Matrix metalloproteinase 9 (MMP-9) activity, hippocampal extracellular free water, and cognitive deficits are associated with each other in early phase psychosis.

Increasing evidence points toward the role of the extracellular matrix, specifically matrix metalloproteinase 9 (MMP-9), in the pathophysiology of psychosis. MMP-9 is a critical regulator of the crosstalk between peripheral and central inflammation, extracellular matrix remodeling, hippocampal development, synaptic pruning, and neuroplasticity. Here, we aim to characterize the relationship between plasma MMP-9 activity, hippocampal microstructure, and cognition in healthy individuals and individuals with early phase psychosis. We collected clinical, blood, and structural and diffusion-weighted magnetic resonance imaging data from 39 individuals with early phase psychosis and 44 age and sex-matched healthy individuals. We measured MMP-9 plasma activity, hippocampal extracellular free water (FW) levels, and hippocampal volumes. We used regression analyses to compare MMP-9 activity, hippocampal FW, and volumes between groups. We then examined associations between MMP-9 activity, FW levels, hippocampal volumes, and cognitive performance assessed with the MATRICS battery. All analyses were controlled for age, sex, body mass index, cigarette smoking, and years of education. Individuals with early phase psychosis demonstrated higher MMP-9 activity (p < 0.0002), higher left (p < 0.05) and right (p < 0.05) hippocampal FW levels, and lower left (p < 0.05) and right (p < 0.05) hippocampal volume than healthy individuals. MMP-9 activity correlated positively with hippocampal FW levels (all participants and individuals with early phase psychosis) and negatively with hippocampal volumes (all participants and healthy individuals). Higher MMP-9 activity and higher hippocampal FW levels were associated with slower processing speed and worse working memory performance in all participants. Our findings show an association between MMP-9 activity and hippocampal microstructural alterations in psychosis and an association between MMP-9 activity and cognitive performance. Further, more extensive longitudinal studies should examine the therapeutic potential of MMP-9 modulators in psychosis.

El trastorno del lenguaje de las personas con esquizofrenia y su relación con la gravedad y la funcionalidad / The language disorder of people with schizophrenia and its relationship with severity and functionality

RESUMEN: Objetivo: estudiar las características del lenguaje en pacientes que padecen esquizofrenia u otros trastornos psicóticos. Método: 55 pacientes diagnosticados de esquizofrenia (50) y trastorno esquizoafectivo (5). Se aplica la escala TLC de Andreasen, la escala EEAG para la funcionalidad, la CGI para la gravedad. Se recogen datos sociodemográficos. Resultados: Las medias son: edad: 61,47 años, internamiento: 19,47 años, CGI: 5,8, EEAG: 32,5. La subescala de desconexión de la TLC puntúa de media: 8,43, y la de Subproducción verbal: 1,2. La desconexión correlaciona negativamente con EEAG, y positivamente con CGI. La Subproducción verbal correlaciona con CGI. Conclusiones: Los participantes presentan un grado de gravedad elevado y de funcionalidad bajo. Presentan alteraciones importantes del lenguaje, particularmente de pobreza del habla, pero también de desconexión verbal. Con puntuaciones que varían de leve a moderado. Ambas subescalas correlacionan con gravedad. Además, la desconexión es mayor en los pacientes con peor funcionalidad. La alteración del lenguaje en esquizofrenia está relacionada con la gravedad y la funcionalidad, lo cual tiene importantes consecuencias en la vida de las personas que padecen esta enfermedad.

ABSTRACT Objective: to study the characteristics of language in patients suffering from schizophrenia or other psychotic disorders. Method: 55 patients diagnosed with schizophrenia (50) and schizoaffective disorder (5). The Andreasen TLC scale, the EEAG scale for functionality and the CGI for gravity are applied. Sociodemographic data are collected. Results: Mean age: 61.47 years, mean years hospitalized: 19.47 years, CGI: 5.8, EEAG: 32.5. The TLC disconnection subscale scores on average: 8.43, and the Verbal Underproduction: 1.2. Disconnection correlates negatively with EEAG, and positively with CGI. Verbal underproduction correlates with CGI. Conclusions: The participants present a high degree of severity and low functionality. They present significant language alterations, poor speech, and verbal disconnection. With scores ranging from mild to moderate. Both subscales correlate with severity. In addition, the Disconnection is greater in patients with worse functionality. Language impairment in schizophrenia is related to severity and functionality, which has important consequences in the lives of people with this disease.

N-Skatyltryptamines-Dual 5-HT6R/D2R Ligands with Antipsychotic and Procognitive Potential.

A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT1A, 5-HT2A, 5-HT6, and D2 receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D2 receptor antagonists with additional 5-HT6R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT6R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT6R agonists was more ambiguous-in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18, we tried to sort out the difference between ligands exhibiting the D2R antagonist function combined with 5-HT6R agonism, and mixed D2/5-HT6R antagonists in murine models of psychosis.

Psychosis in a primary hyperparathyroidism patient with mild hypercalcemia: A case report.

INTRODUCTION: Primary hyperparathyroidism (PHPT) is characterized by hypercalcemia and an elevated level of serum parathyroid hormone (PTH). PHPT presents with a complex set of renal, skeletal, and neuropsychological symptoms. Parathyroidectomy (PTX) is a radical treatment that is recommended for all physically symptomatic patients with PHPT. However, psychiatric symptoms are not considered as an indication for surgery. There remains an important issue from the view of perioperative management of whether PTX should be performed with the presence of uncontrolled psychiatric symptoms or deferred until severe psychiatric symptoms have been controlled. We report a case of mild hypercalcemia that caused severe psychosis in PHPT, which improved dramatically following PTX and resulted in successful postoperative management. PATIENT CONCERN: Our patient was a 68-year-old Japanese woman. She was diagnosed with PHPT, which was triggered by mild hypercalcemia. She was due to receive an operation for osteoporosis and kidney stones. She had severe psychosis, despite medication. Blood examinations revealed mild hypercalcemia (10.4 mg/dL, 8.8-10.1 mg/dL) and elevated serum levels of intact PTH (184.0 pg/mL, 10-65 pg/mL). DIAGNOSIS: She was diagnosed with severe psychosis caused by mild hypercalcemia in PHPT. INTERVENTIONS: Although she was treated with 37.5 mg quetiapine and 2 mg risperidone daily, she was excessively sedated and rejected oral treatment. Therefore, we decided to perform the operation. OUTCOMES: Immediately following surgery, serum levels of calcium, and intact PTH were normalized. Her psychotic symptoms ceased completely 5 days after surgery. CONCLUSION: We emphasize that PHPT presents with various severe psychiatric symptoms, even in mild hypercalcemia. Psychiatric symptoms may be the only salient symptoms in PHPT, and thus clinicians should suspect PHPT in patients with psychiatric symptoms and mild hypercalcemia. Furthermore, PTX is recommended for PHPT-even in the presence of severe uncontrolled psychiatric symptoms, which carries risks for postoperative management-because psychiatric symptoms are expected to improve and good postoperative management is possible.

DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia.

We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.

Abnormal synaptic pruning during adolescence underlying the development of psychotic disorders.

PURPOSE OF REVIEW: Excessive synaptic pruning has first been suggested by Irwin Feinberg (1982) as an important pillar in the pathophysiology in schizophrenia (SCZ). This article reviews recent developments highlighting factors implicated in aberrant synaptic pruning and its contribution to disease onset and emergence of cognitive symptoms in SCZ. Unraveling these factors provides new insights for potential prevention and treatment strategies for psychotic disorders. RECENT FINDINGS: Increased pruning in SCZ was recently confirmed by a positron emission tomography-study employing the novel tracer [11C]UCB-J, demonstrating the consequential loss of synaptic density. Recent evidence supports the contributing role of astrocytes and increased complement-mediated microglial pruning in disease onset and cognitive symptoms in SCZ. Increased microglial pruning is mediated specifically by C4. Furthermore, environmental factors (e.g., infections and stress) can lead to dysbiosis which was recently linked to microglial activation and pruning in SCZ. SUMMARY: Recent findings render the pruning machinery a potential target for early treatment and prevention in individuals at high risk for SCZ. Minocycline can improve cognition in SCZ, probably by reducing excessive pruning. Probiotics might also have beneficial effects on cognition, although recent findings are not encouraging. N-acetyl-cysteine recovers functional connectivity in SCZ both in vitro and in vivo, making it an interesting candidate.

The 1316T>C missenses mutation in MTHFR contributes to MTHFR deficiency by targeting MTHFR to proteasome degradation.

5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare hereditary disease characterized by defects in folate and homocysteine metabolism. Individuals with inherited MTHFR gene mutations have a higher tendency to develop neurodegeneration disease as Alzheimer' disease and atherosclerosis. MTHFR is a rate-limiting enzyme catalyzing folate production, various SNPs/mutations in the MTHFR gene have been correlated to MTHFR deficiency. However, the molecular mechanisms underpinning the pathogenic effects of these SNPs/mutations have not been clearly understood. In the present study, we reported a severe MTHFR deficiency patient with late-onset motor dysfunction and sequenced MTHFR gene exons of the family. The patient carries an MD-associating SNP (rs748289202) in one MTHFR allele and the rs545086633 SNP with unknown disease relevance in the other. The rs545086633 SNP (p.Leu439Pro) results in an L439P substitution in MTHFR protein, and drastically decreases mutant protein expression by promoting proteasomal degradation. L439 in MTHFR is highly conserved in vertebrates. Our study demonstrated that p.Leu439Pro in MTHFR is the first mutation causing significant intracellular defects of MTHFR, and rs545086633 should be examined for the in-depth diagnosis and treatment of MD.

Predictive value of oxidative stress biomarkers in drug­free patients with schizophrenia and schizo-affective disorder.

Several studies have suggested that oxidative stress may represent one of the primary etiological mechanisms of schizophrenia (SZ) and schizoaffective disorder (SAD) which can be targeted by therapeutic intervention. The present study was conducted over a period of 24 months, between June 2016 and June 2018. All enrolled subjects were Tunisian, forty five drug­free male patients with SZ (mean age: 37.6 years), twenty one drug­free male patients with SAD (mean age: 28.8 years) and hundred and one age and gender matched controls (mean age: 34.2 years) were enrolled in the study. Plasma reduced glutathione (GSH) and Total thiols levels were significantly decreased in patients compared to controls (respectively p<0.001; p=0.050). In addition, malondialdehyde (MDA), advanced oxidation protein products (AOPP) and protein carbonyls (PC) concentrations and glutathione peroxidase (GSH-Px) activity were significantly increased in patients compared to controls (p<0.001; p<0.001; p<0.001 and p=0.003 respectively). The binary logistic regression analysis revealed that MDA, AOPP, PC and GSH-Px could be considered as independent risk factors for SZ and SAD. When using ROC analysis, a remarkable increase in the area under the curve (AUC) with higher sensitivity (Se) and specificity (Sp) for MDA, AOPP, PC and GSH-Px combined markers was observed. The present study indicated that the identification of the predictive value of this four-selected biomarkers related to oxidative stress in drug free patients should lead to a better identification of the etiological mechanism of SZ or SAD.

Psychiatric Prodrome in Anti-NMDAR-Associated Encephalopathy: Clinical and Pathophysiologic Considerations.

OBJECTIVE: To present a review of the literature on the clinical presentation and pathophysiology of anti-N-methyl-d-aspartate receptor encephalopathy (ANMDARE) with attention to both the more commonly recognized psychotic symptom prodrome and the less well-understood depressive symptom prodrome. DATA SOURCES: The search for clinical neuropsychiatric phenomena and proposed mechanisms involved in ANMDARE pathophysiology was conducted in PubMed. English-language articles published up to September 2019 were identified using a combination of the following search terms: N-methyl-d-aspartate, anti-NMDA receptor encephalitis, schizophrenia, psychosis, depression, major depressive disorder, bipolar I disorder, bipolar II disorder, anxiety, and posttraumatic stress disorder. STUDY SELECTION: From 150 articles identified from the initial search, the 73 most relevant clinical studies, reviews, and case reports related to the study objectives were included. DATA EXTRACTION: Sources were individually analyzed by the 3 authors for the most clinically relevant information. RESULTS: The pathophysiology and mechanisms involved in anti-NMDA receptor antibody delivery to the brain are incompletely characterized, but antibody binding appears to involve the GluN1 subunit in most cases. Psychotic symptoms are the most commonly recognized components of prodromal psychiatric illness in ANMDARE, which may lead to an initial diagnosis of schizophrenia. In addition to psychotic symptoms, there are reports of depressive symptoms occurring before the emergence of, co-occurring with, or instead of psychotic symptoms in ANMDARE. CONCLUSIONS: In addition to the better-known psychotic prodrome, depressive symptomatology can occur in ANMDARE patients. ANMDARE should be considered in patients with initial presentation of either psychotic or atypical depressive illnesses. Early recognition of these psychiatric prodromal states as antecedents to ANMDARE could lead to improved diagnosis and better management of this potentially life-threatening autoimmune disorder.

Timing of menarche and abnormal hippocampal connectivity in youth at clinical-high risk for psychosis.

The "estrogen hypothesis" suggests that estrogen is a protective factor against psychotic disorders such as schizophrenia. Although the precise protective mechanisms are still unclear, one potential explanation lies in the role that increased estrogens play in mediating hippocampal plasticity, as this may reduce hippocampal dysconnectivity that is characteristically observed in psychosis. In support of this view, later age at menarche- less available estrogen during critical early adolescent development- is related to earlier onset of psychosis and increased symptom severity. Furthermore, if estrogens have protective effects, then we should see this effect in the psychosis risk period in those at clinical high-risk (CHR) for psychosis - i.e., individuals showing attenuated symptoms at imminent risk for transitioning to a psychotic diagnosis. This study examined whether earlier age at menarche would result in more normative hippocampal connectivity in CHR youth; menarche is an easily assessed, developmental marker associated with the availability of estrogens. Resting-state connectivity was examined in sixty female participants (26 CHR and 34 healthy control; age 12-21) using a cross-sectional approach; hippocampal connectivity was found to relate to age at menarche. Later age at menarche in the CHR group related to increased hippocampal dysconnectivity to the occipital cortex (a region with a neurotrophic response to estrogen) compared to the controls. Results suggest that earlier availability of estrogens may have neuroprotective effects on hippocampal plasticity. Findings have relevance for understanding sex differences and etiology, as well as guiding novel treatments.

Maintenance phase treatment of psychotic disorders in outpatients from Serbia - focus on long-term benzodiazepine use.

Introduction: Prescribing trends in maintenance therapy of patients with primary psychotic disorders (PSD) may vary worldwide. Present study aimed to investigate prescription patterns in a sample of outpatients with PSD from Serbia.Methods: In a sample of 73 PSD outpatients we analysed the rate of antipsychotic polypharmacy and psychotropic polypharmacy, concomitant continual benzodiazepine use, and associations between therapy, psychotic symptoms and quality of life.Results: Maintenance therapy (median daily dose 321 mg of chlorpromazine equivalents) predominantly consisted of monotherapy with second generation antipsychotics (45.2%), followed by antipsychotic polypharmacy based on first and second generation combination (25.0%). The median number of psychotropic drugs was 3. Benzodiazepines were continually prescribed to more than 60% of patients (mean daily dose 2.9 ± 2.0 mg lorazepam equivalents). Patients with benzodiazepine use had significantly more psychotropic medications and more antipsychotic polypharmacy, poorer quality of life and more severe psychopathology in comparison to another group.Conclusion: The present study demonstrated new information regarding the prescription patterns of psychotropic drugs in outpatients with PSD in Serbia, amplified with clinically relevant information. This study also revealed distinct prescription patterns concerning antipsychotic/benzodiazepine polypharmacy. Overall, such findings are likely to contribute to improving clinical practice and care for patients with PSD in general.KeypointsPresent exploratory research aimed to elucidate trends of antipsychotics polypharmacy and concomitant use of psychotropic medications including benzodiazepines in the maintenance treatment of outpatients with schizophrenia and other psychotic disorders, amplified with clinically relevant information (symptoms and quality of life).'Antipsychotic (AP) polypharmacy' was defined as concurrent use of more than one AP for at least 1 month; 'Psychotropic polypharmacy' was defined as the combination of AP and a different class of psychotropic drugs medication for at least one month.The median number of prescribed psychotropic drugs was 3 (mean 3.1 ± 1.1) and the average AP daily dose was moderate (median 321 mg of chlorpromazine equivalents). However, the rates of AP polypharmacy (45.2%) and benzodiazepine prescription on a continual basis (>60%) found in our sample could be considered relatively high.Outpatients with higher AP daily dose and higher BPRS symptom score were receiving more benzodiazepines.For improvement of the local, as well as general clinical practice and care for patients with psychotic disorders, and for education in psychiatry, such analyses need to be done on a regular basis and on larger samples.

Striatal and Thalamic Auditory Response During Deep Brain Stimulation for Essential Tremor: Implications for Psychosis.

INTRODUCTION: The P50, a positive auditory-evoked potential occurring 50 msec after an auditory click, has been characterized extensively with electroencephalography (EEG) to detect aberrant auditory electrophysiology in disorders like schizophrenia (SZ) where 61-74% have an auditory gating deficit. The P50 response occurs in primary auditory cortex and several thalamocortical regions. In rodents, the gated P50 response has been identified in the reticular thalamic nucleus (RT)-a deep brain structure traversed during deep brain stimulation (DBS) targeting of the ventral intermediate nucleus (VIM) of the thalamus to treat essential tremor (ET) allowing for interspecies comparison. The goal was to utilize the unique opportunity provided by DBS surgery for ET to map the P50 response in multiple deep brain structures in order to determine the utility of intraoperative P50 detection for facilitating DBS targeting of auditory responsive subterritories. MATERIALS AND METHODS: We developed a method to assess P50 response intraoperatively with local field potentials (LFP) using microelectrode recording during routine clinical electrophysiologic mapping for awake DBS surgery in seven ET patients. Recording sites were mapped into a common stereotactic space. RESULTS: Forty significant P50 responses of 155 recordings mapped to the ventral thalamus, RT and CN head/body interface at similar rates of 22.7-26.7%. P50 response exhibited anatomic specificity based on distinct positions of centroids of positive and negative responses within brain regions and the fact that P50 response was not identified in the recordings from either the internal capsule or the dorsal thalamus. CONCLUSIONS: Detection of P50 response intraoperatively may guide DBS targeting RT and subterritories within CN head/body interface-DBS targets with the potential to treat psychosis and shown to modulate schizophrenia-like aberrancies in mouse models.

Clinical evolution of patients treated with aripiprazole long-acting injectable: a preliminary, prospective, observational study.

Objective: To evaluate the effectiveness of 6-month treatment with aripiprazole long-acting injectable (LAI) in improving psychotic symptoms, social functioning and side effects and reducing co-administered antipsychotic drugs.Methods: Multicentre, observational, prospective study that enrolled 53 patients with diagnosis of schizophrenia spectrum disorders who initiated or switched to aripiprazole LAI. The effectiveness of aripiprazole LAI was assessed through the Positive and Negative Syndrome Scale (PANSS), the Udvalg for Kliniske Undersogelser scale for side effects, the Global Assessment of Functioning and the Clinical Global Impression-Schizophrenia (CGI-SCH).Results: Upon treatment with aripiprazole LAI, patients significantly improved all the domains of PANSS (p < .05). Adverse event severity significantly improved after a 6-month aripiprazole LAI treatment (p < .05). Differences from baseline to month 6 in Global Assessment of Functioning score were significant (p = .0002). The proportion of severely ill patients decreased upon treatment with aripiprazole LAI (CGI-SCH scale). Prolactin levels were normalised after a 6-month treatment (from 43.0 to 14.7 ng/mL). Co-administered antipsychotic drugs significantly decreased after a 6-month treatment with aripiprazole LAI.Conclusion: A 6-month treatment with aripiprazole LAI improved the clinical status of our patients without modifying their metabolic profile, and allowed the reduction of co-administered antipsychotic drugs.Practice implicationsLong-acting injectable antipsychotics are effective treatment options for the maintenance of patients with schizophrenia and related disorders, and to ensure treatment adherence. This study describes the evolution of patients over six months of treatment with aripiprazole long-acting injectable. The results from this study support previous data on the efficacy and safety of this atypical antipsychotic. This study may be of wide interest to the community of psychiatrists and may help clinicians optimise treatment adherence in patients with schizophrenia spectrum disorders.Key pointsAripiprazole long-acting injectable is an atypical antipsychotic intended to improve treatment adherence and prevent relapses.This multicentre prospective study evaluated the effectiveness of aripiprazole long-acting injectable over six months of treatment on the control of a comprehensive set of clinical variables.Clinical rating scales showed that treatment with aripiprazole long-acting injectable improved clinical symptoms and social functioning, and reduced the severity of adverse events.Aripiprazole long-acting injectable contributed to the maintenance of adequate metabolic profiles and the normalisation of prolactin levels.Patients significantly decreased co-administered antipsychotic drugs after 6-month treatment with aripiprazole.

Innate Immune Cells and C-Reactive Protein in Acute First-Episode Psychosis and Schizophrenia: Relationship to Psychopathology and Treatment.

Innate immunity has been linked to initiation of Alzheimer's disease and multiple sclerosis. Moreover, risk of first-episode psychosis (FEP) and schizophrenia (Sz) is increased after various infections in predisposed individuals. Thus, we hypothesized an analogous role of innate immunity with increased C-reactive protein (CRP) in non-affective psychosis. Differential blood count, CRP, neutrophil and monocyte-macrophage activation markers, cortisol and psychotic symptoms (Positive and Negative Syndrome Scale [PANSS]) were assessed in controls (n = 294) and acutely ill unmedicated FEP (n = 129) and Sz (n = 124) patients at baseline and after 6 weeks treatment. Neutrophils, monocytes, and CRP were increased in patients vs controls at baseline (P < .001), and neutrophil and monocyte counts correlated positively with activation markers. Eosinophils were lower at baseline in FEP (P < .001) and Sz (P = .021) vs controls. Differences in neutrophils (P = .023), eosinophils (P < .001), and CRP (P < .001) were also present when controlling for smoking and cortisol, and partially remitted after antipsychotic treatment. FEP patients with high neutrophils (P = .048) or monocytes (P = .021) had higher PANSS-P scores at baseline but similar disease course. CRP correlated with PANSS-P at baseline (ρ = 0.204, P = .012). Improvement of positive symptoms after treatment correlated with declining neutrophils (ρ = 0.186, P = .015) or CRP (ρ = 0.237, P = .002) and rising eosinophils (ρ = -0.161, P = .036). In FEP, normalization of neutrophils (ρ = -0.231, P = .029) and eosinophils (ρ = 0.209, P = .048) correlated with drug dosage. In conclusion, innate immune system activation correlated with PANSS-P, supporting the immune hypothesis of psychosis. Neutrophil and monocyte counts and CRP levels may be useful markers of disease acuity, severity, and treatment response.

A longitudinal perspective on the pharmacotherapy of 24 adult patients with Phelan McDermid syndrome.

Over the past years, 24 patients with Phelan-McDermid syndrome were carefully investigated with respect to history, somatic and neurologic antecedents, treatment history, behavioural issues, and psychiatric symptoms including possible catatonic features and regression phenomena. Patients were originally referred for specialized diagnosis and treatment advice because of recurrent challenging behaviours along with instable mood. In all, standardized neuropsychiatric examination was performed including assessment of intellectual and adaptive functioning as well as communication and behaviour concerns. Psychiatric diagnoses were actualized in interdisciplinary consultation meetings according to ICD-10 guidelines. The course of disease was periodically monitored with respect to treatment efficacy and psychopathology over a period varying from one to five years. In 18 patients, a deletion encompassing part of or the entire SHANK3 gene was found. All comprised two or more genes in addition to SHANK3. In six patients, a pathogenic variant in this gene was detected. The psychopathological profile of all patients (nine were published before) was characterized by symptoms from the autism and schizoaffective spectrum while in five, periodic catatonic symptoms were also established. In their third decade, four patients with the deletion subtype developed a regression-like gradual decline of functioning. Based on actual psychiatric classification, in 18 patients, a diagnosis of atypical bipolar disorder was established of which symptoms typically started from late adolescence onward. In most patients, treatment with mood stabilizing agents in combination with individually designed contextual measures, and if indicated with the addition of an atypical antipsychotic, resulted in gradual stabilization of mood and behaviour.

Internalising symptoms mediate the longitudinal association between childhood inflammation and psychotic-like experiences in adulthood.

Psychotic-like experiences (PLEs) are part of a continuum of psychosis. Previous longitudinal studies highlighted a relationship between peripheral inflammation during childhood and onset of PLEs in adulthood. In this study, we tested if this association is mediated by internalising and externalising symptoms experienced during childhood and adolescence. To test this hypothesis, we used data from the Avon Longitudinal Study of Parents and Children (ALSPAC). We investigated a subsample of 4525 individuals from this cohort with data on interleukin 6 (IL-6) and C-reactive protein (CRP) in childhood (age 9 years). We measured PLEs at age 18 years, and we used latent growth curve modelling to estimate longitudinal trajectories of internalising and externalising symptoms from ages 9 to 16 years. The individual predicted values of the intercept (set at baseline, 9 years) and the slope (rate of annual change) were then used in the mediation analysis. There was evidence for full mediation by the intercept of internalising symptoms. Our findings suggest that inflammation during childhood may be relevant for the future onset of PLEs via its association with a high level of internalising symptoms. These findings, although obtained from a non-clinical population, provide an additional step in advancing knowledge on the relationship between inflammation and symptoms of the psychosis continuum.

Childhood trauma and glucose metabolism in patients with first-episode psychosis.

Although the associations between first-episode psychosis (FEP) and metabolic abnormalities on one side, and childhood trauma (CT) and risk of developing psychosis on the other are both well established, evidence on the relationship between CT and metabolic dysregulation in terms of abnormal glucose metabolism is very limited. We tested whether, already at illness onset, FEP patients with a history of CT show dysregulation of a broad range of glucose metabolism markers. In particular, in 148 FEP patients we evaluated serum concentrations of c-peptide, insulin, plasminogen-activator-inhibitor-1 (PAI-1), resistin, visfatin, glucagon, glucagon-like peptide-1 (GLP-1), gastric-inhibitor-peptide (GIP), leptin, and ghrelin. We also assessed CT with the Childhood Experience of Care and Abuse Questionnaire, and stressful life events (SLEs) with a semi-structured interview. Psychopathology, cannabis and tobacco habits, Body Mass Index (BMI) were recorded. Serum concentrations of markers were analyzed from peripheral blood. Ninety-five patients (56 % males, mean age 29.5) reported CT. Multivariate models showed that CT is associated only with the concentrations of c-peptide and insulin after adjusting for age, sex, BMI and SLEs. FEP patients who had experienced CT showed higher c-peptide and insulin serum concentrations. Our study reports that CT might be associated with the metabolic abnormalities in the first stage of psychosis, suggesting that a thorough anamnestic evaluation at psychosis onset that would include the history of CT could be helpful for clinicians in order to implement early programmes of healthy lifestyle education and to guide choice of therapeutic interventions for trauma.