Validating mitochondrial electron transport chain content in individuals at clinical high risk for psychosis.

Altered mitochondrial electron transport chain function has been implicated in the pathophysiology and etiology of schizophrenia. To date, our previously published study (i.e. first cohort) is still the only study to demonstrate that mitochondrial electron transport chain is not altered in white blood cells from individuals at clinical high risk for psychosis. Here, we aimed to replicate our previous findings with an independent set of samples and validate the levels of mitochondrial complex I-V content in individuals at clinical high risk for psychosis. We demonstrated that the second cohort (i.e. validation cohort) expressed similar results as the first cohort. We combined the first cohort study with the second cohort and once more validated a lack of differential levels in mitochondrial complex I-V content between the two groups. In addition, we were able to validate a correlation between complex III content and prodromal negative symptom severity when the two cohorts studies were combined. Additionally, a correlation between complex V content and prodromal disorganization symptom severity was found when the two cohorts were combined. In conclusion, our results showed that dysfunction of the mitochondrial electron transport chain is not detected in peripheral blood mononuclear cells of individuals in the putative prodromal stage of schizophrenia.

PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia.

BACKGROUND: Patients with schizophrenia (SCZ) experience chronic cognitive deficits. Histone deacetylases (HDACs) are enzymes that regulate cognitive circuitry; however, the role of HDACs in cognitive disorders, including SCZ, remains unknown in humans. We previously determined that HDAC2 mRNA levels were lower in dorsolateral prefrontal cortex (DLPFC) tissue from donors with SCZ compared with controls. Here we investigated the relationship between in vivo HDAC expression and cognitive impairment in patients with SCZ and matched healthy controls using [11C]Martinostat positron emission tomography (PET). METHODS: In a case-control study, relative [11C]Martinostat uptake was compared between 14 patients with SCZ or schizoaffective disorder (SCZ/SAD) and 17 controls using hypothesis-driven region-of-interest analysis and unbiased whole brain voxel-wise approaches. Clinical measures, including the MATRICS consensus cognitive battery, were administered. RESULTS: Relative HDAC expression was lower in the DLPFC of patients with SCZ/SAD compared with controls, and HDAC expression positively correlated with cognitive performance scores across groups. Patients with SCZ/SAD also showed lower relative HDAC expression in the dorsomedial prefrontal cortex and orbitofrontal gyrus, and higher relative HDAC expression in the cerebral white matter, pons, and cerebellum compared with controls. CONCLUSIONS: These findings provide in vivo evidence of HDAC dysregulation in patients with SCZ and suggest that altered HDAC expression may impact cognitive function in humans. FUNDING: National Institute of Mental Health (NIMH), Brain and Behavior Foundation, Massachusetts General Hospital (MGH), Athinoula A. Martinos Center for Biomedical Imaging, National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH Shared Instrumentation Grant Program.

Beneficial and adverse effects of antipsychotic medication on cognitive flexibility are related to COMT genotype in first episode psychosis.

This study evaluated the ability to flexibly shift cognitive set and to consistently maintain a new response preference using the Penn Conditional Exclusion Test (PCET). The relationship of performance errors with catechol-O-methyltransferase (COMT) rs4680 (Val158Met) genotype (Met carriers vs. Val homozygotes) on test performance before and after antipsychotic treatment in 32 first episode psychosis (FEP) patients was examined. After treatment, patients demonstrated a mixture of beneficial and adverse cognitive outcomes that varied in relation to COMT genotype. Met carriers showed decreased perseverative and regressive errors, reflecting improved cognitive flexibility and enhanced stability of behavioral preferences, respectively. In contrast, Val homozygotes exhibited an increase in regressive errors after treatment. These findings suggest that Val homozygotes may be vulnerable to adverse effects of antipsychotic medication on cognitive processes that maintain consistent adaptive response preferences, an ability linked to the striatum in rodent models.

Early Loss of Blood-Brain Barrier Integrity Precedes NOX2 Elevation in the Prefrontal Cortex of an Animal Model of Psychosis.

The social isolation rearing of young adult rats is a model of psychosocial stress and provides a nonpharmacological tool to study alterations reminiscent of symptoms seen in psychosis. We have previously demonstrated that social isolation in rats leads to increased oxidative stress and to cerebral NOX2 elevations. Here, we investigated early alterations in mRNA expression leading to increased NOX2 in the brain. Rats were exposed to a short period of social isolation (1 week) and real-time polymerase chain reaction (PCR) for mRNA expression of genes involved in blood-brain barrier (BBB) formation and integrity (ORLs, Vof 21 and Vof 16, Leng8, Vnr1, and Trank 1 genes) was performed. Real-time PCR experiments, immunohistochemistry, and Western blotting analysis showed an increased expression of these genes and related proteins in isolated rats with respect to control animals. The expression of specific markers of BBB integrity, such as matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), occludin 1, and plasmalemmal vesicle associated protein-1 (PV-1), was also significantly altered after 1 week of social isolation. BBB permeability, evaluated by quantification of Evans blue dye extravasation, as well as interstitial fluid, was significantly increased in rats isolated for 1 week with respect to controls. Isolation-induced BBB disruption was also accompanied by a significant increase of Interleukin 6 (IL-6) expression. Conversely, no differences in NOX2 levels were detected at this time point. Our study demonstrates that BBB disruption precedes NOX2 elevations in the brain. These results provide new insights in the interplay of mechanisms linking psychosocial stress to early oxidative stress in the brain, disruption of the BBB, and the development of mental disorders.

Effects of intronic single nucleotide polymorphisms (iSNPs) of a polysialyltransferase, ST8SIA2 gene found in psychiatric disorders on its gene products.

Polysialic acid (polySia) is a linear homopolymer of sialic acid and mainly modifies neural cell adhesion molecule. PolySia plays important roles in synapse formation, learning and memory, social behavior and is associated with several diseases. Gene analyses of one of the biosynthetic enzymes for polySia, ST8SIA2, have revealed that several SNPs and genetic variations in the ST8SIA2 gene are associated with several psychiatric disorders; however, the mechanisms underlying these associations remain unknown. Here, we analyzed the effects of two iSNPs of ST8SIA2, rs2168351 and rs3784730, which are associated with bipolar disorder and autism spectrum disorder, respectively, on the expression of mRNA, ST8SIA2 and its final product, polySia in mouse neuroblastoma and human adenocarcinoma cell lines. We found that both iSNPs affected the expression of pre-mRNA and mRNA of ST8SIA2, and altered the cellular levels of ST8SIA2 and polySia. Taken together, these results indicate that impairment of the regulated expression of ST8SIA2 and the resulting downstream effects on gene products by these two iSNPs contribute to the development of these psychiatric disorders.

[Glutamate dehydrogenase activity in platelets of patients with endogenous psychosis]. / Aktivnost' trombotsitarnoi glutamatdegidrogenazy u bol'nykh s endogennymi psikhozami.

OBJECTIVE: to evaluation of glutamate dehydrogenase (GDH) enzymatic activity in platelets of patients with endogenous psychoses. MATERIAL AND METHODS: Enzymatic cectivity of GDH evaluated in 69 patients with schizophrenia (n=48) or schizoaffective disorder (n=21) in comparison with control group (n=34) and elucidation of possible link between their platelet GDH activity and clinical psychopathological condition. RESULTS AND CONCLUSION: Generally, GDH activity in patients before antipsychotic treatment was significantly lower, than in control group. Significant differences were revealed in GDH activity before the treatment between subgroups of patients with first episode psychosis (FEP, n=34), chronic patients (n=35), and control group (n=34), wherein GDH activity correlated with PANSS in FEP patients before the treatment course. No links were found in patients with chronic schizophrenia. Besides, significant links between GDH activity determined before the treatment course and PANSS scores after the treatment were found in FEP patients: the higher were levels of platelet GDH activity in FEP patients, the lower were their PANSS scores after the treatment. CONCLUSION: Initial (baseline) levels of platelet GDH activity can have value for prognosis of antipsychotic pharmacotherapy efficacy in patients with FEP.

Catechol-O-Methyltransferase Val158Met Polymorphism and Clinical Response to Antipsychotic Treatment in Schizophrenia and Schizo-Affective Disorder Patients: a Meta-Analysis.

BACKGROUND: The catechol-O-methyltransferase (COMT) enzyme plays a crucial role in dopamine degradation, and the COMT Val158Met polymorphism (rs4680) is associated with significant differences in enzymatic activity and consequently dopamine concentrations in the prefrontal cortex. Multiple studies have analyzed the COMT Val158Met variant in relation to antipsychotic response. Here, we conducted a meta-analysis examining the relationship between COMT Val158Met and antipsychotic response. METHODS: Searches using PubMed, Web of Science, and PsycInfo databases (03/01/2015) yielded 23 studies investigating COMT Val158Met variation and antipsychotic response in schizophrenia and schizo-affective disorder. Responders/nonresponders were defined using each study's original criteria. If no binary response definition was used, authors were asked to define response according to at least 30% Positive and Negative Syndrome Scale score reduction (or equivalent in other scales). Analysis was conducted under a fixed-effects model. RESULTS: Ten studies met inclusion criteria for the meta-analysis. Five additional antipsychotic-treated samples were analyzed for Val158Met and response and included in the meta-analysis (ntotal=1416). Met/Met individuals were significantly more likely to respond than Val-carriers (P=.039, ORMet/Met=1.37, 95% CI: 1.02-1.85). Met/Met patients also experienced significantly greater improvement in positive symptoms relative to Val-carriers (P=.030, SMD=0.24, 95% CI: 0.024-0.46). Posthoc analyses on patients treated with atypical antipsychotics (n=1207) showed that Met/Met patients were significantly more likely to respond relative to Val-carriers (P=.0098, ORMet/Met=1.54, 95% CI: 1.11-2.14), while no difference was observed for typical-antipsychotic-treated patients (n=155) (P=.65). CONCLUSIONS: Our findings suggest that the COMT Val158Met polymorphism is associated with response to antipsychotics in schizophrenia and schizo-affective disorder patients. This effect may be more pronounced for atypical antipsychotics.

Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency.

BACKGROUND: Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inborn defect disturbing the remethylation of homocysteine to methionine (<200 reported cases). This retrospective study evaluates clinical, biochemical genetic and in vitro enzymatic data in a cohort of 33 patients. METHODS: Clinical, biochemical and treatment data was obtained from physicians by using a questionnaire. MTHFR activity was measured in primary fibroblasts; genomic DNA was extracted from cultured fibroblasts. RESULTS: Thirty-three patients (mean age at follow-up 11.4 years; four deceased; median age at first presentation 5 weeks; 17 females) were included. Patients with very low (<1.5%) mean control values of enzyme activity (n = 14) presented earlier and with a pattern of feeding problems, encephalopathy, muscular hypotonia, neurocognitive impairment, apnoea, hydrocephalus, microcephaly and epilepsy. Patients with higher (>1.7-34.8%) residual enzyme activity had mainly psychiatric symptoms, mental retardation, myelopathy, ataxia and spasticity. Treatment with various combinations of betaine, methionine, folate and cobalamin improved the biochemical and clinical phenotype. During the disease course, patients with very low enzyme activity showed a progression of feeding problems, neurological symptoms, mental retardation, and psychiatric disease while in patients with higher residual enzyme activity, myelopathy, ataxia and spasticity increased. All other symptoms remained stable or improved in both groups upon treatment as did brain imaging in some cases. No clear genotype-phenotype correlation was obvious. DISCUSSION: MTHFR deficiency is a severe disease primarily affecting the central nervous system. Age at presentation and clinical pattern are correlated with residual enzyme activity. Treatment alleviates biochemical abnormalities and clinical symptoms partially.

Atypical neuroleptic malignant syndrome in patients treated with aripiprazole and clozapine: a case-series study and short review.

OBJECTIVES: Neuroleptic malignant syndrome (NMS) requires emergency treatment and can be fatal. Combined aripiprazole and clozapine therapy is rarely used in clinical settings, and NMS related this combination still lacks evaluation. Herein, we present two cases of atypical NMS treated with aripiprazole and clozapine. METHODS: Case 1 was a schizophrenic male with a history of NMS under treatment with aripiprazole 20 mg. He was hospitalized and maintained with aripiprazole 5 mg and clozapine 225 mg. On the 25th day, atypical NMS occurred with rigidity, elevated creatine kinase, and stupor, which subsided with supportive therapy. He was discharged under treatment with aripiprazole 15 mg and fluoxetine 60 mg. Case 2 was a female with schizoaffective disorder without a history of NMS. She was hospitalized and maintained with clozapine 50 mg and aripirazole 30 mg. On the 11th day, atypical NMS occurred with mild fever, delirium, and rigidity, which subsided under supportive therapy. RESULTS AND CONCLUSIONS: Our cases highlight the atypical features of NMS in patients being treated with combined ari-piprazole and clozapine. Consciousness change, modest elevation of creatine kinase, and leukocytosis were the most consistent findings; hyperthermia accounts for only some of the cases. This is a reminder of the importance of earlier detection of the soft signs and atypical features of NMS under this combined treatment.

Lower glutamic acid decarboxylase 65-kDa isoform messenger RNA and protein levels in the prefrontal cortex in schizoaffective disorder but not schizophrenia.

BACKGROUND: Altered gamma-aminobutyric acid (GABA) signaling in the prefrontal cortex (PFC) has been associated with cognitive dysfunction in patients with schizophrenia and schizoaffective disorder. Levels of the GABA-synthesizing enzyme glutamic acid decarboxylase 67-kDa isoform (GAD67) in the PFC have been consistently reported to be lower in patients with these disorders, but the status of the second GABA-synthesizing enzyme, glutamic acid decarboxylase 65-kDa isoform (GAD65), remains unclear. METHODS: GAD65 messenger RNA (mRNA) levels were quantified in PFC area 9 by quantitative polymerase chain reaction from 62 subjects with schizophrenia or schizoaffective disorder and 62 matched healthy comparison subjects. In a subset of subject pairs, GAD65 relative protein levels were quantified by confocal immunofluorescence microscopy. RESULTS: Mean GAD65 mRNA levels were 13.6% lower in subjects with schizoaffective disorder but did not differ in subjects with schizophrenia relative to their matched healthy comparison subjects. In the subjects with schizoaffective disorder, mean GAD65 protein levels were 19.4% lower and were correlated with GAD65 mRNA levels. Lower GAD65 mRNA and protein levels within subjects with schizoaffective disorder were not attributable to factors commonly comorbid with the diagnosis. CONCLUSIONS: In concert with previous studies, these findings suggest that schizoaffective disorder is associated with lower levels of both GAD65 and GAD67 mRNA and protein in the PFC, whereas subjects with schizophrenia have lower mean levels of only GAD67 mRNA and protein. Because cognitive function is generally better preserved in patients with schizoaffective disorder relative to patients with schizophrenia, these findings may support an interpretation that GAD65 downregulation provides a homeostatic response complementary to GAD67 downregulation that serves to reduce inhibition in the face of lower PFC network activity.

Relationship between the COMT-Val158Met and BDNF-Val66Met polymorphisms, childhood trauma and psychotic experiences in an adolescent general population sample.

OBJECTIVE: Psychotic experiences occur at a much greater prevalence in the population than psychotic disorders. There has been little research to date, however, on genetic risk for this extended psychosis phenotype. We examined whether COMT or BDNF genotypes were associated with psychotic experiences or interacted with childhood trauma in predicting psychotic experiences. METHOD: Psychiatric interviews and genotyping for COMT-Val158Met and BDNF-Val66Met were carried out on two population-based samples of 237 individuals aged 11-15 years. Logistic regression was used to examine for main effects by genotype and childhood trauma, controlling for important covariates. This was then compared to a model with a term for interaction between genotype and childhood trauma. Where a possible interaction was detected, this was further explored in stratified analyses. RESULTS: While childhood trauma showed a borderline association with psychotic experiences, COMT-Val158Met and BDNF-Val66Met genotypes were not directly associated with psychotic experiences in the population. Testing for gene x environment interaction was borderline significant in the case of COMT-Val158Met with individuals with the COMT-Val158Met Val-Val genotype, who had been exposed to childhood trauma borderline significantly more likely to report psychotic experiences than those with Val-Met or Met-Met genotypes. There was no similar interaction by BDNF-Val66Met genotype. CONCLUSION: The COMT-Val158Met Val-Val genotype may be a genetic moderator of risk for psychotic experiences in individuals exposed to childhood traumatic experiences.

COMT Val158Met genotype selectively alters prefrontal [18F]fallypride displacement and subjective feelings of stress in response to a psychosocial stress challenge.

Catechol-O-methyltransferase (COMT) plays an essential role in degradation of extracellular dopamine in prefrontal regions of the brain. Although a polymorphism in this gene, COMT Val(158)Met, affects human behavior in response to stress little is known about its effect on dopaminergic activity associated with the human stress response, which may be of interest for stress-related psychiatric disorders such as psychosis. We aimed to investigate the effect of variations in COMT genotype on in vivo measures of stress-induced prefrontal cortex (PFC) dopaminergic processing and subjective stress responses. A combined sample of healthy controls and healthy first-degree relatives of psychosis patients (n = 26) were subjected to an [(18)F]fallypride Positron Emission Tomography scan. Psychosocial stress during the scan was induced using the Montreal Imaging Stress Task and subjective stress was assessed every 12 minutes. Parametric t-maps, generated using the linear extension of the simplified reference region model, revealed an effect of COMT genotype on the spatial extent of [(18)F]fallypride displacement. Detected effects of exposure to psychosocial stress were unilateral and remained restricted to the left superior and right inferior frontal gyrus, with Met-hetero- and homozygotes showing less [(18)F]fallypride displacement than Val-homozygotes. Additionally, Met-hetero- and homozygotes experienced larger subjective stress responses than Val-homozygotes. The direction of the effects remained the same when the data was analyzed separately for controls and first-degree relatives. The human stress response may be mediated in part by COMT-dependent dopaminergic PFC activity, providing speculation for the neurobiology underlying COMT-dependent differences in human behaviour following stress. Implications of these results for stress-related psychopathology and models of dopaminergic functioning are discussed.

Estrés y factores protectores en individuos en riesgo ultra-alto de psicosis, pacientes con un primer episodio de psicosis e individuos de control sanos / Stress and protective factors in individuals at ultra-high risk for psychosis, first episode psychosis and healthy controls

Los modelos de esquizofrenia de vulnerabilidad al estrés consideran que el estrés psicosocial es un importante factor en el inicio y la agravación de los síntomas psicóticos, pero en los estadios iniciales de la psicosis dicha investigación es limitada. Los factores protectores frente a los efectos del estrés podrían ser la clave para entender algunos hallazgos poco concluyentes y para el establecimiento de intervenciones psicosociales óptimas. En el presente estudio se compararon los niveles de estrés autorreferido, la autoestima, el apoyo social y el afrontamiento activo en 32 pacientes con un primer episodio de psicosis (PEP), en 30 individuos en riesgo ultra-alto (RUA) de psicosis y en 30 individuos de control sanos. En ambos grupos de pacientes se evaluaron las asociaciones con los síntomas de psicosis. Los individuos en RUA refirieron niveles de estrés significativamente mayores, comparados con los pacientes PEP. En ambos grupos de pacientes fue evidente una menor autoestima comparado con los individuos de control, y el grupo RUA mencionó un menor apoyo social y afrontamiento activo que los individuos de control. En el grupo de pacientes PEP estas diferencias de grupo no pudieron explicarse por la edad ni por la dosis de medicación antipsicótica. En el grupo RUA, los mayores niveles de estrés y la menor autoestima se asociaron a síntomas positivos y depresivos más graves en la escala breve de valoración psiquiátrica (Brief Psychiatric Rating Scale). En los análisis de regresión múltiple se puso de manifiesto que el estrés fue la única variable predictora significativa de la valoración de ambos síntomas y que la autoestima no moderó la relación. Los hallazgos del presente estudio ponen de relieve que los individuos en RUA de psicosis experimentan niveles elevados de estrés psicosocial y deficiencias destacadas en los factores de protección. Los resultados sugieren que las intervenciones psicosociales destinadas a reducir los niveles de estrés y a mejorar la resistencia y la capacidad de recuperación en esta población podrían ser beneficiosas para mejorar los desenlaces (AU)

Stress-vulnerability models of schizophrenia regard psychosocial stress as an important factor in the onset and aggravation of psychotic symptoms, but such research in the early phases of psychosis is limited. Protective factors against the effects of stress might be the key to understanding some inconclusive findings and to the development of optimal psychosocial interventions. The present study compared self-reported levels of stress, self-esteem, social support and active coping in 32 patients with a first episode of psychosis (FEP), 30 individuals at ultra-high risk for psychosis (UHR) and 30 healthy controls. Associations with symptoms of psychosis were assessed in both patient groups. Individuals at UHR reported significantly higher stress levels compared to FEP patients. Both patient groups showed lower self-esteem compared to controls, and the UHR group reported lower social support and active coping than controls. These group differences could not be explained by age and dose of antipsychotic medication in the FEP group. In the UHR group, higher stress levels and lower self-esteem were associated with more severe positive and depressive symptoms on the Brief Psychiatric Rating Scale. Multiple regression analyses revealed that stress was the only significant predictor for both symptom measures and that the relationship was not moderated by self-esteem. Our findings show that individuals at UHR for psychosis experience high levels of psychosocial stress and marked deficits in protective factors. The results suggest that psychosocial interventions targeted at reducing stress levels and improving resilience in this population may be beneficial in improving outcomes (AU)

Identification of sialyltransferase 8B as a generalized susceptibility gene for psychotic and mood disorders on chromosome 15q25-26.

We previously identified a significant bipolar spectrum disorder linkage peak on 15q25-26 using 35 extended families with a broad clinical phenotype, including bipolar disorder (types I and II), recurrent unipolar depression and schizoaffective disorder. However, the specific gene(s) contributing to this signal had not been identified. By a fine mapping association study in an Australian case-control cohort (n = 385), we find that the sialyltransferase 8B (ST8SIA2) gene, coding for an enzyme that glycosylates proteins involved in neuronal plasticity which has previously shown association to both schizophrenia and autism, is associated with increased risk to bipolar spectrum disorder. Nominal single point association was observed with SNPs in ST8SIA2 (rs4586379, P = 0.0043; rs2168351, P = 0.0045), and a specific risk haplotype was identified (frequency: bipolar vs controls = 0.41 vs 0.31; χ(2) = 6.46, P = 0.011, OR = 1.47). Over-representation of the specific risk haplotype was also observed in an Australian schizophrenia case-control cohort (n = 256) (χ(2) = 8.41, P = 0.004, OR = 1.82). Using GWAS data from the NIMH bipolar disorder (n = 2055) and NIMH schizophrenia (n = 2550) cohorts, the equivalent haplotype was significantly over-represented in bipolar disorder (χ(2) = 5.91, P = 0.015, OR = 1.29), with the same direction of effect in schizophrenia, albeit non-significant (χ(2) = 2.3, P = 0.129, OR = 1.09). We demonstrate marked down-regulation of ST8SIA2 gene expression across human brain development and show a significant haplotype×diagnosis effect on ST8SIA2 mRNA levels in adult cortex (ANOVA: F(1,87) = 6.031, P = 0.016). These findings suggest that variation the ST8SIA2 gene is associated with increased risk to mental illness, acting to restrict neuronal plasticity and disrupt early neuronal network formation, rendering the developing and adult brain more vulnerable to secondary genetic or environmental insults.

Does steroid sulfatase deficiency influence postpartum psychosis risk?

Postpartum (or puerperal) psychosis (PP) occurs shortly after childbirth in 0.1-0.2% of women, and is characterised by delusions, mood swings, confused thinking, and disorganised behaviour. The condition is disturbing for patients and their family members and loved ones, and affected individuals may be at increased risk of harming themselves or their offspring. The features of PP indicate a substantial biological basis to its pathogenesis, although currently little is known about possible risk factors. Based on recent results from animal model and human studies, I propose that reduced function of the enzyme steroid sulfatase in the mother represents a unifying and physiologically plausible candidate mechanism for the neural and endocrinological disturbances seen in cases of PP.

COMT implication in cognitive and psychiatric symptoms in chromosome 22q11 microdeletion syndrome: a selective review.

22q11.2 deletion syndrome (22q11DS) is a genetic syndrome associated with a microdeletion of the chromosome 22 band q11.2 with an estimated prevalence between 1:2,500 and 1:4,000. Studies of school-age children have shown that individuals with 22q11DS have high rates of psychiatric morbidity. In particular, by late adolescence, about 30% of patients with 22q11DS develop psychotic symptoms. One of the genes located in the microdeletion region of 22q11DS is the Catechol-O-Methyl transferase (COMT) which codes for an enzyme critically involved in the catabolic clearance of dopamine. COMT is critically involved in cognitive related disturbances, and it has often been suggested as a sensitive factor in the development of psychiatric disorders. Several studies have been conducted on the impact of COMT functional polymorphism in 22q11DS and its related cognitive/psychiatric correlates. In this review, we summarize mainly current knowledge on the correlation between schizophrenia/cognitive related symptoms and COMT genetic variations in 22q11DS. A selective literature review on this topic was undertaken. COMT might play an important role in modulating cognitive functions in 22q11DS but a clear relationship between COMT polimorphism and schizophrenia in 22q11DS need further investigation. Despite controversial results, 22q11DS represent a powerful model for studying the role of COMT and other genetic variations in schizophrenia. This is due to high risk in 22qDS patients of developing this disorder and their relative genetic homogeneity. Further research is needed to evaluate all of the polymorphic markers in the COMT gene and its nearby regulatory elements for association with schizophrenia. Identification of specific COMT-dependent molecular, cellular and circuit deficits will provide targets for the development of more efficient treatments for the cognitive and psychiatric symptoms in 22q11DS.

Xenobiotic metabolizing and transporter genes: gene-gene interactions in schizophrenia and related disorders.

AIMS: In this study we explored possible epistasis between CYP2D6 (*3, *4, *5, *6 and *1xN), CYP3A5 (*3), CYP1A2 (*1C and *1F) and ABCB1 (G2677T) in schizophrenia and related disorders. MATERIALS & METHODS: A total of 344 patients diagnosed with schizophrenia and related disorders, and 484 healthy controls participated in the present study. We analyzed gene-gene interactions by multifactor dimensionality reduction. RESULTS: A four-way model including ABCB1 G2677T, CYP3A5*3, CYP1A2*1F and CYP2D6*4 variants had the best overall performances (accuracy: 0.573) and a crossvalidation consistency of 10/10 (permutation testing p < 0.004). CONCLUSION: Our results suggest a significant involvement of CYPs and transporters in brain metabolism and homeostasis, and provide evidence of gene-gene interactions among xenobiotic metabolizing and transporter genes in the context of schizophrenia.

Chronic adolescent exposure to Δ-9-tetrahydrocannabinol in COMT mutant mice: impact on psychosis-related and other phenotypes.

Cannabis use confers a two-fold increase in the risk for psychosis, with adolescent use conferring even greater risk. A high-low activity catechol-O-methyltransferase (COMT) polymorphism may modulate the effects of adolescent Δ-9-tetrahydrocannabinol (THC) exposure on the risk for adult psychosis. Mice with knockout of the COMT gene were treated chronically with THC (4.0 and 8.0 mg/kg over 20 days) during either adolescence (postnatal days (PDs) 32-52) or adulthood (PDs 70-90). The effects of THC exposure were then assessed in adulthood across behavioral phenotypes relevant for psychosis: exploratory activity, spatial working memory (spontaneous and delayed alternation), object recognition memory, social interaction (sociability and social novelty preference), and anxiety (elevated plus maze). Adolescent THC administration induced a larger increase in exploratory activity, greater impairment in spatial working memory, and a stronger anti-anxiety effect in COMT knockouts than in wild types, primarily among males. No such effects of selective adolescent THC administration were evident for other behaviors. Both object recognition memory and social novelty preference were disrupted by either adolescent or adult THC administration, independent of genotype. The COMT genotype exerts specific modulation of responsivity to chronic THC administration during adolescence in terms of exploratory activity, spatial working memory, and anxiety. These findings illuminate the interaction between genes and adverse environmental exposures over a particular stage of development in the expression of the psychosis phenotype.

Cholinesterase inhibitors as adjunctive therapy in patients with schizophrenia and schizoaffective disorder: a review and meta-analysis of the literature.

BACKGROUND: Cognitive deficits have been described in patients with schizophrenia from the first descriptions of dementia praecox to current concepts of cognitive dysmetria. Nevertheless, little is known about how to deal with them. In Alzheimer disease, cholinergic deficit is found and cholinesterase inhibitors have been used to delay the progression of memory and cognitive dysfunction. Several lines of evidence suggest that the cholinergic system may be disrupted in schizophrenia. OBJECTIVE: To evaluate cognitive and clinical effects of adjunctive cholinesterase inhibitors in patients with schizophrenia and schizoaffective disorder. METHOD: We conducted a literature search on PubMed and EMBASE (up to December 2008) for articles that investigated adjunctive cholinesterase inhibitors in patients with schizophrenia. The terms 'schizophrenia', 'acetylcholinesterase inhibitors', 'rivastigmine', 'donepezil', 'galantamine' and 'cognitive deficit' were searched with restriction for English language and without a year limit. All articles that presented original data from randomized, double-blind, placebo-controlled trials with donepezil, rivastigmine or galantamine in patients with schizophrenia or schizoaffective disorder were included in the meta-analysis. Studies were excluded for the following reasons: (i) case study/letter/correspondence/review; (ii) animal study; (iii) molecular/genetic investigation; and (iv) inclusion of patients with schizophrenia and co-morbid dementia. Few appropriate data for meta-analysis were found because of the large heterogeneity of the assessment instruments used. Nevertheless, effects of cholinesterase inhibitors in some cognitive domains (executive function, memory and language), psychopathology (using the Positive and Negative Syndrome Scale) and extrapyramidal symptoms could be analysed. RESULTS: Six open-label and 24 double-blind studies were found. In five open-label studies there was an improvement in memory, attention and executive functions. Thirteen double-blind studies (four with rivastigmine, six with donepezil and three with galantamine) contributed to the meta-analysis. Significant improvement was found in this analysis for memory and the Trail Making test part A. CONCLUSIONS: The reviewed studies suggest that specific cognitive deficits (memory, and the motor speed and attention part of executive function) of patients with schizophrenia and schizoaffective disorder are responsive to rivastigmine, donepezil and galantamine as adjunctive therapy. Confirmatory studies are needed to determine the clinical utility of this treatment strategy.