Women diagnosed with premenstrual dysphoric disorder (PMDD) report significant symptom relief when treated with selective serotonin reuptake inhibitors, but few studies have addressed the possibility of capturing this effect in behavioral, laboratory-based tests. This study examined the effects of intermittent treatment with escitalopram (vs. placebo) on a behavioral measure of impulsivity and inattentiveness in women reporting high levels of premenstrual irritability and anger.

Participants (N = 27) rated cardinal PMDD mood symptoms over three menstrual cycles using Visual Analogue Scales. In Cycles 2 and 3, participants displaying cyclicity with respect to the irritability/anger item received escitalopram (20 mg) or placebo in a randomized, single-blind, crossover design. The participants completed the Conners Continuous Performance Test (CPT 3) in the luteal phase of the intervention cycles. Additionally, they filled out the UPPS Impulsive Behavior Scale, once in the luteal phase and once in the follicular phase of the placebo cycle.

In line with previous reports, escitalopram caused a significant reduction in self-rated irritability and anger in the luteal phase. When on escitalopram, the participants demonstrated a lower frequency of anticipatory responses and greater consistency in response speed in the CPT 3. With respect to self-reported impulsivity, participants reported higher levels of urgency and lower levels of sensation seeking in the luteal placebo phase versus the follicular phase.

The finding that escitalopram impacted the outcome of the CPT 3 test in women with premenstrual irritability highlights the possible role of impulsivity in this condition.

Motivational dysfunction is a core feature of depression and can have debilitating effects on everyday function. However, it is unclear which cognitive processes underlie impaired motivation and whether impairments persist following remission. Decision-making concerning exerting effort to obtain rewards offers a promising framework for understanding motivation, especially when examined with computational tools.

Effort-based decision-making was assessed using the Apple Gathering Task, where participants decide whether to exert effort via a grip-force device to obtain varying levels of reward; effort levels were individually calibrated and varied parametrically. We present a comprehensive computational analysis of decision-making, initially validating our model in healthy volunteers (N = 67), before applying it in a case–control study including current (N = 41) and remitted (N = 46) unmedicated depressed individuals and healthy volunteers with (N = 36) and without (N = 57) a family history of depression.

Four fundamental computational mechanisms that drive patterns of effort-based decisions, which replicated across samples, were identified: overall bias to accept effort challenges; reward sensitivity; and linear and quadratic effort sensitivity. Traditional model-agnostic analyses showed that both depressed groups showed lower willingness to exert effort. In contrast with previous findings, computational analysis revealed that this difference was primarily driven by lower effort-acceptance bias, but not altered effort or reward sensitivity.

This work provides insight into the computational mechanisms underlying motivational dysfunction in depression. Lower willingness to exert effort could represent a trait-like factor contributing to symptoms and a fruitful target for treatment and prevention.

Repetitive transcranial magnetic stimulation (rTMS) is a well-established intervention for treatment-resistant depression. However, its effects on patient-reported outcomes, such as quality of life (QoL), have not been fully characterized, especially among older adults. This study compares the impact of rTMS on QoL in younger (<60 years) versus older (≥60 years) adults with major depressive disorder.

We analyzed data from 531 participants with depression (ages 18–89 years) from two randomized clinical trials (THREE-D and FOUR-D). All participants received either unilateral or bilateral rTMS or theta burst stimulation. QoL was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form at baseline, end of treatment, and 12-week follow-up, and compared between younger adults (age < 60 years; n = 360) and older adults (age ≥ 60 years, n = 171). The clinical relevance of the changes was evaluated through effect sizes, using a predefined threshold of 12 points as the minimal clinically important difference, and comparisons with community norms.

After rTMS treatment, both younger and older adults experienced statistically significant improvements in QoL, with medium to large effect sizes. The effect was sustained over 12 weeks of follow-up. At baseline, only 0.3% of younger adults and 2.3% of older adults reported normal QoL, which significantly increased to, respectively, 19.8 and 19.4% by the end of treatment, and 23.7 and 26.8% at the 12-week follow-up.

rTMS yielded acute and sustained clinically meaningful improvements in QoL, with similar effects among younger and older adults with depression. The magnitude of improvement was comparable to, or exceeded, that reported in antidepressant trials.

Heightened reactivity in the amygdala measured by functional magnetic resonance imaging during emotional processing is considered a potential biomarker for clinical depression. Still, it is unknown whether this is also true for depressive symptoms in the general population, and – when in remission after recurrent depressive episodes – it is associated with future episodes.

Using the UK Biobank population study (n = 11,334), we investigated the association of amygdala reactivity during negative facial stimuli, focusing on lifetime depression (trait), depressive symptoms (state), and the modulating effect of antidepressant (AD) treatment thereof. We employed normative modeling (NM) to better incorporate population heterogeneity of the amygdala activity.

In line with a previous study, depressive symptoms (state) over the last 2 weeks were not associated with the amygdala reactivity signal. Rather, our results indicate a significant positive association (p = 0.03, ω2 = 0.001) between amygdala response and the recurrence of depressive episodes (trait). Longitudinal analysis revealed that the group that had experienced a single depressive episode before showed a significantly increased amygdala response after additional episodes (p = 0.03, ω2 = 0.017). ADs were not associated with amygdala response directly, but decreased associations within episode recurrence severity.

The amygdala response to negative stimuli was associated with an individual’s risk of recurrence of depressive episodes, and AD treatment reduced these associations. This study highlights the relevance of amygdala reactivity as a trait, but not a state biomarker for (recurrent) depression. Moreover, it demonstrates the benefit of applying NM in the context of population data.

Although exposure and response prevention (EX/RP) is recommended as a first-line treatment for obsessive-compulsive disorder (OCD), responses vary among patients. This study was the first to use network analysis to examine how OCD symptom networks change with EX/RP and vary across different progress trajectories.

Data from four clinical trials with 334 adults with OCD who received manualized EX/RP were pooled. The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) was administered at baseline, midpoint, and post-treatment. OCD symptom networks were constructed using individual Y-BOCS items at these three time points, both for the entire sample and for three different progress trajectories (dramatic, moderate, and little-to-no progress) previously identified using growth mixture modeling. Network measures, including global efficiency, modularity, and weighted degree centrality, were computed to quantitatively assess network properties across treatment.

Network analysis revealed two distinct modules at baseline: resistance/control and interference/distress. In the full sample, these two modules became integrated over time, as indicated by significant increases in global efficiency and weighted degree centrality and decreases in modularity; at post-treatment, the network shifted toward a fully connected network, and the strength of associations between nodes increased. These changes were most pronounced in the dramatic progress class.

Our findings indicated that effective EX/RP treatment was associated with more integrated OCD symptom networks, which may serve as an indicator of treatment response. Future research should examine how these shifts in network connectivity correspond to changes in underlying brain circuitry and/or to early identification of treatment responders.

Schizophrenia progresses through high-risk, first-episode, and chronic stages, each associated with altered spontaneous brain activity. Resting state functional MRI studies highlight these changes, but inconsistencies persist, and the genetic basis remains unclear.

A neuroimaging meta-analysis was conducted to assess spontaneous brain activity alterations in each schizophrenia stage. The largest available genome-wide association study (GWAS) summary statistics for schizophrenia (N = 53,386 cases, 77,258 controls) were used, followed by Hi-C-coupled multimarker analysis of genomic annotation (H-MAGMA) to identify schizophrenia-associated genes. Transcriptome-neuroimaging association and gene prioritization analyses were performed to identify genes consistently linked to brain activity alterations. Biological relevance was explored by functional enrichment.

Fifty-two studies met the inclusion criteria, covering the high-risk (Nhigh-risk = 409, Ncontrol = 475), first-episode (Ncase = 1842, Ncontrol = 1735), and chronic (Ncase = 1242, Ncontrol = 1300) stages. High-risk stage showed reduced brain activity in the right median cingulate and paracingulate gyri. First-episode stage revealed increased activity in the right putamen and decreased activity in the left gyrus rectus and right postcentral gyrus. Chronic stage showed heightened activity in the right inferior frontal gyrus and reduced activity in the superior occipital gyrus and right postcentral gyrus. Across all stages, 199 genes were consistently linked to brain activity changes, involved in biological processes such as nervous system development, synaptic transmission, and synaptic plasticity.

Brain activity alterations across schizophrenia stages and genes consistently associated with these changes highlight their potential as universal biomarkers and therapeutic targets for schizophrenia.

Euthymic bipolar disorder (euBD) patients exhibit deficits in neurocognitive and social cognitive functioning compared to healthy controls (HCs). Our prior research has shown that the excitatory/inhibitory (E/I) imbalance in the default mode network (DMN) is linked to executive function in euBD. Neurocognitive impairments are associated with social cognition deficits in individuals with mental disorders. Given this connection, this study posits E/I imbalance within the DMN is associated with social cognition, with executive function as a mediator.

Seventy-five HCs and 49 euBD individuals were recruited. Using the emotion recognition task, Diagnostic Analysis of Nonverbal Accuracy 2-Taiwan version (DANVA-2-TW) and cognitive flexibility task, Wisconsin Card Sorting Test (WCST), we assessed emotion recognition and prefrontal function. Proton magnetic resonance spectroscopy (1H-MRS) measured metabolites in the posterior cingulate cortex (PCC) and medial prefrontal cortex/anterior cingulate cortex (mPFC/ACC), quantifying excitatory glutamate+glutamine (Glx) and inhibitory GABA to calculate the E/I ratio.

euBD patients showed poorer emotion recognition (p = 0.020) and poorer cognitive flexibility (fewer WCST categories completed, p = 0.002). A negative association was found between emotion recognition and the E/I ratio in the mPFC/ACC of the BD patients (r = −0.30, p = 0.034), which was significantly mediated by cognitive flexibility (Z = −2.657, p = 0.007).

The BD patients demonstrate deficits in emotion recognition, linked to an altered E/I balance in the prefrontal cortex, and the cognitive flexibility, a key aspect of executive function, mediates the impact of the E/I ratio on emotion recognition accuracy in euBD patients.

Depression is characterized by divergent changes in positive and negative affect. Emerging roles of inflammation in depression portend avenues for novel immunomodulator-based monotherapy, targeting mechanistically distinct symptoms such as anhedonia and pessimism.

To investigate links between these divergent affective components and inflammation, we used a probabilistic reinforcement-learning fMRI paradigm, testing for evidence of hyposensitivity to reward, and hypersensitivity to punishment in low-inflammation depression cases (loCRP depression; CRP ≤ 3 mg/L; N = 48), high-inflammation depression cases (hiCRP depression; CRP > 3 mg/L; N = 31), and healthy controls (HC; CRP ≤ 3 mg/L; N = 45). We aimed to (i) determine whether depression cases with high and low inflammation showed aberrant neural activation to monetary gains and losses compared to controls, and (ii) examine if these alterations correlated with a continuous measure of C-reactive protein (CRP) in depression, as well as indices of anhedonia and pessimism derived from behavioral instruments in depression.

Voxel-wise activation was observed in key brain regions sensitive to monetary reward (ventromedial prefrontal cortex, vmPFC; nucleus accumbens, NAc) and punishment (insula) outcomes across all three groups. However, there was no significant difference in activation between groups. Within depression cases, increasing CRP scaled negatively with activation in the right vmPFC and left NAc but not insula cortex. However, there was no significant association between regional activation and severity of anhedonia or pessimism.

Our results support the previously reported association between CRP and striatal reward reactivity in depression but do not extend this to processing of negatively valenced information.

Despite growing healthcare coverage, disparities in access to and outcomes of psychiatric care persist, even in countries with universal healthcare. How socioeconomic status (SES), travel time, and social support individually and jointly affect psychiatric clinical trajectories remains largely unexplored.

We analyze electronic health records (EHRs) from patients diagnosed with bipolar disorder, major depressive disorder, or schizophrenia at Clínica San Juan de Dios Manizales. Using zero-inflated and standard negative binomial regression, we quantify the effects of SES, travel time, and family/social support on utilization, clinical outcomes, and symptoms of mania, psychosis, and suicidality. A mixed-effects model examines how care-seeking patterns affect visit-to-visit variability in outcomes.

Among 21,095 patients, utilization is lower for those with low SES (rate ratio [RR] 0.92, 95% CI: 0.90–0.95, p = 1.27e−10) and longer travel times (RR 0.94, 95% CI: 0.93–0.95, p = 1.19e−53). Patients with low SES are more likely to have severe symptoms (e.g., delusions: RR 1.28, 95% CI: 1.20–1.37, p = 2.57e−15) and require hospitalization (RR 1.10, 95% CI: 1.05–1.15, p = 1.94e−04), suggesting they primarily seek care when critical. Longer travel differentially affects those with low SES. However, the relationship between SES and adverse outcomes is less pronounced when living with family (e.g., hospitalizations: LRT, χ2 = 47.08, df = 3, p = 3.35e−10). Frequent outpatient care is associated with lower odds of hospitalization, suicidality, and other symptoms.

Findings demonstrate use of EHRs to model patient outcomes, the important role of social support, and need for improved healthcare accessibility.

Structural imaging studies of borderline personality disorder (BPD) have identified regions of reduced and increased cortical volume, as well as volume reductions in the hippocampus and amygdala, although with considerable variability across studies. Examining adolescent patients with the disorder can reduce potential confounding effects such as later development of affective and other comorbid disorders.

Fifty-one adolescents (48 females, 3 males) with BPD and without comorbid disorders and with 43 matched healthy controls underwent whole-brain voxel-based morphometry (VBM). Hippocampus and amygdala volumes were also measured using conventional volumetric techniques.

At a threshold of p = 0.05 corrected, the BPD patients exhibited a cluster of grey matter volume reduction in the left temporo-parietal junction (TPJ). No evidence of volume reductions in the hippocampus or amygdala was found. Comparison between the female-only subsamples (48 BPD patients and 37 controls) yielded similar findings. The cluster of volume reduction in the left TPJ continued to be seen in 37 drug-naïve patients.

According to this study, the initial stage of BPD is characterized by decreased grey matter volume in the left TPJ, a region that is implicated in various aspects of social cognition. Given that the volume loss was detected prior to adulthood, in individuals without comorbidities, and among patients who were drug naïve, this finding could be significant for understanding the developmental trajectory of the disease.

Suicide represents a significant public health concern. Suicide prevention strategies are shifting toward transdiagnostic perspectives examining interrelated risk factors, but their interrelationships remain unclear. This study investigated relationships between psychopathological dimensions, impulsivity, and childhood maltreatment in individuals with suicidal ideation (SI), comparing those with versus without intention to act using network analysis.

Data were obtained from the Suicide Prevention and Intervention Study project. Participants were categorized into two groups based on their intention to act according to the Columbia Suicide Severity Rating Scale. Psychological symptoms, impulsivity traits, and childhood maltreatment were assessed. Network analysis was performed, and centrality measures were computed.

A total of 1,265 individuals were categorized into the SI without intention to act (n = 345) and SI with intention to act (n = 920) groups. The former showed lower depression and hostility scores, and lower prevalence of major depressive and anxiety disorders. Network analyses revealed that in the SI without intention to act group, obsessive-compulsive symptoms were central, connecting to depression and anxiety, while negatively correlating with non-planning impulsivity. In contrast, the SI with intention to act group showed a more densely interconnected network where emotional abuse served as a bridge between childhood maltreatment and other psychopathological dimensions.

This study identifies symptom interaction patterns between individuals with SI without and with intention to act. Understanding these relationships may improve suicide risk assessment and inform personalized interventions, potentially reducing the transition from ideation to action. Trauma-focused approaches addressing emotional abuse may be especially relevant for individuals at high risk.

Impulsivity is among the strongest correlates of substance involvement (i.e. a broad continuum of substance-related behaviors), and distinct domains (e.g. sensation seeking [SS] and urgency) are differentially correlated, phenotypically and genetically, with unique substance involvement stages. Examining whether polygenic influences for distinct impulsivity domains are differentially predictive of early substance use initiation – a major risk factor for later problematic use – may improve our understanding of the role of impulsivity in addiction etiology.

Data collected from participants of genetically inferred European ancestry enrolled in the Adolescent Brain Cognitive Development StudySM (n = 4,808) were used to estimate associations between polygenic scores (PGSs) for UPPS-P impulsivity domains (i.e. SS, lack of premeditation [LPREMED]/perseverance [LPERSEV], and negative/positive urgency [NU/PU]) and substance (i.e. any, alcohol, nicotine, and cannabis) use initiation by age 15 years. Mediation models examined whether child impulsivity (ages 9–11 years) mediated links between PGSs and substance use initiation.

SS-PGS was significantly associated with any substance and alcohol use initiation (odds ratio [ORs] > 1.10, psFDR < 0.05). LPERSEV and NU/PU PGSs were nominally associated with alcohol and nicotine use initiation, respectively (ORs > 1.06, ps < 0.05, psFDR > 0.05). No significant associations were observed for LPREMED-PGS or cannabis use initiation. Measured impulsivity domains accounted for 5–9% of associations between UPPS-P PGSs and substance use initiation.

Genetic influences for distinct impulsivity domains have differential associations with early substance use initiation, with SS showing the most robust associations, highlighting valuable etiological insight into the earliest stages of substance involvement that may be leveraged to improve prevention and intervention strategies.

Cardiovascular diseases (CVD) and depression frequently co-occur, yet the biological mechanisms underpinning this comorbidity remain poorly understood. This may reflect complex, non-linear associations across multiple biological pathways. We aimed to identify molecular biomarkers linking depressive symptoms and cardiovascular phenotypes using a network-based integrative approach.

Data were obtained from the Young Finns Study (N = 1,686; mean age = 37.7 years; 58.3% female), including 21 depressive symptoms (Beck Depression Inventory), 17 CVD-related indicators, 6 risk factors, 228 metabolomic, and 437 lipidomic variables. Mutual information was used to capture both linear and non-linear associations among variables. A multipartite projection network was constructed to quantify how depressive symptoms and cardiovascular phenotypes are biologically connected via shared metabolites and lipids. Biomarkers were ranked by their contribution to these projected associations. Results were validated in an independent cohort from the UK Biobank.

Specific depressive symptoms – crying, appetite changes, and loss of interest in sex – showed strong projected associations with diastolic blood pressure, systolic blood pressure, and cardiovascular health scores. Key mediators included creatinine, valine, leucine, phospholipids in very large HDL, triglycerides in small LDL, and apolipoprotein B. Important lipid mediators included sphingomyelins, phosphatidylcholines, triacylglycerols, and diacylglycerols. Replication analysis in the UK Biobank identified many overlaps in metabolite profiles, supporting generalizability.

This network-based analysis revealed symptom-specific biological pathways linking CVD and depression. The identified biomarkers may offer insights into shared mechanisms and support future prevention and treatment strategies for cardiometabolic–psychiatric comorbidity.

The treatment response for the negative symptoms of schizophrenia is not ideal, and the efficacy of antidepressant treatment remains a matter of considerable controversy. This systematic review and meta-analysis aimed to assess the efficacy of adjunctive antidepressant treatment for negative symptoms of schizophrenia under strict inclusion criteria.

A systematic literature search (PubMed/Web of Science) was conducted to identify randomized, double-blind, effect-focused trials comparing adjuvant antidepressants with placebo for the treatment of negative symptoms of schizophrenia from database establishment to April 16, 2025. Negative symptoms were examined as the primary outcome. Data were extracted from published research reports, and the overall effect size was calculated using standardized mean differences (SMD).

A total of 15 articles, involving 655 patients, were included in this review. Mirtazapine (N = 2, n = 48, SMD −1.73, CI −2.60, −0.87) and duloxetine (N = 1, n = 64, SMD −1.19, CI −2.17, −0.21) showed significantly better efficacy for negative symptoms compared to placebo. In direct comparisons between antidepressants, mirtazapine showed significant differences compared to reboxetine, escitalopram, and bupropion, but there were no significant differences between other antidepressants or between antidepressants and placebo. No publication bias for the prevalence of this condition was observed.

These findings suggest that adjunctive use of mirtazapine and duloxetine can effectively improve the negative symptoms of schizophrenia in patients who are stably receiving antipsychotic treatment. Therefore, incorporating antidepressants into future treatment plans for negative symptoms of schizophrenia is a promising strategy that warrants further exploration.

Major depressive disorder (MDD) patients exhibit a mood-congruent emotional processing bias within the amygdala toward negative facial stimuli at both unconscious and conscious levels. Therefore, our study aimed to investigate the temporal and spatial dynamics of amygdala along with its interactions with the whole brain during implicit and explicit conditions in MDD.

Thirty MDD patients and 26 healthy controls (HCs) underwent magnetoencephalography (MEG) recordings and performed implicit and explicit emotional face recognition tasks with happy, sad, and neutral facial expressions. Using the amygdala as a seed region, time frequency representations (TFR) and functional connectivity (FC) were calculated. Pearson correlation analyses measured the relationship between TFR and FC values with clinical symptoms.

During implicit processing, MDD patients exhibited left amygdala activation in the gamma power (60–70 Hz) before 250 ms in response to sad facial stimuli compared to HCs. In the implicit mode, there were increased FC between the right amygdala and several brain regions in the occipitoparietal lobes, as well as higher FC between the left amygdala and putamen in MDD patients. Additionally, the right amygdala was positively correlated with the severity of depression and anxiety during implicit processing.

MDD patients had lateralized amygdala activation in response to sad facial expressions during unconscious emotional recognition of facial stimuli. Our study provided valuable insights into the spatiotemporal dynamics of facial emotional recognition associated with depressive and anxiety-related cognitive bias during implicit and explicit processing.

Impulsivity, a multifaceted construct, is a core feature of borderline personality disorder (BPD), associated with functional impairment and suicide mortality. Findings on motor inhibitory control, a key dimension of impulsivity, in BPD are heterogeneous.

This PRISMA-guided meta-analysis examines motor inhibitory control in adults with BPD compared to healthy controls (HCs), using Stop-Signal Task and Go/No-Go Task data. Thirty-seven datasets from 35 articles were included.

Results from random-effect models suggest that BPD patients exhibit significantly higher motor inhibitory control deficits than HCs, with a small to moderate effect size. Contrary to common assumptions, a mixed-model effect found that emotional factors did not moderate inhibitory control in BPD. Finally, the meta-analysis revealed that self-reported impulsivity measures did not correlate with task performance, suggesting that subjective and objective measures of impulsivity may assess different facets of the construct.

These findings highlight the need for greater standardization of task-based measures of impulsivity, as methodological heterogeneity and quality currently limit replicability across studies.