We aimed to investigate the risks of all-cause and cause-specific mortality associated with dose-dependent benzodiazepine and Z-drug (BZDR) use in the Finnish population initiating new BZDR use with five-year follow-up. Study subjects were included if BZDR use had started in 2006 with no BZDR dispensing during the preceding years 2004-2005. The information drug dispensing was modeled with PRE2DUP method as time-varying measure updated at every dispensing and then divided into three dose categories which were low dose (< 1.0 Defined Daily Doses [DDDs] per day), medium to high dose (1.0-< 3.0 DDDs/day) and very high-dose (≥ 3.0 DDDs/day). Risk of mortality was studied with Cox regression models. The study included 48,124 incident BZDR users aged 18-65 years (44.4% male). During the 5-year follow-up, 2294 (4.9%) individuals died. Compared to non-use periods, BZDRs use was associated with increased mortality risk (adjusted Hazard Ratio HR 1.28, 95% Confidence Interval CI 1.16-1.41). Compared to the time periods when BZDRs were not used, both medium to high-dose use (aHR 1.58, 1.36-1.74) and very-high-dose use (aHR 2.68, 95% CI 2.20-3.26) were associated with an increased risk of all-cause mortality, whereas low dose use was not. The highest risk estimates were observed during very high-dose use and for potentially preventable deaths such as overdoses (aHR 6.18, 95% CI 3.77-10.12), suicides (aHR 4.46, 95% CI 2.79-7.13), and accidents (aHR 3.77, 95% CI 2.66-5.35). Persons using BZDRs in very high doses are at a six-fold increased risk of overdose deaths compared to non-use, and those using BZDRs in medium to high doses are at a three-fold increased risk. In low doses, however, the risk of all-cause mortality was not elevated. The mortality risk strongly associates with higher doses and is often characterized by concomitant use of more than one BZDRs at the same time.
Disturbances in sleep and circadian rhythms are features of several psychiatric disorders. The pineal gland regulates these rhythms via melatonin, with pineal gland volume (PGV) serving as a structural proxy. We conducted a meta-analysis to synthesize evidence on differences in PGV between patients with psychiatric disorders and healthy controls and the association between PGV and sleep outcomes. Systematic searches of PubMed, Embase, Scopus, and Web of Science were performed (August 2025). Study quality was assessed using the Newcastle-Ottawa Scale. Random-effects meta-analyses using restricted maximum likelihood (REML) estimation were conducted for correlation and group-comparison outcomes. Subgroup analyses were performed by diagnostic category. Fourteen studies compared PGV between psychiatric patients and healthy controls, and seven studies examined associations between PGV and sleep outcomes. PGV was significantly lower in patients with psychiatric disorders compared with healthy controls (1055 patients, 712 controls, Hedges' g = -0.54 [-0.68, -0.41], p < 0.001). Reductions were most pronounced in schizophrenia spectrum disorders (g = -0.63 [-0.81, -0.46], p < 0.001), and were approximately twice the magnitude observed in mood disorders (g = -0.33 [-0.59, -0.06], p = 0.027). The pooled association between larger PGV and better sleep was weak and nonsignificant (47 patients, 713 controls, Zr = 0.18 [-0.08, 0.43], p = 0.136), with substantial heterogeneity (I2 = 82%), likely reflecting variability in sleep assessment and study populations. Across psychiatric disorders, PGV is reduced relative to healthy controls, with the largest and most consistent reductions observed in schizophrenia spectrum disorders. In contrast, evidence for an association between PGV and sleep outcomes remains inconclusive. These findings suggest that reduced PGV may represent a trait-like structural alteration linked to psychiatric illness, particularly schizophrenia spectrum disorders, rather than a direct marker of sleep disturbance. PROSPERO: CRD420251138624.
Cognition is a common symptom dimension in major mood disorders and is associated with impairments in daily life functioning. Assessments that capture cognitive difficulties reflective of those that people experience in the real world are therefore much needed; however, most cognitive assessments lack ecological validity. A recently developed, fully immersive VR platform for cognitive assessment (CAVIR) has proven to be feasible, well-tolerated, sensitive to cognitive impairment in psychiatric populations, and associated with measures of daily functioning. Here we aimed to assess the validity of a newly developed English language version of CAVIR in people with primary mood disorders (PMD) and controls (HC). We enrolled 40 people with PMD including Bipolar I Disorder, Bipolar II Disorder, and Major Depressive Disorder, and 40 healthy controls. Participants were administered the CAVIR, the MATRICS Consensus Cognitive Battery (MCCB), symptom ratings, and measures of daily functioning (FAST, UPSA-B). Patients scored worse than controls on the CAVIR composite and all subtests (p = 0.02-p < 0.0001), except the executive functioning task (p = 0.85). Comparing the composite and domain scores of CAVIR to their corresponding domains on the MCCB revealed modest to moderate, significant correlations on the composite and all domains except executive functioning. The CAVIR was associated with both performance-based (UPSA-B) and interview rated (FAST) measures of functioning. This newly translated English language version of CAVIR performed very similarly to the original version and was sensitive to cognitive impairments in people with PMD. CAVIR composite and most subtests were correlated with an established paper and pencil cognitive battery and were associated with measures of functioning. The CAVIR is self-administered, quick, and requires minimal training, making it a useful tool for assessing cognition.
Bipolar disorder (BD) carries a suicide risk 20 times higher than the general population, with up to 60% of patients attempting suicide. Current interventions have failed to reduce its incidence; static factors have shown limited predictive utility. Emerging evidence suggests dynamic monitoring approaches may offer complementary value. This study examined whether quantifiable differences in mood regulation patterns exist across the suicidality continuum among patients diagnosed with BD. We analyzed daily self-reported mood, anxiety, and energy levels from 164 participants recruited from two Canadian academic hospitals (April 2021-August 2024). Participants were stratified into six groups based on suicide attempt history, current polarity, and active suicidality status. Using time-series analysis, we computed autocorrelation and cross-correlation functions to examine temporal relationships within and between variables across 1-7 day lags. Data comprised 64,351 valid observations over 461.5 ± 236.6 days of follow-up. Participants with the highest suicide risk (previous attempt, in a current depressive episode with active suicidality) demonstrated significantly higher day-to-day autocorrelation compared to the lowest-risk participants (no prior attempts and currently euthymic) for mood (0.53 vs. 0.29, p = 0.01), energy (0.52 vs. 0.23, p = 0.02), and anxiety series (0.55 vs. 0.32, p = 0.04). Cross-correlation analysis revealed mood-energy decoupling during active suicidality; as well as a stronger negative mood-anxiety correlation in those with a prior attempt, even during euthymia. Higher autocorrelation patterns are indicative of a pathologically stable mood regulation in high-risk individuals, potentially serving as dynamic biomarkers for suicide risk stratification and targeted intervention development. Our findings demonstrate that a more aggressive approach to treating comorbid anxiety may be essential for reducing the risk of future attempts. They also challenge traditional conceptualizations equating euthymia with the absence of suicide risk, suggesting neurobiological vulnerability despite symptomatic remission.
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For decades, a persistent claim has been that autobiographical memory loss after electroconvulsive therapy (ECT) for depression might actually contribute to ECT efficacy by reducing or even eliminating autobiographical memories. To test this claim, the primary aim of this study is to examine the association between autobiographical memory loss and remission of depression. The hypothesis is that remitted patients have more autobiographical memory loss after ECT compared to non-remitted patients. In 71 patients with major depressive disorder undergoing ECT, autobiographical memory consistency (Kopelman Autobiographical Memory Interview) and depression severity (Montgomery-Åsberg Depression Rating Scale) were assessed before and within 1 week after treatment. Logistic regression analyses were conducted to examine the association between both autobiographical memory loss (i.e., memory consistency) and remission (MADRS < 10), including age, episode duration, baseline MADRS score, and treatment condition as covariates. All logistic regression models were significant. The overall autobiographical memory consistency-score (OR = 1.072, 95% CI [1.018-1.130], p = 0.009) and the consistency-score for recent memories (OR = 1.043, 95% CI [1.006-1.082], p = 0.021) were significantly associated with the odds of remission but in the opposite direction of the hypothesis. A higher age and shorter episode duration further increased the likelihood of remission. Additionally, post hoc analyses showed that the trajectories of autobiographical memory performance over time differed between remitters and non-remitters, indicating a slight decrease in autobiographical memories for more recent events in non-remitters and no change in remitters. This study shows that, contrary to the hypothesis, remitted patients have less autobiographical memory loss, particularly for recent memories than non-remitters. This refutes the premise that the loss of autobiographical memories contributes to the therapeutic effectiveness of ECT.
Psychiatric history is the strongest risk factor for postpartum depression (PPD). Obstetric complications, more prevalent among women with a psychiatric history, are also independent risk factors. However, the mechanisms linking these factors to PPD remain unclear. We examined whether obstetric complications mediate the association between psychiatric history and PPD. This cohort study utilized Danish nationwide Edinburgh Postnatal Depression Scale (EPDS) screenings (2015-2021) linked with register data. Psychiatric history was defined as psychiatric diagnoses (ICD-10: F00-99) or filled psychotropic prescriptions (ATC: N05A, N05BE01, N06A, N06BA) from 1995 until conception. Complications were defined as a composite measure of complications occurring between conception and delivery. PPD symptoms were defined as a positive EPDS score (≥ 11), and PPD diagnosis was defined as a depression diagnosis (ICD-10: F32-33) or antidepressant prescription fill (ATC: N06A indicated for depression). Of 170,218 mothers (163,326 in analyses), 23.9% had a psychiatric history. These mothers had higher levels of PPD symptoms (13.4% vs. 6.1%), PPD diagnosis (7.0% vs. 0.4%), and complications (34.1% vs. 28.5%) compared to those without. (A) Psychiatric history (PPD symptoms: OR = 2.32 [95% CI, 2.22; 2.41]; PPD diagnosis: OR = 5.09 [95% CI, 4.48; 5.79]) and complications (PPD symptoms: OR = 1.16 [95% CI, 1.11; 1.21]; PPD diagnosis: OR = 1.18 [95% CI, 1.04; 1.34]) were independently associated with PPD. (B) Psychiatric history did not modify the association between complications and PPD (PPD symptoms: OR = 1.20 [95% CI, 1.14; 1.26] vs. 1.09 [95% CI, 1.02; 1.17]; PPD diagnosis: OR = 1.22 [95% CI, 1.00; 1.49] vs. 1.15 [95% CI, 0.97; 1.36]). (C) Complications mediated only a small fraction of the association between psychiatric history and PPD (proportion mediated: PPD symptoms = 0.68% [95% CI, 0.50%; 1.00%], PPD diagnosis = 0.42% [95% CI, 0.14%; 0.79%]). Psychiatric history and complications are independently associated with PPD, but complications explain only a negligible portion. These findings suggest that the link between psychiatric vulnerability and PPD is primarily driven by direct mechanisms rather than mediation through complications.
Cognitive impairment is a core feature of mood disorders that contributes to reduced functioning and poorer prognosis, thereby emerging as an important treatment target. Persistent trait-related impairments present within both affective and non-affective cognition. Nevertheless, the relationship between affective and non-affective cognitive domains remains unclear, including whether impairments in emotion regulation and facial expression recognition are secondary to deficits in non-affective cognition. Mapping out the hierarchical structure of affective and non-affective cognitive domains may elucidate core cognitive impairments that represent the most relevant treatment targets. Network analysis was employed to explore the associations between affective and non-affective cognitive domains in individuals with mood disorders (N = 380) and healthy controls (HC; N = 225) pooled from two previous studies. Partial correlation networks were constructed separately for individuals with mood disorders and HC comprising measures of non-affective cognition (working memory and executive function, attention and processing speed, verbal learning, and verbal memory) and affective cognition (emotion regulation success, facial expression recognition speed and accuracy). For both mood disorders and HC, 'working memory and executive function' and 'attention and processing speed' emerged as central cognitive domains. Emotion regulation showed a significantly weaker association with 'working memory and executive function' in mood disorders relative to HC. Additionally, facial expression recognition speed was associated with 'attention and processing speed' across both groups. Our findings suggest that working memory, executive function, attention, and processing speed are core cognitive domains in mood disorders. Further, the weak association between executive function and emotion regulation in mood disorders may indicate a reduced reliance on cognitive control processes during emotion regulation. These findings underscore the importance of targeting both affective and non-affective cognition in pro-cognitive interventions to improve emotion regulation and potentially mitigate the risk of mood episodes.
Sunlight has profound impacts on physical and mental health, beyond vision, including effects on circadian rhythms, alertness, mood, and sleep. A family history of any mood disorders is strongly associated with psychiatric disorders including bipolar disorder. The purpose of this study was to evaluate the association between a family history of any mood disorder in patients with bipolar I disorder and solar insolation at varied international onset locations. Data for this analysis were available from 5842 patients with a diagnosis of bipolar I disorder obtained at 83 collection sites in both hemispheres. This included 4752 patients from 71 collection sites in the northern hemisphere and 1090 patients from 12 collection sites in the southern hemisphere. Patient data variables were obtained from records or interviews. Solar insolation data were obtained from The National Aeronautics and Space Administration (NASA) Power database for each onset location, and the ratio of the mean monthly minimum/mean monthly maximum solar insolation was calculated. Typically, the ratio is largest near the equator (little yearly change in solar insolation) and smallest near the poles (large yearly change in solar insolation). A significant relationship was found between a family history of any mood disorder, the ratio of the mean monthly minimum/mean monthly maximum solar insolation, and gender. The odds of a family history of mood disorder increased as patient location nears the poles and decreased near the equator. Female gender also increased the odds of having a family history of a mood disorder. This study highlighted the association between family history, solar insolation, and gender in international patients with bipolar I disorder. Given the profound effects of sunlight on human health, the family of patients with bipolar disorder who live in the same location with the same solar insolation, and especially females, may be at increased risk for a mood disorder.
Diabetes, obesity and bipolar disorder often co-occur and may have shared pathophysiology. Glucagon-like peptide 1 receptor agonists (GLP-1RA) treat diabetes and obesity but their impact on bipolar disorder is unknown. In this era of stagnated pharmacotherapy, we examined psychiatric hospitalisation and absence from work due to sick leave as potential measures of relapse in people diagnosed with bipolar disorder who were also prescribed antidiabetic medications, including GLP-1RA. The study cohort was derived from the National Swedish Registers and included all people with a diagnosis of bipolar disorder who used any antidiabetic medication, between the years 2009 and 2024. GLP-1RA individually and as a group were compared with non-use of GLP-1RA, and directly with other second-line antidiabetic medications. A within-individual design was utilised for all comparisons to reduce confounding. The main outcome was psychiatric hospitalisation for any reason, with secondary outcomes being psychiatric hospitalisation after a relapse of bipolar disorder, and sick leave due to psychiatric reasons. Within-individual stratified Cox models with adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were used. 14,694 people were included in the study, of whom 5200 used GLP-1RA. Semaglutide was associated with a 21% (aHR 0.79, 95% CI 0.69-0.91) lower risk of psychiatric hospitalisation compared with non-use of GLP-1RA in that same individual. Liraglutide and dulaglutide were not specifically associated with a lower hospitalisation risk. Semaglutide was also linked to a 17% (aHR 0.83, 95% CI 0.69-0.99) lower risk of relapse of bipolar disorder. Absences from work due to sick leave were not significantly associated with the specific antidiabetic medications studied. In people with both bipolar disorder and diabetes and/or obesity, the use of semaglutide was linked to lower rates of psychiatric hospitalisation compared with time periods when GLP-1RA were not used by that individual. Liraglutide and dulaglutide were not associated with reduced psychiatric hospitalisation, implying this is not a class effect. This finding with semaglutide should be further tested in a randomised controlled trial.
Repetitive transcranial magnetic stimulation (rTMS) has been demonstrated to be an effective and well tolerated treatment for depression, and it is being investigated also for other indications. This study presents the Swedish National Quality Register for rTMS (Q-rTMS). The registry comprises epidemiological data, data from standardized rating scales, details on treatment settings, and a registry-specific patient questionnaire. A presentation of the Q-rTMS including the types of data collected, the organizational structure of the register, as well as a brief overview of the volume of data accumulated between the registry's inception in 2018 and the end of 2024. As of 2024, the register contained data from a total of 3083 unique individuals and 3842 treatment series, collected from 27 different rTMS providers. The most common indication for rTMS was depression (International Classification of Diseases, Tenth Revision diagnoses (ICD-10): F32-F34, 74.1%) followed by bipolar affective disorder (ICD-10: F31, 14.2%). The average age was 43.2 years, and 56.5% were women. The register included matched pre- and post-treatment data exceeding 60% completeness for the Montgomery-Åsberg Depression Rating Scale-Self Assessment (MADRS-S), the Clinical Global Impression-Severity (CGI-S), and the EuroQol five-dimensional questionnaire (EQ-5D-5L). The Q-rTMS combines high coverage with longitudinal documentation of clinically relevant outcome measures and may hence contribute to population-based real-world effectiveness research in rTMS for depression. Significant outcomes: ○. This paper presents the Swedish Q‐rTMS, describing the types of data collected and the organizational structure of the registry. ○. The Q‐rTMS is currently the largest population‐based registry of its kind and represents a valuable resource for real‐world effectiveness research in rTMS. ○. Data from the Q‐rTMS may be linked with other Swedish registries, allowing for enriched datasets and long‐term outcome follow‐up. Limitations. Reporting to Q‐rTMS is voluntary, and response rates vary across the variables collected in the registry.
Postpartum depression (PPD) can be measured in various ways, including questionnaire-based symptom scores or through administrative health databases. We examined the overlap between symptom-based and register-based PPD definitions and assessed the consistency in exposure-outcome associations. We linked Danish nationwide health registers to PPD screening records (Edinburgh Postnatal Depression Scale, EPDS) at 2 months postpartum from women screened between January 1, 2015, and December 31, 2021. We defined symptom-based PPD as an EPDS ≥ 11, and register-based PPD as an antidepressant prescription or hospital depression diagnosis within 1 year postpartum. We estimated the overlap between women with register-based and symptom-based PPD, as well as between continuous EPDS scores and register-based treatment indicators. We evaluated consistency between the two definitions using logistic regression analyses for socioeconomic, obstetric, demographic- and health-related exposures from which we obtained odds ratios (ORs) for each PPD definition and calculated ratio of odds ratios (ROR). Among 157,193 mothers (132,593 unique), 11,193 (7.1%) had symptom-based PPD and 2409 (1.5%) had register-based PPD. Of those with symptom-based PPD, 8.8% also had register-based PPD, while 40.8% of those with register-based PPD had symptom-based PPD. We observed a higher overlap with higher EPDS scores. Consistency was highest for obstetric variables but varying for demographic- and health-related exposures (ROR register-based vs. symptom-based 1.84 [95% CI 1.67-2.03] for psychiatric history and 0.75 [95% CI 0.68-0.83] for primiparity). We observed substantial differences and limited overlap between symptom-based and register-based PPD. Register-based measures capture hospital-based diagnoses and pharmacological treatment only, but not all treatment within the healthcare system, and differences may reflect a combination of severity, symptom transience, misclassification, and timing of measurement. Consistency in exposure-outcome associations varied, particularly for certain exposures. Our findings underline the importance of considering both the nature and implications of PPD definitions in epidemiological research.
This case-control study examined social barriers in adults with ADHD compared to non-neurodivergent adults, focusing on autistic traits, cognitive/affective empathy, theory of mind (ToM), and social anxiety/avoidance. A total of 142 adults with ADHD and 104 non-neurodivergent groups were assessed using the following self-report measures: the Adult ADHD Self-Report Scale, the Hospital Anxiety Depression Scale, the Autism Spectrum Quotient, the Empathy Quotient, and the Liebowitz Social Anxiety Scale. ToM was evaluated using the Reading the Mind in the Eyes Test. Additionally, psychiatric interviews were conducted, incorporating diagnostic evaluation via the Structured Clinical Interview for DSM-5 Disorders-Clinician Version, along with collection of sociodemographic and clinical data, and documentation of real-life narratives of social struggles to contextualize and deepen the interpretation of the quantitative findings. Adults with ADHD exhibited significantly higher levels of autistic traits and social anxiety/avoidance, along with lower cognitive and affective empathy scores, compared to controls, while ToM abilities did not differ significantly between groups. Moreover, regression analyses indicated that challenges in social skills and communication, low cognitive empathy, heightened affective empathy, and difficulties in attention switching accounted for variance in social anxiety/avoidance, independent of confounding sociodemographic and clinical factors, including the presence of co-occurring psychiatric conditions and the severity of ADHD, depression, and anxiety symptoms. While adults with ADHD exhibit intact basic ToM abilities, challenges in social-cognitive processes are associated with their social barriers. Targeted interventions such as social skills training, executive function coaching, and anxiety management may improve social outcomes and quality of life, as also highlighted by the real-life narratives-although further longitudinal, multi-method research is warranted.
There is limited research examining the relationship between blood alcohol concentration (BAC) and other risk factors among suicide deaths in Finland. Our study aimed to investigate the relationship of an elevated (more than zero) blood alcohol concentration with medical history, including sociodemographic characteristics and disease diagnoses. Data was collected from suicide deaths in Finland from 2016 to 2024 and verified by official cause-of-death investigations, which included forensic autopsy, toxicology results, and other key information from death certificates and national healthcare registries. A condition recorded in both the death certificate (autopsy) and healthcare register was considered as confirmed diagnosis. BAC, as expressed as a percentage, was grouped into three categories: nil (BAC = 0.000), low-to-medium (BAC = 0.010%-0.099%), and high (BAC = 0.100%-0.500%). Descriptive statistics, correlation, and stepwise logistic regression to estimate odds ratios (ORs) for BAC categories were undertaken. The number of suicide deaths from 2016 to 2024 in Finland was n = 6892, with 5183 men (75.2%) and 1709 women (24.8%). BAC reports were available for n = 6835. Independent factors associated with a low-to-medium or high BAC at death were alcohol use (ORs: 41.80-275.27), longer than 1 day since last healthcare visit (ORs: 1.54-2.53), previous suicide attempt(s) (ORs: 1.42-1.65), and female gender (only for high BAC, OR: 1.30). There were reduced odds for schizophrenia spectrum diagnosis (OR: 0.17), bipolar disorder (OR: 0.29), age groups 10-19 (ORs: 0.30-0.65), 80 and over (ORs: 0.15-0.39), and 70-79 years (only for high BAC, OR: 0.43). Our findings show that individuals with documented habitual alcohol use, female gender, previous suicide attempts, and less frequent healthcare visits had higher odds of intoxication at suicide. Meanwhile, being aged under 20, over 70, or diagnosed with schizophrenia or bipolar disorders reduced the odds. The results highlight the need for proactive healthcare engagement and integrated alcohol-use interventions in suicide prevention strategies.
We aimed to synthesize the evidence on confusional states and neurocognitive changes associated with the concurrent use of lithium and electroconvulsive therapy (ECT). We conducted a systematic search of PubMed, EMBASE, Web of Science, Scopus, Cochrane Library, CINAHL, PsycArticles, and clinical trials registries up to September 2025. Eligible studies compared the incidence of confusional states or changes in neurocognitive test scores in patients receiving lithium and ECT (Li-ECT) and those receiving ECT without lithium. We performed separate meta-analyses and calculated odds ratios (OR) with 95% confidence intervals (CI) for dichotomous outcomes and standardized mean differences (SMD) for continuous outcomes. Additionally, case reports describing cognitive effects of Li-ECT were synthesized. Sixteen studies were included: 11 studies (n = 66,156) assessed confusional states and five (n = 341) evaluated neurocognitive changes. The Restricted Maximum-Likelihood meta-analysis showed no significant association between lithium use and confusional states (OR 2.09; 95% CI: 0.94-4.66; p = 0.07), whereas a Paule-Mandel sensitivity analysis suggested a significant association (OR 2.38; 95% CI: 1.20-4.74; p = 0.01). No significant differences were observed in changes in global cognitive functioning, autobiographical memory or verbal fluency test scores ([SMD = 0.25; 95% CI: -0.98-1.49; p = 0.69], [SMD = 0.27; 95% CI: -1.37; 1.9; p = 0.75], [SMD = -0.89; 95% CI: -3.18; 1.39; p = 0.44]). Current evidence does not show a significant increase in cognitive side effects associated with lithium use during ECT. However, methodological limitations, sensitivity to meta-analytic assumptions and clinical heterogeneity preclude definitive conclusions. Large prospective studies using standardized cognitive assessments are needed to confirm the tolerability of concurrent lithium and ECT use. While our findings support the cautious continuation of lithium during ECT, individualized clinical decision-making remains crucial to maximize efficacy and minimize cognitive burden.
Neuroleptic malignant syndrome (NMS) is a life-threatening adverse reaction to antipsychotic medications. Dantrolene is commonly used to manage NMS; however, supportive evidence from large-scale clinical studies remains limited. This study aimed to evaluate the clinical impact of early dantrolene administration in intensive care unit (ICU)-admitted patients with NMS using a nationwide inpatient database in Japan. A retrospective cohort study was conducted using the Japanese Diagnosis Procedure Combination database from April 2010 to March 2023. Patients aged ≥ 16 years diagnosed with NMS and admitted to the ICU were included. The exposure of interest was dantrolene administration within the first 2 days of admission. The primary outcome was in-hospital mortality; secondary outcomes included ICU and hospital length of stay. Baseline adjustment between the dantrolene-treated and untreated groups was performed using two methods: propensity score matching (PSM) and generalized linear mixed models (GLMMs). A total of 2234 patients met the inclusion criteria, including 1475 treated with dantrolene and 759 without. In both analyses, dantrolene use was associated with an increase in in-hospital mortality (adjusted OR: 2.03, 95% CI: 1.16-3.54; p = 0.01 in GLMM, adjusted OR: 1.92, 95% CI: 1.17-3.24; p = 0.01 in PSM). Dantrolene was also associated with prolonged ICU stay (mean difference: 1.66, 95% CI: 1.05-2.26; p < 0.001 in GLMM and 2.03, 95% CI: 1.31-2.76; p < 0.001 in PSM) and hospital stay (mean difference: 6.85, 95% CI: 3.48-10.21; p < 0.001 in GLMM and 6.81 days, 95% CI: 3.46-10.16; p < 0.001 in PSM). Subgroup analyses stratified by age (< 65 vs. ≥ 65 years) yielded similar trends. In the largest study of NMS to date, early initiation of dantrolene was associated with higher in-hospital mortality and prolonged ICU/hospital stay. These findings suggest that routine use of dantrolene in NMS should be reevaluated.