Insomnia symptoms in major depressive disorder (MDD) are clinically heterogeneous, ranging from presleep rumination and prolonged sleep latency to repeated nocturnal awakenings and early-morning awakening. Their clinical significance and treatment implications may also differ between active MDD and residual insomnia symptoms during partial remission. This narrative review examines how these presentations may inform the use of sedating antidepressants and dual orexin receptor antagonists (DORAs). Sedating antidepressants, including mirtazapine, trazodone, doxepin, and other tricyclic antidepressants, differ in dose-dependent antidepressant activity, receptor profile, and adverse-effect burden. DORAs directly target orexin-mediated wake drive and have the strongest evidence for insomnia disorder, particularly sleep-maintenance outcomes, although evidence in active MDD remains limited. Because clinical presentations neither establish an underlying mechanism nor reliably predict treatment response, the proposed framework should be used as a hypothesis-generating aid rather than a validated treatment algorithm. Pharmacological selection should also consider suicide risk, substance-use history, comorbid sleep disorders, concomitant central nervous system depressants, and next-day functioning.

Sleep disturbance is a common feature of depressive disorders and may be influenced by antidepressant-associated alterations in sleep architecture. Mirtazapine is a noradrenergic and specific serotonergic antidepressant with a distinctive pharmacologic profile involving histamine H1 receptor antagonism, alpha-2 adrenergic antagonism, and serotonergic receptor modulation, which may contribute to its effects on sleep regulation. This focused narrative review examines the neurobiological mechanisms through which mirtazapine may influence sleep architecture and summarizes available human polysomnographic (PSG) evidence, with particular emphasis on N3 sleep and slow-wave sleep-related measures. Current evidence suggests that mirtazapine can produce measurable changes in objective sleep architecture; however, findings specifically regarding N3 sleep and slow-wave sleep remain preliminary and mixed. Available studies are limited by small sample sizes, heterogeneous populations, variable treatment durations, differences in comparator conditions, and methodological variability. Although selected studies have reported increases in slow-wave sleep measures or N3 sleep, available evidence does not establish a consistent dose-response relationship or demonstrate that sedative effects directly translate into enhancement of slow-wave sleep. Mechanistic evidence supports several biologically plausible pathways through which mirtazapine may influence sleep regulation, including histaminergic, adrenergic, and serotonergic effects; however, human PSG studies evaluate the integrated effects of the complete medication and cannot establish receptor-specific mechanisms responsible for observed sleep changes. Future studies using standardized PSG protocols, quantitative electroencephalography (EEG) analysis, larger samples, longer treatment durations, and direct dose comparisons are needed to clarify whether mirtazapine-associated alterations in sleep architecture contribute meaningfully to clinical outcomes.

Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD). Consequently, potentially inappropriate medication (PIM) use is particularly common among older adults with AD. Psychotropic polypharmacy may increase the risk of various adverse outcomes beyond cognitive decline. Although geriatric prescribing criteria and dementia-care guidelines offer important safety recommendations, a clinically integrated framework for potentially inappropriate psychotropic medication use in older adults with AD remains insufficiently developed. This article is a narrative review rather than a systematic review or meta-analysis. The authors searched the literature in PubMed, Embase, and the Cochrane Library, focusing on studies, guidelines, consensus statements, regulatory safety warnings, and medication-safety criteria published between January 2015 and June 2026. This review specifically examines anticholinergic drugs, antipsychotics, benzodiazepines and Z-drugs, tricyclic antidepressants, and select newer antidepressants-including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), mirtazapine, trazodone, and paroxetine-guided by the 2023 American Geriatrics Society (AGS) Beers Criteria®. Current evidence indicates that these medications may contribute to cognitive decline through anticholinergic burden, sedation, and pharmacodynamic interactions with cholinesterase inhibitors, such as donepezil and memantine. However, the strength of evidence varies considerably across drug classes and study designs, ranging from randomized controlled trials to observational studies and expert consensus. This study also summarizes current nonpharmacological strategies and proposes a structured clinical medication review framework. Overall, this review highlights the importance of minimizing inappropriate psychotropic use in AD, prioritizing non-pharmacological interventions, and conducting individualized risk-benefit assessments in clinical practice.

The One Health philosophy highlights the need to sustainably balance and optimise the health of humans, animals, and ecosystems. Pharmaceuticals are essential for human health, but their usage poses downstream risks to aquatic life. Thus, pharmaceuticals need to be environmentally friendlier whilst delivering the same intended health outcomes. Chiral switch, whereby racemic formulations are replaced with enantiopure versions, is proposed to reduce the environmental burden of pharmaceuticals under the One Health philosophy. This research aimed to develop enantioselective methodologies applicable to complex environmental matrices to inform the chiral switch of commonly prescribed pharmaceuticals. This was achieved using cation exchange solid-phase extraction (SPE) and two separate chiral-high performance liquid chromatography (HPLC) methods for selective detection and quantification of 16 pharmaceuticals (anti-depressants, beta-blockers, calcium-channel blocker, central nervous system stimulant, skeletal muscle relaxant) and primary metabolites in wastewaters. An InfinityLab Poroshell 120 Chiral-V was used to separate cationic enantiomers and CHIRALPAK® ZWIX(+) for zwitterions with enantioresolutions ranging from 0.6 to 4.2. Quantitation limits and trueness values of the SPE-chiral HPLC methods ranged from 6.5 × 10[-2] ng L[-1] to 42 ng L[-1] and from 60% to 119%, respectively. Application of the methodology to wastewater samples revealed several analytes were in non-racemic composition including citalopram, fluoxetine, mirtazapine, desmethylmirtazapine, and ritalinic acid. Greatest enantiomer enrichment was observed for desmethylmirtazapine with a maximum enantiomeric fraction of 0.80. Furthermore, to the best of our knowledge this is the first study to report the enantiomeric composition of baclofen, amlodipine, hydroxyatenolol and ritalinic acid in wastewater. Further application of these newly developed methods can help develop more accurate environmental risk assessments of pharmaceutical enantiomers to inform the proposed chiral switch decision making process in healthcare.

Sick sinus syndrome (SSS) presents significant challenges in psychiatric medication management because of the potential for worsening cardiac conduction and interactions with antiarrhythmic therapy. A 35-year-old woman with generalized anxiety disorder (GAD) and insomnia was treated with bupropion, hydroxyzine, melatonin, and intermittent quetiapine, alongside comorbid SSS and supraventricular tachycardia managed post-ablation with metoprolol. A review of her regimen identified several cardiac safety concerns: quetiapine's potential interference with flecainide, hydroxyzine-associated QT prolongation, and bupropion's CYP2D6 inhibition that could increase flecainide levels. Management prioritized minimizing arrhythmogenic risk by discontinuing quetiapine, restricting hydroxyzine to low doses, and continuing melatonin, supplemented by stress testing and reassessment of psychotropic options. This case highlights the importance of careful psychotropic selection in patients with SSS, favoring lower-risk agents, such as mirtazapine, which is one of the safest among several possible alternatives, while maintaining close ECG monitoring and coordinated cardiology and psychiatry collaboration to reduce drug-drug interactions and optimize safety.

The WikiGuidelines organization seeks to improve the process of guideline writing. WikiGuideline consensus statements use a dichotomized approach to recommendations, such that recommendations are made only when sufficient randomized controlled data are available. In the absence of such data, a clinical review is provided. After applying this approach to the care of patients who inject drugs (PWID), this consensus statement recommends that patients with opioid use disorder (OUD) be offered treatment in the form of opioid agonist therapies. Patients with stimulant use disorder, specifically amphetamine use disorder, should be offered mirtazapine. Patients with stimulant use disorder, regardless of drug of choice, do best when offered behavioral therapies, such as contingency management. For hospitalized patients admitted with complications of substance use, the addition of substance use care teams has demonstrated improved outcomes. Further, patients with hepatitis C who inject drugs should be offered treatment, which can be completed in a variety of low-barrier settings. Several other questions did not meet the threshold for clear recommendations; and therefore, clinical reviews are offered instead.

Progressive multifocal leukoencephalopathy (PML) is a rare and life-threatening demyelinating disease of the central nervous system that occurs almost exclusively in the setting of impaired cell-mediated immunity. An 86-year-old woman with a history of PR3-ANCA-associated vasculitis treated with rituximab presented to the emergency department with progressive left-sided weakness and gait instability. Brain MRI demonstrated an enlarging white matter lesion without contrast enhancement or mass effect. JC virus was detected in the cerebrospinal fluid, thereby confirming the diagnosis of PML. Rituximab therapy was discontinued and mirtazapine initiated. Other treatment options were not considered feasible in this case. The patient deteriorated rapidly and died within three months from initial presentation at the emergency department. PML occurring in association with rituximab therapy is exceedingly rare. The potential for disease attenuation with new immunomodulating therapies underscores the importance of considering PML in immunosuppressed patients presenting with rapidly progressive central nervous system deficits.

Depression is a common comorbidity in patients with chronic liver disease (CLD) and is associated with poorer clinical outcomes. Due to concerns about hepatic metabolism and limited tolerability, the use of traditional antidepressants is often restricted. Mirtazapine is a noradrenergic and specific serotonergic antidepressant. Driven by its unique rigid tetracyclic scaffold and enantiomeric properties, Mirtazapine exhibits multi-target binding that may affect multiple shared pathways in CLD and depression. Preclinical studies have shown that in models of metabolic Dysfunction-Associated Steatotic Liver Disease, cirrhosis, and hepatocellular carcinoma, Mirtazapine can attenuate liver tissue injury, suppress hepatic stellate cell activation, and modulate inflammatory responses and oxidative stress levels. Additionally, the drug may provide indirect clinical benefits by alleviating patients' depressive symptoms, improving sleep quality, and promoting appetite recovery. However, mirtazapine is consistently associated with a range of metabolic adverse effects, including weight gain, insulin resistance, and hepatic steatosis. These effects may exacerbate the metabolic burden in patients with CLD, thereby limiting its clinical utility. Therefore, when prescribing this agent to patients with comorbid depression, clinicians must carefully balance its anti-inflammatory and anti-fibrotic benefits against metabolic risks to achieve rational individualized medication.