Cannabis and anhedonia: A systematic review.

This paper employs a systematic review to examine the correlation between anhedonia and marijuana use, exploring whether individuals with anhedonia use marijuana as a coping mechanism or if marijuana use plays a role in the onset of anhedonia. The search utilised PubMed and Web of Science databases, following PRISMA guidelines for paper selection. A total of 21 papers were selected to address this inquiry, and assessments were carried out using the Risk of Bias in Non-randomized Studies of Exposures (ROBINS-E) tool. The results revealed that 17 studies exhibited moderate and low risk of bias. The evaluation encompassed a total of 12,427 participants, including both animals and humans. Experimental animal studies focused on exploring the association between cannabidiol (CBD) and anhedonia, while human studies primarily employed observational research, examining various forms of anhedonia in individuals with or without mental disorders such as depression or psychosis. These studies also delved into understanding the effects of anhedonia during adolescence and explored the causal relationship between these concepts. The findings indicate a reciprocal rather than unidirectional relationship, establishing that initial anhedonia predisposes individuals to cannabis use, and subsequent consumption significantly intensifies the anhedonia experienced. Particularly, the studies placed special emphasis on adolescents and individuals with mental disorders.

Perceived Family Functioning of Adolescents with Affective Disorders: A Multicentric Cross-Sectional Study.

Purpose: This study aims to investigate the status of family functioning and dissatisfaction of family function from the perception of adolescents with affective disorders and explore associated factors. Methods: This was a multicentric cross-sectional study conducted from April 2022 to February 2023. Adolescents with affective disorders were surveyed in representative samples drawn from three hospitals in Sichuan province, China. Data were obtained from 235 participants regarding their demographic characteristics, family characteristics, disease-related characteristics, and family functioning. Results: The study found family functioning and its' dissatisfaction both lower than national norms from the perspectives of adolescents. Younger age, single-parent family, and reconstituted family were predictors of not close of cohesion. Younger age, lower educational level of father, and reconstituted family were associated with less change of flexibility. Less times of hospitalizations, higher educational level of father, stem family were more satisfy with cohesion. Higher educational level of father, and stem family were also associated with greater satisfaction with flexibility. Conclusion: The study demonstrated that the family function of adolescents of affective disorders was poor, more attention should be paid to it. Age, family structure, number of hospitalizations and the educational level of father were influencing factors of family functioning. Therefore, it is important for medical worker to assess demographic and family characteristics of adolescents with affective disorders. Younger children, children of reconstituted family and single-parent family, children with repeated hospitalizations and fathers of lower level of education should be given emphasized in implementation of interventions. Based on the evaluation results, personalized family therapy has been proved to be an affective measure and could be used in clinical work.

Interactions between Cognitive, Affective, and Respiratory Profiles in Chronic Respiratory Disorders: A Cluster Analysis Approach.

This study conducted at Leamna Pulmonology Hospital investigated the interrelations among cognitive, affective, and respiratory variables within a cohort of 100 patients diagnosed with chronic respiratory conditions, utilizing sophisticated machine learning-based clustering techniques. Spanning from October 2022 to February 2023, hospitalized individuals confirmed to have asthma or COPD underwent extensive evaluations using standardized instruments such as the mMRC scale, the CAT test, and spirometry. Complementary cognitive and affective assessments were performed employing the MMSE, MoCA, and the Hamilton Anxiety and Depression Scale, furnishing a holistic view of patient health statuses. The analysis delineated three distinct clusters: Moderate Cognitive Respiratory, Severe Cognitive Respiratory, and Stable Cognitive Respiratory, each characterized by unique profiles that underscore the necessity for tailored therapeutic strategies. These clusters exhibited significant correlations between the severity of respiratory symptoms and their effects on cognitive and affective conditions. The results highlight the benefits of an integrated treatment approach for COPD and asthma, which is personalized based on the intricate patterns identified through clustering. Such a strategy promises to enhance the management of these diseases, potentially elevating the quality of life and everyday functionality of the patients. These findings advocate for treatment customization according to the specific interplays among cognitive, affective, and respiratory dimensions, presenting substantial prospects for clinical advancement and pioneering new avenues for research in the domain of chronic respiratory disease management.

Habenular volume changes after venlafaxine treatment in patients with major depression.

BACKGROUND: Habenula, a hub brain region controlling monoaminergic brain center, has been implicated in major depressive disorder (MDD) and as a possible target of antidepressant response. Nevertheless, the effect of antidepressant drug treatment on habenular volumes remains unknown. The objective of the present research was to study habenular volume change after antidepressant treatment in patients with MDD, and assess whether it is associated with clinical improvement. METHODS: Fifty patients with a current major depressive episode (MDE) in the context of MDD, and antidepressant-free for at least 1 month, were assessed for habenula volume (3T MRI with manual segmentation) before and after a 3 months sequence of venlafaxine antidepressant treatment. RESULTS: A 2.3% significant increase in total habenular volume (absolute volume: P = 0.0013; relative volume: P = 0.0055) and a 3.3% significant increase in left habenular volume (absolute volume: P = 0.00080; relative volume: P = 0.0028) were observed. A significant greater variation was observed in male patients (4.8%) compared to female patients. No association was observed between habenular volume changes and response and remission. Some habenula volume changes were associated with improvement of olfactory pleasantness. CONCLUSION: Habenular volumes increased after 3 months of venlafaxine treatment in depressed patients. Further studies should assess whether cell proliferation and density or dendritic structure variations are implied in these volume changes.

Combined EEG-tDCS approach in resting state to reduce comorbid anxiety and depressive symptoms in affective disorders: A sham-controlled pilot study.

Continuous challenges have been imposed on mental health science by Anxiety and Depression disorders as the most prevalent and debilitating psychiatric conditions worldwide. Pharmacologic and cognitive behavioral therapies, either alone or in combination, have been considered as the first-line therapies, however, resistant symptomatology is prevalent in comorbid conditions with symptoms remaining after interventions. The demand for new therapeutic solutions has given space to the development of non-invasive brain stimulation techniques (NIBS), and the transmagnetic direct current stimulation (tDCS) has been reported as a safe and well-tolerated technique for the treatment of several mental health conditions, including Anxiety and Depression disorders. Relying on quantitative electroencephalography(qEEG)- tDCS approach, the current study aims to inspect the effect of tDCS intervention on patients who suffer from anxiety-depression comorbidity, in particular, the impact of tDCS intervention on qEEG spectral power activity and resting-state connectivity organization during eyes closed and eyes open protocols. QEEG data were acquired from eight patients suffering from moderate to severe anxiety-depression comorbid symptoms along with poor coping skills to manage stress and negative affect. Twelve control subjects allocated in the control group exhibiting low to moderate symptoms in both anxiety and depression conditions went also through the qEEG data acquisition. In addition, a sham-controlled study was conducted, and the patient group went through resting-state qEEG-tDCS neuromodulation once a week for ten weeks. Various-stage qEEG recordings were performed to inspect the efficacy of tDCS treatment during the modulation of brain regions involved in the regulation of affective responses. Our results demonstrated that after tDCS neuromodulation, the patients' groups exhibited decreased absolute power abnormalities over the left anterior cingulate cortex and reduced abnormal activity in the alpha band over posterior regions; improved functional connectivity indexes; decreased anxiety and depressive scores while positive affect score was improved. Besides the promising improvements, our study did not find a significant tDCS effect on perceived stress and negative affect scores. Consistently, significant differences in absolute spectral power over the left anterior cingulate cortex were detected among the patient group, as compared to the controls, as expected. Therefore, our study offers preliminary data to understand the neuroplasticity changes that potentially result from the manipulation of cortical excitability during affective regulation protocols followed by the consequent decrease of comorbid anxiety and depressive symptomatology. The pilot study was followed by prospective registration with ChiCTR2200062142.

Clinical and personal predictors of functioning in affective disorders: Exploratory results from baseline and 6-month follow-up of a randomised controlled trial.

Comprehensive knowledge of factors causing and sustaining functional impairment in patients with affective disorders is warranted. The aim is to investigate associations between clinical factors (such as affective symptoms) and personal factors (such as personality traits, coping strategies, and childhood trauma experiences) on functioning and improvement of functioning in patients with affective disorders. This exploratory study includes data from 103 patients with bipolar disorder and unipolar depressive disorder. Clinician-rated functioning was assessed at baseline using the Functioning Assessment Short Test (FAST), and performance-based functioning was assessed at baseline and 6-month follow-up using the Assessment of Motor and Process Skills (AMPS). Data on clinical and personal factors were collected at baseline. Personal factors were measured by the Eysenck Personality Inventory (EPQ), Coping Inventory for Stressful Situations (CISS) and Childhood Trauma Questionnaire (CTQ). Pearson correlations and multiple linear regression models were used to analyse the association of clinical and personal factors with baseline functioning (FAST) and to identify predictors of improvement in functioning (AMPS) from baseline to follow-up. At baseline, greater depressive symptom severity, the personality trait neuroticism, emotional coping, and childhood trauma all correlated with poorer functioning (higher FAST scores). In multiple linear regression models, depression severity, emotional coping and childhood trauma were significant predictors of poorer functioning. More childhood trauma was a predictor of less functional improvement measured by AMPS at 6-month follow-up. In conclusion, maladaptive coping styles and depressive symptoms contribute to functional impairment in patients with affective disorders, while childhood trauma has a negative impact on long-term functional outcomes.

Epigenetic and Coping Mechanisms of Stress in Affective Disorders: A Scoping Review.

This review aims to explore the intricate relationship among epigenetic mechanisms, stress, and affective disorders, focusing on how early life experiences and coping mechanisms contribute to susceptibility to mood disorders. Epigenetic factors play a crucial role in regulating gene expression without altering the DNA (deoxyribonucleic acid) sequence, and recent research has revealed associations between epigenetic changes and maladaptive responses to stress or psychiatric disorders. A scoping review of 33 studies employing the PRISMA-S (Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Statement) guidelines investigates the role of stress-induced epigenetic mechanisms and coping strategies in affective disorder occurrence, development, and progression. The analysis encompasses various stress factors, including childhood trauma, work-related stress, and dietary deficiencies, alongside epigenetic changes, such as DNA methylation and altered gene expression. Findings indicate that specific stress-related genes frequently exhibit epigenetic changes associated with affective disorders. Moreover, the review examines coping mechanisms in patients with bipolar disorder and major depressive disorder, revealing mixed associations between coping strategies and symptom severity. While active coping is correlated with better outcomes, emotion-focused coping may exacerbate depressive or manic episodes. Overall, this review underscores the complex interplay among genetic predisposition, environmental stressors, coping mechanisms, and affective disorders. Understanding these interactions is essential for developing targeted interventions and personalized treatment strategies for individuals with mood disorders. However, further research is needed to elucidate specific genomic loci involved in affective disorders and the clinical implications of coping strategies in therapeutic settings.

Weakened effective connectivity between salience network and default mode network during resting state in adolescent depression.

Adolescent major depressive disorder (MDD) is associated with altered resting-state connectivity between the default mode network (DMN) and the salience network (SN), which are involved in self-referential processing and detecting and filtering salient stimuli, respectively. Using spectral dynamical causal modelling, we investigated the effective connectivity and input sensitivity between key nodes of these networks in 30 adolescents with MDD and 32 healthy controls while undergoing resting-state fMRI. We found that the DMN received weaker inhibition from the SN and that the medial prefrontal cortex and the anterior cingulate cortex showed reduced self-inhibition in MDD, making them more prone to external influences. Moreover, we found that selective serotonin reuptake inhibitor (SSRI) intake was associated with decreased and increased self-inhibition of the SN and DMN, respectively, in patients. Our findings suggest that adolescent MDD is characterized by a hierarchical imbalance between the DMN and the SN, which could affect the integration of emotional and self-related information. We propose that SSRIs may help restore network function by modulating excitatory/inhibitory balance in the DMN and the SN. Our study highlights the potential of prefrontal-amygdala interactions as a biomarker and a therapeutic target for adolescent depression.

Gratitude, freedom and refusal.

This paper is an exploration of gratitude as a fundamental concept in psychoanalysis. Melanie Klein's classic article "Envy and Gratitude" (1957) named gratitude at one pole on an axis of human suffering and flourishing, but with a few notable exceptions, the article stimulated research into envy. This paper explores the historical and philosophical traditions that have, to some extent unconsciously, influenced our contemporary understandings of gratitude. The paper also works to explore the social and ethical meanings of gratitude as well as gratitude's psychoanalytic significance. The aim is to uncover the overall psychic significance of gratitude and its place in human flourishing.

Effects of Recreational Cannabis Legalization on Mental Health: Scoping Review.

OBJECTIVE: Recreational cannabis legalization (RCL) is expanding rapidly. RCL's effects on mental health issues are of particular concern because cannabis use is more frequent among people receiving psychiatric care and is associated with several psychiatric disorders. The authors conducted a scoping review to examine the evidence and discern gaps in the literature concerning the effects of RCL on mental health and to assess the factors responsible for an observed heterogeneity in research results. METHODS: This scoping literature review followed PRISMA guidelines. Five databases-MEDLINE, CINAHL, Embase, APA PsycInfo, and Web of Science-were searched for English- or French-language reports published between January 1, 2012, and April 30, 2023. RESULTS: Twenty-eight studies from the United States and Canada were found. The studies were classified by category of the study's data (patients receiving psychiatric care [k=1], death records [k=4], emergency department or hospital records [k=10], and the general population [k=13]) and by the diagnosis (schizophrenia or psychoses, mood disorders, anxiety disorders and symptoms, suicide or suicidal ideation, or other mental health issues) examined. The review findings revealed a paucity of research and indicated mixed and largely inconclusive results of the studies examined. Research gaps were found in the examination of potential changes in cannabis use patterns among people receiving psychiatric care and in the availability of longitudinal studies. CONCLUSIONS: Clinicians, researchers, and policy makers need to collaborate to address the research gaps and to develop evidence-based policies that reflect a thorough understanding of the effects associated with RCL.

APOE Genotype, ApoE Plasma Levels, Lipid Metabolism, and Cognition in Monozygotic Twins with, at Risk of, and without Affective Disorders.

Background: Lipids influence brain function and mental health. Understanding the role of apolipoproteins in affective disorders could provide valuable insights and potentially pave the way for novel therapeutic approaches. Methods: We examined the apolipoprotein E genotype and ApoE-levels, lipid profiles, and the correlation with cognition in 204 monozygotic (MZ) twins with unipolar or bipolar disorder in remission or partial remission (affected, AT), their unaffected co-twins (high-risk, HR), and twins with no personal or family history of affective disorder (low-risk, LR). Results: The APOE genotype was not associated with affective disorders. No significant group differences in ApoE levels were found between the three risk groups. Post hoc analysis group-wise comparisons showed higher ApoE levels in the AT than HR twins and in the concordant AT twin pairs relative to the discordant twin pairs. Within the discordant twin pairs, higher ApoE levels were observed in the affected twins (AT = 39.4 mg/L vs. HR = 36.8 mg/L, p = 0.037). Limitations: The present study could benefit from a larger sample size. We did not assess dietary habits. Conclusions: The results did not support our main hypothesis. However, exploratory post hoc analysis suggests a role for plasma ApoE and triglycerides in affective disorders. Future research is needed.

Family dysfunction, stressful life events, and mental health problems across development in the offspring of parents with an affective disorder.

BACKGROUND: Offspring of parents with affective disorders (OAD) are at risk of developing a wide range of mental disorders. Deficits in the rearing environment and high levels of stress are well-known risk factors for negative outcomes in OAD. Building on prior research, we aim to examine the longitudinal relationships between family dysfunction, stressful life events, and mental health in OAD and control offspring of parents with no affective disorder. In the present study, we hypothesized that high levels of family dysfunction would be associated with more internalizing and externalizing problems across time in OAD than in controls, and that family dysfunction would mediate the relationship between stressful life events in adolescence and poor mental health in adulthood, particularly in OAD. METHODS: As part of the TRacking Adolescents' Lives Survey (TRAILS), 2230 participants (51% female, Mage = 11.1 years, SD = 0.6, at baseline) and their parents completed measures across six time points, spanning 15 years. Mental health, family dysfunction, and stressful life events were assessed with the Youth and Adult Self-Report, Family Assessment Device, and an in-house measure, respectively. RESULTS: Multi-group structured equation modeling revealed that family dysfunction was linked to internalizing and externalizing problems in OAD, but not controls, across time. Risk status did not moderate family dysfunction's mediation of the relationship between stressful life events and negative outcomes in adulthood. CONCLUSIONS: OAD show high sensitivity to dysfunction in the rearing environment across childhood and adolescence, which supports the use of family based interventions to prevent the development of mental disorders in high-risk youth.

[Features of the clinical picture of affective disorders in women during the menopausal transition and early postmenopause]. / Osobennosti klinicheskoi kartiny affektivnykh rasstroistv u zhenshchin v period menopauzal'nogo perekhoda i rannei postmenopauzy.

OBJECTIVE: To determine the clinical and psychopathological features of affective disorders in women in the perimenopausal and early postmenopausal periods. MATERIAL AND METHODS: The study included 90 female patients receiving inpatient psychiatric care for affective disorders, among them 41 patients were perimenopausal (group 1) and 49 were early postmenopausal (group 2). Clinical and psychopathological, psychometric (the Hospital Anxiety and Depression Scale - HADS, the Hamilton Depression and Anxiety Scales - HAM-D and HAM-A, the Hypomania Checklist-32 - HCL-32, the Bipolarity Index (BI), the Insomnia Severity Index - ISI, the Pittsburgh Sleep Quality Index - PSQI) and statistical methods were used. RESULTS: Symptoms of atypical (63.4%) and anxious (87.8%) depression predominated among perimenopausal patients, and melancholic depression (59.2%) prevailed in early postmenopause. Patients in group 1 had higher anxiety scores on HADS and HAM-A compared to group 2 (p=0.003 and p=0.01). At the same time, early postmenopausal women had higher depression scores on the HADS and HAM-D (p=0.001). ISI and PSQI scores in postmenopause were significantly higher than in perimenopause (p=0.001 and p=0.009). CONCLUSION: The clinical features of affective disorders as well as severity and nature of the accompanying sleep disturbances vary depending on the stage of menopause, which must be considered when prescribing additional methods for examination and treatment of these disorders.

The Emotion Beliefs Questionnaire: Psychometric properties, norms, and links to affective outcomes.

BACKGROUND: The Emotion Beliefs Questionnaire was recently developed to measure beliefs about the controllability and usefulness of negative and positive emotions. These are beliefs that have been theorised to be influential for emotion regulation and psychological outcomes. However, to date there are few studies utilising large, representative samples to examine the EBQ's psychometric properties and affective correlates. Our aim was to fill this gap by examining the EBQ's psychometric properties and exploring associations between emotion beliefs, emotion regulation, and affective disorder symptoms. METHODS: A sample of 1175 adults recruited from the general population in the United States completed measures of emotion beliefs, emotion regulation, and affective disorder symptoms. RESULTS: Confirmatory factor analyses supported the EBQ's intended subscale structure, where controllability and usefulness beliefs were separated by valence. This structure was invariant across gender, age, and education categories. The EBQ correlated in expected ways with other measures, demonstrating good validity, and had good to excellent levels of internal consistency reliability. LIMITATIONS: This study used a non-clinical sample that was predominantly White. Future work should utilise clinical and cross-cultural samples to maximise generalisability of findings. CONCLUSIONS: Our findings indicate that the EBQ is a psychometrically sound tool for measuring the multidimensional emotion belief construct. The EBQ may have clinical utility in the conceptualisation, assessment, and treatment of maladaptive emotion beliefs. Furthermore, our results highlight the importance of considering the potential influence of maladaptive emotion beliefs in emotion dysregulation and affective disorder symptoms.

Waning waves of mood: The declining trend of hospitalized patients with affective disorders in Germany.

INTRODUCTION: Affective disorders profoundly affect individuals' emotional well-being and quality of life. This study investigates the epidemiology of affective disorders in Germany from 2011 to 2021, focusing on incidence rates, age- and sex-standardized rates, and developmental trends. METHODS: Using nationwide data of ICD-10 diagnosis codes from 2011 to 2021, this cross-sectional study analyzed inpatient cases of affective disorders in individuals aged 20 years or older. Age- and sex-standardized incidence rates were calculated based on the population size of each birth cohort in the 16 German federal states. Incidence rate ratios (IRRs) for 2011 to 2021 and 2019 to 2021 were compared with a two-sample z-test. RESULTS: Between 2011 and 2021, F30 (manic episode) showed a decline of 42.8 % to an incidence of 4.9 per 100,000 inhabitants, even though not statistically significant (p = 0.322). F31 (bipolar affective disorder) remained relatively stable with a reduction of 15.3 % to an incidence of 13.6 per 100,000 inhabitants in 2021 (p = 0.653). F32 (depressive episode) decreased statistically significant by 25.7 % to an incidence of 64.1 per 100,000 inhabitants (p = 0.072). F33 (recurrent depressive disorder) slightly increased by 18.3 % to an incidence of 94.6 per 100,000 inhabitants (p = 0.267). No statistically significant differences were found when comparing the COVID-19 pandemic year 2021 to 2019 incidences (p ≥ 0.529). CONCLUSION: The study provides valuable insights into the changing landscape of affective disorders in Germany over the past decade. The observed decline in incidence rates underscores the importance of continued efforts to promote mental health awareness and access to care.

Treating neuropathic pain and comorbid affective disorders: Preclinical and clinical evidence.

INTRODUCTION: Neuropathic pain (NP) significantly impacts quality of life and often coexists with affective disorders such as anxiety and depression. Addressing both NP and its psychiatric manifestations requires a comprehensive understanding of therapeutic options. This study aimed to review the main pharmacological and non-pharmacological treatments for NP and comorbid affective disorders to describe their mechanisms of action and how they are commonly used in clinical practice. METHODS: A review was conducted across five electronic databases, focusing on pharmacological and non-pharmacological treatments for NP and its associated affective disorders. The following combination of MeSH and title/abstract keywords were used: "neuropathic pain," "affective disorders," "depression," "anxiety," "treatment," and "therapy." Both animal and human studies were included to discuss the underlying therapeutic mechanisms of these interventions. RESULTS: Pharmacological interventions, including antidepressants, anticonvulsants, and opioids, modulate neural synaptic transmission to alleviate NP. Topical agents, such as capsaicin, lidocaine patches, and botulinum toxin A, offer localized relief by desensitizing pain pathways. Some of these drugs, especially antidepressants, also treat comorbid affective disorders. Non-pharmacological techniques, including repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and photobiomodulation therapy, modulate cortical activity and have shown promise for NP and mood disorders. CONCLUSIONS: The interconnection between NP and comorbid affective disorders necessitates holistic therapeutic strategies. Some pharmacological treatments can be used for both conditions, and non-pharmacological interventions have emerged as promising complementary approaches. Future research should explore novel molecular pathways to enhance treatment options for these interrelated conditions.

Reactivation of herpesvirus type 6 and IgA/IgM-mediated responses to activin-A underpin long COVID, including affective symptoms and chronic fatigue syndrome.

BACKGROUND: Persistent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), reactivation of dormant viruses, and immune-oxidative responses are involved in long COVID. OBJECTIVES: To investigate whether long COVID and depressive, anxiety, and chronic fatigue syndrome (CFS) symptoms are associated with IgA/IgM/IgG to SARS-CoV-2, human herpesvirus type 6 (HHV-6), Epstein-Barr Virus (EBV), and immune-oxidative biomarkers. METHODS: We examined 90 long COVID patients and ninety healthy controls. We measured serum IgA/IgM/IgG against HHV-6 and EBV and their deoxyuridine 5'-triphosphate nucleotidohydrolase (duTPase), SARS-CoV-2, and activin-A, C-reactive protein (CRP), advanced oxidation protein products (AOPP), and insulin resistance (HOMA2-IR). RESULTS: Long COVID patients showed significant elevations in IgG/IgM-SARS-CoV-2, IgG/IgM-HHV-6, and HHV-6-duTPase, IgA/IgM-activin-A, CRP, AOPP, and HOMA2-IR. Neural network analysis yielded a highly significant predictive accuracy of 80.6% for the long COVID diagnosis (sensitivity: 78.9%, specificity: 81.8%, area under the ROC curve = 0.876); the topmost predictors were as follows: IGA-activin-A, IgG-HHV-6, IgM-HHV-6-duTPase, IgG-SARS-CoV-2, and IgM-HHV-6 (all positively) and a factor extracted from all IgA levels to all viral antigens (inversely). The top 5 predictors of affective symptoms due to long COVID were IgM-HHV-6-duTPase, IgG-HHV-6, CRP, education, IgA-activin-A (predictive accuracy of r = 0.636). The top 5 predictors of CFS due to long COVID were in descending order: CRP, IgG-HHV-6-duTPase, IgM-activin-A, IgM-SARS-CoV-2, and IgA-activin-A (predictive accuracy: r = 0.709). CONCLUSION: Reactivation of HHV-6, SARS-CoV-2 persistence, and autoimmune reactions to activin-A combined with activated immune-oxidative pathways play a major role in the pathophysiology of long COVID as well as the severity of its affective symptoms and CFS.