| 1 | J. Histochem. Cytochem. 2004 Oct 52: 1367-76 |
|---|---|
| PMID | 15385583 |
| Title | Biochemical and histochemical evidence of nonspecific binding of alpha7nAChR antibodies to mouse brain tissue. |
| Abstract | Alpha 7 nicotinic acetylcholine receptors are involved in learning and memory, and are implicated in the pathology of Alzheimer's disease and schizophrenia. Detection of alpha7 subunits can be accomplished via immunodetection or alpha-bungarotoxin-binding techniques. Standard protocols for immunohistochemistry and Western blotting were followed using several commercially available antibodies. Various mice were evaluated, including non-transgenics, APP, PS1, APP+PS1, and alpha7 knockouts. Initial results with amyloid-depositing mice revealed alpha7 immunolabeled astrocytes, in addition to expected neuronal staining. Subsequent studies with intrahippocampal injections of lipopolysaccharide (LPS) into alpha7 knockout mice showed that both neuronal and astrocytic labeling by alpha7 antibodies was nonspecific. On Western blots of mouse brain proteins, none of the bands detected with antibodies directed against alpha7 subunits diminished in the alpha7 knockout mice. Although LPS-related changes in the expression of some bands were found, these also were unaffected by the alpha7 genotype of the mice. In general, the Western staining patterns for these antibodies revealed few overlAPPing bands. These immunodetection data are in contrast to genotyping results and mRNA analyses that confirmed the disruption of the alpha7 allele and lack of alpha7 message in the knockouts. These findings suggest caution in interpreting results when using several commercially available alpha7 nicotinic receptor antibodies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Anal. Chem. 2006 Jun 78: 3571-6 |
| PMID | 16737209 |
| Title | Altered levels of acute phase proteins in the plasma of patients with schizophrenia. |
| Abstract | schizophrenia is a relatively common psychiatric syndrome that affects virtually all brain functions. We investigated the plasma proteome of 22 schizophrenia male patients and 20 healthy male controls using two-dimensional gel electrophoresis and mass spectrometry. In total, we have identified 66 protein spots in human plasma and found that seven of them showed altered changes in schizophrenia patients, as compared to healthy controls, which mainly were acute phase proteins (APPs). Among these APPs, haptoglobin alpha2 chain (p < 0.001), haptoglobin beta chain (p < 0.001), alpha1-antitrypsin (p = 0.001), and complement factor B precursor (p = 0.022) showed overexpression in schizophrenia patients, whereas apolipoprotein A-I (p = 0.034) and transthyretin (p = 0.035) were found to be significantly decreased in patients. In addition, the expression of apolipoprotein A-IV (p = 0.018) was significantly up-regulated in schizophrenia patients, as compared to controls. We also found these APP genes, which were differentially expressed in this study, overlap in the schizophrenia susceptibility loci. Our findings further support the hypothesis that the inflammatory response system is linked to the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Mol. Psychiatry 2006 Aug 11: 787-93 |
| PMID | 16718279 |
| Title | Ontogenic reduction of Aph-1b mRNA and gamma-secretase activity in rats with a complex neurodevelopmental phenotype. |
| Abstract | Selectively bred apomorphine susceptible (APO-SUS) rats display a complex behavioral phenotype remarkably similar to that of human neurodevelopmental disorders, such as schizophrenia. We recently found that the APO-SUS rats have only one or two Aph-1b gene copies (I/I and II/II rats, respectively), whereas their phenotypic counterpart has three copies (III/III). Aph-1b is a component of the gamma-secretase enzyme complex that is involved in multiple (neuro)developmental signaling pathways. Nevertheless, surprisingly little is known about gamma-secretase expression during development. Here, we performed a longitudinal quantitative PCR study in embryos and the hippocampus of I/I, II/II and III/III rats, and found gene-dosage dependent differences in Aph-1b, but not Aph-1a, mRNA expression throughout pre- and post-natal development. On the basis of the developmental mRNA profiles, we assigned relative activities to the various Aph-1a and -1b gene promoters. Furthermore, in the three rat lines, we observed both tissue-specific and temporal alterations in gamma-secretase cleavage activity towards one of its best-known substrates, the amyloid-beta precursor protein APP. We conclude that the low levels of Aph-1b mRNA and gamma-secretase activity observed in the I/I and II/II rats during the entire developmental period may well underlie their complex phenotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | J. Alzheimers Dis. 2007 Aug 12: 73-92 |
| PMID | 17851196 |
| Title | Genetics of Alzheimer's disease. A rapidly evolving field. |
| Abstract | Genetic factors have a variable impact on Alzheimer's Disease (AD), ranging from familial forms that are transmitted in an autosomal dominant fashion to sporadic AD, where a polygenic component is present. Most genes conferring susceptibility to AD are related to amyloid-beta deposition (APP; PS1; PS2; APOE; Cystatin-C; ubiquilin-1), oxidative stress (NOS2; NOS3) and inflammatory response (IL-1 alpha; IL-1 beta; IL-6; TNF-alpha). Genome-wide analyses, transcriptomics and proteomics APProaches have pointed also to proapoptotic genes as increasing AD liability. Depression and psychotic symptoms that occur in a large proportion of AD patients have been associated with monoamine genes coding for metabolic enzymes (COMT), transporters (5-HTTLPR) and receptors (DRD1; DRD3). Genetic testing may be useful to confirm the diagnosis of AD in individuals with clinical signs of dementia, while it is generally not recommended as a predictive testing for AD in asymptomatic individuals. Drugs currently in use to treat AD are effective in only 20% of patients; their therapeutic effect is predominantly under genetic control (CYP26 gene; APOE). Environmental factors have been shown to moderate the effects of genes on psychiatric disorders such as depression, schizophrenia and ADHD. The study of gene-environment interactions in AD, that are still poorly understood, is essential to predict disease-risk in asymptomatic individuals. Genomics will provide a dynamic picture of biological processes in AD and new targets for the forthcoming anti-AD drugs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2007 Apr 31: 756-60 |
| PMID | 17289236 |
| Title | Clinical and social determinants of psychotropic drug prescription for schizophrenia outpatients in China. |
| Abstract | To date, few studies have investigated prescription patterns of psychotropic drugs in Chinese patients with schizophrenia in general and outpatients in particular. This study examined the role that socio-demographic and clinical factors play in determining psychotropic drug prescriptions for schizophrenia outpatients in China. Two hundred and fifty-five and 250 clinically stable outpatients with schizophrenia were randomly selected and interviewed in Hong Kong (HK) and Beijing (BJ) respectively, using standardized assessment instruments. Prescriptions of psychotropic drugs for all 505 subjects were collected at the time of the assessment. The relationship between antipsychotic drug prescription patterns and a host of socio-demographic and clinical variables was analyzed and compared between the two study sites. Prescription patterns were quite different for the two ethnically homogenous and clinically very similar samples. In multiple logistic regression analyses, the use of depot antipsychotics (DA) and site (HK vs BJ) both significantly predicted antipsychotic polypharmacy (APP), while symptoms of anxiety, use of clozapine and APP and site predicted use of DA. Age, number of hospitalizations, site, and use of DA predicted use of clozapine. No significant differences were found between the quality of life domains of patients with respect to APP, DA, and clozapine. A complex web of economic and clinical factors and health policies plays an important role in determining psychotropic drug prescription practices for Chinese outpatients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Hum Brain Mapp 2007 Oct 28: 931-9 |
| PMID | 17133402 |
| Title | 'Prefrontal' cognitive performance of healthy subjects positively correlates with cerebral FDOPA influx: an exploratory [18F]-fluoro-L-DOPA-PET investigation. |
| Abstract | Dopamine neurotransmission influences those cognitive processes, which are generally regarded as prefrontal cortical functions. In previous positron-emission-tomography (PET) studies, net blood-brain clearance of [18F]-fluoro-l-DOPA (FDOPA) correlated with impaired cognitive performance in patients with Parkinson's disease or schizophrenia. We hypothesized that FDOPA influx also correlates with performance of cognitive tasks associated with prefrontal functioning in healthy volunteers. The net blood-brain clearance of FDOPA (K(in)(APP)) was mAPPed in a group of 11 healthy volunteers and calculated in striatal volumes-of-interest. The Wisconsin-Card-Sorting-Test (WCST), Stroop-Test, Trail-Making-Test (TMT-A/B), and Continuous-Performance-Test (CPT-M) had been administered previously to the same subjects. No correlation of K(in) (APP) with perseverative errors in WCST or age could be found. However, there were significant positive correlations between the magnitude of K(in)(APP) in caudate nucleus, putamen, and midbrain with performance of the TMT-B, CPT-M, and the Stroop test. Highest correlations were found between the time needed to perform the Stroop interference task and the K(in)(APP) of striatal areas (Caudate nucleus: -0.780, P = 0.005; putamen: -0.870, P < 0. 001). Thus, the present findings reveal a strong correlation between dopamine synthesis capacity in striatum of healthy volunteers and performance of cognitive tasks linked to the prefrontal cortex. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Schizophr. Res. 2008 Dec 106: 229-36 |
| PMID | 18790604 |
| Title | Levels of [(3)H]pirenzepine binding in Brodmann's area 6 from subjects with schizophrenia is not associated with changes in the transcription factor SP1 or BACE1. |
| Abstract | Decreased muscarinic M1 receptor (CHRM1) mRNA has been reported in Brodmann's area (BA) 6 from subjects with schizophrenia. We have extended this study by measuring levels of CHRM1 ([(3)H]pirenzepine binding), CHRM3 ([(3)H]4-DAMP binding), the transcription factor SP1 and the CHRM1 downstream target beta-site APP-cleaving enzyme 1 (BACE1) in BA 6 from 19 subjects with schizophrenia and 19 control subjects. Radioligand binding was quantified using either in situ radioligand binding with autoradiography or, in cohorts of 10 control subjects and 10 subjects with schizophrenia, membrane enriched fraction (MEF) CNS ([(3)H]pirenzepine binding only). Levels of SP1 and BACE1 were measured by Western blotting. [(3)H]pirenzepine binding to tissue sections was in two layers, binding to tissue sections (Binding layer 1: p<0.01; Binding layer 2: p<0.001) and MEF (p<0.05) were decreased in schizophrenia. Levels of [(3)H]4-DAMP binding, SP1 and BACE1 were not altered in subjects with the disorder. This study shows a decrease in levels of CHRM1 in BA 6 from subjects with schizophrenia; as CHRM1 and BA 6 are important in maintaining normal cognitive function, these data support the hypothesis that decreased levels of cortical CHRM1 may contribute to the cognitive deficits associated with schizophrenia. Our findings on BACE1 suggest that the schizophrenia phenotype reported in BACE(-/-) mice is not simply due to lack of that protein in the cortex. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Int J Clin Pharmacol Ther 2008 May 46: 245-51 |
| PMID | 18538110 |
| Title | Clinical and social correlates with the use of depot antipsychotic drugs in outpatients with schizophrenia in China. |
| Abstract | To date, no study has investigated the use of depot antipsychotic medication (DA) in Chinese outpatients with schizophrenia. This study explored the frequency and sociodemographic and clinical correlates of DA in schizophrenia outpatients in both Hong Kong (HK) and Beijing (BJ), China. 505 clinically stable outpatients with schizophrenia were randomly selected and interviewed in HK and BJ using standardized assessment instruments. Their basic sociodemographic and clinical data and psychotropic drug prescriptions were collected at the time of a diagnostic interview. 117 (23.2%) patients were prescribed DA, 36.1 and 10% of the HK and BJ samples, respectively. Prescription of DA was associated with a history of suicide, less use of clozapine, more frequent antipsychotic polypharmacy (APP), more frequent admissions, and study site (HK vs. BJ). In multiple logistic regression analysis, study site, less frequent prescription of clozapine, history of suicide, and more frequent use of APP remained significantly associated with DA. There was wide variation in the frequency of DA prescribing between HK and BJ even though the ethnic and clinical characteristics of the two samples were nearly identical. This suggests that sociocultural and economic factors, as well as traditions in psychiatric training and practice all played a role in determining the use of DA. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Proc. Natl. Acad. Sci. U.S.A. 2008 Apr 105: 5585-90 |
| PMID | 18385378 |
| Title | Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice. |
| Abstract | beta-Site APP-cleaving enzyme 1 (BACE1) is required for the penultimate cleavage of the amyloid-beta precursor protein (APP) leading to the generation of amyloid-beta peptides that is central to the pathogenesis of Alzheimer's disease. In addition to its role in endoproteolysis of APP, BACE1 participates in the proteolytic processing of neuregulin 1 (NRG1) and influences the myelination of central and peripheral axons. Although NRG1 has been genetically linked to schizophrenia and NRG1(+/-) mice exhibit a number of schizophrenia-like behavioral traits, it is not known whether altered BACE1-dependent NRG1 signaling can cause similar behavioral abnormalities. To test this hypothesis, we analyze the behaviors considered to be rodent analogs of clinical features of schizophrenia in BACE1(-/-) mice with impaired processing of NRG1. We demonstrate that BACE1(-/-) mice exhibit deficits in prepulse inhibition, novelty-induced hyperactivity, hypersensitivity to a glutamatergic psychostimulant (MK-801), cognitive impairments, and deficits in social recognition. Importantly, some of these manifestations were responsive to treatment with clozapine, an atypical antipsychotic drug. Moreover, although the total amount of ErbB4, a receptor for NRG1 was not changed, binding of ErbB4 with postsynaptic density protein 95 (PSD95) was significantly reduced in the brains of BACE1(-/-) mice. Consistent with the role of ErbB4 in spine morphology and synaptic function, BACE1(-/-) mice displayed reduced spine density in hippocampal pyramidal neurons. Collectively, our findings suggest that alterations in BACE1-dependent NRG1/ErbB4 signaling may participate in the pathogenesis of schizophrenia and related psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Psychiatry Clin. Neurosci. 2009 Aug 63: 529-37 |
| PMID | 19496999 |
| Title | Dopamine D2/3 receptor binding potential and occupancy in midbrain and temporal cortex by haloperidol, olanzapine and clozapine. |
| Abstract | Aberrant dopamine transmission in extrastriatal brain regions has been repeatedly illustrated among patients with schizophrenia. Differences between typical and second-generation antipsychotics in dopamine D(2) receptor modulation within various brain areas remain a topic for debate. The aim of the present study was therefore to investigate dopamine D(2/3) receptor APParent binding potential (BP(APP)) and occupancy in midbrain and temporal cortex among clozapine-, olanzapine- and haloperidol-treated schizophrenia patients. Dopamine D(2/3) binding was studied on single-photon emission computed tomography ligand [(123)I]epidepride in 13 schizophrenia patients treated with medication (two with haloperidol, four with olanzapine and seven with clozapine), six drug-naïve patients and seven healthy controls. Statistically significant differences in midbrain dopamine D(2/3) receptor BP(APP) (P = 0.015) and occupancy (P = 0.016) were observed between the clozapine, olanzapine and haloperidol groups. The lowest occupancy was found in clozapine-treated patients (5%), followed by olanzapine-treated patients (28%), compared to haloperidol-treated patients (40%). No significant differences were observed in the temporal poles. Occupancy changed substantially depending on the comparison group used (either drug-naïve vs healthy controls) in the examined brain areas (P = 0.001), showing an overestimation with all antipsychotics when the healthy control group was used. Both typical and second-generation antipsychotics occupy cortical dopamine D(2/3) receptors, thus mediating therapeutic efficacy. Observed differences in midbrain dopamine D(2/3) occupancy between classical antipsychotics and second-generation antipsychotics may have clinical relevance by modulating altered nigrostriatal dopamine neurotransmission during the acute phase of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | J. Neurosci. 2010 Aug 30: 10431-40 |
| PMID | 20685985 |
| Title | Biochemical and functional interaction of disrupted-in-schizophrenia 1 and amyloid precursor protein regulates neuronal migration during mammalian cortical development. |
| Abstract | Although clinically distinct, schizophrenia and Alzheimer's disease are common and devastating disorders that profoundly impair cognitive function. For Alzheimer's disease, key mechanistic insights have emerged from genetic studies that identified causative mutations in amyloid precursor protein (APP) and presenilin. Several genes have been associated with schizophrenia and other major psychoses, and understanding their normal functions will help elucidate the underlying causes of these disorders. One such gene is disrupted-in-schizophrenia 1 (DISC1). DISC1 and APP have been implicated separately in cortical development, with each having roles in both neuronal migration and neurite outgrowth. Here, we report a previously unrecognized biochemical and functional interaction between DISC1 and APP. Using in utero electroporation in the living rat brain, we show that DISC1 acts downstream of APP and Disabled-1 to regulate cortical precursor cell migration. Specifically, overexpression of DISC1 rescues the migration defect caused by a loss of APP expression. Moreover, knockdown of APP in cultured embryonic neurons results in altered subcellular localization of DISC1. Using transfected cells and normal brain tissue, we show that APP and DISC1 coimmunoprecipitate and that the intracellular domain of APP interacts with the N-terminal domain of DISC1. Based on these findings, we hypothesize that the APP cytoplasmic region transiently interacts with DISC1 to help regulate the translocation of DISC1 to the centrosome, where it plays a key role in controlling neuronal migration during cortical development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Eur Arch Psychiatry Clin Neurosci 2011 Mar 261: 85-93 |
| PMID | 20652295 |
| Title | The illness and everyday living: close interplay of psychopathological syndromes and psychosocial functioning in chronic schizophrenia. |
| Abstract | The interaction of psychopathological states and psychosocial functioning determine the long-term course of schizophrenia and its treatment. To be able to achieve this interplay better, exact assessment of psychosocial functioning is needed besides measurement of psychopathology. Using the Personal and Social Performance (PSP) Scale, examination of the association between psychosocial functioning and psychopathology was conducted in a sample of 103 patients with chronic schizophrenia. Rating instruments were in addition Global Assessment of Functioning Scale and Social and Occupational Functioning Assessment Scale, as well as Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Scale, and Mini-ICF-APP-Rating for Mental Disorders (Mini-ICF-APP). Besides good psychometric properties for the PSP scale in this chronic sample, we found, as expected, significant associations between the two relevant outcome domains: results showed significant negative correlations between PSP and PANSS. Findings prove the close interplay between social functioning and psychopathology in the chronic course of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | BMC Bioinformatics 2011 -1 12 Suppl 13: S20 |
| PMID | 22373040 |
| Title | Construction and analysis of the protein-protein interaction networks for schizophrenia, bipolar disorder, and major depression. |
| Abstract | schizophrenia, bipolar disorder, and major depression are devastating mental diseases, each with distinctive yet overlAPPing epidemiologic characteristics. Microarray and proteomics data have revealed genes which expressed abnormally in patients. Several single nucleotide polymorphisms (SNPs) and mutations are associated with one or more of the three diseases. Nevertheless, there are few studies on the interactions among the disease-associated genes and proteins. This study, for the first time, incorporated microarray and protein-protein interaction (PPI) databases to construct the PPI network of abnormally expressed genes in postmortem brain samples of schizophrenia, bipolar disorder, and major depression patients. The samples were collected from Brodmann area (BA) 10 of the prefrontal cortex. Abnormally expressed disease genes were selected by t-tests comparing the disease and control samples. These genes were involved in housekeeping functions (e.g. translation, transcription, energy conversion, and metabolism), in brain specific functions (e.g. signal transduction, neuron cell differentiation, and cytoskeleton), or in stress responses (e.g. heat shocks and biotic stress).The diseases were interconnected through several "switchboard"-like nodes in the PPI network or shared abnormally expressed genes. A "core" functional module which consisted of a tightly knitted sub-network of clique-5 and -4s was also observed. These cliques were formed by 12 genes highly expressed in both disease and control samples. Several previously unidentified disease marker genes and drug targets, such as SBNO2 (schizophrenia), SEC24C (bipolar disorder), and SRRT (major depression), were identified based on statistical and topological analyses of the PPI network. The shared or interconnecting marker genes may explain the shared symptoms of the studied diseases. Furthermore, the "switchboard" genes, such as APP, UBC, and YWHAZ, are proposed as potential targets for developing new treatments due to their functional and topological significance. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | Rinsho Shinkeigaku 2011 Nov 51: 928-9 |
| PMID | 22277421 |
| Title | ["Atypical" method for understanding dementia. How can studying epigenetics contribute?]. |
| Abstract | The pathological hallmark of neurodegeneration is presence of intra- and extra neuronal inclusion bodies such as Lewy bodies in Parkinson's disease, senile plaques and neurofibrillary tangles in Alzheimer's disease. These are consisted of aggregated conformationally abnormal proteins. The precise mechanism of aggregation remains unknown, but increased expression of aggregation-prone proteins can lead to their aggregation. For example, in Down syndrome, duplication of the 21(st) chromosome, which contains the amyloid beta precursor protein (APP) gene, leads to accumulation of amyloid beta and Alzheimer's disease pathology and multiplication of APP gene is shown to be the cause of familial Alzheimer's disease. Moreover, in rare cases of PD, duplication or triplication of SNCA gene leads to alpha-synuclein accumulation, with triplication producing a more severe phenotype than duplication, suggesting that SNCA expression level determines the severity of the pathology. Lastly, animal models of neurodegenerative disorders are generated by over-expression of causal genes, further supporting the conclusion that increased gene expression is related to pathogenesis. Additional evidence indicates that SNCA promoter polymorphisms increases alpha-synuclein expression and increases susceptibility to sporadic PD. In addition to promoter polymorphisms, epigenetic modification can alter downstream gene expression. Epigenetic regulation includes histone modification and DNA methylation, of which CpG island methylation can be gene-specific; in several different cancers, CpG methylation inhibits binding of the transcription machinery, causing silencing of a specific oncogene, which leads to carcinogenesis. In central nervous system disorders, CpG methylation has been associated with psychiatric disorders, such as autism and schizophrenia. We found several cases of Parkinson's disease with epigenetic abnormality in SNCA gene. Thus, we believe that studying epigenetics can provide previously unknown causes for dementia and other neurodegenerative disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | Perm J 2011 -1 15: 52-6 |
| PMID | 21841926 |
| Title | Reducing antipsychotic polypharmacy among psychogeriatric and adult patients with chronic schizophrenia. |
| Abstract | At the Institute of Mental Health/Woodbridge Hospital, 55% of the long-stay patients are on more than two antipsychotics for treatment of chronic schizophrenia. Our aim was to reduce antipsychotic polypharmacy (APP) among chronic schizophrenia inpatients at the long-term wards at the Institute of Mental Health, Singapore from 2006 to 2008. Using Clinical Practice Improvement Program (CPIP) methodology and using a Plan, Do, Study, Act APProach, we surveyed patients, physicians, and nurses for responses regarding reducing the amount of APP for psychiatric patients. The first CPIP (CPIP1) was conducted from August 2006 to January 2007, and focused on psychogeriatric chronic schizophrenia inpatients. This methodology was spread to a second CPIP (CPIP2) from April 2008 to October 2008, which focused on adult chronic schizophrenia inpatients. Both CPIPs were successful in the reduction of APP within the geriatric and adult long-term patients. For CPIP1, eight patients had their antipsychotics reduced. There was a reduction of an average chlorpromazine-equivalent dose per day from 375 mg per patient to 170 mg. For CPIP2, the average number of antipsychotics was reduced from 2.9 to 2.27 from July 2008 to October 2008. There was a reduction of an average chlorpromazine-equivalent dose per day from 1523 mg per patient to 1246 mg. There was no documented relapse within six months of implementation of both the projects. APP in long-term patients suffering from chronic schizophrenia can be safely reduced with proper clinical titration, aided by guidelines and protocols. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Pharmacoepidemiol Drug Saf 2011 May 20: 441-9 |
| PMID | 21523847 |
| Title | Patient characteristics and process factors associated with antipsychotic polypharmacy in a nationwide sample of psychiatric inpatients in Italy. |
| Abstract | The present study investigated: (i) the rate of prescription of antipsychotic (AP) polypharmacy (APP) in a large, representative sample of psychiatric inpatients; and (ii) the relationship between APP prescription and the characteristics of patients and facilities. The sample included 1022 psychiatric patients scheduled to be discharged from acute inpatient facilities with drug therapies including AP. Demographic and clinical data were obtained from the treating physician or retrieved from patients' records through a standardized Patient Form. Patients were administered the 24-item Brief Psychiatric Rating Scale. Three indicators were used to describe the process of care in the facilities: a Restrictiveness score, a Standardization score, and a Treatment score. A multilevel mixed-effect logistic regression was used to predict APP using patient and facility as the variables. APP was prescribed to 333 (32.5%) patients, the most common patterns being a first-generation and a second-generation AP (n?=?178, 17.6%) or of two first-generation APs (n?=?80, 7.8%). Patients with a diagnosis of schizophrenia and poorer insight into illness at admission were significantly more likely to receive APP. The availability of more complex therapeutic interventions in the facility was also associated with APP. In our nationwide sample of psychiatric inpatients, APP was frequently prescribed to treat the more severe patients. However, it was also associated with process of care characteristics such as delivery of more complex therapeutic interventions, and was therefore not used only to control patient behavior. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | J Clin Psychopharmacol 2012 Dec 32: 809-13 |
| PMID | 23131883 |
| Title | Common use of antipsychotic polypharmacy in older Asian patients with schizophrenia (2001-2009). |
| Abstract | The aim of this study was to survey the use of antipsychotic polypharmacy (APP) in older Asian patients with schizophrenia and examine its demographic and clinical correlates. Information on hospitalized patients with schizophrenia aged 55 or older was extracted from the database of the Research on Asian Psychotropic Prescription Patterns study. Data on 1439 patients in 6 Asian countries and territories including China, Hong Kong, Japan, Korea, Singapore, and Taiwan were analyzed. Sociodemographic and clinical characteristics and antipsychotic prescriptions were recorded using a standardized protocol and data collection procedure. The frequency of APP prescription was 51.6% in the pooled sample with wide intercountry variations. Multiple logistic regression analysis of the whole sample showed that patients on APP had higher antipsychotic doses and also were more likely to receive first-generation antipsychotics. Use of APP was common in older Asian patients with schizophrenia. Given the limited evidence supporting its efficacy, the potentially severe side effects and high costs, APP should be used with caution in this population. The reasons for and outcomes of the use of APP in this patient population merit further exploration. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | Psychiatr. Clin. North Am. 2012 Sep 35: 661-81 |
| PMID | 22929872 |
| Title | Antipsychotic polypharmacy: a comprehensive evaluation of relevant correlates of a long-standing clinical practice. |
| Abstract | Antipsychotic polypharmacy (APP) is common in the treatment of schizophrenia spectrum disorders. The literature indicates that APP is related to patient, illness, and treatment variables that are proxy measures for greater illness acuity, severity, complexity, and chronicity. The largely unknown relative risks and benefits of APP need to be weighed against the known risks and benefits of clozapine for treatment-resistant patients. To inform evidence-based clinical practice, controlled, high-quality antipsychotic combination and discontinuation trials are necessary to determine the effectiveness, safety, and role of APP in the management of severely ill patients with insufficient response to antipsychotic monotherapy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | Neurosci. Lett. 2012 May 515: 125-30 |
| PMID | 22450048 |
| Title | M1 muscarinic acetylcholine receptor interacts with BACE1 and regulates its proteosomal degradation. |
| Abstract | A prime culprit in the pathogenesis of Alzheimer's disease (AD) is overproduction/aggregation of ?-amyloid (A?), which is derived from ?-Amyloid Precursor Protein through sequential cleavages by ?-site APP cleaving protein 1 (BACE1) and ?-secretase. The level/activity of BACE1 is elevated in sporadic AD and identification of proteins that affect BACE1 is important in AD research. Here we found that M1 Muscarinic acetylcholine receptor (M1 mAChR), an important G protein-coupled receptor involved in cholinergic neuronal activity, can interact with BACE1 and mediate its proteosomal degradation. Moreover, overexpression and downregulation of M1 mAChR can decrease and increase the levels of BACE1, as well as the generation of A?, respectively. These findings point to a novel coupling of BACE1 and M1 mAChR in AD and possibly schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 20 | Pharmacopsychiatry 2012 Jan 45: 7-12 |
| PMID | 21989602 |
| Title | Antipsychotic polypharmacy in inpatients with schizophrenia in Asia (2001-2009). |
| Abstract | This study aimed to identify trends in the use of antipsychotic polypharmacy (APP) and their demographic and clinical correlates in the treatment of schizophrenia in Asia between 2001 and 2009. A total of 6,761 schizophrenia inpatients in 9 Asian countries and territories were examined; 2,399 in 2001, 2,136 in 2004, and 2,226 in 2009. Patients? socio-demographic and clinical characteristics and prescriptions of psychotropic drugs were recorded using a standardized protocol and data collection procedure. The proportion of APP prescription decreased from 46.8 % in 2001, to 38.3 % in 2004, and increased to 43.4 % in 2009, with wide intercountry variations at each survey. Multiple logistic regression analysis of the whole sample revealed that patients on APP were younger, had a higher dose of antipsychotics in chlorpromazine equivalents, and more severe positive and negative symptoms. They were also more likely to receive depot and fi rst-generation antipsychotic drugs. The frequency of APP prescription varied between countries and territories, suggesting that a host of clinical and socio-cultural factors played a role in determining APP use in Asia. To resolve the discrepancy between treatment recommendation and clinical practice, regular reviews of prescription patterns are needed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 21 | Neuropharmacology 2012 Mar 62: 1230-41 |
| PMID | 21195721 |
| Title | DISC1-binding proteins in neural development, signalling and schizophrenia. |
| Abstract | In the decade since Disrupted in schizophrenia 1 (DISC1) was first identified it has become one of the most convincing risk genes for major mental illness. As a multi-functional scaffold protein, DISC1 has multiple identified protein interaction partners that highlight pathologically relevant molecular pathways with potential for pharmaceutical intervention. Amongst these are proteins involved in neuronal migration (e.g. APP, Dixdc1, LIS1, NDE1, NDEL1), neural progenitor proliferation (GSK3?), neurosignalling (Girdin, GSK3?, PDE4) and synaptic function (Kal7, TNIK). Furthermore, emerging evidence of genetic association (NDEL1, PCM1, PDE4B) and copy number variation (NDE1) implicate several DISC1-binding partners as risk factors for schizophrenia in their own right. Thus, a picture begins to emerge of DISC1 as a key hub for multiple critical developmental pathways within the brain, disruption of which can lead to a variety of psychiatric illness phenotypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 22 | Development 2012 Nov 139: 3986-96 |
| PMID | 22992957 |
| Title | Pancortins interact with amyloid precursor protein and modulate cortical cell migration. |
| Abstract | Neuronal precursor cell migration in the developing mammalian brain is a complex process requiring the coordinated interaction of numerous proteins. We have recently shown that amyloid precursor protein (APP) plays a role in migration into the cortical plate through its interaction with two cytosolic signaling proteins, disabled 1 (DAB1) and disrupted in schizophrenia 1 (DISC1). In order to identify extracellular factors that may signal through APP to regulate migration, we performed an unbiased mass spectrometry-based screen for factors that bind to the extracellular domain of APP in the rodent brain. Through this screen, we identified an interaction between APP and pancortins, proteins expressed throughout the developing and mature cerebral cortex. Via co-immunoprecipitation, we show that APP interacts with all four of the mammalian pancortin isoforms (AMY, AMZ, BMY, BMZ). We demonstrate that the BMZ and BMY isoforms of pancortin can specifically reduce ?-secretase- but not ?-secretase-mediated cleavage of endogenous APP in cell culture, suggesting a biochemical consequence of the association between pancortins and APP. Using in utero electroporation to overexpress and knock down specific pancortin isoforms, we reveal a novel role for pancortins in migration into the cortical plate. Interestingly, we observe opposing roles for alternate pancortin isoforms, with AMY overexpression and BMZ knock down both preventing proper migration of neuronal precursor cells. Finally, we show that BMZ can partially rescue a loss of APP expression and that APP can rescue effects of AMY overexpression, suggesting that pancortins act in conjunction with APP to regulate entry into the cortical plate. Taken together, these results suggest a biochemical and functional interaction between APP and pancortins, and reveal a previously unidentified role for pancortins in mammalian cortical development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 23 | Schizophr. Res. 2012 Jun 138: 18-28 |
| PMID | 22534420 |
| Title | Prevalence and correlates of antipsychotic polypharmacy: a systematic review and meta-regression of global and regional trends from the 1970s to 2009. |
| Abstract | To assess the prevalence and correlates of antipsychotic polypharmacy (APP) across decades and regions. Electronic PubMed/Google Scholar search for studies reporting on APP, published from 1970 to 05/2009. Median rates and interquartile ranges (IQR) were calculated and compared using non-parametric tests. Demographic and clinical variables were tested as correlates of APP in bivariate and meta-regression analyses. Across 147 studies (1,418,163 participants, 82.9% diagnosed with schizophrenia [IQR=42-100%]), the median APP rate was 19.6% (IQR=12.9-35.0%). Most common combinations included first-generation antipsychotics (FGAs)+second-generation antipsychotics (SGAs) (42.4%, IQR=0.0-71.4%) followed by FGAs+FGAs (19.6%, IQR=0.0-100%) and SGAs+SGAs (1.8%, IQR=0.0-28%). APP rates were not different between decades (1970-1979:28.8%, IQR=7.5-44%; 1980-1989:17.6%, IQR=10.8-38.2; 1990-1999:22.0%, IQR=11-40; 2000-2009:19.2% IQR=14.4-29.9, p=0.78), but between regions, being higher in Asia and Europe than North America, and in Asia than Oceania (p<0.001). APP increased numerically by 34% in North America from the 1980s 12.7%) to 2000s (17.0%) (p=0.94) and decreased significantly by 65% from 1980 (55.5%) to 2000 (19.2%) in Asia (p=0.03), with non-significant changes in Europe. APP was associated with inpatient status (p<0.001), use of FGAs (p<0.0001) and anticholinergics (<0.001), schizophrenia (p=0.01), less antidepressant use (p=0.02), greater LAIs use (p=0.04), shorter follow-up (p=0.001) and cross-sectional vs. longitudinal study design (p=0.03). In a meta-regression, inpatient status (p<0.0001), FGA use (0.046), and schizophrenia diagnosis (p=0.004) independently predicted APP (N=66, R(2)=0.44, p<0.0001). APP is common with different rates and time trends by region over the last four decades. APP is associated with greater anticholinergic requirement, shorter observation time, greater illness severity and lower antidepressant use. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 24 | Behav Brain Funct 2012 -1 8: 11 |
| PMID | 22369141 |
| Title | Association between ghrelin gene (GHRL) polymorphisms and clinical response to atypical antipsychotic drugs in Han Chinese schizophrenia patients. |
| Abstract | Ghrelin (GHRL) is a pivotal peptide regulator of food intake, energy balance, and body mass. Weight gain (WG) is a common side effect of the atypical antipsychotics (AAPs) used to treat schizophrenia (SZ). Ghrelin polymorphisms have been associated with pathogenic variations in plasma lipid concentrations, blood pressure, plasma glucose, and body mass index (BMI). However, it is unclear whether GHRL polymorphisms are associated with WG due to AAPs. Furthermore, there is no evidence of an association between GHRL polymorphisms and SZ or the therapeutic response to AAPs. We explored these potential associations by genotyping GHRL alleles in SZ patients and controls. We also examined the relation between these SNPs and changes in metabolic indices during AAP treatment in SZ subgroups distinguished by high or low therapeutic response. Four SNPs (Leu72Met, -501A/C, -604 G/A, and -1062 G > C) were genotyped in 634 schizophrenia patients and 606 control subjects. There were no significant differences in allele frequencies, genotype distributions, or the distributions of two SNP haplotypes between SZ patients and healthy controls (P > 0.05). There was also no significant difference in symptom reduction between genotypes after 8 weeks of AAP treatment as measured by positive and negative symptom scale scores (PANSS). However, the -604 G/A polymorphism was associated with a greater BMI increase in response to AAP administration in both APP responders and non-responders as distinguished by PANSS score reduction (P < 0.001). There were also significant differences in WG when the responder group was further subdivided according to the specific AAP prescribed (P < 0.05). These four GHRL gene SNPs were not associated with SZ in this Chinese Han population. The -604 G/A polymorphism was associated with significant BW and BMI increases during AAP treatment. Patients exhibiting higher WG showed greater improvements in positive and negative symptoms than patients exhibiting lower weight gain or weight loss. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 25 | Psychiatr Danub 2013 Sep 25: 306-10 |
| PMID | 24048402 |
| Title | Antipsychotics: to combine or not to combine? |
| Abstract | Antipsychotic monotherapy is strongly recommended in the treatment of schizophrenia. However, antipsychotic polypharmacy (APP) is common in clinical practice, and APPears to be related to illness severity and duration, treatment-refractoriness, hospitalization status, duration of hospitalization, geographic region and age. Given the high number of different antipsychotic combinations reported in the literature and prescribed in clinical practice, there are perhaps more differences than similarities between such combinations. While the majority of combinations increase side-effect burden, limited evidence suggests benefits of certain combinations.Until more data are available, APP should be reserved for difficult-to treat patients, with careful consideration of pharmacodynamics properties and doses of each drug, as well as close monitoring. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 26 | Trends Pharmacol. Sci. 2013 Apr 34: 215-25 |
| PMID | 23452816 |
| Title | ?-Secretase: its biology as a therapeutic target in diseases. |
| Abstract | ?-Secretase (BACE1, ?-site APP cleaving enzyme 1) is an aspartic proteinase that has multiple functions in various physiological processes, such as cell differentiation, immunoregulation, and cell death. There is increasing evidence that changes in BACE1 activity are involved in many diseases, such as Alzheimer's disease (AD), schizophrenia, epileptic behavior, and others. However, a deeper understanding of the molecular biology of BACE1 is necessary for further exploration of cell development, immunological regulation, and disease pathogenesis. Here, we review the molecular and cellular biology of BACE1, including its enzymatic properties, structure, biosynthesis, and physiological functions to provide a new perspective and rational assessment of drugability. Lastly, we discuss proposed strategies to control BACE1 activity for possible therapeutic APPlication. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 27 | Hum. Mol. Genet. 2013 Feb 22: 816-24 |
| PMID | 23148125 |
| Title | A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk. |
| Abstract | We assessed the role of rare copy number variants (CNVs) in Alzheimer's disease (AD) using intensity data from 3260 AD cases and 1290 age-matched controls from the genome-wide association study (GWAS) conducted by the Genetic and Environmental Risk for Alzheimer's disease Consortium (GERAD). We did not observe a significant excess of rare CNVs in cases, although we did identify duplications overlAPPing APP and CR1 which may be pathogenic. We looked for an excess of CNVs in loci which have been highlighted in previous AD CNV studies, but did not replicate previous findings. Through pathway analyses, we observed suggestive evidence for biological overlap between single nucleotide polymorphisms and CNVs in AD susceptibility. We also identified that our sample of elderly controls harbours significantly fewer deletions >1 Mb than younger control sets in previous CNV studies on schizophrenia and bipolar disorder (P = 8.9 × 10(-4) and 0.024, respectively), raising the possibility that healthy elderly individuals have a reduced rate of large deletions. Thus, in contrast to diseases such as schizophrenia, autism and attention deficit/hyperactivity disorder, CNVs do not APPear to make a significant contribution to the development of AD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 28 | J ECT 2013 Dec 29: 271-6 |
| PMID | 23859980 |
| Title | Antipsychotic polypharmacy in a treatment-refractory schizophrenia population receiving adjunctive treatment with electroconvulsive therapy. |
| Abstract | Antipsychotic polypharmacy (APP) is frequent, but its pattern is unknown in treatment-refractory schizophrenia-spectrum patients receiving electroconvulsive therapy (ECT). We performed a retrospective chart review of ECT-treated inpatients hospitalized at 2 Danish University hospitals from 2003 to 2008, focusing on APP patterns in patients with schizophrenia-spectrum disorders (n = 79, 13.2%). In addition to univariate analyses, a multivariate logistic regression analysis was performed to identify independent predictors of APP. Of 79 antipsychotic-treated patients (aged 48.6 ± 14.2 years; illness duration, 18.3 ± 10.6 years) ultimately treated with ECT, 86.1% received 2 or more psychotropic medications, including mood stabilizers (19.0%), antidepressants (32.9%), and APP (72.2%; 2 antipsychotics = 41.8%, 3 = 21.5%, 4-5 = 7.6%). Most patients received first-generation antipsychotic (FGA) + second-generation antipsychotic (SGA) (48.1%), followed by SGA + SGA (24.1%), SGA monotherapy (22.8%), and FGA monotherapy (5.1%). Individual antipsychotics included olanzapine (44.3%), risperidone (26.6%), clozapine (26.6%), quetiapine (22.1%), ziprasidone (13.9%), aripiprazole (10.1%), and sertindole (3.8%). Antipsychotic polypharmacy was associated with a greater number of FGAs (0.8 ± 0.7 vs 0.1 ± 0.4, P < 0.0001) and SGAs (1.7 ± 0.8 vs 0.8 ± 0.4, P < 0.0001), zuclopenthixol use (31.6% vs 0%, P = 0.0019), olanzapine use (52.6% vs 22.7%, P = 0.017), less serotonin-noradrenaline reuptake inhibitor use (3.5% vs 18.2%, P = 0.027), and a trend toward more good to excellent ECT response (86.0% vs 68.2%, P = 0.071). In the logistic regression analysis, APP was independently associated with a higher number of FGAs (P = 0.0002) and olanzapine use (P = 0.0098) (r = 0.314, P < 0.0001). Only 22.6% of this treatment-refractory population received clozapine, yet 72.4% received APP. Following the results from our study as well as the general level of evidence, patients with refractory schizophrenia-spectrum disorder should receive clozapine or ECT before being tried on APP. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 29 | Psychiatry Res 2013 Oct 209: 406-11 |
| PMID | 23602697 |
| Title | Antipsychotic polypharmacy: a Japanese survey of prescribers' attitudes and rationales. |
| Abstract | While combining antipsychotics is common in schizophrenia treatment, the literature on the reasons for antipsychotic polypharmacy (APP) is limited. We aimed to identify prescriber attitudes and rationales for APP in Japan where high APP utilization is reported. Two-hundred and seventeen psychiatrists participated in the survey, which assessed APP attitudes and behaviors. Prescribing APP to 47.7±24.7% (mean±S.D.) of their patients, psychiatrists reported that they were "moderately" concerned about APP. The most APP-justifiable factors were (1="not at all" to 5="extreme") cross titration (4.50±0.67), randomized controlled evidence (3.67±0.83), and treatment of comorbid conditions (3.31±0.83). Conversely, APP-discouraging factors were chronic side effects (4.14±0.64), difficulty determining cause and effect (4.07±0.74), and acute side effects (3.99±0.81). Comparing high to low APP prescribers (>50% vs. ?50% of patients), no differences emerged regarding APP justification and concerns. In multivariate analyses, high APP use was associated with practice at a psychiatric hospital (OR: 2.70, 95% CI: 1.29-5.67, p=0.009), concern about potential drug-drug interactions (OR: 1.56, 95% CI: 1.04-2.35, p=0.031), and less reliance on case reports of APP showing efficacy (OR: 0.64, 95% CI: 0.44-0.92, p=0.017) (r(2)=0.111, p=0.001). High and low APP prescribers shared a comparable degree of justifications and concerns. Future research should examine the impact of cultural determinants on APP. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 30 | Epidemiol Psychiatr Sci 2013 Mar 22: 81-91 |
| PMID | 22989494 |
| Title | Validation of the Italian version of Mini-ICF-APP, a short instrument for rating activity and participation restrictions in psychiatric disorders. |
| Abstract | Aims. The assessment of limitations in social capacities can be done with the Mini-ICF-APP, a rating scale built in reference to the International Classification of Functioning, Disability and Health (ICF). The aim of this study was to assess the reliability and the convergent validity of the Italian version of this scale. Methods. We recruited 120 consecutive patients diagnosed with schizophrenia, major depression, bipolar I disorder and anxiety disorders. Included measures were the Brief Psychiatric Rating Scale (BPRS), the Clinical Global Impression Scale (CGI-S), the Personal and Social Performance Scale (PSP) and the Social and Occupational Functioning Assessment Scale (SOFAS). Results. The median CGI-S and BPRS scores were 5 and 16.5. Mean Mini-ICF-APP total score was 18.1. schizophrenics' Mini-ICF-APP score was higher, while that of anxious patients was lower than in the other diagnoses. Intra-class correlations (ICC) revealed a significant inter-rater agreement for total score (ICC 0.987) and for each item of the Mini-ICF-APP. The test-retest agreement was also highly significant (ICC 0.993). The total score of the Mini-ICF-APP obtained good negative correlations with PSP (r s = -0.767) and with SOFAS scores (r s = -0.790). The distribution items of the Mini-ICF-APP showed some skewness, indicating that self-care (item 12) and mobility (item 13) were amply preserved in most patients. The Mini-ICF-APP total score was significantly correlated with both CGI-S (r s = 0.777) and BPRS (r s = 0.729). Conclusions. As a short instrument, the Mini-ICF-APP scale seems to be well suited to everyday psychiatric practice as a means of monitoring changes in psychosocial functioning, in particular in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 31 | Epidemiol Psychiatr Sci 2013 Mar 22: 81-91 |
| PMID | 22989494 |
| Title | Validation of the Italian version of Mini-ICF-APP, a short instrument for rating activity and participation restrictions in psychiatric disorders. |
| Abstract | Aims. The assessment of limitations in social capacities can be done with the Mini-ICF-APP, a rating scale built in reference to the International Classification of Functioning, Disability and Health (ICF). The aim of this study was to assess the reliability and the convergent validity of the Italian version of this scale. Methods. We recruited 120 consecutive patients diagnosed with schizophrenia, major depression, bipolar I disorder and anxiety disorders. Included measures were the Brief Psychiatric Rating Scale (BPRS), the Clinical Global Impression Scale (CGI-S), the Personal and Social Performance Scale (PSP) and the Social and Occupational Functioning Assessment Scale (SOFAS). Results. The median CGI-S and BPRS scores were 5 and 16.5. Mean Mini-ICF-APP total score was 18.1. schizophrenics' Mini-ICF-APP score was higher, while that of anxious patients was lower than in the other diagnoses. Intra-class correlations (ICC) revealed a significant inter-rater agreement for total score (ICC 0.987) and for each item of the Mini-ICF-APP. The test-retest agreement was also highly significant (ICC 0.993). The total score of the Mini-ICF-APP obtained good negative correlations with PSP (r s = -0.767) and with SOFAS scores (r s = -0.790). The distribution items of the Mini-ICF-APP showed some skewness, indicating that self-care (item 12) and mobility (item 13) were amply preserved in most patients. The Mini-ICF-APP total score was significantly correlated with both CGI-S (r s = 0.777) and BPRS (r s = 0.729). Conclusions. As a short instrument, the Mini-ICF-APP scale seems to be well suited to everyday psychiatric practice as a means of monitoring changes in psychosocial functioning, in particular in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 32 | Epidemiol Psychiatr Sci 2013 Mar 22: 81-91 |
| PMID | 22989494 |
| Title | Validation of the Italian version of Mini-ICF-APP, a short instrument for rating activity and participation restrictions in psychiatric disorders. |
| Abstract | Aims. The assessment of limitations in social capacities can be done with the Mini-ICF-APP, a rating scale built in reference to the International Classification of Functioning, Disability and Health (ICF). The aim of this study was to assess the reliability and the convergent validity of the Italian version of this scale. Methods. We recruited 120 consecutive patients diagnosed with schizophrenia, major depression, bipolar I disorder and anxiety disorders. Included measures were the Brief Psychiatric Rating Scale (BPRS), the Clinical Global Impression Scale (CGI-S), the Personal and Social Performance Scale (PSP) and the Social and Occupational Functioning Assessment Scale (SOFAS). Results. The median CGI-S and BPRS scores were 5 and 16.5. Mean Mini-ICF-APP total score was 18.1. schizophrenics' Mini-ICF-APP score was higher, while that of anxious patients was lower than in the other diagnoses. Intra-class correlations (ICC) revealed a significant inter-rater agreement for total score (ICC 0.987) and for each item of the Mini-ICF-APP. The test-retest agreement was also highly significant (ICC 0.993). The total score of the Mini-ICF-APP obtained good negative correlations with PSP (r s = -0.767) and with SOFAS scores (r s = -0.790). The distribution items of the Mini-ICF-APP showed some skewness, indicating that self-care (item 12) and mobility (item 13) were amply preserved in most patients. The Mini-ICF-APP total score was significantly correlated with both CGI-S (r s = 0.777) and BPRS (r s = 0.729). Conclusions. As a short instrument, the Mini-ICF-APP scale seems to be well suited to everyday psychiatric practice as a means of monitoring changes in psychosocial functioning, in particular in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 33 | Neurobiol. Dis. 2014 Jan 61: 55-71 |
| PMID | 24076101 |
| Title | Development of allosteric modulators of GPCRs for treatment of CNS disorders. |
| Abstract | The discovery of allosteric modulators of G protein-coupled receptors (GPCRs) provides a promising new strategy with potential for developing novel treatments for a variety of central nervous system (CNS) disorders. Traditional drug discovery efforts targeting GPCRs have focused on developing ligands for orthosteric sites which bind endogenous ligands. Allosteric modulators target a site separate from the orthosteric site to modulate receptor function. These allosteric agents can either potentiate (positive allosteric modulator, PAM) or inhibit (negative allosteric modulator, NAM) the receptor response and often provide much greater subtype selectivity than orthosteric ligands for the same receptors. Experimental evidence has revealed more nuanced pharmacological modes of action of allosteric modulators, with some PAMs showing allosteric agonism in combination with positive allosteric modulation in response to endogenous ligand (ago-potentiators) as well as "bitopic" ligands that interact with both the allosteric and orthosteric sites. Drugs targeting the allosteric site allow for increased drug selectivity and potentially decreased adverse side effects. Promising evidence has demonstrated potential utility of a number of allosteric modulators of GPCRs in multiple CNS disorders, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, as well as psychiatric or neurobehavioral diseases such as anxiety, schizophrenia, and addiction. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 34 | Australas Psychiatry 2014 Dec 22: 546-50 |
| PMID | 25147317 |
| Title | Prevalence and nature of antipsychotic polypharmacy among inpatients with schizophrenia spectrum disorders at an Australian mental health service. |
| Abstract | Though antipsychotic polypharmacy (APP) is widely utilised in many clinical settings for the treatment of people with schizophrenia, the extent of this practice varies considerably between different regions, countries and clinical settings. Studies from Australasia exploring the prevalence and factors associated with APP are sparse and have yielded inconsistent results. We conducted a systematic retrospective audit of the medical records of all admissions in 2010 in the adult wards of a metropolitan public mental health service in Western Australia, having a diagnosis of schizophrenia or schizoaffective disorder. We analysed the rates of APP use, and its association with selected demographic and clinical variables. The prevalence of APP among our sample of 229 patients was high, at 43.2%. APP was associated with a longer hospital stay (p=0.033) and voluntary admission (p=0.027); but APP was not significantly related to: age, gender, diagnosis and treatment by different psychiatrists. Substantial difference exists between everyday clinical practice and recommendations of practice guidelines of schizophrenia, regarding the use of APP. Prospective studies from different settings exploring the relevant clinical, patient, prescriber and system-related issues are warranted, to comprehend the rationale behind high utilisation of APP in clinical practice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 35 | Schizophr. Res. 2014 Sep 158: 100-4 |
| PMID | 25096540 |
| Title | Affective prosody perception in symptomatically remitted patients with schizophrenia and bipolar disorder. |
| Abstract | Affect perception has frequently been shown to be impaired in patients suffering from schizophrenia or bipolar disorder (BD), but it remains unclear whether these impairments exist during symptomatic remission and whether the two disorders differ from each other in this regard. Most previous studies have investigated facial affect recognition, but not the ability to decode mental states from emotional tone of voice, i.e. affective prosody perception (APP). Accordingly, the present study directly compared APP in symptomatically remitted patients with schizophrenia or BD and healthy control subjects and investigated its relationship with residual symptomatology in patients. Patients with schizophrenia and BD showed comparable APP impairments despite being symptomatically remitted. In comparison to healthy control subjects, overall APP deficits were found in BD but not in schizophrenia patients. Both patient groups were particularly impaired in the identification of anger and confounded it with neutral prosody. In addition, schizophrenia patients frequently confused sadness with hAPPiness, anger, or fright. There was an inverse association between the degree of residual positive symptoms and the ability to correctly recognize hAPPiness in schizophrenia patients. Overall, these data indicate that impairments in APP represent an enduring deficit and a trait marker of both schizophrenia and BD and that the level of impairment is comparable between disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 36 | Pharmacol Rep 2014 Aug 66: 613-7 |
| PMID | 24948062 |
| Title | The prevalence of antipsychotic polypharmacy in schizophrenic patients discharged from psychiatric units in Poland. |
| Abstract | The term antipsychotic polypharmacy (APP) refers to the concurrent use of two or more antipsychotic drugs in schizophrenia. The aim of this study was to investigate the range of APP in schizophrenic patients discharged from psychiatric units in Poland, and to determine its demographical and clinical correlates. Data on the pharmacological treatment of 207 patients with a diagnosis of schizophrenia, discharged from six psychiatric hospitals from September-December 2011 were recorded by experienced psychiatrists. Clinical and demographical information was obtained on each patient. The severity of symptoms at admission, and their improvement during hospitalization were assessed using the Clinical Global Impression Scale. At discharge, 52.7% of the patients were prescribed one, 42.5% two and 4.8% three antipsychotic drugs (AP). When two AP were APPlied, it was usually a combination of two second generation antipsychotics (SGA) (46%), or of both first generation antipsychotics (FGA) and SGA (48%). The SGA's olanzapine and risperidone were those most commonly prescribed. Patients treated with two or more AP had a higher number of previous hospitalizations than patients receiving antipsychotic monotherapy. Mood stabilizers were prescribed for nearly one third of the patients, while antidepressants and benzodiazepines were prescribed for fewer than 10%. The prevalence of polypharmacy in Poland is similar to that reported in other countries. This may suggest that, in a substantial proportion of schizophrenic patients clinical response to the antipsychotic monotherapy is unsatisfactory. Further studies focusing on the efficacy and safety of strategies in the treatment of patients with schizophrenia not responding to antipsychotic monotherapy are necessary. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 37 | Pharmacol Rep 2014 Aug 66: 613-7 |
| PMID | 24948062 |
| Title | The prevalence of antipsychotic polypharmacy in schizophrenic patients discharged from psychiatric units in Poland. |
| Abstract | The term antipsychotic polypharmacy (APP) refers to the concurrent use of two or more antipsychotic drugs in schizophrenia. The aim of this study was to investigate the range of APP in schizophrenic patients discharged from psychiatric units in Poland, and to determine its demographical and clinical correlates. Data on the pharmacological treatment of 207 patients with a diagnosis of schizophrenia, discharged from six psychiatric hospitals from September-December 2011 were recorded by experienced psychiatrists. Clinical and demographical information was obtained on each patient. The severity of symptoms at admission, and their improvement during hospitalization were assessed using the Clinical Global Impression Scale. At discharge, 52.7% of the patients were prescribed one, 42.5% two and 4.8% three antipsychotic drugs (AP). When two AP were APPlied, it was usually a combination of two second generation antipsychotics (SGA) (46%), or of both first generation antipsychotics (FGA) and SGA (48%). The SGA's olanzapine and risperidone were those most commonly prescribed. Patients treated with two or more AP had a higher number of previous hospitalizations than patients receiving antipsychotic monotherapy. Mood stabilizers were prescribed for nearly one third of the patients, while antidepressants and benzodiazepines were prescribed for fewer than 10%. The prevalence of polypharmacy in Poland is similar to that reported in other countries. This may suggest that, in a substantial proportion of schizophrenic patients clinical response to the antipsychotic monotherapy is unsatisfactory. Further studies focusing on the efficacy and safety of strategies in the treatment of patients with schizophrenia not responding to antipsychotic monotherapy are necessary. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 38 | Int. J. Neuropsychopharmacol. 2014 Jul 17: 1095-105 |
| PMID | 23673334 |
| Title | Prevalence and correlates of antipsychotic polypharmacy in children and adolescents receiving antipsychotic treatment. |
| Abstract | Antipsychotic polypharmacy (APP), which is common in adults with psychotic disorders, is of unproven efficacy and raises safety concerns. Although youth are increasingly prescribed antipsychotics, little is known about APP in this population. We performed a systematic PubMed search (last update 26 January 2013) of studies reporting the prevalence of APP in antipsychotic-treated youth. Summary statistics and statistical tests were calculated at the study level and not weighted by sample size. Fifteen studies (n = 58 041, range 68-23 183) reported on APP in youth [mean age = 13.4 ± 1.7 yr, 67.1 ± 10.2% male, 77.9 ± 27.4% treated with second-generation antipsychotics (SGAs)]. Data collected in these studies covered 1993-2008. The most common diagnoses were attention-deficit hyperactivity disorder (ADHD; 39.9 ± 23.5%) and conduct disorder/oppositional defiant disorder (CD/ODD; 33.6 ± 24.8). In studies including predominantly children (mean age = <13 yr, N = 5), the most common diagnosis were ADHD (50.6 ± 25.4%) and CD/ODD (39.5 ± 27.5%); while in studies with predominantly adolescents (mean age = ?13 yr, N = 7) the most common diagnoses were schizophrenia-spectrum disorders (28.6 ± 23.8%), anxiety disorders (26.9 ± 14.9%) and bipolar-spectrum disorders (26.6 ± 7.0%), followed closely by CD/ODD (25.8 ± 17.7). The prevalence of APP among antipsychotic-treated youth was 9.6 ± 7.2% (5.9 ± 4.5% in child studies, 12.0 ± 7.9% in adolescent studies, p = 0.15). Higher prevalence of APP was correlated with a bipolar disorder or schizophrenia diagnosis (p = 0.019) and APP involving SGA+SGA combinations (p = 0.0027). No correlation was found with APP definition [?1 d (N = 10) vs. >30-?90 d (N = 5), p = 0.88]. Despite lacking safety and efficacy data, APP in youth is not uncommon, even in samples predominantly consisting of non-psychotic patients. The duration, clinical motivations and effectiveness of this practice require further study. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 39 | Mol. Psychiatry 2015 Jul 20: 874-9 |
| PMID | 25224257 |
| Title | DISC1 regulates trafficking and processing of APP and A? generation. |
| Abstract | We report the novel regulation of proteolytic processing of amyloid precursor protein (APP) by DISC1, a major risk factor for psychiatric illnesses, such as depression and schizophrenia. RNAi knockdown of DISC1 in mature primary cortical neurons led to a significant increase in the levels of intracellular ?-C-terminal fragment of APP (APP-CTF?) and the corresponding N-terminal-secreted ectodomain product sAPP?. DISC1 knockdown also elicited a significant decrease in the levels of amyloid beta (A?)42 and A?40. These aberrant proteolytic events were successfully rescued by co-expression of wild-type DISC1, but not by mutant DISC1 lacking the amino acids required for the interaction with APP, suggesting that APP-DISC1 protein interactions are crucial for the regulation of the C-terminal proteolysis. In a genetically engineered model in which a major full-length DISC1 isoform is depleted, consistent changes in APP processing were seen: an increase in APP-CTF? and decrease in A?42 and A?40 levels. Finally, we found that knockdown of DISC1 increased the expression of APP at the cell surface and decreased its internalization. The presented DISC1 mechanism of APP proteolytic processing and A? peptide generation, which is central to Alzheimer's disease pathology, suggests a novel interface between neurological and psychiatric conditions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 40 | Int J Ment Health Syst 2015 -1 9: 37 |
| PMID | 26526168 |
| Title | Assessment of functioning in patients with schizophrenia and schizoaffective disorder with the Mini-ICF-APP: a validation study in Italy. |
| Abstract | The aim of the study was to evaluate validity of the Italian Mini-ICF-APP (Mini-ICF Rating for Limitations of Activities and Participation in Psychological Disorders) in schizophrenia and related disorders. 74 outpatients affected by schizophrenia or schizoaffective disorders attending a University-based community mental health centre were recruited to the study. All participants underwent comprehensive evaluation using standardized instruments to assess clinical, neurocognitive and functional status. Concurrent validity of Mini-ICF-APP was evaluated and compared to severity scores obtained using the Clinical Global Impression-schizophrenia scale (CGI-SCH), Positive and Negative Syndrome scale (PANSS), Mini Mental State Examination test (MMSE), Brief Assessment of Cognition in schizophrenia scale (BACS) and Personal and Social Performance scale (PSP). Construct validity was evaluated by comparing scores obtained at Mini-ICF-APP by remitted versus non-remitted patients, and by recovered versus unrecovered patients. Discriminant validity was evaluated comparing scores on Mini-ICF-APP and Subjective Well-being (SWN) scale. the total score and 12 out of the 13 Mini-ICF-APP items correlated significantly with total score at PSP; Mini-ICF-APP total score was moreover significantly correlated with total scores at CGI-SCH, PANSS, MMSE, as well as with several BACS items. Total scores obtained at Mini-ICF-APP were significantly higher among remitted and recovered patients. No relevant correlations were found between scores of Mini-ICF-APP and SWN scales. The total score and 12 out of the 13 Mini-ICF-APP items correlated significantly with total score at PSP; Mini-ICF-APP total score was moreover significantly correlated with total scores at CGI-SCH, PANSS, MMSE, as well as with several BACS items. Total scores obtained at Mini-ICF-APP were significantly higher among remitted and recovered patients. No relevant correlations were found between scores of Mini-ICF-APP and SWN scales. the Italian version of Mini-ICF-APP is a valid instrument for use in evaluating functioning in chronic patients with schizophrenia and related disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 41 | Neuropsychiatr Dis Treat 2015 -1 11: 2315-22 |
| PMID | 26396515 |
| Title | Identification of two novel mutations, PSEN1 E280K and PRNP G127S, in a Malaysian family. |
| Abstract | Alzheimer's disease (AD) is the most common form of dementia, which can be categorized into two main forms: early onset AD and late onset AD. The genetic background of early onset AD is well understood, and three genes, the APP, PSEN1, and PSEN2 have been identified as causative genes. In the current study, we tested three siblings from Malaysia who were diagnosed with early onset dementia, as well as their available family members. The family history was positive as their deceased father was similarly affected. Patients were tested for mutations in APP, PSEN1, PSEN2, and PRNP. A novel variant, E280K, was discovered in exon 8 of PSEN1 in the three siblings. In silico analyses with SIFT, SNAP, and PolyPhen2 prediction tools and three-dimensional modeling were performed, and the results suggested that the mutation is probably a pathogenic variant. Two additional pathogenic mutations were previously been described for codon 280, E280A, and E280G, which could support the importance of the E280 residue in the PS1 protein contributing to the pathogenic nature of E280K. Additional ten family members were screened for the E280K mutation, and all of them were negative. Six of them presented with a variety of neuropsychiatric symptoms, including learning disabilities, epilepsy, and schizophrenia, while four family members were asymptomatic. A novel PRNP G127S mutation was found in a step-niece of the three siblings harboring the PSEN1 E280K mutation. In silico predictions for PRNP G127S mutation suggested that this might be possibly a damaging variant. Additional studies to characterize PRNP G127S would be necessary to further understand the effects of this mutation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 42 | Eur Neuropsychopharmacol 2015 Oct 25: 1669-76 |
| PMID | 26256007 |
| Title | Frequency and correlates of antipsychotic polypharmacy among patients with schizophrenia in Denmark: A nation-wide pharmacoepidemiological study. |
| Abstract | Although evidence for efficacy of antipsychotic polypharmacy (APP) is sparse, APP is common in schizophrenia. The national Danish health registers were accessed to examine in schizophrenia patients: (1) cross-sectional prevalences of APP (1996-2012); (2) geographic variations in APP (2012); and (3) correlates of APP (2012). APP increased from 17.2% in 1996 to 30.8% in 2006 (p<0.001), declining to 24.6% in 2012 (p<0.001) (overall trend 1996-2012: ?=0.653, 95% confidence interval (CI):0.327-0.979, p<0.001). Comparing the 1996-2005 and 2006-2012 cohorts APP occurred significantly faster in the 2006 cohort after schizophrenia diagnosis (p<0.0001). The predominant APP type changed from first-generation antipsychotic combinations in 1996 (77.3%) to first+second-generation antipsychotic combinations in 2003 (70.3%) and second-generation antipsychotic combinations in 2012 (59.2%). In 2012, the prevalence of APP varied from 19.4% in Copenhagen to 29.3% in the region of Zealand. Independent correlates of APP, explaining 37.9% of the variance, included a higher number of patients per psychiatrist (OR=1.04/10 patients, CI=1.03-1.06, p<0.001),lower proportion of males (OR=0.80, CI=0.74-0.86), younger age (OR=1.00, CI=0.99-1.00), several schizophrenia subtypes (paranoid: OR=1.24, CI=1.11-1.38,hebephrenic: OR=1.30, CI=1.03-1.63, other: OR=1.95 CI=1.17-3.24, unspecified: OR=1.21 CI=1.05-1.40), living alone (OR=1.12, CI=1.01-1.24), being institutionalized (OR=1.23, CI=1.06-1.42), receiving early retirement pension (OR=1.21, CI=1.10-1.34), higher Charlson Co-morbidity Index score (OR=1.13, CI=1.07-1.19), higher antipsychotic defined daily doses (OR=3.05, CI=-2.95-3.16), treatment with clozapine (OR=3.09, 95% CI=2.78-3.44), and treatment with antidepressants (OR=1.97 (CI=1.83-2.13), long-acting injectable antipsychotics (OR=1.48, CI=1.34-1.63), and anticholinergics (OR=1.74, CI=1.51-2.01). APP remains common in schizophrenia with substantial temporal and geographical variation, being associated with indicators of illness severity and chronicity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 43 | World J Psychiatry 2015 Jun 5: 193-209 |
| PMID | 26110121 |
| Title | Auditory hallucinations: A review of the ERC "VOICE" project. |
| Abstract | In this invited review I provide a selective overview of recent research on brain mechanisms and cognitive processes involved in auditory hallucinations. The review is focused on research carried out in the "VOICE" ERC Advanced Grant Project, funded by the European Research Council, but I also review and discuss the literature in general. Auditory hallucinations are suggested to be perceptual phenomena, with a neuronal origin in the speech perception areas in the temporal lobe. The phenomenology of auditory hallucinations is conceptualized along three domains, or dimensions; a perceptual dimension, experienced as someone speaking to the patient; a cognitive dimension, experienced as an inability to inhibit, or ignore the voices, and an emotional dimension, experienced as the "voices" having primarily a negative, or sinister, emotional tone. I will review cognitive, imaging, and neurochemistry data related to these dimensions, primarily the first two. The reviewed data are summarized in a model that sees auditory hallucinations as initiated from temporal lobe neuronal hyper-activation that draws attentional focus inward, and which is not inhibited due to frontal lobe hypo-activation. It is further suggested that this is maintained through abnormal glutamate and possibly gamma-amino-butyric-acid transmitter mediation, which could point towards new pathways for pharmacological treatment. A final section discusses new methods of acquiring quantitative data on the phenomenology and subjective experience of auditory hallucination that goes beyond standard interview questionnaires, by suggesting an iPhone/iPod APP. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 44 | Schizophr. Res. 2015 Jul 165: 201-11 |
| PMID | 25956630 |
| Title | Protein expression of targets of the FMRP regulon is altered in brains of subjects with schizophrenia and mood disorders. |
| Abstract | Fragile X mental retardation protein (FMRP) is an RNA binding protein with 842 target mRNAs in mammalian brain. Silencing of the fragile X mental retardation 1 (FMR1) gene leads to loss of expression of FMRP and upregulated metabotropic glutamate receptor 5 (mGluR5) signaling resulting in the multiple physical and cognitive deficits associated with fragile X syndrome (FXS). Reduced FMRP expression has been identified in subjects with autism, schizophrenia, bipolar disorder, and major depression who do not carry the mutation for FMR1. Our laboratory has recently demonstrated altered expression of four downstream targets of FMRP-mGluR5 signaling in brains of subjects with autism: homer 1, amyloid beta A4 precursor protein (APP), ras-related C3 botulinum toxin substrate 1 (RAC1), and striatal-enriched protein tyrosine phosphatase (STEP). In the current study we investigated the expression of the same four proteins in lateral cerebella of subjects with schizophrenia, bipolar disorder, and major depression and in frontal cortex of subjects with schizophrenia and bipolar disorder. In frontal cortex we observed: 1) reduced expression of 120 kDa form of APP in subjects with schizophrenia and bipolar disorder; 2) reduced expression of 61 kDa and 33k Da forms of STEP in subjects with schizophrenia; 3) reduced expression of 88 kDa form of APP in subjects with bipolar disorder; and 3) trends for reduced expression of 88 kDa form of APP and homer 1 in subjects with schizophrenia and bipolar disorder, respectively. In lateral cerebella there was no group difference, however we observed increased expression of RAC1 in subjects with bipolar disorder, and trends for increased RAC1 in subjects with schizophrenia and major depression. Our results provide further evidence that proteins involved in the FMRP-mGluR5 signaling pathway are altered in schizophrenia and mood disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 45 | Transl Psychiatry 2015 -1 5: e561 |
| PMID | 25942042 |
| Title | d-serine levels in Alzheimer's disease: implications for novel biomarker development. |
| Abstract | Alzheimer's disease (AD) is a severe neurodegenerative disorder still in search of effective methods of diagnosis. Altered levels of the NMDA receptor co-agonist, d-serine, have been associated with neurological disorders, including schizophrenia and epilepsy. However, whether d-serine levels are deregulated in AD remains elusive. Here, we first measured D-serine levels in post-mortem hippocampal and cortical samples from nondemented subjects (n=8) and AD patients (n=14). We next determined d-serine levels in experimental models of AD, including wild-type rats and mice that received intracerebroventricular injections of amyloid-? oligomers, and APP/PS1 transgenic mice. Finally, we assessed d-serine levels in the cerebrospinal fluid (CSF) of 21 patients with a diagnosis of probable AD, as compared with patients with normal pressure hydrocephalus (n=9), major depression (n=9) and healthy controls (n=10), and results were contrasted with CSF amyloid-?/tau AD biomarkers. d-serine levels were higher in the hippocampus and parietal cortex of AD patients than in control subjects. Levels of both d-serine and serine racemase, the enzyme responsible for d-serine production, were elevated in experimental models of AD. Significantly, d-serine levels were higher in the CSF of probable AD patients than in non-cognitively impaired subject groups. Combining d-serine levels to the amyloid/tau index remarkably increased the sensitivity and specificity of diagnosis of probable AD in our cohort. Our results show that increased brain and CSF d-serine levels are associated with AD. CSF d-serine levels discriminated between nondemented and AD patients in our cohort and might constitute a novel candidate biomarker for early AD diagnosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 46 | Genes Brain Behav. 2015 Jun 14: 411-8 |
| PMID | 25912880 |
| Title | Physiological and behavioral effects of amphetamine in BACE1(-/-) mice. |
| Abstract | ?-Site APP-cleaving Enzyme 1 (BACE1) is a protease that has been linked to schizophrenia, a severe mental illness that is potentially characterized by enhanced dopamine (DA) release in the striatum. Here, we used acute amphetamine administration to stimulate neuronal activity and investigated the neurophysiological and locomotor-activity response in BACE1-deficient (BACE1(-/-) ) mice. We measured locomotor activity at baseline and after treatment with amphetamine (3.2 and 10 mg/kg). While baseline locomotor activity did not vary between groups, BACE1(-/-) mice exhibited reduced sensitivity to the locomotor-enhancing effects of amphetamine. Using high-performance liquid chromatography (HPLC) to measure DA and DA metabolites in the striatum, we found no significant differences in BACE1(-/-) compared with wild-type mice. To determine if DA neuron excitability is altered in BACE1(-/-) mice, we performed patch-clamp electrophysiology in putative DA neurons from brain slices that contained the substantia nigra. Pacemaker firing rate was slightly increased in slices from BACE1(-/-) mice. We next measured G protein-coupled potassium currents produced by activation of D2 autoreceptors, which strongly inhibit firing of these neurons. The maximal amplitude and decay times of D2 autoreceptor currents were not altered in BACE1(-/-) mice, indicating no change in D2 autoreceptor-sensitivity and DA transporter-mediated reuptake. However, amphetamine (30 µm)-induced potassium currents produced by efflux of DA were enhanced in BACE1(-/-) mice, perhaps indicating increased vesicular DA content in the midbrain. This suggests a plausible mechanism to explain the decreased sensitivity to amphetamine-induced locomotion, and provides evidence that decreased availability of BACE1 can produce persistent adaptations in the dopaminergic system. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 47 | Behav Brain Funct 2015 -1 11: 10 |
| PMID | 25889058 |
| Title | Association between 5q23.2-located polymorphism of CTXN3 gene (Cortexin 3) and schizophrenia in European-Caucasian males; implications for the aetiology of schizophrenia. |
| Abstract | The objective of the study was to examine several polymorphisms in DISC1 and CTNX3 genes as possible risk factors in schizophrenia. DISC1 (disrupted-in-schizophrenia 1) has been studied extensively in relation to mental disease while CTXN3, has only recently emerged as a potential "candidate" gene in schizophrenia. CTXN3 resides in a genomic region (5q21-34) known to be associated with schizophrenia and encodes a protein cortexin 3 which is highly enriched in brain. We used ethnically homogeneous samples of 175 male patients and 184 male control subjects. All patients were interviewed by two similarly qualified psychiatrists. Controls were interviewed by one of the authors (O.S.). Genotyping was performed, following amplification by polymerase chain reaction (PCR), using fragment analysis in a standard commercial setting (APPlied Biosystems, USA). We have found a statistically significant association between rs6595788 polymorphism of CTXN3 gene and the risk of schizophrenia; the presence of AG genotype increased the risk 1.5-fold. Polymorphisms in DISC1 gene showed only marginally statistically significant association with schizophrenia (rs17817356) or no association whatsoever (rs821597 and rs980989) while two polymorphisms (rs9661837 and rs3737597) were found to be only slightly polymorphic in the samples. Evidence available in the literature suggests that altered expression of cortexin 3, either alone, or in parallel with changes in DISC1, could subtly perturb GABAergic neurotransmission and/or metabolism of amyloid precursor protein (APP) in developing brain, thus potentially exposing the affected individual to an increased risk of schizophrenia later in life. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 48 | Neurobiol. Aging 2015 May 36: 2004.e1-8 |
| PMID | 25726360 |
| Title | Rare structural genetic variation in human prion diseases. |
| Abstract | Prion diseases are a diverse group of neurodegenerative conditions, caused by the templated misfolding of prion protein. Aside from the strong genetic risk conferred by multiple variants of the prion protein gene (PRNP), several other variants have been suggested to confer risk in the most common type, sporadic Creutzfeldt-Jakob disease (sCJD) or in the acquired prion diseases. Large and rare copy number variants (CNVs) are known to confer risk in several related disorders including Alzheimer's disease (at APP), schizophrenia, epilepsy, mental retardation, and autism. Here, we report the first genome-wide analysis for CNV-associated risk using data derived from a recent international collaborative association study in sCJD (n = 1147 after quality control) and publicly available controls (n = 5427). We also investigated UK patients with variant Creutzfeldt-Jakob disease (n = 114) and elderly women from the Eastern Highlands of Papua New Guinea who proved highly resistant to the epidemic prion disease kuru, who were compared with healthy young Fore population controls (n = 395). There were no statistically significant alterations in the burden of CNVs >100, >500, or >1000 kb, duplications, or deletions in any disease group or geographic region. After correction for multiple testing, no statistically significant associations were found. A UK blood service control sample showed a duplication CNV that overlAPPed PRNP, but these were not found in prion disease. Heterozygous deletions of a 3' region of the PARK2 gene were found in 3 sCJD patients and no controls (p = 0.001, uncorrected). A cell-based prion infection assay did not provide supportive evidence for a role for PARK2 in prion disease susceptibility. These data are consistent with a modest impact of CNVs on risk of late-onset neurologic conditions and suggest that, unlike APP, PRNP duplication is not a causal high-risk mutation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 49 | Transl Psychiatry 2015 -1 5: e502 |
| PMID | 25646591 |
| Title | Influence of maternal infections on neonatal acute phase proteins and their interaction in the development of non-affective psychosis. |
| Abstract | Although primary infections with Toxoplasma gondii or herpes viruses during pregnancy are established teratogens, chronic maternal infections with these pathogens are considered far less serious. However, such chronic infections have been associated with neuropsychiatric disorders in the offspring. The risks of non-affective psychoses, including schizophrenia, in offspring associated with these exposures during pregnancy have not been completely defined. We used data from neonatal dried blood samples from 199 cases of non-affective psychosis and 525 matched controls (born 1975-1985). We measure immunoglobulin G antibodies directed at T. gondii, cytomegalovirus and herpes simplex virus type-1 and -2, as well as levels of nine acute phase proteins (APPs). We assessed the interaction between maternal antibodies and neonatal APP in terms of risk of non-affective psychosis. Among controls, maternal exposure to T. gondii or cytomegalovirus, but not to the other herpes viruses, was associated with significantly higher levels of neonatal APPs. Among cases, none of the maternal exposures were associated with any significant change in APPs. We observed increased RR for non-affective psychosis associated with maternal infection with T. gondii (odds ratio 2.1, 95% confidence interval 1.1-4.0) or cytomegalovirus (1.7, 0.9-3.3) only among neonates with low APP levels. These findings suggest that chronic maternal infection with T. gondii or cytomegalovirus affect neonatal markers of innate immunity. Deficient fetal immune responses in combination with maternal chronic infections may contribute to subsequent risk for psychosis. A greater understanding of the maternal-fetal immunological interplay may ultimately lead to preventive strategies toward neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 50 | Psychogeriatrics 2015 Mar 15: 7-13 |
| PMID | 25515355 |
| Title | Antipsychotic polypharmacy among elderly patients with schizophrenia and dementia during hospitalization at a Taiwanese psychiatric hospital. |
| Abstract | This study was to investigate the prescribing patterns for antipsychotic drugs in elderly hospitalized patients with a diagnosis of schizophrenia or dementia at a psychiatric hospital in Taiwan from 2007 to 2012. This study also explored the predictors of antipsychotic polypharmacy (APP). We collected patients' demographic data, including year of admission, age, gender, and length of hospital stay, and drug-related information. Second-generation antipsychotic (SGA) monotherapy was the most common type of therapy in both those with dementia and with schizophrenia, and quetiapine and risperidone were the most commonly prescribed drugs for these conditions, respectively. In late-life schizophrenia, 33.8% of the patients used first-generation antipsychotics (FGA) alone. Regarding APP, a combination of FGA and SGA and combinations of SGA were most commonly noted in schizophrenia patients and dementia patients, respectively. Overall, APP increased from 2007 to 2012. It was significantly more common in patients with dementia (odds ratio: 3.49, 95% confidence interval: 1.29-9.39, P = 0.014), less concurrent use of hypnotics and sedatives (odds ratio: 0.41, 95% confidence interval: 0.17-0.99, P = 0.046), and a higher-than-recommended dose of antipsychotic drugs (odds ratio: 4.98, 95% confidence interval: 2.75-9.02, P < 0.001). FGA are still commonly used for the late-life schizophrenia at our hospital. Given their potentially hazardous side effects, FGA must be employed with caution. The use of APP involving SGA increased over the 6?years of the study period, especially among patients with dementia. However, the use of SGA in dementia began to decline after the US Food and Drug Administration's 2005 warning about SGA being associated with increased mortality in dementia patients, which contrasts with the trends examined in this study. Further controlled trials exploring the efficacy, safety, and tolerability of APP in this population are warranted to gain an additional insight into this practice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 51 | Aust N Z J Psychiatry 2015 Feb 49: 129-36 |
| PMID | 24923760 |
| Title | Antipsychotic polypharmacy in schizophrenia patients in China and its association with treatment satisfaction and quality of life: findings of the third national survey on use of psychotropic medications in China. |
| Abstract | This study examined the use, demographic and clinical correlates of antipsychotic polypharmacy (APP) and its associations with treatment satisfaction and quality of life (QOL) in schizophrenia patients in China. A total of 4239 patients in 45 nationwide Chinese psychiatric hospitals/centers were interviewed in 2012 in the third cross-sectional study, with the first two having been conducted in 2002 and 2006. Patients' socio-demographic and clinical characteristics, including psychopathology, side effects, satisfaction with treatment and QOL, were recorded using a standardized protocol and data collection procedure. The proportion of APP prescriptions in 2012 was 34.2%, which was significantly higher than the frequency of APP in 2002 (26.1%) and 2006 (26.4%) (p<0.001). Of patients on APP, 91.1% received two antipsychotics, 8.6% received three and 0.3% received four or more antipsychotics. Multiple logistic regression analyses revealed that compared to those on antipsychotic monotherapy, patients on APP and their families had lower satisfaction with treatment, had higher QOL in the mental domain, younger age of onset, more side effects, higher doses of antipsychotics and were more likely to receive first-generation antipsychotics and less likely to receive benzodiazepines (total R (2)=0.31, p<0.001). APP was found in about one in three schizophrenia patients. The prevalence of APP seems to have been increasing since 2002. Considering the increased frequency of drug-induced side effects and the patients' and their relatives' dissatisfaction with antipsychotic treatment, further examination of the rationale and APPropriateness of APP and its alternatives is warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 52 | JMIR Ment Health 2016 -1 3: e16 |
| PMID | 27150677 |
| Title | New Tools for New Research in Psychiatry: A Scalable and Customizable Platform to Empower Data Driven Smartphone Research. |
| Abstract | A longstanding barrier to progress in psychiatry, both in clinical settings and research trials, has been the persistent difficulty of accurately and reliably quantifying disease phenotypes. Mobile phone technology combined with data science has the potential to offer medicine a wealth of additional information on disease phenotypes, but the large majority of existing smartphone APPs are not intended for use as biomedical research platforms and, as such, do not generate research-quality data. Our aim is not the creation of yet another APP per se but rather the establishment of a platform to collect research-quality smartphone raw sensor and usage pattern data. Our ultimate goal is to develop statistical, mathematical, and computational methodology to enable us and others to extract biomedical and clinical insights from smartphone data. We report on the development and early testing of Beiwe, a research platform featuring a study portal, smartphone APP, database, and data modeling and analysis tools designed and developed specifically for transparent, customizable, and reproducible biomedical research use, in particular for the study of psychiatric and neurological disorders. We also outline a proposed study using the platform for patients with schizophrenia. We demonstrate the passive data capabilities of the Beiwe platform and early results of its analytical capabilities. Smartphone sensors and phone usage patterns, when coupled with APPropriate statistical learning tools, are able to capture various social and behavioral manifestations of illnesses, in naturalistic settings, as lived and experienced by patients. The ubiquity of smartphones makes this type of moment-by-moment quantification of disease phenotypes highly scalable and, when integrated within a transparent research platform, presents tremendous opportunities for research, discovery, and patient health. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 53 | JMIR Res Protoc 2016 -1 5: e77 |
| PMID | 27125771 |
| Title | Feasibility of PRIME: A Cognitive Neuroscience-Informed Mobile App Intervention to Enhance Motivated Behavior and Improve Quality of Life in Recent Onset Schizophrenia. |
| Abstract | Despite improvements in treating psychosis, schizophrenia remains a chronic and debilitating disorder that affects APProximately 1% of the US population and costs society more than depression, dementia, and other medical illnesses across most of the lifespan. Improving functioning early in the course of illness could have significant implications for long-term outcome of individuals with schizophrenia. Yet, current gold-standard treatments do not lead to clinically meaningful improvements in outcome, partly due to the inherent challenges of treating a population with significant cognitive and motivational impairments. The rise of technology presents an opportunity to develop novel treatments that may circumvent the motivational and cognitive challenges observed in schizophrenia. The purpose of this study was two-fold: (1) to evaluate the feasibility and acceptability of implementing a Personalized Real-Time Intervention for Motivation Enhancement (PRIME), a mobile APP intervention designed to target reward-processing impairments, enhance motivation, and thereby improve quality of life in recent onset schizophrenia, and (2) evaluate the empirical benefits of using an iterative, user-centered design (UCD) process. We conducted two design workshops with 15 key stakeholders, followed by a series of in-depth interviews in collaboration with IDEO, a design and innovation firm. The UCD APProach ultimately resulted in the first iteration of PRIME, which was evaluated by 10 RO participants. Results from the Stage 1 participants were then used to guide the next iteration that is currently being evaluated in an ongoing RCT. Participants in both phases were encouraged to use the APP daily with a minimum frequency of 1/week over a 12-week period. The UCD process resulted in the following feature set: (1) delivery of text message (short message service, SMS)-based motivational coaching from trained therapists, (2) individualized goal setting in prognostically important psychosocial domains, (3) social networking via direct peer-to-peer messaging, and (4) community "moments feed" to capture and reinforce rewarding experiences and goal achievements. Users preferred an experience that highlighted several of the principles of self-determination theory, including the desire for more control of their future (autonomy and competence) and an APProach that helps them improve existing relationships (relatedness). IDEO, also recommended an APProach that was casual, friendly, and nonstigmatizing, which is in line with the recovery model of psychosis. After 12-weeks of using PRIME, participants used the APP, on average, every other day, were actively engaged with its various features each time they logged in and retention and satisfaction was high (20/20, 100% retention, high satisfaction ratings). The iterative design process lead to a 2- to 3-fold increase in engagement from Stage 1 to Stage 2 in almost each aspect of the platform. These results indicate that the neuroscience-informed mobile APP, PRIME, is a feasible and acceptable intervention for young people with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 54 | J. Psychopharmacol. (Oxford) 2016 May 30: 436-43 |
| PMID | 26905920 |
| Title | Antipsychotic polypharmacy and augmentation strategies prior to clozapine initiation: a historical cohort study of 310 adults with treatment-resistant schizophrenic disorders. |
| Abstract | Antipsychotic polypharmacy (APP) is commonly used in schizophrenia despite a lack of robust evidence for efficacy, as well as evidence of increased rates of adverse drug reactions and mortality. We sought to examine APP and the use of other adjunctive medications in patients with treatment-resistant schizophrenic disorders (ICD-10 diagnoses F20-F29) immediately prior to clozapine initiation, and to investigate clinical and sociodemographic factors associated with APP use in this setting. Analysis of case notes from 310 patients receiving their first course of clozapine at the South London and Maudsley NHS Trust (SLaM) was undertaken using the Clinical Record Interactive Search (CRIS) case register. Medication taken immediately prior to clozapine initiation was recorded, and global clinical severity was assessed at time points throughout the year prior to medication assessment using the Clinical Global Impression - Severity scale (CGI-S). Logistic regression was used to investigate factors associated with APP. The point prevalence of APP prior to clozapine initiation was 13.6% (n=42), with 32.6% of subjects prescribed adjuvant psychotropic medications. APP was associated with increasing number of adjuvant medications (odds ratio (OR) 1.97, 95% confidence interval (CI) 1.27-3.06), concurrent depot antipsychotic prescription (OR 2.64, CI 1.24-5.62), concurrent antidepressant prescription (OR 4.40, CI 1.82-10.63) and a CGI-S over the previous year within the two middle quartiles (Quartile 2 vs 1 OR 6.19, CI 1.81-21.10; Quartile 3 vs 1 OR 4.45, CI 1.29-15.37; Quartile 4 vs 1 OR 1.88, CI 0.45-7.13). APP and augmentation of antipsychotics with antidepressants, mood stabilizers and benzodiazepines are being employed in treatment-resistant schizophrenia prior to clozapine. The conservative APP rate observed may have been influenced by an initiative within SLaM that reduced APP rates during the study window. Efforts to reduce the use of poorly evidenced prescribing should focus on adjuvant medications as well as APP. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 55 | J. Psychopharmacol. (Oxford) 2016 May 30: 436-43 |
| PMID | 26905920 |
| Title | Antipsychotic polypharmacy and augmentation strategies prior to clozapine initiation: a historical cohort study of 310 adults with treatment-resistant schizophrenic disorders. |
| Abstract | Antipsychotic polypharmacy (APP) is commonly used in schizophrenia despite a lack of robust evidence for efficacy, as well as evidence of increased rates of adverse drug reactions and mortality. We sought to examine APP and the use of other adjunctive medications in patients with treatment-resistant schizophrenic disorders (ICD-10 diagnoses F20-F29) immediately prior to clozapine initiation, and to investigate clinical and sociodemographic factors associated with APP use in this setting. Analysis of case notes from 310 patients receiving their first course of clozapine at the South London and Maudsley NHS Trust (SLaM) was undertaken using the Clinical Record Interactive Search (CRIS) case register. Medication taken immediately prior to clozapine initiation was recorded, and global clinical severity was assessed at time points throughout the year prior to medication assessment using the Clinical Global Impression - Severity scale (CGI-S). Logistic regression was used to investigate factors associated with APP. The point prevalence of APP prior to clozapine initiation was 13.6% (n=42), with 32.6% of subjects prescribed adjuvant psychotropic medications. APP was associated with increasing number of adjuvant medications (odds ratio (OR) 1.97, 95% confidence interval (CI) 1.27-3.06), concurrent depot antipsychotic prescription (OR 2.64, CI 1.24-5.62), concurrent antidepressant prescription (OR 4.40, CI 1.82-10.63) and a CGI-S over the previous year within the two middle quartiles (Quartile 2 vs 1 OR 6.19, CI 1.81-21.10; Quartile 3 vs 1 OR 4.45, CI 1.29-15.37; Quartile 4 vs 1 OR 1.88, CI 0.45-7.13). APP and augmentation of antipsychotics with antidepressants, mood stabilizers and benzodiazepines are being employed in treatment-resistant schizophrenia prior to clozapine. The conservative APP rate observed may have been influenced by an initiative within SLaM that reduced APP rates during the study window. Efforts to reduce the use of poorly evidenced prescribing should focus on adjuvant medications as well as APP. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 56 | J Clin Psychiatry 2016 Jan 77: e14-20 |
| PMID | 26845273 |
| Title | Switching from 2 antipsychotics to 1 antipsychotic in schizophrenia: a randomized, double-blind, placebo-controlled study. |
| Abstract | Antipsychotic polypharmacy (APP) is employed routinely, although it remains controversial because robust evidence supporting its efficacy is lacking. In addition, it is associated with increased costs, higher antipsychotic dosing, and greater risk of side effects. Surprisingly, no prospective, randomized, double-blind studies have addressed this issue; the present investigation set out to fill this gap in knowledge. A 12-week, double-blind, randomized, placebo-controlled, single-site study was carried out in individuals with schizophrenia or schizoaffective disorder (DSM-IV) receiving a designated primary antipsychotic plus a secondary antipsychotic, with doses stabilized for each. Individuals were randomly assigned to APP (N = 17), reflecting current treatment, or antipsychotic monotherapy (APM) (N = 18), in which the secondary antipsychotic was discontinued. Assessments occurred weekly during month 1 and every 2 weeks during months 2 and 3; the primary outcome measure was the Brief Psychiatric Rating Scale (BPRS) total score. Other measures included the Clinical Global Impressions (CGI) scale, Simpson-Angus Scale, and Barnes Akathisia Scale. The study was carried out between August 2006 and March 2011. Withdrawal due to clinical deterioration occurred in 1 individual receiving APP (5.8%) and in 4 individuals in the APM group (22.2%). Overall, however, there was no indication of clinical worsening with APM, as measured using BPRS and CGI scale. Almost 80% (n = 14) of individuals with schizophrenia or schizoaffective disorder currently receiving APP could be safely transitioned to APM with no clinical deterioration. For those who do deteriorate, risk APPears greatest in the first several months. From another perspective, results also indicate that a minority of individuals benefit from APP, and research focusing on identifying this group may represent the best strategy to curb excessive use of APP. ClinicalTrials.gov identifier: NCT00493233. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 57 | Int J Clin Pharmacol Ther 2016 Jan 54: 36-42 |
| PMID | 26521927 |
| Title | Antipsychotic polypharmacy and quality of life in patients with schizophrenia treated in primary care in China. |
| Abstract | In China, maintenance treatment for clinically stable patients with schizophrenia is usually provided by primary care physicians, but their prescribing patterns have not been studied. This study examined the frequency as well as demographic and clinical correlates of antipsychotic polypharmacy (APP) and its impact on quality of life (QOL) in patients with schizophrenia treated in primary care in China. A total of 623 community-dwelling patients from 18 randomly selected primary care services were interviewed. Patients' socio-demographic and clinical characteristics, including number of hospitalizations, antipsychotic drug-induced side effects, and QOL were recorded using a standardized protocol and data collection procedure. The rate of APP prescription was 31% (193/623). Of the patients on APP, 89.6% received 2 antipsychotics, 10.4% received 3 or more antipsychotics. Clozapine (35.6%) was the most commonly prescribed second generation antipsychotic (SGA), while perphenazine (17.8%) was the most commonly prescribed first generation antipsychotic (FGA). Multiple logistic regression analyses revealed that patients on APP were more likely to receive SGAs and anticholinergics, had fewer hospitalizations, younger age of onset, and higher doses of antipsychotics. There were no significant differences between the two groups in any of the QOL domains. APProximately a third of Chinese patients with schizophrenia in primary care receive APP. Further examination of the rationale and APPropriateness of APP and its alternatives is warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 58 | Neuropsychopharmacology 2016 Jan 41: 440-53 |
| PMID | 26062786 |
| Title | Disrupted-in-Schizophrenia-1 Attenuates Amyloid-? Generation and Cognitive Deficits in APP/PS1 Transgenic Mice by Reduction of ?-Site APP-Cleaving Enzyme 1 Levels. |
| Abstract | Disrupted-in-schizophrenia-1 (DISC1) is a genetic risk factor for a wide range of major mental disorders, including schizophrenia, major depression, and bipolar disorders. Recent reports suggest a potential role of DISC1 in the pathogenesis of Alzheimer's disease (AD), by referring to an interaction between DISC1 and amyloid precursor protein (APP), and to an association of a single-nucleotide polymorphism in a DISC1 intron and late onset of AD. However, the function of DISC1 in AD remains unknown. In this study, decreased levels of DISC1 were observed in the cortex and hippocampus of 8-month-old APP/PS1 transgenic mice, an animal model of AD. Overexpression of DISC1 reduced, whereas knockdown of DISC1 increased protein levels, but not mRNA levels of ?-site APP-Cleaving Enzyme 1 (BACE1), a key enzyme in amyloid-? (A?) generation. Reduction of BACE1 protein levels by overexpression of DISC1 was accompanied by an accelerating decline rate of BACE1, and was blocked by the lysosomal inhibitor chloroquine, rather than proteasome inhibitor MG-132. Moreover, overexpression of DISC1 in the hippocampus with an adeno-associated virus reduced the levels of BACE1, soluble A?40/42, amyloid plaque density, and rescued cognitive deficits of APP/PS1 transgenic mice. These results indicate that DISC1 attenuates A? generation and cognitive deficits of APP/PS1 transgenic mice through promoting lysosomal degradation of BACE1. Our findings provide new insights into the role of DISC1 in AD pathogenesis and link a potential function of DISC1 to the psychiatric symptoms of AD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |