psychosis

Lurasidone in the Treatment of Bipolar Depression: : Systematic Review of Systematic Reviews

Copyright © 2017 Michele Fornaro et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction. A burgeoning number of systematic reviews considering lurasidone in the treatment of bipolar depression have occurred since its Food and Drug Administration extended approval in 2013. While a paucity of available quantitative evidence still precludes preliminary meta-analysis on the matter, the present quality assessment of systematic review of systematic reviews, nonetheless, aims at highlighting current essential information on the topic. Methods. Both published and unpublished systematic reviews about lurasidone mono- or adjunctive therapy in the treatment of bipolar depression were searched by two independent authors inquiring PubMed/Cochrane/Embase/Scopus from inception until October 2016. Results. Twelve included systematic reviews were of moderate-to-high quality and consistent in covering the handful of RCTs available to date, suggesting the promising efficacy, safety, and tolerability profile of lurasidone. Concordance on the drug profile seems to be corroborated by a steadily increasing number of convergent qualitative reports on the matter. Limitations. Publication, sponsorship, language, citation, and measurement biases. Conclusions. Despite being preliminary in nature, this overview stipulates the effectiveness of lurasidone in the acute treatment of Type I bipolar depression overall. As outlined by most of the reviewed evidence, recommendations for future research should include further controlled trials of extended duration.Peer reviewe

The emerging role of dopamine-glutamate interaction and of the postsynaptic density in bipolar disorder pathophysiology: Implications for treatment

Aberrant synaptic plasticity, originating from abnormalities in dopamine and/or glutamate transduction pathways, may contribute to the complex clinical manifestations of bipolar disorder (BD). Dopamine and glutamate systems cross-talk at multiple levels, such as at the postsynaptic density (PSD). The PSD is a structural and functional protein mesh implicated in dopamine and glutamate-mediated synaptic plasticity. Proteins at PSD have been demonstrated to be involved in mood disorders pathophysiology and to be modulated by antipsychotics and mood stabilizers. On the other side, post-receptor effectors such as protein kinase B (Akt), glycogen synthase kinase-3 (GSK-3) and the extracellular signal-regulated kinase (Erk), which are implicated in both molecular abnormalities and treatment of BD, may interact with PSD proteins, and participate in the interplay of the dopamine-glutamate signalling pathway. In this review, we describe emerging evidence on the molecular cross-talk between dopamine and glutamate signalling in BD pathophysiology and pharmacological treatment, mainly focusing on dysfunctions in PSD molecules. We also aim to discuss future therapeutic strategies that could selectively target the PSD-mediated signalling cascade at the crossroads of dopamine-glutamate neurotransmission

Switching antipsychotics: Imaging the differential effect on the topography of postsynaptic density transcripts in antipsychotic-naïve vs. antipsychotic-exposed rats

The postsynaptic density (PSD) has been regarded as a functional switchboard at the crossroads of a dopamine-glutamate interaction, and it is putatively involved in the pathophysiology of psychosis. Indeed, it has been demonstrated that antipsychotics may modulate several PSD transcripts, such as PSD-95, Shank, and Homer. Despite switching antipsychotics is a frequent strategy to counteract lack of efficacy and/or side effect onset in clinical practice, no information is available on the effects of sequential treatments with different antipsychotics on PSD molecules. The aim of this study was to evaluate whether a previous exposure to a typical antipsychotic and a switch to an atypical one may affect the expression of PSD transcripts, in order to evaluate potential neurobiological correlates of this common clinical practice, with specific regards to putative synaptic plasticity processes. We treated male Sprague-Dawley rats intraperitoneally for 15days with haloperidol or vehicle, then from the sixteenth day we switched the animals to amisulpride or continued to treat them with vehicle or haloperidol for 15 additional days. In this way we got six first treatment/second treatment groups: vehicle/vehicle, vehicle/haloperidol, vehicle/amisulpride, haloperidol/vehicle, haloperidol/haloperidol, haloperidol/amisulpride. In this paradigm, we evaluated the expression of brain transcripts belonging to relevant and interacting PSD proteins, both of the Immediate-Early Gene (Homer1a, Arc) and the constitutive classes (Homer1b/c and PSD-95). The major finding was the differential effect of amisulpride on gene transcripts when administered in naïve vs. antipsychotic-pretreated rats, with modifications of the ratio between Homer1a/Homer1b transcripts and differential effects in cortex and striatum. These results suggest that the neurobiological effects on PSD transcripts of amisulpride, and possibly of other antipsychotics, may be greatly affected by prior antipsychotic treatments and may impact significantly on the switching procedure

The Effects of Antipsychotics on the Synaptic Plasticity Gene Homer1a Depend on a Combination of Their Receptor Profile, Dose, Duration of Treatment, and Brain Regions Targeted

Antipsychotic agents modulate key molecules of the postsynaptic density (PSD), including the Homer1a gene, implicated in dendritic spine architecture. How the antipsychotic receptor profile, dose, and duration of administration may influence synaptic plasticity and the Homer1a pattern of expression is yet to be determined

Translating preclinical findings in clinically relevant new antipsychotic targets: focus on the glutamatergic postsynaptic density. Implications for treatment resistant schizophrenia

There is a growing interest in new molecular targets for antipsychotic therapy. Multiple signal transduction systems have been recently implicated in the pathophysiology of schizophrenia. However, the weight of each specific mechanism remains controversial. A need for a more vigorous approach to the pharmacotherapy of schizophrenia arises from the bedside: about 30-40% of patients do not respond to antipsychotic therapy. Postsynaptic Density (PSD) proteins have recently attracted attention for their role in signal transduction modulation and for their potential implication in psychosis and cognition. The involvement of PSD in the pathophysiology of schizophrenia is supported by post mortem studies, preclinical animal models, modulation by antipsychotics, and association of PSD genes with schizophrenia in GWAS. Taken together, these studies underline the role of PSD modulation, its effects on striatal function and its relationship with motor, executive- and cognitive-like functions suggesting a potential role of PSD proteins as a potential target of novel intervention in the treatment of refractory psychosis