Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder.

The neuropathology of Parkinson's disease is characterized by α-synuclein (α-syn) aggregation and dopaminergic (DAergic) neurodegeneration. While neuronal loss in C. elegans α-syn-induced neurodegeneration models is temporally age-dependent, prior research indicates it is uncoupled from the organismal aging process. Here we examined transgenic C. elegans expressing human A53T α-syn in DAergic neurons to determine the impact of localized DA metabolism on both neurodegeneration and organismal lifespan. Increasing endogenous DA levels through overexpression of tyrosine hydroxylase (CAT-2) exacerbated A53T-induced DAergic degeneration, whereas DA depletion via Δcat-2 mutation rescued neuronal survival. By mutating a DA-interaction motif within α-syn, neurodegeneration was rendered insensitive to DA manipulation, thus confirming a structural basis for in vivo toxicity. We identified a DA-α-syn interaction that acts as a common upstream bridge whereby localized stress induces physiological responses in C. elegans. Genetically, this biochemical interaction acts as a pleiotropic trigger driving two compartmentalized responses: localized DAergic neurodegeneration via oxidative stress, and organism-wide, TFEB/hlh-30-dependent proteostatic remodeling that extends lifespan. Modulating autophagy, without exacerbating DA-mediated oxidative stress, represents a promising strategy to preserve adaptive systemic remodeling while limiting targeted neuronal damage.

Depression is a common psychiatric disorder during pregnancy and the postnatal period. Consequently, antidepressant treatment is primordial for the safety of the mother and the neonate. Clomipramine (CMI) is a tricyclic antidepressant that has been prescribed even when the evidence suggests potential adverse effects on the neurodevelopment of the offspring, considering that antidepressant drugs can be transferred through breast milk. Nevertheless, in some cases, when the benefits outweigh the risks, it is used to treat severe depression in pregnant women. In rodents, postnatal administration of CMI causes persistent behavioral and neurophysiological alterations in adulthood. By contrast, a rewarding experience, such as mating, improves motivational and copulatory behavior in rodents through neuroplasticity in brain structures involved in reproduction. In a previous work, we reported that postnatal exposure to CMI disrupts the motivational and copulatory components of female sexual behavior during a single copulatory test. Therefore, the purpose of this study was to examine the effects of postnatal CMI treatment on female sexual behavior and reproductive tissues, and to determine whether sexual experience serves as a modulatory factor that ameliorates its potential impact on sexual performance. Female pups were divided in two groups, CMI group (30 mg/Kg) and the control group (NaCl 0.9%). Each group received a daily subcutaneous injection with CMI or saline solution from the 8th to 21st postnatal days. Behavioral test and histological analysis were performed at 3 months of age. The results indicated that postnatal CMI administration disrupts receptive but not proceptive behaviors. Repeated sexual encounters with males partially reversed the receptivity impairment in CMI-treated females, as it occurs in control rats. Histological data showed that CMI reduces the population of primordial and primary follicles; however, no morphological modifications were detected in the uterine layers. In conclusion, the data show that even when sexual experience partially improved copulatory behavior in female rats exposed to CMI during the postnatal period, ovarian development was affected, which could compromise fertility.

A proportion of patients with obsessive-compulsive disorder (OCD) continue to experience disabling symptoms despite standard serotonergic treatment, antipsychotic augmentation, and psychological input. Contamination-focused OCD can be especially persistent when rituals are embedded in the home environment and reinforced by family patterns. Recent work has drawn attention to glutamatergic dysfunction, NMDA-AMPA signaling, and synaptic plasticity as possible treatment targets in refractory OCD. The Cheung glutamatergic regimen has been proposed as an oral, low-cost, ketamine-informed glutamatergic strategy using dextromethorphan, CYP2D6 inhibition, piracetam, and L-glutamine to modulate glutamatergic plasticity. The supporting evidence for this proposed regimen remains preliminary, largely case-based, and not independently replicated. A 26-year-old woman presented with several years of contamination fears, repetitive handwashing, prolonged bathing lasting up to 1.5 hours, home-dominant cleaning concerns, anxiety, depressive symptoms, fatigue, somatic complaints, nightmares, and motivational impairment. Baseline screening showed a Patient Health Questionnaire-9 (PHQ-9) of 18 and a Generalized Anxiety Disorder-7 (GAD-7) of 14, with passive suicidal ideation endorsed on one item. Over approximately nine months, treatment was adjusted in routine outpatient care. A glutamatergic-oriented augmentation strategy was used as part of a complex, evolving regimen built around dextromethorphan, piracetam, and later L-glutamine, with pharmacokinetic potentiation via CYP2D6-inhibiting antidepressants, including fluoxetine, bupropion, and later low-dose paroxetine. Low-dose risperidone, clomipramine, pregabalin, propranolol, cyproheptadine, and other symptom-focused adjuncts were used and adjusted according to response and tolerability. Mood, energy, somatic chest discomfort, motivation, and resilience improved. Bathing time decreased from approximately 1.5 hours to about 30 minutes, and ritual preoccupation was at one point described as 20-30% reduced. The PHQ-9 self-harm item changed from "several days" at the first standardized assessment to "not at all" at Day 41, although passive ideation was again endorsed for several days during later stress. She resumed job-seeking, attended interviews, exercised, learned new skills, and coped better than expected with the illness and death of a long-term pet. Residual contamination and cleaning symptoms remained most prominent at home. No Yale-Brown Obsessive Compulsive Scale, formal ritual count, or structured home-versus-outside severity scale was recorded. This case is best read as a hypothesis-generating clinical observation rather than evidence of regimen-specific efficacy. The response was incomplete but clinically meaningful, especially in affective, somatic, motivational, and functional domains. Larger controlled studies are needed, and home-targeted exposure-based work remains essential.

Background: Treatment-resistant obsessive-compulsive disorder (TR-OCD) remains a major therapeutic challenge. Although current guidelines recommend optimized serotonin reuptake inhibitor (SRI) therapy, clomipramine switching, exposure and response prevention, and antipsychotic augmentation, a substantial proportion of patients continue to experience severe and disabling symptoms. In such cases, clinicians may consider pharmacological intensification strategies beyond guideline-endorsed algorithms. Methods: This study combines a structured narrative synthesis of pharmacological strategies for TR-OCD with a retrospective observational case series from a tertiary OCD referral clinic. Treatment resistance was defined as failure to achieve at least a 35% reduction in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score after at least two adequate SRI trials, including clomipramine, and optimized exposure and response prevention when available. Five patients treated with pharmacological intensification strategies were included. The primary outcome was percentage change in Y-BOCS score at 12 weeks. Results: The case series illustrates five strategies used in highly refractory OCD: supratherapeutic SSRI dosing, SSRI plus mirtazapine augmentation, dual SSRI therapy, serotonergic intensification in a clozapine-treated patient, and glutamatergic/GABAergic augmentation with topiramate. Baseline Y-BOCS scores ranged from 28 to 32. At 12 weeks, symptom reduction ranged from 23% to 36%. One patient met criteria for response, three showed near-response, and one demonstrated partial improvement. No cases of serotonin toxicity or clinically significant cardiac complications occurred. Conclusions: These cases suggest that carefully monitored pharmacological intensification may be feasible in selected specialist settings, but efficacy and safety require confirmation in prospective controlled studies. Recommendations: Pharmacological intensification should be reserved for highly refractory patients managed in specialist services, implemented with gradual titration, structured serotonin toxicity and electrocardiographic monitoring, and explicit individualized risk-benefit discussion; dual SSRI therapy should be regarded as the most experimental and highest-risk serotonergic option; and prospective controlled studies incorporating standardized functional outcomes are needed to refine patient-selection criteria and clarify which patients may benefit.

Drug uptake is constrained by epithelial barriers, such as the intestine and the blood-brain barrier, which express efflux pumps such as the ABC-transporter ABCB1. Therefore, drugs targeting the central nervous system frequently require co-administration of efflux inhibitors to facilitate sufficient target engagement. Conversely, certain drugs designed to target distinct molecular pathways may inadvertently affect ABC transporters. However, detailed functional studies of putative human ABCB1 inhibitors is challenging due to difficulties in obtaining sufficiently high amounts of protein needed. Bacterial ABC transporters, such as BmrA from Bacillus subtilis, share structural and functional similarities with ABCB1 and thus provide a reasonable alternative model system. This study investigates clomipramine, an antidepressant known to reduce multidrug resistance in human cells by a yet undefined mechanism. We demonstrate that clomipramine inhibits the ATPase activity of both full-length BmrA and its isolated nucleotide-binding domain. Using binding assays and molecular modeling, multiple clomipramine binding sites were identified in BmrA, which are also conserved in human ABCB1. Critically, one predicted site overlaps with the ATP-binding pocket. The results underscore the potential side-effects of clomipramine and highlight the value of bacterial models such as BmrA for studying novel inhibitors when studies on human proteins are not feasible.

BACKGROUND Sexsomnia, a subtype of non-REM (NREM) parasomnia, consists of atypical sexual behaviors during sleep and presents with diagnostic and therapeutic challenges due to its under-recognition and overlap with other sleep and psychiatric disorders. Thus, its early diagnosis is quite challenging and important. CASE REPORT A 29-year-old man presented with a 2-year history of abnormal nocturnal sexual behaviors including pelvic thrusting, masturbation, and attempted intercourse during sleep reported by his partner, consistent with sexsomnia. All episodes occurred with complete amnesia. The symptoms intensified during periods of anxiety, occupational stress, and long work hours. The behaviors caused distress for his partner, resulting in a strain on their relationship. The patient reported a history of childhood sleep terrors and a family history of parasomnia. He exhibited no significant medical comorbidities or signs of obstructive sleep apnea, as supported by low STOP-BANG and Epworth Sleepiness Scale scores. Polysomnography and neurological imaging results were unremarkable. Initial therapy with fluoxetine (20 mg/day), melatonin (3 mg nightly), and clomipramine (25 mg nightly) was unsuccessful, but self-administered valerian root supplementation achieved a 90% reduction in symptoms due to its GABAergic effects. Subsequent treatment with vortioxetine (20 mg daily) led to complete remission, continued during a 3-month follow-up period. CONCLUSIONS This report emphasizes the importance of individualized approaches in diagnosing and managing sexsomnia. The patient's positive response to valerian root highlights the potential role of natural supplements in managing selected cases. It further highlights the need for increased clinical awareness and future research into natural and behavioral interventions for sleep-related sexual disorders.

Background and Objectives: Potential anti-neoplastic effects of resveratrol, which has antioxidant features combined with clomipramine, which has antineoplastic features, or with gemcitabine, used as a nucleoside analog widely used in chemotherapy, were evaluated together and individually on the HL-60 leukemia cells in this in vitro screening study. Materials and Methods: HL-60 cells were treated with gemcitabine, clomipramine, resveratrol, or their combinations at concentrations ranging from 1 to 200 µM. Cell viability was assessed at 24, 48, and 72 h using the trypan blue exclusion method, and results are expressed as a percentage of time-matched untreated controls. Cell proliferation was further evaluated by bromodeoxyuridine (BrdU) immunohistochemical labeling. All experiments were performed in triplicate, and statistical analyses were conducted using one-way analysis of variance (ANOVA) with post hoc comparisons. Results: Gemcitabine markedly reduced HL-60 cell viability at all concentrations and time points (p < 0.001), indicating strong time-dependent cytotoxicity, with a significant drop in BrdU proliferation index at 48 h (p < 0.001). Clomipramine exhibited a biphasic response: high concentrations decreased viability (p < 0.05), while low concentrations allowed partial recovery by 72 h. Resveratrol showed concentration-dependent cytotoxicity, with reduced viability at high concentration and near-control levels at low concentration by 72 h; BrdU indices remained significantly lower than control (p < 0.001). Combination treatments with gemcitabine showed no additive cytotoxic or antiproliferative effects (p > 0.05). A transient enhanced effect was observed in the clomipramine + resveratrol group at 24 h (p < 0.01 vs. clomipramine; p < 0.05 vs. gemcitabine). Conclusions: Gemcitabine, clomipramine, and resveratrol all exhibited inhibitory effects on cell proliferation in HL-60 cell cultures. However, the combination treatments did not show additional cytotoxicity or additive effects. These findings suggest that while each of these compounds individually has the potential to inhibit cell growth, their combined application does not enhance the cytotoxic effects beyond those observed with single treatments. These findings highlight the necessity of a rational approach when considering novel drug combinations.

Diabetes is one of the main cause and major risk factor for the development of neurodegenerative and neuropsychiatric disorders, including depression, with rising prevalence and increasing co-morbidities worldwide. However, the relationship between diabetes and depression in animal models has not been thoroughly investigated. The present study aimed to investigate the antidepressant potential of empagliflozin (EMPA) in diabetic mice subjected to a chronic unpredictable mild stress (CUMS) model, focusing on its interaction with the corticotropin-releasing factor 1 receptor (CRF1). Initially, diabetes was induced in animals by injection of streptozotocin (STZ) at low dose (35 mg/kg, i.p.), followed by CUMS to provoke depression-like state (1-20 days). EMPA at doses of 5 and 10 mg/kg was administered orally as the test compound, while metformin (MET; 200 mg/kg) and clomipramine (CLMP, 10 mg/kg) alone and in combination (MET + CLMP) were used as standard treatments. All treatments were given once daily for 14 consecutive days (21-35 days). Behavioral assessments were carried out from days 36 to 41, using several paradigms like splash tests, sucrose preference test, open field test, tail suspension test, and forced swim test, respectively. EMPA, particularly at 10 mg/kg, significantly improved behavioral outcomes, indicated by increased distance traveled, higher open-arm entries, reduced immobility time, and shorter grooming latency. Biochemically, EMPA restored antioxidant levels (glutathione and catalase), reduced lipid peroxidation in the brain, and decreased blood corticosterone (CORT) levels. In silico molecular docking and MD-simulation analysis revealed strong binding affinity and interactions between EMPA and CRF1. This proposes that the potential of EMPA to regulate CUMS-induced aggravated depression in diabetic animals may be mediated through CRF1 modulation. These results suggested that EMPA has potential as a therapeutic agent for depression, especially in diabetic conditions linked to oxidative stress, likely through the CRF1-receptor.

Depression poses a major global health challenge, highlighting the urgent need for valid animal models to elucidate its pathogenesis and develop novel treatments. This review offers a comprehensive characterization and validation of an original rodent model of depression induced by chronic exposure to variable-frequency ultrasound (20-45 kHz), termed the ultrasound model (US-model). We hypothesize that this model uniquely recapitulates a state of "information uncertainty", providing a highly relevant framework for studying depression amid modern urban environments. Based on extensive experimental data collected over 10 years (2013-2024), the model has been systematically evaluated using three key criteria for validity. First, the US-model demonstrates face validity, recapitulating core behavioral abnormalities such as anhedonia, behavioral despair, social withdrawal, anxiety, and cognitive deficits. Second, its construct validity is supported by the faithful reproduction of key pathophysiological mechanisms, including monoamine system dysfunction, impaired neuroplasticity, neuroinflammation, oxidative stress, and hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. Finally, the model exhibits strong predictive validity, showing sensitivity to various established classes of antidepressants (e.g., fluoxetine, clomipramine), novel compounds (e.g., vindeburnol, neuropeptides), electroconvulsive therapy, and agents with antioxidant or anti-inflammatory properties. Compared to classic models, the US-model may offer several potential advantages such as a relatively high degree of standardization and an arguably more ethical profile, as it is less invasive. In conclusion, the US-model of depression represents a reliable and reproducible tool to investigate the pathogenesis of affective disorders and screen new therapeutic agents.

BACKGROUND: Patients with obsessive–compulsive disorder (OCD) and comorbid major depressive disorder (MDD) represent a severe subgroup with increased treatment resistance, greater functional impairment, and limited therapeutic options. Intranasal esketamine is a rapidly acting treatment for resistant depression, with emerging interest in potential anti-obsessional effects. However, prospective data in this comorbid population remain lacking. METHODS: We present eight adult cases (mean age 47.3 ± 8.8 years) with treatment-resistant OCD (TR-OCD) and comorbid MDD treated at Bellvitge University Hospital. All patients had failed at least two adequate SSRI trials, clomipramine, cognitive-behavioral therapy with exposure and response prevention, and at least one pharmacological augmentation strategy. Intranasal esketamine (56–84 mg/session) was administered according to the standard antidepressant protocol over 12 weeks. Response was defined as ≥ 35% reduction in Y-BOCS and ≥ 50% reduction in MADRS. RESULTS: Depressive symptoms improved substantially, with MADRS scores decreasing by 48.8% at Week 12 (p = 0.0026). Obsessive-compulsive symptoms showed a more modest and heterogeneous reduction, with a 30.3% decrease in Y-BOCS scores (p = 0.0037). Four of the eight participants (50.0%) achieved depression response, including two (25.0%) remissions, and four of the eight participants (50.0%) met OCD response criteria. Depressive symptoms improved earlier, whereas OCD symptoms followed a slower and more variable trajectory. CONCLUSIONS: Repeated intranasal esketamine may offer a therapeutic window for patients with severe TR-OCD and comorbid MDD. These preliminary findings support further controlled studies to clarify its role, optimal administration, and integration with psychotherapy.