Search Results (36)

Background: Attention-Deficit/Hyperactivity Disorder (ADHD) in adults is frequently accompanied by psychiatric comorbidities that worsen outcomes and complicate treatment. Pharmacological management is central in care, yet its impact on co-occurring disorders remains uncertain. This systematic review evaluated the effectiveness of commonly prescribed medications for adult ADHD (methylphenidate, atomoxetine, bupropion, and lisdexamfetamine) on comorbid mood, anxiety, personality, and substance use disorders. Tricyclic antidepressants were also included in the search strategy; however, no eligible adult studies assessing imipramine or desipramine in patients with ADHD and psychiatric comorbidity were identified. Methods: A systematic search of the literature was conducted to identify studies examining these medications in adults with ADHD and at least one psychiatric comorbidity. Eligible studies reported clinical outcomes for both ADHD symptoms and the co-occurring disorder. Data were extracted and narratively synthesized, with particular attention paid to treatment effects and sources of heterogeneity. Results: Across the included studies, pharmacological treatments consistently improved core ADHD symptomatology. Their effects on psychiatric comorbidity were more variable. Some evidence suggested beneficial outcomes for selected anxiety disorder subtypes and for features of Cluster B personality disorders, possibly related to reductions in emotional dysregulation and impulsivity. Findings regarding substance use disorders were mixed: several studies reported reduced craving or substance use, but long-term stabilization was inconsistent. Marked heterogeneity in study design, populations, and outcome measures limited comparability. Conclusions: Current pharmacological treatments for adult ADHD show reliable efficacy for core symptoms but inconsistent benefits across comorbid psychiatric conditions. While targeted improvements may occur in specific domains, the evidence base is insufficient to define optimal long-term strategies for adults with ADHD and complex comorbidity. Rigorous, longitudinal studies are needed to clarify medication effects on distinct comorbid profiles and to inform integrated treatment planning. Full article

Background: Thunbergia alata is employed in traditional medicine to treat culture-bound syndromes such as “susto” (fright) or “espanto” (fearfulness). These conditions may correlate with depressive disorders. However, there is no evidence that this species has antidepressant properties. Aims: To characterize the antidepressant-like effect of an aqueous extract of T. alata in different paradigms and to analyze the role of brain monoamines in such actions. Methods: Independent groups of mice were treated with saline or the extract (1, 5, 10, 50, and 100 mg/kg; p.o.) and evaluated in the tail suspension (TST) and forced swimming tests (FST). Biochemical mechanisms were analyzed using inhibitors of monoamine synthesis, ligands of serotonergic receptors, and in vitro assays of MAO-A and MAO-B activity. Acute and sub-acute toxicity was evaluated. Results: The extract significantly reduced the immobility time of mice in both the TST and the FST, without affecting locomotor activity, as did the prototypical antidepressant desipramine. PCPA, AMPT, and NAN-190 abolished the extract’s effects on despair, while serotonergic ligands (8-OH-DPAT, fluoxetine, and pindolol) facilitated their antidepressant action. T. alata inhibited MAO-A and B activity. High doses of the extract produced no change in organ morphology; LD₅₀ was >2000 mg/kg. Conclusions: This is the first study to demonstrate that an aqueous extract of T. alata produces antidepressant effects mediated by the monoamine brain levels, especially serotonin. In addition to its use in culture-bounded syndromes, the present findings of safety and efficacy give support to the proposal that T. alata may be used in the treatment of depression. Full article

We investigated whether the functional involvement of α1-adrenergic receptors (α1-AR) in the effects induced by antidepressant drugs, desipramine, and milnacipran varies depending on the α1-AR subtype. First, using a mouse line with triple knockout (KO) of genes encoding all three α1-AR subtypes (ABD-KO) and autoradiographic analysis, we demonstrated that the inactivation of α1-AR did not affect the density of other types of adrenergic receptors, α2- and β-AR in the mouse brain. Subsequently, we utilized three mouse knockout lines with selective knockout of the gene encoding a single α1-adrenergic receptor subtype (A-KO, B-KO, and D-KO). We analyzed the impact of these mutations on tissue levels of monoaminergic neurotransmitters in the hypothalamus (HY). Next, we assessed how a specific mutation affects the chronic effects of desipramine and milnacipran in the selected brain regions of male and female mice at various molecular levels: mRNA expression of genes encoding for α1-AR subtypes, gene expression profiling, and phosphorylation of selected signaling proteins (ERK1/2, Akt, GSK3β). The main finding is that the deletion of the α1D subtype predominantly reduced the chronic effects of milnacipran at the examined transcriptomic and proteomic levels. The pattern of changes differed by gender. Our study revealed the functional diversity between α1-AR subtypes in the molecular mechanisms of antidepressants’ drug action. Full article

Background: Depression is one of the leading causes of disability worldwide. Among pharmacological treatments, fluvoxamine—an early SSRI with a distinct pharmacological profile—has been recently reappraised for its broader clinical relevance. Objective: To assess the efficacy of fluvoxamine in the treatment of depression compared to placebo and other antidepressants through a comprehensive overview of systematic reviews and meta-analyses. Methods: A systematic search was conducted in MEDLINE and the Cochrane Central Register of Controlled Trials, including systematic reviews and meta-analyses of randomized controlled trials evaluating fluvoxamine’s efficacy. Reviews were eligible if they included adults diagnosed with depressive disorders based on the DSM or ICD criteria. Reviews focusing on other psychiatric disorders, comorbidities, tolerability, or economic evaluations were excluded. Data extraction included effect size measures and methodological quality assessments using the AMSTAR-2 tool. Results were synthesized by comparing fluvoxamine to placebo, tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and other antidepressants. Results: A total of 74 reviews were identified, of which 14 systematic reviews met the inclusion criteria after screening and full-text analysis. These reviews, published between 1994 and 2021, predominantly involved nine pairwise meta-analyses and five network meta-analyses, comparing fluvoxamine with placebo and various antidepressants. Fluvoxamine demonstrated consistent superiority over placebo in achieving treatment response and remission outcomes. Comparisons with imipramine, clomipramine, amitriptyline, dothiepin, paroxetine, fluoxetine, citalopram, mianserin, nortriptyline, and moclobemide generally revealed no significant differences in efficacy. However, some reviews indicated that venlafaxine and mirtazapine were superior to fluvoxamine in certain outcomes, while fluvoxamine demonstrated greater efficacy than desipramine in one review. Sertraline and milnacipran showed mixed or review-quality-dependent results, with one low-quality review favoring milnacipran. Most reviews assessed outcomes over a median follow-up of six weeks using standardized depression rating scales. Conclusions: Fluvoxamine is a robust and effective antidepressant, demonstrating consistent efficacy comparable to other antidepressants and superior to placebo. While no single antidepressant was universally superior, fluvoxamine’s unique pharmacological profile and favourable safety characteristics support its clinical utility. Further research is needed to explore its role in personalized treatment strategies and emerging therapeutic contexts, such as comorbid anxiety and post-traumatic stress disorder. Full article

This review concentrates on the application of carbon-based materials in the development and fabrication of voltammetric sensors of antidepressant drugs used in the treatment of moderate to severe depression, anxiety disorders, personality disorders, and various phobias. Voltammetric techniques offer outstanding sensitivity and selectivity, accuracy, low detection limit, high reproducibility, instrumental simplicity, cost-effectiveness, and short time of direct determination of antidepressant drugs in pharmaceutical and clinical samples. Moreover, the combination of voltammetric approaches with the unique characteristics of carbon and its derivatives has led to the development of powerful electrochemical sensing tools for detecting antidepressant drugs, which are highly desirable in healthcare, environmental monitoring, and the pharmaceutical industry. In this review, carbon-based materials, such as glassy carbon and boron-doped diamond, and a wide spectrum of carbon nanoparticles, including graphene, graphene oxides, reduced graphene oxides, single-walled carbon nanotubes, and multi-walled carbon nanotubes were described in terms of the sensing performance of agomelatine, alprazolam, amitriptyline, aripiprazole, carbamazepine, citalopram, clomipramine, clozapine, clonazepam, desipramine, desvenlafaxine, doxepin, duloxetine, flunitrazepam, fluoxetine, fluvoxamine, imipramine, nifedipine, olanzapine, opipramol, paroxetine, quetiapine, serotonin, sertraline, sulpiride, thioridazine, trazodone, venlafaxine, and vortioxetine. Full article

Background/Objectives: Index substrates are used to understand the processes involved in pharmacokinetic (PK) drug–drug interactions (DDIs). The aim of this analysis is to review metabolite measurement in clinical DDI studies, focusing on index substrates for cytochrome P450 (CYP) enzymes, including CYP1A2 (caffeine), CYP2B6 (bupropion), CYP2C8 (repaglinide), CYP2C9 ((S)-warfarin, flurbiprofen), CYP2C19 (omeprazole), CYP2D6 (desipramine, dextromethorphan, nebivolol), and CYP3A (midazolam, triazolam). Methods: All data used in this evaluation were obtained from the Certara Drug Interaction Database. Clinical index substrate DDI studies with PK data for at least one metabolite, available from literature and recent new drug application reviews, were reviewed. Further, for positive DDI studies, a correlation analysis was performed between changes in plasma exposure of index substrates and their marker metabolites. Results: A total of 3261 individual index DDI studies were available, with 45% measuring at least one metabolite. The occurrence of metabolite measurement in clinical DDI studies varied widely between index substrates and enzymes. Discussion and Conclusions: For substrates such as caffeine, bupropion, omeprazole, and dextromethorphan, the use of the metabolite/parent area under the curve ratio can provide greater sensitivity to DDI or reduce intrasubject variability. In some cases (e.g., omeprazole, repaglinide), the inclusion of metabolite measurement can provide mechanistic insights to understand complex interactions. Full article

Vibrio cholerae is an important foodborne pathogen. Cholix cytotoxin (Cholix), produced by V. cholerae, is a novel eukaryotic elongation factor 2 (eEF2) adenosine diphosphate ribosyltransferase that causes host cell death by inhibiting protein synthesis. However, the role of Cholix in the infectious diseases caused by V. cholerae remains unclear. Some bacterial cytotoxins are carried by host extracellular vesicles (EVs) and transferred to other cells. In this study, we investigated the effects of EV inhibitors and EV-regulating proteins on Cholix-induced hepatocyte death. We observed that Cholix-induced cell death was significantly enhanced in the presence of EV inhibitors (e.g., dimethyl amiloride, and desipramine) and Rab27a-knockdown cells, but it did not involve a sphingomyelin-dependent pathway. RNA sequencing analysis revealed that desipramine, imipramine, and EV inhibitors promoted the Cholix-activated c-Jun NH2-terminal kinase (JNK) pathway. Furthermore, JNK inhibition decreased desipramine-enhanced Cholix-induced poly (ADP-ribose) polymerase (PARP) cleavage. In addition, suppression of Apaf-1 by small interfering RNA further enhanced Cholix-induced PARP cleavage by desipramine. We identified a novel function of desipramine in which the stimulated JNK pathway promoted a mitochondria-independent cell death pathway by Cholix. Full article

In the small intestine, nutrients from ingested food are absorbed and broken down by enterocytes, which constitute over 95% of the intestinal epithelium. Enterocytes demonstrate diet- and segment-dependent metabolic flexibility, enabling them to take up large amounts of glutamine and glucose to meet their energy needs and transfer these nutrients into the bloodstream. During glycolysis, ATP, lactate, and H⁺ ions are produced within the enterocytes. Based on extensive but incomplete glutamine oxidation large amounts of alanine or lactate are produced. Lactate, in turn, promotes hypoxia-inducible factor-1α (Hif-1α) activation and Hif-1α-dependent transcription of various proton channels and exchangers, which extrude cytoplasmic H⁺-ions into the intestinal lumen. In parallel, the vitamin C-dependent and duodenal cytochrome b-mediated conversion of ferric iron into ferrous iron progresses. Finally, the generated electrochemical gradient is utilized by the divalent metal transporter 1 for H⁺-coupled uptake of non-heme Fe²⁺-ions. Iron efflux from enterocytes, subsequent binding to the plasma protein transferrin, and systemic distribution supply a wide range of cells with iron, including erythroid precursors essential for erythropoiesis. In this review, we discuss the impact of vitamin C on the redox capacity of human erythrocytes and connect enterocyte function with iron metabolism, highlighting its effects on erythropoiesis. Full article

Background/Objectives: Several psychological conditions, including stress and depression, can adversely affect oral health; in fact, antidepressants, commonly used to treat depressive disorders, may have conflicting effects on the periodontal status of individuals. The aim of this review was to determine the effects of antidepressants on the periodontium. Methods: A literature search was conducted using electronic databases, Pubmed/MEDLINE, Cochrane Library, focusing on the use of antidepressants and their effects on periodontal health in animals or humans. Results: Seventeen articles have been included with the use of amitriptyline (two studies), desipramine (one study), imipramine (two studies), desvenlafaxine (one study), fluoxetine (six studies), venlafaxine (three studies) and tianeptine (two studies). One study evaluated several categories of antidepressants, such as selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), tricyclic, atypical and monoamine oxidase inhibitors (MAO). Most trials showed improvements in periodontal health, especially with fluoxetine, but also with imipramine, desipramine, desvenlafaxine and tianeptine; on the contrary, worsening of clinical periodontal indices and increased loss of alveolar bone were reported with venlafaxine. Conclusions: This review suggests that in the presence of comorbidity between periodontitis and depression, pharmacological treatment with SNRIs, SSRIs and mixed antidepressants is associated with improvement in periodontal parameters, except for venlafaxine. Healthcare professionals (especially oral and mental health professionals) should investigate proper adherence to medication therapy in patients with a history of periodontitis and depression. Further clinical trials are needed to confirm these results. Full article

Prolonged exposure to HIV-1 transactivator of transcription (Tat) protein dysregulates monoamine transmission, a physiological change implicated as a key factor in promoting neurocognitive disorders among people living with HIV. We have demonstrated that in vivo expression of Tat in Tat transgenic mice decreases dopamine uptake through both dopamine transporter (DAT) and norepinephrine transporter (NET) in the prefrontal cortex. Further, our novel allosteric inhibitor of monoamine transporters, SRI-32743, has been shown to attenuate Tat-inhibited dopamine transport through DAT and alleviates Tat-potentiated cognitive impairments. The current study reports the pharmacological profiles of SRI-32743 in basal and Tat-induced inhibition of human NET (hNET) function. SRI-32743 exhibited less affinity for hNET binding than desipramine, a classical NET inhibitor, but displayed similar potency for inhibiting hDAT and hNET activity. SRI-32743 concentration-dependently increased hNET affinity for [³H]DA uptake but preserved the V_max of dopamine transport. SRI-32743 slowed the cocaine-mediated dissociation of [³H]Nisoxetine binding and reduced both [³H]DA and [³H]MPP+ efflux but did not affect d-amphetamine-mediated [³H]DA release through hNET. Finally, we determined that SRI-32743 attenuated a recombinant Tat_1–86-induced decrease in [³H]DA uptake via hNET. Our findings demonstrated that SRI-32743 allosterically disrupts the recombinant Tat_1–86–hNET interaction, suggesting a potential treatment for HIV-infected individuals with concurrent cocaine abuse. Full article

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, including abemaciclib, have been approved for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced, and metastatic breast cancer. Despite the high therapeutic efficacy of CDK4/6 inhibitors, they are associated with various adverse effects, including potentially fatal interstitial lung disease. Therefore, a combination of CDK4/6 inhibitors with letrozole or fulvestrant has been attempted but has demonstrated limitations in reducing adverse effects, highlighting the need to develop new combination therapies. This study proposes a combination strategy using CDK4/6 inhibitors and tricyclic antidepressants to enhance the therapeutic outcomes of these inhibitors while reducing their side effects. The therapeutic efficacies of abemaciclib and desipramine were tested in different cancer cell lines (H460, MCF7, and HCT-116). The antitumor effects of the combined abemaciclib and desipramine treatment were evaluated in a xenograft colon tumor model. In vitro cell studies have shown the synergistic anticancer effects of combination therapy in the HCT-116 cell line. The combination treatment significantly reduced tumor size compared with control or single treatment without causing apparent toxicity to normal tissues. Although additional in vivo studies are necessary, this study suggests that the combination therapy of abemaciclib and desipramine may represent a novel therapeutic approach for treating solid tumors. Full article

Astrocytes actively participate in neurotransmitter homeostasis by bidirectional communication with neuronal cells, a concept named the tripartite synapse, yet their role in dopamine (DA) homeostasis remains understudied. In the present study, we investigated the kinetic and molecular mechanisms of DA transport in cultured striatal astrocytes of adult rats. Kinetic uptake experiments were performed using radiolabeled [³H]-DA, whereas mRNA expression of the dopamine, norepinephrine, organic cation and plasma membrane monoamine transporters (DAT, NET, OCTs and PMAT) and DA receptors D1 and D2 was determined by qPCR. Additionally, astrocyte cultures were subjected to a 24 h treatment with the DA receptor agonist apomorphine, the DA receptor antagonist haloperidol and the DA precursor L-DOPA. [³H]-DA uptake exhibited temperature, concentration and sodium dependence, with potent inhibition by desipramine, nortriptyline and decynium-22, suggesting the involvement of multiple transporters. qPCR revealed prominent mRNA expression of the NET, the PMAT and OCT1, alongside lower levels of mRNA for OCT2, OCT3 and the DAT. Notably, apomorphine significantly altered NET, PMAT and D1 mRNA expression, while haloperidol and L-DOPA had a modest impact. Our findings demonstrate that striatal astrocytes aid in DA clearance by multiple transporters, which are influenced by dopaminergic drugs. Our study enhances the understanding of regional DA uptake, paving the way for targeted therapeutic interventions in dopaminergic disorders. Full article

Knowledge of gender-specific drug distributions in different organs are of great importance for personalized medicine and reducing toxicity. However, such drug distributions have not been well studied. In this study, we investigated potential differences in the distribution of imipramine and chloroquine, as well as their metabolites, between male and female kidneys. Kidneys were collected from mice treated with imipramine or chloroquine and then subjected to atmospheric pressure matrix-assisted laser desorption ionization-mass spectrometry imaging (AP-MALDI-MSI). We observed differential distributions of the drugs and their metabolites between male and female kidneys. Imipramine showed prominent distributions in the cortex and medulla in male and female kidneys, respectively. Desipramine, one of the metabolites of imipramine, showed significantly higher (*** p < 0.001) distributions in the medulla of the male kidney compared to that of the female kidney. Chloroquine and its metabolites were accumulated in the pelvis of both male and female kidneys. Interestingly, they showed a characteristic distribution in the medulla of the female kidney, while almost no distributions were observed in the same areas of the male kidney. For the first time, our study revealed that the distributions of imipramine, chloroquine, and their metabolites were different in male and female kidneys. Full article

Astrocytes are crucial in the regulation of neurotransmitter homeostasis, and while their involvement in the dopamine (DA) tripartite synapse is acknowledged, it necessitates a more comprehensive investigation. In the present study, experiments were conducted on primary astrocyte cultures from the striatum and cortex of neonatal rats. The pharmacological intricacies of DA uptake, including dependence on time, temperature, and concentration, were investigated using radiolabelled [³H]-DA. The mRNA expression of transporters DAT, NET, PMAT, and OCTs was evaluated by qPCR. Notably, astrocytes from both brain regions exhibited prominent mRNA expression of NET and PMAT, with comparatively lower expression of DAT and OCTs. The inhibition of DA uptake by the DAT inhibitor, GBR12909, and NET inhibitors, desipramine and nortriptyline, impeded DA uptake in striatal astrocytes more than in cortical astrocytes. The mRNA expression of NET and PMAT was significantly upregulated in cortical astrocytes in response to the DA receptor agonist apomorphine, while only the mRNA expression of NET exhibited changes in striatal astrocytes. Haloperidol, a DA receptor antagonist, and L-DOPA, a DA precursor, did not induce significant alterations in transporter mRNA expression. These findings underscore the intricate and region-specific mechanisms governing DA uptake in astrocytes, emphasizing the need for continued exploration to unravel the nuanced dynamics of astrocytic involvement in the DA tripartite synapse. Full article

Cholesterol-rich membrane domains, also called lipid rafts (LRs), are specialized membrane domains that provide a platform for intracellular signal transduction. Membrane proteins often cluster in LRs that further aggregate into larger platform-like structures that are enriched in ceramides and are called ceramide-rich platforms (CRPs). The role of CRPs in the regulation of intestinal epithelial functions remains unknown. Down-regulated in adenoma (DRA) is an intestinal Cl⁻/HCO₃⁻ antiporter that is enriched in LRs. However, little is known regarding the mechanisms involved in the regulation of DRA activity. The air–liquid interface (ALI) was created by removing apical media for a specified number of days; from 12–14 days post-confluency, Caco-2/BBe cells or a colonoid monolayer were grown as submerged cultures. Confocal imaging was used to examine the dimensions of membrane microdomains that contained DRA. DRA expression and activity were enhanced in Caco-2/BBe cells and human colonoids using an ALI culture method. ALI causes an increase in acid sphingomyelinase (ASMase) activity, an enzyme responsible for enhancing ceramide content in the plasma membrane. ALI cultures expressed a larger number of DRA-containing platforms with dimensions >2 µm compared to cells grown as submerged cultures. ASMase inhibitor, desipramine, disrupted CRPs and reduced the ALI-induced increase in DRA expression in the apical membrane. Exposing normal human colonoid monolayers to ALI increased the ASMase activity and enhanced the differentiation of colonoids along with basal and forskolin-stimulated DRA activities. ALI increases DRA activity and expression by increasing ASMase activity and platform formation in Caco-2/BBe cells and by enhancing the differentiation of colonoids. Full article