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While verbal memory is among the most compromised cognitive domains in schizophrenia (SZ), its neural substrates remain elusive. Here, we explored the structural and functional brain network correlates of verbal memory impairment in SZ. We acquired diffusion and resting-state functional MRI data of 49 SZ patients, classified as having preserved (VMP, n = 22) or impaired (VMI, n = 26) verbal memory based on the List Learning task, and 55 healthy controls (HC). Structural and functional connectivity matrices were obtained and analyzed to assess associations with disease status (SZ vs. HC) and verbal memory impairment (VMI vs. VMP) using two complementary data-driven approaches: threshold-free network-based statistics (TFNBS) and hybrid connectivity independent component analysis (connICA). TFNBS showed altered connectivity in SZ patients compared with HC (p

Background and Hypothesis Treatment resistant schizophrenia (TRS) affects almost 30% of patients with schizophrenia and has been considered a different phenotype of the disease. In vivo characterization of brain metabolic patterns associated with treatment response could contribute to elucidate the neurobiological underpinnings of TRS. Here, we used 2-[18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) to provide the first head-to-head comparative analysis of cerebral glucose metabolism in TRS patients compared to schizophrenia responder patients (nTRS), and controls. Additionally, we investigated, for the first time, the differences between clozapine responders (Clz-R) and non-responders (Clz-nR). Study Design 53 participants underwent FDG-PET studies (41 patients and 12 controls). Response to conventional antipsychotics and to clozapine was evaluated using a standardized prospective procedure based on PANSS score changes. Maps of relative brain glucose metabolism were processed for voxel-based analysis using Statistical Parametric Mapping software. Study Results Restricted areas of significant bilateral relative hypometabolism in the superior frontal gyrus characterized TRS compared to nTRS. Moreover, reduced parietal and frontal metabolism was associated with high PANSS disorganization factor scores in TRS (P < .001 voxel level uncorrected, P < .05 cluster level FWE-corrected). Only TRS compared to controls showed significant bilateral prefrontal relative hypometabolism, more extensive in CLZ-nR than in CLZ-R (P < .05 voxel level FWE-corrected). Relative significant hypermetabolism was observed in the temporo-occipital regions in TRS compared to nTRS and controls. Conclusions These data indicate that, in TRS patients, altered metabolism involved discrete brain regions not found affected in nTRS, possibly indicating a more severe disrupted functional brain network associated with disorganization symptoms.

Few longitudinal studies have so far investigated the impact of sustained COVID-19 among people with pre-existing psychiatric disorders. We conducted a prospective study involving people with serious mental illness (n = 114) and healthy controls (n = 41) to assess changes in the Perceived Stress Scale, Generalized Anxiety Disorder Scale, Patient Health Questionnaire, and Specific Psychotic Experiences Questionnaire scores 18 months after the COVID-19 pandemic outset. Subjects underwent interviews with a mental health professional in April 2020 and at the end of the local third wave (October 2021). A significant increase in perceived stress was found in healthy controls, especially females. Psychiatric patients showed a significant worsening of anxiety symptoms compared to baseline records (t = -2.3, p = 0.036). Patients who rejected vaccination had significantly higher paranoia scores compared to those willing to get vaccinated (U = 649.5, z = -2.02, p = 0.04). These findings indicate that COVID-19's sustained emergency may cause enduring consequences on mental health, soliciting further investigations.

Aim Early age at schizophrenia onset (EOS) has been associated with a worse clinical course, although previous studies reported substantial heterogeneity. Despite the relevance of the subject, the relationship between the age of onset and treatment resistant schizophrenia (TRS) is less clear. Methods We screened 197 non-affective psychotic patients. Of these, 99 suffered from schizophrenia and were putative TRS and were included in a prospective 4-to-8-week trial to assess their response to antipsychotics. According to status (TRS/nonTRS) and age-at-onset (early: ≤18 years, EOS; adult: >18 years, adult onset schizophrenia [AOS]) patients were subdivided in EOS-TRS, EOS-nonTRS, AOS-TRS, AOS-nonTRS. Multiple clinical variables were measured and compared by analysis of covariance (ANCOVA), using age as a covariate. Two-way analysis of variance (ANOVA) was used to assess whether significant differences were attributable to TRS status or age-at-onset. Results The rate of TRS patients was significantly higher in EOS compared to AOS. At the ANCOVA, EOS-TRS had significantly worse clinical, cognitive, and psychosocial outcomes compared to the other groups. Overall, EOS-TRS were more impaired than EOS-nonTRS, while significant differences with AOS-TRS were less consistent, albeit appreciable. Two-way ANOVA demonstrated that, in the majority of the investigated variables, the significant differences among groups were attributable to the TRS status effect rather than to age-at-onset or combined effects. Conclusions These results suggest that refractoriness to antipsychotics may be strongly linked to the early onset of psychotic symptoms, possibly as a result of common neurobiology.

Cariprazine is a novel antipsychotic drug that exerts partial agonism of dopamine D2/D3 receptors with preferential binding to the D3 receptor, antagonism of 5HT2B receptors, and partial agonism of 5HT1A. Currently, cariprazine has shown clinical efficacy in patients with schizophrenia and with bipolar disorder, as well as adjunctive treatment in patients with Major Depressive Disorder (MDD) and drug-resistant MDD. In the present case series, we report on two patients with treatment-resistant schizophrenia and partial response to clozapine who benefit from combination with cariprazine. The effects of cariprazine combination were remarkable also concerning the adverse metabolic effects of clozapine.

Treatment resistant schizophrenia (TRS), the lack of response to at least two antipsychotics administered at adequate dose and duration, epitomizes in psychiatry one of the most difficult-to-treat pathologies, epidemiologically relevant (affecting one-third of schizophrenia patients) and with severe consequences for the patients in terms of overall functioning. After 50 years, only one drug is approved for TRS: clozapine. Furthermore, a few patients do not respond even to clozapine and are indicated as clozapine-resistant patients. In this review and expert opinion, we have critically appraised the current literature, discussing the role of old and new agents in treating resistant schizophrenia. The search for therapy against TRS, beyond clozapine or in addition to clozapine, has emerged over time, capturing mainly three types of strategies: 1. Add-on of a second-generation antipsychotic (i.e. amisulpride); 2. Add-on of a second antipsychotic with significantly different receptor profile compared to the older ones (e.g. aripiprazole and cariprazine); 3. Novel strategies beyond dopamine D2/D3 receptor occupancy (e.g. xanomeline + trospium, TAAR1-agonists, sodium benzoate, and D-amino acids). More high-quality clinical trials applying the current operationalized criteria for TRS and clozapine-resistance are required to evaluate the efficacy of alternative and add-on treatments.

Background: 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. Methods: In situ hybridization for Homer1a was performed on rat tissue sections from cortical and striatal regions of interest (ROI) after acute or chronic administration of three antipsychotics with divergent receptor profile: Haloperidol, asenapine, and olanzapine. Univariate and multivariate analyses of the effects of topography, treatment, dose, and duration of antipsychotic administration were performed. Results: All acute treatment regimens were found to induce a consistently higher expression of Homer1a compared to chronic ones. Haloperidol increased Homer1a expression compared to olanzapine in striatum at the acute time-point. A dose effect was also observed for acute administration of haloperidol. Conclusions: Biological effects of antipsychotics on Homer1a varied strongly depending on the combination of their receptor profile, dose, duration of administration, and throughout the different brain regions. These molecular data may have translational valence and may reflect behavioral sensitization/tolerance phenomena observed with prolonged antipsychotics.

Treatment-resistant schizophrenia (TRS) or suboptimal response to antipsychotics affects almost 30% of schizophrenia (SCZ) patients, and it is a relevant clinical issue with significant impact on the functional outcome and on the global burden of disease. Among putative novel treatments, glycine-centered therapeutics (i.e. sarcosine, glycine itself, D-Serine, and bitopertin) have been proposed, based on a strong preclinical rationale with, however, mixed clinical results. Therefore, a better appraisal of glycine interaction with the other major players of SCZ pathophysiology and specifically in the framework of dopamine – glutamate interactions is warranted. New methodological approaches at cutting edge of technology and drug discovery have been applied to study the role of glycine in glutamate signaling, both at presynaptic and post-synaptic level and have been instrumental for unveiling the role of glycine in dopamine-glutamate interaction. Glycine is a non-essential amino acid that plays a critical role in both inhibitory and excitatory neurotransmission. In caudal areas of central nervous system (CNS), such as spinal cord and brainstem, glycine acts as a powerful inhibitory neurotransmitter through binding to its receptor, i.e. the Glycine Receptor (GlyR). However, glycine also works as a co-agonist of the N-Methyl-D-Aspartate receptor (NMDAR) in excitatory glutamatergic neurotransmission. Glycine concentration in the synaptic cleft is finely tuned by glycine transporters, i.e. GlyT1 and GlyT2, that regulate the neurotransmitter's reuptake, with the first considered a highly potential target for psychosis therapy. Reciprocal regulation of dopamine and glycine in forebrain, glycine modulation of glutamate, glycine signaling interaction with postsynaptic density proteins at glutamatergic synapse, and human genetics of glycinergic pathways in SCZ are tackled in order to highlight the exploitation of this neurotransmitters and related molecules in SCZ and TRS.

International audience; Type-5 metabotropic glutamate receptors (mGlu5) have been implicated in the mechanism of resilience to stress. They form part of the postsynaptic density (PSD), a thickening of the glutamatergic synapse that acts as a multimodal hub for multiple cellular signaling. Perinatal stress in rats triggers alterations that make adult offspring less resilient to stress. In the present study, we examined the expression of gene encoding the mGlu5 (Grm5), as well as those encoding the short and long isoforms of Homer proteins in different brain regions of the offspring of dams exposed to repeated episodes of restraint stress during pregnancy (“perinatally stressed” or PRS offspring). To this end, we investigated unconditioned behavioral response using the light/dark box test, as well as the expression of PSD genes (Homer1a, Homer1b, and Grm5), in the medial prefrontal cortex, cortex, caudate-putamen, amygdala, and dorsal hippocampus. PRS rats spent significantly less time in the light area than the control group. In the amygdala, Homer1a mRNA levels were significantly increased in PRS rats, whereas Homer1b and Grm5 mRNA levels were reduced. In contrast, the transcript encoding for Homer1a was significantly reduced in the medial prefrontal cortex, caudate-putamen, and dorsal hippocampus of PRS rats. We also evaluated the relative ratio between Homer1a and Homer1b/Grm5 expression, finding a significant shift toward the expression of Homer1a in the amygdala and toward Homer1b/Grm5 in the other brain regions. These topographic patterns of Homer1a, Homer1b, and mGlu5 gene expression were significantly correlated with risk-taking behavior measured in the light/dark box test. Remarkably, in the amygdala and in other brain regions, Homer1b and Grm5 expression showed positive correlation with time spent in the light box, whereas Homer1a in the amygdala showed a negative correlation with risk-taking behavior, in contrast with all other brain regions analyzed, wherein these correlations were positive. These results suggest that perinatal stress programs the developmental expression of PSD molecules involved in mGlu5 signaling in discrete brain regions, with a predominant role for the amygdala.

Background Schizophrenia (SCZ) is a debilitating mental illness characterized by a highly complex, heterogeneous, non-mendelian genetic background. Recent progress in dissecting genetic architecture of SCZ has accelerated over the last decade due to new advanced technologies. Genome-Wide Association Studies (GWAS) on extremely large samples of patients identified and replicated hundreds of Single-Nucleotide Polymorphism (SNPs), each exhibiting only a modest effect. The analysis of genomic Copy Number Variations (CNVs) clarified the role of rare structural variants conferring significant risk by disrupting multiple genes involved in neurodevelopmental pathways, and linked to SCZ. In this scenario, the aim of our study is to carry out a genetic characterization of a cohort of patients affected by SCZ, in order to assess the risk of recurrence, to elucidate putative pathogenetic mechanisms and, whenever possible, to conceive tailored interventions and therapies. Methods 34 patients (8 women and 26 men) affected by SCZ and admitted to Day Hospital at Psychiatric Division for Treatment Resistant Psychosis of the University of Naples Federico II were recruited, and underwent: i) psychopathological evaluation and assessment of clinical response to antipsychotics; ii) genetic counseling; iii) further diagnostic investigation by using Comparative Genomic Hybridization (CGH) + Single Nucleotide Polymorphism (SNP) microarray with 2x400k Agilent’s platform “GenetiSure” for detecting unbalanced chromosomal abnormalities and regions of homozygosity (ROHs). Results Structural pathogenetic rearrangements resulted in 9 (27%) patients. Those identified were the following: 15q13.3 deletion, 16p13.11 duplication, 22q11.22 deletion (TOP3B), 22q11.22 (PRODH, DGCR5, DGCR6), RBFOX1 deletion, TCF4 deletion, derivative X chromosome (X;Y translocation). Potentially pathogenic rearrangements, involving genes associated with psychiatric disorders or implicated in neurodevelopment, resulted in 15 patients (44%). No relevant CNVs were detected in 10 patients (29%), although they showed the presence of ROHs that may contain susceptibility loci, since many neurodevelopmental genes map onto or near these specific regions. Certain of these rearrangements occur in many patients, and certain patients showed likewise multiple rearrangements. Discussion The analysis of CNVs and SNPs allowed us to characterize the genetic disease structure in the whole cohort of patients and helped to refine the diagnosis in a few cases, thereby ascertaining an underlying specific genetic condition. A further extension of the study, in terms of sample size and more accurate investigations (i.e genetic mapping of ROHs) is underway. According to literature, rare risk-associated CNVs account for 2% of SCZ cases, but their higher prevalence (27%) in our sample may be influenced by a larger percentage of Treatment Resistant and more severely ill patients (since they were recruited in a highly specialized Unit for Treatment Resistant Psychosis). Therefore, our future purpose is to demonstrate a robust genetic modulation of Treatment Resistant endophenotypes of SCZ. Moreover, we believe that the role of genetic counseling in psychiatric services should be emphasized, and that genetic testing in this field should not be restricted to suspected childhood neuropsychiatric disorders. According to the neurodevelopmental hypothesis of SCZ, that suggests a brain development disruption in early life (due to genetic and early environmental factors), prompting to a subsequent later emergence of the disease in adulthood, even chronic complex adult mental illness, such as SCZ, deserves detailed investigations and a more exhaustive genetic evaluation.

Objective: Selective serotonin reuptake inhibitors (SSRIs) are the cornerstone of treatment of major depressive disorder (MDD). However, non-response is common, often necessitating combination strategies. The present study assessed the efficacy of vortioxetine as an add-on therapy in patients with SSRI-resistant MDD. Methods: The charts of 36 adult outpatients with DSM-IV-TR MDD who had not achieved a response after at least 8 weeks of treatment with an SSRI were reviewed retrospectively. Subjects were treated with vortioxetine (5-20 mg/day) for 8 weeks added to the current SSRI. The main outcome measures were change from baseline in total Hamilton Scale for Depression (HAM-D) score and the rate of response (a 50% or greater reduction in HAM-D score and a Clinical Global Impression ‐ Improvement module [CGI-I] score of 1 or 2 at endpoint). HAM-D scores ≤ 7 were considered as remission. Additional outcome measures included the Snaith-Hamilton Pleasure Scale (SHAPS) and the Scale for Suicide Ideation (SSI). Results: 32 patients completed the 8 weeks of treatment. At 8 weeks, a significant reduction in HAM-D score was observed (p ≤ 0.001), with response obtained by 41.7% and remission by 33.3% of patients. Significant reductions in SHAPS and SSI were also observed (p ≤ 0.001 for both scales). Conclusions: Adjunctive vortioxetine may be useful and well-tolerated in stage I treatment-resistant depression. However, the limitations of this study (such as small sample size, absence of randomization and control group, retrospective design, etc.) must be considered.

Background Schizophrenia has been conceptualized both as synaptic plasticity and a functional connectivity disorder. Data on brain connectivity can be rendered in the form of network models. In our study we want to evaluate a particular kind of the structural and functional interaction between region of interest (ROI) relevant to schizophrenia pathophysiology: we evaluated the expression of Immediate Early Gene (IEG), Homer1a (H1a), in the different ROI and its functional interaction after Haloperidol (antipsychotic drug) acute administration. H1a is an IEG expressed in an activity-dependent manner, coding for a protein involved in the activity-induced reorganization of glutamatergic synapses. Methods Sprague-Dawley rats were randomly assigned to two treatment groups (n=23), receiving vehicle (NaCl 0.9%; VEH) or haloperidol 0.8 mg/kg (HAL) i.p. injection. H1a induction was evaluated using in situ hybridization. Signal intensity analysis was performed in 34 ROIs in the cortex, in the caudate-putamen and the nucleus accumbens. Student’s t-test was used to detect treatment effects. A signal correlation analysis was performed, computing all possible pairwise Pearson correlations among ROIs separately in the two groups. Using significant correlations, two networks were created for HAL and VEH groups, and their network, node, and edge properties were assessed. Results Bonferroni-corrected Student’s t-tests revealed statistically significant differences between the two treatment groups. Haloperidol significantly induced Homer1a gene expression compared to vehicle in all ROIs of the striatum (dmCP: p Discussion Haloperidol acute administration led to a modification of the gene expression pattern in the brain regions considered herein, and consequently to differential functional connectivity. The observed disruption in the functional correlations of the nucleus accumbens may play a role in the affective, motivational and emotional consequences of haloperidol administration, with the loss of functional correlations with the lateral subregions of the caudate-putamen being potentially more relevant to the motor side-effects of haloperidol. These functional connectivity changes are potentially related to neural activity and synaptic plasticity within the glutamate system and may play a role in antipsychotic therapeutic and side effects. As far as we know, this is the first network analysis study on after haloperidol acute treatment of a gene deeply correlated to dendritic spine architecture.

The term alexithymia is a complex multidimensional construct that literally means “no words for mood”. There are two kind of alexithymia: primary and secondary or otherwise called trait and state alexithymia. There is still an unresolved debate about the nature of alexithymia as a trait or a state. The etiology of alexithymia has not been completely determined because of the numerous factors influencing its development. Alexithymia has been observed among patients with a variety of psychiatric disorders and medical conditions. The aim of this systematic review was to review studies investigating the correlations between alexithymia, depression and anxiety in breast cancer surgery women. Literature search was conducted in January, 2016. PubMed and Scopus databases were used to find studies for inclusion in the systematic review. Correlations between alexithymia, depression and anxiety evidenced that alexithymia may be considered a stable personality trait and an important factor to the development of anxiety symptoms. However, limitations of these studies must be considered and further investigations are needed.

Background Clozapine is the gold standard for Treatment Resistant Schizophrenia (TRS) and its use is strongly recommended after failure of two/three antipsychotics. Nonetheless, prescribing trends do not appear to follow the global guidelines and switching to clozapine is often delayed or improper. Reasons for clozapine underuse are quite understood, whereas little is known on clozapine misuse. In fact, more stringent operative criteria to define TRS should be used in clinical practice, taking advantage of standardized assessment tools in order to avoid false TRS positive. In these perspectives, we studied the patterns of clozapine prescription in a sample of TRS and non-TRS patients, in order to identify psychopathological variables associated with lifetime exposure to clozapine. Methods 198 consecutive patients have been screened for eligibility criteria from 2016 until 2019 at Treatment Resistant Psychosis Centre of the University of Naples “Federico II”. Only stabilized schizophrenic patients aged between 18 and 65 were enrolled. All relevant clinical-demographic data were recorded. TRS diagnosis was based on TRRIP working group operational criteria and clear pseudo-resistance factors were excluded. Patients were subdivided into two groups: those having received or currently under clozapine treatment (eCLZ) and those never treated by clozapine (nCLZ). Patients were assessed for psychotic symptoms (PANSS), cognitive performances (BACS), neurological soft signs (NES), functional capacity (UPSA), social functioning (PSP and SLOF scales), and severity of illness (CGI-S). Results Among the patients included (92), eCLZ were 50 (54.3%), of which 20% being non-TRS. Compared to nCLZ, eCLZ had a significantly earlier age at onset, more hospitalizations, higher daily antipsychotic doses; eCLZ patients had significantly higher scores on the CGI-S, PANSS total, PANSS Negative, General Psychopathology and PAUSS subscale and, according to the Five Factor PANSS Model, higher score on Negative and Disorganization Factors; eCLZ had also more impaired Working Memory performances, higher NES Total score, lower PSP and all SLOF areas scores, except Area4. Then we use univariate and multivariate analysis to delineate predictors of clozapine exposure and to evaluate whether these factors may organize in proximal (independent) and distal (mediated) associations. We found five independently associated variables that mediate all the other ones: high antipsychotic doses, higher disease severity, suicide attempts, impaired working memory, more severe Stereotyped Thinking. Discussion While it is expected that some TRS patients might not receive clozapine, the observation that non-TRS patients had been exposed to clozapine may surprise. A possible explanation may be the lack of systematized procedure to diagnose TRS, which is often merely coincident with a nonspecific lack of response to antipsychotics. Due to mediation analysis, we further gained insights into the hierarchy of these variables’ impact on clozapine prescription and we finally compose a complex network of proximal and distal factors predicting clozapine exposure in schizophrenic patients. The above-mentioned independent variables significantly associated with clozapine exposure let intend that eCLZ patients may belong to a subset of more severely ill ones, beyond reaching the response threshold. Earlier onset patients may suffer from a more severe disease, be more prone to suicide attempts, and less responsive to antipsychotics. This result needs to be replicated in wider samples, and this relevant therapeutic issue should be further debated in order to gather robust evidence to support or discourage clozapine off-label use and misuse.

Background Earlier age at schizophrenia onset has been associated with worse prognosis, greater symptom severity, social withdrawal, poorer cognitive performances, however much heterogeneity and inconsistency in findings have been reported in these studies. Treatment Resistant Schizophrenia (TRS) is defined as the persistence of significant symptoms despite at least two adequate treatment trials, each for a minimum duration and dosage. Patients affected by TRS display worse cognitive functioning, social performances and a greater prevalence of Neurological Soft Signs compared to non-TRS. To date, no studies have explored whether early onset TRS patients differ in multiple clinical, cognitive, and social outcomes compared to early onset non-TRS patients and to adult onset patients. The objective of this study is to investigate the relationship of the condition of non-response to antipsychotic agents with age at onset of the first psychotic episode Methods We recruited 99 non-affective psychotic patients, that were referred to our academic outpatient unit for supposed resistance to antipsychotics. The diagnosis of TRS was made by a structured diagnostic flowchart, according to published guidelines. Patients underwent a wide set of clinical and cognitive evaluations by trained raters. According to the age of the first episode of psychosis, patients were subdivided in early onset (EO, 20 years). Clinical and demographic variables were compared by Student’s t and Chi square tests. Then, patients were subdivided in EO-TRS, EO-nonTRS, AO-TRS, AO-nonTRS and their clinical outcomes were compared by ANCOVA, using age as a covariate. The 2way ANOVA was used to assess whether significant differences among groups were attributable to Diagnosis (TRS vs. non-TRS), Age at Onset (EO vs. AO), or combined effects. Results Compared to AO schizophrenia patients, EO had more relevant cognitive impairments (although limited to discrete domains), more severe neurological soft signs, more severe psychotic symptoms, mostly in the disorganized and autistic trait domains, and exhibited more severe social and functional impairments. The rate of TRS patients was significantly higher in the EO group and the rate of non-TRS was significantly higher in the AO group (X=6.31, df=1, p=0.012). At the ANCOVA, EO-TRS patients had significantly longer duration of disease, more severe disease, and were under higher antipsychotic doses. Neurological soft signs were more relevant in the group of EO-TRS, while Visuospatial memory and verbal memory were more impaired in this group compared to the others. Also, this subgroup of patients exhibited the highest scores on PANSS total and subscales, and more impaired psychosocial functioning at the PSP, the UPSA, and the SLOF. Notably, in many cases, EO-TRS were more impaired than EO-nonTRS, while significant differences with AO-TRS were less consistent. 2way ANOVA demonstrated that in the majority of the investigated variables the significant differences among groups were attributable to a Diagnosis effect rather than to Age at Onset or combined effects. Discussion The study confirmed previous observations in patients subdivided into EO vs. AO ones. However, EO patients were more frequently TRS. The group of EO-TRS had the most severe and impaired outcomes. These results were mostly dependent on the condition of non-response to antipsychotic agents rather than to the earlier age at onset of psychotic symptoms. The neurobiology of TRS may cause both the most severe clinical course and the earlier age at onset of these patients. Heterogeneity in previous reports on EO schizophrenia may stem from fluctuating relative rates of TRS/non-TRS patients included in some studies compared to others.

This post-hoc study was aimed at assessing whether disease severity was higher in a sample of Treatment Resistant Schizophrenia patients (TRS) compared to schizophrenia patients responsive to antipsychotics (non-TRS). Determinants of disease severity were also investigated in these groups. Eligible patients were screened by standardized diagnostic algorithm to categorize them as TRS or non-TRS. All patients underwent the following assessments: CGI-S; PANSS; DAI; NES; a battery of cognitive tests. Socio-demographic and clinical variables were also recorded. TRS patients exhibited significantly higher disease severity and psychotic symptoms, either as PANSS total score or subscales' scores. A preliminary correlation analysis ruled out clinical and cognitive variables not associated with disease severity in the two groups. Hierarchical linear regression showed that negative symptoms were the clinical variable explaining the highest part of variation in disease severity in TRS, while in non-TRS patients PANSS-General Psychopathology was the variable explaining the highest variation. Mediation analysis showed that negative symptoms mediate the effects of verbal fluency dysfunctions and high-level neurological soft signs (NSS) on TRS' disease severity. These results show that determinants of disease severity sharply differ in TRS and non-TRS patients, and let hypothesize that TRS may stem from cognitive disfunctions and putatively neurodevelopmental aberrations.

An increasing amount of research aims at recognizing the molecular mechanisms involved in long-lasting brain architectural changes induced by antipsychotic treatments. Although both structural and functional modifications have been identified following acute antipsychotic administration in humans, currently there is scarce knowledge on the enduring consequences of these acute changes. New insights in immediate-early genes (IEGs) modulation following acute or chronic antipsychotic administration may help to fill the gap between primary molecular response and putative long-term changes. Moreover, a critical appraisal of the spatial and temporal patterns of IEGs expression may shed light on the functional "signature" of antipsychotics, such as the propensity to induce motor side effects, the potential neurobiological mechanisms underlying the differences between antipsychotics beyond D2 dopamine receptor affinity, as well as the relevant effects of brain region-specificity in their mechanisms of action. The interest for brain IEGs modulation after antipsychotic treatments has been revitalized by breakthrough findings such as the role of early genes in schizophrenia pathophysiology, the involvement of IEGs in epigenetic mechanisms relevant for cognition, and in neuronal mapping by means of IEGs expression profiling. Here we critically review the evidence on the differential modulation of IEGs by antipsychotics, highlighting the association between IEGs expression and neuroplasticity changes in brain regions impacted by antipsychotics, trying to elucidate the molecular mechanisms underpinning the effects of this class of drugs on psychotic, cognitive and behavioral symptoms.

Loxapine is a first generation antipsychotic, belonging to the dibenzoxazepine class. Recently, loxapine has been reformulated at a lower dose, producing an inhaled powder that can be directly administered to the lungs to treat the agitation associated with psychiatric disorders, such as schizophrenia and bipolar disorder. Thus, the aim of this narrative and clinical mini-review was to evaluate the efficacy and tolerability of inhaled loxapine in the treatment of acute agitation in patients with psychiatric disorders. The efficacy of inhaled loxapine has been evaluated in one Phase II trial on patients with schizophrenia, and in two Phase III trials in patients with schizophrenia and bipolar disorder. Moreover, there are two published case series on patients with borderline personality disorder and dual diagnosis patients. Inhaled loxapine has proven to be effective and generally well tolerated when administered to agitated patients with schizophrenia and bipolar disorder. Two case series have suggested that inhaled loxapine may also be useful to treat agitation in patients with borderline personality disorder and with dual diagnosis, but further studies are needed to clarify this point. However, the administration of inhaled loxapine requires at least some kind of patient collaboration, and is not recommended in the treatment of severe agitation in totally uncooperative patients. Moreover, the drug-related risk of bronchospasm must always be kept in mind when planning to use inhaled loxapine, leading to a careful patient assessment prior to, and after, administration. Also, the higher costs of inhaled loxapine, when compared to oral and intramuscular medications, should be taken into account when selecting it for the treatment of agitation.

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.

To summarize risks related to (1) illness and (2) second-generation antipsychotic (SGA) treatment in pregnant women and their offspring. Concerning illness-related risks, we focused on bipolar disorder and schizophrenia, psychiatric disorders for which SGAs are preferentially prescribed. Objective: To summarize risks related to (1) illness and (2) secondgeneration antipsychotic (SGA) treatment in pregnant women and their offspring. Concerning illness-related risks, we focused on bipolar disorder and schizophrenia, psychiatric disorders for which SGAs are preferentially prescribed. Data Sources: PubMed, Ovid, Scopus, PsycINFO, and Cochrane Library were searched from the date of the first available article to October 2015 using the following key terms: pregnancy OR gestation OR bipolar disorder OR schizophrenia. We also included cross-references from identified articles. Study Selection: We included 49 English-language articles regarding illnessrelated and SGA-related risks in bipolar disorder and schizophrenia. First, searches were done for epidemiologic or experimental studies (from January 2000 to October 2015), then for systematic reviews and meta-analyses. Data Extraction: Data were extracted independently, after removing duplicates and studies that were not relevant or not pertinent. Results: Abrupt discontinuation of treatment-exposed mothers with bipolar disorder or schizophrenia led to a high risk of relapses during pregnancy. Both bipolar disorder and schizophrenia were linked to a slightly increased risk of obstetric complications for mothers (schizophrenia) and the newborn (bipolar disorder and schizophrenia), although data on drug exposure during pregnancy were not given in the majority of studies. Maternal morbidity (schizophrenia but not bipolar disorder) may be associated with the worst neonatal outcomes (stillbirth, neonatal or infant deaths, and intellectual disability). Untreated bipolar disorder and schizophrenia may be considered independent risk factors for congenital malformations, while SGAs were not associated with increased recurring defects in fetuses. Evidence regarding the potential effects of SGAs on child neurodevelopment remains reassuring. Conclusion: After taking into account the parents' will and after they provide informed consent, the most reasonable and less harmful choice for treating future mothers with bipolar disorder or schizophrenia appears to be maintaining them at the safest minimum dosage.

Dopamine-glutamate interplay dysfunctions have been suggested as pathophysiological key determinants of major psychotic disorders, above all schizophrenia and mood disorders. For the most part, synaptic interactions between dopamine and glutamate signaling pathways take part in the postsynaptic density, a specialized ultrastructure localized under the membrane of glutamatergic excitatory synapses. Multiple proteins, with the role of adaptors, regulators, effectors, and scaffolds compose the postsynaptic density network. They form structural and functional crossroads where multiple signals, starting at membrane receptors, are received, elaborated, integrated, and routed to appropriate nuclear targets. Moreover, transductional pathways belonging to different receptors may be functionally interconnected through postsynaptic density molecules. Several studies have demonstrated that psychopharmacologic drugs may differentially affect the expression and function of postsynaptic genes and proteins, depending upon the peculiar receptor profile of each compound. Thus, through postsynaptic network modulation, these drugs may induce dopamine-glutamate synaptic remodeling, which is at the basis of their long-term physiologic effects. In this review, we will discuss the role of postsynaptic proteins in dopamine-glutamate signals integration, as well as the peculiar impact of different psychotropic drugs used in clinical practice on postsynaptic remodeling, thereby trying to point out the possible future molecular targets of "synapse-based" psychiatric therapeutic strategies.