| 1 | Schizophr. Res. 2005 Sep 77: 261-70 |
|---|---|
| PMID | 15890497 |
| Title | Cortical gene expression in the neonatal ventral-hippocampal lesion rat model. |
| Abstract | schizophrenia is a chronic, debilitating psychotic illness of unknown etiology that has been the subject of many genetic studies. We studied the neonatal ventral-hippocampal lesioned rat as an animal model of schizophrenia in order to identify novel candidate genes for schizophrenia. Temporal and frontal cortices were assessed using cDNA microarrays for differences in mRNA expression associated with the lesion, haloperidol treatment and in two rat strains with differential sensitivity to the behavioural effects of the lesion. Genes that had altered expression levels as a result of the lesion, that were normalized by haloperidol treatment, and that differed between rat strains were selected. The pattern of differential transcription was confirmed with quantitative PCR for all six candidate genes: large conductance calcium-activated potassium channel, subfamily M, beta member 1 (Kcnmb1); doublecortex (dcx); adenylyl cyclase-associated protein 1 (CAP1); adenosine monophosphate deaminase 2-isoform L (AMPD2); malic enzyme 3, NADP(+)-dependent, mitochondrial (Me3); and aspartylglucosaminidase (AGA). None of these genes has been extensively studied in schizophrenia, and further work with post-mortem tissue and genetic studies are ongoing. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | J Coll Physicians Surg Pak 2005 Jun 15: 345-8 |
| PMID | 15924839 |
| Title | Gender differences in age at onset of schizophrenia. |
| Abstract | To evaluate the gender differences in age at onset of schizophrenia. Prospective case control study. Department of Psychiatry, AGA Khan University Hospital, Karachi between January to December 2002. Sixty patients admitted consecutively to psychiatry ward and meeting the inclusion criteria were enrolled for the study. Age at onset of illness was defined as age at onset of gross psychotic symptoms, age at first contact with psychiatrist and age at index admission. Statistical method included two independent samples t-test. Data was dichotomized into those with family history of schizophrenia versus those without family history of illness and then Chi-square test of association was applied. The mean age of onset of illness was 23.96 years in females and 24.13 years in males. In all other measures used to assess the onset of illness, females were overrepresented at the younger age group. 56.7% patients had a family history of psychotic disorder. Among them the mean ages at onset of illness were 20.59 years in females and 21.85 years in males ( c 0.04 df =58). The illness occurred at a younger age in those with positive family history of schizophrenia (21.22 years) than those without it (25.14 years) with dissipation of gender difference in the former. There was no significant gender difference in age at onset of disorder in this study. Family history of schizophrenia appears to be the most significant factor that eliminates the gender differences in age at onset of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Hum. Genet. 2006 Jun 119: 558-70 |
| PMID | 16604350 |
| Title | Genome scans and gene expression microarrays converge to identify gene regulatory loci relevant in schizophrenia. |
| Abstract | Multiple linkage regions have been reported in schizophrenia, and some appear to harbor susceptibility genes that are differentially expressed in postmortem brain tissue derived from unrelated individuals. We combined traditional genome-wide linkage analysis in a multiplex family with lymphocytic genome-wide expression analysis. A genome scan suggested linkage to a chromosome 4q marker (D4S1530, LOD 2.17, theta = 0) using a dominant model. Haplotype analysis using flanking microsatellite markers delineated a 14 Mb region that cosegregated with all those affected. Subsequent genome-wide scan with SNP genotypes supported the evidence of linkage to 4q33-35.1 (LOD = 2.39) using a dominant model. Genome-wide microarray analysis of five affected and five unaffected family members identified two differentially expressed genes within the haplotype AGA and GALNT7 (aspartylglucosaminidase and UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 7) with nominal significance; however, these genes did not remain significant following analysis of covariance. We carried out genome-wide linkage analyses between the quantitative expression phenotype and genetic markers. AGA expression levels showed suggestive linkage to multiple markers in the haplotype (maximum LOD = 2.37) but to no other genomic region. GALNT7 expression levels showed linkage to regulatory loci at 4q28.1 (maximum LOD = 3.15) and in the haplotype region at 4q33-35.1 (maximum LOD = 2.37). ADH1B (alcohol dehydrogenase IB) was linked to loci at 4q21-q23 (maximum LOD = 3.08) and haplotype region at 4q33-35.1 (maximum LOD = 2.27). Seven differentially expressed genes were validated with RT-PCR. Three genes in the 4q33-35.1 haplotype region were also differentially expressed in schizophrenia in postmortem dorsolateral prefrontal cortex: AGA, HMGB2, and SCRG1. These results indicate that combining differential gene expression with linkage analysis may help in identifying candidate genes and potential regulatory sites. Moreover, they also replicate recent findings of complex trans- and cis- regulation of genes. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Schizophr. Res. 2006 Oct 87: 1-5 |
| PMID | 16750903 |
| Title | Mutation analysis of DARPP-32 as a candidate gene for schizophrenia. |
| Abstract | Dopamine- and cAMP-regulated phosphoprotein of relative molecular mass 32kDa (DARPP-32) plays a pivotal role in the signal transduction of several neurotransmitters and neuromodulators that are implicated in the pathophysiology of a variety of neuropsychiatric disorders. A postmortem study reported a significantly reduced DARPP-32 expression in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia, suggesting possible involvement of DARPP-32 in the pathophysiology of schizophrenia. Hence, DARPP-32 was considered as a candidate gene for schizophrenia in this study. We first systemically searched for mutations in the DARPP-32 gene in 50 Han Chinese patients with schizophrenia from Taiwan. Five molecular variants were identified, including a C-to-G substitution (g.-2036C>G) in the putative core promoter that obliterated a predictive AP-2 transcription factor binding site, a G deletion in the untranslated exon 2 (g.1238delG), a G-to-A and an A-to-G substitutions in intron 2 (IVS2+31G>A) and intron 6 (IVS6+32A>G), respectively, and a three-base pair deletion of AGA in exon 6 that resulted in deletion of a glutamate at codon 135 (E135del). Further SNP- and haplotype-based association study in 249 patients and 273 control subjects, however, did not detect association of these markers with schizophrenia. Hence, our results suggest that the reduced DARPP-32 protein in patients with schizophrenia is unlikely caused by mutations in the DARPP-32 gene itself and the DARPP-32 gene is also unlikely a major susceptibility gene for schizophrenia. Nevertheless, the identification of these molecular variants should help the study of gene regulation and structure-function relationship of DARPP-32, and the association study of DARPP-32 gene with other neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | BMC Psychiatry 2008 -1 8: 56 |
| PMID | 18637176 |
| Title | Perceptions about the cause of schizophrenia and the subsequent help seeking behavior in a Pakistani population - results of a cross-sectional survey. |
| Abstract | There is a cultural variability around the perception of what causes the syndrome of schizophrenia. Generally patients with schizophrenia are considered dangerous. They are isolated and treatment is delayed. Studies have shown favorable prognosis with good family and social support, early diagnosis and management. Duration of untreated psychosis is a bad prognostic indicator. We aimed to determine the perceptions regarding the etiology of schizophrenia and the subsequent help seeking behavior. This cross-sectional study was carried out on a sample of 404 people at the out patient departments of AGA Khan University Hospital Karachi. Data was collected via a self-administered questionnaire. Questions were related to a vignette of a young man displaying schizophrenic behavior. Data was analyzed on SPSS v 14. The mean age of the participants was 31.4 years (range = 18-72) and 77% of them were males. The majorities were graduates (61.9%) and employed (50%). Only 30% of the participants attributed 'mental illness' as the main cause of psychotic symptoms while a large number thought of 'God's will' (32.3%), 'superstitious ideas' (33.1%), 'loneliness' (24.8%) and 'unemployment' (19.3%) as the main cause. Mental illness as the single most important cause was reported by only 22%. As far as management is concerned, only 40% reported psychiatric consultation to be the single most important management step. Other responses included spiritual healing (19.5%) and Sociachanges (10.6) while 14.8% of respondents said that they would do nothing. Gender, age, family system and education level were significantly associated with the beliefs about the cause of schizophrenia (p < 0.05). While these variables plus 'religious inclination' and 'beliefs about cause' were significantly associated with the help seeking behavior of the participants. Despite majority of the study population being well educated, only a few recognized schizophrenia as a mental illness and many held superstitious beliefs. A vast majority of Pakistanis have non-biomedical beliefs about the cause of schizophrenia. Their help seeking behavior in this regard is inappropriate and detrimental to the health of schizophrenic patients. Areas for future research have been identified. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | BMC Psychiatry 2008 -1 8: 56 |
| PMID | 18637176 |
| Title | Perceptions about the cause of schizophrenia and the subsequent help seeking behavior in a Pakistani population - results of a cross-sectional survey. |
| Abstract | There is a cultural variability around the perception of what causes the syndrome of schizophrenia. Generally patients with schizophrenia are considered dangerous. They are isolated and treatment is delayed. Studies have shown favorable prognosis with good family and social support, early diagnosis and management. Duration of untreated psychosis is a bad prognostic indicator. We aimed to determine the perceptions regarding the etiology of schizophrenia and the subsequent help seeking behavior. This cross-sectional study was carried out on a sample of 404 people at the out patient departments of AGA Khan University Hospital Karachi. Data was collected via a self-administered questionnaire. Questions were related to a vignette of a young man displaying schizophrenic behavior. Data was analyzed on SPSS v 14. The mean age of the participants was 31.4 years (range = 18-72) and 77% of them were males. The majorities were graduates (61.9%) and employed (50%). Only 30% of the participants attributed 'mental illness' as the main cause of psychotic symptoms while a large number thought of 'God's will' (32.3%), 'superstitious ideas' (33.1%), 'loneliness' (24.8%) and 'unemployment' (19.3%) as the main cause. Mental illness as the single most important cause was reported by only 22%. As far as management is concerned, only 40% reported psychiatric consultation to be the single most important management step. Other responses included spiritual healing (19.5%) and Sociachanges (10.6) while 14.8% of respondents said that they would do nothing. Gender, age, family system and education level were significantly associated with the beliefs about the cause of schizophrenia (p < 0.05). While these variables plus 'religious inclination' and 'beliefs about cause' were significantly associated with the help seeking behavior of the participants. Despite majority of the study population being well educated, only a few recognized schizophrenia as a mental illness and many held superstitious beliefs. A vast majority of Pakistanis have non-biomedical beliefs about the cause of schizophrenia. Their help seeking behavior in this regard is inappropriate and detrimental to the health of schizophrenic patients. Areas for future research have been identified. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | PLoS ONE 2009 -1 4: e7409 |
| PMID | 19823577 |
| Title | Pathways to care: duration of untreated psychosis from Karachi, Pakistan. |
| Abstract | Substantial amount of time is lost before initiation of treatment in schizophrenia. The delay in treatment is labelled as Duration of Untreated Psychosis (DUP). Most of these estimates come from western countries, where health systems are relatively better developed. There is dearth of information on pathway to care from developing countries. Patients with ICD-10 based diagnosis of schizophrenia were enrolled by convenient method of sampling. The pathway to care was explored through a semi-structured questionnaire. Onset, course and symptoms of psychosis were assessed using Interview for the Retrospective Assessment of the Onset of schizophrenia (IRAOS). Ethical approval of the project was taken from The AGA Khan University, Ethics Review Committee. Of the enrolled 93 subjects, 55 (59%) were males and 38 (41%) were females. In our sample, 1.56 mean (median, 2) attempts were made prior to successful help seeking. The duration of untreated psychosis was 14.8 months (St. Deviation; 29.4). DUP was 16.8 months (St. Deviation; 34.9) for males and 11.8 months (St. Deviation; 18.9) for females. In the pathway to care, psychiatrists featured prominently as initial care providers. In the first attempt at help-seeking, 43% patients were initially taken to psychiatrists. After the initial consultation, 45% were prescribed psychotropic medication while 7% were hospitalized. Only 9% subjects were given the diagnosis of schizophrenia initially. When participants were inquired about the reasons for delay, 29% reported financial difficulties as the barrier to care. Positive symptoms of psychosis were present in 57% subjects while negative symptoms were present in 30% subjects. There was a statistically significant difference (Chi-square; 7.928, df: 1, Sig 0.005) between DUP and the positive and negative symptoms category. In the absence of well developed primary care health system in Pakistan, majority of patients present to psychiatrists as a first contact. DUP, as a measurement of help seeking behaviour, tends to be shorter with positive symptoms of schizophrenia. Substantial amount of time is lost due to non recognition of disease and subsequently, inadequate treatment. Secondary prevention strategies should focus on families, which play an important role in the treatment-seeking process of psychotic patients. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Schizophr Bull 2009 Nov 35: 1163-82 |
| PMID | 18552348 |
| Title | Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii. |
| Abstract | Many genes implicated in schizophrenia can be related to glutamatergic transmission and neuroplasticity, oligodendrocyte function, and other families clearly related to neurobiology and schizophrenia phenotypes. Others appear rather to be involved in the life cycles of the pathogens implicated in the disease. For example, aspartylglucosaminidase (AGA), PLA2, SIAT8B, GALNT7, or B3GAT1 metabolize chemical ligands to which the influenza virus, herpes simplex, cytomegalovirus (CMV), rubella, or Toxoplasma gondii bind. The epidermal growth factor receptor (EGR/EGFR) is used by the CMV to gain entry to cells, and a CMV gene codes for an interleukin (IL-10) mimic that binds the host cognate receptor, IL10R. The fibroblast growth factor receptor (FGFR1) is used by herpes simplex. KPNA3 and RANBP5 control the nuclear import of the influenza virus. Disrupted in schizophrenia 1 (DISC1) controls the microtubule network that is used by viruses as a route to the nucleus, while DTNBP1, MUTED, and BLOC1S3 regulate endosomal to lysosomal routing that is also important in viral traffic. Neuregulin 1 activates ERBB receptors releasing a factor, EBP1, known to inhibit the influenza virus transcriptase. Other viral or bacterial components bind to genes or proteins encoded by CALR, FEZ1, FYN, HSPA1B, IL2, HTR2A, KPNA3, MED12, MED15, MICB, NQO2, PAX6, PIK3C3, RANBP5, or TP53, while the cerebral infectivity of the herpes simplex virus is modified by Apolipoprotein E (APOE). Genes encoding for proteins related to the innate immune response, including cytokine related (CCR5, CSF2RA, CSF2RB, IL1B, IL1RN, IL2, IL3, IL3RA, IL4, IL10, IL10RA, IL18RAP, lymphotoxin-alpha, tumor necrosis factor alpha [TNF]), human leukocyte antigen (HLA) antigens (HLA-A10, HLA-B, HLA-DRB1), and genes involved in antigen processing (angiotensin-converting enzyme and tripeptidyl peptidase 2) are all concerned with defense AGAinst invading pathogens. Human microRNAs (Hsa-mir-198 and Hsa-mir-206) are predicted to bind to influenza, rubella, or poliovirus genes. Certain genes associated with schizophrenia, including those also concerned with neurophysiology, are intimately related to the life cycles of the pathogens implicated in the disease. Several genes may affect pathogen virulence, while the pathogens in turn may affect genes and processes relevant to the neurophysiology of schizophrenia. For such genes, the strength of association in genetic studies is likely to be conditioned by the presence of the pathogen, which varies in different populations at different times, a factor that may explain the heterogeneity that plagues such studies. This scenario also suggests that drugs or vaccines designed to eliminate the pathogens that so clearly interact with schizophrenia susceptibility genes could have a dramatic effect on the incidence of the disease. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | J Coll Physicians Surg Pak 2010 Mar 20: 167-70 |
| PMID | 20392378 |
| Title | Magnetic resonance imaging findings in patients with schizophrenia. |
| Abstract | To determine structural abnormalities in the brain of patients with schizophrenia by Magnetic Resonance Imaging (MRI). Comparative study. The Departments of Radiology and Psychiatry, the AGA Khan University Hospital, Karachi, from January 2007 to June 2008. Thirty-three cases of schizophrenia (n=33) and thirty-three age-matched controls, (n=33) were enrolled for this study. Screening Magnetic Resonance Imaging (MRI) of brain was done in order to see structural changes in brain matter. Findings were compared among groups using chi-square and Fisher's exact test with significance at p < 0.05. Among the total of 66 (n=66) MRI films studied for brain abnormalities, brain atrophy, presence of septum pellucidum and enlarged Virchow-Robins spaces were significantly associated with schizophrenia (p < 0.001). There was no significant difference between cases and controls for ventricular dilatation (p=0.5). Sinusitis was mostly associated with controls and well correlated with their symptoms (p < 0.001). Brain atrophy was the most commonly seen brain change in the studied sample of patients with schizophrenia. MRI brain can be used to identify structural abnormalities in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Schizophr Bull 2011 Jan 37: 94-100 |
| PMID | 19494248 |
| Title | Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population. |
| Abstract | Celiac disease (CD) and schizophrenia have approximately the same prevalence, but epidemiologic data show higher prevalence of CD among schizophrenia patients. The reason for this higher co-occurrence is not known, but the clinical knowledge about the presence of immunologic markers for CD or gluten intolerance in schizophrenia patients may have implications for treatment. Our goal was to evaluate antibody prevalence to gliadin (AGA), transglutaminase (tTG), and endomysium (EMA) in a group of individuals with schizophrenia and a comparison group. AGA, tTG, and EMA antibodies were assayed in 1401 schizophrenia patients who were part of the Clinical Antipsychotic Trials of Intervention Effectiveness study and 900 controls. Psychopathology in schizophrenia patients was assessed using the Positive and Negative Symptoms Scale (PANSS). Logistic regression was used to assess the difference in the frequency of AGA, immunoglobulin A (IgA), and tTG antibodies, adjusting for age, sex, and race. Linear regression was used to predict PANSS scores from AGA and tTG antibodies adjusting for age, gender, and race. Among schizophrenia patients, 23.1% had moderate to high levels of IgA-AGA compared with 3.1% of the comparison group (?(2) = 1885, df = 2, P < .001.) Moderate to high levels of tTG antibodies were present in 5.4% of schizophrenia patients vs 0.80% of the comparison group (?(2)?= 392.0, df = 2, P < .001). Adjustments for sex, age, and race had trivial effects on the differences. Regression analyses failed to predict PANSS scores from AGA and tTG antibodies. Persons with schizophrenia have higher than expected titers of antibodies related to CD and gluten sensitivity. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | Schizophr Bull 2013 Jul 39: 867-71 |
| PMID | 22516148 |
| Title | Increased prevalence of transglutaminase 6 antibodies in sera from schizophrenia patients. |
| Abstract | Gluten can cause extraintestinal manifestations with or without gastrointestinal symptoms and elevated antitissue transglutaminase 2 (tTG2) autoantibodies. Organ-specific gluten reaction involves immune response toward other transglutaminase (TG) isoforms including tTG3 (expressed in the skin, leading to dermatitis herpetiformis) and tTG6 (expressed in the brain, causing gluten ataxia). This analysis focuses on tTG6 antibodies, which have never been studied before in schizophrenia (SZ) and its relationships to tTG2 and to antigliadin antibodies. We previously showed an increased prevalence of tTG2 antibodies in gluten sensitive SZ patients compared with healthy controls (HC) that was not paralleled by an increased prevalence of antiendomysial antibody. To elucidate this discrepancy, we examined those tTG2 positive SZ patients for the presence of tTG6 antibody. We also searched for tTG6 antibodies in our sample of antigliadin (AGA) positive and AGA and tTG2 negative SZ patients. Seventy-four tTG2 positive SZ patients were compared with 148 age and gender-matched HC. Of the 74 tTG2 positive SZ patients, 16 were positive for tTG6 IgA for a prevalence of 22%. Only 4 HC were positive for tTG6 IgA for a prevalence of 2.7%. Among the AGA positive SZ patients, the prevalence of tTG6 IgA was 21.3% while 13.1% of the AGA and tTG2 negative SZ patients were positive for tTG6 IgA. The HC had a prevalence of 6%. Our results indicate a higher prevalence of tTG6 antibodies in SZ that may represent a biomarker useful to identify SZ patients who would benefit from a gluten-free diet. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | Schizophr. Res. 2014 Nov 159: 539-42 |
| PMID | 25311778 |
| Title | Gluten sensitivity and relationship to psychiatric symptoms in people with schizophrenia. |
| Abstract | The relationship between gluten sensitivity and schizophrenia has been of increasing interest and novel mechanisms explaining this relationship continue to be described. Our study in 100 people with schizophrenia compared to 100 matched controls replicates a higher prevalence of gluten sensitivity and higher mean antigliadin IgG antibody levels schizophrenia (2.9 ± 7.7 vs. 1.3 ± 1.3, p = 0.046, controlled for age). Additionally, we examined symptoms within the schizophrenia group and found that while positive symptoms are significantly lower in people who have elevated antigliadin antibodies (AGA; 4.11 ± 1.36 vs. 6.39 ± 2.99, p = 0.020), no robust clinical profile differentiates between positive and negative antibody groups. Thus, identifying people in schizophrenia who may benefit from a gluten-free diet remains possible by blood test only. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 13 | J Coll Physicians Surg Pak 2014 Mar 24: 198-202 |
| PMID | 24613118 |
| Title | Early psychosis symptoms. |
| Abstract | To determine the prodromal symptoms of schizophrenia in the pathways to help-seeking. A cross-sectional study. The Department of Psychiatry, the AGA Khan University, Karachi, from 2008 to 2009. A total of 93 patients were interviewed in the pathways to care of schizophrenia. The diagnosis was based on ICD-10 criteria. The pathways to care were assessed through a semi-structured questionnaire. The onset, course and symptoms of psychosis were assessed through Interview for Retrospective Assessment at Age at Onset of Psychosis (IROAS). Fifty five (59%) participants were male while 41% (n=38%) were female. Using IROAS, 108 symptoms were identified as concerning behaviour. Alternatively, 60 (55%) concerning behaviours were reported in the open-ended inquiry of the reasons for help seeking as assessed by the pathways to care questionnaire with a statistically significant difference between most symptoms category. The difference was most pronounced (p < 0.001) for depressed mood (66%), worries (65%), tension (63%), withdrawal/mistrust (54%) and loss of self-confidence (53%). Thought withdrawal (22%) and passivity (15%) were elicited only through structured interview (IROAS). When symptoms were categorized together, about 83% of the subjects presented with affective and non-specific prodromal symptoms. Roughly, 10% of the subjects presented with positive symptoms and 3% presented with the negative symptoms of psychosis. The non-specific, affective symptoms appear to predominate the prodromal phase of the illness. Prodromal symptoms of schizophrenia include non-specific, affective symptoms. Attention needs to be paid on identifying the prodromal symptoms and change in social functioning in order to identify those who are at risk of longterm psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic |