ABSTRACT Background After remission from a first episode psychosis (FEP), international clinical guidelines recommend continuation of antipsychotic medication for at least 1 year, although many patients wish to reduce or discontinue medication due to side effects or long‐term health concerns. Evidence on the cost‐effectiveness of early dose reduction or discontinuation compared to continuation remains limited. Methods A trial‐based cost‐utility analysis was conducted alongside the ongoing HAMLETT study, in which 347 remitted FEP participants were randomized to either early guided dose reduction or discontinuation or maintenance treatment for 1 year. Both healthcare and societal perspectives over a 24‐month time horizon were considered. Health outcomes were expressed as quality‐adjusted life years (QALYs) derived from the EQ‐5D‐5L questionnaire using Dutch valuation tariffs. Costs were estimated using patient reported healthcare utilization and administrative pharmacy data. Incremental costs and effects were analysed using seemingly unrelated regression with uncertainty assessed through nonparametric bootstrapping and multiple sensitivity analyses. Results Early dose reduction or discontinuation was associated with lower quality‐adjusted life years and higher or comparable costs compared with maintenance treatment over the 2‐year analysis period. In the base‐case societal perspective analysis, incremental costs were €23,563 and incremental effects were −0.077 QALYs, resulting in an incremental net monetary benefit of ‐€27,430 at a willingness‐to‐pay threshold of €50,000 per QALY at 24 months. Results were consistent across several scenarios with only approximately 9% probability that early dose reduction or discontinuation was cost‐effective at the assumed willingness‐to‐pay threshold. However, a sex‐at‐birth subgroup analysis suggested a small and uncertain positive incremental net monetary benefit among female participants. Conclusion Over a 24‐month period, early dose reduction or discontinuation of antipsychotic medication after remission from a FEP is unlikely to be cost‐effective compared with maintenance treatment from both healthcare and societal perspectives. Whether longer term functional improvements associated with early dose reduction translate into cost‐effective benefits remains uncertain and requires follow‐up. Trial Registration: EudraCT number: 2017‐002406‐12
Background Stressful life events (SLEs) are a well-established etiologic risk factor for major depressive disorder (MDD). The kindling hypothesis proposes that their role diminishes as episodes recur, with illness becoming progressively autonomous from environmental triggers. It remains unclear whether this reflects true within-person change or a compositional shift-whereby more highly recurrent patients are those whose episodes were stress-independent from the outset.Methods We analyzed data from life history calendars, a structured method for reconstructing lifetime sequences of depressive episodes and antecedent life events, from 5843 Korean women with recurrent MDD (>= 2 lifetime episodes) contributing 17,338 episode observations (KOMOGEN-D), with replication in 708 Chinese women contributing 1905 episode observations (CONVERGE).Results Consistent with the kindling hypothesis, the proportion of episodes preceded by any SLE declined substantially and monotonically across episode order, from 94.8% (95% CI, 94.2%-95.4%) at the first episode to 77.7% (95% CI, 71.2%-84.2%) at the seventh (OR per episode increase, 0.66; 95% CI, 0.62-0.71). Inter-episodic intervals shortened with episode order (beta = -1.50 years; 95% CI, -1.61 to -1.38), indicating that episodes became more frequent. Within-individual analyses revealed that more participants had decreasing than increasing SLE counts across episodes, with more frequent transitions from SLE-associated to non-SLE-associated episodes than the reverse. Stratification by SLE type showed that independent SLEs decreased across episodes, whereas dependent SLEs increased. The main findings were replicated in CONVERGE, although some within-person transition analyses were limited by smaller sample size.Conclusions Across two large cohorts collected in different cultural settings, SLE involvement preceding episodes decreased across episode order while the rate of recurrence accelerated, and within-person analyses supported stress-episode decoupling as an individual-level process. These findings provide some of the strongest evidence yet assembled that the course of recurrent MDD is consistent with the kindling hypothesis: episodes become progressively less dependent on external stressors, shifting toward a more autonomous illness. These results have direct implications for stratifying recurrence risk by episode stage and for identifying the point in the illness course at which preventive strategies should shift emphasis from targeting environmental stressors toward sustained pharmacological or psychological relapse prevention.
ABSTRACT Objective This network meta‐analysis (NMA) aimed to evaluate the comparative efficacy of non‐invasive brain stimulation (NIBS) interventions for late‐life depression (LLD), with treatment rankings provided as a secondary outcome. Methods We conducted a systematic review and NMA of randomized controlled trials (RCTs) assessing NIBS for major depressive disorder in adults aged ≥ 60 years. Comprehensive searches of PubMed, EMBASE, and Cochrane Library were performed up to June 2025. Two reviewers independently selected studies, extracted data, and assessed quality using the Cochrane Risk of Bias tool. A random‐effects NMA was implemented using the netmeta package in R. Certainty of evidence was evaluated using the GRADE framework. Primary outcomes included changes in depressive symptoms, measured by the standard mean difference (SMD). Secondary outcomes included response rates and remission rates. Results Twenty‐five RCTs involving 1344 participants and 15 NIBS modalities were included. Bilateral electroconvulsive therapy (BL‐ECT; SMD = 1.13, 95% CI 0.37–1.90) and high‐frequency repetitive transcranial magnetic stimulation over the left dorsolateral prefrontal cortex (rTMS‐10Hz‐F3; SMD = 0.42, 95% CI 0.02–0.81) consistently outperformed sham across all efficacy outcomes. Both interventions formed closed loops of the network geometry, enabling formal assessment of agreement between direct and indirect evidence. Although inconsistency was detected in the symptom severity network, both interventions demonstrated consistent benefits across efficacy outcomes and retained moderate‐certainty evidence. Conclusion BL‐ECT and rTMS‐10Hz‐F3 emerged as the most consistently effective NIBS treatments for LLD, supported by moderate‐certainty evidence. Other highly‐ranked modalities require cautious interpretation due to sparse data. Registration: PROSPERO (CRD42024628560).
ABSTRACT Introduction Bipolar disorder (BD) is a chronic psychiatric illness characterized by recurrent manic and depressive episodes, affecting 2% of the global population. It is associated with premature mortality, including cardiovascular disease (CVD)‐related mortality. Although clinically important, the absolute burden and incidence of cardiovascular outcomes in BD remain incompletely characterized. This systematic review and meta‐analysis synthesized observational evidence on CVD prevalence and incidence in adults with BD. Methods Following PRISMA guidelines and prospectively registered in PROSPERO (CRD42023484712), we searched PubMed, Web of Science, Embase, Scopus, and PsycInfo, screening 11,909 records. Thirty‐two observational studies in adults with BD were included after Newcastle–Ottawa Scale assessment. Data were extracted on overall CVD, coronary artery disease, cerebrovascular disease, peripheral arterial disease, comorbidities, and psychotropic exposure. Pooled prevalence and incidence rate ratios were calculated using random‐effects models when data were comparable. Results The pooled CVD prevalence in BD was 7.70% (95% CI: 5.07–11.52), with coronary artery disease at 6.89% (95% CI: 4.05–11.47), cerebrovascular disease at 4.45% (95% CI: 2.13–9.05), and peripheral arterial disease at 3.30% (95% CI: 1.66–6.45). However, prevalence estimates showed extreme heterogeneity and should be interpreted as broad indicators of absolute burden rather than precise estimates for a single BD population. In controlled incidence studies, BD was associated with increased CVD incidence (IRR 1.66, 95% CI: 1.32–2.08), with elevated coronary and cerebrovascular estimates. Clinical variable analyses involving medication use, lifestyle factors, and cardiometabolic comorbidities were not feasible because reporting was insufficient and noncomparable. Conclusion Adults with BD show substantial cardiovascular burden and increased incidence. However, extreme heterogeneity, limited incidence data, observational designs, and insufficient moderator reporting limit the precision and generalizability of pooled estimates. These findings support integrated cardiovascular screening in BD populations and future prospective studies. Trail Registration PROSPERO CRD42023484712
Introduction Network meta-analyses suggest dexamphetamines (dAMP) may yield more favourable short-term outcomes than methylphenidate (MPH) in adults with ADHD, yet evidence on long-term comparative persistence remains scarce. This study compared 12-month treatment persistence between MPH and dAMP in a large multicentre cohort and explored associations with ADHD clinical presentations and objectively measured core symptoms.Methods Stimulant persistence was defined by the primary outcome, 'time-to-transition', the interval from initiation to switching stimulant classes, transitioning to non-stimulants or complete discontinuation. Patients were censored at 12 months or at last clinical contact. A multivariable mixed-effects Cox proportional hazard model with a random intercept for clinicians was used to estimate hazard ratios (HR) and assess the relative impact of stimulant class on persistence, including its interactions with DSM-based clinical presentations and objective indices.Results Among 12,995 participants (49% female), 62% initiated dAMP and 38% MPH. Median time-to-transition was 33.1 weeks for dAMP versus 15.0 weeks for MPH. MPH was associated with a 45% increased hazard for non-persistence compared to dAMP (HR = 1.45, 95% CI [1.36-1.55]). Regarding clinical and objective factors, hyperactive/impulsive presentation (HR = 1.14, p = 0.025) and objective impulsivity (HR = 1.05, p = 0.002) were independently associated with non-persistence. A significant interaction was observed between stimulant class and objective hyperactivity (p = 0.003), indicating that dAMP's persistence advantage became more pronounced with increasing motor activity (HR = 1.09). Nevertheless, these associations were secondary to the overarching effect of the stimulant class itself.Conclusion Treatment with dAMP demonstrates significantly superior 12-month persistence compared to MPH in adults with ADHD. While clinical and objective measures of impulsivity and hyperactivity identify patients at higher risk for treatment non-persistence, dAMP's advantage remains consistent across all presentations. These findings suggest that prioritizing dAMP may enhance long-term treatment persistence in adult ADHD clinical practice.
