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Targeting distinct facets of anhedonia via transcutaneous auricular vagus nerve stimulation: Effects on heart rate variability and reward-based behavior.

Anhedonia, a core feature of major depressive disorder, is associated with disrupted reward processing and may represent a mechanistically relevant target for neuromodulation. This study examined the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on reward-related behavior and autonomic regulation in individuals with higher (n = 34) and lower (n = 34) depressive symptomatology. In a randomized, within-subject crossover design, participants received active taVNS and sham stimulation on two separate days. During each session, incentive motivation and reward learning were assessed using the Effort Expenditure for Rewards Task and the Probabilistic Reward Task (PRT), respectively, with stimulation condition and task order counterbalanced. Findings revealed that taVNS effects on heart rate variability (HRV) were modulated by baseline HRV levels and depressive status; specifically, they enhanced HRV at low baseline levels and reduced it at high baseline levels in participants with lower depressive symptomatology, with opposite patterns in individuals with higher symptoms. Moreover, compared to sham, taVNS enhanced the willingness to exert effort for rewards, particularly at low reward probabilities, with a more pronounced effect in the group characterized by higher depressive symptoms. No significant effects were observed on reward learning, as indexed by the PRT. Additionally, taVNS reduced self-reported anxiety across groups. Despite the limitation of a single stimulation session, these findings suggest that taVNS modulates motivational effort allocation in individuals with higher depressive symptoms, supporting its potential relevance for targeting reward-related dysfunctions in mood disorders.

Anhedonia

Psychopharmacological studies in genetically determined subgroups of psychiatric patients.

1. As a prerequisite for psychopharmacological studies in subgroups of psychiatric patients two approaches will be described: a. A multiaxial classification system for affective disorders (MULTI-CLAD). b. Studies of ABO- and HLA-systems in patients with affective disorders. HLA: In 107 manic-melancholic patients selected according to the very strict MULTI-CLAD criteria confirmatory evidence was obtained that there is a positive association between affective disorders and HLA-Bw 16; the results were also strongly suggestive of a positive association between HLA-7 and such disorders. ABO: In sixty-six manic-melancholic patients selected along the same criteria, the differences between all patients combined versus controls were not significant, but a significantly higher percentage of bipolar patients (70%) than of unipolar patients (22%) had blood group O, while a significantly higher percentage of unipolar patients (65%) than of bipolar patients (23%) had blood group A. 2. The findings are in the process of further study involving some 300 patients from the Psychochemistry out-patient-clinic. The purpose is to see whether less selected groups of patients with affective disorders show less marked profiles for ABO and HLA, as this will have importance for the selection of subgroups of patients for psychopharmacological studies.

ABO Blood-Group System

Epigenetic clues: Predicting maternal depression through DNA methylation.

Perinatal depression (PND) is a prevalent and multifactorial mood disorder affecting approximately 10-20 % of women globally, with higher burdens reported in low- and middle-income countries. Despite the availability of screening tools such as the Edinburgh Postnatal Depression Scale, these approaches primarily identify risk without elucidating underlying biological mechanisms. Emerging evidence highlights the role of epigenetic regulation particularly DNA methylation as a key mediator linking genetic susceptibility and environmental exposures during the perinatal period. This review synthesizes current knowledge on DNA methylation dynamics in maternal depression, emphasizing both candidate gene and epigenome-wide association study (EWAS) approaches. Candidate gene studies have identified differential methylation in stress-related pathways, including HPA axis genes (NR3C1, FKBP5), serotonergic signalling (SLC6A4), and oxytocin pathways (OXTR), though findings remain limited by poor reproducibility and small sample sizes. In contrast, EWAS provides a hypothesis-free framework, identifying novel differentially methylated positions and regions associated with PND, including predictive CpG panels with potential diagnostic utility. The review also highlights the importance of tissue specificity, temporal epigenetic remodeling across pregnancy, and the interplay between maternal and fetal epigenomes. Furthermore, methodological challenges such as heterogeneity in study design, lack of replication, and analytical inconsistencies remain barriers to clinical translation. Integrating genetic, epigenetic, and environmental data through multi-omics approaches may enhance predictive accuracy and improve early intervention strategies. Overall, DNA methylation represents a promising avenue for understanding the biological underpinnings of PND and developing robust biomarkers for risk prediction and personalized care.

Humans

Contribution of copy number variations to education, socioeconomic status and cognition from a genome-wide study of 305,401 subjects.

Educational attainment (EA), socioeconomic status (SES) and cognition are phenotypically and genetically linked to health outcomes. However, the role of copy number variations (CNVs) in influencing EA/SES/cognition remains unclear. Using a large-scale (n = 305,401) genome-wide CNV-level association analysis, we discovered 33 CNV loci significantly associated with EA/SES/cognition, 20 of which were novel (deletions at 2p22.2, 2p16.2, 2p12, 3p25.3, 4p15.2, 5p15.33, 5q21.1, 8p21.3, 9p21.1, 11p14.3, 13q12.13, 17q21.31, and 20q13.33, as well as duplications at 3q12.2, 3q23, 7p22.3, 8p23.1, 8p23.2, 17q12 (105 kb), and 19q13.32). The genes identified in gene-level tests were enriched in biological pathways such as neurodegeneration, telomere maintenance and axon guidance. Phenome-wide association studies further identified novel associations of EA/SES/cognition-associated CNVs with mental and physical diseases, such as 6q27 duplication with upper respiratory disease and 17q12 (105 kb) duplication with mood disorders. Our findings provide a genome-wide CNV profile for EA/SES/cognition and bridge their connections to health. The expanded candidate CNVs database and the residing genes would be a valuable resource for future studies aimed at uncovering the biological mechanisms underlying cognitive function and related clinical phenotypes.

Humans

Depression and loss: a theme in Robert Burton's "Anatomy of melancholy" (1621).

Robert Burton's Anatomy of Melancholy (1621) can hardly be thought of as a modern study in psychiatry, but it contains more elements of modern theory than have been recognized. Attempts to recommend the book to modern readers have missed the point that Burton, more clearly than other seventeenth century writers on melancholy, sees traumatic loss of attachment figures, status symbols and personal health as predisposing to mood disorders. In this he strongly anticipates such work as that of John Bowlby in Attachment and Loss (1969), 1973). Burton's theory is divided between the humoural physiological theory descending from Galen and the observation that loss is a frequent precursor of melancholy. He cannot reconcile the two, writing a book only poised on the verge of modernity. The Anatomy of Melancholy nevertheless very fully discusses etiological "hunches" which have found verification in recent studies of traumatic loss.

Adjustment Disorders

Recurrent unipolar depressions with a 48-hour cycle: report of a case.

Since 1804 there have been twelve case reports of patients with mood disorders showing a regular periodicity of 48 hours, eight bipolar and four unipolar. This paper describes an additional patient, a 57-year-old man with a 48-hour unipolar cycle. Although his 24-hour serum cortisol pattern was abnormal, there were few clear-cut biological abnormalities. Possible mechanisms are discussed, and comparisons made with previous reports of similar patients.

Adrenal Cortex Hormones

The associations between functional dyspepsia and potential risk factors: A comprehensive Mendelian randomization study.

BACKGROUND: Previous cross-sectional studies have identified multiple potential risk factors for functional dyspepsia (FD). However, the causal associations between these factors and FD remain elusive. Here we aimed to fully examine the causal relationships between these factors and FD utilizing a two-sample MR framework. METHODS: A total of 53 potential FD-related modifiable factors, including those associated with hormones, metabolism, disease, medication, sociology, psychology, lifestyle and others were obtained through a comprehensive literature review. Independent genetic variants closely linked to these factors were screened as instrumental variables from genome-wide association studies (GWASs). A total of 8875 FD cases and 320387 controls were available for the analysis. The inverse variance weighted (IVW) method was employed as the primary analytical approach to assess the relationship between genetic variants of risk factors and the FD risk. Sensitivity analyses were performed to evaluate the consistency of the findings using the weighted median model, MR-Egger and MR-PRESSO methods. RESULTS: Genetically predicted depression (OR 1.515, 95% confidence interval (CI) 1.231 to 1.865, p = 0.000088), gastroesophageal reflux disease (OR 1.320, 95%CI 1.153 to 1.511, p = 0.000057) and years of education (OR 0.926, 95%CI 0.894 to 0.958, p = 0.00001) were associated with risk for FD in univariate MR analyses. Multiple medications, alcohol consumption, poultry intake, bipolar disorder, mood swings, type 1 diabetes, elevated systolic blood pressure and lower overall health rating showed to be suggestive risk factors for FD (all p<0.05 while &#x2265;0.00167). The positive causal relationship between depression, years of education and FD was still significant in multivariate MR analyses. CONCLUSIONS: Our comprehensive MR study demonstrated that depression and lower educational attainment were causal factors for FD at the genetic level.

Humans

Bulk serum extracellular vesicles from stressed mice show a distinct proteome and induce behavioral and molecular changes in naive mice.

Chronic stress can trigger several pathologies including mood disorders for which no clear diagnostic molecular markers have been established yet. Attractive biomarker sources are extracellular vesicles (EVs). Evs are released by cells in health and disease and contain genetic material, proteins and lipids characteristic of the cell state. Here we show that Evs recovered from the blood of animals exposed to a repeated interrupted stress protocol (RIS) have a different protein profile compared to those obtained from control animals. Proteomic analysis indicated that proteins differentially present in bulk serum Evs from stressed animals were implicated in metabolic and inflammatory pathways and several of them were previously related to psychiatric disorders. Interestingly, these serum Evs carry brain-enriched proteins including the stress-responsive neuronal protein M6a. Then, we used an in-utero electroporation strategy to selectively overexpress M6a-GFP in brain neurons and found that M6a-GFP could also be detected in bulk serum Evs suggesting a neuronal origin. Finally, to determine if these Evs could have functional consequences, we administered Evs from control and RIS animals intranasally to na&#xef;ve mice. Animals receiving stress EVs showed changes in behavior and brain M6a levels similar to those observed in physically stressed animals. Such changes could therefore be attributed, or at least in part, to EV protein transfer. Altogether these findings show that EVs may participate in stress signaling and propose proteins carried by EVs as a valuable source of biomarkers for stress-induced diseases.

Animals

Lithium prophylaxis of corticotropin-induced psychosis.

Corticotropin is one of the few accepted treatments for acute exacerbations of multiple sclerosis and retrobulbar neuritis. Psychosis is a serious side effect usually necessitating discontinuation of the drug therapy. Because mood disorders preponderated in most patients previously described with this psychosis, 27 patients were empirically treated with lithium carbonate concurrently with corticotropin. In none of the patients treated with lithium did a psychotic reaction occur, although in a comparable group of 44 patients previously treated identically with corticotropin but without lithium, six (14%) became psychotic.

Acute Disease

[The epidemiological approach to depression (author's transl)].

The epidemiological method is indispensable to the clinical investigator, the practising clinician and the public health worker. In the field of mood disorders epidemiological inquiry has been hampered by the subjective nature of the phenomena under study, the problems of assessment and diagnosis, observer bias and the unrepresentative nature of small population samples. Nontheless, it is argued that the difficulties are similar to those encountered elsewhere in medicine and examples are given of epidemiological contributions to an understanding of depression.

Adolescent

[Course of psychopathologic and extrapyramidal motor symptoms during long-term treatment of schizophrenic patients with psycholeptic drugs (author's transl)].

65 chronic-schizophrenic outpatients were treated with fluphenazinedecanoate for 24 months. Hallucinations and delusions remitted between week 24 and 36, formal disturbances of thinking occurred in 50% of the patients up to the 24th week, mood disorders and disorders and schizophrenic changes in personality could only gradually be controlled. In the first 3 months of treatment the incidence and intensity of rigor grew up to the critical point after 24 weeks of treatment; by the 60th week of treatment it had completely vanished. Akathisia reached its peak after the first and the 36th week and two different populations could be distinguished. 8% of the patients showed dyskinetic reactions up to the 12th week; 20% of the patients showed hyper- and dyskinesia after 72 weeks of treatment. 30 to 40% of the patients required anticholinergics between the 12th and 48th weeks; after the 84th week this medication was no longer necessary.

Adolescent

Some aspects of depression.

Depressive illness remains an underdiagnosed, and often misdiagnosed entity, in all branches of medicine. Some of the factors involved are discussed: doctor, patient, environment, diagnosis, treatment. Disorders of mood, affective disorders, or simple depressive illnesses are by no means new to the human race.

Amitriptyline

[Classification of endogenous psychoses from a genetic viewpoint].

The family-heredity findings serving as criteria for the classification of functional psychoses are discussed, presenting recent data. The global morbidity risk of the resp. psychosis showing secondary cases similar (homotypical) to the index case and no increased incidence of cases of the other type may be interpreted by the theory of two separated genetically transmitted diseases (schizophrenias and affective disorders). The classical schizophrenic subtypes differ in their global schizophrenia morbidity risk and show a tendency toward homotypical secondary cases. Monopolar and bipolar affective disorders were found to be very close together concerning family-genetic data-Schizo-affective psychotics were found to have among their relatives the highest incidence of all types of functional psychoses at all, a high rate of schizophrenics (esp. catatonic type) and affective psychotics and no homotypical secondary cases.

Affective Disorders, Psychotic

Perspectives in the treatment of the psychoneurological disorders: affective disorders.

1. Current research strategies in the pharmacotherapy of the affective disorders are reviewed in an attempt to highlight major trends and areas of particular promise. 2. There has been some progress toward the identification of biologically defined subgroups by assessing amine metabolites in urine or cerebrospinal fluid which may lead to a more rational choice of therapies for depressed patients. 3. The use of drugs with receptor agonist properties may help define biological substrates altered in affective illness and lead to new approaches to treatment, such as utilization of low doses of receptor agonists which may preferentially stimulate presynaptic receptors. 4. Study of time-dependent and adaptive changes in receptor sensitivity may also add an important perspective in conceptualizing the cyclic process in manic-depressive illness and its treatment.

Animals

A 10-year follow-up study of 97 epileptics.

1) Of 267 patients with epilepsy who were examined in our clinic during the period between 1964 and 1966, 97 were investigated in a 10-year follow-up study. The patients were selected according to the following criteria: the age of onset of seizures was 10 years or older and the follow-up period was 10 years after the onset of seizures. Of the 97 patients, 36 were followed up by mail. 2) In the adult 10-year follow-up study, seizures disappeared in 43.3%, decreased in 34.0%, remained unchanged in 16.5%, and were aggravated in 6.2% of the 97 patients. Comparing the five-year follow-up study with the present study, the rate of cases which were free of seizures for three years was 22.7% in the five-year study and 43.3% in this study. The seizures were controlled for at least three years in 22.9% of the cases with partial seizure and in 63.3% of the cases with generalized seizure. The worst prognoses were found in cases with versive seizure in which the seizure was unchanged and/or aggravated in 4 (44.4%) of 9 cases. Of 16 cases with psychomotor seizure, 25% were unchanged or aggravated. 3) Comparing the impaired consciousness seizure with the psychomotor seizure, there was a tendency for the psychomotor seizures to remain as a single type of partial seizure, while the impaired consciousness seizure tended to develop easily into a secondarily generalized seizure. 4) Of the 97 patients, three were personality disorders in 19 cases (19.6%), episodic psychotic state in 2 cases (2.1%), and mental retardation in 6 cases (6.2%). Disorders of mood, irritability and explosiveness associated with personality disorders were improved in three of six cases whose seizures disappeared. Personality disorders were found in half of those cases with partial complex seizures. No correlation was found between mental symptoms and the prognosis of seizures. 5) The EEG was improved in 15 (27.8%) of a total of 54 cases, unchanged in 35 (64.8%) and aggravated in 4 (7.4%). In comparing the prognosis of clinical seizure with changes in the EEG, the seizures improved in 40 (74.1%) of the cases, whereas the EEG improved in only 15 (27.8%) of 54 cases. Most of the clinical seizures were controlled or decreased, whether the EEG improved or not.

Adolescent

Perspectives and practical applications in psychopharmacogenetics.

1. Individual response to drugs is to a great extent influenced by hereditary factors. 2. The interaction between genetic and environmental factors affecting drug metabolism in man is of crucial importance to the understanding of therapeutic response in psychopharmacology. This proposition is illustrated for various psychotropic drugs such as the monoamineoxydase inhibitors (MAOI), tricyclic drugs and lithium salts as well as for enzymes involved in the synthesis and degradation of biogenic amines. 3. New perspectives in pharmacogenetics and their relevance to psychopharmacology are discussed.

Antidepressive Agents, Tricyclic

Early detection of high risk subjects in affective disorders.

1. Family, twin and linkage studies indicate that genetic factors are involved in the etiology of major affective disorders. 2. Recent clinical and biological research suggest that affective disorders are an heterogeneous group of illnesses, with variable genetic determination. 3. Since Lithium carbonate has been proven to be an effective prophylactic treatment in affective disorders, the question arises whether early detection of affective illness is possible and what are the implications for genetic counseling and primary prevention of affective illness.

Bipolar Disorder