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.

We report a case of a 62-year-old woman presenting with a 6-year history of purpuric patches and macules on the lower extremities, initially misdiagnosed as allergic purpura and treated with prednisone. Skin biopsy revealed dilated dermal vessels with perivascular collagen deposition, positive for collagen IV and diastase-periodic acid-Schiff (D-PAS) staining, consistent with cutaneous collagenous vasculopathy (CCV). Treatment included hydroxychloroquine, vitamin C, doxepin, and topical mucopolysaccharide polysulfate cream. Prednisone was tapered by one tablet every 3 days. After 4 weeks, the rash improved significantly with no new lesions. We would like to present a case of CCV.

Objective: To establish a rapid method for the determination of doxepin and its metabolite nordoxepin residues in plasma samples by PRiME mixed cation-exchange solid-phase extraction coupled with ultra-performance liquid chromatography-high resolution mass spectrometry (PRiME MCX-UPLC-HRMS) . Methods: Plasma samples were extracted with 2% (V/V) aqueous phosphoric acid and purified by a PRiME MCX SPE cartridge. The target compounds were separated on an aurorasil MMP-G column (100 mm×2.1 mm, 3 μm) and gradient elution was performed with the mobile phases 5.0 mmol/L ammonium formate -0.1% (V/V) aqueous formic acid and methanol, and were determined in electrospray positive ionization mode (ESI(+)) and full mass scan-data dependent ms(2) scan (Full mass-ddMS(2)) mode, and the internal standard method was used for quantification. The limits of detection (LODs) and limits of quantification (LOQs) were calculated at signal-to-noise ratios of 3 and 10, respectively. Results: The linear ranges of doxepin and its metabolite nordoxepin were 1.0-100.0 ng/ml with correlation coefficients of 0.9988-0.9999. The LODs and LOQs for doxepin and its metabolite nordoxepin were determined to be 0.18-0.22 ng/ml and 0.54-0.66 ng/ml, respectively. The spiked recoveries of doxepin and its metabolite nordoxepin in plasma at the four concentration levels of 1.0 ng/ml, 10.0 ng/ml, 50.0 ng/ml and 80 ng/ml ranged from 90.8% to 105%, with relative standard deviations (RSDs) of 1.31%-4.59%. Conclusion: The method was rapid, sensitive and accurate and was suitable for the monitoring and analysis of doxepin and its metabolite nordoxepin in plasma samples from clinical patients.

Candida species are associated with invasive infections characterized by causing high rates of mortality and morbidity, particularly when linked to biofilm formation. The present study investigated the in vitro antifungal activity of doxepin (DOX) against fluconazole-resistant strains of Candida spp., including 10 clinical isolates, 2 ATCC strains and 1 CDC strain. Antifungal susceptibility assays were performed on planktonic cells and biofilms, followed by cytometric analyses, including reactive oxygen species (ROS) production, mitochondrial depolarization, phosphatidylserine externalization, and cell viability. Molecular analyses involved docking and gene expression by qRT-PCR. DOX exhibited fungicidal activity against all strains, with MIC50 values ranging from 64 to 256 μg/mL, as well as significant reduction of biofilm formation. In combination with amphotericin B, a predominantly synergistic effect was observed, with increased efficacy at lower concentrations. Mechanistically, DOX induced oxidative stress, mitochondrial dysfunction, and apoptosis, reducing fungal viability. The in silico ADME profile showed high gastrointestinal absorption, indicating potential for oral bioavailability, compatible with systemic use. Furthermore, it established stable interactions with the Als3 and Sap5 proteins, also promoting changes in the expression of virulence-related genes, such as als3, sap5, ece1, and hwp1. These findings indicate that DOX exhibits promising antifungal activity for the treatment of Candida infections, particularly highlighting its potential against biofilms.

Insomnia is a common reason for patients to seek medical care. A careful history should be obtained to identify predisposing, precipitating, and perpetuating factors contributing to sleep disturbance. Cognitive behavioral therapy for insomnia is the first-line treatment for chronic insomnia, offering effectiveness with minimal risk, though access may be limited by availability. Pharmacologic therapy should ideally be reserved for short-term use and initiated only after setting clear expectations and considering potential risks. Evidence-based medication options include low-dose doxepin, melatonin receptor agonists, dual orexin receptor antagonists, and nonbenzodiazepine benzodiazepine receptor agonists. Ongoing follow-up is essential to monitor treatment response.

The goal of the current study is to formulate a Doxepin hydrochloride ion triggered trans-nasal gel. The developed formulations were evaluated for gel strength, gelation time, viscosity, mucoadhesion strength, ex-vivo drug permeability drug content, and stability. According to the findings, mucoadhesive strength and viscosity increased as pectin and hydroxypropyl methylcellulose (HPMC) K4M concentrations increased, whereas gelation time and the percentage of drug recovery decreased. With 3.5% pectin and 1.5% HPMC, the improved formulation C2F2 demonstrated the greatest drug release of 97.96% via sheep nasal mucosa. The stability study over a period of three months showed no change in viscosity, pH and drug content. The discovered ion-triggered intra nasal formulations shows enhanced locomotor activity and mobility in mice, when used to treat depression.

The increasing use of antidepressant combinations necessitates a deeper understanding of drug-drug interactions. This study investigated serum concentration-dependent CYP2D6 inhibition by bupropion (via hydroxybupropion) and doxepin at antidepressant doses, using venlafaxine and risperidone as victim drugs.Therapeutic drug monitoring data from inpatients at the University Hospital of Würzburg (2018-2023) were retrospectively analyzed across four interaction groups (hydroxybupropion-venlafaxine, doxepin-venlafaxine, doxepin-risperidone, and hydroxybupropion-risperidone) with controls lacking CYP2D6 inhibitors. Associations between inhibitor concentrations and victim drug levels were assessed linearly. Nonlinear regression (four-parameter logistic model) was applied to relate inhibitor concentrations to metabolite-to-parent ratios; when the model fit was adequate, the half-maximal inhibitory concentration/90% inhibitory concentration values were estimated. Receiver operating characteristic analysis identified inhibitor concentration thresholds for phenoconversion to poor metabolizer status.Hydroxybupropion and doxepin concentrations were positively associated with venlafaxine, risperidone, and venlafaxine active moiety levels (p ≤ 0.02). Adequate sigmoidal curve fitting demonstrated a concentration-dependent inverse association between inhibitor levels and metabolite-to-parent ratios for venlafaxine with hydroxybupropion and doxepin, and risperidone with hydroxybupropion, but not risperidone with doxepin. The half-maximal inhibitory concentration values were 120.4 ng/mL and 28.16 ng/mL for hydroxybupropion (venlafaxine and risperidone, respectively) and 24.4 ng/mL for doxepin (venlafaxine). Phenoconversion thresholds were identified for hydroxybupropion (venlafaxine: 328.5 ng/mL and risperidone: 110.5 ng/mL) and doxepin (venlafaxine: 35 ng/mL and risperidone: 70.5 ng/mL).Hydroxybupropion and doxepin exert serum concentration-dependent inhibition of CYP2D6 activity, significantly affecting the metabolism of venlafaxine and risperidone. These effects and a phenoconversion into poor metabolizer status were detectable at subtherapeutic hydroxybupropion and therapeutic antidepressant doxepin levels. Monitoring inhibitor and victim-drug concentrations may aid in managing clinically relevant CYP2D6-mediated interactions.

Doxepin, a tricyclic antidepressant, exhibits substantial interindividual variability in pharmacokinetics, mainly attributable to genetic polymorphisms of cytochrome P450 (CYP) enzymes, particularly CYP2D6. Such variability may lead to clinically relevant differences in drug exposure, therapeutic response, and adverse effects when doxepin is used for antidepressant therapy. The present study aimed to develop and validate physiologically based pharmacokinetic (PBPK) models of doxepin and its active metabolite, N-desmethyldoxepin, incorporating CYP2D6 genetic polymorphisms to support precision pharmacotherapy. PBPK models were constructed using PK-Sim® (version 12.0) based on published clinical pharmacokinetic and pharmacogenomic data obtained after oral administration of doxepin. Model development was performed in a non-genotyped population. Subsequently, it extended to CYP2D6 ultra-rapid (UM), normal (NM), intermediate (IM), and poor metabolizer (PM) phenotypes by integrating genotype-specific metabolic activity. Model performance was evaluated by comparing predicted plasma concentration-time profiles, area under the concentration-time curve (AUC), and maximum plasma concentration (Cmax) with observed clinical data. The model's predictive capability was further assessed using goodness-of-fit analysis, visual predictive checks, and geometric mean fold error (GMFE). The PBPK models adequately reproduced the observed pharmacokinetics of doxepin and N-desmethyldoxepin, with most predicted AUC and Cmax values falling within a twofold error range across both non-genotyped and CYP2D6-genotyped populations. Simulations demonstrated an apparent genotype-dependent increase in doxepin exposure as CYP2D6 metabolic capacity decreased, consistent with clinical observations. Similarly, N-desmethyldoxepin exposure showed an inverse relationship with CYP2D6 activity, reflecting differences in metabolite formation and elimination. Despite the limited availability of genotype-specific concentration-time data for the metabolite, the model captured observed exposure trends, supporting its mechanistic plausibility. In conclusion, a PBPK framework integrating CYP2D6 genetic polymorphisms was successfully developed for doxepin and its active metabolite. The model reliably predicts genotype-dependent pharmacokinetic variability and provides a mechanistic basis for individualized dose optimization. This PBPK approach may serve as a valuable tool to support precision pharmacotherapy for doxepin, particularly in the context of antidepressant treatment.