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Treatment Resistant Schizophrenia (TRS) is the persistence of significant symptoms despite adequate antipsychotic treatment. Although consensus guidelines are available, this condition remains often unrecognized and an average delay of 4–9 years in the initiation of clozapine, the gold standard for the pharmacological treatment of TRS, has been reported. We aimed to determine through a machine learning approach which domain of the Positive and Negative Syndrome Scale (PANSS) 5-factor model was most associated with TRS. In a cross-sectional design, 128 schizophrenia patients were classified as TRS (n = 58) or non-TRS (n = 60) after a structured retrospective-prospective analysis of treatment response. The random forest algorithm (RF) was trained to analyze the relationship between the presence/absence of TRS and PANSS-based psychopathological factor scores (positive, negative, disorganization, excitement, and emotional distress). As a complementary strategy to identify the variables most associated with the diagnosis of TRS, we included the variables selected by the RF algorithm in a multivariate logistic regression model. according to the RF model, patients with higher disorganization, positive, and excitement symptom scores were more likely to be classified as TRS. The model showed an accuracy of 67.19%, a sensitivity of 62.07%, and a specificity of 71.43%, with an area under the curve (AUC) of 76.56%. The multivariate model including disorganization, positive, and excitement factors showed that disorganization was the only factor significantly associated with TRS. Therefore, the disorganization factor was the variable most consistently associated with the diagnosis of TRS in our sample. [ABSTRACT FROM AUTHOR]

Once considered only scaffolding proteins at glutamatergic postsynaptic density (PSD), Homer1 proteins are increasingly emerging as multimodal adaptors that integrate different signal transduction pathways within PSD, involved in motor and cognitive functions, with putative implications in psychiatric disorders. Regulation of type I metabotropic glutamate receptor trafficking, modulation of calcium signaling, tuning of long-term potentiation, organization of dendritic spines' growth, as well as meta- and homeostatic plasticity control are only a few of the multiple endocellular and synaptic functions that have been linked to Homer1. Findings from preclinical studies, as well as genetic studies conducted in humans, suggest that both constitutive (Homer1b/c) and inducible (Homer1a) isoforms of Homer1 play a role in the neurobiology of several psychiatric disorders, including psychosis, mood disorders, neurodevelopmental disorders, and addiction. On this background, Homer1 has been proposed as a putative novel target in psychopharmacological treatments. The aim of this review is to summarize and systematize the growing body of evidence on Homer proteins, highlighting the role of Homer1 in the pathophysiology and therapy of mental diseases. • Homer1 is a key molecule of the dendritic spine, a scaffolding and adaptor protein of PSD. • The shorter inducible isoform, Homer1a, acts as dominant negative regulator. • Long constitutive Homer1b/c links mGluRI to multiple intracellular signaling. • Homer1 has been involved in the pathophysiology of many psychiatric disorders. • Homer1 is implicated in the response to psychopharmacological agents. [ABSTRACT FROM AUTHOR]

Despite multiple available treatments for bipolar depression (BD), many patients face sub-optimal responses. Transcranial direct current stimulation (tDCS) has been advocated in the management of different conditions, including BD, especially in treatment-resistant cases. The optimal dose and timing of tDCS, the mutual influence with other concurrently administered interventions, long-term efficacy, overall safety, and biological underpinnings nonetheless deserve additional assessment. The present study appraised the existing clinical evidence about tDCS for bipolar depression, delving into the putative biological underpinnings with a special emphasis on cellular and molecular levels, with the ultimate goal of providing a translational perspective on the matter. Two separate systematic reviews across the PubMed database since inception up to August 8th 2022 were performed, with fourteen clinical and nineteen neurobiological eligible studies. The included clinical studies encompass 207 bipolar depression patients overall and consistently document the efficacy of tDCS, with a reduction in depression scores after treatment ranging from 18% to 92%. The RCT with the largest sample clearly showed a significant superiority of active stimulation over sham. Mild-to-moderate and transient adverse effects are attributed to tDCS across these studies. The review of neurobiological literature indicates that several molecular mechanisms may account for the antidepressant effect of tDCS in BD patients, including the action on calcium homeostasis in glial cells, the enhancement of LTP, the regulation of neurotrophic factors and inflammatory mediators, and the modulation of the expression of plasticity-related genes. To the best of our knowledge, this is the first study on the matter to concurrently provide a synthesis of the clinical evidence and an in-depth appraisal of the putative biological underpinnings, providing consistent support for the efficacy, safety, and tolerability of tDCS. • tDCS might be more beneficial in bipolar than in unipolar depression. • Controlled evidence is insufficient to definitively confirm and quantify efficacy. • tDCS is much safer than the other bipolar depression treatments, including rTMS. • Biological mechanisms: calcium homeostasis, neurotrophins, inflammation, plasticity [ABSTRACT FROM AUTHOR]

Almost fifty years after its first introduction into clinical care, clozapine remains the only evidence-based pharmacological option for treatment-resistant schizophrenia (TRS), which affects approximately 30% of patients with schizophrenia. Despite the long-time experience with clozapine, the specific mechanism of action (MOA) responsible for its superior efficacy among antipsychotics is still elusive, both at the receptor and intracellular signaling level. This systematic review is aimed at critically assessing the role and specific relevance of clozapine's multimodal actions, dissecting those mechanisms that under a translational perspective could shed light on molecular targets worth to be considered for further innovative antipsychotic development. In vivo and in vitro preclinical findings, supported by innovative techniques and methods, together with pharmacogenomic and in vivo functional studies, point to multiple and possibly overlapping MOAs. To better explore this crucial issue, the specific affinity for 5-HT 2 R, D1R, α 2c , and muscarinic receptors, the relatively low occupancy at dopamine D2R, the interaction with receptor dimers, as well as the potential confounder effects resulting in biased ligand action, and lastly, the role of the moiety responsible for lipophilic and alkaline features of clozapine are highlighted. Finally, the role of transcription and protein changes at the synaptic level, and the possibility that clozapine can directly impact synaptic architecture are addressed. Although clozapine's exact MOAs that contribute to its unique efficacy and some of its severe adverse effects have not been fully understood, relevant information can be gleaned from recent mechanistic understandings that may help design much needed additional therapeutic strategies for TRS. [ABSTRACT FROM AUTHOR]

Early life stress may induce synaptic changes within brain regions associated with behavioral disorders. Here, we investigated glutamatergic functional connectivity by a postsynaptic density immediate-early gene-based network analysis. Pregnant female Sprague–Dawley rats were randomly divided into two experimental groups: one exposed to stress sessions and the other serving as a stress-free control group. Homer1 expression was evaluated by in situ hybridization technique in eighty-eight brain regions of interest of male rat offspring. Differences between the perinatal stress exposed group (PRS) (n = 5) and the control group (CTR) (n = 5) were assessed by performing the Student's t- test via SPSS 28.0.1.0 with Bonferroni correction. Additionally, all possible pairwise Spearman's correlations were computed as well as correlation matrices and networks for each experimental group were generated via RStudio and Cytoscape. Perinatal stress exposure was associated with Homer1a reduction in several cortical, thalamic, and striatal regions. Furthermore, it was found to affect functional connectivity between: the lateral septal nucleus, the central medial thalamic nucleus, the anterior part of the paraventricular thalamic nucleus, and both retrosplenial granular b cortex and hippocampal regions; the orbitofrontal cortex, amygdaloid nuclei, and hippocampal regions; and lastly, among regions involved in limbic system. Finally, the PRS networks showed a significant reduction in multiple connections for the ventrolateral part of the anteroventral thalamic nucleus after perinatal stress exposure, as well as a decrease in the centrality of ventral anterior thalamic and amygdaloid nuclei suggestive of putative reduced cortical control over these regions. Within the present preclinical setting, perinatal stress exposure is a modifier of glutamatergic early gene-based functional connectivity in neuronal circuits involved in behaviors relevant to model neurodevelopmental disorders. • Homer1a may be considered as molecular tool to map brain functional connectivity. • Perinatal stress exposure reduces Homer1a levels in the evaluated brain regions. • Perinatal stress exposure disrupts functional connections in the whole the brain. • Perinatal stress represents a vulnerability factor for psychiatric disorders. • Perinatal stress exposure could impact neurodevelopmental processes. [ABSTRACT FROM AUTHOR]