Major Psychoses Research Articles

Gray Matter Neuritic Microstructure Deficits in Schizophrenia and Bipolar Disorder

BackgroundPostmortem studies have demonstrated considerable dendritic pathologies among persons with schizophrenia and to some extent among those with bipolar I disorder. Modeling gray matter (GM) microstructural properties is now possible with a recently proposed diffusion-weighted magnetic resonance imaging modeling technique: neurite orientation dispersion and density imaging. This technique may bridge the gap between neuroimaging and histopathological findings. MethodsWe performed an extended series of multishell diffusion-weighted imaging and other structural imaging series using 3T magnetic resonance imaging. Participants scanned included individuals with schizophrenia (n = 36), bipolar I disorder (n = 29), and healthy controls (n = 35). GM-based spatial statistics was used to compare neurite orientation dispersion and density imaging–driven microstructural measures (orientation dispersion index and neurite density index [NDI]) among groups and to assess their relationship with neurocognitive performance. We also investigated the accuracy of these measures in the prediction of group membership, and whether combining them with cortical thickness and white matter fractional anisotropy further improved accuracy. ResultsThe GM-NDI was significantly lower in temporal pole, anterior parahippocampal gyrus, and hippocampus of the schizophrenia patients than the healthy controls. The GM-NDI of patients with bipolar I disorder did not differ significantly from either schizophrenia patients or healthy controls, and it was intermediate between the two groups in the post hoc analysis. Regardless of diagnosis, higher performance in spatial working memory was significantly associated with higher GM-NDI mainly in the frontotemporal areas. The addition of GM-NDI to cortical thickness resulted in higher accuracy to predict group membership. ConclusionsGM-NDI captures brain differences in the major psychoses that are not accessible with other structural magnetic resonance imaging methods. Given the strong association of GM-NDI with disease state and neurocognitive performance, its potential utility for biological subtyping should be further explored.

Auditory Vigilance and Working Memory in Youth at Familial Risk for Schizophrenia or Affective Psychosis in the Harvard Adolescent Family High Risk Study.

The degree of overlap between schizophrenia (SCZ) and affective psychosis (AFF) has been a recurring question since Kraepelin's subdivision of the major psychoses. Studying nonpsychotic relatives allows a comparison of disorder-associated phenotypes, without potential confounds that can obscure distinctive features of the disorder. Because attention and working memory have been proposed as potential endophenotypes for SCZ and AFF, we compared these cognitive features in individuals at familial high-risk (FHR) for the disorders. Young, unmedicated, first-degree relatives (ages, 13-25 years) at FHR-SCZ (n=41) and FHR-AFF (n=24) and community controls (CCs, n=54) were tested using attention and working memory versions of the Auditory Continuous Performance Test. To determine if schizotypal traits or current psychopathology accounted for cognitive deficits, we evaluated psychosis proneness using three Chapman Scales, Revised Physical Anhedonia, Perceptual Aberration, and Magical Ideation, and assessed psychopathology using the Hopkins Symptom Checklist -90 Revised. Compared to controls, the FHR-AFF sample was significantly impaired in auditory vigilance, while the FHR-SCZ sample was significantly worse in working memory. Both FHR groups showed significantly higher levels of physical anhedonia and some psychopathological dimensions than controls. Adjusting for physical anhedonia, phobic anxiety, depression, psychoticism, and obsessive-compulsive symptoms eliminated the FHR-AFF vigilance effects but not the working memory deficits in FHR-SCZ. The working memory deficit in FHR-SZ was the more robust of the cognitive impairments after accounting for psychopathological confounds and is supported as an endophenotype. Examination of larger samples of people at familial risk for different psychoses remains necessary to confirm these findings and to clarify the role of vigilance in FHR-AFF. (JINS, 2016, 22, 1026-1037).

Systematically characterizing dysfunctional long intergenic non-coding RNAs in multiple brain regions of major psychosis.

Schizophrenia (SZ) and bipolar disorder (BD) are severe neuropsychiatric disorders with serious impact on patients, together termed “major psychosis”. Recently, long intergenic non-coding RNAs (lincRNAs) were reported to play important roles in mental diseases. However, little was known about their molecular mechanism in pathogenesis of SZ and BD. Here, we performed RNA sequencing on 82 post-mortem brain tissues from three brain regions (orbitofrontal cortex (BA11), anterior cingulate cortex (BA24) and dorsolateral prefrontal cortex (BA9)) of patients with SZ and BD and control subjects, generating over one billion reads. We characterized lincRNA transcriptome in the three brain regions and identified 20 differentially expressed lincRNAs (DELincRNAs) in BA11 for BD, 34 and 1 in BA24 and BA9 for SZ, respectively. Our results showed that these DELincRNAs exhibited brain region-specific patterns. Applying weighted gene co-expression network analysis, we revealed that DELincRNAs together with other genes can function as modules to perform different functions in different brain regions, such as immune system development in BA24 and oligodendrocyte differentiation in BA9. Additionally, we found that DNA methylation alteration could partly explain the dysregulation of lincRNAs, some of which could function as enhancers in the pathogenesis of major psychosis. Together, we performed systematical characterization of dysfunctional lincRNAs in multiple brain regions of major psychosis, which provided a valuable resource to understand their roles in SZ and BD pathology and helped to discover novel biomarkers.

Theory of mind and executive functions in schizophrenia and bipolar disorder: A cross-diagnostic latent class analysis for identification of neuropsychological subtypes

ObjectiveExecutive dysfunction is a common feature of schizophrenia and bipolar disorder (BP). While deficits in social cognitive abilities, including theory of mind (ToM), have been suggested to be specific to schizophrenia, available evidence suggests that there is also a significant overlap in social cognitive performances of both disorders. However, there is significant heterogeneity of executive dysfunction and ToM deficits in BP and schizophrenia. Cross-diagnostic data-driven methods can reveal potential neurocognitive subtypes characterized by relatively selective deficits in social cognition. MethodsNeurocognitive subgroups were investigated using latent class analysis, based on executive functions and ToM, in a mixed sample of 97 clinically stable patients with schizophrenia or BP and 27 healthy controls. ResultsFour neurocognitive subgroups, including a “neuropsychologically normal” cluster, a severe global impairment cluster and two clusters of mixed cognitive profiles were found. Severe impairment cluster was characterized by particularly severe ToM deficits and predominantly included patients with schizophrenia. Schizophrenia patients in this cluster had severe negative symptoms. In contrast, individuals with BP compared to schizophrenia patients were more likely to be included in the “neuropsychologically normal” cluster. ConclusionIdentification of distinctive neurobiological subtypes of patients based on social and non-social cognitive profiles can improve classification of major psychoses. Neurocognitive subgroupings of patients might be also beneficial for intervention strategies including cognitive rehabilitation.

Liability indicators aggregate many years before transition to illness in offspring descending from kindreds affected by schizophrenia or bipolar disorder

ObjectivesOffspring born to patients with affective and non-affective psychoses display indicators of brain dysfunctions that affected parents carry. Such indicators may help understand the risk trajectory. MethodsWe followed up the clinical/developmental trajectories of 84 young offspring born to affected parents descending from the Quebec kindreds affected by schizophrenia or bipolar disorder. We longitudinally characterized childhood trajectories using 5 established risk indicators: cognitive impairments, psychotic-like experiences, non-psychotic DSM diagnosis and episodes of poor functioning, trauma and drug use. ResultsOverall, offspring individually presented a high rate of risk indicators with 39% having 3 or more indicators. Thirty-three offspring progressed to an axis 1 DSM-IV disorder, 15 of whom transitioned to a major affective or non-affective disorder. The relative risks for each risk indicator were low in these vulnerable offspring (RR=1.92 to 2.99). Remarkably, transitioners accumulated more risk indicators in childhood-adolescence than non-transitioners (Wilcoxon rank test; Z=2.64, p=0.008). Heterogeneity in the risk trajectories was observed. Outcome was not specific to parent's diagnosis. ConclusionYoung offspring descending from kindreds affected by major psychoses would accumulate risk indicators many years before transition. A clustering of risk factors has also been observed in children at risk of metabolic-cardiovascular disorders and influences practice guidelines in this field. Our findings may be significant for the primary care surveillance of millions of children born to affected parents in the G7 nations. Future longitudinal risk research of children at genetic risk should explore concurrently several intrinsic and environmental risk modalities to increase predictivity.

Sex Steroids and Major Psychoses: Which Role for DHEA-S and Progesterone?

Objective: Endocrine pathways seem to play a role in the etiology of major psychoses. The identification of biomarkers associated with psychotic symptoms in schizophrenia (SKZ) and mood disorders would allow the identification of high-risk subjects for delusions and hallucinations. The aim of this study was to evaluate dehydroepiandrosterone sulfate (DHEA-S) and progesterone plasma levels in drug-free patients with major psychoses and their relation with the diagnosis and history of psychotic symptoms. Methods: Eighty-nine consecutive drug-free male inpatients with SKZ or mood disorders were recruited, and DHEA-S and progesterone plasma levels were measured. The groups, divided according to pathological/normal-range hormone levels, were compared in terms of clinical variables using χ² tests with Bonferroni's corrections or multivariate analyses of variance. The same analyses were performed for groups divided according to the presence/absence of lifetime psychotic symptoms. Binary logistic regression analysis was performed using hormone levels as independent variables and history of lifetime psychotic symptoms as a dependent one. Results: A higher number of patients with abnormal DHEA-S levels was found to have a family history of major depressive disorder (p < 0.05). Higher DHEA-S levels (F = 8.31; p = 0.005) were found in patients with a history of psychotic symptoms. In addition, binary logistic regression confirmed that DHEA-S levels were associated with a higher probability of lifetime psychotic symptoms (p = 0.037). Conclusions: Our results confirm previous data about the role of endocrine factors in the etiology of major psychoses. A high DHEA-S level might be a risk factor for psychotic symptoms. Studies with larger samples are needed to confirm these data.

Allele-Skewed DNA Modification in the Brain: Relevance to a Schizophrenia GWAS

Numerous recent studies have suggested that phenotypic effects of DNA sequence variants can be mediated or modulated by their epigenetic marks, such as allele-skewed DNA modification (ASM). Using Affymetrix SNP microarrays, we performed a comprehensive search of ASM effects in human post-mortem brain and sperm samples (total n = 256) from individuals with major psychosis and control individuals. Depending on the phenotypic category of the brain samples, 1.4%-7.5% of interrogated SNPs exhibited ASM effects. Next, we investigated ASM in the context of genetic studies of schizophrenia and detected that brain ASM SNPs were significantly overrepresented among sub-threshold SNPs from a schizophrenia genome-wide association study (GWAS). Brain ASM SNPs showed a much stronger enrichment in a schizophrenia GWAS than in 17 large GWASs of non-psychiatric diseases and traits, arguing that ASM effects are at least partially tissue specific. Studies of germline and control brain ASM SNPs supported a causal association between ASM and schizophrenia. Finally, significantly higher proportions of ASM SNPs than of non-ASM SNPs were detected at loci exhibiting epigenetic signatures ofenhancers and promoters, and they were overrepresented within transcription factor binding regions and DNase I hypersensitive sites. All of these findings collectively indicate that ASM SNPs should be prioritized in follow-up GWASs.

ID 515 – Mood dysregulation, sex and sex hormones predict stress response circuitry deficits

Inspired by the NIMH RDoC initiative to determine biosignatures associated with regulation of arousal and negative affect across psychiatric disorders, we used a mild visual stress task to conduct a functional magnetic resonance imaging (fMRI) study investigating the impact of depressed mood on stress circuitry function in major depressive disorder, psychosis and healthy controls ( n = 99). fMRI data were analyzed using SPM8 and task-related connectivity was assessed by generalized psychophysiological interaction (gPPI). Hyperactivity in subcortical arousal regions in response to stress was shared across diagnoses. Sex-specific analyses revealed that in females but not males depressed mood predicted increase in R AMYG response and decrease in (1) R AMYG–R HIPP, (2) R AMYG-R OFC, and (3) HYPO–R OFC connectivity during stress. Follow-up analyses showed that the positive relationship between depressed mood and stress-related increase in R AMYG–R HIPP connectivity was present in males with high but not low free androgens. Overall, these findings demonstrated that females with depressed mood were unable to recruit regions inhibiting subcortical arousal during stress, possibly explaining why women are more vulnerable to mood disorders than men, and that testosterone might have protective effects on stress circuitry function in men.

Metabotropic Glutamate 2/3 Receptors and Epigenetic Modifications in Psychotic Disorders: A Review

Schizophrenia and Bipolar Disorder are chronic psychiatric disorders, both considered as “major psychosis”; they are thought to share some pathogenetic factors involving a dysfunctional gene x environment interaction. Alterations in the glutamatergic transmission have been suggested to be involved in the pathogenesis of psychosis. Our group developed an epigenetic model of schizophrenia originated by Prenatal Restraint Stress (PRS) paradigm in mice. PRS mice developed some behavioral alterations observed in schizophrenic patients and classic animal models of schizophrenia, i.e. deficits in social interaction, locomotor activity and prepulse inhibition. They also showed specific changes in promoter DNA methylation activity of genes related to schizophrenia such as reelin, BDNF and GAD67, and altered expression and function of mGlu2/3 receptors in the frontal cortex. Interestingly, behavioral and molecular alterations were reversed by treatment with mGlu2/3 agonists. Based on these findings, we speculate that pharmacological modulation of these receptors could have a great impact on early phase treatment of psychosis together with the possibility to modulate specific epigenetic key protein involved in the development of psychosis.In this review, we will discuss in more details the specific features of the PRS mice as a suitable epigenetic model for major psychosis. We will then focus on key proteins of chromatin remodeling machinery as potential target for new pharmacological treatment through the activation of metabotropic glutamate receptors.

Acceptance and Commitment Therapy Compared to Treatment as Usual in Psychosis: A Systematic Review and Meta-Analysis

Introduction: Schizophrenia and psychotic disorders are chronic conditions. Although antipsychotic medications are the first line of treatment, many patients continued to have symptoms. Acceptance and Commitment Therapy (ACT) is a therapy that applies mindfulness to teach patients accepting the existence of symptoms rather than avoid them. A meta-analysis was conducted to measure the efficacy of ACT in treatment of Methods: A systematic review search was conducted using the following keywords: acceptance and commitment therapy, randomized, clinical trials, psychosis, schizophrenia, and major depressive disorder AND psychosis. All studies were read by two authors and checked for eligibility. Studies were included if randomly allocate to ACT or usual treatment (TAU), and psychosis as diagnosis. Mantel and Haenszel approach was used to determine the heterogeneity in the study. For quantitative outcomes, standardized mean difference between ACT and TAU was used to summarize effect size, while relative risk was used for categorical outcomes along with 95% confidence interval. Results: 217 studies were identified. 92 studies were selected for review after removing the duplications. A total of 4 studies were included in quantitative-synthesis. The mean age for the participants was 38 years of age. Regarding treatment outcomes, there was a significant difference between the two arms in the degree of change of negative symptoms (p=0.008), but the difference was not significant for positive symptoms. There was a reduction of re-hospitalization rate at 4 months in ACT compared to TAU in participants with Conclusions: ACT is a promising adjunctive therapy for patient with

Age of Onset in Schizophrenia Spectrum Disorders: Complex Interactions between Genetic and Environmental Factors.

In this study we evaluated the role of a candidate gene for major psychosis, Sialyltransferase (ST8SIA2), in the risk to develop a schizophrenia spectrum disorders, taking into account exposure to stressful life events (SLEs). Eight polymorphisms (SNPs) were tested in 94 Schizophreniainpatients and 176 healthy controls. Schizophrenia patients were also evaluated for SLEs in different life periods. None of the SNPs showed association with schizophrenia. Nevertheless, when crossing genetic variants with childhood SLEs, we could observe trends of interaction with age of onset. Though several limitations, our results support a protective role of ST8SIA2 in individuals exposed to moderate childhood stress.

Genome-wide DNA methylome reveals the dysfunction of intronic microRNAs in major psychosis.

BackgroundDNA methylation is thought to be extensively involved in the pathogenesis of many diseases, including major psychosis. However, most studies focus on DNA methylation alteration at promoters of protein-coding genes, despite the poor correlation between DNA methylation and gene expression.MethodsWe analyzed differentially methylated regions and differentially expressed genes in patients with schizophrenia and bipolar disorder and normal subjects. Gene expression and DNA methylation were analyzed with RNA-seq and MeDIP-seq of post-mortem brain tissue (brain region BA9) cohort in five schizophrenia, seven bipolar disorder cases and six controls, respectively.ResultsHere, we performed a large-scale integrative analysis using MeDIP-seq, coupled with RNA-seq, on brain samples from major psychotic and normal subjects and observed obvious discrepancy between DNA methylation and gene expression. We found that differentially methylated regions (DMRs) were distributed across different types of genomic elements, especially introns. These intronic DMRs were significantly enriched for diverse regulatory elements, such as enhancers and binding sites of certain transcriptional factors (e.g., Pol3). Notably, we found that parts of intronic DMRs overlapped with some intragenic miRNAs, such as hsa-mir-7-3. These intronic DMR-related miRNAs were found to target many differentially expressed genes. Moreover, functional analysis demonstrated that differential target genes of intronic DMR-related miRNAs were sufficient to capture many important biological processes in major psychosis, such as neurogenesis, suggesting that miRNAs may function as important linkers mediating the relationships between DNA methylation alteration and gene expression changes.ConclusionsCollectively, our study indicated that DNA methylation alteration could induce expression changes indirectly by affecting miRNAs and the exploration of DMR-related miRNAs and their targets enhanced understanding of the molecular mechanisms underlying major psychosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-015-0139-4) contains supplementary material, which is available to authorized users.

Metabolic issues in patients affected by schizophrenia: clinical characteristics and medical management.

Patients affected by psychotic disorders are more likely to develop high rates of co-morbidities, such as obesity, type 2 diabetes, dyslipidemias, hypertension, metabolic syndrome, myocardial infarction, stroke etc., in the long-term. These morbidities have a significant impact on the life-expectancy of these patients. Patients with chronic psychoses show a 2–3-fold increased risk of death mostly from cardiovascular and metabolic diseases. Although there may be an independent link, between schizophrenia and metabolic conditions the cardio-metabolic risk is mostly related to an unhealthy lifestyle and the usage of antipsychotic agents (especially Second Generation Antipsychotics or atypical) even when these remain effective treatments in the management of major psychoses. Recently, many international organizations have developed screening and monitoring guidelines for the control of modifiable risk factors in order to reduce the rate of co-morbidity and mortality among patients affected by schizophrenia. This paper is a review of current knowledge about the metabolic issues of patients affected by schizophrenia and describes clinical characteristics and medical management strategies for such conditions.

Integrating mental health into primary care in Nigeria: report of a demonstration project using the mental health gap action programme intervention guide.

BackgroundThe World Mental Health Surveys conducted by the World Health Organization (WHO) have shown that huge treatment gaps for severe mental disorders exist in both developed and developing countries. This gap is greatest in low and middle income countries (LMICs).Efforts to scale up mental health services in LMICs have to contend with the paucity of mental health professionals and health facilities providing specialist services for mental, neurological and substance use (MNS) disorders. A pragmatic solution is to improve access to care through the facilities that exist closest to the community, via a task-shifting strategy. This study describes a pilot implementation program to integrate mental health services into primary health care in Nigeria.MethodsThe program was implemented over 18 months in 8 selected local government areas (LGAs) in Osun state of Nigeria, using the WHO Mental Health Gap Action Programme Intervention Guide (mhGAP-IG), which had been contextualized for the local setting.A well supervised cascade training model was utilized, with Master Trainers providing training for the Facilitators, who in turn conducted several rounds of training for front-line primary health care workers. The first set of trainings by the Facilitators was supervised and mentored by the Master Trainers and refresher trainings were provided after 9 months.ResultsA total of 198 primary care workers, from 68 primary care clinics, drawn from 8 LGAs with a combined population of 966,714 were trained in the detection and management of four MNS conditions: moderate to severe major depression, psychosis, epilepsy, and alcohol use disorders, using the mhGAP-IG. Following training, there was a marked improvement in the knowledge and skills of the health workers and there was also a significant increase in the numbers of persons identified and treated for MNS disorders, and in the number of referrals. Even though substantial retention of gained knowledge was observed nine months after the initial training, some level of decay had occurred supporting the need for a refresher training.ConclusionIt is feasible to scale up mental health services in primary care settings in Nigeria, using the mhGAP-IG and a well-supervised cascade-training model. This format of training is pragmatic, cost-effective and holds promise, especially in settings where there are few specialists.Electronic supplementary materialThe online version of this article (doi:10.1186/s12913-015-0911-3) contains supplementary material, which is available to authorized users.

High Precision DNA Modification Analysis of HCG9 in Major Psychosis.

New epigenetic technologies may uncover etiopathogenic mechanisms of major psychosis. In this study, we applied padlock probe-based ultra-deep bisulfite sequencing for fine mapping of modified cytosines of the HLA complex group 9 (nonprotein coding) gene in the postmortem brains of individuals affected with schizophrenia or bipolar disorder and unaffected controls. Significant differences between patients and controls were detected in both CpG and CpH modifications. In addition, we identified epigenetic age effects, DNA modification differences between sense and anti-sense strands, and demonstrated how DNA modification data can be used in clustering of patient populations. Our findings revealed new epigenetic complexities but also highlighted the potential of DNA modification approaches in the search of heterogeneous causes of major psychiatric disease.

Circuit- and Diagnosis-Specific DNA Methylation Changes at γ-Aminobutyric Acid-Related Genes in Postmortem Human Hippocampus in Schizophrenia and Bipolar Disorder.

Dysfunction related to γ-aminobutyric acid (GABA)-ergic neurotransmission in the pathophysiology of major psychosis has been well established by the work of multiple groups across several decades, including the widely replicated downregulation of GAD1. Prior gene expression and network analyses within the human hippocampus implicate a broader network of genes, termed the GAD1 regulatory network, in regulation of GAD1 expression. Several genes within this GAD1 regulatory network show diagnosis- and sector-specific expression changes within the circuitry of the hippocampus, influencing abnormal GAD1 expression in schizophrenia and bipolar disorder. To investigate the hypothesis that aberrant DNA methylation contributes to circuit- and diagnosis-specific abnormal expression of GAD1 regulatory network genes in psychotic illness. This epigenetic association study targeting GAD1 regulatory network genes was conducted between July 1, 2012, and June 30, 2014. Postmortem human hippocampus tissue samples were obtained from 8 patients with schizophrenia, 8 patients with bipolar disorder, and 8 healthy control participants matched for age, sex, postmortem interval, and other potential confounds from the Harvard Brain Tissue Resource Center, McLean Hospital, Belmont, Massachusetts. We extracted DNA from laser-microdissected stratum oriens tissue of cornu ammonis 2/3 (CA2/3) and CA1 postmortem human hippocampus, bisulfite modified it, and assessed it with the Infinium HumanMethylation450 BeadChip (Illumina, Inc). The subset of CpG loci associated with GAD1 regulatory network genes was analyzed in R version 3.1.0 software (R Foundation) using the minfi package. Findings were validated using bisulfite pyrosequencing. Methylation levels at 1308 GAD1 regulatory network-associated CpG loci were assessed both as individual sites to identify differentially methylated positions and by sharing information among colocalized probes to identify differentially methylated regions. A total of 146 differentially methylated positions with a false detection rate lower than 0.05 were identified across all 6 groups (2 circuit locations in each of 3 diagnostic categories), and 54 differentially methylated regions with P < .01 were identified in single-group comparisons. Methylation changes were enriched in MSX1, CCND2, and DAXX at specific loci within the hippocampus of patients with schizophrenia and bipolar disorder. This work demonstrates diagnosis- and circuit-specific DNA methylation changes at a subset of GAD1 regulatory network genes in the human hippocampus in schizophrenia and bipolar disorder. These genes participate in chromatin regulation and cell cycle control, supporting the concept that the established GABAergic dysfunction in these disorders is related to disruption of GABAergic interneuron physiology at specific circuit locations within the human hippocampus.

The use of dynamic susceptibility contrast (DSC) MRI to automatically classify patients with first episode psychosis

Hemodynamic changes in the brain have been reported in major psychosis in respect to healthy controls, and could unveil the basis of structural brain modifications happening in patients. The study of first episode psychosis is of particular interest because the confounding role of chronicity and medication can be excluded. The aim of this work is to automatically discriminate first episode psychosis patients and normal controls on the basis of brain perfusion employing a support vector machine (SVM) classifier. 35 normal controls and 35 first episode psychosis underwent dynamic susceptibility contrast magnetic resonance imaging, and cerebral blood flow and volume, along with mean transit time were obtained. We investigated their behavior in the whole brain and in selected regions of interest, in particular the left and right frontal, parietal, temporal and occipital lobes, insula, caudate and cerebellum. The distribution of values of perfusion indexes were used as features in a support vector machine classifier. Mean values of blood flow and volume were slightly lower in patients, and the difference reached statistical significance in the right caudate, left and right frontal lobes, and in left cerebellum. Linear SVM reached an accuracy of 83% in the classification of patients and normal controls, with the highest accuracy associated with the right frontal lobe and left parietal lobe. In conclusion, we found evidence that brain perfusion could be used as a potential marker to classify patients with psychosis, who show reduced blood flow and volume in respect to normal controls.

Re-conceptualising Major Psychosis and Mood Disorders as Staged Illnesses : Towards Change in Clinical Services and Treatment

Major psychosis and mood disorders are neuroprogressive illnesses that develop from prodrome to episodic onset to relapse and recurrence and finally chronic, debilitating illness. There is considerable evidence supporting a staged model for mental illness. Moreover, acknowledging the staged progression of major psychiatric illness creates new opportunities for intervention. Conventional treatments focus on symptom reduction and prevention of relapse, with many services requiring triage levels that exclude all but the most severe patients. This generally results in most of the mental health resources being directed towards patients in the later stages of illness. Re-conceptualising major psychosis and mood disorders as staged illnesses suggests that there is a potential for improvement with regards to illness burden for patients and reduced health care costs if a greater portion of mental health resources were directed towards patients in early stages of illness and toward treatments that may prevent neuroprogression. Successful service models for early intervention already exist, such as Orygen Youth Mental Health in Australia, and many treatments that may impede the progression of mental illness have been identified. Ongoing research is investigating mechanisms by which illness neuroprogression occurs and is evaluating the neuroprotective capabilities of treatments. There is already sufficient experience and knowledge, as well as stage appropriate treatment and possible neuroprotective agents with mechanisms of action that may counteract the mechanisms of neuroprogression. There are sufficient tools to apply the staging model to our treatment and services now, and doing so will lead to better outcomes for patients.

A Unique Case of Addiction to Trifluoperazine in a Non-psychotic Patient

Introduction Trifluoperazine, a typical antipsychotic, has been frequently used in psychotic disorders for many years. Sudden discontinuation of trifluoperazine is known to cause relapse of psychotic symptoms in patients suffering from major psychosis. The Case History Mr P, a 34 years old male, professor of physics, was admitted on August 12, 2014, his fourth admission in the last one year, with chief complaints of extreme restlessness, tremors of the hands and blurring of vision for two days prior admission. The patient had been taking 12-16 tablets of a combination of trifluoperazine 5mg and trihexyphenidyl 2mg for about one week prior to his hospitalization. The patient described experiencing a feeling of numbness once he took the aforementioned tablets which 'insulated' him from problems at home. He reported experiencing severe restlessness and anxiety if he did not take the tablets. The patient was diagnosed as suffering from Obsessive Compulsive Disorder one year back when he had presented with chief complaints of recurrent disturbing thoughts as to whether he had kept his car keys in a particular pocket and whether he had locked his car or not. To relieve the extreme anxiety provoked by these thoughts, he would be compelled to carry out checking compulsions. He was started at that time on Paroxetine and a combination of trifluoperazine and trihexyphenidyl. The recurrent thoughts and compulsive acts were relieved in about a month. He stopped taking paroxetine of his own but continued taking the combination of trifluoperazine and trihexyphenidyl following which he was hospitalized with us. Discussion There have been sporadic reports of addiction to antipsychotic drugs, including trihexyphenydyl, risperidone and quetiapine. Most of them are associated with a typical withdrawal syndrome on sudden stoppage of antipsychotic drug in question which is the prime reason behind the patient taking to the antipsychotic drug again. Most of the patients were known cases of schizophrenia or another long term psychotic illness. The case presented here is unique in the sense that the patient does not suffer from any psychotic illness. Conclusion Obviously, the problem of addiction is complex. This case points to the need for a fresh research into the mechanisms leading to dependence to a particular drug.

Mesial temporal lobe epilepsy with psychiatric comorbidities: a place for differential neuroinflammatory interplay.

BackgroundDespite the strong association between epilepsy and psychiatric comorbidities, few biological substrates are currently described. We have previously reported neuropathological alterations in mesial temporal lobe epilepsy (MTLE) patients with major depression and psychosis that suggest a morphological and neurochemical basis for psychopathological symptoms. Neuroinflammatory-related structures and molecules might be part of the altered neurochemical milieu underlying the association between epilepsy and psychiatric comorbidities, and such features have not been previously investigated in humans.MethodsMTLE hippocampi of subjects without psychiatric history (MTLEW), MTLE + major depression (MTLE + D), and MTLE + interictal psychosis (MTLE + P) derived from epilepsy surgery and control necropsies were investigated for reactive astrocytes (glial fibrillary acidic protein (GFAP)), activated microglia (human leukocyte antigen, MHC class II (HLA-DR)), glial metallothionein-I/II (MT-I/II), and aquaporin 4 (AQP4) immunohistochemistry.ResultsWe found an increased GFAP immunoreactive area in the molecular layers, granule cell layer, and cornus ammonis region 2 (CA2) and cornus ammonis region 1 (CA1) of MTLEW and MTLE + P, respectively, compared to MTLE + D. HLA-DR immunoreactive area was higher in cornus ammonis region 3 (CA3) of MTLE + P, compared to MTLE + D and MTLEW, and in the hilus, when compared to MTLEW. MTLEW cases showed increased MT-I/II area in the granule cell layer and CA1, compared to MTLE + P, and in the parasubiculum, when compared to MTLE + D and MTLE + P. Differences between MTLE and control, such as astrogliosis, microgliosis, increased MT-I/II, and decreased perivascular AQP4 in the epileptogenic hippocampus, were in agreement to what is currently described in the literature.ConclusionsNeuroinflammatory-related molecules in MTLE hippocampus show a distinct pattern of expression when patients present with a comorbid psychiatric diagnosis, similar to what is found in the pure forms of schizophrenia and major depression. Future studies focusing on inflammatory characteristics of MTLE with psychiatric comorbidities might help in the design of better therapeutic strategies.