Structural brain abnormalities and aggressive behaviour in schizophrenia: Mega-analysis of data from 2095 patients and 2861 healthy controls via the ENIGMA consortium.

Background: Schizophrenia is associated with an increased risk of aggressive behaviour, which may partly be explained by illness-related changes in brain structure. However, previous studies have been limited by group-level analyses, small and selective samples of inpatients and long time lags between exposure and outcome. Methods: This cross-sectional study pooled data from 20 sites participating in the international ENIGMA-Schizophrenia Working Group. Sites acquired T1-weighted and diffusion-weighted magnetic resonance imaging scans in a total of 2095 patients with schizophrenia and 2861 healthy controls. Measures of grey matter volume and white matter microstructural integrity were extracted from the scans using harmonised protocols. For each measure, normative modelling was used to calculate how much patients deviated (in z-scores) from healthy controls at the individual level. Ordinal regression models were used to estimate the associations of these deviations with concurrent aggressive behaviour (as odds ratios [ORs] with 99% confidence intervals [CIs]). Mediation analyses were performed for positive symptoms (i.e., delusions, hallucinations and disorganised thinking), impulse control and illness insight. Aggression and potential mediators were assessed with the Positive and Negative Syndrome Scale, Scale for the Assessment of Positive Symptoms or Brief Psychiatric Rating Scale. Results: Aggressive behaviour was significantly associated with reductions in total cortical volume (OR [99% CI] = 0.88 [0.78, 0.98], p = .003) and global white matter integrity (OR [99% CI] = 0.72 [0.59, 0.88], p = 3.50 × 10-5) and additional reductions in dorsolateral prefrontal cortex volume (OR [99% CI] = 0.85 [0.74, 0.97], p =.002), inferior parietal lobule volume (OR [99% CI] = 0.76 [0.66, 0.87], p = 2.20 × 10-7) and internal capsule integrity (OR [99% CI] = 0.76 [0.63, 0.92], p = 2.90 × 10-4). Except for inferior parietal lobule volume, these associations were largely mediated by increased severity of positive symptoms and reduced impulse control. Conclusions: This study provides evidence that the co-occurrence of positive symptoms, poor impulse control and aggressive behaviour in schizophrenia has a neurobiological basis, which may inform the development of therapeutic interventions.

The Neurobiological Underpinnings of Obsessive-Compulsive Symptoms in Psychosis, Translational Issues for Treatment-Resistant Schizophrenia.

Almost 25% of schizophrenia patients suffer from obsessive-compulsive symptoms (OCS) considered a transdiagnostic clinical continuum. The presence of symptoms pertaining to both schizophrenia and obsessive-compulsive disorder (OCD) may complicate pharmacological treatment and could contribute to lack or poor response to the therapy. Despite the clinical relevance, no reviews have been recently published on the possible neurobiological underpinnings of this comorbidity, which is still unclear. An integrative view exploring this topic should take into account the following aspects: (i) the implication for glutamate, dopamine, and serotonin neurotransmission as demonstrated by genetic findings; (ii) the growing neuroimaging evidence of the common brain regions and dysfunctional circuits involved in both diseases; (iii) the pharmacological modulation of dopaminergic, serotoninergic, and glutamatergic systems as current therapeutic strategies in schizophrenia OCS; (iv) the recent discovery of midbrain dopamine neurons and dopamine D1- and D2-like receptors as orchestrating hubs in repetitive and psychotic behaviors; (v) the contribution of N-methyl-D-aspartate receptor subunits to both psychosis and OCD neurobiology. Finally, we discuss the potential role of the postsynaptic density as a structural and functional hub for multiple molecular signaling both in schizophrenia and OCD pathophysiology.

Schizophrenia Synaptic Pathology and Antipsychotic Treatment in the Framework of Oxidative and Mitochondrial Dysfunction: Translational Highlights for the Clinics and Treatment.

Schizophrenia is a worldwide mental illness characterized by alterations at dopaminergic and glutamatergic synapses resulting in global dysconnectivity within and between brain networks. Impairments in inflammatory processes, mitochondrial functions, energy expenditure, and oxidative stress have been extensively associated with schizophrenia pathophysiology. Antipsychotics, the mainstay of schizophrenia pharmacological treatment and all sharing the common feature of dopamine D2 receptor occupancy, may affect antioxidant pathways as well as mitochondrial protein levels and gene expression. Here, we systematically reviewed the available evidence on antioxidants' mechanisms in antipsychotic action and the impact of first- and second-generation compounds on mitochondrial functions and oxidative stress. We further focused on clinical trials addressing the efficacy and tolerability of antioxidants as an augmentation strategy of antipsychotic treatment. EMBASE, Scopus, and Medline/PubMed databases were interrogated. The selection process was conducted in respect of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Several mitochondrial proteins involved in cell viability, energy metabolism, and regulation of oxidative systems were reported to be significantly modified by antipsychotic treatment with differences between first- and second-generation drugs. Finally, antioxidants may affect cognitive and psychotic symptoms in patients with schizophrenia, and although the evidence is only preliminary, the results indicate that further studies are warranted.

Canonical and Non-Canonical Antipsychotics' Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia.

Schizophrenia is a severe psychiatric illness affecting almost 25 million people worldwide and is conceptualized as a disorder of synaptic plasticity and brain connectivity. Antipsychotics are the primary pharmacological treatment after more than sixty years after their introduction in therapy. Two findings hold true for all presently available antipsychotics. First, all antipsychotics occupy the dopamine D2 receptor (D2R) as an antagonist or partial agonist, even if with different affinity; second, D2R occupancy is the necessary and probably the sufficient mechanism for antipsychotic effect despite the complexity of antipsychotics' receptor profile. D2R occupancy is followed by coincident or divergent intracellular mechanisms, implying the contribution of cAMP regulation, ß-arrestin recruitment, and phospholipase A activation, to quote some of the mechanisms considered canonical. However, in recent years, novel mechanisms related to dopamine function beyond or together with D2R occupancy have emerged. Among these potentially non-canonical mechanisms, the role of Na2+ channels at the dopamine at the presynaptic site, dopamine transporter (DAT) involvement as the main regulator of dopamine concentration at synaptic clefts, and the putative role of antipsychotics as chaperones for intracellular D2R sequestration, should be included. These mechanisms expand the fundamental role of dopamine in schizophrenia therapy and may have relevance to considering putatively new strategies for treatment-resistant schizophrenia (TRS), an extremely severe condition epidemiologically relevant and affecting almost 30% of schizophrenia patients. Here, we performed a critical evaluation of the role of antipsychotics in synaptic plasticity, focusing on their canonical and non-canonical mechanisms of action relevant to the treatment of schizophrenia and their subsequent implication for the pathophysiology and potential therapy of TRS.

A Postsynaptic Density Immediate Early Gene-Based Connectome Analysis of Acute NMDAR Blockade and Reversal Effect of Antipsychotic Administration.

Although antipsychotics' mechanisms of action have been thoroughly investigated, they have not been fully elucidated at the network level. We tested the hypothesis that acute pre-treatment with ketamine (KET) and administration of asenapine (ASE) would modulate the functional connectivity of brain areas relevant to the pathophysiology of schizophrenia, based on transcript levels of Homer1a, an immediate early gene encoding a key molecule of the dendritic spine. Sprague-Dawley rats (n = 20) were assigned to KET (30 mg/kg) or vehicle (VEH). Each pre-treatment group (n = 10) was randomly split into two arms, receiving ASE (0.3 mg/kg), or VEH. Homer1a mRNA levels were evaluated by in situ hybridization in 33 regions of interest (ROIs). We computed all possible pairwise Pearson correlations and generated a network for each treatment group. Acute KET challenge was associated with negative correlations between the medial portion of cingulate cortex/indusium griseum and other ROIs, not detectable in other treatment groups. KET/ASE group showed significantly higher inter-correlations between medial cingulate cortex/indusium griseum and lateral putamen, the upper lip of the primary somatosensory cortex, septal area nuclei, and claustrum, in comparison to the KET/VEH network. ASE exposure was associated with changes in subcortical-cortical connectivity and an increase in centrality measures of the cingulate cortex and lateral septal nuclei. In conclusion, ASE was found to finely regulate brain connectivity by modelling the synaptic architecture and restoring a functional pattern of interregional co-activation.

Dopamine Dynamics and Neurobiology of Non-Response to Antipsychotics, Relevance for Treatment Resistant Schizophrenia: A Systematic Review and Critical Appraisal.

Treatment resistant schizophrenia (TRS) is characterized by a lack of, or suboptimal response to, antipsychotic agents. The biological underpinnings of this clinical condition are still scarcely understood. Since all antipsychotics block dopamine D2 receptors (D2R), dopamine-related mechanisms should be considered the main candidates in the neurobiology of antipsychotic non-response, although other neurotransmitter systems play a role. The aims of this review are: (i) to recapitulate and critically appraise the relevant literature on dopamine-related mechanisms of TRS; (ii) to discuss the methodological limitations of the studies so far conducted and delineate a theoretical framework on dopamine mechanisms of TRS; and (iii) to highlight future perspectives of research and unmet needs. Dopamine-related neurobiological mechanisms of TRS may be multiple and putatively subdivided into three biological points: (1) D2R-related, including increased D2R levels; increased density of D2Rs in the high-affinity state; aberrant D2R dimer or heteromer formation; imbalance between D2R short and long variants; extrastriatal D2Rs; (2) presynaptic dopamine, including low or normal dopamine synthesis and/or release compared to responder patients; and (3) exaggerated postsynaptic D2R-mediated neurotransmission. Future points to be addressed are: (i) a more neurobiologically-oriented phenotypic categorization of TRS; (ii) implementation of neurobiological studies by directly comparing treatment resistant vs. treatment responder patients; (iii) development of a reliable animal model of non-response to antipsychotics.

Dysregulated Signaling at Postsynaptic Density: A Systematic Review and Translational Appraisal for the Pathophysiology, Clinics, and Antipsychotics' Treatment of Schizophrenia.

Emerging evidence from genomics, post-mortem, and preclinical studies point to a potential dysregulation of molecular signaling at postsynaptic density (PSD) in schizophrenia pathophysiology. The PSD that identifies the archetypal asymmetric synapse is a structure of approximately 300 nm in diameter, localized behind the neuronal membrane in the glutamatergic synapse, and constituted by more than 1000 proteins, including receptors, adaptors, kinases, and scaffold proteins. Furthermore, using FASS (fluorescence-activated synaptosome sorting) techniques, glutamatergic synaptosomes were isolated at around 70 nm, where the receptors anchored to the PSD proteins can diffuse laterally along the PSD and were stabilized by scaffold proteins in nanodomains of 50-80 nm at a distance of 20-40 nm creating "nanocolumns" within the synaptic button. In this context, PSD was envisioned as a multimodal hub integrating multiple signaling-related intracellular functions. Dysfunctions of glutamate signaling have been postulated in schizophrenia, starting from the glutamate receptor's interaction with scaffolding proteins involved in the N-methyl-D-aspartate receptor (NMDAR). Despite the emerging role of PSD proteins in behavioral disorders, there is currently no systematic review that integrates preclinical and clinical findings addressing dysregulated PSD signaling and translational implications for antipsychotic treatment in the aberrant postsynaptic function context. Here we reviewed a critical appraisal of the role of dysregulated PSD proteins signaling in the pathophysiology of schizophrenia, discussing how antipsychotics may affect PSD structures and synaptic plasticity in brain regions relevant to psychosis.

Neural substrates of verbal memory impairment in schizophrenia: A multimodal connectomics study.

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 < .05, FWER-corrected), with distributed structural changes and functional reorganization centered around sensorimotor areas. Specifically, functional connectivity was reduced within the visual and somatomotor networks and increased between visual areas and associative and subcortical regions. Only a tiny cluster of increased functional connectivity between visual and bilateral parietal attention-related areas correlated with verbal memory dysfunction. Hybrid connICA identified four robust traits, representing fundamental patterns of joint structural-functional connectivity. One of these, mainly capturing the functional connectivity profile of the visual network, was significantly associated with SZ (HC vs. SZ: Cohen's d = .828, p < .0001) and verbal memory impairment (VMP vs. VMI: Cohen's d = -.805, p = .01). We suggest that aberrant connectivity of sensorimotor networks may be a key connectomic signature of SZ and a putative biomarker of SZ-related verbal memory impairment, in consistency with bottom-up models of cognitive disruption.

Altered Patterns of Brain Glucose Metabolism Involve More Extensive and Discrete Cortical Areas in Treatment-resistant Schizophrenia Patients Compared to Responder Patients and Controls: Results From a Head-to-Head 2-[18F]-FDG-PET Study.

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.

Antipsychotics-Induced Changes in Synaptic Architecture and Functional Connectivity: Translational Implications for Treatment Response and Resistance.

Schizophrenia is a severe mental illness characterized by alterations in processes that regulate both synaptic plasticity and functional connectivity between brain regions. Antipsychotics are the cornerstone of schizophrenia pharmacological treatment and, beyond occupying dopamine D2 receptors, can affect multiple molecular targets, pre- and postsynaptic sites, as well as intracellular effectors. Multiple lines of evidence point to the involvement of antipsychotics in sculpting synaptic architecture and remodeling the neuronal functional unit. Furthermore, there is an increasing awareness that antipsychotics with different receptor profiles could yield different interregional patterns of co-activation. In the present systematic review, we explored the fundamental changes that occur under antipsychotics' administration, the molecular underpinning, and the consequences in both acute and chronic paradigms. In addition, we investigated the relationship between synaptic plasticity and functional connectivity and systematized evidence on different topographical patterns of activation induced by typical and atypical antipsychotics.

Update on novel antipsychotics and pharmacological strategies for treatment-resistant schizophrenia.

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

Disorganization domain as a putative predictor of Treatment Resistant Schizophrenia (TRS) diagnosis: A machine learning approach.

BACKGROUND: 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. METHODS: 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. RESULTS: 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.

Linking Inflammation, Aberrant Glutamate-Dopamine Interaction, and Post-synaptic Changes: Translational Relevance for Schizophrenia and Antipsychotic Treatment: a Systematic Review.

Evidence from clinical, preclinical, and post-mortem studies supports the inflammatory/immune hypothesis of schizophrenia pathogenesis. Less evident is the link between the inflammatory background and two well-recognized functional and structural findings of schizophrenia pathophysiology: the dopamine-glutamate aberrant interaction and the alteration of dendritic spines architecture, both believed to be the "quantal" elements of cortical-subcortical dysfunctional network. In this systematic review, we tried to capture the major findings linking inflammation, aberrant glutamate-dopamine interaction, and post-synaptic changes under a direct and inverse translational perspective, a paramount picture that at present is lacking. The inflammatory effects on dopaminergic function appear to be bidirectional: the inflammation influences dopamine release, and dopamine acts as a regulator of discrete inflammatory processes involved in schizophrenia such as dysregulated interleukin and kynurenine pathways. Furthermore, the link between inflammation and glutamate is strongly supported by clinical studies aimed at exploring overactive microglia in schizophrenia patients and maternal immune activation models, indicating impaired glutamate regulation and reduced N-methyl-D-aspartate receptor (NMDAR) function. In addition, an inflammatory/immune-induced alteration of post-synaptic density scaffold proteins, crucial for downstream NMDAR signaling and synaptic efficacy, has been demonstrated. According to these findings, a significant increase in plasma inflammatory markers has been found in schizophrenia patients compared to healthy controls, associated with reduced cortical integrity and functional connectivity, relevant to the cognitive deficit of schizophrenia. Finally, the link between altered inflammatory/immune responses raises relevant questions regarding potential new therapeutic strategies specifically for those forms of schizophrenia that are resistant to canonical antipsychotics or unresponsive to clozapine.

Relationships between early age at onset of psychotic symptoms and treatment resistant schizophrenia.

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.

Evaluation of a few discrete clinical markers may predict categorization of actively symptomatic non-acute schizophrenia patients as treatment resistant or responders: A study by ROC curve analysis and multivariate analyses.

Here, we used Receiver Operating Characteristic (ROC) curve analysis to determine whether clinical factors may aid predicting the categorization of schizophrenia patients as Treatment Resistant (TRS) or antipsychotic responsive schizophrenia (ARS). Patients with an established condition of TRS or ARS were assessed for: clinical presentation and course; neurological soft signs (NES); psychopathology by PANSS; cognitive performances; quality of life scale (QLS); functional capacity; social functioning (PSP and SLOF scales). In ROC curve analysis, significance indicated that the Area under curve (AUC) allowed distinguishing between TRS and ARS. Multivariate analyses were additionally used to provide independent predictive analysis. Multiple clinical variables showed significant AUCs. The largest significant AUCs were found for: NES total score; SLOF Area2; QLS subscale; antipsychotic doses. The highest sensitivity was found for NES total score, the highest specificity for previous hospitalizations. The highest Odds Ratio of being included within the TRS category were found for: NES total score (7.5); QLS total score (5.49); and previous hospitalizations (4.76). This same circumscribed group of variables was also found to be predictive of TRS when adopting stepwise logistic regression or discriminant analysis. We concluded that the evaluation of few clinical factors may provide reliable and accurate predictions on whether one schizophrenia patient may be categorized as a TRS.