Barry Karlsson

Background: Dementia is more prevalent in individuals with intellectual disability (ID) than in the general population. Identifying signs of dementia is important to access relevant evaluations, treatment and care. The role of mobility in identifying dementia in ID is not well understood. The aims of the study were to describe mobility‐related problems in a cohort of adults with ID and to investigate if these problems could be associated with dementia. Methods: Mobility‐related items were selected from clinical carer‐rated instruments and participants' dementia statuses were based on assessments at two points in time. Fisher's exact test was used for comparisons between groups with and without suspected dementia. Logistic regression, adjusted for age and level of ID, was used to investigate associations between mobility and subsequent dementia. Results: At baseline ( N = 85), the median age was 58 years, 39% were female, and 37% had Trisomy 21. Pain and low physical endurance were present in more than 50% of the participants. Low physical endurance was more prevalent among participants with suspected dementia than in those without suspected dementia ( p = 0.016). Low physical endurance, adjusted for age and level of ID, was associated with dementia after 6 years (OR 9.349, p = 0.019). Conclusions: Low physical endurance, when combined with other observations, could help carers identify individuals with ID who should be referred for a dementia assessment. However, the results need to be confirmed in larger samples.

Background: Treatment-resistant depression (TRD) is an operational category based on inadequate outcome after adequate antidepressant treatment. The same label may encompass insufficient treatment exposure, an incorrect primary diagnosis, clinically important comorbidity, or depressive illnesses with different maintaining mechanisms. This heterogeneity limits the clinical meaning of treatment history alone and complicates individualized care. Objective: To integrate evidence on diagnostic reassessment, suicide risk, neurobiology, psychological and functional factors, and treatment, and to define a clinically testable personalized medicine framework for TRD. Methods: Targeted PubMed/MEDLINE searches were conducted from database inception through 31 July 2026 and supplemented by reference-list searching. Two authors independently assessed publications for relevance, and disagreements were resolved by discussion and consensus. Ninety-six sources were included and synthesized narratively. Results: Inadequate exposure or adherence can produce pseudo-resistance, whereas bipolar spectrum illness, neurodevelopmental or trauma-related conditions, personality pathology, sleep or substance-related disorders, and medical disease may represent alternative diagnoses, comorbidities, or modifiers of treatment course. Glutamatergic signaling, impaired plasticity, stress-system dysregulation, inflammation, circadian disturbance, metabolism, and neural circuitry contribute to heterogeneity at the group level but do not define validated individual subtypes. Established pharmacological, psychological, and neuromodulatory interventions should be selected according to diagnosis, severity, urgency, previous response, comorbidity, functional impairment, safety, feasibility, and patient preference. Conclusions: TRD is an operational treatment-history category, not a unitary disease. A personalized medicine approach begins with confirmation of major depressive disorder, adequate treatment exposure and adherence, followed by parallel treatment of depression and clinically relevant comorbidity. Biomarkers should guide allocation only when they provide prospectively validated predictive value beyond high-quality clinical and functional assessment.

Background: Attention-deficit/hyperactivity disorder (ADHD) has traditionally been understood through executive and frontostriatal models, but increasing evidence suggests that metabolic, inflammatory, circadian, and neuroendocrine mechanisms may also contribute to clinical heterogeneity. The hypothalamus is a central regulatory hub for appetite, sleep–wake organization, stress responsivity, autonomic function, and endocrine signalling. Objective: This review evaluated evidence linking ADHD with hypothalamic inflammation and related metabolic, inflammatory, circadian, and neuroendocrine dysregulation, with particular emphasis on appetite regulation, sleep and circadian function, stress reactivity, and pharmacological treatment response and tolerability. Methods: A systematic literature search was conducted in PubMed/MEDLINE, Embase, PsycINFO, Scopus, and Web of Science Core Collection from database inception to 31 May 2026. Human observational and intervention studies formed the primary evidence base. Evidence was synthesized narratively. Where available, quantitative findings from previously published meta-analyses were summarized to provide an overview of the strength and consistency of the evidence. Results: The reviewed evidence indicates that ADHD is associated with increased obesity risk, altered appetite-related hormones, immune-inflammatory changes, delayed circadian timing, atypical cortisol responsivity, and treatment-related effects on appetite, sleep, cardiovascular physiology, and tolerability. The strongest quantitative evidence concerned obesity, inflammatory markers, appetite hormones, and type 2 diabetes risk. Direct evidence for hypothalamic inflammation in ADHD remains limited, but converging indirect findings support hypothalamic and neuroendocrine mechanisms as biologically plausible contributors in a subgroup of individuals with ADHD. Conclusions: ADHD appears to be associated with broader metabolic, inflammatory, circadian, and neuroendocrine vulnerabilities beyond its core attentional and behavioural symptoms. Hypothalamic pathways should be interpreted as a mechanistic hypothesis rather than an established causal mechanism. Future longitudinal and multimodal studies are needed to clarify causality and identify biologically defined ADHD subgroups.

Background: Central stimulants improve core ADHD symptoms, yet day-to-day benefit and tolerability vary under sustained psychosocial or financial stress. We reviewed clinical outcomes relevant to stress-linked vulnerability and integrated mechanistic evidence on stress-sensitive prefrontal–nucleus accumbens dopamine–glutamate pathways. Methods: Narrative evidence synthesis with systematic searches of MEDLINE/PubMed, Embase and PsycINFO (2010–March 2025). Dual screening and data extraction; risk of bias (RoB 2/ROBINS-I) and GRADE certainty by outcome domain. Meta-analysis was prespecified but not executed because no domain met pooling criteria; findings are presented narratively by outcome domain and stress context. Results: Fifteen primary studies met inclusion (8 RCTs; 7 cohorts). Stimulants consistently improved inattention/working memory and daytime task efficiency. Evidence for emotion- and stress-linked outcomes (emotion dysregulation, irritability, sleep disturbance/fatigue, anxiety/depression, real-world functioning) was mixed and context-dependent. In samples exposed to higher psychosocial stress or financial strain, functional benefits appeared attenuated and irritability, sleep disturbance and fatigue relatively more frequent. Signals suggested moderation by drug class, dose and timing (notably late-day “booster” dosing), but direct comparative evidence was limited. Overall certainty was moderate for core symptoms and low-to-moderate for stress-linked outcomes. Conclusion: Stimulants remain effective for core ADHD symptoms, but sustained stress may narrow the therapeutic window. Clinical safeguards include dose timing (avoid routine evening/booster dosing), sleep protection, load management, and proactive treatment of comorbidity. Stress-stratified trials with standardised outcomes are needed. Registration: Not preregistered; protocol prespecified.