Methylphenidate is sometimes used to address residual symptoms of major depressive disorder (MDD), but concerns about psychiatric destabilization and limited long-term evidence have constrained its use. We examined the psychiatric safety of methylphenidate in adults with MDD in a large, real-world cohort.

Using the TriNetX Global Collaborative Network, we identified adults with MDD who initiated methylphenidate and matched them 1:1 with controls who did not receive methylphenidate. Patients with attention-deficit/hyperactivity disorder, bipolar disorder, mania, or recent psychiatric destabilization were excluded. The primary outcome was a composite of all-cause hospitalization or emergency room visits; secondary outcomes included hospitalization, emergency visits, suicidal behavior, manic episodes, and recurrence of MDD. Hazard ratios (HRs) were estimated with Cox proportional hazards models after propensity score matching.

Of 425,190 eligible patients, 3,211 matched pairs were included (mean age, 55.8 years; 58% female). Over 1 year, the composite outcome occurred less frequently in the methylphenidate group than in controls (574 vs. 694; HR, 0.85; 95% CI, 0.76–0.95). No significant differences were observed for hospitalization, emergency visits, suicidal behavior, manic episodes, or MDD recurrence. Results were consistent across subgroups defined by sex, age, and antidepressant class.

In adults with MDD, methylphenidate use was associated with a lower risk of hospitalization or emergency visits and was not linked to increased risk of suicidality, mania, or recurrence. These findings support the psychiatric safety of methylphenidate as an adjunctive treatment for selected patients, though longer follow-up is needed.

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.

The effectiveness of electroconvulsive therapy (ECT) for depression strongly depends on patient characteristics. Clinical factors may increase (e.g. age, psychotic symptoms) or decrease (e.g. episode duration) response rates.

This prospective study aimed to develop an instrument for the prediction of ECT response in patients with unipolar depression.

N = 45 patients were assessed using the Göttingen Response to ECT Assessment Tool (GREAT; seven items, 0 to 14 points). Clinical outcome was measured using the Montgomery Åsberg Depression Rating Scale (MADRS). Response was defined as ≥ 50% MADRS-improvement or a clinical global impression improvement (CGI-I) score ≤ 2. Analyses were conducted between responders and non-responders.

Results showed a high correlation between GREAT-score and dichotomous response (r = 0.585) as well as MADRS-improvement (r = 0.554, both p < 0.001). Receiver operating characteristic (ROC)-analysis yielded an area under the curve (AUC) of 0.841 (asymptotic significance: p < 0.001). A cut-off point at ≥7 points predicted ECT response in individual cases with 80% accuracy. GLM-analyses showed a significantly better MADRS-improvement for patients with a GREAT-score ≥ 7 v. < 7 (interaction-effect: p < 0.001).

Our prospective study shows that an instrument consisting of seven clinical items is able to predict ECT response in depression with good accuracy. Limitations include a relatively small sample size and the lack of further potential predictors suggested by recent studies. GREAT will thus be modified to further improve its accuracy. Currently, it may give clinicians a relevant estimate of the likelihood and the extent of the individual response to ECT.

Ketamine and esketamine produce rapid and sustained antidepressant effects in persons with treatment-resistant depression (TRD). Although it is posited that these effects are largely attributed to N-methyl-D-aspartate receptor antagonism, the potential involvement of the opioid system remains unclear. This systematic review investigates whether ketamine and esketamine antidepressant efficacy is mediated through the opioid system.

We conducted a systematic search of preclinical and clinical studies investigating the potential involvement of the opioid system in the antidepressant effects of ketamine and esketamine. Database searches on PubMed, Cochrane Library, Embase and PsycINFO occurred from inception to September 27, 2025.

16 studies were identified: 12 clinical (n = 790) and 4 preclinical studies. Clinical designs included randomized controlled trials, case reports, pre-post studies and observational cohort studies. Preclinical studies utilized animal models of depression. Only one study examined esketamine. Naltrexone (nonselective opioid antagonist) attenuated ketamine’s effects in three studies, while four reported no such effect and one reported mixed evidence. Genetic markers of opioid receptor subtypes (i.e., OPRM1 and OPRD1) were examined in three studies, but results were inconclusive, potentially due to limited evidence. Separately, opioid use was not associated with ketamine response. Few studies directly examined opioid receptor subtypes.

The reported mixed findings suggest that the opioid system may exert a partial mediating effect of ketamine in TRD. However, given the inconsistent attenuation of ketamine’s antidepressant effects by opioid receptor antagonists, the opioid system likely functions as a context-dependent modulator rather than a primary mediator, particularly at standard antidepressant doses.

While breast cancer is rare in men, its incidence is rising, prompting more research into the mental health impacts of the disease in male patients. Anxiety, depression and sleep disorders are well-documented in women with breast cancer, but the effects on men are not as well understood, underscoring a need for gender-specific analysis.

This retrospective cohort study used data from the Health Insurance Review & Assessment Service from 2009 to 2017, examining patients diagnosed with ductal carcinoma in situ or invasive breast cancer. A propensity score matching at a 5:1 ratio resulted in a sample size of 280 men and 1,400 women for analysis. The study assessed the cumulative incidence of anxiety, depression and sleep disorders, along with potential risk factors for these conditions.

Out of 75,936 breast cancer patients, 0.4% (281) were men. Women exhibited a significantly higher incidence of mental health conditions compared to men (p = 0.017), particularly in terms of anxiety. However, there were no significant gender differences in the incidence of depression or sleep disorders. Women demonstrated a higher risk of developing anxiety disorders (hazard ratio: 1.498, 95% CI: 1.057–2.123, p = 0.023). After adjusting for confounders, gender differences in depression and sleep disorders were not statistically significant.

Women with breast cancer experience higher rates of anxiety disorders, while depression and sleep disorders show no gender disparity. These findings suggest that mental health care approaches should be adapted to better support men with breast cancer and address their unique mental health needs.

Psychometric methods are used to remove underperforming items and reduce error in existing measures, albeit different approaches can produce different results. This study aimed to determine the implications of applying different psychometric methods for clinical trial outcomes.

Individual participant data from 15 antidepressant treatment trials from Vivli.org were analyzed. Baseline (pretreatment) and 8-week (range 4–12 weeks) outcome data from the Montgomery-Asberg Depression Rating Scale were subjected to best-practice factor analysis (FA), item response theory (IRT), and network analysis (NA) approaches. Trial outcomes for the original summative scores and psychometric-model scores were assessed using multilevel models. Percentage differences in Cohen’s d effect sizes for the original summative and psychometrically modeled scores were the effects of interest.

Each method produced unidimensional models, but the modified scales varied from 7 to 10 items. Treatment effects (d = 0.072) were unchanged for IRT (10 items), decreased by 1.3%–2.8% (eight-item abbreviated d = 0.070; weighted score d = 0.071) for NA, and increased by 11%–12.5% (seven-item abbreviated model d = 0.081; weighted score d = 0.080) for FA.

IRT and NA yielded negligible differences in effect outcomes relative to original trials. FA increased effect sizes and may be the most effective method for identifying the items on which placebo and treatment group outcomes differ.

Major depressive disorder (MDD) is a significant public health concern, and current treatments often have limitations in effectiveness and adherence. Psilocybin, a psychedelic compound found in certain mushrooms, is being explored as a potential treatment for depression. It primarily acts through the serotonin 5-HT2A receptor but interacts with 5-HT1A and 5-HT2C receptors. Its precise mechanisms remain under investigation.

(1) To consolidate evidence on psilocybin’s efficacy and safety for depression and the role of 5HT2a, (2) to identify limitations in the literature, and (3) to highlight areas needing further research.

This systematic review follows PRISMA guidelines and analyses 22 studies, including randomised controlled trials (RCTs) and open-label studies. The studies cover various populations, including individuals with treatment-resistant depression, different dosing regimens, and adjunctive therapies.

Psilocybin therapy shows substantial and rapid antidepressant effects, often after one or two sessions with psychological support. Improvements are sustained for weeks or months in many cases. Psilocybin is generally well-tolerated, with mild adverse effects such as anxiety during administration and transient headaches, which are manageable in controlled settings.

Psilocybin demonstrates promise as a novel treatment for depression, especially for individuals unresponsive to conventional antidepressants. Further research is needed to refine dosing, explore long-term effects, and understand its mechanisms of action.

With numbers of very old adults (85+ years) expected to increase, and very old adults often being excluded from research and clinical trials, further knowledge about depressive disorders, antidepressant treatment and mortality among this demographic is of pressing importance.

To investigate the impact of depressive disorders and antidepressant treatment on 2-year mortality among very old adults and to explore any differences between men and women.

This cross-sectional study used data from the Umeå 85+/Gerontological Regional Database home visit interviews. The data were collected between 2000 and 2017. The total sample consisted of 2551 participants, of whom 918 had a depressive disorder. Logistic and Cox regression models were used to explore factors associated with depressive disorders and time to death. Mortality rates were illustrated and analysed using Kaplan–Meier curves and log-rank tests.

Having a depressive disorder both with and without antidepressant treatment was associated with increased risk of death within 2 years for both men and women. No survival differences were found between responders and non-responders to treatment. Depressive disorders were significant predictors of 2-year mortality in men. Antidepressant treatment was not independently associated with mortality.

Depressive disorders are significantly associated with increased 2-year mortality among very old adults, especially men, and measures to reduce mortality are urgently needed. Further exploration of the effects of antidepressant treatment among very old adults is warranted.

Increasing attention has been recently devoted to treatment-resistant depression (TRD); however, its clinical characteristics, potential risk factors, and course are still debated. Most recently, childhood trauma exposure has been correlated to TRD, but systematic investigation on the role of lifetime trauma is still lacking. The aim of this paper was to revise current evidence on early and recent trauma exposure in TRD.

A systematic search was conducted from the 1st of June to the 20th of February 2024 in accordance with the PRISMA 2020 guidelines and using the electronic databases PubMed, Web of Science, and Embase.

The primary database search produced a total of 1998 record, and finally, the search yielded a total of 22 publications, including 18 clinical studies, 3 case reports, and 1 case series, all from the period 2014 to 2024.

Limitations include a small sample size of some studies and the lack of homogeneity in the definition of TRD. Furthermore, we only considered articles in English, we excluded preprints or abstracts, and we included case reports.

This review highlights the role of early and recent trauma in TRD, even in the absence of a full-blown post-traumatic stress disorder (PTSD), highlighting the need for a thorough assessment of trauma in patients with TRD and of its role as a therapeutic target.

Attention deficit/hyperactivity disorder (ADHD) prevalence has increased in the last 10 years, most likely due to increased recognition by clinicians. Even so, an issue with under-diagnostics may persist. Historically ADHD has been described as a male-dominant disorder. However, recent evidence shows that ADHD prevalence is similar between the sexes, but that the related impairment or symptomatology might vary. This study estimated the prevalence of undiagnosed ADHD symptoms (pADHD) and explored the sex-stratified symptomatology and associations with self-perceived health-related quality of life (HRQL) and experience of depressive symptoms.

This was done in a unique cohort of 50,937 healthy blood donors – individuals who successfully maintain regular commitments despite potential ADHD symptoms. ADHD symptoms were estimated using the Adult ADHD Self-Report Scale (ASRS), health-related quality of life (HRQL) measured using mental and physical component scores (MCS/PCS) estimated based on a 12-item Short-Form Health Survey (SF-12) with a higher score indicating better HRQL, and depressive symptoms were measured using Major Depression Inventory (MDI) with higher score indicating more depressive symptoms.

In total, 3% were classified with pADHD (sex ratio 1:1). pADHD was associated with reduced MCS and PCS, and increased MDI score. Males scored on average higher on inattentive symptoms compared to females, whereas females scored on average higher on hyperactive-impulsive symptoms. Individuals scoring high on the combined inattentive and hyperactive-impulsive ADHD symptom presentation were most likely to be impaired in terms of higher MDI scores and lower PCS when compared to non-ADHD controls.

In conclusion, ADHD symptoms are common in this seemingly healthy and undiagnosed population. Symptom presentations differ between sexes and the type of presentation seems to impact the association with depressive symptoms and level of reduced HRQL.

This systematic review and meta-analysis evaluates the prevalence of disruptive mood dysregulation disorders (DMDD) in community-based and clinical populations.

PubMed and PsychINFO databases were searched, using terms specific to DMDD, for studies of prevalence and comorbidity rates conducted in youths below 18.

Fourteen studies reporting data from 2013 to 2023 were included. The prevalence of DMDD in the community-based samples was 3.3% (95% confidence interval [CI], 1.4–6.0) and 21.9% (95% CI, 15.5–29.0) in the clinical population. The differences in the identification strategy of DMDD were associated with significant heterogeneity between studies in the community-based samples, with a prevalence of 0.82% (95% CI, 0.11–2.13) when all diagnosis criteria were considered. Anxiety, depressive disorders, and ADHD were the most frequent comorbidity present with DMDD. The association with other neurodevelopmental disorders remained poorly investigated.

Caution is required when interpreting these findings, considering the quality of the reviewed data and the level of unexplained heterogeneity among studies. This review stresses the importance of considering a strict adhesion to DMDD criteria when exploring its clinical correlates.

Depressive disorders are a major public health issue in Western societies, particularly among adolescents, young adults and women. The COVID-19 pandemic has exacerbated mental health challenges, increasing depression and anxiety symptoms, especially in younger people. This study focuses on the hard-hit Emilia-Romagna Region (ERR) in Italy, examining changes in antidepressant (AD) drug use post-COVID-19 to understand the pandemic’s effect on mental health.

A population-based interrupted time series design and a segmented regression analysis was carried out on ERR pharmaceutical data (FED, direct dispensation pharmaceuticals, AFT, territorial pharmaceutical assistance) out to estimate changes in AD use during the three pandemic years (2020, 2021 and 2022) compared to 2017–2019.Analyses were stratified by age, gender, citizenship, population density of the area of residence.

A notable increase in AD consumption compared to what was expected was observed among younger age groups, and especially in females. In the 12–19 age group, a gradual increase was recorded from January 2021 until it reached +48% in 2022 (+58% among women, +30% among men). An even more remarkable growth in AD usage among non-Italian residents in the same age group was recorded compared to expected. A relevant increase, although smaller, was detected among individuals in the 20–34 age group, with a peak of +9% in 2022. These differences persisted up until the end of the observation period.

The study suggests that the COVID-19 pandemic may have had a lasting negative impact on the mental health of younger individuals. The observed increase in AD use may foreshadow a potential long-term need for enhanced mental healthcare and services directed at this subpopulation.

Despite the frequent co-occurrence of depression and diabetes, gender differences in their relationship remain unclear.

This exploratory study examined if gender modifies the association between depressive symptoms, prediabetes and diabetes with cognitive-affective and somatic depressive symptom clusters.

Cross-sectional analyses were conducted on 29 619 participants from the 2007–2018 National Health and Nutrition Examination Survey. Depressive symptoms were measured by the nine-item Patient Health Questionnaire. Multiple logistic regression was used to analyse the relationship between depressive symptoms and diabetes. Multiple linear regression was used to analyse the relationship between depressive symptom clusters and diabetes.

The odds of having depressive symptoms were greater in those with diabetes compared to those without. Similarly, total symptom cluster scores were higher in participants with diabetes. Statistically significant diabetes–gender interactions were found in the cognitive-affective symptom cluster model. Mean cognitive-affective symptom scores were higher for females with diabetes (coefficient = 0.23, CI: 0.10, 0.36, P = 0.001) than males with diabetes (coefficient = −0.05, CI: −0.16, 0.07, P = 0.434) when compared to the non-diabetic groups.

Diabetes was associated with higher cognitive-affective symptom scores in females than in males. Future studies should examine gender differences in causal pathways and how diabetic states interact with gender and influence symptom profiles.

Despite strong evidence of efficacy of electroconvulsive therapy (ECT) in the treatment of depression, no sensitive and specific predictors of ECT response have been identified. Previous meta-analyses have suggested some pre-treatment associations with response at a population level.

Using 10 years (2009–2018) of routinely collected Scottish data of people with moderate to severe depression (n = 2074) receiving ECT we tested two hypotheses: (a) that there were significant group-level associations between post-ECT clinical outcomes and pre-ECT clinical variables and (b) that it was possible to develop a method for predicting illness remission for individual patients using machine learning.

Data were analysed on a group level using descriptive statistics and association analyses as well as using individual patient prediction with machine learning methodologies, including cross-validation.

ECT is highly effective for moderate to severe depression, with a response rate of 73% and remission rate of 51%. ECT response is associated with older age, psychotic symptoms, necessity for urgent intervention, severe distress, psychomotor retardation, previous good response, lack of medication resistance, and consent status. Remission has the same associations except for necessity for urgent intervention and, in addition, history of recurrent depression and low suicide risk. It is possible to predict remission with ECT with an accuracy of 61%.

Pre-ECT clinical variables are associated with both response and remission and can help predict individual response to ECT. This predictive tool could inform shared decision-making, prevent the unnecessary use of ECT when it is unlikely to be beneficial and ensure prompt use of ECT when it is likely to be effective.

Psychotic symptoms and elevated fasting blood glucose (FBG) are frequently observed in people with major depressive disorder (MDD), but there is a lack of research into this relationship within this cohort.

This study aimed to preliminarily explore the prevalence of psychotic symptoms and their predictors among patients with MDD and elevated FBG.

This study enrolled 1718 patients with first-episode and drug-naïve (FEDN) MDD. Sociodemographic data and physical and biochemical indicators were collected. Clinical symptoms were assessed with tools such as the Hamilton Rating Scale for Anxiety, Hamilton Rating Scale for Depression (HRSD) and Positive and Negative Syndrome Scale positive subscale.

The odds ratio for psychotic symptoms in those with MDD and elevated FBG (18.7%) was 2.33 times higher than those with MDD without elevated FBG. Presence of psychotic symptoms was significantly correlated with HRSD score, suicide attempts, and total cholesterol and thyroid-stimulating hormone levels. The combination of HRSD score, suicide attempts and thyroid-stimulating hormone levels among patients with MDD and elevated FBG effectively distinguished between individuals with and without psychotic symptoms, achieving an area under the curve of 0.87.

Psychotic symptoms are frequently observed among FEDN MDD patients with elevated FBG, and depressive symptoms, suicide attempts and thyroid-stimulating hormone levels are related to psychotic symptoms in this cohort.

This study aims to explore the outcome with iv ketamine treatment in a real-world clinical setting, primarily measured as posttreatment days hospitalised.

The psychiatric medical records of 46 patients having received iv ketamine on a psychiatric treatment indication between 2015 and 2018 were retrospectively examined. Analysis comparing the number and duration of hospital admissions before and after ketamine treatment as well as logistic regression analysis to investigate clinical predictors of effectiveness, were performed. To assess patients’ severity of depressed symptoms records were screened for MADRS-S scores.

No significant difference between pre- and posttreatment hospital days (p = 0.170), or number of hospitalisations (p = 0.740) were found. The response rate was 31% and remission rate 21%. None of the predictors showed statistical significance in the logistic model.

Iv ketamine treatment showed effectiveness in reducing depressive symptoms even with complex patients in a real-world clinical setting. However, this did not translate to a reduction in hospitalisation. Highlighting the multifaceted challenges posed when implementing iv ketamine treatment in clinical practice.

Comorbid depression substantially affects the management of glycemia and diabetes-related complications among patients with type 2 diabetes mellitus. In this study, we sought to determine the association between weight change over 4 years and depression risk among patients with type 2 diabetes mellitus.

This population-based retrospective cohort study from the National Health Insurance Services of Korea included 1 111 345 patients with type 2 diabetes who were divided into groups according to body weight change over 4 years. Body weight changes were compared with the preceding 4-year period (2005–2008). Depression was defined according to the International Classification of Diseases 10th revision code for depression (F32 and F33) on one or more inpatient or outpatient claims.

During a median follow-up of 7.4 years, 244 081 cases of depression were identified. We observed a U-shaped association between body weight change and depression risk with a higher risk among both groups of weight loss (hazard ratio (HR) 1.17, 95% CI 1.15–1.19 for ⩾ −10%; HR 1.07, 95% CI 1.06–1.08 for −10 to −5%) and weight gain (HR 1.06, 95% CI 1.04–1.08 for ⩾10%; HR 1.02, 95% CI 1.01–1.04 for 5–10%) compared with the stable weight group (−5 to 5%).

A U-shaped association between body weight change and depression risk was observed in this large nationwide cohort study. Our study suggests that patients with type 2 diabetes and weight change, either gain or loss, could be considered a high-risk group for depression.