Aim: This case report explores the relationship between psychotic symptoms and excessive alcohol consumption in schizophrenia, examining its role in self-medication, premature liver damage, and treatment challenges. Case report: We describe a 31-year-old male with schizophrenia, who was nonadherent to antipsychotic treatment, and who repeatedly manifested excessive alcohol consumption during the exacerbations of psychotic symptoms, claiming that his alcohol drinking was for the purpose of self-medicating for auditory hallucinations. Despite temporary perceived relief, the patient developed severe alcohol-related liver damage, including alcoholic hepatitis and portal hypertension, at a remarkably early age. This case challenges the classical self-medication hypothesis, as alcohol use likely worsened both psychiatric and physical outcomes. Conclusions: This report highlights the complex relationship between psychosis and alcohol misuse, underscoring the need to explore alternative mechanisms linking auditory hallucinations to alcohol consumption. It also emphasizes early recognition of alcohol-related liver damage in schizophrenia. When liver function is impaired, careful selection of antipsychotic treatment is critical. The atypical antipsychotic amisulpride, with its minimal hepatic metabolism, appears to be a promising option for controlling psychotic symptoms and reducing alcohol cravings in such cases.

We investigated whether antipsychotic treatment response was influenced by the C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase (MTHFR), and A66G of methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR)-genes central to folate and homocysteine metabolism and methylation, pathways often altered in schizophrenia patients. To our knowledge, no study has examined associations of C677T and A1298C with changes in schizophrenia symptom severity after antipsychotic treatment, while studies on metabolic outcomes remain sparse and inconsistent. The MTRR A66G has been assessed only once for metabolic parameters-not symptom severity-and sex-stratified analyses are lacking for all polymorphisms. A total of 186 antipsychotic-naïve first-episode or nonadherent chronic psychosis patients and 242 controls were genotyped using PCR-RFLP. Clinical assessments-including Positive and Negative Syndrome Scale (PANSS) scores, PANSS factor scores, and metabolic parameters (fasting plasma lipids and glucose levels, and body mass index)-were conducted at baseline and after 8 weeks. Genotype and allele frequencies did not differ between patients and controls. Significant associations emerged only for symptom changes, specifically within PANSS factor domains, in a sex-dependent manner. Female MTHFR 1298-A allele carriers (AA and AC) showed greater improvement in PANSS negative factor scores, whereas male MTRR 66-G allele carriers (GG and AG) showed reduced improvement in PANSS cognitive factor scores. Effect sizes were strong to very strong, with relatively modest contributions. MTHFR A1298C and MTRR A66G have sex-dependent impacts on symptomatic improvement-but not metabolic outcomes-after antipsychotic treatment. Accordingly, folate-homocysteine genetic markers and sex-specific factors can guide the development of personalized antipsychotic treatment approaches.

Several studies have shown antipsychotic effects of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib as an add-on treatment to antipsychotic treatment. The functional rs689466 (A/G) polymorphism in the gene encoding COX-2 (also known as the prostaglandin-endoperoxide synthase 2 gene) has been correlated with schizophrenia risk and the niacin skin flush response among chronic patients under antipsychotic treatment. Here, we investigated whether this polymorphism was associated with antipsychotic treatment in a group of total psychosis patients (N = 186), as well as a subgroup of patients treated with clozapine (N = 74). Antipsychotic-naïve first-episode patients and non-adherent chronic psychosis patients were genotyped by polymerase chain reaction/restriction fragment length polymorphism analysis. At baseline and after 8 weeks of treatment with various antipsychotic medications, we assessed the patients' Positive and Negative Syndrome Scale (PANSS) scores, factors, and metabolic syndrome-related parameters, including fasting plasma lipid and glucose levels and body mass index. In the total patient group, the COX-2 polymorphism was not associated with PANSS psychopathology scores or metabolic parameters. However, in the subgroup of patients treated with clozapine, the COX-2 polymorphism was associated with changes in plasma HDL cholesterol. Specifically, compared to patients homozygous for the A allele, the subgroup of patients treated with clozapine and positive for the G allele (i.e., GG or AG genotype) exhibited significantly higher increases in HDL cholesterol levels. The COX-2 polymorphism had a moderate effect size but made a relatively weak contribution to variations in the HDL cholesterol level (∼9.6 %).

Aim: Some of the symptoms of major depressive disorder and some aspects of quality of life (QoL) are amenable to effective nursing interventions. The specific aim of this research was to examine the association of QoL of patients with major depressive disorder with the severity of individual symptoms amenable to effective nurse intervention. Subjects and Methods: A unicentric, cross-sectional study was performed on a consecutive sample of 72 outpatients diagnosed with a major depressive disorder (ICD - 10: F32 and F33). Inclusion criteria were diagnosis of major depressive disorder, age 18-65 years, both sexes, outpatient treatment. The primary outcome was the subjective assessment of health-related QoL as measured by the visual-analogue scale of the EQ - 5D - 5L questionnaire. Results: We found a negative association between more severe pessimism as well as self-dislike of any intensity with QoL in patients with major depressive disorder. We have not confirmed the hypothesis regarding the association between sadness and QoL. Conclusion: Nurse interventions that decrease patient pessimism and self-dislike could contribute to QoL improvement in patients with major depressive disorder. This investigation could contribute to focused cognitive-behavioral interventions of psychiatric nurses in multidisciplinary care for outpatients with major depressive disorder, achieving better treatment outcomes and particularly improvements of QoL.

Bolesnici s teškim duševnim bolestima koje uključuju shizofreniju, veliki depresivni poremećaj i bipolarni afektivni poremećaj žive 15 – 25 godina kraće u odnosu na pripadnike opće populacije. Visoka stopa neprirodnih smrti (prvenstveno suicida) uvelike pridonosi skraćenom trajanju životnog vijeka u bolesnika s teškim duševnim bolestima. Kardiovaskularna oboljenja pokazala su se glavnim uzrokom prirodnih smrti u bolesnika s teškim duševnim bolestima, što je slično kao i u pripadnika opće populacije. Mnogi čimbenici rizika za kardiovaskularne bolesti u bolesnika s teškim duševnim bolestima, kao što su nezdrava prehrana, pušenje i nedovoljna tjelesna aktivnost, prisutni su i u pripadnika opće populacije. Dodatne čimbenike rizika kod bolesnika s teškim duševnim bolestima predstavljaju upotreba psihofarmaka te genetički čimbenici podložnosti, a riziku za kardiovaskularna oboljenja mogla bi pridonijeti i zanimljiva interakcija kardiovaskularnih čimbenika rizika. U znanstvenoj literaturi malo je sistemskih studija o kardiovaskularnim čimbenicima rizika u bolesnika s teškim duševnim bolestima, posebice o njihovoj interakciji. U kliničkoj su praksi komorbidne kardiovaskularne bolesti u bolesnika s teškim duševnim bolestima nerijetko nedovoljno prepoznate i liječene. U ovom radu iznesene su spoznaje o najvažnijim kardiovaskularnim čimbenicima rizika u bolesnika s teškim duševnim bolestima, pri čemu se ističe važnost multidisciplinarnog pristupa timova psihijatara i kardiologa u prevenciji kardiovaskularnih bolesti. Nadalje, iznesene su spoznaje o ulozi genetičkih čimbenika podložnosti za kardiovaskularne bolesti u bolesnika s teškim duševnim bolestima, s osvrtom na rezultate cjelogenomskih studija povezanosti. Konačno, raspravljaju se klinički značajne interakcije kardiovaskularnih lijekova i psihofarmaka te moguće neuropsihijatrijske nuspojave lijekova za kardiovaskularne bolesti.

Aim of the study We investigated the association between obesity and body mass index (BMI) with Positive and Negative Syndrome Scale (PANSS) psychopathology, age at disease onset, and parameters linked to the metabolic syndrome (fasting plasma lipid and glucose levels), among antipsychotic-naïve first-episode schizophrenia (AN-FES) patients and nonadherent chronic schizophrenia individuals. Subject or material and methods We recruited a total of 187 AN-FES patients or nonadherent chronic individuals for this study. Clinical and anthropometric data together with plasma lipid and glucose parameters were collected immediately after patients’ admission to the hospital. Patients were classified as obese with body mass index (BMI) ≥ 30, or as non-obese if overweight (BMI: 25 – 29.9) or of normal body weight (BMI: 18.5 – 24.9). Results After controlling for the possible confounders we found that only BMI significantly predicted clinical and metabolic variables. Among AN-FES patients, higher BMI values predicted lower levels of HDL cholesterol (HDL-c), and higher ratios for LDL cholesterol (LDL-c)/HDL-c and triglyceride/HDL-c, while among nonadherent individuals, higher BMI values predicted higher number of psychotic episodes, and lower PANSS general psychopathology scores. The contribution of BMI ranged from approximately 5.8% to 29.6%, with the lowest contribution observed for number of psychotic episodes, and the highest contribution for the LDL-c/HDL-c ratio. Discussion Our results indicate that AN-FES patients and nonadherent chronic patients differed in the effects of BMI. Conclusions Higher BMI contributes to an increased risk for dyslipidemia among AN-FES patients and to the higher number of psychotic episodes, and less severe clinical psychopathology among nonadherent chronic schizophrenia individuals.

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.

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.

An interaction between smoking and antipsychotic medications could potentially affect treatment efficacy and promote metabolic side effects. We investigated the contribution of smoking status towards Positive and Negative Syndrome Scale (PANSS) scores and metabolic syndrome- related parameters (plasma lipid and glucose concentrations, and body mass index) among two groups of unmedicated patients with psychosis from the Croatian population: antipsychotic-naïve first-episode patients and nonadherent chronic patients. Previous data are inconsistent regarding the effects of smoking on clinical psychopathology among antipsychotic-naïve or minimally medicated patients with first-episode psychosis, and no studies have examined the potential influence of smoking on clinical psychopathology and metabolic parameters among nonadherent patients with chronic psychosis. Information about smoking status and antipsychotic nonadherence was obtained via auto-anamnestic and hetero-anamnestic information. PANSS data were obtained while patients were in a psychotic state during the illness requiring hospitalization. Plasma total cholesterol, LDL cholesterol, HDL cholesterol (HDL- c), triglyceride, and glucose levels were determined after a 12-hour fasting period. Compared with non-smoking antipsychotic-naïve first-episode individuals, antipsychotic-naïve smokers exhibited significantly lower depression factor scores, and significantly higher triglyceride levels and triglyceride/HDL- c ratio (p < 0.05). Compared with non-smoking nonadherent chronic individuals, nonadherent smokers exhibited significantly lower negative symptoms and negative factor scores, and lower HDL- c levels. Contributions of smoking to clinical and metabolic parameters ranged from ~ 3.4 % to 10 %. Our present results indicated that smoking may be associated with less severe clinical psychopathology, and with increased risk for metabolic abnormalities, among unmedicated patients with first-episode psychosis and chronic psychosis.

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 %).

Sergej Nadalin1, Vjekoslav Peitl2,3, Dalibor Karlović2,3, Sanja Dević Pavlić4, Mislav Škrobo2, Melita Uremović3, Lena Zatković5, Alena Buretić-Tomljanović4 1Department of Psychiatry, General Hospital “Dr. Josip Benčević”, Slavonski Brod, Croatia, 2Department of Psychiatry, University Hospital Center Sestre Milosrdnice, Zagreb, Croatia, 3School of Medicine, Catholic University of Croatia, Zagreb, Croatia, 4Department of Medical Biology and Genetics, Faculty of Medicine, University of Rijeka, Rijeka, Croatia, 5Hospital Pharmacy, Clinical Hospital Center Rijeka, Rijeka, Croatia Original paper

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.

Cilj: Porod carskim rezom kontinuirano se povezuje s povećanim rizikom za pojavu komponenti metaboličkog sindroma kod ispitanika u općoj populaciji, dok su podatci za bolesnike sa shizofrenijom manjkavi i proturječni. U ovom smo istraživanju ispitali pridonosi li, i u kojoj mjeri, vrsta poroda vrijednostima indeksa tjelesne mase (ITM) te koncentracijama lipida i glukoze u plazmi na dvjema skupinama bolesnika sa shizofrenijom koji ne primaju terapiju: u bolesnika s prvom epizodom shizofrenije (N = 48) i u kroničnih bolesnika neadherentnih prema antipsihotičnoj terapiji (N = 83). Ispitanici i metode: Podatci o vrsti poroda i neadherentnosti prema antipsihotičnoj terapiji prikupljeni su iz autoanamneze i heteroanamneze. Određivanje ukupnog kolesterola, LDL kolesterola (engl. low density lipoprotein cholesterol), HDL kolesterola (engl. high density lipoprotein cholesterol), triglicerida i glukoze u plazmi realizirano je nakon 12-satnog gladovanja. Rezultati: Učestalost poroda carskim rezom iznosila je 8,4 %. Koncentracije triglicerida i vrijednosti ITM-a bile su značajno više u bolesnika rođenih carskim rezom u odnosu na bolesnike rođene vaginalnim porodom: 1,5 (0,6 – 4,3) vs. 1,1 (0,3 – 3,1); z = -2,21, p = 0,027. Vrsta poroda pridonosi s približno 3,3 % varijabilnosti koncentracija triglicerida. Zaključci: Naši rezultati upućuju da vrsta poroda utječe u manjoj mjeri na koncentracije triglicerida u plazmi u bolesnika sa shizofrenijom koji nisu na terapiji antipsihotičnim lijekovima. Porod carskim rezom predstavlja rizični čimbenik za povišene koncentracije triglicerida.

Genetic and nongenetic factors associated with an increased inflammatory response may mediate a link between severe coronavirus disease 2019 (COVID-19) and serious mental illness (SMI). However, systematic assessment of inflammatory response-related factors associated with SMI that could influence COVID-19 outcomes is lacking. In the present review, dietary patterns, smoking and the use of psychotropic medications are discussed as potential extrinsic risk factors and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphisms are considered as potential intrinsic risk factors. A genetics-based prediction model for SMI using ACE-I/D genotyping is also proposed for use in patients experiencing severe COVID-19. Furthermore, the literature suggests that ACE inhibitors may have protective effects against SMI or severe COVID-19, which is often linked to hypertension and other cardiovascular comorbidities. For this reason, we hypothesize that using these medications to treat patients with severe COVID-19 might yield improved outcomes, including in the context of SMI associated with COVID-19.

We have read with great interest several recent articles on the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene and its potential relevance to the risk of a SARS-CoV-2 infection and the severity of the consequent coronavirus disease 2019 (COVID-19).1Delanghe J.R. Speeckaert M.M. De Buyzere M.L The host's angiotensin-converting enzyme polymorphism may explain epidemiological findings in COVID-19 infections.Clin Chim Acta. 2020; 505: 192-193https://doi.org/10.1016/j.cca.2020.03.031.2Crossref PubMed Scopus (0) Google Scholar, 2Delanghe J.R. Speeckaert M.M. De Buyzere M.L COVID-19 infections are also affected by human ACE1 D/I polymorphism.Clin Chem Lab Med. 2020; 58: 1125-1126https://doi.org/10.1515/cclm-2020-0425.3Crossref PubMed Scopus (0) Google Scholar, 3Yamamoto N. Ariumi Y. Nishida N. Yamamoto R. Bauer G. Gojobori T. et al.SARS-CoV-2 infections and COVID-19 mortalities strongly correlate with ACE1 I/D genotype.Gene. 2020; 758144944https://doi.org/10.1016/j.gene.2020.144944Crossref Scopus (108) Google Scholar, 4Cenanovic M. Dogan S. Asic A. Besic L. Marjanovic D. Distribution of the ACE1 D allele in the bosnian-herzegovinian population and its possible role in the regional epidemiological picture of COVID-19.Genet Test Mol Biomarkers. 2021; 25: 55-58https://doi.org/10.1089/gtmb.2020.0207Crossref PubMed Scopus (5) Google Scholar, 5Bellone M. Calvisi S.L. ACE polymorphisms and COVID-19-related mortality in Europe.J Mol Med (Berl). 2020; 98: 1505-1509https://doi.org/10.1007/s00109-020-01981-0Crossref PubMed Scopus (30) Google Scholar, 6Aung A.K. Aitken T. Teh B.M. Yu C. Ofori-Asenso R. Chin K.L. et al.Angiotensin converting enzyme genotypes and mortality from COVID-19: an ecological study.J Infect. 2020; 81: 961-965https://doi.org/10.1016/j.jinf.2020.11.012.7Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar These epidemiological studies, which analyzed either European populations1Delanghe J.R. Speeckaert M.M. De Buyzere M.L The host's angiotensin-converting enzyme polymorphism may explain epidemiological findings in COVID-19 infections.Clin Chim Acta. 2020; 505: 192-193https://doi.org/10.1016/j.cca.2020.03.031.2Crossref PubMed Scopus (0) Google Scholar, 5Bellone M. Calvisi S.L. ACE polymorphisms and COVID-19-related mortality in Europe.J Mol Med (Berl). 2020; 98: 1505-1509https://doi.org/10.1007/s00109-020-01981-0Crossref PubMed Scopus (30) Google Scholar, 6Aung A.K. Aitken T. Teh B.M. Yu C. Ofori-Asenso R. Chin K.L. et al.Angiotensin converting enzyme genotypes and mortality from COVID-19: an ecological study.J Infect. 2020; 81: 961-965https://doi.org/10.1016/j.jinf.2020.11.012.7Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar or global populations that included Europe,2Delanghe J.R. Speeckaert M.M. De Buyzere M.L COVID-19 infections are also affected by human ACE1 D/I polymorphism.Clin Chem Lab Med. 2020; 58: 1125-1126https://doi.org/10.1515/cclm-2020-0425.3Crossref PubMed Scopus (0) Google Scholar, 3Yamamoto N. Ariumi Y. Nishida N. Yamamoto R. Bauer G. Gojobori T. et al.SARS-CoV-2 infections and COVID-19 mortalities strongly correlate with ACE1 I/D genotype.Gene. 2020; 758144944https://doi.org/10.1016/j.gene.2020.144944Crossref Scopus (108) Google Scholar, 4Cenanovic M. Dogan S. Asic A. Besic L. Marjanovic D. Distribution of the ACE1 D allele in the bosnian-herzegovinian population and its possible role in the regional epidemiological picture of COVID-19.Genet Test Mol Biomarkers. 2021; 25: 55-58https://doi.org/10.1089/gtmb.2020.0207Crossref PubMed Scopus (5) Google Scholar have reported conflicting results (Table 1). Variability in results may arise, due to various factors, including differences in the ethnicities/countries included in the analysis, which might reflect differences in genetic background; differences in other biological, environmental, and social risk parameters; and differences in the prevalence of the ACE I/D polymorphism. Indeed, it is well documented that the frequency of the ACE-D allele varies according to the ethnic/geographic origin of the study cohort. The prevalence of the ACE-D allele increases from Eastern to Western countries, worldwide. The prevalence in Asian populations (approximately 25–40%) is lower than the prevalence in Caucasian (generally approximately 40–60%) and African (60%) populations. Therefore, we focused our interest on studies that analyzed the European region, which also provided conflicting results, despite the similarities among these populations, in terms of ancestry, other risk covariates for COVID-19, and strategies for controlling the pandemic.Table 1Epidemiological studies on associations between ACE I/D polymorphisms and COVID-19 prevalence/mortality.Author (reference)Geographic regionDate assessedACE I/D allele/genotypeAssociation with COVID-19 prevalence and/or mortalityDelanghe (1)Europe (25 countries)20 March 2020D allelenegative associationDelanghe (2)European (26 countries), North African and Middle Eastern countries1 April 2020D allelenegative associationYamamoto (3)European (19 countries), Middle Eastern, South Asian, and East Asian countries23 May 2020II genotypenegative associationAung (4)Worldwide countries (9 European)8 June 2020DD genotypeno associationII genotypenegative associationCenanovic (5)Europe (18 countries)10 July 2020D alleleno associationBellone (6)Europe (24 countries)5 August 2020DD genotypepositive associationII genotypenegative association Open table in a new tab Several factors could potentially explain the variable results, including the study design (i.e., the source and method of data collection), the approach to data analysis (e.g., adjustments for potential confounders), or the timing of the analysis. In addition, previous studies analyzed data during the first wave of the pandemic, when most European countries were under total lockdown. The opening of borders at the end of June 2020 led to an increase in social contacts and virus transmission, which caused the second COVID-19 wave in the early autumn of 2020. The epidemiological situation changed markedly during the second wave of the pandemic. Countries that had largely avoided the pandemic during the first wave, such as the Czech Republic, or countries with a favorable epidemiological situation, such as those in Southeast Europe, were affected by the second wave. In this study, we conducted a replication analysis in the European population to investigate the impact of the ACE I/D polymorphism on the prevalence and mortality of COVID-19 after the second wave of the pandemic. Data were collected on February 1, 2021, one year after the World Health Organization declared the outbreak as a Public Health Emergency of International Concern and at a time when the populations of European countries had not yet been immunized by vaccinations. Thirty-four European countries were included in the analysis: Albania, Austria, Belarus, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, the Czech Republic, Croatia, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Lithuania, Moldova, Montenegro, The Netherlands, Norway, Poland, Portugal, Romania, Russia, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey, the United Kingdom, and Ukraine. We performed a multiple regression analysis, after adjusting for possible confounders, including the number of diagnostic tests, the onset of the epidemic (days) in each country, and the Human Development Index (HDI). We retrieved data on the prevalence (number of cases/106 inhabitants), mortality (number of deaths/106 inhabitants), the number of diagnostic tests per 106 persons, and the time elapsed since the onset of the epidemic (days since January 1, 2020), in each country, from the Worldometer website (https://www.worldometers.info/coronavirus/#countries).7Worldmeter COVID-19 Coronavirus pandemic. https://www.worldometers.info/coronavirus/#countries Accessed 1 Feb 2021.Google Scholar The HDI reflects three main dimensions of human development: life expectancy at birth, education, and gross national income per capita. For each country, these data were obtained from the United Nations Human Development Reports website (http://hdr.undp.org/en/content/latest-human-development-index-ranking).8Human Development Index RankingHuman Development Reports. United Nations Development Programme, 2020http://hdr.undp.org/en/content/latest-human-development-index-rankingGoogle Scholar Data on the distribution of ACE genotypes were collected from recent studies.3Yamamoto N. Ariumi Y. Nishida N. Yamamoto R. Bauer G. Gojobori T. et al.SARS-CoV-2 infections and COVID-19 mortalities strongly correlate with ACE1 I/D genotype.Gene. 2020; 758144944https://doi.org/10.1016/j.gene.2020.144944Crossref Scopus (108) Google Scholar, 5Bellone M. Calvisi S.L. ACE polymorphisms and COVID-19-related mortality in Europe.J Mol Med (Berl). 2020; 98: 1505-1509https://doi.org/10.1007/s00109-020-01981-0Crossref PubMed Scopus (30) Google Scholar, 6Aung A.K. Aitken T. Teh B.M. Yu C. Ofori-Asenso R. Chin K.L. et al.Angiotensin converting enzyme genotypes and mortality from COVID-19: an ecological study.J Infect. 2020; 81: 961-965https://doi.org/10.1016/j.jinf.2020.11.012.7Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar The multiple regression analysis revealed no significant associations between the ACE I/D polymorphism and the log-transformed prevalence of COVID-19 (DD genotype: partial r = 0.161, P = 0.386; ID genotype: partial r = −0.375, P = 0.841; II genotype: partial r = −0.129, P = 0.490). Moreover, the ACE I/D polymorphism was not associated with the log-transformed mortality (DD genotype: partial r = 0.191, P = 0.302; ID genotype: partial r = 0.343, P = 0.855; II genotype: partial r = −0.218, P = 0.238). The lack of associations between the ACE I/D polymorphisms and COVID-19 prevalence or mortality could arise from the fact that there was a significant change in the age structure of patients during the pandemic. During the second pandemic wave, the number of younger patients increased. Importantly, in European populations, the prevalence of the ACE-D allele was found to be age-dependent; thus, higher frequencies of the ACE-D allele were detected among older individuals,9Zajc Petranović M. Skarić-Jurić T. Smolej Narančić N. Tomas Z. Krajačić P. Miličić J. et al.Angiotensin-converting enzyme deletion allele is beneficial for the longevity of Europeans.Age (Dordr). 2012; 34: 583-595https://doi.org/10.1007/s11357-011-9270-0Crossref PubMed Scopus (26) Google Scholar who were most affected by COVID-19 infections during first pandemic wave. Population-level studies have some inherent limitations, due to the ecological study design. Therefore, future studies are needed, based on the different clinical strata of COVID-19 manifestations (i.e., asymptomatic, mild, severe and fatal), to clarify the impact of the ACE I/D polymorphism on SARS-CoV-2 infections. Moreover, the frequencies of the ACE-D allele and ACE-DD genotype are associated with many different diseases and/or conditions,10Dević Pavlić S. Nadalin S. Starčević Čizmarević N. Buretić-Tomljanović A. Radojčić Badovinac A. Ristić S Could angiotensin-converting enzyme 1 I/D polymorphism be a modificator of COVID-19 response in different populations, diseases, and/or conditions?.J Renin Angiotensin Aldosterone Syst. 2020; 211470320320957157https://doi.org/10.1177/1470320320957157Crossref Scopus (2) Google Scholar including some that might increase the risk of COVID-19 mortality, such as diabetes and hypertension. Therefore, it might be relevant, in future studies, to include those diseases and/or conditions as potential confounders. The authors declare no conflict of interest. This work was supported by the University of Rijeka, Croatia (uniri-biomed-18-137).

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 similar to 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.