Abstract Introduction Narcolepsy affects approximately 1 in 2000 people and causes disabling sleepiness. Schizophrenia affects 1 in 133 people and confers significant impairments across domains. Rates of co-occurrence are not exactly known. One cohort study observed 8.1% of persons with narcolepsy (PWN) as having a psychosis comorbidity and a 4-fold greater risk for psychosis in PWN. Some wakefulness promoting medications used in narcolepsy treatment, such as modafinil, methylphenidate and amphetamine, may exacerbate psychosis by increasing dopamine activity. There are case reports of sodium oxybate exacerbating psychosis. We explore a case of a patient with co-morbid narcolepsy and schizophrenia, and discuss the treatment considerations encountered. Report of case(s) A 21-year-old man with was admitted for auditory hallucinations and bizarre behaviour. He put his cell phone in his microwave to prevent his conversations from being overheard. He was diagnosed with schizophrenia. The patient had a polysomnographic confirmed diagnosis of narcolepsy with cataplexy that predated this by 9 years. His methylphenidate extended-release 20mg was discontinued for concerns that it was precipitating psychosis. He was previously intolerant to modafinil (emotional numbing) and Concerta (appetite suppression) as per chart review. Paliperidone was effective for psychosis but worsened sleepiness, which was disabling. A retrial of modafinil worsened auditory hallucinations and delusions of persecution, and discontinued. He was discharged on paliperidone IM with well-controlled psychosis but sleepiness remained. Conclusion As an outpatient, caffeine 100mg up to 4x per day PRN was trialed but insufficient in promoting improvements to wakefulness. A new pitolisant was was successful in treatment without exacerbation of psychosis. Unfortunately, after 8 weeks of treatment, the patient lost access to pitolisant for one month due to insurance coverage issues, during which his irresistible sleepiness and cataplexy returned. The pitolsant was restarted upon insurance approval, and his wakefulness and cataplexy again improved. He remains stable on pitolisant 40mg and paliperidone 75mg IM q4 weekly. He has residual but non-disabling sleepiness. In conclusion, some traditional stimulants may worsen psychosis in PWN. Pitolisant, an inverse H3 agonist, which does not theoretically affect dopamine pathways, may be a suitable treatment for sleepiness and cataplexy in comorbid psychosis. Support (if any)

Introduction Older adults with treatment-resistant depression (TRD) are at significant risk for decreased psychological well-being and overall functional decline. We examined neural correlates of psychological well-being measures in older adults with TRD. Methods We report the results of the secondary baseline analysis of Optimizing Outcomes of Treatment-Resistant Depression in Older Adults- Neurocognitive and Neuroimaging Biomarkers (OPTIMUM-Neuro) study, a pragmatic, randomized, comparative effectiveness trial of augmentation or switch pharmacotherapy strategies for older adults aged > 60 gt; 60 years with TRD. Participants were recruited from five academic medical centers (four in the USA and one in Canada).Participants completed baseline psychological well-being measures and functional and structural magnetic resonance imaging (MRI) scans. Psychological well-being (PWB) was assessed with the use of the National Institutes of Health (NIH) Toolbox Emotion Battery subscales for Positive Affect (PA) and General Life Satisfaction (GLS). Additionally, perceived stress was measured using the Perceived Stress Scale (PSS).General linear models were used to examine associations between psychological well-being measures and brain functional connectivity at baseline, controlling for age, sex and race. Both within-network and between-network connectivity measures were examined. Results Participants (n=219) were an average of 67.6 ± 5.3 years, 72.2% female, and 90.0% White with a baseline MADRS score of 14.9 ± 9.1. We found a significant negative association between higher perceived stress and default mode network (DMN) connectivity (β=-14.2, SE=7.0, p=0.04) and a significant positive association between higher general life satisfaction and DMN connectivity (β=27.1, SE=7.6, p=0.0004), controlling for age, sex, and race.Further, we found significant associations between PSS and DMN-to-visual network connectivity (β=13.2, SE=6.5, p=0.04), DMN-to-salience/ventral attention network connectivity (β=12.3, SE=6.0, p=0.04), and DMN-to-dorsal attention network connectivity (β=13.3, SE=6.7, p=0.05); similarly with NIH Toolbox PWB-GLS, there were significant negative associations with DMN-to-visual network connectivity (β=-17.6, SE=7.5, p=0.02), DMN-to-salience/ventral attention network connectivity (β=-13.9, SE=6.7, p=0.04), and DMN-to-dorsal attention network connectivity (β=-15.6, SE=7.2, p=0.03). Conclusions Our findings suggest that domains of psychological well-being in treatment-resistant late-life depression have distinct neural correlates related to functional connectivity. In this cohort of older adults with TRD, higher life satisfaction was associated with increased functional connectivity of the DMN, a key network of well-being. Consistently, higher perceived stress led to decreased functional connectivity in that same network.In addition, higher perceived stress was associated with increased functional connectivity between the DMN and visual, salience/ventral attention, and dorsal attention networks, whereas higher life satisfaction was associated with reduced connectivity between the DMN and these task-positive networks.Future studies will examine longitudinal changes in the DMN connectivity and other brain structural and functional data in relationship to measures of resilience and wellbeing.

Intravenous (IV) ketamine is an emerging intervention for treatment-resistant depression (TRD), yet the temporal dynamics of response and the optimal number of infusions remain unclear, particularly in real-world clinical populations with psychiatric comorbidities. We conducted a retrospective chart review of 209 adults with TRD treated with IV ketamine at an interventional psychiatry program. Patients received four or six infusions over 2-3 weeks. Depressive and anxiety symptoms were assessed at baseline and before each infusion using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Generalized Anxiety Disorder-7 (GAD-7). One-week and one-month post-treatment assessments were available only for the four-infusion cohort due to procedural changes during early program implementation. Longitudinal symptom change was examined using linear mixed-effects models, and latent symptom-response patterns were identified through group-based trajectory modeling. Treatment response was defined as ≥50% symptom reduction, and remission as MADRS ≤10 or GAD-7 ≤ 4. Significant reductions in MADRS and GAD-7 scores were observed across treatment (p < 0.001). End-of-treatment response and remission rates were numerically higher in the six-infusion group than in the four-infusion group, though these differences were not statistically significant. Four distinct trajectory classes emerged for both depressive and anxiety symptoms, with anxiety improving more slowly and less robustly. Durability comparisons between infusion protocols could not be made because follow-up data were collected only in the four-infusion group; durability after six infusions remains unknown. IV ketamine produced statistically significant but modest symptom improvement, with substantial heterogeneity in treatment trajectories, underscoring the need for individualized, measurement-based care in real-world TRD populations.

Abstract Introduction Adults with treatment-resistant late-life depression (TRLLD) have high rates of sleep problems. However, little is known about the occurrence and change in sleep during pharmacotherapy of TRLLD or how sleep affects treatment response. We investigated the bidirectional relationship between sleep and treatment outcomes in the Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) study, the largest comparative effectiveness trial of pharmacotherapy for TRLLD to date. Methods This analysis examined: (1) occurrence of reduced sleep in 634 participants in the OPTIMUM randomized controlled trial; (2) how their sleep changed during pharmacotherapy; and (3) whether treatment outcomes differed among participants with consistent insufficient sleep [n = 164], worsened sleep [n = 62], or with improved sleep [n = 158]). We used item #4 (scale 0 – 6) from the Montgomery-Asberg Depression Rating Scale (MADRS) to assess insufficient sleep, representing reduced sleep duration or depth compared to usual sleep pattern. Scores >2 indicate a meaningful reduction in duration or sleep depth. Patients who scored >2 on item #4 throughout the trial were classified as having consistent insufficient sleep; patients who reported an increased score (and >2 at trial end) were classified as having worsened sleep; and patients who reported a decreased scores (and ≤2 at trial end) were classified as having improved sleep. Treatment response was defined as a > 50% reduction in the total MADRS score (minus item #4 ) at trial end. Results About half (51%, n= 323) of participants with TRLLD reported reduced or insufficient sleep before treatment. At trial end, consistent insufficient sleep and worsened sleep were each associated with treatment non-response. Improve sleep was not a significant predictor of treatment response, however participants with consistent sufficient sleep or improved sleep were three times more likely to experience treatment response compared to patients with insufficient sleep and worsened sleep. Conclusion Insufficient or reduced sleep are modifiable factors that may improve treatment outcomes in TRLLD. Given that sleep complaints including insomnia are associated with greater risk of depressive relapse and treatment non-response, a tailored treatment plan for those at greatest risk of sleep disturbance with concomitant depression may facilitate better outcomes. Support (if any)

Structured psychiatric interviews improve diagnostic reliability but are resource-intensive to administer. We developed a multi-agent large language model (LLM) framework to support protocolized structured interviewing and module-level psychiatric screening. The system orchestrates four agents, Questioner, Evaluator, Navigator, and Diagnoser, to administer interview modules, interpret free-text responses, enforce bounded clarification loops, identify safety-related red flags and trigger escalation, and apply encoded decision rules to produce screening outcomes. Prior to any model processing, responses undergo automated redaction of personally identifiable and protected health information. We conducted a simulation-based technical evaluation using 1350 interviews across 15 neuropsychiatric screening modules (e.g., anxiety, depression, and bipolar disorders) with systematic variation in symptom direction, disclosure depth, and emotional tone. To test robustness to language variability, we additionally evaluated reconstructed conversation bundles derived from the deidentified MentalChat16K dataset. In the primary evaluation, module-level decisions showed 87.8% concordance with rule-based expected outcomes (95% CI: 85.9–89.6), with sensitivity 88.9% (95% CI: 86.5–91.2) and specificity 86.7% (95% CI: 84.0–89.2) relative to predefined item-level endorsements. Post hoc comparator analyses showed higher F2 for the multi-agent framework (88.5%) than single-pass LLM (49.5%) or deterministic rule-based (61.9%) transcript-scoring baselines. On a 2000-sentence red flag benchmark stratified by explicit/implicit and active/passive ideation, the classifier achieved 93.9% accuracy, 94.2% sensitivity, and 93.6% specificity. In pilot feedback from mental health clinicians, descriptive ratings suggested favorable perceptions of clarity, workflow fit, and perceived safety for clinician-supervised use. These results support proof-of-concept technical feasibility for a protocol-adherent, auditable agentic LLM framework for structured psychiatric screening.

INTRODUCTIONS:Lithium remains the first-line maintenance treatment for bipolar disorder (BD), yet its safety in older-age BD (OABD) is uncertain due to limited large-scale data. OABD patients often experience more severe physical comorbidities compared to younger BD patients, but systematic evidence regarding lithium's association with these conditions is lacking. This study examined the association between lithium use and physical comorbidities across age groups using the international Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) dataset. METHODS:A cross-sectional analysis was conducted using combined Wave 1 and 2 data from GAGE-BD project, encompassing 37 studies from 20 sites worldwide. Participants aged ≥ 18 years with BD were classified according to current lithium use. Physical comorbidities were harmonised into eight organ-system domains. Sociodemographic and clinical variables were compared between individuals receiving lithium treatment and those not prescribed lithium. Generalised linear mixed models adjusted for age, site and lithium × age interaction were applied to evaluate associations with physical comorbidities. RESULTS:Of the 2873 total participants included in the study, 1069 were currently receiving lithium treatment and 1804 were not prescribed lithium. Participants treated with lithium showed a lower overall prevalence of physical comorbidities compared with those not receiving lithium. Regression analyses revealed significant age-by-lithium interactions for cardiovascular (χ2 = 9.27, p = 0.002), respiratory (χ2 = 7.56, p = 0.006), genitourinary (χ2 = 8.66, p = 0.003) and endocrine (χ2 = 16.96, p < 0.001) comorbidities. Model-estimated curve crossings occurred at approximately 43 years (cardiovascular), 32 years (respiratory), 51 years (genitourinary) and 59 years (endocrine), above which predicted prevalence was lower among participants treated with lithium, whereas no differences were observed for gastrointestinal, hepatic, renal or musculoskeletal systems. CONCLUSIONS:Lithium use in OABD was associated with a lower burden of specific physical comorbidities, particularly cardiovascular, respiratory and endocrine conditions. Although prescription bias cannot be excluded, the findings challenge the perception that lithium exacerbates physical health risks in older adults. Instead, they support lithium's continued use-with appropriate monitoring-as a safe and effective treatment option for OABD, and highlight the need for prospective studies to further clarify the relationship between lithium exposure and physical health outcomes.

Bipolar disorder (BD) is associated with substantial disability and caregiver burden. In Pakistan, prevalence is unusually high, and limited mental health services place families at the center of care. Cultural and religious beliefs strongly shape how the illness is recognized, understood and managed. This study explored how individuals living with BD and their caregivers understand and navigate the illness within this context. Semi-structured interviews were conducted with 12 adults diagnosed with BD (type I or II) and 12 caregivers recruited through a national registry. Open-ended questions explored illness understanding, caregiving challenges, cultural influences and preferences for family intervention. Interviews were conducted in Roman Urdu, audio-recorded, transcribed verbatim and analyzed using Braun and Clarke's reflexive thematic analysis. Purposive and snowball sampling ensured diversity in gender, socioeconomic status and residence. Patients described blended biomedical and cultural explanations of BD, symptom-related disruption, treatment barriers, stigma and coping through routines and religious practices. Caregivers reported confusion at illness onset, financial and emotional burden, inconsistent support and the need to navigate biomedical and spiritual care pathways. Both groups emphasized the need for accessible, family-inclusive interventions. The findings support development of culturally tailored, scalable and faith-sensitive family interventions.

The PACt-MD study demonstrated that combined cognitive remediation (CR) and transcranial direct current stimulation (tDCS) slows global cognitive decline in individuals with mild cognitive impairment (MCI) or remitted major depressive disorder (rMDD) over a median follow-up of four years. Prefrontal theta-gamma coupling (TGC), measured via electroencephalography (EEG), is a marker of prefrontal cortical function and may index cognitive compensation, the mechanism thought to underlie CR+tDCS effects. This secondary analysis investigated whether baseline TGC influenced the efficacy of CR+tDCS, hypothesizing that participants with high baseline TGC-indicating better prefrontal function-would benefit more from CR+tDCS than those with low baseline TGC. TGC was assessed during an N-back task at baseline in 260 participants (mean age=71.9, SD = 6.0) and dichotomized by median split into high vs low groups. Cognition was evaluated two months post-baseline and annually up to six years. Baseline TGC significantly moderated the effects of CR+tDCS on global cognition (χ²=12.46, p = 0.006), verbal memory (χ²=16.93, p = 0.0007), and executive function (χ²=18.57, p = 0.0003). In the high-TGC group, global cognition declined more slowly with active CR+tDCS compared to sham. No such difference was observed in the low-TGC group. Lower baseline TGC may reflect reduced capacity for cognitive compensation, limiting CR+tDCS effectiveness in at-risk older adults. Higher TGC may identify those most likely to benefit from this intervention. ClinicalTrials.gov Identifier: NCT02386670.

BackgroundCognitive remediation (CR) combined with transcranial direct current stimulation (tDCS) has been shown to slow cognitive decline in older adults with mild cognitive impairment (MCI) or remitted major depressive disorder (rMDD). Dysregulated angiogenesis is implicated in early neurodegeneration and may influence response to these interventions.ObjectiveTo determine whether baseline plasma angiogenesis markers moderate short-term and long-term cognitive response to CR + tDCS in older adults at risk for dementia.MethodsNineteen angiogenesis-related plasma biomarkers were measured at baseline in participants from the PACt-MD randomized controlled trial. Participants received active or sham CR plus active or sham tDCS for 8 weeks, followed by semi-annual booster sessions and online CR between visits. Cognitive assessments occurred at baseline, 8 weeks, and yearly. Elastic net regression identified relevant markers and baseline variables associated with the 8-week cognitive change. For selected markers, treatment*marker interactions were tested using multivariable linear regression adjusted for relevant demographic, clinical, and genetic covariates. Significant interactions were further examined using likelihood ratio tests in linear mixed-effects models across follow-up.ResultsIn 271 participants, angiopoietin-2, endocan, and VCAM-1 were identified as relevant markers. Out of these three markers, only angiopoietin-2 interacted with treatment (β(SE) = 0.17(0.08), p = 0.04, padj = 0.11, f2 = 0.02), with lower levels associated with greater 8-week cognitive improvement in the active treatment group, controlling for covariates. This moderating effect persisted during follow-up (χ2LRT(3) = 24.9, p < 0.001).ConclusionsLower baseline angiopoietin-2 may identify older adults with MCI or rMDD that are more likely to benefit from CR + tDCS.ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT02386670; NCT02386670.

BackgroundIn 2023/2024, there were 15 psychiatrists/100,000 Canadians with inequitable distribution across Canada and unprecedented demand for mental health and addiction services. Psychiatry human resource planning in Canada has not occurred for more than a decade. The objectives of this study were to understand the current state and future directions related to Psychiatry Human Resources in the Canadian mental health care system.MethodsUsing Delphi methods, we surveyed the 17 chairs of the academic departments of psychiatry in Canada and held focus groups. The Royal College and subspecialty programs were also engaged. Themes were extracted, summarized and refined. The refined themes were distributed via an online survey to all 17 chairs for final review and input, ensuring alignment and consensus across institutions.ResultsCommon themes focused on: the role of psychiatrists working in teams to provide care for complex mental disorders and addictions; need for innovative models of care including use of physician extenders, technology to reach the larger population of patients with mild to moderate disorders, working closely with primary care in collaborative care models. Due to the large proportion of Canadian psychiatrists being 35 years or more in practice (26%) and close to retirement, the chairs supported the need to expand the number of residency positions for psychiatry and continue strong recruitment efforts for international medical graduates. Although the majority of chairs supported shortening the general psychiatry residency program from 5 to 4 years, the Association of Chairs of Psychiatry of Canada (ACPC) could not reach a consensus on this issue. Pan-Canadian licensing for psychiatrists should be considered due to inequitable distribution of psychiatrists in Canada and advances in virtual care post-COVID-19 pandemic.ConclusionsThis study will contribute to the dialogue on psychiatry human resources planning in Canada.

INTRODUCTION:Bipolar disorder (BD) is a chronic mental health condition characterized by extreme mood swings, which significantly affects both the individual and their family system. Given the psychosocial impact of BD on families, family interventions (FI) have emerged as a promising approach to improve treatment outcomes. This review explores the effectiveness of FI in managing BD, focusing on various intervention types, their outcomes, and clinical implications. METHODS:This review followed PRISMA guidelines and registered with PROSPERO (registration number: CRD42023410879). We included studies involving adults diagnosed with BD and their family members, focusing on family-based interventions. Studies were identified through systematic searches in five bibliographic databases and managed using Covidence 2.0. Data extraction and synthesis included primary and secondary outcomes related to clinical, behavioral, and lifestyle measures. Risk of bias was assessed using the Joanna Briggs Institute (JBI) critical appraisal tool for quasi-experimental studies. RESULTS:Family-focused interventions were found to reduce relapse rates, enhance medication adherence, and improve family communication. Psychoeducational interventions also demonstrated a significant reduction in symptom severity and hospitalization rates. However, findings regarding the long-term sustainability of these outcomes were mixed, and some interventions showed limited generalizability across diverse family structures and cultural contexts. CONCLUSION:FIs are critical in treating BD by improving both clinical and relational outcomes. However, the heterogeneity of family structures and cultural factors calls for more tailored approaches to ensure long-term efficacy. Future research should focus on developing culturally sensitive interventions and exploring the mechanisms by which family dynamics influence treatment adherence and recovery in BD.

Abstract Introduction Bipolar affective disorder (BAD) is a mood disorder characterized by episodes of mania. It typically starts in late adolescence and early adulthood. However, 5-10% of bipolar patients will start having symptoms later in their lives. Obstructive sleep apnea (OSA) is characterised by repetitive upper airway collapse during sleep, causing intermittent hypoxia, sleep fragmentation and cardiovascular sequelae. In moderate to severe OSA, CPAP remains the gold standard treatment. In this report, we will present a case of a 43-year-old patient who had his first manic episode after 3 months of starting CPAP for OSA. Report of case(s) Mr. R, a 43-year-old Man, presented to the emergency department with symptoms of euphoria, pressured speech, hyperactivity and grandiosity. He was admitted to the inpatient psychiatry ward and diagnosed with BAD Type 1, most recent episode manic. He has a family history of schizophrenia. Three months prior to admission, he had been diagnosed with sleep apnea. Collateral information indicates that the patient spoke of increased restlessness, “making new epiphanies”, decreased need for sleep, having “superpowers of the mind” and being preoccupied with oxygen in the brain immediately after CPAP initiation and progressed in the weeks leading to admission. Substance use was only notable for 2-3 liquor shots weekly. Conclusion To our knowledge this is the 6th case report regarding CPAP-related mania. While our patient developed mania requiring admission after 3 months of CPAP, the previous cases reflected mania starting as early as 10 days after CPAP initiation. Another case described manic onset after 2 months. Other cases involved almost only men, aged at least 40 years. Patients with untreated bipolar disorder may experience shortened REM latency and prolonged REM sleep. In people with OSA, they may exhibit hypoxemia, and slow wave and REM sleep suppression due to frequent arousals. The potential REM rebound and increased oxygenation post-CPAP initiation is a putative mechanism of precipitating mania. Post-CPAP normalization of serum testosterone has been hypothesized as another cause. This report presents a case of an OSA patient who developed his first manic episode after starting CPAP. Further research is needed to better understand the pathophysiology of any such association. Support (if any)

INTRODUCTION:Non-adherence is a barrier to the effectiveness of physical activity (PA) interventions for major depressive disorder (MDD). This systematic review and meta-analysis identified reported adherence-related outcomes, compared adherence rates of PA and non-PA interventions in MDD, and determined predictors of adherence. METHODS:MEDLINE, APA PsycINFO, CINAHL Plus, and SPORTDiscus were searched until September 5, 2024. Pooled estimated risk differences (RDs) and 95% confidence intervals (CIs) were calculated using fixed-effects or random-effects models. Meta-regression explored predictors of adherence. RESULTS:Ninety-seven studies were included in this review, and 91 studies in the meta-analysis. Adherence-related outcomes for analyses included rates of intervention receipt, retention, protocol adherence, and session attendance. Retention was the most commonly reported outcome, with no significant difference between PA and non-PA interventions. Similarly, there were no significant differences in intervention receipt and session attendance. However, PA interventions had significantly lower protocol adherence than non-PA interventions (RD = -0.15; 95% CI: -0.23, -0.08). Severe baseline depressive symptoms, longer intervention durations, and in-person delivery predicted retention rates. Longer PA sessions predicted intervention receipt and supervision of activities predicted attendance rates. CONCLUSION:Participants with MDD demonstrate lower protocol adherence to PA interventions than to interventions without a PA component. This result was based on a paucity of studies. Rates of intervention receipt, retention, and attendance were comparable in PA and non-PA interventions. Studies could benefit from including individuals with greater depressive symptom severity and supervised activity. With replication, findings could improve the design of, and increase adherence to, PA interventions in MDD.

OBJECTIVE:The Anticholinergic Drug Scale (ADS) is a commonly used measure of anticholinergic exposure. This study describes an expanded and revised version of the ADS (rADS) and its relationship with cultured cell-based serum anticholinergic activity (cSAA) and cognitive measures. STUDY PARTICIPANTS:Adults aged 60 years and older with mild cognitive impairment (MCI), remitted major depressive disorder (rMDD), or both, participate in the Prevention of Alzheimer's Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation (PACt-MD) study. STUDY DESIGN:Cross-sectional investigation of data from the PACt-MD study. MEASURES:The rADS includes ratings for 1047 distinct products, about twice as many as the originally published scale; previously published ratings were revised for 40 drugs. Total rADS scores were calculated as sums of ratings of all drugs taken by participants; cSAA was measured in the participants' sera; cognitive performance included measures of executive function, language, processing speed, verbal memory, visuospatial memory, working memory, and an overall composite score. STATISTICAL ANALYSIS:The relationship between rADS total scores and cSAA was examined using a Spearman rank correlation coefficient. Relationships between rADS total scores and cognitive performance measures were explored in multivariable linear regression models. RESULTS:The sample included 310 participants (mean [standard deviation] age: 72 (6) years; 61.6% were women, and 81.6% had MCI [with or without rMDD]). Total rADS scores were positively correlated with cSAA (Spearman's correlation coefficient: 0.178, p = 0.0016). Total rADS scores were not significantly associated with cognitive performance. CONCLUSIONS:The revised scale is recommended as a replacement for the original ADS since it includes ratings for more drugs and was significantly, albeit weakly, associated with cSAA, similar to previous findings using the original ADS.

Background Difficult-to-treat depression (DTD) in older adults is associated with high rates of disability, hospitalization, and mortality. As the effectiveness of once daily theta burst stimulation (TBS) has been demonstrated in older adults, we aimed to explore the feasibility and clinical effects of an accelerated bilateral TBS protocol. Methods This single arm, open-label trial enrolled outpatients aged 60 years and over with a current major depressive episode and nonresponse to at least one antidepressant. Participants received continuous TBS (600 pulses) to the right dorsolateral prefrontal cortex (DLFPC) followed by intermittent TBS (600 pulses) to the left DLPFC, 8 times daily for 5 consecutive days. The primary outcome measures were proportion of participants retained in the study and change in Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcomes included rates of remission defined by MADRS ≤ 10, changes in measures of anxiety and suicidality, and measures of tolerability including number of serious adverse events. Results 79 participants enrolled in the study over a period of 2.5 years, 78 (67.7 ± 5.9 yrs, 75.6 % female) of whom received majority of TBS sessions. MADRS scores decreased a mean ( ± SD) 8.5 ± 6.7 points following treatment completion (F(2,154) = 61.6, p < 0.0001) and this improvement persisted 4 weeks later (p < 0.0001). The remission rate was 18% at treatment end and increased to 24 % 4 weeks later. Symptoms of anxiety (p < 0.01) and suicidal ideation (p = 0.03) also improved at treatment end. Treatment was well-tolerated and no serious adverse events were reported. Conclusions Accelerated TBS is feasible in older patients with DTD; its efficacy is comparable to once daily TBS; and it is well-tolerated. If these results are confirmed in a larger randomized trial, accelerated TBS may become a preferred treatment option for older depressed patients. Clinicaltrials.gov Identifier NCT05119699