Investigating metabolic differences between pre-pubertal Flinders sensitive (FSL) and resistant (FRL) line rats and determine the impact of early-life adversity on these differences. Untargeted metabolomic profiling of whole-brain tissue from postnatal day 25 Flinders line rats, exposed to maternal separation with early weaning (MSEW), or not, was done by using gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). Irrespective of MSEW, FSL rats had higher urea and lower glutamine, norvaline and valine concentrations than age-matched FRL controls. Across strains, MSEW reduced gamma-aminobutyric acid (GABA), glutamate, glutamine, lactate, phenylalanine, norvaline and valine concentrations, whist elevating 2-keto-3-methylbutyric acid, glycerophosphate, and urea. This effect was most pronounced in FRL rats. Pre-pubertal FSL rats displayed distinct metabolic signatures associated with altered energy and amino acid metabolism. Early-life stress further disrupts these pathways, highlighting key metabolites as potential targets in the expansion of the biological constructs underlying the pre-pubertal FSL/FRL model.
A previous study by our research group identified psychomotor and neurofunctional impairments following SARS-CoV-2 infection. This study continues that investigation, aiming to evaluate whether these impairments persisted over time, as part of the broader characterisation of long COVID. Moreover, it was explored potential correlations with variables such as age, blood type, symptoms, and medical care. From an initial pool of 214 subjects, 30 post-COVID-19 participants and 30 healthy controls were selected after strict exclusion criteria. The assessments protocol included eight psychomotor tests - Fine Motor Development (Diadochokinesia, Puppets, Fan, and Paper) and Balance (Immobility, Static Balance on One Foot, Feet in Line, and Persistence) - as well as three cognitive screening tasks from the Mini-Mental State Examination: Episodic Memory After Distracters, Verbal Fluency, and Clock tests. Evaluations were performed at three time points: baseline (post-COVID-19), 12 weeks, and 24 weeks. Participants were stratified by age (18-30, 31-45, and 46-64 years), symptoms profile, medical care, and blood type. COVID-19 induced psychomotor and neurofunctional sequelae lasting at least 24 weeks post-infection. These impairments were more pronounced and persistent in the 31-45-years age group, while memory-related impairments were more evident in the 18-30 age group. Body pain, coryza, and sore throat were key symptoms linked to long-term sequelae. Rh-negative blood type was suggested as a potential risk factor. The findings support that long COVID included sustained psychomotor and neurofunctional sequelae, premature senescence, and associations with specific clinical and biological variables.
Defined by DSM-5-TR as a neurodevelopmental disorder Attention-Deficit/Hyperactivity Disorder (ADHD) has attracted ever-mounting attention from the public, coupled with a growing interest from clinicians, researchers, and patients. This is reflected in significantly higher demand for clinical assessments and frequent media reports of a surge in ADHD cases across the lifespan. These trends are puzzling as it is unknown what they truly reflect: an improvement in clinical detection or a concerning degree of overdiagnosis? A key reason for this uncertainty is our limited understanding of the disorder and imprecision of the diagnosis - a long-running subject of criticism. To better understand these issues, in this article we deconstruct ADHD through the lens of its DSM-5-TR diagnostic criteria - the basis upon which the diagnosis is routinely made. Our in-depth analysis reveals major problems associated with the diagnostic criteria with respect to their arbitrariness, vagueness, redundancy, and context-dependent normality, which together substantially undermine the validity and reliability of the diagnosis, and the ADHD construct itself, blunting the precision of ADHD research, clinical decisions and the effectiveness of treatment - all of which are contingent on having a robust diagnosis in the first place. Hence, our detailed deconstruction of the diagnosis of ADHD is critical as it provides the necessary groundwork for its accurate reconstruction - an essential step towards developing a valid, reliable, and clinically meaningful diagnostic foundation that will inform research and improve clinical care for patients with attentional and hyperactivity-impulsivity problems.
The comorbidity of psychiatric and metabolic conditions is prevalent and poses a heavy burden on public health. Several biopsychosocial factors are known to influence both metabolic and psychiatric health, including inflammation, eating behavior, physical activity, and early life stress. Few studies, however, have examined the constellation of interrelationships among multiple risk domains simultaneously. Using a sample of 200 medically healthy adults enrolled in a parent study, we used Gaussian Graphical Modeling, a type of network analysis, to characterize interdependent cross-sectional associations between early life stress (childhood trauma), health behaviors (diet quality and physical activity), blood-based biomarkers of metabolic functioning (insulin resistance, HDL cholesterol, triglycerides) and inflammation (C-reactive protein [CRP]), and three domains of mental health symptoms (depressive, anxious, and post-traumatic stress symptoms). We hypothesized that the network structure would highlight a pattern whereby higher CRP, poorer diet quality, lower physical activity, and higher childhood trauma would associate with increased risk for both metabolic and psychiatric impairments. Findings revealed a positive conditional association between CRP and childhood trauma, which may function as an intermediary process to increase risk for both metabolic impairments and psychiatric symptoms in adulthood. Further, higher physical activity was associated with lower insulin resistance and fewer depressive symptoms, and better diet quality was associated with lower CRP levels. Results highlight potential avenues for interventions aimed at reducing inflammation, improving health behavior, and addressing the effects of childhood trauma to improve physical and mental health comorbidities.
Major depressive disorder (MDD) is a neuro-immune, oxidative, and nitrosative stress (NIMETOX) disorder, in which peripheral immune-redox pathways intersect with metabolic networks leading to neurotoxicity within the limbic-prefrontal affective circuits. Comprehensive metabolomics analysis in well-phenotyped patients is vital to elucidate their metabolic profile. To identify metabolic abnormalities that differentiate in patients with severe MDD from healthy controls(HCs) through high-resolution, untargeted metabolomics. Serum samples from 125 MDD inpatients and 40 HCs were analyzed utilizing liquid chromatography(LC) and mass spectrometry(MS). A meticulously regulated multistage machine-learning pipeline with leakage-prevention protocols was employed to analyze differences between MDD and controls and to predict phenome scores. Feature selection showed that 16 metabolites and 6 functional modules reliably distinguished MDD. The functional profile of the metabolites indicates a convergence of lipotoxicity, phospholipid(PL) remodeling, disruptions in fatty acid(FA) metabolism, mitochondrial redox imbalance, ether-lipid metabolism, and antioxidant depletion. This MDD metabotype was not affected by metabolic syndrome(MetS). A substantial portion of the variance in overall depression severity (72.5%), physiosomatic symptoms (55.8%), and suicidal ideation(SI) (23.6%) was accounted for by increased lipotoxicity, PL remodeling, and FA storage/signaling. The recurrence of illness (27.7%) was associated with a self-reinforcing lipid-redox-inflammatory module that maintains cellular stress. The MDD metabotype represents a cohesive metabolic network that is associated with the NIMETOX pathogenesis of MDD. Metabolomics provides a comprehensive foundation for subtyping and precision psychiatry. Lipoxygenase-15, lipotoxicity, phospholipase A2, and lipid-redox intersections might be important drug targets to treat MDD.
Longitudinal studies on population representative samples offer unique insights. The Estonian Children Personality Behaviour and Health Study (ECPBHS; EstChild) was launched in 1998 on two birth cohort samples at age 9 or 15 with an exceptional participation rate, has been monitored at ages 15, 18, 25 and 33, and also recruited parents of the target subjects. This multidisciplinary investigation has been focused on behavioural neuroscience, illuminating findings on what could be discerned from biomarkers, candidate genes, gene × environment interactions, and epigenetic markers in representative samples, and in birth cohorts living through societal transformation. ECPBHS analysed how biomarkers and lifestyle are associated with real-life behaviours and developmental trajectories, phenotypes such as neuroticism, bulimia, aggressiveness or attention deficit, and outcomes from incidence of psychiatric disorders to the obtaining of university education. Novel evidence has been observed on clustering of fears and the inner structure of impulsivity and reward sensitivity, together with clues how these may have co-emerged with metabolic types. New insights have been provided to understand the classic biomarkers, cholesterol and platelet monoamine oxidase activity, as well as several functional gene variants. Hypotheses how to synthetise molecular genetics and sociology, how sex or gender matters in the light of gene × environment interactions and how family and parental roles shape the behaviour of offspring have been put forward. The ECPBHS has offered clues on why in biological psychiatry many replication attempts are predestined to fail, and how to learn from such failures.
Psychedelics such as psilocybin are known for their hallucinogenic properties and have also been reported to produce long-lasting therapeutic effects in depression and possibly also other psychiatric disorders. Several lines of evidence suggest that psilocybin exerts its effects through activation of 5-HT2A receptors located postsynaptically to serotonergic neurons, for example, in the frontal cortex, parts of the limbic system, including the amygdala and hippocampus, and striatum. The present study was conducted to shed further light on psilocybin-induced changes in gene expression. Samples from the medial prefrontal cortex, cingulate cortex, hippocampus, amygdala, and striatum were collected from 24 male Wistar rats 90 min after they had been injected with either saline or psilocybin (2 mg/kg) and subjected to multi-region transcriptional profiling using 3prime-RNASeq technology. Nfkbia and Sgk1 were upregulated in all the studied regions, Ddit4 was upregulated in four regions, and Gpd1, Apold1, Sox9, Tsc22d3, and Slc2a1 were differentially expressed in two regions. Other cases of differentially expressed genes were region-specific. Whereas psilocybin was not found to alter the expression of genes encoding enzymes, transporters, or receptors implicated in the serotonergic signalling, or those specifically involved in the regulation of the synaptic activity of other neurotransmitters, a common denominator for many of the genes impacted by psilocybin is that they have previously been found to be activated by glucocorticoids.
This systematic review and meta-analysis aimed to quantify the magnitude of placebo and nocebo effects in pharmacological trials for OCRDs and identify clinical and methodological moderators influencing these effects. A comprehensive literature search was conducted across multiple databases and clinical trial registries up to May 2025. Randomised, placebo-controlled trials involving pharmacological interventions for OCRDs were included. The primary outcomes were placebo effect size and placebo response rate; secondary outcomes included nocebo response rate and side effect profile. Data were extracted independently and meta-analysed using random effects models. Meta-regression was performed to assess moderators of placebo response. Fifteen eligible trials (N = 640; placebo N = 341) were included. The pooled placebo effect size was moderate (SMC = -0.63; 95% CI -0.77 to -0.48), with low heterogeneity (I2 = 4.73%). The placebo response rate was 21%, and the nocebo response rate was 18%. Despite testing a broad range of potential moderators, including clinical characteristics, methodological design, and medication class, no significant predictors of placebo effect size were identified. Side effects were reported in nearly one-third of placebo recipients, underscoring the relevance of nocebo effects. Placebo and nocebo responses are noteworthy in trials for OCRDs and may influence perceived treatment efficacy. Variability in placebo responses is not well explained by currently measurable moderators. Further research is needed to explore neurobiological, psychological, and methodological contributors to expectancy effects in OCRD pharmacotherapy trials.
Depressive disorder (DD) is a widespread mental illness that lacks objective diagnostic biomarkers, complicating early detection and personalized treatment. This study investigated the diagnostic value of serum interferon-gamma (IFN-γ), nerve growth factor (NGF), and their ratio, alongside thyroid peroxidase antibody (TPOAb) and glial fibrillary acidic protein (GFAP), in patients with DD compared to healthy controls. A total of 238 participants (118 with DD and 120 controls) were enrolled. Depression severity was assessed using DSM-5 and HAM-D criteria. Serum biomarkers were measured using enzyme-linked immunosorbent assays (ELISA), and receiver operating characteristic (ROC) analysis was performed to assess diagnostic performance. DD patients exhibited significantly lower IFN-γ and higher NGF levels than controls (both p < 0.001), resulting in a markedly reduced IFN-γ/NGF ratio. The IFN-γ/NGF ratio achieved the highest diagnostic accuracy (AUC = 0.858, sensitivity = 82.20%, specificity = 77.50%), outperforming IFN-γ (AUC = 0.766) and NGF (AUC = 0.848) alone. TPOAb and GFAP levels did not differ significantly between groups. The IFN-γ/NGF ratio is a promising biomarker for depressive disorder, offering superior diagnostic accuracy over individual immune or neurotrophic markers. This composite index may support more objective and biologically informed diagnosis in clinical psychiatry.
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Attention deficit and hyperactivity disorder (ADHD) is a prevalent neuropsychiatric disorder (Drechsler et al., 2020). Recently, psychedelics have become of interest regarding developing treatment options for ADHD. The aim of this systematic review is to find all studies from the APA PsychInfo and MEDLINE databases, where psychedelics have been used for ADHD and assess whether further clinical studies are warranted. APA PsychInfo and MEDLINE were searched on the 20th of August 2025 for studies discussing ADHD and lysergic acid diethylamide (LSD) or psilocybin or dimethyltryptamine (DMT) or mescaline or phencyclidine or 3,4-methylenedioxymethamphetamine (MDMA) or ketamine. Primary research articles in English where the effects of the psychedelics mentioned on ADHD in humans were included. N = 1023 results were identified. Six studies were included - one randomised controlled trial (RCT) finding no statistically important difference compared to placebo, 3 cross sectional studies where respondents reported positive effect of psychedelics and one where the statistically important improvement was measured by the Child Bipolar Questionnaire. In addition, one case study, where both, depressive symptoms and functioning improved with ketamine. There is not sufficient evidence to give recommendations on psychedelic use for ADHD. In addition, it is not known whether patients, whose depressive symptoms have responded positively to ketamine, have also had ADHD. Also, no research was found on how psychedelics affect patient subgroups with different etiopathology causing their symptoms. Although only six studies filled the inclusion criteria, they bring out valuable implications for further research.
We tested the hypothesis that resuming dietary control in early-treated phenylketonuria (PKU) is associated with improvements in white matter integrity, using data from the ReDAPT study, which previously demonstrated cognitive and psychiatric improvements with reduced phenylalanine (Phe) levels. We re-initiated dietary control for early-treated patients with PKU and assessed the T1w/T2w ratio from standard T1-and T2-weighted magnetic resonance images, a marker of myelination and microstructural integrity. General linear mixed-effects model (GLMM) analyses were performed to assess change in the T1w/T2w ratio from baseline over twelve months after resumption of dietary control. Seven participants (mean age 31 years; five female) with neuroimaging were included, with a mean of 16 years off diet and baseline Phe levels of 1157 µmol/L. GLMM analyses showed significant increases in T1w/T2w ratio over time for the whole brain (β = 0.47 [95%CI = 0.28, 0.66]), left hemisphere (β = 0.36 [95%CI = 0.19, 0.54]) and right hemisphere regions of interest (β = 0.52 [95%CI = 0.30, 0.72]). Longer time off diet was also positively associated with greater T1w/T2w changes. There was no evidence for the effects of gender or age at baseline. This study demonstrated significant increases in the T1w/T2w ratio in PKU patients as they resumed dietary control over a 12-month period. Raw Phe levels were not strongly associated with neuroimaging measures. These findings support the importance of lifelong treatment for PKU and also demonstrate the potential reversibility of white matter changes in the disease.
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Emotion regulation, while closely linked to depressive symptoms, has seldom been examined together with them in studies of the relationship between chronotype and suicidality. We therefore examined whether chronotype predicts suicidality through the sequential mediation of poor emotion regulation and depressive symptoms. In addition, we examined whether these mediation pathways differ between morning-type and evening-type groups. This study included 3109 Korean adults from the general population. Chronotype, depressive symptoms, emotion regulation, and suicidality were assessed using the Composite Scale of Morningness, Self-Rating Depression Scale, Emotion Regulation Skills Questionnaire, and the Suicidality module of the Mini International Neuropsychiatric Interview, respectively. Chronotype did not have a direct effect on suicidality. Instead, eveningness was indirectly linked to higher suicidality. Specifically, individuals with stronger eveningness tendencies reported poorer emotion regulation, which increased depressive symptoms; depressive symptoms, in turn, predicted suicidal ideation, which emerged as a significant predictor of suicide attempts. Subgroup analyses revealed that the same sequential pathway was significant only among evening-types, but not among morning-types. Chronotype appears to play a role in suicide risk in the general population. Screening for chronotype and focusing on emotion regulation and depressive symptoms may enhance prevention efforts tailored to chronotype, especially for evening-type individuals.
Dementia is a group of symptoms, characterized by a loss of cognition that interferes with everyday tasks, difficulty focusing, planning, problem solving, and behavioral changes, such as apathy, anxiety, or depression. The leading cause of dementia is Alzheimer's disease, but vascular dementia or mild cognitive impairment are also frequently occurring. There are six drugs legislated in Europe for use in the treatment of dementia. There are unmet clinical needs to find more effective, better tolerated or complementary therapeutic options. The aim of this study is to comprehensively analyze the results of clinical trials and other human studies regarding the efficacy and safety of herbal interventions used in patients with dementia. We enrolled a total of 48 studies for this systematic review, of which 27 were included into the statistical analysis of effect size (Cohen's d). We found significant improvements mainly after administration of Ginkgo biloba, Crocus sativus, Salvia officinalis, and Melissa officinalis.It should be emphasized that some herbs and herbal formulations demonstrated efficacy comparable to that of donepezil, a widely used and approved medication, suggesting potential for phytopharmaceutical therapies as complementary approaches. In some studies, the observed effects were similar to those reported for conventional treatments, indicating promising directions for further research in Alzheimer's disease and dementia. In light of the evidence, phytopharmaceuticals have a promising role as a co-therapeutic option or alternative for patients with dementia who do not tolerate or have contraindications to standard medications. However, further research is necessary to translate these initial promising results into clinical practice. Phytopharmaceuticals have a promising role as a complementary or alternative option for dementia patients who cannot tolerate or respond to standard medications. Certain phytopharmaceuticals demonstrated comparable short-term symptomatic effects to standard treatments in small trials; however, evidence is insufficient to support equivalence or superiority. Many of the studies reviewed are limited by very small sample sizes, which is associated with a high risk of bias when interpreting large effect sizes (Cohen's d). The short duration of interventions (often only 3 to 6 months) is insufficient to assess whether phytotherapeutics can constitute disease-modifying treatments (DMTs).
Electroconvulsive therapy (ECT) is an effective treatment of severe manifestations of mental illness. Since delay in initiation of ECT can have detrimental effects, prediction of the need for ECT could improve outcomes via more timely treatment initiation. Therefore, this study aimed to predict the need for ECT following admission to a psychiatric hospital. This study was based on electronic health record (EHR) data from routine clinical practice. Adult patients admitted to a hospital within the Psychiatric Services of the Central Denmark Region between January 2013 and November 2021 were included in the study. The outcome was initiation of ECT >7 days (to not include patients admitted for planned ECT) and ≤67 days after admission. The data was randomly split into an 85% training set and a 15% test set. On the 7th day of the inpatient stay, machine learning models (extreme gradient boosting (XGBoost)) were trained to predict initiation of ECT and subsequently tested on the test set. The cohort consisted of 41,610 patients with 164,961 admissions. In the held out test set, the trained model predicted ECT initiation with an area under the receiver operating characteristic curve of 0.94, 47% sensitivity, 98% specificity, positive predictive value (PPV) of 24% and negative predictive value (NPV) of 99%. The top predictors were the highest suicide assessment score and mean Brøset violence checklist score in the preceding three months. EHR data from routine clinical practice may be used to predict need for ECT. This may lead to more timely treatment initiation.
Low heart rate variability (HRV) levels may be a susceptibility factor for major depressive disorder (MDD). Sleep-state HRV may be more likely to reveal the pathological features of MDD compared with resting state HRV (RS-HRV). This study aimed to elucidate HRV alterations in the sleep states of patients with MDD. Physiological signal data from the resting state before sleep, first non-rapid eye movement (NREM) and rapid eye movement (REM) stages, and last NREM and REM stages were acquired using polysomnography. The RS-HRV indices (the standard deviation [SD] of all normal-to-normal [NN] intervals [SDNN], the square root of the mean of the sum of the squares of the differences between adjacent NN intervals [RMSSD], the percentage difference between adjacent NN intervals >50 ms [pNN50], high-frequency [HF], low-frequency [LF], very low frequency [VLF], SD1, and sample entropy [SampEn]) were lower in patients with MDD than in healthy controls (HCs). Patients with MDD had lower SDNN, RMSSD, pNN50, HF, LF, VLF, SD1, SD2, and SampEn and higher SD2/SD1, α1, and α2 than HCs in the NREM stage. They also had lower SDNN, RMSSD, pNN50, HF, LF, VLF, SD1, SD2, and SampEn and higher LF/HF than HCs in the REM stage. Fewer indices changed significantly during different sleep stages in patients with MDD than in HCs. Patients with MDD had a generalised reduction in HRV in both RS and sleep state and decreased dynamic changes during sleep. Altered autonomic nervous system activity has been implicated in MDD pathology.
Schizophrenia (SCZ) shows marked biological heterogeneity, with negative symptoms linked to poor outcomes and hypothesised immune dysregulation. This study examined whether a peripheral cytokine-long non-coding RNA (lncRNA) panel could distinguish patients with SCZ and Brief Negative Symptom Scale (BNSS)-defined subgroups from healthy controls (HC). Forty-one hospitalised patients with SCZ completed the BNSS and the Positive and Negative Syndrome Scale (PANSS). Twenty HCs, frequency-matched for age and sex, served as comparison samples. Severe negative-symptom subgroups were defined using two BNSS criteria: a broader (SNS1) and a more restrictive (SNS2) threshold. Serum cytokines - interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), interleukin-10 (IL-10) - and leukocyte lncRNAs (MALAT1, NEAT1, MEG3) were quantified by enzyme-linked immunosorbent assay and quantitative RT-PCR. Covariate-adjusted logistic and multinomial models (adjusting for age, sex, body mass index, and smoking) assessed discrimination using area under the receiver-operating-characteristic curve (AUC) and interquartile-range odds ratios (OR_IQR). IL-6 correlated with PANSS Total (ρ = 0.48, p = 0.001) and Negative (ρ = 0.34, p = 0.032) scores and was higher in SCZ than HC (p = 0.033), with further increases in SNS subgroups. NEAT1 was significantly reduced only within BNSS-defined subgroups (p ≤ 0.025). The dual-marker pattern (IL-6 ↑, NEAT1 ↓) showed the strongest discrimination for SNS1 versus HC (AUC = 0.85) and the steepest multinomial contrasts for SNS2 (IL-6 OR_IQR = 4.98; NEAT1 OR_IQR = 0.11). Elevated IL-6 and decreased NEAT1 define a peripheral signature linked to negative-symptom severity in SCZ and may support biologically informed stratification and longitudinal research.
Emerging evidence suggests that immune dysregulation may play a key role in the pathophysiology of psychosis. However, longitudinal studies integrating both innate and adaptive immune components in the same sample remain scarce. This study aimed to examine a broad spectrum of immunological parameters in first-episode psychosis (FEP) patients, both at onset and after treatment, in comparison to healthy controls. Thirty-two minimally treated FEP patients (no lifetime psychotropic exposure >1 month) and 26 healthy controls were assessed at baseline. 20 patients completed a follow-up approximately one year later. Immunological markers – including complete blood count (leukocyte, neutrophil, lymphocyte, monocyte), C-reactive protein (CRP), SAA, complement components (C3, C4), and immunoglobulins (IgG, IgA, IgM, IgE) – were measured at both time points. First-episode psychosis was confirmed using SCID (DSM-IV). Symptom severity was evaluated using PANSS and BPRS. ROC and logistic regression analyses were performed to assess predictive value. Neutrophil, monocyte, C3, C4 levels and neutrophil-to-lymphocyte ratio (NLR) were significantly elevated in patients at both time points, with no change over time. CRP was elevated at T1 but normalised at follow-up. In contrast, immunoglobulin levels showed temporal and dimensional associations with symptom severity. NLR was correlated with negative symptoms during the acute phase, while IgG was associated with positive symptoms during remission. Elevated NLR and C4 predicted patient status in logistic regression analysis. This longitudinal study provides a system-level immunological profile across illness phases in FEP. The findings underscore distinct and dynamic contributions of innate and adaptive immunity to the onset and progression of psychosis.
This study aimed to investigate the differences on cognitive performance across four cognitive domains – verbal memory, language fluency, visuospatial ability and cognitive inhibition – between drospirenone and ethinyl oestradiol (DRSP/EE) users and naturally cycling women in the luteal phase (LP). The goal was to determine whether hormonal suppression associated with DRSP/EE use is linked to domain-specific cognitive alterations. A total of 48 young adult women were assessed: 23 using DRSP/EE (with pharmacologically suppressed endogenous hormonal levels) and 25 naturally cycling during the LP. Participants completed standardised neuropsychological tasks measuring verbal memory, language fluency, visuospatial ability and cognitive inhibition. Group comparisons analyses were conducted. Significant group differences were observed in verbal memory, visuospatial ability and cognitive inhibition, while no significant group differences were found in language fluency. Women using DRSP/EE showed significantly lower performance in verbal memory (U = 165, p = 0.009, r = 0.38) and visuospatial ability (U = 155, p = 0.006, r = 0.40) tasks compared to naturally cycling women. In contrast, they demonstrated higher performance in cognitive inhibition, quantified by a significantly higher Stroop interference score (t(46) = 2.710, p = 0.009, d = 0.783). The present findings suggest that the use of DRSP/EE oral contraceptives is associated with differences across specific cognitive domains compared to naturally cycling women in the LP. The observed pattern – lower performance in hippocampus-related domains (verbal memory and visuospatial ability) paired with higher performance on a frontal-lobe-dependent task (cognitive inhibition) – is consistent with existing evidence suggesting that suppression of endogenous ovarian hormones may differentially influence cognitive functions. These behavioural associations underscore the need for further domain-specific research into the long-term cognitive implications of combined oral contraceptives.