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Purpose Evidence on the association between dairy intake and depression is conflicting. Given numerous dietary guidelines recommend the consumption of low-fat dairy products, this study examined associations between total dairy, high-fat dairy, and low-fat dairy intake and the prevalence of elevated depressive symptoms. Associations between dairy products, which differed in both fat content and fermentation status, and depressive symptoms were also explored. Methods This cross-sectional study included 1600 Finnish adults (mean age 63 ± 6 years; 51% female) recruited as part of the Kuopio Ischaemic Heart Disease Risk Factor Study. Dairy intake was assessed using 4-day food records. Elevated depressive symptoms were defined as having a score ≥ 5 on the Diagnostic and Statistical Manual of Mental Disorders-III Depression Scale, and/or regularly using one or more prescription drugs for depressive symptoms. Results In total, 166 participants (10.4%) reported having elevated depressive symptoms. Using multivariate logistic regression models, intake in the highest tertile of high-fat dairy products (OR 0.64, 95% CI 0.41–0.998, p trend = 0.04) and high-fat non-fermented dairy products (OR 0.60, 95% CI 0.39–0.92, p trend = 0.02) were associated with reduced odds for having elevated depressive symptoms. Whereas no significant association was observed between intake of total dairy, low-fat dairy, or other dairy products, and depressive symptoms. Conclusion Higher intake of high-fat dairy and high-fat non-fermented dairy products were associated with reduced odds for having elevated depressive symptoms in middle-aged and older Finnish adults. Given the high global consumption of dairy products, and widespread burden of depression, longitudinal studies that seek to corroborate these findings are required.

Despite the putative health benefits of fermented dairy products, evidence on the association between fermented dairy and nonfermented dairy intake, and depression incidence is limited.This study examined cross-sectional and prospective associations between total dairy, fermented dairy, and nonfermented dairy intake with 1) the presence of elevated depressive symptoms and 2) the risk of a future hospital discharge or outpatient diagnosis of depression.Data from 2603 Finnish men (aged 42-60 y), recruited as part of the Kuopio Ischaemic Heart Disease Risk Factor Study, were included. Multivariable logistic regression models were used to examine ORs and 95% CIs for elevated depressive symptoms (Human Population Laboratory scale ≥5 points) at baseline. Cox proportional hazards regression models were used to estimate HRs and 95% CIs between dairy categories and risk of depression diagnoses.In cross-sectional analyses, fermented dairy intake in the highest (compared with lowest) tertile was associated with lower odds of having elevated depressive symptoms (adjusted OR: 0.70; 95% CI: 0.52, 0.96). Each 100-g increase in nonfermented dairy intake was associated with higher odds of having elevated depressive symptoms (adjusted OR: 1.06; 95% CI: 1.01, 1.10). During a mean follow-up time of 24 y, 113 males received a diagnosis of depression. After excluding cheese intake, higher fermented dairy intake was associated with a lower risk of depression diagnosis (adjusted HR: 0.62; 95% CI: 0.38, 1.03), which was strengthened after excluding those with elevated depressive symptoms at baseline (adjusted HR: 0.55; 95% CI: 0.31, 0.99), whereas nonfermented dairy intake in the highest tertile was associated with a 2-fold higher risk of depression (adjusted HR: 2.02; 95% CI: 1.20, 3.42).Fermented dairy and nonfermented dairy intake were differentially associated with depression outcomes when examined cross-sectionally and over a mean period of 24 y. These findings suggest that dairy fermentation status may influence the association between dairy intake and depression in Finnish men. The KIHD study was registered at clinicaltrials.gov as NCT03221127.

Background Alexithymia has been related to adult health care use. We investigated the association between alexithymia and the utilization of primary health care services by adolescents and young adults. Methods The participants (n = 751, aged 13–18 years) in this 5-year follow-up study were assessed with the 20-item Toronto Alexithymia Scale (TAS-20) and its three subscales, difficulty identifying feelings (DIF), difficulty describing feelings (DDF) and externally oriented thinking (EOT), and the 21-item Beck Depression Inventory (BDI). Primary health care data were gathered from health care centre registers in 2005–10. Generalized linear models and mediation analyses were used. Results An increase in the TAS-20 total score correlated with a higher number of primary health care and emergency care visits, but in multivariate general linear models, TAS-20 total scores were no longer significant. Younger age, female gender and an increase in the baseline EOT score are associated with a higher number of both primary health care and emergency room visits. In females, a smaller change in the EOT score from baseline to follow-up was associated with a higher number of primary health care visits. In mediation analyses, EOT had a direct effect on a higher number of primary health care and emergency room visits, whereas the BDI score mediated the incremental effect of DIF and DDF on visit numbers. Conclusions The results suggest that an EOT style independently increases health care use by adolescents, whereas the effects of difficulties identifying and describing feelings on health care use are mediated by symptoms of depression.

Self-cutting is common among adolescents. However, studies examining protective factors are rare. It has been suggested that social support may protect against self-cutting in adolescence. The aim of this study was to investigate the possible association of social relationships with the initiation of self-cutting. Methods The participants were community-dwelling Finnish adolescents (N = 4171) aged 13-18 years at baseline. The follow-up assessment was conducted 5 years later (N = 794). Those adolescents who had self-cut before the baseline assessment (N = 134) were excluded from the analysis, leaving a total of 660 participants to be analyzed. In this group, 37 adolescents initiated self-cutting during the 5-year follow-up period and 623 did not. Cox's proportional hazards models were used with several adjustments for possible confounding factors. Findings A higher age, male gender, good relationships with siblings, weekly meetings with friends, and personal experience of not being lonely associated with the noninitiation of self-cutting during the follow-up period. Good relationships with parents or peers had no association with the initiation of self-cutting. Depressive symptoms mediated the effect of subjective loneliness on initiating self-cutting. Conclusions Social support produced by friends may have a protective effect against self-cutting.

Excessive alcohol use results in cerebellar damage in adults, but there has been less research on how alcohol use during adolescence affects the cerebellum. In this study, we observed that heavy drinking from adolescence to young adulthood was associated with altered volumes of cerebellar lobules. The study included two groups consisting of 33 heavy-drinking and 25 light-drinking participants. The heavy-drinking participants were highly functional young adults without alcohol use disorder, but with a history of regular heavy alcohol consumption. The participants were 13–18 years old at baseline and were followed for 10 years. At the age of 21–28 years, the participants underwent magnetic resonance imaging (MRI). From the MR images, the cerebellum was segmented into 12 lobules using the CERES pipeline. Heavy drinking did not influence the absolute cerebellar volume, but changes were observed in posterior cerebellar lobules associated with motor and cognitive functions. The absolute volume (p = 0.038) and gray matter volume (p = 0.034) of Crus II (hemispheres combined) were smaller in the heavy-drinking group. Furthermore, the relative volume of the right VIIIB lobule was larger in the HD group (p = 0.036). However, there were no differences in the absolute right VIIIB volumes (p = 0.198) between the groups. Our results suggest changes in the cerebellum in healthy young adults with a history of heavy drinking from adolescence. The exact implications and significance of these findings require further research.

OBJECTIVE Type 2 diabetes is a chronic disease and a serious global public health concern increasing both mortality and morbidity. Previous studies have found evidence for an association between early psychological stress and diabetes later in life. METHODS This study examined the association between parental alcohol problems and parental divorce and the incidence of type 2 diabetes in Finnish men aged 42 to 61 years (n = 754) in a prospective setting. Information on parental alcohol problems and parental divorce was derived from school records and subjective experiences of the same events from self-rated questionnaires. The average follow-up time for the participants until the first type 2 diabetes diagnosis was 23.3 years (25th-75th percentile, 21.2-27.9 years). RESULTS Cox regression analyses revealed that parental alcohol problems (hazard ratio = 3.09, 95% confidence interval = 1.38-6.88) were associated with an increased risk of type 2 diabetes during the follow-up, even after adjustment for age, marital status, education, Human Population Laboratory Depression Scale scores, smoking, alcohol consumption, body mass index, and serum high-sensitivity C-reactive protein. In a similar model, parental divorce (hazard ratio = 1.69, 95% confidence interval = 0.40-7.05) was not associated with an increased risk of type 2 diabetes during the follow-up. CONCLUSIONS Our findings suggest that not all adverse childhood experiences contribute equally to the risk of type 2 diabetes. Parental alcohol problems, but not parental divorce, were associated with an increased risk of type 2 diabetes in men. These findings highlight the need for early interventions targeting parents with excessive alcohol consumption to reduce their offspring's risk of life-style-related disorders.

The purpose of this study was to examine the factor structure of the Adolescent Dissociative Experiences Scale (A-DES) questionnaire with item response theory (IRT) methods, including an assessment of measurement invariance with differential item functioning (DIF) analysis. Three abbreviated versions of the A-DES (with 20, 10, and 5 items) were constructed based on the IRT and DIF statistics. The respondents in this population-based study (N = 4,072) were 12- to 19-year-old Finnish junior and senior high school students. A one-factor model of the A-DES was best supported, and the original theoretical four-factor model showed poor fit. The A-DES turned out to have high measurement invariance with respect to age, gender, transgender tendencies, having multiple friends, the use of illegal substances, and experience of being bullied. Compared to the full 30-item A-DES, abbreviated versions of the questionnaire retained acceptable information value and empirical reliability in the clinically relevant range of symptomatology. Further psychometric studies are needed especially with regards to clinical use.

Major depressive disorder (MDD) is a recurrent disorder that incurs a high societal burden. However, the etiology of MDD remains unclear. The functioning of several systems associated with the etiopathogenesis of MDD, such as inflammatory and stress systems, is partially modulated by the dipeptide carnosine.The study comprised 99 MDD patients and 253 non-depressed controls aged 20-71 years. Fasting serum samples were analyzed using ultra-performance liquid chromatography coupled to mass spectrometry to determine the serum levels of carnosine and its constituent, histidine. We compared these metabolites in three different settings: 1) MDD patients vs. non-depressed controls and 2) remitted vs. non-remitted MDD patients, as well as 3) changes in the metabolite levels during the follow-up period within a) the remitted group and b) the non-remitted group. In addition, we assessed the possible effect of medications on the measured metabolites.We observed higher serum levels of carnosine in the MDD group compared to the control group at baseline (OR = 1.895, 95%CI = 1.223-2.937, p = 0.004). Elevated serum levels of carnosine were also associated with a longer duration of the depressive episode (Z = 0.406, p = 0.001). However, the use of any antipsychotic medication (n = 36) was associated with lowered carnosine levels (p = 0.010 for use vs. non-use). At the follow-up, remitted and non-remitted participants displayed no significant differences in their carnosine levels (Z = -0.14, p = 0.891) or histidine (Z = -1.39 p = 0.164).An increase in circulating carnosine may characterize depressive episodes and may represent a protective homeostatic reaction against MDD-related oxidative stress and inflammation.

Sense of coherence (SOC) scale measures one’s orientation to life. SOC is the core construct in Antonovsky’ssalutogenic model of health. It has been shown that weak SOC correlates with poor perceived health, low qualityof life, and increased mortality. Some studies have indicated that SOC is not stable across life, but there are noprevious studies on how a change of SOC is reflected in mortality. However, there is some evidence that a changein perceived quality of life is associated with mortality. The study explores the association between the change inSOC and mortality using longitudinal data from a cohort of middle-aged Finnish men recruited between 1986and 1989. Approximately 11 years after the baseline examinations, between 1998 and 2001, 854 men returnedthe SOC questionnaire a second time. The baseline SOC was adjusted for the regression to the mean phenomenonbetween the two measurements. The hazard ratios of the SOC difference scores were adjusted for initial SOC ageand 12 somatic risk factors of mortality (alcohol consumption, blood pressure, body mass index, cholesterolconcentration, physical activity, education, smoking, marital status, employment status, history of cancer, his-tory of cardiovascular disease and diabetes). SOC was not stable among middle-aged Finnish men and a declinein SOC was associated with an increased hazard of all-cause mortality. In the fully adjusted model, a decrease ofone standard deviation (SD) of the SOC mean difference increased the mortality hazard by about 35 %, two SDsdecrease about 70 %, and 2.5 SDs about 100 %. Strengthening SOC showed a limited association with decreasingmortality hazards in the age-adjusted model. Policies, strategies, or plans, supporting SOC in the middle-age mayhelp to decrease mortality and increase quality of life in later years. CC BY 4.0Corresponding author: E-mail address: ilkkapi@uef.fi (I. Piiroinen)

Background While considered less severe than major depressive disorder (MDD), chronic depression has a devastating effect on people's lives. Metabolic alterations related to chronicity are still widely unknown. We investigated metabolic alterations in patients with depression and compared the episodic and chronic forms. Methods The study participants comprised 76 adolescent outpatients (33 MDD, 43 chronic depression). Patients’ serum samples were analyzed with targeted metabolite analysis, yielding results for 102 metabolites associated, for example, with amino acid, energy, lipid, and one-carbon metabolism. Results After controlling for background factors, the chronic depression group had higher levels of choline (Cohen's d = 0.52 and unadjusted 95% confidence interval [0.05, 0.98]), glutamine (d = 0.42 [-0.04, 0.88]), glycine (d = 0.41 [-0.04, 0.87]), glycine betaine (d = 0.48 [0.02, 0.94]), guanidinoacetic acid (d = 0.23 [-0.23, 0.68]), octanoylcarnitine (d = 0.60 [0.13, 1.06]), phosphoethanolamine (d = 0.34 [-0.12, 0.79]) and succinate (d = 0.61 [0.14, 1.07]), and lower levels of glutamate (d = -0.66 [-1.12, -0.18]) when compared to the MDD group, although these differences did not remain after correction for multiple testing. Limitations The sample size was small for targeted metabolomic analysis, and the study did not include a healthy control group. Conclusions These preliminary results indicate putative differences in one-carbon metabolism and energy metabolism between chronic depression and MDD, possibly due to long-term chronic stress. Metabolic profiles appear to have the potential firstly to identify and distinguish different types of depression, and secondly to help in personalizing treatments in the future.

Our aim was to analyze metabolite profile changes in serum associated with moderate-to-heavy consumption of alcohol in young adults and to evaluate whether these changes are connected to reduced brain gray matter volumes. These study population consisted of young adults with a 10-year history of moderate-to-heavy alcohol consumption (n = 35) and light-drinking controls (n = 27). We used the targeted liquid chromatography mass spectrometry method to measure concentrations of metabolites in serum, and 3.0 T magnetic resonance imaging to assess brain gray matter volumes. Alterations in amino acid and energy metabolism were observed in the moderate-to-heavy drinking young adults when compared to the controls. After correction for multiple testing, the group of moderate-to-heavy drinking young adults had increased serum concentrations of 1-methylhistamine (p = 0.001, d = 0.82) when compared to the controls. Furthermore, concentrations of 1-methylhistamine (r = 0.48, p = 0.004) and creatine (r = 0.52, p = 0.001) were negatively correlated with the brain gray matter volumes in the females. Overall, our results show association between moderate-to-heavy use of alcohol and altered metabolite profile in young adults as well as suggesting that some of these changes could be associated with the reduced brain gray matter volume. (C) 2018 Elsevier Inc. All rights reserved.

Objectives Loneliness and social isolation both increase mortality and are likely to affect health via several pathways. However, information on the potential pathways remains scarce. We investigated the associations between loneliness, social isolation, and mortality, and possible mechanisms underlying these connections. Methods The analyzed data comprised a prospective population-based cohort of Finnish men (42–61 years at baseline, n = 2588) who were followed up for an average of 23.2 years. Mortality data were obtained from the national population register in 2012. Cox proportional hazards analysis with adjustments for possible confounding factors was used to examine the associations between loneliness and social isolation at baseline and all-cause, injury, cancer, and cardiovascular disease (CVD) mortality. Mediation analysis was conducted to investigate the mechanisms underlying the associations of loneliness and social isolation with mortality. Results Loneliness predicted all-cause mortality, even after adjustments for all covariates. Loneliness predicted cancer mortality, except after adjustments for lifestyle variables or Human Population Laboratory (HPL) depression scores, and also predicted CVD mortality, except after adjustments for HPL depression scores. Social isolation predicted all-cause mortality and injury mortality. The effect of social isolation on all-cause mortality was mediated by loneliness and HPL depression scores. Conclusions Our findings suggest that both loneliness and social isolation increase the risk of all-cause mortality, while they have differing effects on different causes of death. Loneliness and depressive symptoms may mediate the effect of social isolation on increased mortality.

Purpose of the article There is growing interest in loneliness and its various adverse effects on mental and physical health. While depression is one of the adverse health effects associated with loneliness, there have been some limitations in previous studies: 1) Research has mostly been carried out either in depressed patient samples or in general population samples with depressive symptoms as an outcome, 2) the follow-up times have been rather short, and 3) the mechanisms through which loneliness associates with depression are still unclear. Materials and methods We examined the association between loneliness and incident depression and possible mechanisms underlying this association in a population-based sample of middle-aged men (N = 2339; mean age 53; mean follow-up time 23.5 years). The association between loneliness and depression was explored with Cox proportional hazard analysis, and mediation analyses were performed with the PROCESS macro for SPSS. We used 13 health and lifestyle-related variables as covariates for adjustments in multivariate models and as mediators in simple mediation models. Results Those with depression as an outcome (n = 99) had significantly higher loneliness scale scores at baseline, and baseline loneliness was associated with depression, despite adjustments for potential confounding factors. No mediating factors were observed. Conclusions There was a strong direct association between loneliness and the incidence of depression. Based on our results, we encourage future researchers to look for possible mediators in wider range of variables.

Background and purpose Image guided adaptive brachytherapy, the standard treatment for locally advanced cervical cancer (LACC), is a complex medical procedure that requires an experienced multidisciplinary team. The aims of this analysis were to assess (1) the learning curve of brachytherapy team, (2) dose-volume parameters, (3) the use of an interstitial component, and (4) the overall treatment time (OTT). Materials and methods Our study cohort comprised 117 LACC patients treated in Kuopio University Hospital with magnetic resonance imaging guided intracavitary (IC) or combined intracavitary/interstitial (IC/IS) high dose rate brachytherapy during 2009-2018. Target volumes and organs at risk (OAR) were contoured according to ICRU/GEC-ESTRO recommendations. Treatment plans were optimized individually without using standard loading patterns. Results Mean dose to 90% of the high-risk clinical target volume (HR-CTV D90) improved after the first 15 patients, however the team's learning curve to reliably fulfill the main planning aim (PA) of 85 Gy required a total 43 patients and more than 10 patients annually. Significant difference was detected between IC and IC/IS brachytherapy in achieving the PA of HR-CTV D90. Especially, HR-CTV volumes >30 cm3 benefitted from IS needles. Needle insertion did not cause serious complications. With the brachytherapy program, the OTT of patients from outside institutions was reduced to the same level as our own patients. Conclusion Brachytherapy requires good experience of multidisciplinary team and the continuous development of the program to fulfill PA and to avoid OTT prolongation. The use of IS needles is safe and improves the fulfillment of PA to target volume.

OBJECTIVE The aim of the study was to investigate the association between sense of coherence (SOC) and all-cause mortality in the general adult population. METHODS We conducted a systematic review and meta-analysis of prospective cohort studies. We searched eight electronic bibliographic databases for eligible studies. A random effects model and the restricted maximum likelihood method were used to calculate the pooled effect size. RESULTS Eight studies were eligible for the meta-analysis. The studies included 48,138 participants, of whom 5307 died during a median follow-up of 14.1 years (range, 8-29.5 years). Their age ranged from 20 to 80 years, and 53% of them were men. In the meta-analysis model of crude values, the risk of all-cause mortality for individuals with a weak SOC (lowest tertile) was 1.30 (95% confidence interval [CI] = 1.09-1.55, p = .003, I = 78.84%) compared with individuals with a strong SOC (highest tertile). In the model adjusted for age, the risk remained almost the same (risk ratio = 1.26, 95% CI = 1.15-1.38, p < .001, I = 69.59%). In the model adjusted for several other risk factors for mortality, the risk was still 1.17 (95% CI = 1.07-1.27, p < .001, I = 57.85%). CONCLUSIONS This meta-analysis shows that a weak SOC is associated with an increased risk of all-cause mortality in the general adult population. Future studies are needed to further develop assessment tools for SOC with good psychometric properties and to determine the disease processes that mediate the association of SOC with mortality.

Background: The aims of this study were to investigate the stability of alexithymia from adolescence to young adulthood, as well as the association between alexithymia, peer relationships, and symptoms of depression and dissociation. Methods: The participants (n = 755, aged 13–18 years) were assessed with self-rated questionnaires and the 20-item Toronto Alexithymia Scale (TAS-20) at baseline in 2005 and on follow-up in 2011. Results: The changes in the TAS-20 total score (t = −12.26) and the scores for its subscales, difficulty identifying feelings (DIF) (t = −4.04), difficulty describing feelings (DDF) (t = −5.10), and externally oriented thinking (EOT) (t = −18.23), were statistically significant (p < 0.001). Effect sizes (Cohen's d) for the change indicating absolute stability were small for DIF (−0.15) and DDF (−0.19), medium for TAS-20 total (−0.45), and large for EOT (−0.66) scores. Moderate correlations in test–retests with Spearman's ρ (TAS-20 total 0.46, DIF 0.41, DDF 0.39, EOT 0.43) indicated relative stability, whereas low intraclass correlation coefficients (ICCs) (respectively 0.41, 0.39, 0.37, 0.37) indicated poor reliability of test–retests. In regression analyses, poor relationships with peers, loneliness, and symptoms of depression and dissociation at baseline associated with alexithymia at baseline and on follow-up. Unlike EOT, increases in the TAS-20 total, DIF, and DDF scores during the 6-year follow-up associated with baseline symptoms of depression and dissociation. Conclusions: Alexithymia in adolescence is not always a reliable predictor of alexithymia in young adulthood. Mental health symptoms appear to affect the consistency of alexithymia during adolescent development. publishedVersion

Background Depression is a major public health challenge worldwide, and polyunsaturated fatty acids (PUFAs), especially n-3 PUFAs, have been found to inversely associate with the risk of depression. However, only few cross-sectional studies have investigated the association between dihomo-γ-linolenic acid (DGLA), an n-6 PUFA with anti-inflammatory effects, and depression. The aims of the present study were to examine an association between serum DGLA and the risk of depression, and to study whether the potential association is mediated via inflammation. Methods A 20-year prospective Kuopio Ischaemic Heart Disease Risk Factor (KIHD) follow-up study was conducted from 1984 to 1989 with 2179 middle-aged and older Finnish men (42–60 years old at baseline). The baseline concentrations of serum fatty acids, including DGLA, were determined. A hospital discharge diagnosis of depression was used as the main outcome and obtained from linkage to National Hospital Discharge Register. Serum C-reactive protein (CRP) levels were measured to assess inflammation. Results An inverse association between serum DGLA concentration and incidence of depression was found after adjustment for several potential confounders (Hazard ratio HR 0.53, CI 0.36–0.79, P=0.002). The association between DGLA and depression was not dependent on inflammation (P-interaction=0.618). Limitations Our findings may not be generalizable to individuals below middle-age or women. Moreover, we were unable to consider cases with mild depression in the longitudinal setting. Conclusions Higher serum DGLA concentrations may predict lower risk of develop depression in elderly men. Further studies are warranted to address potential mechanisms as mechanism behind this association remains unclear., final draft, peerReviewed

Globally, cancer is the second leading cause of death. Loneliness has been suggested as a risk factor for cancer mortality. However, connections between loneliness, social isolation, and cancer are poorly understood. In our longitudinal study (mean follow-up: 20.44 years) of 2570 middle-aged men, loneliness, social isolation, and health-related factors were measured at baseline. Cox proportional hazards analysis was used to examine the association between cancer incidence, loneliness, and social isolation. The effect of relationship status on cancer mortality among cancer patients was tested with the Kaplan-Meier method. Loneliness was associated with total cancer incidence after adjustments for tested lifestyle and health-related covariates. Social Isolation was associated with total cancer incidence, except when adjusted for lifestyle, diet, or Human Population Laboratory (HPL) Depression Scale scores. Loneliness was associated with lung cancer incidence, except when adjusted for HPL Depression Scale scores. There was no significant association between social isolation and lung cancer. Neither loneliness nor social isolation were connected with prostate or colorectal cancer. Being single at baseline was associated with worse survival outcomes for cancer patients. Our findings suggest that regardless of the social network size, loneliness among middle-aged men is associated with an increased likelihood of cancer.

Alcohol-related white matter (WM) microstructural changes have not been fully elucidated in adolescents. We aimed to investigate influences of subclinical alcohol use during adolescence on WM microstructure and to characterize those with serum metabolic alterations. 35 moderate-to-heavy drinkers (15 males, 20 females) and 27 controls (12 males, 15 females) were selected based on their ten-year Alcohol Use Disorders Identification Test scores measured at three time points. Magnetic resonance imaging was conducted at endpoint time. Whole brain analysis of fractional anisotropy (FA) was performed. Diffusivity indices in the significant regions were computed for between-group comparisons and correlation analyses with serum metabolite concentrations. Decreased FA was found in moderate-to-heavy drinking men in anterior corpus callosum, superior/anterior corona radiata and right inferior fronto-occipital fasciculus, accompanied by increased radial diffusivity and a smaller area of reduced axial diffusivity, which correlated with serum metabolites playing roles in energy metabolism, myelination and axonal degeneration. No significant difference in FA was detected between female or mixed-gender moderate-to-heavy drinking subjects and controls, supporting gender differences in the relationship between adolescent alcohol use and neurodevelopmental trajectories. Future researches with longitudinal imaging data are warranted for comprehensive evaluation on potentially reversible effects of alcohol use over adolescent brain.

Background and aims Cognitive impairment has been associated with excessive alcohol use, but its neural basis is poorly understood. Chronic excessive alcohol use in adolescence may lead to neuronal loss and volumetric changes in the brain. Our objective was to compare the grey matter volumes of heavy- and light-drinking adolescents. Design This was a longitudinal study: heavy-drinking adolescents without an alcohol use disorder and their light-drinking controls were followed-up for 10 years using questionnaires at three time-points. Magnetic resonance imaging was conducted at the last time-point. Setting The area near Kuopio University Hospital, Finland. Participants The 62 participants were aged 22–28 years and included 35 alcohol users and 27 controls who had been followed-up for approximately 10 years. Measurements Alcohol use was measured by the Alcohol Use Disorders Identification Test (AUDIT)-C at three time-points during 10 years. Participants were selected based on their AUDIT-C score. Magnetic resonance imaging was conducted at the last time-point. Grey matter volume was determined and compared between heavy- and light-drinking groups using voxel-based morphometry on three-dimensional T1-weighted magnetic resonance images using predefined regions of interest and a threshold of P

Long-term alcohol use affects cognitive and neurophysiological functioning as well as structural brain development. Combining simultaneous electroencephalogram (EEG) recording with transcranial magnetic stimulation (TMS) enables direct, in vivo exploration of cortical excitability and assessment of effective and functional connectivity. In the central nervous system, the effects of alcohol are particularly mediated by alterations in gamma-aminobutyric acid (GABA)ergic neurotransmission, and TMS-evoked potentials (TEPs) N45 and N100 in EEG are known to reflect GABAergic function. However, no previous studies have examined the effects of long-term alcohol use in adolescence on TEPs. In this study, a total of 27 young adults with heavy alcohol use in adolescence and 25 age-matched, gender-matched and education-matched controls with little or no alcohol use participated in TMS-EEG measurements. The motor cortex (M1) was stimulated with an intensity of 90 percent of the resting motor threshold of the abductor pollicis brevis muscle. No significant differences were found in the resting motor threshold, TEP latencies or neuropsychological functioning between the groups. We observed an increase in the global mean field power in the time window of 54- to 75-millisecond post-TMS, as well as significant topographical differences in the P60 and N100 in those with a history of heavy drinking. Furthermore, there was a marked increase in the GABAergic N45 amplitude in alcohol users. These findings suggest that long-term alcohol use in adolescence, even when not meeting the diagnostic criteria for a disorder, is associated with changes in connectivity and cortical excitability.

Introduction The purine cycle and altered purinergic signaling have been suggested to play a role in major depressive disorder (MDD). Nevertheless, data on this topic are scarce. Based on previous studies, we hypothesized that compared with non-depressed controls, MDD patients have distinct purine metabolite profiles. Methods The samples comprised 99 MDD patients and 253 non-depressed controls, aged 20–71 years. Background data were collected with questionnaires. Fasting serum samples were analyzed using ultra-performance liquid chromatography coupled to mass spectrometry (UPLC–MS) to determine seven purine cycle metabolites belonging to the purine cycle. We investigated the levels of these metabolites in three settings: (1) MDD patients vs. non-depressed controls and (2) remitted vs. non-remitted MDD patients, and also (3) within-group changes in metabolite levels during the follow-up period. Results In logistic regression adjusted for age, gender, smoking, alcohol use, physical exercise, glycosylated hemoglobin, and high-density lipoprotein cholesterol, lower levels of inosine (OR 0.89, 95% CI 0.82–0.97) and guanosine (OR 0.32, 95% CI 0.17–0.59), and higher levels of xanthine (OR 2.21, 95% CI 1.30–3.75) were associated with MDD vs. the non-depressed group. Levels of several metabolites changed significantly during the follow-up period in the MDD group, but there were no differences between remitted and non-remitted groups. Conclusions We observed altered purine metabolism in MDD patients compared with non-depressed controls. Furthermore, our observations suggest that circulating xanthine may accumulate in MDD patients.

Life satisfaction is known to be associated with several social and mental adversities. We examined whether social activities and relationships in adolescence are related to life satisfaction in young adulthood. The psychosocial background characteristics of the study subjects (n = 787, aged 13–18 years) were recorded by using self-rated questionnaires. Five years later, the Life Satisfaction (LS) scale was used to measure the participants' life satisfaction. Of the baseline variables, a low frequency of meeting with friends and subjective loneliness among males and a low number of recreational sporting hobbies among females associated with lower life satisfaction in young adulthood. The association between the frequency of meeting friends in adolescence and life satisfaction in young adulthood was mediated by the level of loneliness and Beck Depression Inventory (BDI) score in adolescence. We conclude that loneliness in adolescence may associate with low life satisfaction and related problems in young adulthood. Investing in support and social gatherings in the adolescent community may prevent youth loneliness.

Associations between adverse childhood experiences (ACEs) and cholesterol in depressed patients are unclear. Therefore, we compared 78 adult outpatients with major depressive disorder (MDD) with (n = 24) or without (n = 54) experiences of physical violence in childhood. Background data were collected with questionnaires, and total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured from fasting blood samples. Patients with a history of childhood physical violence had lower levels of TC than the control group. No differences were observed in HDL-C, LDL-C, or low-grade inflammation levels between the two groups. In multivariate models, decreased levels of TC were associated with childhood physical violence, and these associations remained significant after adjustments for age, gender, lifestyle, metabolic condition, socioeconomic situation, psychiatric status, suicidality, low-grade inflammation, the chronicity of depression, medications used and somatic diseases. At the 8-month follow-up, the results were essentially the same when the Trauma and Distress Scale (TADS) was used as the measure of ACEs. The specific mechanisms underlying cholesterol alterations associated with ACEs are a topic for future studies. Better understanding of these mechanisms might lead to possible new interventions in the prevention of adverse health effects resulting from ACEs.

Background Serum levels of zinc and copper have been proposed to associate with sleep duration. Mechanisms, such as inflammatory processes, have been suggested to relate this association. However, earlier studies have been conducted in small sample sizes. Human studies investigating the suggested associations while controlling for potential confounding factors are lacking. Methods Population-based data consisted of 2570 men (aged 42–60 years) from Eastern Finland. The participants reported an estimate of their sleep duration. The serum levels of zinc (S–Zn), copper (S–Cu) and high-sensitivity C-reactive protein (hs-CRP) were measured. Analysis of covariance was used for multivariate analyses. Results S–Zn levels and Zn/Cu ratio were lowest in ≤6 h sleep. S–Cu levels were highest in ≥10 h sleep. Elevated levels (>3.0 mmol/l) of hs-CRP were observed in ≤6 h and ≥10 h sleep. After adjustments for age, cumulative smoking history (pack-years), alcohol consumption (g/week), Human Population Laboratory depression scale scores, physical activity (kcal/day), cardiometabolic syndrome, and cardiovascular disease history, sleep duration was significantly associated with levels of both S–Cu and hs-CRP. The association with S–Cu remained statistically significant following further adjustment for hs-CRP in the same model. Conclusions Our data suggests an association between S–Cu and sleep duration in ageing men. Elevated inflammation (measured as serum hs-CRP) does not explain this relationship. Mechanisms underlying the relationship require further investigation, as S–Cu may contribute to sleep regulation through pro-oxidative processes and copper-dependent N-methyl- d -aspartate receptor activity.

Aims The role of the serotonin transporter (SERT) in the pathophysiology of depression is unclear and only a few follow-up studies exist. Our aim was to measure changes in SERT availability during psychodynamic psychotherapy in patients with major depression over a follow-up time of 12 or 18 months. Methods The patients were studied with iodine-123 labelled 2β-carbomethoxy-3β-(4-iodophenyl) serial single-photon emission tomography imaging and clinical rating scales of symptoms. Results Changes in SERT availability had no correlation with the change of symptoms, but the change of SERT availability during psychotherapy in the midbrain was predicted by the baseline severity of the clinical symptoms measured by the Symptom Checklist Depression Scale and the Symptom Checklist Global Severity Index. With cut-off values applied, it was found that SERT availabilities increased in patients with high baseline symptoms, and decreased in patients with low baseline symptoms. Conclusions Together with our earlier finding of decreased SERT in patients with depression, these results indicate a state-dependent and possibly a compensatory role of decreased SERT availability in depression.

Objective To examine the impact of somatic concerns and depressive traits on carotid artery intima–media thickness (IMT) and on the incidence of cardiovascular disease (CVD). Methods In the cross-sectional study of 2682 Finnish men aged 42 to 61 years, a subsample of 1333 men had their carotid artery IMT recorded. In the prospective part of the study participants (n = 1453) were followed up for an average of 20 years. Data on incident CVD (n = 766) were obtained from the National Population Register. For both subsamples, the Minnesota Multiphasic Personality Inventory (MMPI) was used to measure depressive traits and somatic concerns. In addition, composite scales of general ill-being, sleep and pain problems, psychological well-being, energy level, and cheerfulness were formed. Results In the final corrected models there were no significant associations between somatic concerns or depressive traits and IMT. Both somatic concerns and depressive traits predicted a higher CVD incidence after adjustments for age and risk factors. The association between depressive traits and CVD incidence was highest among the subgroup of men with the highest levels of hsCRP, but this result did not reach statistical significance. Of the composite scales, general ill-being predicted a higher CVD incidence in the fully adjusted model, even when all the composite scales were entered into the model simultaneously. Conclusion Somatic concerns and depressive traits predict a higher CVD incidence. In particular, general ill-being contributes to this association. The association between depressive traits and CVD may be moderated by low-grade inflammation.

Low concentrations of serum 25-hydroxyvitamin D [25(OH)D] have been postulated to associate with an increased prevalence of depression. As there are a limited number of publications on this issue, we examined the association between serum 25(OH)D and depression in a general middle-aged or older population. A population-based cross-sectional study. A total of 1602 men and women from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) in Eastern Finland, aged 53-73 y in 1998-2001, were analysed. Depressive symptoms were assessed with the DSM-III depression scale, and those individuals who had scores over 4 (range 0-12) or had reported undergoing current antidepressant therapy, were considered as suffering from depression. Associations were estimated in serum 25(OH)D tertiles using logistic regression. Among the participants, 183 subjects (11.4%) were considered to have depression. The mean age of the subjects was 62.6 years (SD 6.4, range 53.4- 73.8 years). The mean serum 25(OH)D concentration was 43.8 nmol/L (SD 17.7, range 8.5-112.8 nmol/L), concentrations

Long-term alcohol use affects cognitive and neurophysiological functioning as well as structural brain development. Combining simultaneous electroencephalogram (EEG) recording with transcranial magnetic stimulation (TMS) enables direct, in vivo exploration of cortical excitability and assessment of effective and functional connectivity. In the central nervous system, the effects of alcohol are particularly mediated by alterations in gamma-aminobutyric acid (GABA)ergic neurotransmission, and TMS-evoked potentials (TEPs) N45 and N100 in EEG are known to reflect GABAergic function. However, no previous studies have examined the effects of long-term alcohol use in adolescence on TEPs. In this study, a total of 27 young adults with heavy alcohol use in adolescence and 25 age-matched, gender-matched and education-matched controls with little or no alcohol use participated in TMS-EEG measurements. The motor cortex (M1) was stimulated with an intensity of 90 percent of the resting motor threshold of the abductor pollicis brevis muscle. No significant differences were found in the resting motor threshold, TEP latencies or neuropsychological functioning between the groups. We observed an increase in the global mean field power in the time window of 54- to 75-millisecond post-TMS, as well as significant topographical differences in the P60 and N100 in those with a history of heavy drinking. Furthermore, there was a marked increase in the GABAergic N45 amplitude in alcohol users. These findings suggest that long-term alcohol use in adolescence, even when not meeting the diagnostic criteria for a disorder, is associated with changes in connectivity and cortical excitability.

The most thoroughly studied transcranial magnetic stimulation (TMS)-evoked electroencephalogram (EEG) potential (TEP), N100, is often defined as a measure of cortical inhibition. We explored the association of the N100 amplitude with attention in 51 young healthy adults. Navigated TMS with simultaneous EEG registering was applied over the left primary motor cortex at the intensity of 110% of the resting motor threshold. Attention was assessed with the Paced Auditory Serial Addition Test (PASAT). We found a negative Pearson correlation (p = .023, r = −0.317) between the left centroparietal N100 amplitude and the PASAT score. Of the participants, the 17 with the highest PASAT scores and 17 with the lowes scores were selected for further analysis, in which a significant between-group difference in the left centroparietal N100 was found (p = .017). The topographic specificity of this finding was further confirmed with linear mixed model (LMM) analysis, in which significant differences were detected in the N100 amplitude; most prominently in the left centroparietal region (p = .001). A smaller N100 amplitude was associated with better performance in the attention task. Our findings suggest that the GABA-B-ergic TEP N100 is associated with attentional processes and thus represents cortical inhibition beyond motor inhibition.

Background Major depressive disorder (MDD) is characterized by increased oxidative and nitrosative stress. We compared nitric oxide metabolism, i.e., the global arginine bioavailability ratio (GABR) and related serum amino acids, between MDD patients and non-depressed controls, and between remitted and non-remitted MDD patients. Methods Ninety-nine MDD patients and 253 non-depressed controls, aged 20–71 years, provided background data via questionnaires. Fasting serum samples were analyzed using ultra-performance liquid chromatography coupled to mass spectrometry to determine the serum levels of ornithine, arginine, citrulline, and symmetric and asymmetric dimethylarginine. GABR was calculated as arginine divided by the sum of ornithine plus citrulline. We compared the above measures between: 1) MDD patients and controls, 2) remitted (n=33) and non-remitted (n = 45) MDD patients, and 3) baseline and follow-up within the remitted and non-remitted groups. Results Lower arginine levels (OR 0.98, 95% CI 0.97–0.99) and lower GABR (OR 0.13, 95% CI 0.03–0.50) were associated with the MDD vs. the non-depressed group after adjustments for potential confounders. The remitted group showed a decrease in GABR, arginine, and symmetric dimethylarginine, and an increase in ornithine after the follow-up compared with within-group baseline values. The non-remitted group displayed an increase in arginine and ornithine levels and a decrease in GABR. No significant differences were recorded between the remitted and non-remitted groups. Limitations The MDD group was not medication-free. Conclusions Arginine bioavailability may be decreased in MDD. This could impair the production of nitric oxide, and thus add to oxidative stress in the central nervous system.

Background Sleep disturbance is suggested to contribute to the development of dementia. However, prospective longitudinal data from middle-aged populations are scarce. Methods We investigated a population-based sample of 2386 men aged 42–62 years at baseline during 1984–1989. Participants having a history of mental illnesses, psychiatric medication, Parkinson9s disease or dementia within 2 years after baseline (n=296) were excluded. Difficulty falling asleep or maintaining sleep, sleep duration and daytime tiredness were enquired. Dementia diagnoses (n=287) between 1984 and 2014 were obtained through linkage with hospital discharge, national death and special reimbursement registers. Cox proportional hazards analyses were performed for all dementias, and separately for Alzheimer9s disease (n=234) and other phenotypes (n=53). Additional analyses were performed on a subsample of an apolipoprotein E ( APOE ) genotype-tested population (n=1199). Results The risk ratio for dementia was 1.58 (95% CI 1.10 to 2.27) in men with frequent sleep disturbance after adjustments for age, examination year, elevated depressive symptoms, physical activity, alcohol consumption, cumulative smoking history, systolic blood pressure, body mass index, low-density lipoprotein and high-density lipoprotein cholesterol, high-sensitivity C reactive protein, cardiovascular disease history, education years and living alone. Daytime tiredness and sleep duration were not associated with dementia in adjusted analysis. In the APOE subsample, both APOE e4 genotype and frequent sleep disturbance were associated with increased dementia risk, but in the interaction analysis they had no joint effect. Conclusions Self-reported frequent sleep disturbance in middle-aged men may relate to the development of dementia in later life. Having an APOE e4 genotype did not affect the relationship.

Background Previous studies assessing the role of dietary factors in depression have mainly focused on nutrients, while the association between dietary patterns and depression is less studied. Objective The aim was to assess the role of dietary patterns in depression in both cross-sectional and prospective analyses. Design The study population consisted of 1003 Finnish middle-aged or older men from the Kuopio Ischemic Heart Disease Risk Factor Study. Food consumption was assessed by food frequency questionnaire in 1991–1993 and dietary patterns from 25 predefined food groups were extracted by factor analysis. Depressive symptoms were assessed with the self-administered Human Population Laboratory Depression Scale, cut-off point of five or more indicating elevated depressive symptoms. Results Altogether 72 (7.2%) subjects had elevated depressive symptoms. Three dietary patterns were identified: “prudent”, “Western” and “mixed”. In cross-sectional analysis, after adjustments for age, examination year, BMI, smoking, alcohol consumption, education, marital status, leisure-time physical activity , history of mental illness and cardiovascular disease the prudent dietary pattern was associated with a 25% lower prevalence of elevated depressive symptoms (OR: 0.75; 95% CI: 0.57, 0.99; P =0.036), whereas the Western dietary pattern was associated with increased prevalence of elevated depressive symptoms (OR: 1.41; 95% CI: 1.08, 1.84; P =0.011). In the prospective analysis (16.5 follow-up years), the prudent dietary pattern was inversely associated with the risk of getting a hospital discharge diagnosis of depression (HR: 0.66; 95% CI 0.47, 0.93; P =0.018). Conclusions Adherence to healthy dietary pattern is associated with lower risk of getting a hospital discharge diagnosis of depression.

Background Zinc is an immunomodulatory trace element suggested to be beneficial in the augmentation of antidepressant therapy. Cross-sectional studies have also suggested an association between low dietary zinc and depression. This study examined the association between dietary zinc intake and depression in a prospective setting in initially depression-free men during a 20-year follow-up. Methods The study formed a part of the population-based Kuopio Ischemic Heart Disease Risk Factor (KIHD) Study, and comprised 2317 Finnish men aged 42–61 years. Zinc intake was assessed at baseline by a 4-d food record. Baseline depression severity was recorded with the Human Population Laboratory Depression Scale. In the prospective setting, depression was defined as having received a hospital discharge diagnosis of unipolar depressive disorder. Individuals who at baseline had elevated depressive symptoms were excluded (n=283). Results Altogether, 60 (2.7%) individuals received a hospital discharge diagnosis of depression during the 20-year follow-up. In Cox regression analysis adjusted for age, baseline depression severity, smoking, alcohol use, physical exercise and the use of dietary supplements, belonging to the lowest tertile of energy-adjusted zinc intake was not associated with an increased depression risk (RR 1.06, 95% CI 0.59–1.90). Limitations These observations may not be generalizable to women, or to individuals with a depression level not warranting hospitalization. Conclusions Our findings suggest that a low dietary zinc intake may not longitudinally precede depression in men. Dietary zinc intake may not have relevance for the prevention of depression in middle-aged men with a sufficient dietary zinc intake.

The role of nonspecific factors in the outcome of psychotherapy is poorly understood. To study the effects of pretreatment expectancy of scheduled psychotherapy, we examined the effects of an agreed waiting time on the outcome of psychodynamic psychotherapy. Thirty-three treatment-naive outpatients with major depressive disorder were randomly selected to start psychotherapy either directly (DG; n = 17) or after waiting for 6 months (WG; n = 16). In WG, 18% to 60% of the total decline in symptoms took place during the waiting time. After 1 year of active psychotherapy, the anxiety score declined significantly only in WG, and the total length of treatment needed was shorter in WG. No other outcome differences between WG and DG were found. We conclude that scheduled waiting associates with a significant decline in depressive symptoms. Scheduled waiting should be regarded as a preparatory treatment and not as an inert nontreatment control.

Aim: Abundant evidence suggests that depression is a risk factor for cardiovascular disease and metabolic syndrome. Systemic low-grade inflammation and evolving abdominal obesity are hypothesised to be underlying mechanisms explaining the relationship. To test this hypothesis we examined the association of depressive symptoms and inflammation in developing abdominal obesity. Methods: The subjects were 726 non-diabetic men, 42–60 of age at baseline, participating in the Kuopio Ischemic Heart Disease Risk Factor Study. The follow-up data was collected 11 years after the baseline. Low-grade inflammation was defined as serum C-reactive protein ≥2 mg/l and depressive symptoms were assessed by the Human Population Laboratory Depression Scale. Incident abdominal obesity was defined as waist girth >102 cm. Results: Men with low-grade inflammation and depressive symptoms were more likely (OR 4.28, 95% CI 1.93–12.01) to develop abdominal obesity during the 11-year follow-up than in men not having either of these conditions, adjusting for age, smoking, alcohol consumption, prevalent cardiovascular disease, physical activity and socioeconomic status. These men were also more likely (OR 3.94, 95% CI 1.38–11.26) to develop metabolic syndrome. Conclusions: The presence of systemic low-grade inflammation together with depressive symptoms seems to detect men at a particularly high risk of developing abdominal obesity over a long period of time.

Diabet. Med. 29, e126–e132 (2012) Abstract Aims To assess the effect of lifestyle intervention on depressive symptoms during a 36-month randomized clinical trial designed to prevent Type 2 diabetes. Methods A total of 522 middle-aged participants, who were overweight or obese and had impaired glucose tolerance, were randomized to the lifestyle intervention or control group in the Finnish Diabetes Prevention Study. The intervention group received individualized counselling aimed at reducing weight and increasing physical activity. Depressive symptoms were measured using the Beck Depression Inventory among a subgroup of 140 participants. Results On study entry, the mean Beck Depression Inventory scores ± sd were 6.8 ± 5.6 in the intervention group and 6.7 ± 5.5 in the control group. Beck Depression Inventory scores reduced during the intervention study: the mean ± sd (95% CI) reduction was 0.90 ± 4.54 (−1.99 to −0.19) scores in the intervention group and 0.75 ± 4.47 (−1.80 to 0.31) in the control group, with no difference between the groups. In a stepwise linear multivariate regression analysis, the variables with the strongest associations with the change in Beck Depression Inventory scores were baseline Beck Depression Inventory scores, marital status, weight change and change of total energy intake (R2 = 0.209, P