Metabolic changes, inflammation and mortality in psychotic disorders

People with psychotic disorders have an increased risk of obesity, cardiovascular disease and diabetes. Together with a high risk for suicide, these lead to a reduction of the average lifespan by 15-20 years. Identifying clinical predictors of cardiovascular disease and mortality in psychotic disorders is important. This study examined anthropometric measures and lipid and glucose metabolism in people with first-episode psychosis (FEP). Predictors of weight gain and increased waist circumference were analysed. In addition, predictors of systemic low-grade inflammation as measured by high-sensitivity C-reactive protein (hs-CRP), an independent risk factor for cardiovascular disease and mortality, were examined. This study also investigated mortality and factors associated with mortality risk in non-affective psychosis (NAP) during a 13-year follow-up using data from the Health 2000 Study. People with FEP and healthy controls had similar body mass index, waist circumference, hs-CRP and fasting glucose at study baseline. The levels of total and low-density lipoprotein cholesterol, triglyceride, insulin and insulin resistance were increased in FEP as compared to controls already at baseline. Glucose and lipid parameters did not change significantly during the follow-up in FEP. However, marked weight gain (median 9.6 kg) and increase in waist circumference (6.0 cm) were observed during the first year of treatment. Insulin resistance and olanzapine medication at baseline predicted more weight gain during the follow-up. Insulin resistance also predicted increase in waist circumference. An over 2.5-fold increase in hs-CRP was observed during the follow-up in FEP, and the levels of hs-CRP were strongly related to waist circumference and female gender. The mortality risk in NAP was increased threefold, and remained increased over twofold when adjusted for known risk factors for mortality. Antipsychotic medication use was associated with lower natural-cause mortality risk, and smoking with increased risk. In line with previous studies, people with FEP had a significant increase in body weight and waist circumference during the first year of treatment of the psychotic disorder. Insulin resistance predicted weight gain and abdominal obesity, which is a novel and clinically important finding. Low-grade inflammation was strongly related to the increase in abdominal adiposity, suggesting that hs-CRP is primarily a marker of metabolic risk in people with FEP. Smoking cessation should be promoted to reduce the excess mortality in psychotic disorders. Improving detection and quality of treatment of physical diseases in people with psychotic disorders seems necessary to prevent premature mortality.Psykoottisiin häiriöihin liittyy kohonnut lihavuuden, sydän- ja verisuonisairauksien ja diabeteksen riski. Yhdessä häiriöihin liittyvän korkean itsemurhariskin kanssa nämä johtavat 15-20 vuotta lyhyempään keskimääräiseen elinikään. Tämän tutkimuksen tavoite oli tunnistaa varhaisia fyysisten sairauksien ja kuolleisuuden riskiä ennustavia tekijöitä psykoottisia häiriöitä sairastavilla. Tutkimuksessa selvitettiin psykoosiin ensimmäistä kertaa sairastuneiden painon ja vyötärönympäryksen sekä rasva- ja sokeriaineenvaihdunnan muutoksia psykoosin ensimmäisen hoitovuoden aikana. Lisäksi tutkittiin tekijöitä, jotka ennustavat painonnousua ja vyötärönympäryksen kasvua. Matala-asteisen tulehduksen kehittymistä seurattiin määrittämällä herkän C-reaktiivisen proteiinin (CRP) pitoisuus, joka on itsenäinen sydän- ja verisuonitautien sekä kuolleisuuden riskitekijä. Psykoosiin liittyvää kuolleisuutta ja kuolleisuuden riskitekijöitä tutkittiin 13-vuoden seurannan aikana Terveys 2000 -tutkimusaineistoa käyttäen. Tutkimuksen alkaessa ensipsykoosiin sairastuneiden ja verrokkihenkilöiden välillä ei ollut eroa painoindeksissä, vyötärönympäryksessä, paastoglukoosissa tai matala-asteisessa tulehduksessa. Kokonais- ja LDL-kolesteroli, triglyseridit, insuliini ja insuliiniresistenssi olivat kuitenkin koholla ensipsykoosiryhmässä jo tutkimuksen alussa. Glukoosi- ja rasva-arvoissa ei todettu muutoksia seurannan aikana. Ensipsykoosiin sairastuneilla todettiin huomattava painonnousu (mediaani 9,6 kg) ja vyötärönympäryksen kasvu (6,0 cm) ensimmäisen hoitovuoden aikana. Painonnousu oli suurempaa niillä, joilla todettiin tutkimuksen alkaessa insuliiniresistenssi tai käytössä oli olantsapiinilääkitys. Insuliiniresistenssi ennusti myös suurempaa vyötärönympäryksen kasvua. Ensipsykoosiin sairastuneiden herkän CRP:n pitoisuus nousi 2,5-kertaiseksi seurannan aikana. Tämä selittyi vyötärölle kertyneellä rasvalla ja oli korostuneempaa naisilla. Ei-affektiivisia psykoottisia häiriöitä sairastavien kuolemanriski oli tutkimusväestöön verrattuna kolminkertainen. Kun otettiin huomioon yleisesti tunnetut kuolleisuuden riskitekijät, kuolemanriski oli edelleen kaksinkertainen. Psykoosilääkitystä käyttäneillä tautikuolleisuus oli vähäisempää, ja tupakoivilla kuolleisuusriski oli suurempi. Tutkimuksessa todettiin odotetusti, että ensipsykoosiin sairastuvien paino nousee ja vyötärönympärys kasvaa huomattavasti jo ensimmäisen hoitovuoden aikana. Matala-asteisen tulehduksen kehittymisen ensipsykoosissa todettiin liittyvän ensisijaisesti vyötärölihavuuteen. Uutena löydöksenä todettiin, että ensipsykoosin hoidon alussa todettu insuliiniresistenssi voi olla painonnousun ja vyötärölihavuuden varhainen ja kliinisesti käyttökelpoinen riskitekijä. Psykoosiin sairastuneita tulisi tukea tupakoinnin lopettamiseen ennenaikaisen kuolleisuuden vähentämiseksi. Lisäksi fyysisten sairauksien ehkäisyyn, tunnistamiseen ja hoidon laatuun tulisi psykoosiin sairastuneilla kiinnittää erityistä huomiota

Primary Metabolite Responses to Oxidative Stress in Early-Senescing and Paraquat Resistant Arabidopsis thaliana rcd1 (Radical-Induced Cell Death1)

Rcd1 (radical-induced cell death1) is an Arabidopsis thaliana mutant, which exhibits high tolerance to paraquat [methyl viologen (MV)], herbicide that interrupts photosynthetic electron transport chain causing the formation of superoxide and inhibiting NADPH production in the chloroplast. To understand the biochemical mechanisms of MV resistance and the role of RCD1 in oxidative stress responses, we performed metabolite profiling of wild type (Col-0) and rcd1 plants in light, after MV exposure and after prolonged darkness. The function of RCD1 has been extensively studied at transcriptomic and biochemical level, but comprehensive metabolite profiling of rcd1 mutant has not been conducted until now. The mutant plants exhibited very different metabolic features from the wild type under light conditions implying enhanced glycolytic activity, altered nitrogen and nucleotide metabolism. In light conditions, superoxide production was elevated in rcd1, but no metabolic markers of oxidative stress were detected. Elevated senescence-associated metabolite marker levels in rcd1 at early developmental stage were in line with its early-senescing phenotype and possible mitochondrial dysfunction. After MV exposure, a marked decline in the levels of glycolytic and TCA cycle intermediates in Col-0 suggested severe plastidic oxidative stress and inhibition of photosynthesis and respiration, whereas in rcd1 the results indicated sustained photosynthesis and respiration and induction of energy salvaging pathways. The accumulation of oxidative stress markers in both plant lines indicated that MV-resistance in rcd1 derived from the altered regulation of cellular metabolism and not from the restricted delivery of MV into the cells or chloroplasts. Considering the evidence from metabolomic, transcriptomic and biochemical studies, we propose that RCD1 has a negative effect on reductive metabolism and rerouting of the energy production pathways. Thus, the altered, highly active reductive metabolism, energy salvaging pathways and redox transfer between cellular compartments in rcd1 could be sufficient to avoid the negative effects of MV-induced toxicity.Peer reviewe

Low-grade inflammation in first-episode psychosis is determined by increased waist circumference

Psychosis is associated with low-grade inflammation as measured by high-sensitivity C-reactive protein (hs-CRP), a risk factor for cardiovascular events and mortality in the general population. We investigated the relationship between hs-CRP and anthropometric and metabolic changes in first-episode psychosis (FEP) during the first treatment year. We recruited 95 FEP patients and 62 controls, and measured longitudinal changes in hs-CRP, weight, waist circumference, insulin resistance, and lipids. We used linear mixed models to analyze the longitudinal relationship between hs-CRP and clinical, anthropometric and metabolic measures. At baseline, patients with FEP had higher levels of insulin resistance, total and low-density lipoprotein cholesterol, apolipoprotein B, and triglycerides. Baseline weight, waist circumference, hs-CRP, fasting glucose, and high-density lipoprotein cholesterol were similar between patients and controls. Marked increases in anthropometric measures and hs-CRP were observed in FEP during the 12-month follow-up. However, glucose and lipid parameters did not change significantly. In the mixed models, waist circumference and female sex were significant predictors of hs-CRP levels in FEP. Prevention of the early development of abdominal obesity in FEP is crucial, as abdominal obesity is accompanied by chronic low-grade inflammation, which increases further the cardiovascular risk in this vulnerable population.Peer reviewe

Is It Possible to Predict the Future in First-Episode Psychosis?

The outcome of first-episode psychosis (FEP) is highly variable, ranging from early sustained recovery to antipsychotic treatment resistance from the onset of illness. For clinicians, a possibility to predict patient outcomes would be highly valuable for the selection of antipsychotic treatment and in tailoring psychosocial treatments and psychoeducation. This selective review summarizes current knowledge of prognostic markers in FEP. We sought potential outcome predictors from clinical and sociodemographic factors, cognition, brain imaging, genetics, and blood-based biomarkers, and we considered different outcomes, like remission, recovery, physical comorbidities, and suicide risk. Based on the review, it is currently possible to predict the future for FEP patients to some extent. Some clinical features-like the longer duration of untreated psychosis (DUP), poor premorbid adjustment, the insidious mode of onset, the greater severity of negative symptoms, comorbid substance use disorders (SUDs), a history of suicide attempts and suicidal ideation and having non-affective psychosis-are associated with a worse outcome. Of the social and demographic factors, male gender, social disadvantage, neighborhood deprivation, dysfunctional family environment, and ethnicity may be relevant. Treatment non-adherence is a substantial risk factor for relapse, but a small minority of patients with acute onset of FEP and early remission may benefit from antipsychotic discontinuation. Cognitive functioning is associated with functional outcomes. Brain imaging currently has limited utility as an outcome predictor, but this may change with methodological advancements. Polygenic risk scores (PRSs) might be useful as one component of a predictive tool, and pharmacogenetic testing is already available and valuable for patients who have problems in treatment response or with side effects. Most blood-based biomarkers need further validation. None of the currently available predictive markers has adequate sensitivity or specificity used alone. However, personalized treatment of FEP will need predictive tools. We discuss some methodologies, such as machine learning (ML), and tools that could lead to the improved prediction and clinical utility of different prognosticmarkers in FEP. Combination of differentmarkers inMLmodels with a user friendly interface, or novel findings from e.g., molecular genetics or neuroimaging, may result in computer-assisted clinical applications in the near future.Peer reviewe

A Natural History of Erectile Dysfunction in Elderly Men: A Population-Based, Twelve-Year Prospective Study

There is a wide variation in the development and course of erectile dysfunction (ED) in men, which confirms the need for prospective studies. We conducted a cross-sectional analysis among the general male population at the baseline (n = 359) and in a follow-up survey (n = 218) 12 years later. The prospective 12-year study included 189 men. ED was assessed using the International Index of Erectile Function questionnaire. The mean age of the participants was 62.0 years at the baseline, while at the 12-year follow-up it was 71.6 years. The crude prevalence of ED was 61.6% at the baseline and 78.9% at the follow-up, and the prevalence tended to increase with age. All of the men aged 75 years or more had at least mild ED. The incidence of ED in every thousand person years was 53.5. A total of 54.5% of the men experienced ED progression, while 39.2% reported no changes in erectile function, and 6.3% experienced ED regression during the 12-year study. The likelihood of ED progression was higher in the older compared with younger age group (odds ratio, OR 5.2 (95% CI: 1.1–26.2)), and the likelihood of ED regression was lower among men with increased depression symptoms (OR 0.3 (95% CI: 0.1–0.6)) and among men with a decreased interest in their sexual life (OR 0.1 (95% CI: 0.0–0.6)). Lifestyle factors such as the consumption of alcohol and smoking were not significantly associated with ED

Mitä suomalainen tyypin 2 diabeteksen ehkäisytutkimus DPS on opettanut?

Vertaisarvioitu.Suomalainen diabeteksen ehkäisytutkimus (Diabetes Prevention Study, DPS) loi näyttöön pohjautuvan perustan tyypin 2 diabeteksen ehkäisylle elintapaohjauksella Suomessa ja maailmanlaajuisesti. DPS-tutkimuksen tehostettu elintapaohjaus, jonka tavoitteena olivat suositusten mukainen ruokavalio, fyysinen aktiivisuus ja painon väheneminen, vaikutti suotuisasti diabetekseen liittyviin aineenvaihduntahäiriöihin ja pienensi diabeteksen ilmaantuvuutta 58 % henkilöillä, joiden glukoosinsieto oli lähtötilanteessa heikentynyt. Elintapaohjaus tehosi myös perinnöllisen diabetesalttiuden yhteydessä. Jatkoseurannassa elintapaohjauksen vaikutus diabeteksen ilmaantuvuuteen säilyi ainakin 13 vuoden ajan, vaikka elintapaohjaus lopetettiin keskimäärin neljän vuoden jälkeen. DPS-tutkimuksen aineistoa on tähän mennessä analysoitu ja raportoitu sekä sen tuloksia hyödynnetty monipuolisesti, ja osallistujien seuranta jatkuu rekisteritutkimuksena. Näin saamme tietoa myös diabeteksen lisäsairauksien kehittymisestä.Peer reviewe

Association of ADIPOR2 gene variants with cardiovascular disease and type 2 diabetes risk in individuals with impaired glucose tolerance: the Finnish Diabetes Prevention Study

<p>Abstract</p> <p>Background</p> <p>Adiponectin is an adipokine with insulin-sensitising and anti-atherogenic effects. Two receptors for adiponectin, ADIPOR1 and ADIPOR2, have been characterized that mediate effects of adiponectin in various tissues. We examined whether genetic variation in <it>ADIPOR2 </it>predicts the development of cardiovascular disease (CVD) and/or Type 2 Diabetes (T2DM) in individuals with impaired glucose tolerance (IGT) participating the Finnish Diabetes Prevention Study (DPS).</p> <p>Methods</p> <p>CVD morbidity and mortality data were collected during a median follow-up of 10.2 years (range 1-13 years) and conversion from IGT to T2DM was assessed during a median follow-up of 7 years (range 1-11 years). Altogether eight SNPs in the <it>ADIPOR2 </it>locus were genotyped in 484 participants of the DPS. Moreover, the same SNPs were genotyped and the mRNA expression levels of <it>ADIPOR2 </it>were determined in peripheral blood mononuclear cells and subcutaneous adipose tissue samples derived from 56 individuals participating in the Genobin study.</p> <p>Results</p> <p>In the DPS population, four SNPs (rs10848554, rs11061937, rs1058322, rs16928751) were associated with CVD risk, and two remained significant (p = 0.014 for rs11061937 and p = 0.020 for rs1058322) when all four were included in the same multi-SNP model. Furthermore, the individuals homozygous for the rare minor alleles of rs11061946 and rs11061973 had increased risk of converting from IGT to T2DM. Allele-specific differences in the mRNA expression levels for the rs1058322 variant were seen in peripheral blood mononuclear cells derived from participants of the Genobin study.</p> <p>Conclusions</p> <p>Our results suggest that SNPs in the <it>ADIPOR2 </it>may modify the risk of CVD in individuals with IGT, possibly through alterations in the mRNA expression levels. In addition an independent genetic signal in <it>ADIPOR2 </it>locus may have an impact on the risk of developing T2DM in individuals with IGT.</p> <p>Trial registration number</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00981877">NCT00518167</a></p