August 2026

Importance: Postural orthostatic tachycardia syndrome (POTS) is a chronic autonomic disorder characterized by excessive orthostatic tachycardia and multisystem symptoms that affects an estimated 0.1% to 1% of the US population. POTS can substantially impair daily functioning and quality of life. Observations: Common symptoms include lightheadedness, palpitations, fatigue, cognitive dysfunction ("brain fog"), exercise intolerance, nausea, bloating, constipation, diarrhea, and sleep disturbance. However, the true prevalence remains uncertain partly due to underrecognition and lack of a specific diagnostic code for POTS until 2022. In a survey of 4835 patients, approximately 70% reported substantial functional impairment and loss of school or work participation, and median diagnostic delay was 24 months. In 30% to 40% of cases, symptoms began within 3 months after infections, such as SARS-CoV-2, Epstein-Barr virus, and influenza. Initial evaluation should exclude other conditions that cause sinus tachycardia, including thyroid disease, adrenal insufficiency, pheochromocytoma, cardiomyopathy, valvular heart disease, congenital heart disease, chronic lung disease, medications, and anemia. This review summarizes current evidence on pathophysiology, diagnosis, and management of POTS. Conclusions: and Relevance: POTS is a chronic autonomic disorder associated with functional impairment and reduced quality of life that is diagnosed based on characteristic orthostatic symptoms in the absence of orthostatic hypotension after excluding alternative causes of sinus tachycardia. Treatment involves nonpharmacological measures (such as increased fluid and sodium intake), lower-body compression garments, structured exercise training, and individualized pharmacological therapy.

Importance: Dopaminergic dysregulation has been considered the final common pathway for pathophysiology of schizophrenia and related disorders (SRD). However, this model does not adequately explain treatment resistance, cognitive impairment, negative symptoms, and marked biological heterogeneity across patients. Objective: To examine whether SRD are best conceptualized as resulting from a final common dopaminergic pathway or from several partially independent neurochemical mechanisms and to evaluate the implications of these models for treatment development. Evidence Review: Neuroimaging, postmortem and genetic investigations, pharmacologic challenge paradigms, clinical trials, and animal models published between 1980 and 2025 were synthesized. Studies were identified through expert knowledge and targeted searches of PubMed and related databases. Systematic reviews, meta-analyses, and multimodal convergent findings were emphasized. Findings: Positive psychotic symptoms are strongly linked to increased presynaptic dopaminergic activity in the associative striatum, which predicts response to dopamine D2 receptor antagonists. However, approximately one-third of patients exhibit treatment resistance and show no increase in striatal dopamine synthesis capacity. Increasing evidence implicates glutamatergic, gamma-aminobutyric acid (GABA)ergic, serotonergic, cholinergic, endocannabinoid, and opioidergic systems, as well as nonneurotransmitter processes including oxidative stress, mitochondrial dysfunction, and neuroinflammation. The efficacy of the muscarinic M1/M4-preferring agonist xanomeline-trospium, which lacks direct D2 receptor antagonism, suggests that nondopaminergic mechanisms can reduce psychotic symptoms. Neurochemically distinct subgroups within SRD may cut across overlapping clinical phenotypes. Conclusions: and Relevance: Dopaminergic hyperactivity may be a key mechanism for core psychotic symptoms in many patients, but it is unlikely that dopamine dysregulation is a universal final common pathway across symptom domains. A pluralistic model—recognizing multiple interacting neurochemical and cellular processes—may better account for heterogeneity and translational failures. Future development of novel treatments may depend on biomarker-informed stratification, mechanism-based clinical trials, and integration of molecular, circuit-level, and clinical phenotypes.

Importance: Revealing neurobiological markers of antipsychotic nonresponse in psychosis may aid outcome prediction and inform novel treatment targets. Objective: To examine differences in neurometabolites in antipsychotic nonresponsive compared to antipsychotic-responsive psychosis using individual participant data and meta-analysis. Data Sources: Web of Science was searched for studies published between January 1, 1980, and November 1, 2025. Study Selection: Authors of 21 eligible studies identified before August 2024 were invited to contribute individual participant data. Eighteen studies examining neurometabolites by treatment response in psychosis contributed individual participant data for the mega-analysis. These studies plus a further 5 studies were included in the meta-analyses of standardized mean differences and variability. Data Extraction and Synthesis: Individual participant data were analyzed using linear mixed models with study as a random effect. Results: The mega-analysis revealed that antipsychotic nonresponse is associated with elevated levels of glutamate, Glx (the sum of glutamate and glutamine), choline, and myo-inositol in the medial frontal cortex compared to individuals who showed a good antipsychotic response and healthy controls (N = 1,189 from 18 datasets). Elevated medial frontal glutamate plus glutamine in antipsychotic nonresponders compared with responders was also observed prospectively in first-episode psychosis (Glass Δ = 0.41; P = .002), whereas myo-inositol elevations were greatest in individuals meeting criteria for treatment-resistance (Glass Δ = 0.64; P = .001). The meta-analysis of 23 studies (1844 participants) also showed elevated medial frontal choline and myo-inositol in antipsychotic nonresponse compared with response. Conclusions: and Relevance: These findings provide evidence of an association between antipsychotic nonresponse in psychosis with elevations in medial frontal glutamate, choline, and myo-inositol. The presence of elevations in these markers supports the continued investigation of glutamate-acting and inflammatory pathway–associated interventions for psychosis and schizophrenia.

Objective: Preventing recurrence is essential for improving the clinical course of major depressive disorder (MDD) and bipolar disorder (BD). The authors developed the Circadian Rhythm for Mood (CRM) smartphone app, which provides individualized 3-day circadian rhythm stability forecasts and personalized feedback on light exposure targets, daily instability, and mood tracking, using passive wearable data (step count, heart rate, ambient light, sleep timing) via a Fitbit device. Methods: This multicenter, double-blind, sham-controlled randomized clinical trial enrolled 93 adults aged 19–70 with MDD or bipolar I or II disorder across five hospitals in South Korea. All participants were clinically stable for at least two months but had experienced a mood episode within the previous two years. Participants were randomly assigned to receive either the active CRM app or a sham app (identical in appearance but providing only generic, non-circadian-related feedback), both added to treatment as usual, for 12 months. The modified intent-to-treat analysis included 80 participants. Results: The CRM group experienced significantly fewer mood episode recurrences over the 12-month follow-up compared with the sham group (incidence rate ratio [IRR] = 3.39; 95% CI 1.19–6.40; p = 0.018). The effect was most pronounced for depressive episodes (48 of 68 total recurrent episodes; IRR = 2.85; q = 0.009). A large apparent effect was observed for hypomanic episodes (IRR = 15.32; q = 0.017), though this was based on only 16 episodes with a wide confidence interval. Manic episodes were too infrequent (n = 4) to draw firm conclusions (IRR = 3.28; q = 0.514). Conclusions: The CRM smartphone app, paired with a wrist-worn wearable activity tracker, significantly reduced mood episode recurrence in patients with MDD and bipolar disorder compared with a sham intervention. These findings support the CRM app as an innovative, scalable digital chronotherapeutic adjunct to standard care for mood disorders.

Background: Mental health problems in adolescents are increasing. Universal school-based interventions may play an important preventative role. Aims: The aim of the Approaches for Well-being and Mental Health Literacy: Research in Education (AWARE) trial was to evaluate two universal, school-based interventions that previously yielded evidence of impact in other countries: Youth Aware of Mental Health (YAM) and The Mental Health and High School Curriculum Guide (The Guide). Method: AWARE was a multi-school, parallel group, cluster randomised controlled trial in English secondary schools. Schools were allocated on a 1:1:1 ratio to one of two interventions or a usual practice control group, balanced on current levels of mental health provision within schools, school location, deprivation and urbanicity. Eligible participants were pupils in schools across England in Year 9 (aged 13–14 years) at baseline. The statistician, quantitative data analyst and economist were masked. Primary outcomes were depressive symptoms measured with the Short Mood and Feelings Questionnaire for YAM and intended help-seeking, measured with the General Help Seeking Questionnaire for The Guide (both at 3–6 months). Results: 153 schools were randomised, including 12 166 pupils (NYAM = 4028 pupils, Nguide = 3997 pupils, Ncontrol = 4141 pupils). We found that for YAM vs control (N = 5516) there was no improvement in depressive symptoms (s.m.d. = 0.02; 95% CI –0.05 to 0.10), and for The Guide vs control (N = 5409) we found increased intended help-seeking compared with the control group (s.m.d. = 0.10; 95% CI 0.02 to 0.19). A notable minority of schools were unable to deliver YAM because of challenges in implementing it. Increased depressive symptoms scores were observed in both intervention conditions, compared with control at the longer-term follow-up. Conclusions: The findings indicate that participating in The Guide is effective at improving intended help-seeking. However, due to the increases in depressive symptoms associated with each intervention at the long-term follow-up, further consideration is needed before widespread implementation of these interventions in England.

Importance: The incidences of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) have increased markedly over recent decades, raising concerns about the emergence of new risk factors. Current literature typically attributes increased rates to changes in diagnostic practice, stigmatization, and awareness, but critically few studies have explored changes in underlying risk factors. Objective: To assess changes in the genetic risk profile of individuals diagnosed with ASD or ADHD by year of incident diagnosis and explore results in comparison with those expected under simulated scenarios. Design, Setting, and Participants: This cohort study used data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH2015) study, a population-based case-cohort in Denmark among individuals with incident diagnoses for ASD and ADHD made from 1994 to 2016. Data were analyzed from January 2024 until September 2025. Exposure: Year of incident diagnosis. Regression models tested changes in the mean genetic risk profile of individuals diagnosed in each consecutive year (1994-2016), adjusting for age, sex, and ancestry. Main Outcomes and Measures: Polygenic scores for psychiatric (ADHD, ASD, depression, bipolar, and schizophrenia) and cognitive-behavioral (addiction, educational attainment, IQ, neuroticism, and risk-taking) outcomes were used to capture genetic risk profiles of diagnosed individuals. Empirical trends were compared with those expected under different simulated drivers of increasing rates. Results: A more recent ADHD diagnosis was associated with decreased genetic risk for ADHD as shown by difference in mean polygenic score (β estimate per 10-year increase, −0.06 SDs; 95% CI, −0.09 to −0.03 SDs; P = .001) and other disorders, including ASD, bipolar, and schizophrenia (eg, ASD: β per 10-year increase, −0.07 SDs; 95% CI, −0.10 to −0.03 SDs; P < .001). Similarly, a more recent ASD diagnosis was associated with decreased genetic risk for ASD (β per 10-year increase, −0.07 SDs; 95% CI, −0.10 to −0.04 SDs; P < .001) and other disorders and traits, including bipolar disorder, schizophrenia, and educational attainment (eg, bipolar disorder: β per 10-year increase, −0.05 SDs; 95% CI, −0.08 to −0.02 SDs; P = .001). Conclusions: and Relevance: By analyzing multiple polygenic scores together with simulated expectations, this study could disambiguate among competing hypotheses about scenarios that may be associated with increased rates of ADHD and ASD diagnoses. Findings support broadening diagnostic criteria as an explanation for increasing rates, with implications for understanding changes in risk factors and clinical practice.

Background: Premenstrual dysphoric disorder (PMDD) is a condition linked to the menstrual cycle and characterised by cyclic emotional distress, irritability and anger, which can disrupt social functioning. Intermittent selective serotonin reuptake inhibitor treatment is effective in alleviating symptoms, yet the neural underpinnings of its efficacy in PMDD remain unknown. Aims: This randomised, placebo-controlled trial aimed to evaluate the impact of intermittent escitalopram treatment on PMDD symptoms and aggressiveness, and on neural responses to social provocation. Method: Women with PMDD were randomised to receive either intermittent escitalopram (20 mg/day) or placebo during the luteal phase. Outcomes of interest were changes in mood (assessed by the Daily Record of Severity of Problems), self-rated state aggression (measured by the Aggression Questionnaire), and brain reactivity to aggressive stimuli assessed via functional magnetic resonance imaging (fMRI) in combination with the Point Subtraction Aggression Paradigm (PSAP). Results: Intermittent escitalopram treatment significantly reduced PMDD symptoms compared with placebo, in particular irritability or anger (Cohen's d = -0.93, 95% CI [-1.48, -0.38]). Aggressiveness, which was positively associated with these symptoms (Pearson's r = 0.33, 95% CI [0.06, 0.55]), diminished following treatment (Cohen's d = -0.42, 95% CI [1.4 × 10-4, 0.84]), with the reduction in irritability or anger partly mediating this association (standardised indirect effect -0.32, 95% CI [-0.77, -0.03]). Escitalopram treatment was nominally associated with lower reactivity to provocation in the anterior insula, and anterior insula reactivity positively related to irritability or anger at follow-up. Conclusions: This randomised controlled trial confirms escitalopram as an effective treatment for PMDD and points to a potential neural mechanism—modulation of anterior insula reactivity to social provocation—underlying the therapeutic effects of SSRIs on irritability and aggressiveness in PMDD.

Background: Reliable diagnosis is a cornerstone of medical practice, yet concerns about diagnostic reliability have long haunted psychiatry. In the 1970s, the US–UK Diagnostic Project revealed striking international discrepancies in diagnostic practice. Although operationalized diagnostic criteria were introduced to improve reliability, contemporary evidence indicates that substantial problems persist. To investigate this, we conducted a large-scale international study of diagnostic reliability among medical doctors using standardized clinical case vignettes. Material and methods: In this cross-sectional study, medical doctors working in adult psychiatry across 19 countries from two continents assigned ICD-10 diagnoses to written cases. Each doctor was randomly assigned two of nine available cases. Inter-rater reliability among medical doctors was assessed using Krippendorff's α. Diagnostic variability at case-level was quantified using Shannon entropy. We also calculated diagnostic accuracy as concordance with predefined best-estimate reference diagnoses. Results: A total of 1,038 medical doctors provided 1,902 diagnostic assessments across nine cases. Inter-rater reliability among medical doctors was modest (Krippendorff's α = 0.48, CI: 0.46–0.51). Stratifying by doctor type, Krippendorff's α was 0.50 (CI 0.47–0.53) for psychiatrists and 0.45 for psychiatric residents. Overall diagnostic accuracy was 66%, with the lowest accuracy observed for cases depicting schizophrenia spectrum disorders. Diagnostic disagreements followed systematic patterns, with schizophrenia cases frequently misclassified as OCD, personality disorder, or other diagnoses. Conclusions: Diagnostic inter-rater reliability among medical doctors remains limited, even under standardized conditions. The observed patterns of misclassification suggest that the variability in diagnostic assessments reflects systematic differences in clinical conceptualization rather than random error. Our conclusion echoes that of Spitzer and Fleiss, who stated that the reliability of psychiatric diagnosis "is not good." Despite the introduction of operational diagnostic criteria and rule-based classification, the overall reliability of psychiatric diagnosis assessed on written clinical cases remains poor.

The United Kingdom (UK) Government's recent 10 Year Health Plan for England aims to fix a "broken" and increasingly unaffordable health system through a shift from sickness to prevention, hospital to community, and analogue to digital, with a focus on mental as well as physical health. However, the 171-page strategy for a healthy nation does not contain a single reference to nature or biodiversity. We review the significant benefits of nature and biodiversity to health and outline how these benefits can and should be incorporated into the 10 Year Health Plan. We provide examples of effective approaches and techniques, describe challenges to implementation, and propose potential solutions. We focus on mental health, although many benefits will also apply to physical health. Harnessing nature and biodiversity could play a substantial role in supporting the UK's revised goals, particularly preventing illness and enhancing treatment at the community level.

People who use cannabis commonly report stress-relieving effects, yet no studies have simultaneously assessed the acute effects of cannabis on multiple stress systems under placebo-controlled conditions. We conducted a randomized, double-blind, placebo-controlled trial in which 120 people (56 men, 52 women, 12 non-binary/transgender) who regularly use cannabis were assigned to vape placebo, a moderate dose (20 mg Δ9-tetrahydrocannabinol [THC]), or a high dose (40 mg THC) of cannabis. Stress ratings and salivary cortisol samples were obtained before (T0), 5 minutes (T1), and 60 minutes (T2) after vaping. Participants wore an Embrace wristband continuously measuring electrodermal activity (EDA), heart rate (HR), and heart rate variability (HRV). These findings indicate that cannabis intoxication divergently modulates stress physiology, attenuating neuroendocrine and electrodermal responses while elevating cardiovascular arousal and producing subjective stress reductions comparable to placebo. Thus, common perceptions of stress relief do not reflect uniform suppression of stress-related outcomes. This has important implications for the widespread use of cannabis as a coping strategy.

Background: Over the past decades, evidence supporting the antidepressant efficacy of the dopamine agonist pramipexole as an augmentation strategy in mood disorders has accumulated. While dopaminergic treatments have been associated with behavioural adverse effects, the relationship between pramipexole treatment and incident substance use disorder in psychiatric populations remains poorly understood. Substance use disorder has not emerged as a reported adverse outcome in published studies of pramipexole in psychiatric populations. However, existing studies have primarily focused on antidepressant efficacy, short-term safety, and behavioural adverse effects during relatively brief periods of follow-up. Nationwide healthcare registers offer a complementary pharmacoepidemiological approach by enabling the study of uncommon or delayed outcomes in large populations treated under real-world conditions and over extended follow-up periods. Objective: To examine the association between cumulative pramipexole exposure and incident substance use disorder among individuals with unipolar depression or bipolar disorder. We further examined whether this association differed between unipolar depression and bipolar disorder and whether the findings indicated an exposure–response pattern. Methods: We utilised data from Swedish national registries to conduct a nationwide cohort study including individuals with unipolar depression or bipolar disorder treated in specialised mental health care (n = 3105) who were prescribed pramipexole. Cumulative pramipexole exposure was modelled longitudinally and analysed as a time-varying variable. The primary outcome was incident substance use disorder identified in specialised healthcare registers. Associations were examined using Cox proportional hazards models, with analyses separated by diagnostic subgroup. Results: High cumulative exposure to pramipexole was associated with an increased risk of incident substance use disorder in the overall cohort (aHR 1.51, 95% CI 1.02–2.23), whereas intermediate exposure was not associated with elevated risk. In stratified analyses, the association was particularly pronounced among individuals with bipolar disorder, where high cumulative exposure was associated with more than a twofold increased risk (aHR 2.54, 95% CI 1.25–5.16). No significant association was observed among individuals with unipolar depression. Conclusions: High cumulative exposure to pramipexole was associated with increased risk of incident substance use disorder in individuals with mood disorders, with the strongest associations observed in bipolar disorder. Cumulative exposure to pramipexole was associated with an increased risk of incident substance use disorder in this nationwide cohort of individuals with mood disorders, with the strongest associations observed among patients with bipolar disorder and evidence of a dose-response pattern primarily at higher exposure levels. Although these findings require confirmation in further studies, they underscore the need to consider behavioural and addictive risks when prescribing dopaminergic agents in psychiatric populations and support enhanced monitoring strategies in clinically vulnerable groups.

Importance: Few data inform implementation of emerging state-regulated psilocybin programs. Objective: The Open Psychedelic Evaluation Nexus (OPEN) aims to assess the safety and participant outcomes of Oregon's regulated psilocybin services. Design, Setting, and Participants: This cohort study included psilocybin clients enrolled between November 2024 and March 2026, with follow-up through June 2026, at 24 of 26 Oregon psilocybin service centers with active licenses. Eligible participants were consenting Oregon psilocybin services clients supervised by 83 licensed psilocybin facilitators. OPEN's client-facing platform collects confidential data at baseline and at 1 week, 1 month, and 3 months after psilocybin sessions supported by licensed facilitators. Exposure: State-regulated psilocybin services administered by licensed facilitators at Oregon service centers. Main Outcomes and Measures: Mental health outcomes included symptoms of depression (measured by the Patient Health Questionnaire-9 [PHQ-9]), anxiety (measured by the Hospital Anxiety and Depression Scale [HADS]), and posttraumatic stress disorder (PTSD; measured by the 6-item PTSD Checklist [PCL-6]), reported as continuous scores and dichotomized as moderate-to-severe symptoms (PHQ-9, 10 or higher; HADS, 11 or higher; PCL-6, 14 or higher) vs less than moderate symptoms; life satisfaction dichotomized as survey answers of "agree" or "strongly agree" vs less than "agree"; mental well-being; quality of life; overall perceived benefit; and adverse reactions. Results: A total of 346 participants (mean age, 49.5 years; 52.5% women; 86.7% White) were enrolled. At baseline, participants reported interests including self-improvement (68.5%), managing mental health symptoms (64.5%), navigating trauma (51.4%), and seeking greater connection with people, Earth, or nature (45.1%); 44.2% had not previously used psychedelics. Mean (SD) PHQ-9 depression scores declined from 9.3 (6.3) at baseline to 4.2 (4.4) at 1 month and 5.2 (4.9) at 3-month follow-up. Mean HADS anxiety scores decreased from 10.1 (4.3) at baseline to 5.6 (4.0) at 1 month and 6.0 (4.1) at 3 months. Mean (SD) PTSD symptom score (PCL-6) declined from 14.1 (4.9) at baseline to 10.7 (3.8) at 1 month and 10.4 (3.7) at 3 months. Moderate-to-severe mental health symptoms decreased for depression from baseline (42.2%) to 1 month (10.6%) (relative risk [RR], 0.26; 95% CI, 0.20-0.34). At 1 month, 91.5% of participants felt they had benefited from the experience and 64.9% ranked it among the 10 most meaningful experiences of their lives. Retention through 3 months was 90%. Serious adverse reactions were uncommon; only 7 participants reported the experience as harmful at 3 months. Conclusions: and Relevance: In this multisite cohort of participants receiving state-regulated psilocybin services in Oregon, serious adverse reactions were uncommon. Most participants reported improvements in mental health, wellness, and life satisfaction. Longitudinal findings support safety and potential benefits that can inform clinicians, policymakers, and the public as other state-regulated psychedelic services emerge.

Background: Treatment guidelines for borderline personality disorder (BPD) recommend assessment, diagnosis, and psychoeducation. We report on the feasibility and safety of a randomized controlled trial protocol of online psychoeducation, assessment, and personalized feedback as an immediate first step of care for BPD. Methods: Newly diagnosed participants were randomized to receive 10 videos about BPD or general mental health for two weeks. Half the participants receiving BPD videos were randomized to receive personalized feedback on changes in symptom ratings and cognitive performance. Ecological momentary assessment (EMA) evaluated interpersonal interactions, emotions, and behaviors for 30 days. BPD symptoms, depression, and personality functioning were assessed at baseline, after videos, after feedback, and one month later. Results: Eighty-two participants were randomized into three conditions that did not differ significantly in terms of demographics or baseline variables. Dropout occurred for 32.9% of the sample. No differences in rate of emergency room visits, hospitalizations, or other escalations in level of care were reported among groups. Satisfaction was higher for those receiving psychoeducational videos about BPD. Improvement in BPD knowledge in the psychoeducation conditions was significantly greater than the control condition. No statistically significant differences were found regarding reduction of BPD symptoms. The psychoeducation with feedback arm showed significantly greater improvements in self-impairment compared to controls with medium effect size at the final timepoint. Modeling of the relationship between time spent alone and BPD symptoms showed a positive correlation in the control condition, but in the group receiving both psychoeducation about BPD and feedback, this relationship was negative. Conclusion: Online psychoeducational videos and assessment were safe, feasible, and acceptable to participants with newly diagnosed BPD. Psychoeducation with personalized feedback appears to be more effective than either BPD or general psychoeducation alone in improving deficits in self-functioning, which may relate to an increased capacity to be alone with fewer symptoms.

BACKGROUND: The temporal course of antipsychotic drug action in schizophrenia remains poorly understood. We aimed to explore how different symptom domains of schizophrenia improve over time. Such knowledge has important implications for treatment decisions and for understanding the mechanisms of action of antipsychotic drugs. METHODS: We analysed individual patient data from an existing repository comprising six antipsychotic drug trials of 6-12 months' duration in patients with acute schizophrenia (n=2079; 1328 [64%] men, 751 [36%] women; 1577 [76%] White, 502 [24%] non-White; mean age 34·72 years [range 16-73]). We used descriptive statistics to examine improvement trajectories across five PANSS symptom domains according to an established five-factor model (positive symptoms, negative symptoms, hostility and excitement, anxiety and depression, and cognitive and disorganisation). FINDINGS: In all domains initial improvements were seen in the first 5 weeks. However, time-to-response analysis revealed that 50% improvement of the hostility and excitement domain occurred first, followed by positive symptoms and anxiety and depression. INTERPRETATION: Clinicians should be aware of earlier attainment of substantial response of hostility and excitement, then positive symptoms, before substantial reductions in other domains. Treatment changes should not be made prematurely when negative and cognitive and disorganisation symptoms persist, as improvement in these domains lags behind. Researchers should consider these temporal patterns when investigating the mechanisms of action of antipsychotic drugs. FUNDING: None. Clinical Reviews & Meta-Analyses

Importance: Lithium, a long-established cornerstone therapy for bipolar disorder, is a biologically plausible disease-modifying agent for neurodegenerative disorders, including mild cognitive impairment (MCI) and Alzheimer disease (AD). Observations: Rather than targeting a single pathology like amyloid or tau, lithium acts across multiple cellular resilience pathways. Chronic lithium exposure induces the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2), enhances brain-derived neurotrophic factor (BDNF) signaling, inhibits glycogen synthase kinase-3β (GSK-3β), stabilizes mitochondrial function, and reduces oxidative stress. These convergent mechanisms promote neuronal survival and synaptic integrity. In humans, proton magnetic resonance spectroscopy studies found that lithium increased N-acetylaspartate levels, consistent with improved neuronal viability, and structural magnetic resonance imaging (MRI) studies found that lithium preserved gray matter and/or reversed its loss. The recent repletion hypothesis suggests that lithium may also function as a physiological trace element, but these findings await independent replication. Conclusions: and Relevance: These convergent data support a prospective clinical trial of low-dose lithium orotate to slow disease progression in MCI.