Intravenous ketamine is a rapid-acting intervention for treatment-resistant depression (TRD) in adults with major depressive disorder and bipolar disorder (BD). While efficacy is established, a comprehensive integration of clinical, neurophysiological, biomarker, metabolic, and cognitive predictors remains lacking, limiting precision CNS-targeted therapy. To synthesize recent evidence on multimodal predictors of intravenous ketamine response in TRD and propose a preliminary clinical framework to guide personalized treatment. Following PRISMA guidelines, Scopus, PubMed, EMBASE, and MEDLINE were searched for English-language, peer-reviewed studies published within the last 5 years. Eligible studies included adults receiving intravenous ketamine for depressive disorders. Data were descriptively synthesized to identify consistent predictors, evidence clusters, and research gaps. The review included 150 studies. Key predictors of ketamine response included baseline depressive severity, comorbid anxiety, atypical depression and sleep phenotypes, inflammatory and neuroplastic biomarkers (eg, monocyte count, BDNF), metabolic factors (BMI, vitamin B12), genetic/epigenetic variants, neurophysiological signatures (EEG, TMS, fMRI connectivity), cognitive performance, and early symptomatic improvement. Integrative analysis suggests that glutamatergic, circadian, and inflammatory mechanisms interact to shape interindividual variability. Limitations include methodological heterogeneity and scarce long-term outcome data. Intravenous ketamine response in TRD is multifactorial, reflecting clinical phenotype, CNS biomarkers, neurophysiology, metabolism, and genetics. This review proposes a preliminary research framework and pilot clinical questionnaire intended to facilitate future investigation of individualized treatment approaches. However, most proposed predictors remain exploratory and require prospective validation before clinical implementation.

Dextromethorphan/bupropion (DXM/BUP) is the first orally administered antidepressant combining dextromethorphan, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist, and bupropion, a CYP2D6 inhibitor and antidepressant. DXM/BUP was approved by the United States Food and Drug Administration for Major Depressive Disorder (MDD) in adults in August 2022. Given that select psychotropic agents prescribed for MDD may alter glucose and insulin homeostasis, we investigated whether DXM/BUP was associated with disproportionate reporting of diabetes mellitus or hyperglycemia. Disproportionality analyses were conducted using reporting odds ratios (RORs), with DXM/BUP and comparator agents evaluated relative to a reference agent (acetaminophen). Data were obtained from the Food and Drug Administration Adverse Event Reporting System (FAERS) from the year of approval to April 26, 2026. A sensitivity analysis was performed on a restricted dataset from January 1, 2022, to April 30, 2026. Statistical significance was defined as a 95% confidence interval (CI) excluding 1.0. DXM/BUP was not associated with disproportionate reporting of diabetes mellitus (ROR = 0.33, 95% CI [0.07, 1.65], p = 0.18) or hyperglycemia (ROR = 0.10, 95% CI [0.01, 1.67], p = 0.11) relative to acetaminophen. Findings from the restricted 2022-2026 analysis were directionally consistent with the primary analysis. Given the sparse number of reports and wide CIs, these findings should be interpreted as preliminary and underpowered, rather than evidence of metabolic neutrality. Continued pharmacovigilance and prospective investigation are needed to further characterize the metabolic profile of DXM/BUP.

Dementia prevention increasingly targets modifiable midlife risk states contributing to neurodegenerative vulnerability. While vascular and metabolic factors are established, a substantial proportion of risk remains unexplained. Central sensitization syndromes (CSS)-chronic conditions characterized by neural amplification-are highly prevalent, co-occur with depression and sleep disturbance, and involve neuroimmune and network-level mechanisms implicated in early Alzheimer's disease. To synthesize epidemiologic evidence linking CSS with incident dementia and evaluate competing causal explanations, including shared vulnerability, reverse causation, and medication-related confounding. A structured narrative review was conducted of longitudinal cohort and meta-analytic studies assessing incident dementia across CSS-related conditions. Multiple CSS-including migraine, fibromyalgia, irritable bowel syndrome, restless legs syndrome, and PTSD disorder-are associated with modest-to-moderate increases in dementia risk. Multisite chronic pain demonstrates dose-response relationships with hippocampal atrophy and incident dementia. However, many conditions lack dedicated longitudinal studies. Interpretation is limited by residual confounding, reverse causation, healthcare utilization bias, and medication effects. CSS are associated with increased dementia risk but causality remains unproven. Central sensitization may represent a clinically identifiable vulnerability state integrating pain, affective burden, and sleep disruption. This highlights a potentially high-risk population that may not be fully captured by traditional dementia risk models. Biomarker-integrated longitudinal studies and advanced causal modeling are needed to clarify mechanisms.

In addition to their canonical role in sleep-wake regulation, endogenous orexin signaling is implicated in the homeostatic control of reward and motivation, stress and arousal, and glucose-insulin metabolism. Recent research has focused on the development of orexin antagonists, notably seltorexant, as adjunctive treatments in adults with major depressive disorder (MDD). Converging evidence implicates insulin resistance in MDD pathophysiology, highlighting the need to integrate preclinical, pharmacologic, and translational evidence examining the effects of orexin signaling on glucose-insulin homeostasis. A literature review was conducted using PubMed from database inception to June 2025 to identify preclinical and clinical studies examining the metabolic effects of orexin modulation. The search string included the terms related to: orexin, glucose, metabolism, and depression. Results were synthesized qualitatively across experimental models and clinical populations. Evidence indicates that orexin signaling affects multiple aspects of metabolic homeostasis. For example, orexins affect appetitive/consummatory behavior, exert incretin-like effects on insulin release and glucagon suppression, and increase energy expenditure via morphologically transitioning white-to-brown adipose tissue. These effects are mediated through both direct (eg, inhibition of gluconeogenic enzyme expression) and indirect pathways (eg, alterations in sleep architecture and attenuation of sympathoadrenal overactivity). Orexin antagonism, therefore, exerts multi-faceted physiological effects beyond sleep regulation. The antidepressant efficacy of seltorexant in MDD is greater in persons with moderate-to-severe insomnia, while remaining clinically meaningful in persons with less severe insomnia, implicating multiple mechanisms. Modulation of glucose-insulin homeostasis represents a putative, non-mutually exclusive mechanism through which orexin antagonism may contribute to antidepressant effects.

Anxiety disorders are often associated with impairments in memory, attention, decision-making, and psychomotor function, leading to a reduced quality of life (QoL). Alprazolam, commonly prescribed for acute anxiety disorders, has generated interest regarding its potential impact on anxiety-associated cognitive and psychomotor impairment, especially since effects of short-term use have not been well studied. This review summarizes clinical evidence on the short-term (up to 8 weeks) effects of alprazolam on cognitive performance, psychomotor function, and QoL outcomes in individuals with anxiety disorders. A comprehensive search guided by the participants, intervention, comparisons, and outcomes (PICO) framework identified relevant studies in humans that compared alprazolam with placebo or active comparators. From 1210 articles screened, 10 studies met the inclusion criteria and assessed the short-term impact of alprazolam use on cognition (4), psychomotor function (3), and/or QoL (5). Three of the four studies evaluating cognitive function showed that alprazolam use in adults with panic disorder did not result in any major cognitive impairment. Two of the three studies assessing psychomotor performance demonstrated that short-term alprazolam use either improved or preserved performance. One study recommended gradual upward dose titration to minimize potential negative effects. All five studies found alprazolam enhanced patients' QoL. In conclusion, short-term alprazolam use in anxiety disorders appears to conserve cognitive function and psychomotor performance, with a positive impact on QoL. Elucidating alprazolam's effects on cognitive and psychomotor symptoms, beyond its established anxiolytic action, could support more precise identification of patient groups most likely to derive therapeutic benefit.

With the improving survival rates of malignant tumors, the focus of attention in cancer research is shifting toward a better understanding of long-term treatment-related adverse effects that impact quality of life, with particular focus on cancer-related cognitive impairment. This phenomenon, commonly referred to as "chemobrain" in the literature, manifests as deficits in attention, memory, processing speed, and executive functions. Although the frequency of objectively measured cognitive deficits detected through neuropsychological assessments are moderate, subjective complaints often result in significant deterioration of quality of life. The present review aims to provide a multidisciplinary overview of chemobrain, emphasizing its epidemiological characteristics, neurobiological and psychosocial factors, and options for evidence-based psychological interventions. Alongside neurotoxic, inflammatory, hormonal, and neuroendocrine mechanisms associated with chemotherapy, the review highlights distress, cognitive compensation, and discrepancies between subjective complaints and objectively measurable cognitive deficits. Diagnostic challenges and evidence-based psychotherapeutic approaches-especially cognitive behavioral therapy (CBT), mindfulness-based interventions, and rehabilitation-are also discussed. This analysis highlights the complex nature of chemobrain and the need for further research to develop targeted, individualized therapeutic protocols.