| 1 | Psychiatry Res 2000 Feb 93: 13-9 |
|---|---|
| PMID | 10699224 |
| Title | Current antipsychotic dose correlates to mononuclear cell counts in the cerebrospinal fluid of psychotic patients. |
| Abstract | Elevated cerebrospinal fluid (CSF) angiotensin I-converting enzyme (ACE) levels have been evidenced in patients with schizophrenia who have been treated with antipsychotics. In order to explore a possible mononuclear cell origin of CSF ACE, the authors determined CSF ACE and CSF mononuclear cell counts from 25 acutely psychotic patients, who had been drug-free for at least 4 months but started on conventional antipsychotic medication within a few days before sampling. No correlations were found between CSF to serum ACE ratio and CSF mononuclear cell counts. However, CSF total mononuclear cell count, CSF lymphocyte count, and CSF mononuclear phagocyte count evidenced significant positive correlations with current dose of antipsychotic medication expressed as chlorpromazine equivalents. The authors conclude that no indication of a relationship between mononuclear cells and CSF ACE activity was found. Surprisingly, a relationship between chlorpromazine dose and CSF mononuclear cell counts was found, which may indicate drug-related changes in cell-mediated immunity. This finding needs replication and further corroboration in well-designed studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Schizophr. Res. 2000 Jan 41: 335-40 |
| PMID | 10708342 |
| Title | Cerebrospinal fluid angiotensin-converting enzyme (ACE) correlates with length of illness in schizophrenia. |
| Abstract | The aim of the study was to evaluate a possible progression with time of cerebrospinal fluid (CSF) angiotensin-converting enzyme (ACE) levels in treated schizophrenia patients. CSF ACE was determined in duplicate by a sensitive inhibitor-binding assay (IBA) from morning CSF samples of 56 acute and chronic in-patients with schizophrenic psychoses diagnosed according to DSM-IV. CSF ACE correlated significantly with length of schizophrenic psychosis (r=0.39, p=0.003). There was also a positive significant correlation between CSF ACE and duration of current psychotic episode (r=0.39, p=0.003) as well as duration of current hospitalization (r=0.66, p<0.001). These significances were maintained even when patients who were not treated with antipsychotics at the time of sampling were excluded. The correlations also remained significant when controlling for current neuroleptic dose in chlorpromazine equivalents. Serum ACE did not correlate with any clinical variable. No significant correlations between serum or CSF ACE and age, diagnostic subgroup, gender, serum ACE, CSF to serum albumin ratios, or neuroleptic dose in chlorpromazine equivalents were detected. The elevation of CSF ACE seemed to be confined to a subgroup of chronic patients with few positive symptoms. Elevated CSF ACE may reflect an increased solubilization of ACE from cell membranes in the central nervous system or constitute an increased expression of the ACE gene in response to some stimuli. This may be a function of treatment or a result of the deteriorating schizophrenic process. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Schizophr. Res. 2000 Jan 41: 335-40 |
| PMID | 10708342 |
| Title | Cerebrospinal fluid angiotensin-converting enzyme (ACE) correlates with length of illness in schizophrenia. |
| Abstract | The aim of the study was to evaluate a possible progression with time of cerebrospinal fluid (CSF) angiotensin-converting enzyme (ACE) levels in treated schizophrenia patients. CSF ACE was determined in duplicate by a sensitive inhibitor-binding assay (IBA) from morning CSF samples of 56 acute and chronic in-patients with schizophrenic psychoses diagnosed according to DSM-IV. CSF ACE correlated significantly with length of schizophrenic psychosis (r=0.39, p=0.003). There was also a positive significant correlation between CSF ACE and duration of current psychotic episode (r=0.39, p=0.003) as well as duration of current hospitalization (r=0.66, p<0.001). These significances were maintained even when patients who were not treated with antipsychotics at the time of sampling were excluded. The correlations also remained significant when controlling for current neuroleptic dose in chlorpromazine equivalents. Serum ACE did not correlate with any clinical variable. No significant correlations between serum or CSF ACE and age, diagnostic subgroup, gender, serum ACE, CSF to serum albumin ratios, or neuroleptic dose in chlorpromazine equivalents were detected. The elevation of CSF ACE seemed to be confined to a subgroup of chronic patients with few positive symptoms. Elevated CSF ACE may reflect an increased solubilization of ACE from cell membranes in the central nervous system or constitute an increased expression of the ACE gene in response to some stimuli. This may be a function of treatment or a result of the deteriorating schizophrenic process. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Neuropsychobiology 2001 -1 44: 31-5 |
| PMID | 11408790 |
| Title | Association study of angiotensin-converting enzyme gene polymorphism with schizophrenia and polydipsia. |
| Abstract | Angiotensin-converting enzyme (ACE) is a key enzyme in the renin-angiotensin system and can modulate dopamine turnover in the midbrain. Previous studies have revealed changes in the central ACE levels for schizophrenic patients, possibly related to the polydipsia commonly demonstrated for chronic schizophrenia. An insertion (I)/deletion (D) polymorphism of the ACE gene has been associated with ACE levels. Therefore, we elected to investigate the ACE I/D polymorphism for 124 schizophrenic patients and 117 control subjects. No significant differences for the genotype distribution or the allele frequency were revealed comparing controls and schizophrenic patients. The ACE genotypes were not associated with onset age or psychiatric symptoms for the schizophrenic cases. A modest association was revealed for this ACE polymorphism and polydipsia diagnosis for these patients. Using bearers of the D allele as baseline, the ratio for I/I homozygote was 2.31 (95% CI 0.95-5.65). This association needs further replication as it may have implications for the pathogenesis and the treatment of polydipsia for schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Neuropsychobiology 2001 -1 44: 31-5 |
| PMID | 11408790 |
| Title | Association study of angiotensin-converting enzyme gene polymorphism with schizophrenia and polydipsia. |
| Abstract | Angiotensin-converting enzyme (ACE) is a key enzyme in the renin-angiotensin system and can modulate dopamine turnover in the midbrain. Previous studies have revealed changes in the central ACE levels for schizophrenic patients, possibly related to the polydipsia commonly demonstrated for chronic schizophrenia. An insertion (I)/deletion (D) polymorphism of the ACE gene has been associated with ACE levels. Therefore, we elected to investigate the ACE I/D polymorphism for 124 schizophrenic patients and 117 control subjects. No significant differences for the genotype distribution or the allele frequency were revealed comparing controls and schizophrenic patients. The ACE genotypes were not associated with onset age or psychiatric symptoms for the schizophrenic cases. A modest association was revealed for this ACE polymorphism and polydipsia diagnosis for these patients. Using bearers of the D allele as baseline, the ratio for I/I homozygote was 2.31 (95% CI 0.95-5.65). This association needs further replication as it may have implications for the pathogenesis and the treatment of polydipsia for schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Am. J. Med. Genet. 2002 Apr 114: 310-4 |
| PMID | 11920854 |
| Title | Angiotensin converting enzyme gene insertion/deletion polymorphism: case-control association studies in schizophrenia, major affective disorder, and tardive dyskinesia and a family-based association study in schizophrenia. |
| Abstract | Angiotensin converting enzyme (ACE) is a candidate gene for psychiatric disorders. We examined the frequency of a functional insertion/deletion (I/D) polymorphism in the 16th intron of the ACE gene (located on chromosome 17q23) in groups of patients with schizophrenia (n = 104 and 113), major depression (n = 55), and bipolar disorder (n = 87) compared to healthy control subjects (n = 87). There was no evidence for allelic or genotypic association of the polymorphism with any of the disorders or with tardive dyskinesia (TD) in patients with schizophrenia. In a sample of nuclear families (n = 61) made up of one or more patients with schizophrenia recruited with their parents, there was no evidence for biased transmission of ACE I/D alleles. Particularly in the case of schizophrenia, these findings do not support an association of the ACE I/D polymorphism with the phenotypes examined. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Eur Neuropsychopharmacol 2003 May 13: 147-51 |
| PMID | 12729939 |
| Title | Interaction between angiotensin-converting enzyme and catechol-O-methyltransferase genotypes in schizophrenics with poor response to conventional neuroleptics. |
| Abstract | Angiotensin-converting enzyme (ACE) modulates dopamine turnover in the brain and catechol-O-methyltransferase (COMT) enzyme is an important agent in the metabolic inactivation of dopamine and norepinephrine. Functional polymorphism in the COMT and ACE genes causes variation in enzyme activities. We investigated the relationship of COMT and ACE gene polymorphism with response to conventional neuroleptic treatment in schizophrenia. In this study population we had earlier detected that COMT genotype is associated with unsatisfactory drug response. A total of 94 schizophrenic patients were evaluated either as responders (n=43) or non-responders (n=51). The responders had experienced a fair and steady response to conventional neuroleptics. The non-responders had failed to achieve an acceptable response to conventional neuroleptics. We also used a control population of 94 age- and gender-matched blood donors. Genotyping of the COMT and ACE genes was performed by polymerase chain reaction. The risk of having both low activity COMT and high activity ACE genotypes was over 10 times higher (odds ratio=10.89, 95%CI 1.14-103.98, P=0.04) in the non-responders compared to responders. ACE genotype alone did not differ between any groups. This finding may suggest a possible interaction with low activity COMT and high activity ACE genotype in association with poor response to conventional neuroleptics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Eur Neuropsychopharmacol 2003 May 13: 147-51 |
| PMID | 12729939 |
| Title | Interaction between angiotensin-converting enzyme and catechol-O-methyltransferase genotypes in schizophrenics with poor response to conventional neuroleptics. |
| Abstract | Angiotensin-converting enzyme (ACE) modulates dopamine turnover in the brain and catechol-O-methyltransferase (COMT) enzyme is an important agent in the metabolic inactivation of dopamine and norepinephrine. Functional polymorphism in the COMT and ACE genes causes variation in enzyme activities. We investigated the relationship of COMT and ACE gene polymorphism with response to conventional neuroleptic treatment in schizophrenia. In this study population we had earlier detected that COMT genotype is associated with unsatisfactory drug response. A total of 94 schizophrenic patients were evaluated either as responders (n=43) or non-responders (n=51). The responders had experienced a fair and steady response to conventional neuroleptics. The non-responders had failed to achieve an acceptable response to conventional neuroleptics. We also used a control population of 94 age- and gender-matched blood donors. Genotyping of the COMT and ACE genes was performed by polymerase chain reaction. The risk of having both low activity COMT and high activity ACE genotypes was over 10 times higher (odds ratio=10.89, 95%CI 1.14-103.98, P=0.04) in the non-responders compared to responders. ACE genotype alone did not differ between any groups. This finding may suggest a possible interaction with low activity COMT and high activity ACE genotype in association with poor response to conventional neuroleptics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Eur Neuropsychopharmacol 2003 May 13: 147-51 |
| PMID | 12729939 |
| Title | Interaction between angiotensin-converting enzyme and catechol-O-methyltransferase genotypes in schizophrenics with poor response to conventional neuroleptics. |
| Abstract | Angiotensin-converting enzyme (ACE) modulates dopamine turnover in the brain and catechol-O-methyltransferase (COMT) enzyme is an important agent in the metabolic inactivation of dopamine and norepinephrine. Functional polymorphism in the COMT and ACE genes causes variation in enzyme activities. We investigated the relationship of COMT and ACE gene polymorphism with response to conventional neuroleptic treatment in schizophrenia. In this study population we had earlier detected that COMT genotype is associated with unsatisfactory drug response. A total of 94 schizophrenic patients were evaluated either as responders (n=43) or non-responders (n=51). The responders had experienced a fair and steady response to conventional neuroleptics. The non-responders had failed to achieve an acceptable response to conventional neuroleptics. We also used a control population of 94 age- and gender-matched blood donors. Genotyping of the COMT and ACE genes was performed by polymerase chain reaction. The risk of having both low activity COMT and high activity ACE genotypes was over 10 times higher (odds ratio=10.89, 95%CI 1.14-103.98, P=0.04) in the non-responders compared to responders. ACE genotype alone did not differ between any groups. This finding may suggest a possible interaction with low activity COMT and high activity ACE genotype in association with poor response to conventional neuroleptics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 May 119B: 7-12 |
| PMID | 12707930 |
| Title | Genetic approaches to polydipsia in schizophrenia: a preliminary report of a family study and an association study of an angiotensin-converting enzyme gene polymorphism. |
| Abstract | The pathophysiology of polydipsia in patients with schizophrenia is inadequately understood. This study aims to investigate the genetic influence on polydipsia in schizophrenia, and is comprised of a family study and an association study. First, we screened in-patients in 14 psychiatric hospitals and found a total of 36 pairs of a proband and his/her first-degree relative, both of whom were diagnosed with schizophrenia. Among these pairs, a significant familial concordance of polydipsia was found (Fisher's exact test, two-sided, P = 0.0014; odds ratio, 88.20; 95% confidence interval, 7.31-1064.34). These results indicate that genetic factors may underlie the pathophysiology of polydipsia in patients with schizophrenia. Subsequently, we examined the genetic association between polydipsia/water intoxication and the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism in patients with chronic schizophrenia (polydipsics: n = 65; non-polydipsics: n = 97) because several lines of evidence suggested that ACE might be involved in the development of polydipsia in schizophrenia. The D allele of ACE was found to be associated with a non-significant trend toward an increased risk of polydipsia (P = 0.086). Furthermore, a significant allelic association was found between the D allele of ACE and water intoxication (P = 0.0392). This significance remained after the data were adjusted for confounding variables by regression analysis. These results suggest that the ACE D allele may be a risk factor for polydipsia/water intoxication in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | J Assoc Physicians India 2005 May 53: 472-6 |
| PMID | 16124358 |
| Title | Angiotensin-II behaves as an endogenous pro-inflammatory molecule. |
| Abstract | Angiotensin-II regulates vascular tone, stimulates the release of pro-inflammatory cytokines, activates NF-kappaB, increases oxidant stress, and suppresses nitric oxide synthesis, and thus, it functions as an inflammatory molecule. Since ACE is present in many tissues, this suggests that angiotensin-II may play a significant role in atherosclerosis, congestive cardiac failure, stroke, bipolar disorder, schizophrenia, dementia, Alzheimer's disease, psoriasis, atopic and non-atopic dermatitis, eczema, several acute and chronic inflammatory diseases, and cancer, conditions in which inflammation is an aetiopathogenic factor. Thus, ACE inhibitors and/or angiotensin-II receptor blockers could be of benefit in these conditions. Furthermore, structural analogues of ACE inhibitors and angiotensin-II receptor blockers could be developed that possess anti-inflammatory actions without significant action on the cardiovascular system. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Med. Sci. Monit. 2005 May 11: RA155-162 |
| PMID | 15874906 |
| Title | Is angiotensin-II an endogenous pro-inflammatory molecule? |
| Abstract | Angiotensin-II, a product of angiotensin converting enzyme (ACE) action, regulates vascular tone, stimulates the release of pro-inflammatory cytokines, activates NFkappaB, increases oxidant stress, and suppresses nitric oxide synthesis. Thus, angiotensin-II is pro-inflammatory in nature. Hence, increase in ACE activity and the concentrations of angiotensin-II initiate and perpetuate inflammation. Since ACE is present in many tissues including: the uterus, plACEnta, vascular tissue, heart, brain, adrenal cortex and kidney, leukocytes, alveolar macrophages, peripheral monocytes, neuronal cells and epididymal cells, this suggests that angiotensin-II may have a role in atherosclerosis, congestive cardiac failure, stroke, bipolar disorder, schizophrenia, dementia, Alzheimer's disease, psoriasis, atopic and non-atopic dermatitis, eczema, several acute and chronic inflammatory diseases, and cancer, conditions in which inflammation is known to play a significant role. This suggests that ACE inhibitors and/or angiotensin-II receptor blockers could be of significant benefit in the management of these conditions. Alternatively, structural analogues of presently available ACE inhibitors and angiotensin-II receptor blockers could be developed such that they are not only useful in the treatment of hypertension and CHF but also possess anti-inflammatory actions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | Zh Nevrol Psikhiatr Im S S Korsakova 2005 -1 105: 70-3 |
| PMID | 15704489 |
| Title | [Insertion-deletion polymorphism of angiotensin-1-converting enzyme gene in patients with endogenic psychoses]. |
| Abstract | Due to its role in dopamine system functioning in brain, angiotensin-1-converting enzyme (ACE) gene insertion-deletion (I/D) polymorphism is reportedly studied for association with major psychosis. The present study aimed at searching for I/D allele and genotype distribution in patients with major psychosis and healthy subjects and for an association between ACE gene polymorphism and clinical presentations of these disorders. One hundred and ninety-eight patients with schizophrenia (144) and affective disorders (54), 100 male, aged 36.3 +/- 12.8 years, and 247 controls, 87 male, aged 49.6 +/- 13.5 years, have been genotyped. No association was found between ACE gene polymorphism and major psychosis. In the group of males with schizophrenia, genotype distribution differed significantly from that in the male control group (chi2 = 6.24; p = 0.04), with frequencies of the DD genotype and the D allele being higher comparing to the II genotype and the I allele frequency (p = 0.04 and p = 0.01 respectively). It is suggested that in schizophrenia as well as in some other polygenic diseases ACE gene polymorphism might be rather considered as a modifying than a causal factor. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | Biol. Psychiatry 2005 Sep 58: 401-7 |
| PMID | 15978554 |
| Title | Association of an orexin 1 receptor 408Val variant with polydipsia-hyponatremia in schizophrenic subjects. |
| Abstract | Primary polydipsia is a common complication in patients with chronic psychoses, particularly schizophrenia. Disease pathogenesis is poorly understood, but one contributory factor is thought to be dopamine dysregulation caused by prolonged treatment with neuroleptics. Both angiotensin-converting enzyme (ACE) and orexin (hypocretin) signaling can modulate drinking behavior through interactions with the dopaminergic system. We performed association studies on the insertion/deletion (I/D) sequence polymorphism of ACE and single nucleotide polymorphisms within the prepro-orexin (HCRT), orexin receptor 1 (HCRTR1), and orexin receptor 2 (HCRTR2) genes. Genotypes were determined by polymerase chain reaction amplification, followed by either electrophoretic separation or direct sequencing. The ACE I/D polymorphism showed no association with polydipsic schizophrenia. Screening of the orexin signaling system detected a 408 isoleucine to valine mutation in HCRTR1 that showed significant genotypic association with polydipsic-hyponatremic schizophrenia (p = .012). The accumulation of this mutation was most pronounced in polydipsic versus nonpolydipsic schizophrenia (p = .0002 and p = .008, for the respective genotypic and allelic associations). The calcium mobilization properties and the protein localization of mutant HCRTR1 seem to be unaltered. Our preliminary data suggest that mutation carriers might have an increased susceptibility to polydipsia through an undetermined mechanism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | Biol. Psychiatry 2005 Sep 58: 401-7 |
| PMID | 15978554 |
| Title | Association of an orexin 1 receptor 408Val variant with polydipsia-hyponatremia in schizophrenic subjects. |
| Abstract | Primary polydipsia is a common complication in patients with chronic psychoses, particularly schizophrenia. Disease pathogenesis is poorly understood, but one contributory factor is thought to be dopamine dysregulation caused by prolonged treatment with neuroleptics. Both angiotensin-converting enzyme (ACE) and orexin (hypocretin) signaling can modulate drinking behavior through interactions with the dopaminergic system. We performed association studies on the insertion/deletion (I/D) sequence polymorphism of ACE and single nucleotide polymorphisms within the prepro-orexin (HCRT), orexin receptor 1 (HCRTR1), and orexin receptor 2 (HCRTR2) genes. Genotypes were determined by polymerase chain reaction amplification, followed by either electrophoretic separation or direct sequencing. The ACE I/D polymorphism showed no association with polydipsic schizophrenia. Screening of the orexin signaling system detected a 408 isoleucine to valine mutation in HCRTR1 that showed significant genotypic association with polydipsic-hyponatremic schizophrenia (p = .012). The accumulation of this mutation was most pronounced in polydipsic versus nonpolydipsic schizophrenia (p = .0002 and p = .008, for the respective genotypic and allelic associations). The calcium mobilization properties and the protein localization of mutant HCRTR1 seem to be unaltered. Our preliminary data suggest that mutation carriers might have an increased susceptibility to polydipsia through an undetermined mechanism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Med. Hypotheses 2008 -1 70: 430-4 |
| PMID | 17624683 |
| Title | Do polyunsaturated fatty acids behave like an endogenous "polypill"? |
| Abstract | Lowering plasma low density lipoprotein-cholesterol (LDL-C), blood pressure, homocysteine, and preventing platelet aggregation using a combination of a statin, three blood pressure lowering drugs such as a thiazide, a beta blocker, and an angiotensin converting enzyme (ACE) inhibitor each at half standard dose; folic acid; and aspirin - called as polypill - was estimated to reduce cardiovascular events by approximately 80%. Essential fatty acids (EFAs) and their long-chain metabolites and other products prevent platelet aggregation, lower blood pressure, reduce LDL-C, and ameliorate the adverse actions of homocysteine. Thus, EFAs and their metabolites show all the actions expected of the "polypill". Unlike the proposed "polypill", EFAs are endogenous molecules, have no significant side effects, can be taken orally for long periods of time even by pregnant women, lactating mothers, and children; and have been shown to reduce the incidence cardiovascular diseases. I propose that a rational combination of omega-3 and omega-6 fatty acids is as beneficial as that of the "polypill"; and may even show additional benefit in the prevention of depression, schizophrenia, Alzheimer's disease, and enhance cognitive function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | Lipids Health Dis 2008 -1 7: 37 |
| PMID | 18922179 |
| Title | Essential fatty acids and their metabolites could function as endogenous HMG-CoA reductase and ACE enzyme inhibitors, anti-arrhythmic, anti-hypertensive, anti-atherosclerotic, anti-inflammatory, cytoprotective, and cardioprotective molecules. |
| Abstract | Lowering plasma low density lipoprotein-cholesterol (LDL-C), blood pressure, homocysteine, and preventing platelet aggregation using a combination of a statin, three blood pressure lowering drugs such as a thiazide, a beta blocker, and an angiotensin converting enzyme (ACE) inhibitor each at half standard dose; folic acid; and aspirin-called as polypill- was estimated to reduce cardiovascular events by approximately 80%. Essential fatty acids (EFAs) and their long-chain metabolites: gamma-linolenic acid (GLA), dihomo-GLA (DGLA), arachidonic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) and other products such as prostaglandins E1 (PGE1), prostacyclin (PGI2), PGI3, lipoxins (LXs), resolvins, protectins including neuroprotectin D1 (NPD1) prevent platelet aggregation, lower blood pressure, have anti-arrhythmic action, reduce LDL-C, ameliorate the adverse actions of homocysteine, show anti-inflammatory actions, activate telomerase, and have cytoprotective properties. Thus, EFAs and their metabolites show all the classic actions expected of the "polypill". Unlike the proposed "polypill", EFAs are endogenous molecules present in almost all tissues, have no significant or few side effects, can be taken orally for long periods of time even by pregnant women, lactating mothers, and infants, children, and adults; and have been known to reduce the incidence cardiovascular diseases including stroke. In addition, various EFAs and their long-chain metabolites not only enhance nitric oxide generation but also react with nitric oxide to yield their respective nitroalkene derivatives that produce vascular relaxation, inhibit neutrophil degranulation and superoxide formation, inhibit platelet activation, and possess PPAR-gamma ligand activity and release NO, thus prevent platelet aggregation, thrombus formation, atherosclerosis, and cardiovascular diseases. Based on these evidences, I propose that a rational combination of omega-3 and omega-6 fatty acids and the co-factors that are necessary for their appropriate action/metabolism is as beneficial as that of the combined use of a statin, thiazide, a beta blocker, and an angiotensin converting enzyme (ACE) inhibitor, folic acid, and aspirin. Furthermore, appropriate combination of omega-3 and omega-6 fatty acids may even show additional benefits in the form of protection from depression, schizophrenia, Alzheimer's disease, and enhances cognitive function; and serve as endogenous anti-inflammatory molecules; and could be administered from childhood for life long. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | Epilepsia 2008 Aug 49: 1348-57 |
| PMID | 18363708 |
| Title | The renin-angiotensin system is upregulated in the cortex and hippocampus of patients with temporal lobe epilepsy related to mesial temporal sclerosis. |
| Abstract | As reported by several authors, angiotensin II (AngII) is a proinflammatory molecule that stimulates the release of inflammatory cytokines and activates nuclear factor kappaB (NFkappaB), being also associated with the increase of cellular oxidative stress. Its production depends on the activity of the angiotensin converting enzyme (ACE) that hydrolyzes the inactive precursor angiotensin I (AngI) into AngII. It has been suggested that AngII underlies the physiopathological mechanisms of several brain disorders such as stroke, bipolar disorder, schizophrenia, and disease. The aim of the present work was to localize and quantify AngII AT1 and AT2 receptors in the cortex and hippocampus of patients with temporal lobe epilepsy related to mesial temporal sclerosis (MTS) submitted to corticoamygdalohippocampectomy for seizure control. Immunohistochemistry, Western blot, and real-time PCR techniques were employed to analyze the expression of these receptors. The results showed an upregulation of AngII AT1 receptor as well as its messenger ribonucleic acid (mRNA) expression in the cortex and hippocampus of patients with MTS. In addition, an increased immunoexpression of AngII AT2 receptors was found only in the hippocampus of these patients with no changes in its mRNA levels. These data show, for the first time, changes in components of renin-angiotensin system (RAS) that could be implicated in the physiopathology of MTS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | Neuropharmacology 2008 Feb 54: 399-404 |
| PMID | 18037452 |
| Title | Does angiotensin interact with dopaminergic mechanisms in the brain to modulate prepulse inhibition in mice? |
| Abstract | Changes in the levels of angiotensin-converting enzyme (ACE) have been found in brains of schizophrenia patients, suggesting a possible involvement of angiotensin in the illness. Prepulse inhibition (PPI) is a measure of sensorimotor gating and is disrupted in patients with schizophrenia. In a previous study, a reduction of ACE activity, either in ACE knockout mice or after ACE inhibitor treatment, markedly inhibited the disruption of PPI caused by the dopamine receptor agonist, apomorphine. ACE is not specific for the angiotensin system and, therefore, in the present study we assessed pharmacological regulation of PPI in two other, more specific genetic mouse models of altered angiotensin activity. We used renin-enhancer knockout (REKO) mice, which display reduced renin activity, and neuron-specific enolase (NSE)-AT1A mice, which selectively over-express angiotensin AT1A receptors in the brain. Treatment of these mice with apomorphine, the dopamine releaser, amphetamine or the NMDA receptor antagonist, MK-801, significantly disrupted PPI. There was, however, no difference in these effects between the genotypes. These data suggest that genetically induced changes in the activity of the angiotensin system do not alter regulation of PPI in mice. Our previous results on the effects of reduced ACE activity could be explained by mechanisms other than angiotensin, such as effects on enkephalin or bradykinin metabolism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 20 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2009 Aug 33: 1064-9 |
| PMID | 19508883 |
| Title | ARVCF single marker and haplotypic association with schizophrenia. |
| Abstract | We present a schizophrenia association study using an extensive linkage disequilibrium (LD) mapping approach in seven candidate genes with a well established link to dopamine, including receptors (DRD2, DRD3) and genes involved in its metabolism and transport (ACE, COMT, DAT, MAO-A, MAO-B). The sample included 242 subjects diagnosed with schizophrenia and related disorders and 373 hospital-based controls. 84 tag SNPs in candidate genes were genotyped. After extensive data cleaning 70 SNPs were analyzed for association of single markers and haplotypes. One block of four SNPs (rs165849, rs2518823, rs887199 and rs2239395) in the 3' downstream region of the COMT gene which included a non-dopaminergic candidate gene, the ARVCF (Armadillo like VeloCardio Facial) gene, was associated with the risk of schizophrenia. The genetic region including the ARVCF gene in the 22q11.21 chromosome is associated with schizophrenia in a Spanish series. Our results will assist in the interpretation of the controversy generated by genetic associations of COMT and schizophrenia, which could be the result of different LD patterns between COMT markers and the 3' region of the ARVCF gene. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 21 | Psychiatry Res 2009 Jan 165: 175-80 |
| PMID | 18986708 |
| Title | Insertion/deletion polymorphism of the angiotensin-converting enzyme gene is associated with schizophrenia in a Spanish population. |
| Abstract | A number of factors make the angiotensin-converting enzyme (ACE) a candidate gene for psychiatric disorders, including its action on neurotransmitters such as dopamine. An insertion/deletion (I/D) polymorphism in an ACE gene intron is associated with ACE levels. Here we examine whether the ACE I/D polymorphism is a risk factor for schizophrenia. Participants comprised 243 subjects diagnosed with schizophrenia and related disorders, and 291 hospital-based controls. The D allele of the ACE gene was identified as a protective factor, significantly reducing the risk of developing schizophrenia and related disorders (by 40%) and of developing schizophrenia (by 50%). This protection is explained by the additive genotype risk model, in which the protection increases with the number of D alleles. Our results indicate that the ACE D allele is involved in the development of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 22 | Int J Mol Epidemiol Genet 2010 -1 1: 145-57 |
| PMID | 21537387 |
| Title | Implications of the angiotensin converting enzyme gene insertion/deletion polymorphism in health and disease: a snapshot review. |
| Abstract | This review considers the 250+ papers concerning the association of the angiotensin converting enzyme (ACE) gene insertion/deletion polymorphism (rs1799752) and various disease conditions published in 2009. The deletion allele occurs in approximately 55% of the population and is associated with increased activity of the ACE enzyme. It might be predicted that the D allele, therefore, might be associated with pathologies involving increased activity of the renin-angiotensin system. The D allele was seen to be associated with an increased risk of hypertension, pre-eclampsia, heart failure, cerebral infarct, diabetic nephropathy, encephalopathy, asthma, severe hypoglycaemia in diabetes, gastric cancer (in Caucasians) and poor prognosis following kidney transplant. On the positive side, the D allele appears to offer protection against schizophrenia and chronic periodontitis and confers greater up-per-body strength in old age. The I allele, meanwhile, offers improved endurance/athletic performance and aerobic capacity as determined by lung function tests, although it does increase the risk of oral squamous cell carcinoma and obstructive sleep apnoea in hypertensives. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 23 | Genet Test Mol Biomarkers 2010 Dec 14: 753-7 |
| PMID | 21158679 |
| Title | Investigation of association between Angiotensin-converting enzyme gene insertion/deletion polymorphism frequency in Turkish patients with schizophrenia. |
| Abstract | the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene is of increasing interest in etiology and treatment of various neuropsychiatric disorders. The present study aimed at detecting the incidence of ACE gene I/D polymorphism in patients with schizophrenia living in the Eskisehir region (Turkey) and also at determining whether this illness could be associated to ACE gene I/D polymorphism and serum ACE concentrations. in our study, genomic DNA was studied in a total of 237 individuals, 132 of them having been diagnosed as patients with schizophrenia and 105 of them being used as control subjects. In addition, sera from 31 patients with schizophrenia and 26 healthy subjects were used to compare serum ACE concentrations. By using polymerase chain reaction, we determined the frequency of ACE gene I/D polymorphism and measured the serum ACE concentrations by ELISA. distribution of ACE gene I/D polymorphism and allele frequencies between the control group genotype proportions (II 19%, ID 44%, DD 37%) and the patient group (II 19%, ID 45%, DD 36%) were not significantly different. Serum ACE concentrations were 293.15 ± 23.29 ng/mL in the control group and 362.61 ± 19.96 ng/mL in the patients. It was observed that serum ACE concentrations significantly increased in patients with schizophrenia compared with those of the control group (p < 0.05). However, no significant difference could be observed according to genotypes in serum ACE concentration. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 24 | Psychiatr. Genet. 2010 Feb 20: 14-9 |
| PMID | 20010451 |
| Title | Angiotensin-converting enzyme polymorphism in schizophrenia, bipolar disorders, and their first-degree relatives. |
| Abstract | Family, twin and adoption studies have provided major evidence for the role of genetics in numerous psychiatric disorders including schizophrenia (SZ) and bipolar disorders (BDs). As SZ and BD have some susceptibility genes in common and since unaffected first-degree relatives of these patients carry a high likelihood of these susceptibility genes, we aimed to elucidate the role of angiotensin-converting enzyme (ACE) genetic variants in patients with SZ, BD and their first-degree relatives. The study sample comprised 239 patients with SZ, 184 patients with BD, 284 unaffected first-degree biological relatives of patients with SZ and 301 unaffected first-degree biological relatives of patients with BD and 210 healthy controls. The ACE genotypes were determined by polymerase chain reaction. ACE insertion/deletion polymorphism was associated with SZ and BD. DD genotype and D allele distributions in bipolar patients and their first-degree relatives were significantly higher than those of SZ patients, their relatives, and controls. In contrast, II genotype and I allele were reduced in both the patient groups and their relatives as compared with controls. In this study, the D allele might be responsible for clustering of psychotic symptoms and results in the psychotic manifestations of BD, whereas I allele seems to be protective against development of SZ and BD. SZ and BD characterized by similar or different gene variant in ACE could be a useful marker for these psychiatric disorders, if this polymorphism is replicated in the future studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 25 | Cochrane Database Syst Rev 2011 -1 -1: CD004718 |
| PMID | 21678345 |
| Title | Early intervention for psychosis. |
| Abstract | Proponents of early intervention have argued that outcomes might be improved if more therapeutic efforts were focused on the early stages of schizophrenia or on people with prodromal symptoms. Early intervention in schizophrenia has two elements that are distinct from standard care: early detection, and phase-specific treatment (phase-specific treatment is a psychological, social or physical treatment developed, or modified, specifically for use with people at an early stage of the illness).Early detection and phase-specific treatment may both be offered as supplements to standard care, or may be provided through a specialised early intervention team. Early intervention is now well established as a therapeutic approach in America, Europe and Australasia. To evaluate the effects of: (a) early detection; (b) phase-specific treatments; and (c) specialised early intervention teams in the treatment of people with prodromal symptoms or first-episode psychosis. We searched the Cochrane schizophrenia Group Trials Register (March 2009), inspected reference lists of all identified trials and reviews and contacted experts in the field. We included all randomised controlled trials (RCTs) designed to prevent progression to psychosis in people showing prodromal symptoms, or to improve outcome for people with first-episode psychosis. Eligible interventions, alone and in combination, included: early detection, phase-specific treatments, and care from specialised early intervention teams. We accepted cluster-randomised trials but excluded non-randomised trials. We reliably selected studies, quality rated them and extracted data. For dichotomous data, we estimated relative risks (RR), with the 95% confidence intervals (CI). Where possible, we calculated the number needed to treat/harm statistic (NNT/H) and used intention-to-treat analysis (ITT). Studies were diverse, mostly small, undertaken by pioneering researchers and with many methodological limitations (18 RCTs, total n=1808). Mostly, meta-analyses were inappropriate. For the six studies addressing prevention of psychosis for people with prodromal symptoms, olanzapine seemed of little benefit (n=60, 1 RCT, RR conversion to psychosis 0.58 CI 0.3 to 1.2), and cognitive behavioural therapy (CBT) equally so (n=60, 1 RCT, RR conversion to psychosis 0.50 CI 0.2 to 1.7). A risperidone plus CBT plus specialised team did have benefit over specialist team alone at six months (n=59, 1 RCT, RR conversion to psychosis 0.27 CI 0.1 to 0.9, NNT 4 CI 2 to 20), but this was not seen by 12 months (n=59, 1 RCT, RR 0.54 CI 0.2 to 1.3). Omega 3 fatty acids (EPA) had advantage over plACEbo (n=76, 1 RCT, RR transition to psychosis 0.13 CI 0.02 to 1.0, NNT 6 CI 5 to 96). We know of no replications of this finding.The remaining trials aimed to improve outcome in first-episode psychosis. Phase-specific CBT for suicidality seemed to have little effect, but the single study was small (n=56, 1 RCT, RR suicide 0.81 CI 0.05 to 12.26). Family therapy plus a specialised team in the Netherlands did not clearly affect relapse (n=76, RR 1.05 CI 0.4 to 3.0), but without the specialised team in China it may (n=83, 1 RCT, RR admitted to hospital 0.28 CI 0.1 to 0.6, NNT 3 CI 2 to 6). The largest and highest quality study compared specialised team with standard care. Leaving the study early was reduced (n=547, 1 RCT, RR 0.59 CI 0.4 to 0.8, NNT 9 CI 6 to 18) and compliance with treatment improved (n=507, RR stopped treatment 0.20 CI 0.1 to 0.4, NNT 9 CI 8 to 12). The mean number of days spent in hospital at one year were not significantly different (n=507, WMD, -1.39 CI -2.8 to 0.1), neither were data for 'Not hospitalised' by five years (n=547, RR 1.05 CI 0.90 to 1.2). There were no significant differences in numbers 'not living independently' by one year (n=507, RR 0.55 CI 0.3 to 1.2). At five years significantly fewer participants in the treatment group were 'not living independently' (n=547, RR 0.42 CI 0.21 to 0.8, NNT 19 CI 14 to 62). When phase-specific treatment (CBT) was compared with befriending no significant differences emerged in the number of participants being hospitalised over the 12 months (n=62, 1 RCT, RR 1.08 CI 0.59 to 1.99).Phase-specific treatment E-EPA oils suggested no benefit (n=80, 1 RCT, RR no response 0.90 CI 0.6 to 1.4) as did phase-specific treatment brief intervention (n=106, 1 RCT, RR admission 0.86 CI 0.4 to 1.7). Phase-specific ACE found no benefit but participants given vocational intervention were more likely to be employed (n=41, 1 RCT, RR 0.39 CI 0.21 to 0.7, NNT 2 CI 2 to 4). Phase-specific cannabis and psychosis therapy did not show benefit (n=47, RR cannabis use 1.30 CI 0.8 to 2.2) and crisis assessment did not reduce hospitalisation (n=98, RR 0.85 CI 0.6 to 1.3). Weight was unaffected by early behavioural intervention. There is emerging, but as yet inconclusive evidence, to suggest that people in the prodrome of psychosis can be helped by some interventions. There is some support for specialised early intervention services, but further trials would be desirable, and there is a question of whether gains are maintained. There is some support for phase-specific treatment focused on employment and family therapy, but again, this needs replicating with larger and longer trials. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 26 | Br J Psychiatry 2012 Dec 201: 435-43 |
| PMID | 23209089 |
| Title | Differences in the prescribing of medication for physical disorders in individuals with v. without mental illness: meta-analysis. |
| Abstract | There is some concern that patients with mental illness may be in receipt of inferior medical care, including prescribed medication for medical conditions. We aimed to quantify possible differences in the prescription of medication for medical conditions in those with v. without mental illness. Systematic review and random effects meta-analysis with a minimum of three independent studies to warrant pooling by drug class. We found 61 comparative analyses (from 23 publications) relating to the prescription of 12 classes of medication for cardiovascular health, diabetes, cancer, arthritis, osteoporosis and HIV in a total sample of 1 931 509 people. In those with severe mental illness the adjusted odds ratio (OR) for an equitable prescription was 0.74 (95% CI 0.63-0.86), with lower than expected prescriptions for angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (ACE/ARBs), beta-blockers and statins. People with affective disorder had an odds ratio of 0.75 (95% CI 0.55-1.02) but this was not significant. Individuals with a history of other (miscellaneous) mental illness had an odds ratio of 0.95 (95% CI 0.92-0.98) of comparable medication with lower receipt of ACE/ARBs but not highly active antiretroviral therapy (HAART) medication. Results were significant in both adjusted and unadjusted analyses. Individuals with severe mental illness (including schizophrenia) appear to be prescribed significantly lower quantities of several common medications for medical disorders, largely for cardiovascular indications, although further work is required to clarify to what extent this is because of prescriber intent. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 27 | Isr. Med. Assoc. J. 2012 Aug 14: 470-4 |
| PMID | 22977964 |
| Title | Evaluation of the capacity of inpatients with chronic schizophrenia to provide informed consent for participation in clinical trials; use of the Hebrew version of the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR). |
| Abstract | Patient protection requires the provision of informed consent for participation in medical research. The MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) is frequently used for screening the capacity of research subjects to consent to participate in research. To evaluate the utility of the Hebrew translation of the MacCAT-CR for assessing the capacity of patients with chronic schizophrenia to provide informed consent to participate in clinical trials. We evaluated the translated MacCAT-CR by comparingthe capacity of patients with chronic schizophrenia to provide informed consent to participate in clinical trials. The following standardized neurocognitive assessment tools were used: Addenbrooke's Cognitive Examination (ACE) and Frontal Assessment Battery (FAB), as well as the attending doctor's assessment. Twenty-one patients participated. Mean MacCAT-CR score was 12 +/- 10.57 (range 0-32), mean FAB score 9.9 +/- 4.77 (range 1-18), mean ACE 59.14 +/- 16.6 (range 27-86) and mean doctor's assessment 5.24 +/- 1.18 (range 3-7). The Hebrew version of the MacCAT-CR helped identify patients with the capacity to provide informed consent for participation in research. Patients with FAB scores > or = 12 tended to score higher on the Hebrew version of the MacCAT-CR, thus confirming the utility of the Hebrew version of the MacCAT-CR. During the screening process for clinical trials it may be practical to administer the concise FAB questionnaire, and then administer the MacCAT-CR only to those who scored > or = 12 on the FAB. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 28 | Coll Antropol 2014 Dec 38: 1175-7 |
| PMID | 25842752 |
| Title | Virus etiology of schizophrenia: the characteristics of the "*Little Ice Age" and its consequences. |
| Abstract | The data of the "Little Ice Age" (1500-1850) in Croatia and those which applied to human health were especially emphasized were analyzed. They are some which stand out like: importance of the sort of soil and relief, the influence of cutting down of woods and cattle-breeding and especially the war which lasted for 250 years in the territory of Croatia. The important interactions between those parameters were defined. The important correlations were also defined between freezing and long winters as well as wet springs and summers which caused starvation, malnutrition and the increase of infant mortality and also epidemics with enormous psychological stress among people in that period. The result was witch-hunting and burning (which was also advocated in the other parts of Europe) and they sometimes reached the levels of madness. Considering that such events were unknown in the earlier periods (in such proportions) and that (even today) the influence of the slow virus is emphasized in connection to the etiology of schizophrenia so why should't it be supposed that the "Litlle ACE Age" could be the cause of the larger prevalence of schizophrenia in the teritory of Croatia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 29 | Schizophr Bull 2014 Sep 40: 963-72 |
| PMID | 24743863 |
| Title | Inflammatory molecular signature associated with infectious agents in psychosis. |
| Abstract | schizophrenia (SZ) is a devastating mental condition with onset in young adulthood. The identification of molecular biomarkers that reflect illness pathology is crucial. Recent evidence suggested immune and inflammatory cascades in conjunction with infection may play a role in the pathology. To address this question, we investigated molecular changes in cerebrospinal fluid (CSF) from antipsychotic-naïve patients with SZ and at risk mental status for psychosis (ARMS), in comparison with healthy controls (HCs). We measured 90 analytes using a broad multiplex platform focusing on immune and inflammatory cascades then selected 35 with our quality reporting criteria for further analysis. We also examined Toxoplasma gondii (TG) and herpes simplex virus 1 antibody levels in CSF. We report that expression of 15 molecules was significantly altered in the patient groups (SZ and ARMS) compared with HCs. The majority of these molecular changes (alpha-2-macroglobulin [?2M], fibrinogen, interleukin-6 receptor [IL-6R], stem cell factor [SCF], transforming growth factor alpha [TGF?], tumor necrosis factor receptor 2 [TNFR2], IL-8, monocyte chemotactic protein 2 [MCP-2/CCL8], testosterone [for males], angiotensin converting enzyme [ACE], and epidermal growth factor receptor) were consistent between SZ and ARMS patients, suggesting these may represent trait changes associated with psychotic conditions in general. Interestingly, many of these analytes (?2M, fibrinogen, IL-6R, SCF, TGF?, TNFR2, IL-8, MCP-2/CCL8, and testosterone [for males]) were exACErbated in subjects with ARMS compared with subjects with SZ. Although further studies are needed, we optimistically propose that these molecules may be good candidates for predictive markers for psychosis from an early stage. Lastly, reduction of IL-6R, TGF?, and ACE was correlated with positivity of TG antibody in the CSF, suggesting possible involvement of TG infection in the pathology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 30 | Hum Psychopharmacol 2014 May 29: 274-9 |
| PMID | 24615782 |
| Title | Association between the angiotensin-converting enzyme gene insertion/deletion polymorphism and first-episode patients with schizophrenia in a Chinese Han population. |
| Abstract | Angiotensin-converting enzyme (ACE), a key enzyme of the renin-angiotensin system, can modulate dopamine turnover in the midbrain. Previous studies have revealed an association between ACE gene insertion/deletion (I/D) polymorphism and chronic schizophrenia, yet results are conflicting. The primary objective of this study was to examine whether the ACE gene I/D polymorphism is associated with first-episode patients with schizophrenia (FEP) in a Chinese Han population. The presence of the polymorphism was determined in 220 FEP and 538 healthy controls using a case-control design. We assessed the psychopathology in 212 FEP using the Positive and Negative Syndrome Scale (PANSS). The allelic and genotypic frequencies of the ACE gene I/D polymorphism did not significantly differ between FEP and healthy controls (both p>0.05). However, the negative PANSS symptom was significantly higher in FEP with the D/D genotype than those with I/D and I/I genotypes (all p<0.05) even after Bonferroni corrections (all p<0.05). Furthermore, the D allele of the ACE gene was associated with higher negative PANSS symptom score in FEP. Our results indicated that even though the ACE gene I/D polymorphism did not associate with FEP, it may play a role in susceptibility to the negative PANSS symptom of FEP in a Chinese Han population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 31 | Psychiatry Res 2015 Oct 229: 702-7 |
| PMID | 26296754 |
| Title | Angiotensin converting enzyme activity is positively associated with IL-17a levels in patients with schizophrenia. |
| Abstract | Previous studies of our group showed increased plasmatic Angiotensin-I Converting Enzyme (ACE) activity in schizophrenia (SCZ) patients compared to healthy controls, which was also associated to poor cognitive functioning. The ACE main product angiotensin II (Ang-II) has pro-inflammatory properties. Activated immune-inflammatory responses in SCZ and their association with disease progression and cognitive impairments are also well-described. Therefore, we examined here the association of plasma ACE activity and inflammatory mediators in 33 SCZ patients and 92 healthy controls. Non-parametric correlations were used to investigate the association of the enzyme activity and the peripheral levels of immune inflammatory markers as interleukins, tumor necrosis factor (TNF-?), and interferon (IFN-?). Although no significant correlations could be observed for ACE activity and measured cytokines levels in healthy controls, a significant positive correlation for ACE enzymatic activity and IL-17a levels was observed in SCZ patients. Correcting for gender did not change these results. Moreover, a significant association for ACE activity and IFN-? levels was also observed. To our knowledge, this is the first study to show a significant association between higher ACE activity and the levels of cytokines, namely IL-17a and IFN-?, in patients with SCZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 32 | Psychiatry Res 2015 May 227: 71-2 |
| PMID | 25817701 |
| Title | The impact of ACE gene I/D polymorphism on plasma glucose and lipid concentrations in schizophrenia patients. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 33 | J Psychiatr Res 2015 Jan 60: 1-13 |
| PMID | 25287955 |
| Title | Specific and common genes implicated across major mental disorders: a review of meta-analysis studies. |
| Abstract | Major efforts have been directed at family-based association and case-control studies to identify the involvement of candidate genes in the major disorders of mental health. What remains unknown is whether candidate genes are associated with multiple disorders via pleiotropic mechanisms, and/or if other genes are specific to susceptibility for individual disorders. Here we undertook a review of genes that have been identified in prior meta-analyses examining specific genes and specific mental disorders that have core disruptions to emotional and cognitive function and contribute most to burden of illness- major depressive disorder (MDD), anxiety disorders (AD, including panic disorder and obsessive compulsive disorder), schizophrenia (SZ) and bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD). A literature review was conducted up to end-March 2013 which included a total of 1519 meta-analyses across 157 studies reporting multiple genes implicated in one or more of the five disorders studied. A total of 134 genes (206 variants) were identified as significantly associated risk variants for MDD, AD, ADHD, SZ or BD. Null genetic effects were also reported for 195 genes (426 variants). 13 genetic variants were shared in common between two or more disorders (APOE e4, ACE Ins/Del, BDNF Val66Met, COMT Val158Met, DAOA G72/G30 rs3918342, DAT1 40-bp, DRD4 48-bp, SLC6A4 5-HTTLPR, HTR1A C1019G, MTHR C677T, MTHR A1298C, SLC6A4 VNTR and TPH1 218A/C) demonstrating evidence for pleiotrophy. Another 12 meta-analyses of GWAS studies of the same disorders were identified, with no overlap in genetic variants reported. This review highlights the progress that is being made in identifying shared and unique genetic mechanisms that contribute to the risk of developing several major psychiatric disorders, and identifies further steps for progress. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 34 | J Renin Angiotensin Aldosterone Syst 2015 Jun 16: 434-42 |
| PMID | 25143327 |
| Title | The insertion/deletion polymorphism in the angiotensin-converting enzyme and susceptibility to schizophrenia or Parkinson's disease: A meta-analysis. |
| Abstract | The purpose of this study was to examine whether the insertion (I) and deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) confers susceptibility to schizophrenia and Parkinson's disease (PD). A meta-analysis was performed of the associations between the ACE I/D polymorphism and schizophrenia and PD. Thirteen studies with 2024 cases and 2230 controls comprising eight studies on schizophrenia and five on PD were included in the meta-analysis. The meta-analysis revealed no association between the ACE D allele and schizophrenia (OR = 0.990, 95% CI = 0.889-1.102, p = 0.856) or PD (OR = 1.067, 95% CI = 0.907-1.255, p = 0.433). Stratification by ethnicity indicated no association between the ACE D allele and schizophrenia in European, Asian, or Turkish ethnic groups (OR = 0.896, 95% CI = 0.566-1.419, p = 0.640; OR = 1.057, 95% CI = 0.903-1.238, p = 0.492; OR = 1.111, 95% CI = 0.889-1.389, p = 0.354, respectively). Ethnicity-specific meta-analysis was not conducted for PD because only one ethnic PD study was available. This meta-analysis found no association between the ACE I/D polymorphism and schizophrenia or PD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 35 | Transl Psychiatry 2015 -1 5: e691 |
| PMID | 26645626 |
| Title | Convergent evidences from human and animal studies implicate angiotensin I-converting enzyme activity in cognitive performance in schizophrenia. |
| Abstract | In schizophrenia (SCZ), higher angiotensin I-converting enzyme (ACE) levels have been reported in patient's blood and cerebrospinal fluid (CSF). Hereby, we propose to explore whether the ACE activity levels are associated to cognitive performance in SCZ. Seventy-two patients with SCZ or schizoaffective disorder diagnosis, and 69 healthy controls (HCs) underwent a cognitive battery with parallel collection of peripheral blood samples to measure ACE activity. Significant higher ACE activity levels were confirmed in the plasma of SCZ patients compared with HCs (Student's t=-5.216; P<0.001). ACE activity significantly correlated to Hopkins delayed recall measures (r=-0.247; P=0.004) and Hopkins total (r=-0.214; P=0.012). Subjects grouped as high ACE activity (above average) had worse performance compared with low ACE activity level group for Hopkins delayed recall measure, even after correction for clinical condition, age, gender and years of education (P=0.029). The adjusted R squared for this final model was 0.343. This result was evident only comparing extreme groups for ACE activity, when splitting the sample in three groups with similar number of subjects. To clarify this finding, we performed an evaluation of the cognitive performance of transgenic mice with three copies of ACE gene in novel object recognition (NOR) test, which showed that such animals presented impairment in NOR (P<0.05) compared with two copies of wild-type animals. The results observed in SCZ patients and animal model suggest both the association of ACE to cognitive deficits in SCZ. This finding may support the evaluation of novel treatment protocols and/or of innovative drugs for specific intervention of cognitive deficits in SCZ envisioning concomitant ACE activity and behavior evaluations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 36 | Psychiatry Res 2015 Oct 234: 35-43 |
| PMID | 26341951 |
| Title | Adverse childhood experiences influence white matter microstructure in patients with schizophrenia. |
| Abstract | Integrity of brain white matter (WM) tracts in adulthood could be detrimentally affected by exposure to adverse childhood experiences (ACE). Changes of diffusion tensor imaging (DTI) measures suggesting WM disruption have been reported in patients with schizophrenia together with a history of childhood maltreatment. We therefore hypothesized that ACE could be associated with altered DTI measures of WM integrity in patients with schizophrenia. We tested this hypothesis in 83 schizophrenia patients using whole brain tract-based spatial statistics in the WM skeleton with threshold-free cluster enhancement of DTI measures of WM microstructure: axial, radial, and mean diffusivity (MD), and fractional anisotropy (FA). We observed an inverse correlation between severity of ACE and DTI measures of FA, and a positive correlation with MD in several WM tracts including corona radiata, thalamic radiations, corpus callosum, cingulum bundle, superior longitudinal fasciculus, inferior fronto-occipital fasciculus, uncinate fasciculus. Lower FA and higher MD are indexes of a reduction in fibre coherence and integrity. The association of ACE to reduced FA and increased MD in key WM tracts contributing to the functional integrity of the brain suggests that ACE might contribute to the pathophysiology of schizophrenia through a detrimental action on structural connectivity in critical cortico-limbic networks. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 37 | Iran. J. Public Health 2015 Mar 44: 369-73 |
| PMID | 25905080 |
| Title | Association between Insertion/Deletion Polymorphism in Angiotension Converting Enzyme and Susceptibility to Schizophrenia. |
| Abstract | The activity of angiotension converting enzyme (ACE; OMIM: 106180) in different brain regions of patients with schizophrenia changed, suggesting a possible involvement of ACE in psychiatric disorders. Genetic polymorphism of insertion/deletion (I/D; dbSNP rs4646994) in the gene encoding ACE has been well defined. The present case-control study was performed on 363 (268 males, 95 females) in-patients with schizophrenia diagnosis, and 363 (268 males, 95 females) healthy blood donor controls. The genotypes of I/D ACE polymorphism were determined using PCR method. PCR products were separated and sized by electrophoresis on a 2% agarose gel. The insertion allele (I) was detected as a 478 bp band, and the deletion allele (D) was visualized as a 191 bp band. The association between genotypes of the I/D polymorphism and the schizophrenia risk was examined by use of odds ratios (OR) and 95% of confidence intervals (CIs). Among females, the II genotype significantly decreased the risk of schizophrenia compared with the DD genotype (OR=0.18, 95%CI: 0.04-0.72, P=0.015). There was significant linear trend for the number of the I allele and schizophrenia risk among females (Chi(2)=5.19, P=0.023). There was no significant association between I/D polymorphism and susceptibility to schizophrenia among male subjects. There was significant interaction between gender and the II genotype (P=0.031). The II genotype of the I/D polymorphism has a protective effect for schizophrenia among females. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 38 | Schizophr. Res. 2015 May 164: 109-14 |
| PMID | 25701466 |
| Title | ACE I/D genotype-related increase in ACE plasma activity is a better predictor for schizophrenia diagnosis than the genotype alone. |
| Abstract | Angiotensin-I converting enzyme (ACE) is a key component of the renin-angiotensin system (RAS). Although the several contradictory data, ACE has been associated with schizophrenia (SCZ) pathophysiology. Here the ACE activity of SCZ patients and healthy controls (HCs), and its possible correlations with the ACE polymorphism genotype and symptomatic dimensions, was investigated. ACE activity of 86 SCZ patients and 100 HCs paired by age, gender and educational level was measured, using the FRET peptide substrate and the specific inhibitor lisinopril. The ACE insertion/deletion (I/D) genotypes were assessed by the restriction fragment length polymorphism (RFLP) technique. Significantly higher ACE activity was observed in SCZ patients compared to HCs (t=-5.09; p<0.001). The area under the receiver operating characteristic (ROC) curve was 0.701. Mean ACE activity levels were higher for the D-allele carriers (F=5.570; p=0.005), but no significant difference was found among SCZ patients and HCs for genotypes frequencies (Chi-squared=2.08; df=2; p=0.35). Interestingly, we found that the difference between the measured ACE activity for each SCZ patient and the expected average mean value for each respective genotype group (for control subjects) was a better predictor of SCZ than the ACE dichotomized values (high/low) or ACE I/D. Our results suggest that higher levels of ACE activity are associated with SCZ with stronger impact when the genetic background of each individual is considered. This may explain the heterogeneity of the results on ACE previously reported. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 39 | Hum Psychopharmacol 2015 Mar 30: 100-7 |
| PMID | 25694211 |
| Title | Association of angiotensin-converting enzyme gene polymorphism with schizophrenia and depressive symptom severity in a Chinese population. |
| Abstract | Depressive symptoms are frequently observed in schizophrenia patients. Angiotensin-converting enzyme (ACE), a key enzyme of renin-angiotensin system, can catalyze the degradation of neuropeptides and modulate dopaminergic and serotonergic neurotransmission. Previous studies have revealed the association of the ACE gene insertion/deletion polymorphism with depressive disorder and its treatment response but not with the depressive symptoms in schizophrenia. The aim of this study is to examine whether this polymorphism was associated with susceptibility to schizophrenia and with its psychopathological symptoms, especially depressive symptoms in a Han Chinese population. This polymorphism was genotyped in 382 chronic patients and 538 healthy controls. Psychopathology was characterised using the positive and negative syndrome scale. The allelic and genotypic frequencies of this polymorphism significantly differed between patients and controls (both p < 0.001). A significant difference in the positive and negative syndrome scale depressive symptom score was observed among the three genotypes (p < 0.03), with higher score in patients with insertion/insertion (I/I) than with deletion/deletion (D/D) genotypes (p < 0.05). Furthermore, there was a significant linear correlation between the number of I alleles and the depressive symptom score (p < 0.05). The ACE gene insertion/deletion polymorphism may play a role in susceptibility to schizophrenia and also in its depressive symptom severity in a Han Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 40 | J Renin Angiotensin Aldosterone Syst 2015 Dec 16: 917-29 |
| PMID | 24464858 |
| Title | Beneficial effect of candesartan and lisinopril against haloperidol-induced tardive dyskinesia in rat. |
| Abstract | Tardive dyskinesia is a serious motor disorder of the orofacial region, resulting from chronic neuroleptic treatment of schizophrenia. Candesartan (AT1 antagonist) and lisinopril (ACE inhibitor) has been reported to possess antioxidant and neuroprotective effects. The present study is designed to investigate the effect of candesartan and lisinopril on haloperidol-induced orofacial dyskinesia and oxidative damage in rats. Tardive dyskinesia was induced by administering haloperidol (1 mg/kg i.p.) and concomitantly treated with candesartan (3 and 5 mg/kg p.o.) and lisinopril (10 and 15 mg/kg p.o.) for 3 weeks in male Wistar rats. Various behavioral parameters were assessed on days 0, 7, 14 and 21 and biochemical parameters were estimated at day 22. Chronic administration of haloperidol significantly increased stereotypic behaviors in rats, which were significantly improved by administration of candesartan and lisinopril. Chronic administration of haloperidol significantly increased oxidative stress and neuro-inflammation in the striatum region of the rat's brain. Co-administration of candesartan and lisinopril significantly attenuated the oxidative damage and neuro-inflammation in the haloperidol-treated rat. The present study supports the therapeutic use of candesartan and lisinopril in the treatment of typical antipsychotic-induced orofacial dyskinesia and possible antioxidant and neuro-inflammatory mechanisms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 41 | Brain Behav. Immun. 2016 Feb -1: -1 |
| PMID | 26923065 |
| Title | Alteration of transcriptional networks in the entorhinal cortex after maternal immune activation and adolescent cannabinoid exposure. |
| Abstract | Maternal immune activation (MIA) and adolescent cannabinoid exposure (ACE) have both been identified as major environmental risk factors for schizophrenia. We examined the effects of these two risk factors alone, and in combination, on gene expression during late adolescence. Pregnant rats were exposed to the viral infection mimic polyriboinosinic-polyribocytidylic acid (poly I:C) on gestational day (GD) 15. Adolescent offspring received daily injections of the cannabinoid HU210 for 14days starting on postnatal day (PND) 35. Gene expression was examined in the left entorhinal cortex (EC) using mRNA microarrays. We found prenatal treatment with poly I:C alone, or HU210 alone, produced relatively minor changes in gene expression. However, following combined treatments, offspring displayed significant changes in transcription. This dramatic and persistent alteration of transcriptional networks enriched with genes involved in neurotransmission, cellular signalling and schizophrenia, was associated with a corresponding perturbation in the expression of small non-coding microRNA (miRNA). These results suggest that a combination of environmental exposures during development leads to significant genomic remodeling that disrupts maturation of the EC and its associated circuitry with important implications as the potential antecedents of memory and learning deficits in schizophrenia and other neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 42 | J Affect Disord 2016 Jan 189: 290-7 |
| PMID | 26454335 |
| Title | Adverse childhood experiences influence the detrimental effect of bipolar disorder and schizophrenia on cortico-limbic grey matter volumes. |
| Abstract | Adverse childhood experiences (ACE) can lead to several negative consequences in adult life, are highly prevalent in psychiatric disorders where they associate with clinical and brain morphological features. Grey matter volume loss is a central characteristic of bipolar disorder (BD) and schizophrenia (SCZ). The aim of this study is to measure the effect of diagnosis and ACE on GM volume in a sample of patients with BD or SCZ compared with healthy controls (HC). We studied 206 depressed BD patients, 96 SCZ patients and 136 healthy subjects. GM volumes were estimated with 3.0 Tesla MRI and analyzed with VBM technique. The effect of diagnosis was investigated in the whole sample and separately exposed to high and low ACE subjects. An effect of diagnosis was observed in orbitofrontal cortex encompassing BA 47 and insula, and in the thalamus. HC had the highest volume and SCZ patients the lowest with BD patients showing an intermediate volume. This pattern persisted only in subjects with high ACE. No differences were observed for low ACE subjects. The three diagnostic groups differ for age and education, previous and current medications, and treatment periods. Our results underline the importance of ACE on the neural underpinnings of psychiatric psychopathology and suggest a major role of exposure to ACE for the GM deficits to reveal in clinical populations. Exposure to early stress is a crucial factor that must be taken in to account when searching for biomarkers of BD and SCZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |