Association between Insertion-Deletion Polymorphism of the Angiotensin-Converting Enzyme Gene and Treatment Response to Antipsychotic Medications: A Study of Antipsychotic-Naïve First-Episode Psychosis Patients and Nonadherent Chronic Psychosis Patients.

We investigated whether a functional insertion/deletion (I/D) polymorphism of angiotensin-converting enzyme (ACE) influenced antipsychotic treatment. At baseline, and after 8 weeks of treatment with various antipsychotic medications, we assessed patients' Positive and Negative Syndrome Scale (PANSS) scores, PANSS factors, and metabolic-syndrome-related parameters (fasting plasma lipid and glucose levels, and body mass index). A total of 186 antipsychotic-naïve first-episode psychosis patients or nonadherent chronic psychosis individuals (99 males and 87 females) were genotyped by polymerase chain reaction analysis. The ACE-I/D polymorphism was significantly associated with changes in PANSS psychopathology only (p < 0.05). Compared to ACE-II homozygous males, ACE-DD homozygous and ACE-ID heterozygous males manifested significantly greater decreases in PANSS positive score, PANSS excitement factor, and PANSS cognitive factor. ACE-DD homozygous females manifested higher decreases in PANSS depression factor compared to ACE-II homozygous and ACE-ID heterozygous females. The polymorphism's effect size was estimated as moderate to strong, while its contribution to the PANSS psychopathology ranged from ~5.4 to 8.7%, with the lowest contribution observed for PANSS positive score changes and the highest for PANSS depressive factor changes. Our results indicate that ACE-I/D polymorphism had a statistically significant but weak gender-specific impact on psychopathology data, and showed no association between ACE-I/D polymorphism and metabolic-syndrome-related parameters.

The insertion/deletion polymorphism in the angiotensin-converting enzyme gene and nicotine dependence in schizophrenia patients.

We investigated the relationship between the functional insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene and the risk of nicotine dependence in Croatian schizophrenia patients. We also tested whether interactions between ACE-I/D polymorphism and smoking status affected the clinical psychopathology findings in patients as measured using Positive and Negative Symptom Scale (PANSS) scores. Polymerase chain reaction analysis was used to genotype 267 chronically ill schizophrenia patients (140 males/127 females). There were no significant differences in the distribution of ACE genotypes and alleles in male or female schizophrenia patients who were stratified based on their smoking status. However, there was a trend toward a difference in the ACE genotype distribution in female smokers vs. nonsmokers (χ 2 = 5.13, p = 0.077) that was due mainly to the significant overrepresentation of ACE-ID heterozygous genotypes in female smokers compared to nonsmokers (62.3 vs. 42.0%, p = 0.025). ACE-ID heterozygous females had about a twofold higher smoking risk than ACE-II and ACE-DD homozygous carriers (OR = 2.29, 95% CI 1.1-4.7, p = 0.026). We observed no contribution of the ACE genotype-smoking interaction to PANSS psychopathology. This is the first study to investigate the possible association between ACE-I/D polymorphism and nicotine dependence in schizophrenia. Our results suggest that the ACE-I/D polymorphism may be relevant in determining the risk of nicotine dependence in female patients with schizophrenia while the ACE genotype-smoking interaction does not contribute to the clinical expression of schizophrenia.

An association between the PPARα-L162V polymorphism and nicotine dependency among patients with schizophrenia.

OBJECTIVE: Patients with schizophrenia are more likely to be smokers than the general population, which makes them an interesting group with which to study the etiology of nicotine dependency. We studied the prevalence of a gene variant of peroxisome proliferator-activated receptor alpha (PPARα) in schizophrenia, together with nicotine dependency, to investigate whether the PPARα-L162V polymorphism (rs1800206) influences nicotine dependency in schizophrenia. Given evidence suggesting that smoking influences the severity of schizophrenia, together with our recent data linking the PPARα-L162V polymorphism to clinical manifestations of schizophrenia (in the Croatian population), we hypothesized that interactions between the two (smoking and the PPARα-L162V polymorphism) might contribute to disease onset and scores for the Positive and Negative Syndrome Scale. To the best of our knowledge, this is the first study to investigate the possible associations between the PPARα gene and nicotine dependency. PATIENTS AND METHODS: Genotyping was performed for 267 chronically ill schizophrenia patients (males/females: 140/127) by polymerase chain reaction. RESULTS: A significant excess of PPARα-L162V genotypes and PPARα-162V alleles were detected among female smokers in comparison to female nonsmokers (18.2% vs. 2.0%, and 9.1% vs. 1.0%, p<0.01, respectively). We also revealed a significant PPARα genotype-smoking interaction that predicted positive symptom severity among male patients (F=4.43, p<0.05). These data indicated that the PPARα-L162V heterozygous genotype, depending on smoking status, might be of relevance as either protective, or a risk factor, for the severity of positive symptoms. No interaction between the PPARα-L162V polymorphism and smoking for the time of onset of schizophrenia was detected (p>0.05, respectively). CONCLUSION: We demonstrated two significant yet weak effects. The first showed an effect of the PPARα-L162V polymorphism on the risk of nicotine dependency. The second linked the PPARα genotype-smoking interaction to positive symptoms severity among schizophrenia patients; both effects manifested in a gender-specific fashion.

An association between PPARα-L162V polymorphism and increased plasma LDL cholesterol levels after risperidone treatment.

Peroxisome proliferator-activated receptor alpha (PPARα) and antipsychotic medications both influence polyunsaturated fatty acids (PUFA) homeostasis, and thus PPARα polymorphism may be linked to antipsychotic treatment response. Here we investigated whether the functional leucine 162 valine (L162V) polymorphism in PPARα influenced antipsychotic treatment in a group of psychosis patients (N = 186), as well as in a patient subgroup with risperidone, paliperidone, or combination treatment (N = 65). Antipsychotic-naïve first-episode patients and nonadherent chronic individuals were genotyped by polymerase chain reaction analysis. At baseline, and after 8 weeks of treatment with various antipsychotic medications, we assessed the patients' Positive and Negative Syndrome Scale (PANSS) scores; PANSS factors; and metabolic syndrome-related parameters, including fasting plasma lipid and glucose levels, and body mass index. In the total patient group, PPARα polymorphism did not affect PANSS psychopathology or metabolic parameters. However, in the subgroup of patients with risperidone, paliperidone, or combination treatment, PPARα polymorphism influenced changes in plasma LDL cholesterol. Specifically, compared to PPARα-L162L homozygous patients, PPARα-L162V heterozygous individuals exhibited significantly higher increases of LDL cholesterol levels after antipsychotic treatment. The PPARα polymorphism had a strong effect size, but a relatively weak contribution to LDL cholesterol level variations (∼12.8 %).

Clozapine in Treatment-Resistant Schizophrenia and Its Augmentation with Electroconvulsive Therapy in Ultra-Treatment-Resistant Schizophrenia.

Clozapine is considered the gold standard for patients with treatment-resistant schizophrenia (TRS) who have previously tried other antipsychotics at adequate doses (two or more, with at least one being atypical). However, despite optimal treatment, a subgroup of TRS patients with what is known as ultra-treatment-resistant schizophrenia (UTRS) fails to respond to clozapine, which occurs in 40-70% of cases. The most common approach to manage UTRS involves augmenting clozapine with pharmacological or non-pharmacological interventions, with a growing body of evidence that supports the use of electroconvulsive therapy (ECT) as an augmenter. This prospective non-randomized 8-week study, which followed the TRIPP Working Group guidelines and is one of few that separate TRS from UTRS, aimed to evaluate the effectiveness of clozapine in TRS patients and the efficacy of ECT augmentation of clozapine in UTRS patients. Patients with TRS were assigned to receive clozapine alone (clozapine group), whereas UTRS patients received bilateral ECT in addition to their current medication regimen (ECT plus clozapine group). The severity of symptoms was evaluated using the Clinical Global Impression Scale (CGI) and Positive and Negative Syndrome Scale (PANSS) at baseline and at the end of the 8-week trial. Both treatment approaches resulted in improved CGI and PANSS scores. The results suggest that both clozapine and ECT are effective treatment options for patients with TRS and UTRS, respectively, and that adherence to guidelines should provide a better frame for future clinical studies.

Association between PLA2 gene polymorphisms and treatment response to antipsychotic medications: A study of antipsychotic-naïve first-episode psychosis patients and nonadherent chronic psychosis patients.

Here we investigated whether antipsychotic treatment was influenced by three polymorphisms: rs10798059 (BanI) in the phospholipase A2 (PLA2)G4A gene, rs4375 in PLA2G6, and rs1549637 in PLA2G4C. A total of 186 antipsychotic-naïve first-episode psychosis patients or nonadherent chronic psychosis individuals (99 males and 87 females) were genotyped by polymerase chain reaction analysis/restriction fragment length polymorphism. At baseline, and after 8 weeks of treatment with various antipsychotic medications, we assessed patients' Positive and Negative Syndrome Scale (PANSS) scores, PANSS factors, and metabolic syndrome-related parameters (fasting plasma lipid and glucose levels, and body mass index). We found that PLA2G4A polymorphism influenced changes in PANSS psychopathology, and PLA2G6 polymorphism influenced changes in PANSS psychopathology and metabolic parameters. PLA2G4C polymorphism did not show any impact on PANSS psychopathology or metabolic parameters. The polymorphisms' effect sizes were estimated as moderate to strong, with contributions ranging from around 6.2-15.7%. Furthermore, the polymorphisms' effects manifested in a gender-specific manner.

Dysregulated inflammation may predispose patients with serious mental illnesses to severe COVID­19 (Review).

Genetic and nongenetic factors associated with an increased inflammatory response may mediate a link between severe coronavirus disease 2019 (COVID­19) and serious mental illness (SMI). However, systematic assessment of inflammatory response­related factors associated with SMI that could influence COVID­19 outcomes is lacking. In the present review, dietary patterns, smoking and the use of psychotropic medications are discussed as potential extrinsic risk factors and angiotensin­converting enzyme (ACE) insertion/deletion (I/D) gene polymorphisms are considered as potential intrinsic risk factors. A genetics­based prediction model for SMI using ACE­I/D genotyping is also proposed for use in patients experiencing severe COVID­19. Furthermore, the literature suggests that ACE inhibitors may have protective effects against SMI or severe COVID­19, which is often linked to hypertension and other cardiovascular comorbidities. For this reason, we hypothesize that using these medications to treat patients with severe COVID­19 might yield improved outcomes, including in the context of SMI associated with COVID­19.

Niacin skin flush test: a research tool for studying schizophrenia.

BACKGROUND: A body of biochemical evidence suggests that abnormal phospholipid metabolism may play a role in the etiology of schizophrenia, and possibly, other psychiatric and neurological diseases. Niacin, a B-complex vitamin, induces prostaglandin synthesis, vasodilatation, and skin flushing when applied as a solution on the skin or taken orally. In schizophrenia, diminished or absent skin response to niacin represents a robust finding. RESULTS: Attenuated niacin skin-flush response has been analysed as a potential biochemical marker of impaired prostaglandin signaling in schizophrenia. Diminished skin redness after topical application of niacin might be caused by a reduced level of the precursor arachidonic acid in the peripheral membranes, increased activity of the enzyme phospholipase A2, abnormal expression of niacin or prostaglandin receptors, or poor vasomotor activity of cutaneous capillary walls. Heritability estimates established in several studies support niacin skin flush response as a vulnerability trait for the development of psychosis. However, the exact mechanism of a reduced skin flush, the possible influence of the long-term use of antipsychotics, and the usefulness of the test for diagnostic purpose are not clear yet. CONCLUSIONS: Niacin skin flush test is a simple, non-invasive and easily replicable method in the research of schizophrenia. The studies investigating niacin flushing in schizophrenia are numerous but incoherent regarding methods of niacin application and evaluation of the results. New studies, controlling adequately for age, sex, drug abuse, diet, as well as genetic factors that may influence the intensity and reaction time, are necessary to clarify the usefulness of niacin testing in psychiatry.

An association between niacin skin flush response and plasma triglyceride levels in patients with schizophrenia.

The available data suggest that abnormalities of arachidonic acid-related signaling may be of relevance in attenuated niacin-induced flush responses and lipid and glucose metabolism disturbances, which are all common among individuals with schizophrenia. We previously demonstrated attenuated skin flush responses to niacin in patients with schizophrenia. Here we investigated whether these niacin responses might be associated with elevated plasma lipid and glucose concentrations in this patient group. We found that higher plasma triglyceride levels were associated with higher total volumetric niacin response (VNR) values and that the VNR accounted for ~14.2% of the variability in triglyceride levels. Triglyceride levels were significantly higher in patients with a positive niacin skin flush response compared to those with absent niacin skin flushing at the 5-minute interval with niacin concentrations of 0.1 and 0.01 M, and at the 10- and 15-minute intervals with a niacin concentration of 0.001 M.

Association between the ACE-I/D polymorphism and nicotine dependence amongst patients with lung cancer.

The biologically active peptide angiotensin II is cleaved from angiotensinogen by the renin and the angiotensin-converting enzyme (ACE), an enzymatic cascade known as the renin-angiotensin system (RAS). RAS may be important in the etiology of nicotine dependence by influencing dopaminergic signaling. In the present study, the association between an insertion/deletion (I/D) polymorphism of ACE and nicotine dependence amongst patients with lung cancer was assessed. To date, several studies have shown the relevance of this polymorphic variant in both nicotine dependence and lung cancer. However, the present study is the first to address the potential role of the ACE-I/D polymorphism in nicotine dependence among patients with lung cancer. Genotyping was performed in 305 patients with lung cancer (males/females, 214/91). Significantly more male smokers had the ACE-I allele compared with male non-smokers (44.9 vs. 20.0%; P<0.05). The risk of smoking was ~5-fold higher for males with the ACE-I allele (ACE-II homozygous and ACE-ID heterozygous) vs. ACE-DD homozygous (odds ratio, 5.47; 95% confidence interval, 1.4-21.9; P=0.016). The pack-year smoking history in a subgroup of females with squamous cell carcinoma carrying the ACE-I allele was significantly lower compared with ACE-DD (37.1±14.1 vs. 57.0±29.1; F=4.5; P=0.046). The ACE-I/D polymorphism accounted for 17.6% of the smoking severity in this patient group (ß, -0.42; multiple R2 change, 0.176; P=0.046). These results suggest that the ACE-I/D polymorphism contributes to the risk of nicotine dependence and smoking severity in lung cancer patients in a sex-specific manner.

Association between PLA2G6 gene polymorphism for calcium-independent phospholipase A2 and nicotine dependence among males with schizophrenia.

We investigated the relationship between the rs10798059 (BanI) and rs4375 polymorphisms in the phospholipase A2 (PLA2)G4A and PLA2G6 genes and the risk of nicotine dependence in 263 Croatian patients with schizophrenia. We also examined whether interactions between these polymorphisms and smoking contributed to schizophrenia onset and Positive and Negative Syndrome Scale (PANSS) psychopathology. We found no significant differences in the distribution of PLA2G4A genotypes and alleles according to smoking status, and no effect of the PLA2G4A genotype-smoking interaction on disease onset or PANSS. The PLA2G6-TT homozygous genotype was significantly overrepresented in male smokers compared to nonsmokers (34.7% vs. 17.1%, p < 0.05). These patients had ∼2.6-fold higher risk of becoming smokers than males with heterozygous PLA2G6-CT and homozygous PLA2G6-CC genotypes. In addition, male smokers without the PLA2G6-C allele (PLA2G6-TT homozygous) experienced earlier onset than nonsmoking homozygous PLA2G6-TT males. Thus, the PLA2G6 polymorphism affected the risk of nicotine dependence in male patients and the PLA2G6 genotype-smoking interaction was linked to the age of disease onset.

Phospholipid membrane abnormalities and reduced niacin skin flush response in schizophrenia.

OBJECTIVES: Reduced n-3 and n-6 polyunsaturated fatty acids (PUFAs) content in red blood cell (RBC) membranes and abnormal membrane phospholipid metabolism were repeatedly implicated in the etiology of schizophrenia. FINDINGS: Prenatal and perinatal depletion of PUFAs interferes with normal brain development and function. The lack of docosahexaenoic acid - DHA in the brain is reflected in lower membrane DHA/AA (AA - arachidonic acid) ratio, increased activity of AA-metabolizing enzymes, and disturbance of downstream metabolic pathways involved in signaling, growth modulation, brain glucose uptake, immune functions, neurotransmission, synaptogenesis and neurogenesis. Preliminary high-throughput metabolomic studies revealed abnormal biochemical profile in patients with schizophrenia or brief psychotic disorder when compared to healthy controls. The results of both metabolomic and proteomic studies pointed to energy metabolism and lipid biosynthesis being impaired in schizophrenia. The usefulness of antipsychotic medication and supplementation with PUFAs in reverting to the normal metabolic state has been suggested in early treatment of the first psychotic episode. Abnormalities of phospholipid metabolism can be also detected as attenuated niacin skin flush response in the variety of neuropsychiatric disorders. CONCLUSIONS: Disturbances of lipid homeostasis could represent biochemical markers in the preclinical phase of neuropsychiatric illnesses and could serve as triggers in genetically vulnerable individuals. The assessment of patients' lipid status may also help in monitoring the course of the disease and treatment response. In this regard, simple, cheap and fast niacin skin flush test might be valuable. It might help in diagnosis of adolescents and young adults with psychotic behaviour, or in defining the necessity for long-term antipsychotic therapy. Along with antipsychotic medication schizophrenic patients need specific medical nutrition therapies.

An association between the BanI polymorphism of the PLA2G4A gene for calcium-dependent phospholipase A2 and plasma glucose levels among females with schizophrenia.

Abnormal glucose and lipid metabolism may be associated with altered cytosolic Ca2+-dependent phospholipase A2 (cPLA2) signaling in patients with schizophrenia. The relationship between schizophrenia and the functional BanI polymorphism (rs10798059 variant, A/G polymorphism) of the PLA2G4A gene for cPLA2 has been extensively investigated. We previously reported that it can influence several clinical features of schizophrenia, and it was shown to contribute to schizophrenia risk in several population studies. We performed PCR/RFLP genotyping of 263 Croatian patients (males/females: 139/124) to investigate the relationship between the BanI polymorphism and fasting plasma glucose and lipid levels in patients with schizophrenia. Our results indicate that the BanI polymorphic variant contributes significantly to plasma glucose levels in female patients. Females carrying the PLA2G4A-G allele (PLA2G4A-GG homozygous and PLA2G4A-AG heterozygous) presented with lower glucose levels than PLA2G4A-AA homozygous carriers, and the PLA2G4A genotype contributed approximately 6% of plasma glucose level variability in this group of patients.

An association between PLA2G6 and PLA2G4C gene polymorphisms and schizophrenia risk and illness severity in a Croatian population.

We investigated the allele and genotype frequency of the rs4375 and rs1549637 polymorphisms in phospholipase A2 (PLA2)G6 and PLA2G4C genes in 203 patients with schizophrenia and 191 controls in a Croatian population. We hypothesized that these polymorphic variations might influence the age of schizophrenia onset and Positive and Negative Syndrome Scale psychopathology (PANSS) data. We detected a significant overrepresentation of the PLA2G6-CT and PLA2G4C-AT genotype combination in patients compared with controls (14.7% vs. 7.3%, P < 0.05). The combined PLA2G6/PLA2G4C heterozygosity was associated with about a two-fold higher schizophrenia risk. We found no significant influence of the PLA2G6 and PLA2G4C polymorphisms on mean age at first hospital admission (P > 0.05) and that the investigated polymorphisms significantly influenced the clinical psychopathology only in male patients. The PLA2G4C polymorphism accounted for approximately 12% of negative symptom severity; whereas, the PLA2G6/PLA2G4C interaction contributed to a similar extent to total PANSS symptom variations.

The lack of association between angiotensin-converting enzyme gene insertion/deletion polymorphism and nicotine dependence in multiple sclerosis.

OBJECTIVE: Blood-borne angiotensin II is generated from angiotensinogen via cleavage by renin and angiotensin-converting enzyme (ACE), an enzymatic cascade known as the renin-angiotensin system (RAS). Several lines of evidence indicate that ACE, beyond its classical role of mediating blood pressure regulation, might contribute to the etiology of substance addictions by influencing dopaminergic signaling. A functional insertion/deletion (I/D) polymorphism of the ACE gene was associated with risk for being a smoker among individuals with depression and with smoking severity in studies comprising patients with depression and healthy controls. Several reports have described significantly increased ACE activity in cerebrospinal fluid and serum among MS patients. Furthermore, in our previous work with MS patients from Croatian and Slovenian populations, we demonstrated that the ACE-I/D polymorphism contributes to an elevated MS risk among male patients. Here we investigated whether the ACE-I/D polymorphism might influence smoking behavior among patients with MS. PATIENTS AND METHODS: Genotyping was performed in 521 patients (males/females: 139/382) using polymerase chain reaction. RESULTS: We revealed no significant differences in ACE genotype and allele frequencies between smokers and nonsmokers and no significant association between the ACE-I/D polymorphism and either pack-year smoking history or number of cigarettes smoked daily (p > .05, respectively). CONCLUSION: The ACE-I/D polymorphism does not contribute either to risk for nicotine dependence or to smoking severity among MS patients. In the context of reports on the ACE-I/D polymorphism and nicotine dependence among healthy controls and patients with depression, we may speculate that the mechanism by which this polymorphism influences nicotine dependence risk differs in MS compared to depression, although not compared to a healthy population. In addition to angiotensin II, other potential ACE substrates, such as substance P and neurotensin, which also influence dopaminergic neurotransmission (and are proposed to be associated with MS), may deserve study in future.

The impact of PLA2G4A and PTGS2 gene polymorphisms, and red blood cell PUFAs deficit on niacin skin flush response in schizophrenia patients.

We investigated the etiology of the attenuated niacin skin flush response in schizophrenia patients. Skin response to topical niacin of 0.1M, 0.01 M, 0.001 M, and 0.0001 M concentrations was rated using method of volumetric niacin response (VNR) and correlated to two functional A/G polymorphisms in genes: phospholipase A2 group IVA (BanI of the PLA2G4A), and rs689466 of the prostaglandin synthase-2 (PTGS2). We further tested the possible correlation between niacin response and fatty acid (FA) content of red blood cells (RBCs). We detected statistically significant but weak impact of both polymorphisms on niacin flush response in schizophrenia patients. The dosage of the G alleles of both polymorphisms was associated with higher VNR values, although each polymorphic variant accounted for only 1% of the overall flush response variability. Regarding FA content, both n-3 and n-6 polyunsaturated FAs (PUFAs) were significantly reduced in the patient group, but an association with niacin sensitivity was not detected.

The advantages of humeral anteromedial plate osteosynthesis in the middle third shaft fractures.

BACKGROUND: Humeral shaft fractures account for 1.2% of all fractures and occur in a slightly younger population. Their causes include a fall from standing or from height, motor vehicle accident, but can be also pathological. In order to clarify which of both surgeries we performed in our Department for treating humeral shaft fractures had more advantages (anterolateral or anteromedial plating through anterolateral approach) we analyzed incidence of postoperative iatrogenic radial palsies and mean operation time required to complete each surgery. METHODS: During January 1992 to December 2009 on Department of Surgery, Division for Traumatology of Clinical Hospital Center Rijeka, 420 patients (340 males and 80 females with mean age of 38.11 ± 9.29 years) were treated for middle third humeral shaft fracture by anterolateral approach and internal fixation using AO/DCP or LCP plates that was positioned on anteromedial humeral surface in 141 patients (33.57%) and on anterolateral humeral surface in 279 patients (66.43%). RESULTS: None of the patients who had osteosynthesis by using plate on anteromedial humeral sufrace had lesions of the radial nerve. Therefore, χ(2) test revealed significantly higher frequency of postsurgical radial nerve injuries in patients who were treated by anterolateral plating than in patients where anteromedial plating was performed (χ(2) = 17.51; p< 0.05). Anterolateral plating required longer mean operation time than anteromedial plating and the difference in its duration determined by t-test for independent samples showed statistically significant difference (t= 14.57; p< 0.05). CONCLUSION: An anteromedial plating of humeral shaft fractures through anterolateral approach was determinated to be a simple, safe, effective and also fast surgical treatment and we highly recommend it as operative technique for treating humeral shaft fractures.