Treatment-resistant depression (TRD) is a subtype of major depressive disorder (MDD) that fails to respond to first-line pharmacotherapy. This cross-sectional study compared blood concentrations of folic acid, vitamin B12, and homocysteine between female depressed patients with or without TRD, and examined the association of these parameters with the severity of depression. It included 116 female patients treated for MDD, of whom 59 (51%) developed TRD. The diagnosis of MDD was established via a structured clinical interview, while the severity of depression was measured with the Montgomery-Asberg Depression Rating Scale. Blood samples were taken at the initial psychiatric examination to determine the serum levels of folic acid and vitamin B12 and plasma levels of homocysteine. Folic acid levels were significantly lower in the female TRD group (p < 0.001), whereas homocysteine levels were significantly higher in the female TRD group (p < 0.001), compared to the female depressed group without TRD. In the regression analyses, higher levels of homocysteine (p < 0.001) were associated with TRD, while lower levels of folic acid (p = 0.036) were related to higher severity of depression, independently of sociodemographic and clinical parameters. Our findings showed that folate correlated with symptom severity, while homocysteine correlated with the TRD status in female MDD patients.

Heart failure (HF) is a complex systemic syndrome with major neuropsychiatric consequences. Cognitive impairment (e.g., dementia) and depression are common among HF patients, worsening prognosis, increasing hospital admissions, and impairing quality of life. Despite their prevalence, the neurobiological basis of these comorbidities is not yet fully understood. This review uniquely discusses converging neuroendocrine, inflammatory, and neuroplastic mechanisms linking HF, depression, and dementia inside an integrative heart-brain axis highlighting brain-derived neurotrophic factor (BDNF) as an important modulator of synaptic plasticity, neurogenesis, and stress resilience. Understanding the interactions between HF-induced hypothalamic-pituitary-adrenal axis activation, systemic inflammation, and impaired BDNF signaling may contribute to the development of novel multimodal therapeutic strategies targeting neurotrophic pathways and improving cognitive and mental health outcomes in HF.

Major depressive disorder (MDD) is associated with complex metabolic alterations. In this study, we applied a multiplatform metabolomics approach (GC-MS and LC-MS) to characterize the plasma extracellular vesicle (EV) metabolome in healthy controls (N = 50), responsive MDD patients (N = 60), and patients with treatment-resistant depression (TRD; N = 65). Longitudinal analyses were performed following 8-week treatment with duloxetine (N = 30), bright-light therapy (BLT; N = 30), or esketamine (N = 35). A total of 230 metabolites were identified, with the most pronounced metabolic alterations observed in TRD patients, particularly in lipid, amino acid, and energy metabolism pathways. Elevated lysophospholipids and fatty acids in TRD suggested dysregulated lipid metabolism and inflammatory processes. All treatments resulted in clinical improvement, accompanied by partial normalization of metabolic profiles. Duloxetine treatment was associated with modulation of amino acid and glycerophospholipid metabolism, including increases in tryptophan-related metabolites and normalization of specific lipid species. BLT primarily reduced lysophospholipids and mannose levels, while esketamine modulated metabolites related to lipid turnover, short-chain fatty acids, carbohydrate metabolism, and neuroendocrine function, including increased thyrotropin-releasing hormone levels. These findings support the concept that TRD represents a biologically distinct and more metabolically dysregulated subtype of depression and highlight EV-based metabolomics as a promising approach for elucidating disease and treatment mechanisms.

Treatment-resistant depression (TRD) is usually defined as an insufficient response to ≥1 treatment considered adequate in terms of dosage, duration, and compliance, or the failure to respond to electroconvulsive therapy (ECT). Cognitive disturbances are the core symptoms of depression and TRD, and they significantly contribute to the poor functional outcomes and treatment resistance. Patients with TRD have moderate to large cognitive deficits in executive function, verbal learning and memory, attention, visual perception, conceptual transformation, attention conversion, logic reasoning, and problem-solving, in processing speed compared to non-TRD patients. The biological underpinning of cognitive deterioration in TRD is diverse, including alterations in different brain regions and circuits, lower levels of N-acetyl aspartate and the important role of inflammatory processes, while animal studies reveal the involvement of 5-HT1A and 5-HT2 serotonergic and α2C-AR adrenergic receptors. It is important to better elucidate the biological background of cognitive dysfunction in TRD to develop more personalized and targeted treatments. Some therapeutic strategies of cognitive dysfunction in TRD include pharmacotherapy, neuromodulation, psychotherapy, and cognitive remediation. Cognitive disturbances in TRD correspond to both obstacles and challenges, but future studies should incorporate cognitive measurements and therapeutic strategies with individual approach to specifically target cognitive impairment in TRD.

Gradual loss of cognitive abilities is common during ageing but might also result in mild cognitive impairment and dementia. Research suggests that neurotrophins, such as brain derived neurotrophic factor (BDNF), and neurosteroids, such as dehydroepiandrosterone (DHEA) and its sulphate (DHEAS), play crucial role in cognitive functions and are often dysregulated in neurocognitive disorders. This study aimed to investigate variations in the genes for BDNF and sulfotransferase 2A1 (SULT2A1), the enzyme converting DHEA into DHEAS, as well as plasma BDNF and DHEAS levels, in individuals with normal cognition, and mild, moderate, and severe cognitive impairment. Cognitive functions of 453 participants were evaluated using Mini-Mental State Examination (MMSE) and Clock Drawing test (CDT). Genotyping of BDNF (rs6265) and SULT2A1 (rs2637125) polymorphisms was conducted, and plasma BDNF and DHEAS concentrations were determined by enzyme-linked immunosorbent assays (ELISA). Obtained results demonstrated that participants with moderate to severe cognitive impairment had significantly lower plasma BDNF and DHEAS levels, compared to individuals with normal cognition. In contrast to DHEAS, BDNF changes were more pronounced in men than in women. However, no significant associations of BDNF rs6265 and SULT2A1 rs2637125 polymorphisms with cognitive decline, or with plasma BDNF and DHEAS levels, respectively, were observed. Compared to CDT, MMSE was superior in distinguishing plasma BDNF and DHEAS variations, especially between individuals with mild and moderate to severe cognitive impairment. Further studies should investigate the potential of BDNF and DHEAS as peripheral biomarkers of cognitive decline and possible benefits of their replacement therapy in neurocognitive disorders.

INTRODUCTION:Optimal sleep duration is increasingly recognized as an important determinant of overall health, including cognitive functioning. Studies often report a U- or J-shaped relationship between sleep duration and incident dementia or cognitive deterioration, whereas long sleep, the extremes of sleep duration, and the transition to long sleep were particularly detrimental. In preclinical studies, partial or complete sleep deprivation produced inflammation, oxidative stress, as well as increased tau hyperphosphorylation and amyloid-β burden. In humans, although the findings are less pronounced, they still highlight that transitioning to an excessive sleep duration is associated with neurodegeneration. Moreover, the association between sleep duration and dementia is complex and modified by genetic, psychosocial and lifestyle factors, along with psychiatric and somatic comorbidities. AREAS COVERED:The purpose of this perspective is to summarize the current knowledge on the association between sleep duration and dementia. It is based on a literature search for meta-analyses of prospective studies with sleep duration as an exposure and dementia as an outcome. EXPERT OPINION:Sleep duration is a modifiable risk factor for dementia while long sleep may be an early sign of neurodegeneration. Therefore, self-reported sleep duration is an easy-to-use tool for detecting individuals who may be at risk for cognitive deterioration.

Aggression constitutes a significant behavioral issue associated with delinquent behavior, commonly observed in youth diagnosed with conduct disorder (CD) and living in correctional facilities. Catechol-o-methyl-transferase (COMT) gene variants modify the environmental sensitivity associated with the risk of aggression. This study evaluated the association of COMT rs4680 and rs4818 polymorphisms with aggressive behavior in 341 male adolescents living inside and outside a correctional facility, with or without a diagnosis of CD. Aggression was assessed using the Hare Psychopathy Checklist: Youth Version (PCL-YV), Modified Overt Aggression Scale (MOAS) and Swanson, Nolan and Pelham Questionnaire. COMT rs4680 and rs4818 polymorphisms were genotyped using TaqMan SNP Genotyping Assays. A similar prevalence of the COMT genotypes or haplotypes was found between adolescents with or without CD, suicidal behavior, or detention in correctional facility. In youth with CD, the COMT rs4680 A allele was associated with higher MOAS verbal aggression, aggression toward objects, irritability (subjective and open), and PCL-YV interpersonal domain scores compared with carriers of the COMT rs4680 G allele. COMT rs4818 GC carriers with CD had higher scores on the MOAS subjective irritability than GG heterozygotes. These novel findings revealed the association of lower COMT rs4680 and rs4818 activity alleles with aggression in detained male adolescents with CD.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, and its etiology is not completely understood. In addition to older age, various genetic factors also increase the risk of AD, including genes for brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin kinase receptor type B (TrkB). The aim of this study was to investigate the association between polymorphisms in the BDNF gene (rs1519480, rs6265, rs11030104, rs56164415, rs7934165) and the gene for TrkB protein (NTRK2 rs1439050), as determined using DNA isolated from blood samples, and biological markers of AD detected in the cerebrospinal fluid. These markers included A(1-42, total tau (t-tau), phosphorylated tau (p-tau181, p-tau199, and p-tau231), and a novel protein marker, visinin-like protein 1 (VILIP-1). We compared these markers in subjects with AD to those with mild cognitive impairment. Using a multiple linear regression model, adjusted for the effect of diagnosis, age, and sex, the study revealed significant differences in VILIP-1 concentrations among patient groups categorized by NTRK2 genotypes (p = 0.001). GG homozygotes had a significantly higher abundance of VILIP-1 compared to other genotype carriers. Additionally, a significantly higher VILIP-1 concentration (p = 0.007) was observed in carriers of the BDNF haplotype AGTCA (rs1519480/rs6265/rs11030104/rs56164415/rs7934165). Our results suggest that these polymorphisms should be considered when studying VILIP-1 as a potential biomarker for AD.

Treatment-resistant depression (TRD) remains a challenge despite the growing number of interventions. Peripheral interleukin-6 (IL-6) levels have repeatedly been associated with both the presence and response to different treatments in TRD. There is currently no information available on the effects of bright light therapy (BLT) on serum IL-6 levels. This study assessed the effects of BLT on serum IL-6 levels in TRD patients. Serum IL-6 was determined at two points in TRD patients—at baseline and after 4 weeks of BLT—and at a single point in the healthy controls. Depression severity was measured by the Hamilton Rating Scale for Depression (HAMD)-17 and the Montgomery–Åsberg Depression Rating Scale (MADRS). The study included 104 females, 54 diagnosed with TRD (median age 52.5) and 50 healthy controls (median age 44.5). At baseline, patients had higher IL-6 levels than the controls. BLT treatment reduced HAMD-17 and MADRS scores. Serum IL-6 levels were not significantly affected by the 4 weeks of BLT. However, when patients were divided according to treatment response, IL-6 levels were increased in responders to BLT. The neuroinflammatory mechanism may be involved in the etiopathogenesis and the treatment of TRD, while changes in serum IL-6 levels may be potential indicators of response to treatment.

Brain-derived neurotrophic factor (BDNF) plays a crucial role in cognitive functions and dementia. In individuals with mild cognitive impairment (MCI) and dementia, we have investigated BDNF Val66Met genotype distribution, peripheral BDNF DNA methylation, mRNA and protein levels, and cognitive performance using the Mini-Mental State Examination (MMSE) and Clock Drawing Test (CDT). Lower BDNF_IV1 methylation had predictive value for dementia. Patients with mild-to-moderate dementia had lower levels of BDNF_IV2 methylation, whereas patients with severe dementia had higher levels than the MCI group, while BDNF_IV2 methylation positively correlated with CDT scores. An insignificant decline in BDNF mRNA levels in dementia patients positively correlated with significantly lower BDNF plasma levels, especially pronounced in severe dementia patients. BDNF mRNA and protein levels were positively correlated with CDT and MMSE scores, respectively. BDNF Val66Met polymorphism was associated with methylation of the BDNF_IX amplicon, but not with methylation in BDNF promoters I and IV, peripheral BDNF gene and protein expression, MMSE and CDT scores, or dementia. Methylation at the BDNF Val66Met site was positively correlated with overall BDNF_IX methylation and methylation at 5 BDNF_IX CpG loci but negatively correlated with methylation of BDNF_IV1, BDNF_IV3, and BDNF_I1 amplicons. Further studies should evaluate the translational potential of these peripheral BDNF-based biomarkers for dementia.

BACKGROUND:Arterial stiffness, salivary alpha-amylase activity and cortisol concentration have been associated with stress response in different experimental models. However, the values and dynamics of those potential biomarkers of stress have not been examined in patients with acute stress disorder (ASD). METHODS:This study included 88 patients (61 females; mean age 42.53) with ASD and 65 healthy subjects (43 females; mean age 41.66). Patients, evaluated according to the DSM-5 criteria, have filled out the Acute Stress Disorder Scale (ASDS) and the Hamilton Anxiety Rating Scale (HAM-A), and their arterial stiffness (expressed as pulse wave velocity and augmentation index), salivary alpha-amylase activity and cortisol concentration were assessed at baseline and after 4-weeks of follow-up. Healthy control subjects had their arterial stiffness, salivary alpha-amylase activity and cortisol concentration measured only at baseline. RESULTS:At baseline, participants with ASD had higher salivary cortisol concentration and alpha-amylase activity, higher BMI, were more often smokers and exhibited lower education levels than healthy controls. Both groups did not differ in arterial stiffness. After 4 weeks, ASD patients had similar symptom severity, arterial stiffness, saliva cortisol concentration and alpha-amylase activity compared to their baseline values. CONCLUSION:Single unpredictable and highly stressful event may not only induce ASD, but is also associated with the persistence of psychopathology and increased salivary biomarkers of stress. Patients with ASD may require increased medical attention to prevent both psychiatric and somatic consequences of stress.

Brain-derived neurotrophic factor (BDNF) is implicated in the etiology of schizophrenia, and peripheral BDNF levels are affected by the short-term antipsychotic treatment. However, the data on their long-term effects on BDNF levels are scarce, and there is no information whether BDNF levels change during sustained remission in relation to values in healthy individuals. The aim of the present study was to compare serum BDNF levels in patients in long-term remission and healthy controls. This study is an extension of our previous research on the effects of olanzapine and risperidone on serum BDNF in acute-episode patients with schizophrenia. Patients who remained in remission for at least 3 years on the same antipsychotic regimen (40 % of the initial cohort) were included. Symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS). Serum BDNF levels were measured by ELISA in patients in remission (N = 20), evaluated at baseline, after 6 weeks of treatment and after 3 years of treatment, and in healthy individuals (N = 40). At baseline (p = 0.046) and after 6 weeks of treatment (p = 0.028), patients had significantly lower BDNF levels than controls. However, after 3 years of continuous antipsychotic maintenance treatment, serum BDNF levels were increased compared to baseline and values after 6 weeks of treatment in remitted patients, and were also significantly higher in patients than in healthy controls (p = 0.002). Antipsychotic medications appear to have distinct effects on serum BDNF levels in short-and long-term treatment. It remains to be determined if such finding may be related to potential neuroprotective effects of antipsychotic maintenance treatment.

Reduced brain derived neurotrophic factor (BDNF) concentration is reported to be associated with a cognitive decline in schizophrenia, depending on the stage of the disease. Aim of the study was to examine the possible association between plasma BDNF and cognitive decline in chronic stable schizophrenia and mild cognitive impairment (MCI). The study included 123 inpatients of both sexes with schizophrenia, 123 patients with MCI and 208 healthy control subjects. Cognitive abilities were assessed using mini mental state examination (MMSE), Clock Drawing test (CDT) and cognitive subscale of the Positive and Negative Syndrome Scale (PANSS). Plasma BDNF concentration was determined using ELISA. BDNF concentration was lower in patients with schizophrenia and MCI compared to age-matched healthy controls and was similar in carriers of different BDNF Val/66Met genotypes. The MMSE and CDT scores were lower in patients with schizophrenia compared to healthy controls and subjects with MCI. Reduced plasma BDNF was significantly associated with lower MMSE scores in all subjects. BDNF concentration in patients with schizophrenia was not affected by clinical and demographic factors. BDNF Val66Met polymorphism was not associated with the MMSE scores in all participants. Further studies should include longitudinal follow-up and other cognitive scales to confirm these results and offer cognition-improving strategies to prevent cognitive decline in chronic schizophrenia.

INTRODUCTION:The importance of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) diagnosis is rapidly increasing, and there is a growing interest in the use of CSF biomarkers in monitoring the response to therapy, especially in the light of newly available approaches to the therapy of neurodegenerative diseases. AREAS COVERED:In this review we discuss the most relevant measures of neurodegeneration that are being used to distinguish patients with AD from healthy controls and individuals with mild cognitive impairment, in order to provide an overview of the latest information available in the scientific literature. We focus on markers related to amyloid processing, markers associated with neurofibrillary tangles, neuroinflammation, neuroaxonal injury and degeneration, synaptic loss and dysfunction, and markers of α-synuclein pathology. EXPERT OPINION:In addition to neuropsychological evaluation, core CSF biomarkers (Aβ42, t-tau, and p-tau181) have been recommended for improvement of timely, accurate and differential diagnosis of AD, as well as to assess the risk and rate of disease progression. In addition to the core CSF biomarkers, various other markers related to synaptic dysfunction, neuroinflammation, and glial activation (neurogranin, SNAP-25, Nfl, YKL-40, TREM2) are now investigated and have yet to be validated for future potential clinical use in AD diagnosis.

The complex role of the serotonin system in respiratory function and inflammatory diseases such as asthma is unclear. Our study investigated platelet serotonin (5-HT) levels and platelet monoamine oxidase B (MAO-B) activity, as well as associations with HTR2A (rs6314; rs6313), HTR2C (rs3813929; rs518147), and MAOB (rs1799836; rs6651806) gene polymorphisms in 120 healthy individuals and 120 asthma patients of different severity and phenotypes. Platelet 5-HT concentration was significantly lower, while platelet MAO-B activity was considerably higher in asthma patients; however, they did not differ between patients with different asthma severity or phenotypes. Only the healthy subjects, but not the asthma patients, carrying the MAOB rs1799836 TT genotype had significantly lower platelet MAO-B activity than the C allele carriers. No significant differences in the frequency of the genotypes, alleles, or haplotypes for any of the investigated HTR2A, HTR2C and MAOB gene polymorphisms have been observed between asthma patients and healthy subjects or between patients with various asthma phenotypes. However, the carriers of the HTR2C rs518147 CC genotype or C allele were significantly less frequent in severe asthma patients than in the G allele carriers. Further studies are necessary to elucidate the involvement of the serotonergic system in asthma pathophysiology.

IntroductionDespite the growing number of different therapeutic options, treatment of depression is still a challenge. A broader perspective reveals the benefits of bright light therapy (BLT). It stimulates intrinsically photosensitive retinal ganglion cells, which induces a complex cascade of events, including alterations in melatonergic, neurotrophic, GABAergic, glutamatergic, noradrenergic, serotonergic systems, and HPA axis, suggesting that BLT effects expand beyond the circadian pacemaker.Areas coveredIn this review, the authors present and discuss recent data of BLT in major depressive disorder, non-seasonal depression, bipolar depression or depressive phase of bipolar disorder, and seasonal affective disorder, as well as in treatment-resistant depression (TRD). The authors further highlight BLT effects in various depressive disorders compared to placebo and report data from several studies suggesting a response to BLT in TRD. Also, the authors report data showing that BLT can be used both as a monotherapy or in combination with other pharmacological treatments.Expert opinionBLT is an easy-to-use and low-budget therapy with good tolerability. Future studies should focus on clinical and biological predictors of response to BLT, on defining specific populations which may benefit from BLT and establishing treatment protocols regarding timing, frequency, and duration of BLT.

The molecular underpinnings of post-traumatic stress disorder (PTSD) are still unclear due to the complex interactions of genetic, psychological, and environmental factors. Glycosylation is a common post-translational modification of proteins, and different pathophysiological states, such as inflammation, autoimmune diseases, and mental disorders including PTSD, show altered N-glycome. Fucosyltransferase 8 (FUT8) is the enzyme that catalyzes the addition of core fucose on glycoproteins, and mutations in the FUT8 gene are associated with defects in glycosylation and functional abnormalities. This is the first study that investigated the associations of plasma N-glycan levels with FUT8-related rs6573604, rs11621121, rs10483776, and rs4073416 polymorphisms and their haplotypes in 541 PTSD patients and control participants. The results demonstrated that the rs6573604 T allele was more frequent in the PTSD than in the control participants. Significant associations of plasma N-glycan levels with PTSD and FUT8-related polymorphisms were observed. We also detected associations of rs11621121 and rs10483776 polymorphisms and their haplotypes with plasma levels of specific N-glycan species in both the control and PTSD groups. In carriers of different rs6573604 and rs4073416 genotypes and alleles, differences in plasma N-glycan levels were only found in the control group. These molecular findings suggest a possible regulatory role of FUT8-related polymorphisms in glycosylation, the alternations of which could partially explain the development and clinical manifestation of PTSD.

Alzheimer's disease (AD) is often not recognized or is diagnosed very late, which significantly reduces the effectiveness of available pharmacological treatments. Metabolomic analyzes have great potential for improving existing knowledge about the pathogenesis and etiology of AD and represent a novel approach towards discovering biomarkers that could be used for diagnosis, prognosis, and therapy monitoring. In this study, we applied the untargeted metabolomic approach to investigate the changes in biochemical pathways related to AD pathology. We used gas chromatography and liquid chromatography coupled to mass spectrometry (GC-MS and LC-MS, respectively) to identify metabolites whose levels have changed in subjects with AD diagnosis (N = 40) compared to healthy controls (N = 40) and individuals with mild cognitive impairment (MCI, N = 40). The GC-MS identified significant differences between groups in levels of metabolites belonging to the classes of benzene and substituted derivatives, carboxylic acids and derivatives, fatty acyls, hydroxy acids and derivatives, keto acids and derivatives, and organooxygen compounds. Most of the compounds identified by the LC-MS were various fatty acyls, glycerolipids and glycerophospholipids. All of these compounds were decreased in AD patients and in subjects with MCI compared to healthy controls. The results of the study indicate disturbed metabolism of lipids and amino acids and an imbalance of metabolites involved in energy metabolism in individuals diagnosed with AD, compared to healthy controls and MCI subjects.

Neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), monocyte–lymphocyte ratio (MLR) and systemic immune-inflammation index (SII index) are increasingly used as indicators of inflammation in different conditions, including schizophrenia. However, their relationship with negative symptoms, including anhedonia, is largely unknown. Included were 200 patients with schizophrenia and 134 healthy controls (HC), assessed for physical anhedonia (PA), using the Revised Physical Anhedonia Scale (RPAS), and social anhedonia (SA) by the Revised Social Anhedonia Scale (RSAS). Patients were rated by the Positive and Negative Syndrome Scale (PANSS), the Clinical Assessment Interview for Negative Symptoms (CAINS) and the Brief Negative Symptom Scale (BNSS). Most of the negative symptoms were in a weak to moderate positive correlations with blood cell inflammatory ratios, namely, between NLR and MLR with PANSS negative scale, CAINS, and BNSS, and in male patients, between PLR and PANSS negative scale and CAINS. Fewer correlations were detected in females, but also in a positive direction. An exception was SA, given the negative correlation between its severity and the SII index in females, and its presence and higher PLR in males. While different negative symptoms were associated with subclinical inflammation, the relationship between SA and lower inflammatory markers deserves further exploration.