The effect of vitamin D supplementation on depressive symptoms in adults: A systematic review and meta-analysis of randomized controlled trials.

Neurosteroid and immunological actions of vitamin D may regulate depression-linked physiology. Meta-analyses investigating the effect of vitamin D on depression have been inconsistent. This meta-analysis investigated the efficacy of vitamin D in reducing depressive symptoms among adults in randomized placebo-controlled trials (RCT). General and clinical populations, and studies of ill individuals with systemic diseases were included. Light therapy, co-supplementation (except calcium) and bipolar disorder were exclusionary. Databases Medline, PsycINFO, CINAHL and The Cochrane Library were searched to identify relevant articles in English published before April 2022. Cochrane risk-of-bias tool (RoB 2) and GRADE were used to appraise studies. Forty-one RCTs (n = 53,235) were included. Analyses based on random-effects models were performed with the Comprehensive Meta-analysis Software. Results for main outcome (n = 53,235) revealed a positive effect of vitamin D on depressive symptoms (Hedges' g = -0.317, 95% CI [-0.405, -0.230], p < 0.001, I2 = 88.16%; GRADE: very low certainty). RoB assessment was concerning in most studies. Notwithstanding high heterogeneity, vitamin D supplementation ≥ 2,000 IU/day appears to reduce depressive symptoms. Future research should investigate possible benefits of augmenting standard treatments with vitamin D in clinical depression. PROSPERO registration number: CRD42020149760. Funding: Finnish Medical Foundation, grant 4120 and Juho Vainio Foundation, grant 202100353.

Adverse childhood experiences and alexithymia in patients with major depressive disorder.

The purpose of the article: Adverse childhood experiences (ACEs) have been postulated to negatively affect the development of emotional regulation. However, little is known about specific associations between ACEs, depressive symptoms, and alexithymia or its components [i.e. difficulty in identifying feelings (DIF), difficulty in describing feelings to others (DDF) and externally-oriented thinking (EOT)] in patients with major depressive disorder (MDD). The aims of the present cross-sectional study were to (1) compare ACEs (emotional neglect, emotional abuse, physical neglect, physical abuse, sexual abuse) between alexithymic and non-alexithymic patients with MDD; (2) explore whether specific ACEs, depressive symptoms or the interaction between sex and depressive symptoms predicted TAS-20 or its components.Materials and Methods: The study sample consisted of 186 psychiatric outpatients with MDD (aged 21-61 years, mean 33.87 years, SD 10.88) recruited from the Department of Psychiatry, Kuopio University Hospital between 2016-2019. Alexithymia and its components were assessed using the 20-item Toronto Alexithymia Scale (TAS-20). ACEs were assessed with the Trauma and Distress Scale (TADS).Results: Almost all patients with alexithymia and 80% of non-alexithymic patients reported that they had experienced emotional abuse or neglect, at least sometimes. Approximately 60% of MDD patients reported having experienced physical neglect and 30% described physical abuse. Emotional and physical abuse and neglect predicted DDF score.Conclusions: These findings suggest that among MDD patients, early experiences of emotional and physical abuse and neglect is associated with difficulties in describing feelings in adulthood.

Bifrontal active and sham rTMS in treatment-resistant unipolar major depression.

BACKGROUND AND AIM: Prevention of the recurrence of major depression and its residual symptoms requires effective treatment. Our aim was to study the effects of bifrontal active rTMS controlled by sham rTMS in treatment-resistant unipolar major depressive disorder (MDD). METHODS: Thirty-seven patients with treatment-resistant MDD were randomized into two groups. One group received a total of 30 sessions of active bifrontal rTMS (10 Hz rTMS on left dorsolateral prefrontal cortex (DLPFC) and 1 Hz rTMS on right DLPFC) and the other group received bilateral sham rTMS on five days a week for six weeks. RESULTS: Depressive symptoms significantly improved in both the groups, but without a significant group difference. Furthermore, patients with psychotic depression improved similarly to those with moderate or severe depression. CONCLUSIONS: The results of present study indicate a large sham effect of stimulation treatment. The intensive structured treatment protocol may explain the positive outcome in both the groups. It is important to recognize, appreciate, and utilize placebo effects as a significant means of rehabilitation in psychiatric care.

Effects of Scheduled Waiting for Psychotherapy in Patients With Major Depression.

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.

Dietary patterns are associated with the prevalence of alexithymia.

Recent evidence supports the association between healthy dietary patterns and a reduced risk of depression. The objective was: (1) to examine the associations between dietary patterns and alexithymic features; and (2) investigate whether these possible associations are explained by depressive symptoms in a cross-sectional study among the Finnish general population aged 25-65 years. The study population was a part of the population-based Kuopio Depression Study (KUDEP) conducted in central-eastern Finland (n = 1747). Dietary data were collected using a food frequency questionnaire and dietary patterns from 22 predefined food groups, which were extracted by factor analysis. Alexithymia was assessed using the 20-item Toronto Alexithymia Scale (TAS-20) and depression using the 21-item Beck Depression Inventory (BDI-21). Altogether, 173 of the study subjects (9.9%) were alexithymic. Three dietary patterns were identified: "prudent," "Western" and "traditional." Lower scores for a healthy prudent dietary pattern and higher scores for an unhealthy Western dietary pattern were associated with an increased likelihood of belonging to the alexithymic group among subjects with elevated depressive symptoms. Among subjects without depressive symptoms, alexithymia was associated with lower scores in the prudent dietary pattern, but also with higher scores in the traditional dietary pattern. General population subjects with alexithymic features may have unhealthier dietary patterns than non-alexithymic subjects.

Baseline symptom severity predicts serotonin transporter change during psychotherapy in patients with major depression.

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 2ß-carbomethoxy-3ß-(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.

Reduced serum adiponectin levels in alexithymia.

OBJECTIVES: Clinical studies have demonstrated that circulating cytokine profiles may differ between alexithymic and non-alexithymic subjects. We examined whether the levels of adiponectin (µg/ml) and resistin (ng/ml) are independently related to alexithymic features in a population-based sample. METHODS: In 2005, clinical data including laboratory assessments were obtained from a sub-sample (n = 308) of the Kuopio Depression Study general population study including subjects aged 25-64 years. Based on the Toronto Alexithymia Scale score in 1998, 1999, 2001 and 2005, a group of subjects with high alexithymic features (n = 85) was formed and compared with non-alexithymic controls (n = 206). RESULTS: Serum adiponectin levels were significantly lower in subjects with alexithymic features than in non-alexithymic control subjects. No difference was found in resistin levels. Similarly, in a logistic regression model adjusted for age, gender and body mass index (BMI), lowered levels of adiponectin, but not resistin, were associated with an increased likelihood of belonging to the group with alexithymic features. Further adjustments for cardiovascular risk factors (i.e. smoking, BMI, metabolic syndrome, alcohol use, and coronary heart disease), depressive symptoms (Hamilton Depression Rating Scale with 17 items) and the use of antidepressants in addition to age and gender did not change these patterns. CONCLUSIONS: Our findings suggest that a disturbed anti-inflammatory balance may characterize alexithymia. In addition, our results widen the concept of alexithymia and highlight the role of immune system alterations and stress in alexithymic individuals.

Mothers' and their children's emotional and behavioral symptom trajectories and subsequent maternal adjustment: Twenty-seven years of motherhood.

BACKGROUND: This study aims to describe maternal depressive symptoms (MDS) trajectories in a longitudinal study extending from pregnancy to 27 years after the birth of the firstborn child. We also explored the associations of both MDS trajectories and child internalizing and externalizing problem trajectories with maternal adjustment (adaptive functioning, emotional and behavioral problems). METHODS: The population-based study was conducted in Tampere, Finland, and the sample comprised 356 first-time mothers. MDS were screened with the Edinburgh Postnatal Depression Scale during pregnancy, first week after delivery, 2 and 6 months postnatally, and when the child was 4-5, 8-9, 16-17, and 26-27 years of age. The internalizing and externalizing problems of the children were assessed with the Child Behavior Checklist when the child was 4-5, 8-9, and 16-17 years of age. Maternal adaptive functioning and internalizing and externalizing problems were assessed with the Adult Self Report at 26-27 years after the birth of the first child. Complete follow-up data were available for 168 mothers. RESULTS: We describe a three-group trajectory model of MDS (High Stable, Low Stable, Very Low). Elevated depressive symptom patterns were associated with less optimal maternal outcomes regarding both adaptive and problem dimensions. The child's internalizing and externalizing problem trajectories were associated with maternal internalizing and externalizing problems but not with maternal adaptive functioning. LIMITATIONS: Maternal and child measures were based on maternal reports only. CONCLUSIONS: The interconnectedness of the well-being of the mother and child should be noted in health and mental health services for adults and children.

Alcohol use-associated alterations in the circulating metabolite profile in the general population and in individuals with major depressive disorder.

Our aim was to evaluate whether alcohol use is associated with changes in the circulating metabolite profile similar to those present in persons with depression. If so, these findings could partially explain the link between alcohol use and depression. We applied a targeted liquid chromatography mass spectrometry method to evaluate correlates between concentrations of 86 circulating metabolites and self-reported alcohol use in a cohort of the non-depressed general population (GP) (n = 247) and a cohort of individuals with major depressive disorder (MDD) (n = 99). Alcohol use was associated with alterations in circulating concentrations of metabolites in both cohorts. Our main finding was that self-reported alcohol use was negatively correlated with serum concentrations of hippuric acid in the GP cohort. In the GP cohort, consumption of six or more doses per week was associated with low hippuric acid concentrations, similar to those observed in the MDD cohort, but in these individuals it was regardless of their level of alcohol use. Reduced serum concentrations of hippuric acid suggest that already-moderate alcohol use is associated with depression-like changes in the serum levels of metabolites associated with gut microbiota and liver function; this may be one possible molecular level link between alcohol use and depression.

Serum levels of carnosine may be associated with the duration of MDD episodes.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: An increase in circulating carnosine may characterize depressive episodes and may represent a protective homeostatic reaction against MDD-related oxidative stress and inflammation.

Auditory event-related potentials in patients with psychotic illness: a 5-year follow-up.

The auditory processing is diversely impaired in patients with the first-episode psychosis. During acute phase we previously reported reduced amplitudes in attention-dependent auditory evoked electrical brain potentials but not in those of early automatic components. Here seven first-episode patients at the disease onset and 5 years later were studied and compared to control subjects. At follow-up, also the unattended auditory stimuli elicited reduced amplitudes both in primary sensory component (N100, p = .043) and in automatic deviance detection (N200, p = .013) as compared to acute phase. Patients' psychopathology had improved, however they still showed alterations in components detecting automatic stimulus classification which may convey persisting tendency for misinterpretation in auditory perception.

Elevated levels of serum IL-5 are associated with an increased likelihood of major depressive disorder.

BACKGROUND: Inflammatory mediators in both the peripheral circulation and central nervous system (CNS) are dysregulated in major depressive disorder (MDD). Nevertheless, relatively little is known about the role of the T-helper (Th)-2 effector cytokines interleukin (IL)-5 and IL-13 in MDD. METHODS: We examined the serum levels of these cytokines and a Th-1 comparison cytokine, interferon (IFN)-γ, in 116 individuals (MDD, n = 58; controls, n = 58). RESULTS: In our basic multivariate model controlling for the effects of potential confounders on the associations between MDD and the examined cytokines, each 1-unit increase in the serum IL-5 level increased the likelihood of belonging to the MDD group by 76% (OR 1.76, 95% CI 1.03-2.99, p = 0.04; model covariates: age, gender, marital status, daily smoking and alcohol use). The likelihood further increased in models additionally controlling for the effects of the use of antidepressants and NSAIDS, and a diagnosis of asthma. No such associations were detected with regard to IL-13 (OR 1.08, 95% CI 0.96-1.22, p = 0.22) or IFN-γ (OR 1.02, 95% CI 0.99-1.05, p = 0.23). CONCLUSIONS: Elevated levels of IL-5, which uses the neural plasticity-related RAS GTPase-extracellular signal-regulated kinase (Ras-ERK) pathway to mediate its actions in the central nervous system (CNS), could be one of the factors underlying the depression-related changes in CNS plasticity.

[Glucocorticoids and aetiopathogenesis of depression]. / Glukokortikoidien yhteys masennuksen syntyyn ja oirekuvaan.

Current research interest is increasingly directed towards the role of glucocorticoid actions and inflammation. A failure in the stress system regulation appears to largely characterize depression. New research data have substantially diversified the theoretical concept of association between overactivity of HPA-axis and depression. The glucocorticoid effects are regulated by glucocorticoid reseptor gene polymorphisms, and glucocorticoid resistance is often associated with depression. Moreover, immune system disturbances affect the development of depression, and an altered balance of pro- and anti-inflammatory cytokines is also observable. Treatment methods that follow the new developments of the glucocorticoid theory are being developed.

Alexithymia and tissue inflammation.

BACKGROUND: Altered immune responses are seen in depression, and recent data suggest that similar changes could also be observable in alexithymia. We examined whether the inflammatory markers high-sensitivity C-reactive protein (hs-CRP) and interleukin (IL)-6 are independently related to alexithymia or its factors in a population-based sample. METHODS: This study formed a clinical part of the Kuopio Depression (KUDEP) general population study focusing on the mental health of a general population of adults aged 25-64 years (n = 308). Alexithymia was measured using the Toronto Alexithymia Scale (TAS-20), and depressive symptoms were assessed using the Beck Depression Inventory (BDI-21). RESULTS: The levels of IL-6 (in picograms per milliliter) and hs-CRP (in milligrams per liter) were significantly higher in alexithymic than in nonalexithymic subjects (IL-6 effect size, ES: 0.50; hs-CRP ES: 0.27). The BDI scores, hs-CRP and IL-6 explained 33.5% of the variation in TAS scores in the whole study population. According to logistic regression analysis, hs-CRP but not IL-6 increased the likelihood of belonging to the alexithymic group. This observation remained unaltered after additional adjustments for chronic inflammation-related disorders, the use of inflammation-modulating medications and depressive symptoms. CONCLUSIONS: Our findings suggest that the association between hs-CRP and alexithymia resembles that observed in depressed patients. It is, however, independent of depressive symptoms. These findings widen our view on the stress-alexithymia concept.

The patient-therapist interaction and the recognition of affects during the process of psychodynamic psychotherapy for depression.

The perceptions of patients (n = 25) and their therapists about psychodynamic psychotherapy for depression were assessed during the first treatment year using 23 scales. Patients and therapists independently evaluated the impact of depression on the therapeutic experience of the patients. The estimations of the impact of depression by the patients and therapists were concordant in the majority of the subjects, reflecting mutual tuning and a working alliance. The roles of affects and frustrating subjects in the treatment relationship were evaluated as significantly different by the patients and the therapists. The results highlight the importance of working on the expression of affects in the psychotherapy of depression.

Comparison of the level of allostatic load between patients with major depression and the general population.

OBJECTIVE: We compared the level of allostatic load (AL) between patients with major depressive disorder (MDD) and non-depressed controls using two definitions of AL: continuous AL scores (AL index) and clinically significant high AL (≥4). We examined whether MDD was associated with AL independent of basic socioeconomic (age, sex, cohabiting status and level of education) and lifestyle factors (smoking and alcohol use). METHODS: The MDD patient sample consisted of 177 psychiatric outpatients (mean age 33.7, SD 10.7 years), who were recruited from the Department of Psychiatry at Kuopio University Hospital, Finland, in 2016-19. The non-depressed controls (n = 228, mean age 49.8, SD 10.1 years) lived in the municipality of Lapinlahti, Finland. Ten biomarkers were used to construct the two AL variables. These indicators were systolic and diastolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, glucose, creatinine, waist circumference, body mass index (BMI) and C-reactive protein (CRP). RESULTS: The mean AL scores did not significantly differ between MDD patients (2.97) and non-depressed controls (3.12), thus it was not associated with MDD in univariate analysis. In multivariate models a higher AL index was associated with a 1.42 to 1.82 times higher likelihood of belonging to the MDD group. Furthermore, we found that high AL (i.e. AL ≥ 4) was associated with MDD, with the likelihood ranging between 2.27 and 2.96 compared with the non-depressed controls in multivariate models. CONCLUSIONS: Even young adult patients with MDD appear to display clinically significant, high AL compared with non-depressed controls. Thus, it is important to pay attention to the somatic health of depressed patients in addition to their mental health.

Reality of auditory verbal hallucinations.

Distortion of the sense of reality, actualized in delusions and hallucinations, is the key feature of psychosis but the underlying neuronal correlates remain largely unknown. We studied 11 highly functioning subjects with schizophrenia or schizoaffective disorder while they rated the reality of auditory verbal hallucinations (AVH) during functional magnetic resonance imaging (fMRI). The subjective reality of AVH correlated strongly and specifically with the hallucination-related activation strength of the inferior frontal gyri (IFG), including the Broca's language region. Furthermore, how real the hallucination that subjects experienced was depended on the hallucination-related coupling between the IFG, the ventral striatum, the auditory cortex, the right posterior temporal lobe, and the cingulate cortex. Our findings suggest that the subjective reality of AVH is related to motor mechanisms of speech comprehension, with contributions from sensory and salience-detection-related brain regions as well as circuitries related to self-monitoring and the experience of agency.

Serotonin-transporter-linked promoter region polymorphism and serotonin transporter binding in drug-naïve patients with major depression.

AIMS: Both the serotonin transporter and its genetic regulation by the serotonin-transporter-linked polymorphic region have a role in the pathophysiology of depression. Most of the previous studies have found no influence of serotonin-transporter-linked polymorphic region allelic variation on serotonin transporter binding in healthy controls or patients with major depression. Due to the inconsistency of the previous findings, we compared single photon emission computed tomography imaging with the serotonin-transporter-linked polymorphic region genotype in patients with major depressive disorder. METHODS: A total of 23 drug-naïve patients with major depressive disorder were genotyped and brain imaged with ([123I])nor-beta-CIT single photon emission computed tomography. The severity of depression was evaluated with the 17-item Hamilton depression rating scale. RESULTS: Depressed patients homozygous for the short allele had lower ([123I])nor-beta-CIT binding in the medial prefrontal cortex, but not in the midbrain, compared with the other genotypes. CONCLUSION: The decreased medial prefrontal cortical serotonin transporter binding in the patients homozygous for the short allele may be linked to altered function of the serotonin-transporter-linked polymorphic region gene expressed in these patients, especially in the medial prefrontal cortex.

Decreased serum total cholesterol is associated with a history of childhood physical violence in depressed outpatients.

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.