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Obsessive-compulsive disorder (OCD) is a severe and intricate mental illness that profoundly impacts the lives of individuals affected by it. This comprehensive review aims to thoroughly explore all facets of OCD, encompassing its clinical presentations, prevalence as a common mental disorder, its neurological underpinnings, treatment modalities, and broader societal implications. The subsequent overview seeks to advance mental health awareness and foster empathy by integrating diverse perspectives and synthesizing existing research findings. Ongoing research endeavors are delving into the potential therapeutic uses of ketamine, known for its dissociative properties, as well as psychedelic substances in combination with psychotherapeutic interventions, as innovative approaches to treating OCD. Additionally, the utilization of mindfulness-based interventions, particularly mindfulness-based cognitive therapy (MBCT), is actively being investigated, along with the potential effectiveness of repetitive transcranial magnetic stimulation (rTMS) as an adjunct therapy for obsessive-compulsive disorders. The incidence of suicide attempts among individuals diagnosed with OCD varies widely, ranging from 6% to 51.7%, with an average occurrence of 14.2%. In this review, an updated elaboration of all aspects of the disorder has been given. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor (VEGF) signaling is known to be involved in the antidepressant‐like effects of conventional antidepressants, such as desipramine (DMI), a tricyclic antidepressant, and fluoxetine (FLX), a selective serotonin reuptake inhibitor; however, the precise role of neuronal VEGF signaling in mediating these effects remains unclear. Using mice with excitatory neuron‐specific deletion of VEGF and its receptor, fetal liver kinase 1 (Flk‐1) in the forebrain, we examined the effects of forebrain excitatory neuron‐specific deletion of VEGF or Flk‐1 on the antidepressant‐like effects of repeated DMI and chronic FLX administration in the forced swim test (FST). Repeated intraperitoneal (i.p.) injections of DMI (10, 10, and 20 mg/kg at 24, 4, and 1 h before the FST, respectively) significantly decreased immobility in control mice; however, this effect was completely blocked in mice with neuron‐specific VEGF or Flk‐1 deletion. Although chronic treatment with FLX (18 mg/kg/day, i.p.) did not impact immobility in control mice 1 day after the 22nd injection, immobility was significantly reduced 1 day after the preswim and the 23rd FLX injection. However, in mice with neuron‐specific Flk‐1 deletion, chronic FLX treatment significantly increased immobility in the preswim and failed to produce antidepressant‐like effects. Collectively, these findings indicate that neuronal VEGF–Flk‐1 signaling contributes to the antidepressant‐like actions of conventional antidepressants. [ABSTRACT FROM AUTHOR]

Background: Genome wide association studies (GWAS) and candidate gene analyses have identified genetic variants and genes that may increase the risk for suicidal thoughts and behaviors (STBs). Important unresolved issues surround these tentative risk variants such as the characteristics of the associated genes and how they might elicit STBs. Methods: Putative suicidality-related risk genes (PSRGs) were identified by comprehensive literature search and were characterized with respect to evolutionary conservation, participation in gene interaction networks and associated phenotypes. Evolutionary conservation was established with database searches and BLASTP queries, whereas gene-gene interactions were ascertained with GeneMANIA. We then examined whether mutations in risk-gene counterparts in C. elegans produced a diminished motivation phenotype previously connected to suicide risk factors. Results and conclusions: From the analysis, 105 risk-gene candidates were identified and found to be: 1) highly conserved during evolution, 2) enriched for essential genes, 3) involved in significant gene-gene interactions, and 4) associated with psychiatric disorders, metabolic disturbances and asthma/allergy. Evaluation of 17 mutant strains with loss-of-function/deletion mutations in PSRG orthologs revealed that 11 mutants showed significant evidence of diminished motivation that manifested as immobility in a foraging assay. Immobility was corrected in some or all of the mutants with clozapine, lithium and tricyclic antidepressant drugs. In addition, 5-HT2 receptor and muscarinic receptor antagonists restored goal-directed behavior in most or all of the mutants. These studies increase confidence in the validity of the PSRGs and provide initial clues about possible mechanisms that mediate STBs. [ABSTRACT FROM AUTHOR]

Various antidepressants have introduced in clinical practice for pain management, but it is important to understand how to properly use them. We therefore performed a systematic review and network meta‐analysis to compare and rank the efficacy and safety of antidepressants for patients with chronic back pain. We identified eligible randomized controlled trials (RCTs) that investigated the efficacy and safety of antidepressants for chronic back pain from PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov, searching from inception to May 2023. Six categories of antidepressants for the treatment of chronic back pain were included, and the surface under the cumulative ranking probabilities was applied to rank the treatment strategies. Overall, we selected 19 RCTs recruiting 2903 patients for the meta‐analysis. Tricyclic antidepressants presented the best relative effects for relief in pain score (surface under the cumulative ranking, 84.4%). The results of pairwise comparison analyses found the use of serotonin–noradrenaline reuptake inhibitors (SNRIs) significantly reduced pain score and low disability score compared with placebo, irrespective of treatment duration. Noradrenaline–dopamine reuptake inhibitors (relative risk [RR], 2.80; 95% confidence interval [CI], 1.30‐6.03; P =.008) and SNRIs (RR, 1.17; 95% CI, 1.07‐1.27; P <.001) significantly increased the risk of adverse events. SNRIs were associated with an increased risk of withdrawal due to adverse events (RR, 2.37; 95% CI, 1.64‐3.43; P <.001). This study found that antidepressants are more efficacious than placebos for treating chronic back pain, and tricyclic antidepressants are the most likely medications that lead to pain relief. [ABSTRACT FROM AUTHOR]

Background: Evidence‐based use of antidepressant medications is of major clinical importance. We aimed to uncover precription patterns in a large cohort of patients with unipolar depression. Material and Methods: Using Danish nationwide registers, we identified individuals with a first‐time hospital diagnosis of unipolar depression between January 1st, 2001, and December 31st, 2016. Redemeed prescriptions of antidepressants from five years before to five years after diagnosis were retreived. Lithium and relevant antipsychotics were included. Data were analyzed with descriptive statistics including sunburst plots. Cox regressions were used to rank the risk of treatment failure according to antidepressant category and depression severity, as measured by hazard ratios of drug shift. Results: The full study population consisted of 113,175 individuals. Selective Serotonin Reuptake Inhibitors was the predominantly prescribed first‐line group, both before (55.4%) and after (47.7%) diagnosis and across depression severities. Changes of treatment strategy were frequent; 60.8%, 33.7%, and 17.1% reached a second, third, and fourth treatment trial after the hospital diagnosis, respectively. More than half of patients continued their pre‐diagnosis antidepressant after diagnosis. The risk of change of treatment strategy was generally lower in mild–moderate depression and higher in severe depression, with tricyclic antidepressants carrying the highest risk in the former and the lowest risks in the latter. Overall, prescribing were often not in accordance with guidelines. Conclusion: These findings uncover a potential for improving the clinical care for patients with unipolar depression through optimization of the use of marketed antidepressants. [ABSTRACT FROM AUTHOR]

Results: As a result, in Group A, the mean migraine attack severity in periods 1 and 2 was 5.88 2.69 and 5.41 2.48, respectively. In Group B, the mean was 5.15 2.75 in period 1 and 5.66 2.78 in period 2, respectively. The average length of a migraine attack in Group A was 20.30 5.61 h in period 1 and 16.75 5.23 h in period 2. In Group B, the mean was 16.59 3.21 in period 1 and 18.78 5.14 in period 2. Between groups A and B, there was a statistically significant difference. Conclusion: The average number of migraine attacks reduced in the amitriptyline and propranolol groups as the treatment duration increased. Amitriptyline is a popular medication with established effectiveness and manageable levels of negative side effects. It is the tricyclic antidepressant that is most frequently used to prevent headaches. When administered for migraine prevention, it generates a quick response within 3 months. Propranolol is less effective than amitriptyline at reducing the frequency, length, and severity of episodes. Background: Approximately 15% of migraine sufferers need preventative medicine because they have more than two episodes each month. Migraine is a regular, persistent condition that frequently makes victims helpless. Numerous drugs from various classes have so far been used in migraine prophylaxis. Their effectiveness is recurrently overshadowed by their side effects because they must be used for a long time, which occasionally necessitates stopping the drug. Materials and Methods: In the tertiary care teaching hospital's department of medicine, a prospective, comparative, open-label study was initiated. Two groups of 80 patients were randomly chosen. For 3 months, the 40 patients in Group A were given a tablet of amitriptyline 10 mg once daily, whereas the 40 patients in Group B were given a tablet of propranolol 20 mg once a day. At the conclusion of the fourth, eighth, and twelfth weeks, the patients' own self-assessment migraine diary and a 4-point pain scale were used to grade the intensity of the headaches. [ABSTRACT FROM AUTHOR]

Depression is not similar to daily mood fluctuations and temporary emotional responses to day‐to‐day activities. Depression is not a passing problem; it is an ongoing problem. It deals with different episodes consisting of several symptoms that last for at least 2 weeks. It can be seen for several weeks, months, or years. At its final stage, or can say, in its worst condition, it can lead to suicide. Antidepressants are used to inhibit the reuptake of the neurotransmitters by some selective receptors, which increase the concentration of specific neurotransmitters around the nerves in the brain. Drugs that are currently being used for the management of various types of depression include selective serotonin reuptake inhibitors, tricyclic antidepressants, atypical antidepressants, serotonin, noradrenaline reuptake inhibitors, etc. In this review, we have outlined different symptoms, causes, and recent advancements in nitrogen‐containing heterocyclic drug candidates for the management of depression. This article highlights the various structural features along with the structure–activity relationship (SAR) of nitrogen‐containing heterocyclics that play a key role in binding at target sites for potential antidepressant action. The in silico studies were carried out to determine the binding interactions of the target ligands with the receptor site to determine the potential role of substitution patterns at core pharmacophoric features. This article will help medicinal chemists, biochemists, and other interested researchers in identifying the potential pharmacophores as lead compounds for further development of new potent antidepressants. [ABSTRACT FROM AUTHOR]

Microextractions have been developed for the tricyclic antidepressants (TCAs) analysis in biological matrices, including dispersive liquid-liquid microextraction (DLLME). The proposed DLLME employed 490 µL of biological sample (whole blood or plasma), which were added 15 mg of NaCl, 10 µL of medazepam as internal standard (10 µg/mL) and 100 µL of 2 M NaOH. This mixture was homogenized by vortex (2800 rpm/10 s) and 400 µL of hexane (extractor solvent) with 600 µL of methanol (dispersing solvent) were added to the sample. After the vortex step (2800 rpm/5 s), an ultrasonic bath for 300 s was employed. Then, this content was centrifuged (10 min/10000 rpm), organic phase was collected and dried under air flow. After, 30 µL of the mobile phase was used for resuspension and 20 µL is injected into LC-DAD. This method was optimized and fully validated according to UNODC and SWGTOX guidelines, reaching limits of detection equivalent to analytical methodologies that employ mass spectrometry (MS). Also, it was applied in real cases involving suspected exposure to TCAs. So, the developed DLLME for the determination of TCAs in whole blood and plasma samples proved to be a simple, reliable, robust and reproducible method that can be used in toxicology and clinical laboratories. [ABSTRACT FROM AUTHOR]

In this investigation, the function of the smallest fullerene (C20) as a sensor and nano-carrier for the tricyclic antidepressant drug desipramine was scrutinized through density functional theory simulations. The achieved adsorption energies showed the interaction of desipramine with C20 is experimentally possible. The calculated ΔGad, ΔHad and Kth showed the adsorption process is spontaneous, exothermic and reversible. The influences of solvent and temperature on the interactions were also studied and the results showed the adsorption process is more favorable in lower temperatures and the presence of solvent does not have any effect on the nature of interactions. The NBO analysis showed no chemical bond has been created between desipramine and nanostructure and the existing interaction is a physisorption. The frontier molecular orbital analysis results showed the bandgap of fullerene decline - 35.30% from 7.678 (eV) to 2.484 (eV) indicating this nanomaterial can be an ideal sensor for the detection of desipramine. The values of dipole moment and chemical hardness showed C20 can be employed as an appropriate nano-carrier for the drug delivery of desipramine. [ABSTRACT FROM AUTHOR]

Background: Chronic pruritus poses a significant challenge to treating physicians due to multitude of underlying causes and varying treatment strategies. Several topical, systemic, and physical modalities have been tried with variable success. Prescription practices in chronic pruritus are influenced by differential knowledge and experience of physicians, patient-related factors, and resource availability. Aim: The purpose of this survey was to observe the current pattern of practice in Indian dermatologists in the management of chronic pruritus and to identify practice gaps particularly regarding the use of various systemic agents as antipruritics. Materials and Methods: A previously validated questionnaire was sent to consultant dermatologists across India between January 2020 and July 2020. The questionnaire was comprised of six questions (multiple-choice questions as well as open-ended questions) regarding the use of antidepressants, cyclic gamma-aminobutyric acid (GABA) analogues, opioid antagonists, antihistamines, and alternate therapies in the management of chronic pruritus. Results: A total of 700 dermatologists completed the questionnaire (response rate 70%). Overall, antihistamines were the most common drug prescribed in chronic pruritus (more than 95% respondents). Other systemic agents such as opioid antagonists, gabapentinoids, and antidepressants were prescribed by 22.42%, 71.85%, and 75.29% respondents, respectively, in chronic pruritus as either monotherapy or in combination with antihistamines in specific types of itches. Among antidepressants, tricyclic antidepressants (TCAs) (69.29%) were prescribed most often, followed by selective serotonin reuptake inhibitors (SSRIs) (32.29%) and serotonin and norepinephrine reuptake inhibitors (SNRIs) (9.14%). Other treatment options such as omalizumab, thalidomide, ondansetron, ursodeoxycholic acid (UDCA), and rifampicin were used by 10% respondents to alleviate pruritus in special situations. Conclusion: This survey revealed the redundant practice of prescribing antihistamines in chronic pruritus irrespective of etiology among Indian dermatologists. It also revealed a differential approach regarding use of systemic agents such as gabapentinoids, opioid antagonists, and antidepressants, in academic and non-academic institutions. The survey emphasized a barrier in writing prescription of systemic agents such as opioid antagonist and SNRIs due to lack of knowledge and experience, fear of side effects, and inadequate available evidence. [ABSTRACT FROM AUTHOR]

Background: Antipsychotics (AP) have been used to augment antidepressant (AD) medication in treatment‐resistant depression. In this study we examined factors (including severity of depression and initial antidepressant) affecting AP augmentation, as well as which APs were initiated as augmentation in young adults. Methods: Data were extracted from Finnish nationwide registers. Of persons aged 18–29 years diagnosed with a depression during 2004–2017 we focused on incident AD users (who initiated AD 6 months before and after the diagnosis) whose severity level of depression was recorded (N = 21,966). AP augmentation was studied during 1 year after diagnosis of depression. Persons diagnosed with severe depression with psychotic features (n = 1486) were excluded from main analyses and analyzed separately. Results: Overall, 8.4% of new antidepressant users initiated AP augmentation. Risk of augmentation increased with severity of depression as 3.9%, 5.8%, and 14.0% of persons with mild, moderate, and severe depression, respectively, initiated augmentation. Male sex, comorbid anxiety and personality disorders, substance abuse and selfharm/suicide attempt were positively associated with augmentation. Compared to citalopram, use of tricyclic antidepressant, paroxetine and venlafaxine were associated with increased risk of augmentation, while use of bupropion was associated with a decreased risk. Quetiapine and risperidone were the most common APs used in augmentation. Among persons with severe depression with psychotic features, use of sertraline was associated with AP augmentation, whereas use of fluoxetine decreased risk of augmentation. Conclusions: Use of APs as augmentation of AD therapy was common in severe depression. Comorbidities had only a small effect to augmentation, but selection of initial AD was more closely associated to risk of augmentation. Interestingly, use of bupropion decreased risk of augmentation, which warrants further studies, as well as the decrease in risk of augmentation when fluoxetine in case of psychotic depression was used. [ABSTRACT FROM AUTHOR]

The authors investigated the clinical outcomes of commonly used antidepressants among older adults who initiated first-time antidepressants for depression by analyzing the 1-year risk of selected clinically relevant outcomes. This cohort study used nationwide Danish registry data and included all older adults who redeemed a first-time (since 1995) antidepressant prescription with an indication of depression between 2006 and 2017. Only the 10 most frequently redeemed antidepressants were included in the analyses. Outcomes included discontinuation, switching, augmentation, psychiatric hospital contacts, suicide attempt or self-harm, fall-related injuries, cardiovascular events, and all-cause mortality. Incidence rate ratios (IRRs) and 95% confidence intervals were estimated using Poisson regression models, controlling for potential confounders. The study sample included 93,883 older adults (mean age, 78.0 years, SD=7.5 years; 56% female). The most frequently prescribed antidepressants were selective serotonin reuptake inhibitors (citalopram, 47.04%; escitalopram, 11.81%; fluoxetine, 0.55%; paroxetine, 0.52%; sertraline, 11.17%), serotonin-norepinephrine reuptake inhibitors (duloxetine, 0.71%; venlafaxine, 1.54%), a tricyclic antidepressant (amitriptyline, 1.86%), and two atypical antidepressants (mianserin, 1.93%; mirtazapine, 22.87%). Compared with users of sertraline (the reference drug in this analysis, as Danish guidelines recommend it as the first-choice treatment for depression), users of most of the other nine antidepressants had a significantly higher risk of discontinuation (e.g., mirtazapine: IRR=1.55, 95% CI=1.50–1.61; venlafaxine: IRR=1.22, 95% CI=1.12–1.32), switching (amitriptyline: IRR=1.45, 95% CI=1.15–1.81; venlafaxine: IRR=1.47, 95% CI=1.20–1.80), augmentation, cardiovascular events, and mortality. Overall, mirtazapine and venlafaxine users had the most adverse outcomes compared with sertraline users. These results remained consistent in analyses stratified by sex and age (≤75 years vs. >75 years). This real-world evidence suggests that clinical outcomes may vary among initiators of commonly used antidepressants in older adults, which may inform benefit-risk evaluation at treatment initiation, and highlights the importance of careful selection of antidepressant treatment. [ABSTRACT FROM AUTHOR]

The QRS complex duration is commonly used to prognosticate severity, predict outcomes, and indicate treatment in overdose. However, literature to support this practice is mixed in tricyclic antidepressant overdoses and absent in non-tricyclic antidepressant overdoses. Our objective was to assess the validity of QRS complex duration as a prognostic marker in overdose. This was a secondary analysis of cases reported to the Toxicology Investigators Consortium between January 1, 2010, and December 31, 2022. Cases were assessed to determine the six xenobiotics most associated with QRS complex prolongation. All cases involving these six xenobiotics, regardless of QRS complex duration, constituted the study cohort. Inclusion criteria were cases of patients older than 12 years old with single-xenobiotic exposures. Clinical outcomes evaluated were seizure, ventricular dysrhythmia, metabolic acidosis, and death. Of 94,939 total cases, diphenhydramine, amitriptyline, bupropion, quetiapine, nortriptyline, and cocaine were most associated with QRS complex prolongation. Inclusion criteria were met by 4,655 cases of exposure to these xenobiotics. QRS complex prolongation was associated with increased odds ratio of seizure in all included xenobiotics, of ventricular dysrhythmia in all included xenobiotics except nortriptyline, and of metabolic acidosis or death in all included xenobiotics except nortriptyline and quetiapine. A normal QRS complex duration had a negative predictive value of greater than or equal to 93.0 percent of developing metabolic acidosis and 98.0 percent of developing a ventricular dysrhythmia or death from the xenobiotics studied. This study demonstrates that patients with QRS complex prolongation from all six xenobiotics studied had an increased prevalence and odds of developing severe outcomes. Furthermore, patients who did not develop QRS complex prolongation were unlikely to develop a ventricular dysrhythmia, metabolic acidosis, or death. These findings were noted in six xenobiotics that mechanistically can cause QRS complex prolongation through sodium channel or gap junction inhibition. Identification of patients at risk for severe outcomes after overdose can be aided by measuring the QRS complex duration. If prospectively validated, these outcomes have implications on risk stratification, disposition level of care, and appropriateness of treatments. [ABSTRACT FROM AUTHOR]

Measurements of plasma metanephrines and methoxytyramine provide a sensitive test for diagnosis of pheochromocytoma/paraganglioma. False-positive results remain a problem, particularly in patients taking norepinephrine reuptake-blocking drugs. Therefore, in this retrospective observational study, we measured plasma metanephrines and methoxytyramine in 61 patients taking norepinephrine reuptake blockers (tricyclic antidepressants or serotonin-norepinephrine reuptake inhibitors) and 17 others taking selective serotonin reuptake inhibitors, all without pheochromocytoma/paraganglioma. We highlight a singular case with strongly elevated plasma normetanephrine and methoxytyramine concentrations associated with norepinephrine reuptake blockade. Data were compared to results from 252 and 1804 respective patients with and without tumors. Plasma normetanephrine was 40% higher (P < 0.0001) in patients on norepinephrine reuptake blockers and methoxytyramine was 127% higher (P = 0.0062) in patients taking tricyclic antidepressants compared to patients not taking uptake blockers and without tumors. The corresponding false-positive rates rose (P < 0.0001) from 4.8% to 23.0% for normetanephrine and from 0.9% to 28.6% for methoxytyramine. Selective serotonin reuptake inhibitors did not increase plasma concentrations of metabolites. In the highlighted case, plasma normetanephrine and methoxytyramine were elevated more than six times above upper reference limits. A pheochromocytoma/paraganglioma, however, was excluded by functional imaging. All biochemical test results normalized after discontinuation of norepinephrine reuptake blockers. These findings clarify that norepinephrine reuptake blockers usually result in mild elevations of normetanephrine and methoxytyramine that, nevertheless, significantly increase the number of false-positive results. There can, however, be exceptions where increases in normetanephrine and methoxytyramine reach pathological levels. Such exceptions may reflect failure of centrally mediated sympathoinhibition that normally occurs with the norepinephrine reuptake blockade. [ABSTRACT FROM AUTHOR]

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Classically, neuropathic pain is described as a pain caused by a lesion or disease of the somatosensory system. However, one must note that the presence of somatosensory pathology alone does not guarantee a progression to neuropathic pain. This is due, in part, to the fact that neuropathic pain is a notoriously complex disease process, involving sensitization of both the central and peripheral nervous systems. Its causes are also numerous and varied, including trauma, the compression of a nerve, autoimmune disorders, diabetes, and infections. Due to the various manifestations, causes, and symptoms of neuropathic pain, the treatment of this disease process has proved challenging for generations of physicians. This section aims to elaborate on newly proposed mechanisms for pharmacological and targeted therapies, such as neurostimulation, which aim to reduce the negative somatosensory effects of neuropathic pain. [ABSTRACT FROM AUTHOR]

Introduction: Brachioradial pruritis is a rare dysesthesia syndrome that is known to negatively impact quality of life. No consensus exists regarding optimal treatment strategies. Methods: We searched MEDLINE, EMBASE, and the Cochrane Collaboration Clinical Trials Registry from 1966 to 2021 for studies using the title word "brachioradial pruritis" with no language restriction. One author (A.Z.) screened and performed full article reviews of all randomized clinical trials, cohort studies, case-control studies, case reports, and case series describing treatment outcomes among patients with brachioradial pruritis. Results: We identified 239 potential articles with a final set of 45 articles meeting inclusion criteria. Only a single randomized clinical trial was identified, finding no significant benefit of topical capsaicin cream. Treatment modalities with the greatest number of reported successful therapeutic trials include gabapentin and tricyclic antidepressants. In patients with confirmed cervical spine disease, spine-directed therapies such as epidural injections were found to be beneficial. Case reports and small case series describing less-common treatments were also identified. Discussion: The literature is overall limited with the greatest support for gabapentin, pregabalin, tricyclic antidepressants, and spine-directed therapies in appropriate patients with brachioradial pruritis. Future randomized clinical trials are needed to compare the relative effectiveness of available treatments.

Carbonic anhydrases (CAs) are important regulators of pH homeostasis and participate in many physiological and pathological processes. CA activators (CAAs) are becoming increasingly important in the biomedical field since enhancing CA activity may have beneficial effects at neurological level. Here, we investigate selected antihistamines, phenothiazine-based antipsychotics, and tricyclic antidepressants (TCAs) as potential activators of human CAs I, II, IV, and VII. Our findings indicate that these compounds are more effective at activating hCA II and VII compared to hCA I and IV. Overall, hCA VII was the most efficiently activated isoform, particularly by phenothiazines and TCAs. This is especially relevant since hCA VII is the most abundant isoform in the central nervous system (CNS) and is implicated in neuronal signalling and bicarbonate balance regulation. This study offers additional insights into the pharmacological profiles of clinically employed drugs and sets the ground for the development of novel optimised CAAs. [ABSTRACT FROM AUTHOR]

This article discusses a Cochrane Review on the role of antidepressants for patients with hip and knee osteoarthritis. Osteoarthritis is a common form of arthritis that causes pain and functional limitations. Antidepressants, such as tricyclic antidepressants and serotonin noradrenaline reuptake inhibitors, are sometimes recommended for pain management in osteoarthritis patients. The review found that while antidepressants had a small effect on pain and function, the improvements were clinically unimportant. However, a subpopulation of patients may respond well to antidepressants. Antidepressants also had a higher risk of adverse events compared to placebos. The article suggests that a comprehensive approach to managing osteoarthritis, including rehabilitation interventions and patient-centered decision-making, should be considered. [Extracted from the article]

Tricyclic antidepressants are commonly employed in the management of major depressive disorders. The present work describes two visible (VIS) spectrophotometric techniques that utilize the formation of charge transfer complexes between four antidepressant compounds, namely, amitriptyline hydrochloride (AMI), imipramine hydrochloride (IMI), clomipramine hydrochloride (CLO), and trimipramine maleate (TRI) acting as electron donors and two p-benzoquinones, namely, p-chloranilic acid (pCA) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), serving as electron acceptors. The stoichiometry of the compounds produced exhibited a consistent 1:1 ratio in all instances, as established by Job's method. Molar absorptivities, equilibrium association constants, and several other spectroscopic properties were determined for all complexes. The developed spectrophotometric techniques were validated intra-laboratory and successfully applied for quantitative assessment of the four antidepressant active ingredients in several commercial pharmaceutical formulations. The methods are relatively simple, fast, and use readily available laboratory instrumentation, making them easily applicable by most quality control laboratories worldwide. [ABSTRACT FROM AUTHOR]

The article focuses on treatment-resistant depression (TRD) in a patient, Ms. B, with a history of major depressive disorder (MDD) and migraines. Topics include Ms. B's extensive medication history, the definition of TRD, and the consideration of monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) as potential treatment options.

Introduction: Non-adherence to antidepressants is associated with worse disease outcomes (morbidity and mortality) and correlates with higher healthcare resource utilization and costs. Methods: A population-based registry study was conducted to assess nonadherence and to analyze the economic burden of treatment and from nonadherence to antidepressants in 2021. Non-adherence was measured by the Medication Possession Ratio and those below 80% were classified as nonadherent. Results: In 2021, 246,718 patients (10.60% [95% CI: 10.48-10.72]) received antidepressants at a cost of €29 million. The median antidepressant cost per patient/year was €70.08€, ranging from €7.58 for amitriptyline to €396.66 for agomelatine. Out-of-pocket costs represented 6.09% of total expenditures, with a median copayment of €2.78 per patient. The 19.87% [95% CI 19.52-20.22)] of patients were non-adherent to antidepressants, costing €3.9 million (13.30% of total antidepressant costs). Non-adherence rates exceeded 20% for the tricyclic antidepressants, fluoxetine (23.53%), fluvoxamine (22.42%), and vortioxetine (20.58%). Venlafaxine (14.64%) and citalopram (14.88%) had the lowest nonadherence rates, of less than 15%. The median cost of non-adherent medications per patient/year was €18.96 and ranged from €2.50 (amitriptyline) to €133.42 (agomelatine). Conclusion: Reducing non-adherence to antidepressants is critical to improving clinical and economic outcomes. The implementation of interventions and standardized measures, including early detection indicators, is urgently needed. Antidepressants differ with regard to non-adherence and their cost, and this should be considered when prescribing this medication. The Medication Possession Ratio could be used by the healthcare provider and clinician to identify non-adherent patients for monitoring, and to take necessary corrective actions. [ABSTRACT FROM AUTHOR]

Cancer is a major global public health problem with high morbidity. Depression is known to be a high-frequency complication of cancer diseases that decreases patients' life quality and increases the mortality rate. Therefore, antidepressants are often used as a complementary treatment during cancer therapy. During recent decades, various studies have shown that the combination of antidepressants and anticancer drugs increases treatment efficiency. In recent years, further emerging evidence has suggested that the modulation of autophagy serves as one of the primary anticancer mechanisms for antidepressants to suppress tumor growth. In this review, we introduce the anticancer potential of antidepressants, including tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs). In particular, we focus on their autophagy-modulating mechanisms for regulating autophagosome formation and lysosomal degradation. We also discuss the prospect of repurposing antidepressants as anticancer agents. It is promising to repurpose antidepressants for cancer therapy in the future. [ABSTRACT FROM AUTHOR]

Depression, as a common mental illness that is often accompanied by suicidal and homicidal behaviors, is one of the most important diseases in the medical field that requires urgent attention. The pathogenesis of depression is complex, and the current therapeutic drugs such as tricyclic antidepressants (TCAs), monoamine oxidase inhibitors, and secondary serotonin reuptake inhibitors have certain shortcomings. The inflammatory factor hypothesis, one of the pathogenesis of depression, suggests that inflammatory response is a key factor leading to the occurrence and development of depression, and that overactivation of inflammatory factors such as NLRP3, Toll-like receptor 4, and IDO leads to immune-system dysfunction and depression. The other pathogenic hypothesis, the gut flora hypothesis, has also been the focus of recent research. The gut flora may work together with inflammatory factors to cause depression. The approach to treating depression has been by altering the gut flora through drugs or probiotics. However, effective and clear treatment methods are lacking. In this study, by exploring the involvement of intestinal flora and inflammatory factors in the pathogenesis of depression, we found that improving the intestinal flora can affect inflammatory factors and, therefore, provide research ideas for the development of novel drugs to treat depression. [ABSTRACT FROM AUTHOR]

Introduction: Chronic tricyclic antidepressant toxicity is rarely described in children. Symptoms include confusion, ataxia, and seizures. Toxicity may result from dosing error, CYP2C19 and CYP2D6 genetic variability, and drug-drug interactions. Chronic doxepin toxicity has not been previously reported in children. Doxepin is prescribed for insomnia and depression, with a maximum off-label dose of 3 mg/kg in children. We present a case of chronic doxepin toxicity mimicking epilepsy in a child attributable to three potential factors: supratherapeutic dosing, pharmacogenomic variability, and drug-drug interactions. Case Report: A 10-year-old boy with insomnia, diagnosed with epilepsy 6 months prior, presented to an emergency department with confusion, ataxia, and increasing seizure frequency. He was prescribed doxepin for insomnia and four antiepileptics for seizures. After admission, he had two seizures and remained confused. EKGs showed QRS prolongation, suggesting doxepin toxicity. Doxepin-nordoxepin combined serum concentration was 1419 ng/mL (therapeutic 100–300 ng/mL), confirming doxepin toxicity. Outpatient records showed onset of confusion and seizures as doxepin dose was gradually uptitrated to 300 mg nightly (4.41 mg/kg). Symptoms worsened following addition of clobazam (CYP2D6 inhibitor) and topiramate (CYP2C19 inhibitor). Following doxepin discontinuation, all symptoms resolved. CYP2D6 testing showed intermediate metabolizer phenotype (CYP2D6*1/*4; activity score = 1.0; copy number = 2.0). No seizures have occurred in more than one year since doxepin discontinuation. Discussion: Caution must be exercised when prescribing doxepin. Pharmacogenomics, dose, drug-drug interactions, and age should be considered. Chronic toxicity should be contemplated in patients taking doxepin without acute overdose who present with persistent neurologic abnormalities including seizure. [ABSTRACT FROM AUTHOR]

Antidepressants are widely used in neurological practice, and their use in stroke, Alzheimer's disease, depression with cognitive impairment, Parkinson's disease, multiple sclerosis, chronic back pain and chronic migraine is discussed. Antidepressants are used in the presence of severe depressive symptoms, which are observed in 20–30% of neurological patients. The effect of antidepressants is higher in case of combination with recurrent depression. Presence of episodes of depression before the development of a neurological disease, history of effectiveness of antidepressants, hereditary burden of affective disorders, characteristic daily dynamics of symptoms with typical impaired sleep architecture indicate the likelihood of a combined affective disorder. Final establishment of a psychiatric diagnosis is possible with a consultation of a neurological patient by a psychiatrist, but in clinical practice this is realistic only in a small number of patients. The most commonly used antidepressants are selective serotonin reuptake inhibitors, selective serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants in low or medium doses, the duration of their administration is usually at least 3-6 months. In neurological diseases, the effectiveness of only some drugs has been noted, many antidepressants have not been studied in neurological diseases, but this does not exclude their effectiveness. When prescribing antidepressants, it is necessary to take into account possible drug interactions and avoid those combinations that may cause adverse reactions. It is advisable to use antidepressants in complex therapy in combination with an educational program, cognitive behavioral therapy and kinesiotherapy. Many questions regarding the efficacy and safety of treatment, the choice of the optimal antidepressant, its dosage and duration of use require further study.

Imipramine is a tricyclic antidepressant typically reserved for patients with treatment‐resistant mood disorders. A rare side effect of long‐term use of imipramine is a slowly progressive melanin‐associated, slate gray‐blue hyperpigmentation of the skin in a photo‐distributed pattern. We report a case of imipramine‐induced hyperpigmentation developing 50 years after initiating imipramine therapy, whose lesions were essentially devoid of melanin on histopathological exam. This differs from all other reported cases of imipramine‐induced hyperpigmentation in two notable respects. First, the time between initiating imipramine therapy and the onset of pigmentation changes was nearly 30 years longer than prior case reports. Second, the lack of melanin in our samples suggests a divergence from the hypothesized melanin‐imipramine complex mechanism of hyperpigmentation. Instead, we propose a novel pathogenesis of imipramine‐induced hyperpigmentation that is unrelated to melanin. [ABSTRACT FROM AUTHOR]

Tricyclic antidepressants (TCAs) are frequently prescribed for chronic functional pain disorders. Although the mechanism of action targets pain perception, treating patients with TCAs for disorders conceptualized as "functional" can promote stigmatization in these patients because it hints at psychological dimensions of the disorder. The goal of this study was to understand how physicians prescribe TCAs in the face of this challenge. We interviewed eleven gastroenterologists in tertiary care clinics specializing in functional gastrointestinal disorders, such as irritable bowel syndrome. We found that the physicians interviewed (1) were aware of the stigma attached to taking antidepressants for a medical condition, (2) emphasized biological, as opposed to psychological, mechanisms of action, (3) while focusing on biological mechanisms, they nevertheless prescribed TCAs in a way that is highly attentive to the psychology of expectations, making specific efforts to adjust patients' expectations to be realistic and to reframe information that would be discouraging and (4) asked patients to persist in taking TCAs despite common and, at times, uncomfortable side effects. In this context of shared decision making, physicians described nuanced understanding and behaviours necessary for treating the complexity of functional disorders and emphasized the importance of a strong patient-provider relationship. [ABSTRACT FROM AUTHOR]

7 b Scores from 5 to 17 are considered positive as indicated in the ESCD patch test guideline.[1] Six weeks after patch testing, the patient presented with a pruritic papulovesicular reaction on sites of the positive patch test reactions to doxepin hydrochloride tablet 0.01 pet. and 0.01% aq. (Figure 2A-C). Patch testing with doxepin in aqua and strong/extreme positive patch test reactions to doxepin even at 0.01% in pet. and aq. were other unique features. Keywords: allergic contact dermatitis; aqua; case report; deposition; dilution series; doxepin; long-lasting; patch test; persistent; skin accumulation EN allergic contact dermatitis aqua case report deposition dilution series doxepin long-lasting patch test persistent skin accumulation 209 212 4 08/04/23 20230901 NES 230901 Doxepin is a tricyclic antidepressant drug with potent H1- and H2-antihistaminic properties. [Extracted from the article]

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Microemulsions are nanocolloidal systems composed of water, an oil, and a surfactant, sometimes with an additional co-surfactant, which have found a wide range of practical applications, including the extractive removal of contaminants from polluted water. In this study, microemulsion systems, including a nonionic surfactant (Brij 30), water, and esters selected from two homologous series of C1–C6 alkyl acetates and ethyl C1–C4 carboxylates, respectively, were prepared by the surfactant titration method. Phase transitions leading to the formation of Winsor II and Winsor IV microemulsions were observed and phase diagrams were constructed. The dependences of phase transitions on the salinity and pH and the addition of isopropanol as a co-surfactant were also investigated. Some physical properties, namely density, refractive index, electrical conductivity, dynamic viscosity, and particle size, were measured for a selection of Winsor IV microemulsions, providing further insight into some other phase transitions occurring in the monophasic domains of phase diagrams. Finally, Winsor II microemulsions were tested as extraction solvents for the removal of four tricyclic antidepressant drugs from aqueous media. Propyl acetate/Brij 30/H2O microemulsions provided the best extraction yields (>90%), the highest Nernst distribution coefficients (~40–88), and a large volumetric ratio of almost 3 between the recovered purified water and the resulting microemulsion extract. Increasing the ionic strength (salinity) or the pH of the aqueous antidepressant solutions led to an improvement in extraction efficiencies, approaching 100%. These results could be extrapolated to other classes of pharmaceutical contaminants and suggest ester- and nonionic surfactant-based microemulsions are a promising tool for environmental remediation. [ABSTRACT FROM AUTHOR]

Objective: Management of emergency care. Background: Tricyclic antidepressant (TCA) drugs are a common cause of fatal poisoning because of their cardiotoxic and arrhythmogenic effects. Classic supportive management includes sodium bicarbonate, gastrointestinal chelating agents, and vasopressors. Recently, intravenous lipid emulsion (supported by a low evidence level) has also been used. Case Report: We report the case of a 55-year-old woman admitted to our Intensive Care Unit (ICU) with acute imipramine self-poisoning. She arrived at the emergency department 7 hours after imipramine ingestion; she had severe rhabdomyolysis upon admission, with creatine phosphokinase levels at about 52 500 IU/L (normal, <200 IU/L). She quickly developed cardiogenic shock and malign arrhythmia requiring veno-arterial extra corporeal membrane oxygenation (VA-ECMO). Continuous renal replacement therapy (CRRT) with CytoSorb® (CytoSorbents, Monmouth Junction, New York, United Sates of America) was started 19 hours after admission. We performed serial blood measurements of imipramine and its active metabolite desipramine as well as viewing the levels on the CRRT-circuit monitor. Cardiac function improved and ECMO was explanted after 4 days. She also had severe acute respiratory distress syndrome, which resolved spontaneously. The neurologic outcome was favorable despite early myoclonus. The patient regained consciousness on the fifth day. Her clinical evolution was marked by acute ischemia of the lower left limb due to the arterial ECMO cannula. Conclusions: These measurements document the efficacy of the CytoSorb® adsorber in removing a lipophilic drug from a patient's bloodstream. To our knowledge, this is the first published case of CytoSorb® extracorporeal blood purification therapy for acute TCA poisoning. [ABSTRACT FROM AUTHOR]

Migraine is a chronic neurological disorder that frequently coexists with different vestibular and cochlear symptoms (sudden hearing loss, tinnitus, otalgia, aural fullness, hyperacusis, dizziness, imbalance, and vertigo) and disorders (recurrent benign positional vertigo, persistent postural perceptual dizziness, mal de debarquement, and Menière's disease). Despite evidence of an epidemiological association and similar pathophysiology between migraine and these vestibulocochlear disorders, patients suffering from migraine-related symptoms are usually underdiagnosed and undertreated. Current migraine treatment options have shown success in treating vestibulocochlear symptoms. Lifestyle and dietary modifications (reducing stress, restful sleep, avoiding migraine dietary triggers, and avoiding starvation and dehydration) and supplements (vitamin B2 and magnesium) offer effective first-line treatments. Treatment with migraine prophylactic medications such as tricyclic antidepressants (e.g., nortriptyline), anticonvulsants (e.g., topiramate), and calcium channel blockers (e.g., verapamil) is implemented when lifestyle and dietary modifications are not sufficient in improving a patient's symptoms. We have included an algorithm that outlines a suggested approach for addressing these symptoms, taking into account our clinical observations. Greater recognition and understanding of migraine and its related vestibular and cochlear symptoms are needed to ensure the appropriate diagnosis and treatment of affected patients. [ABSTRACT FROM AUTHOR]

Pancreatic adenocarcinoma (PDAC) is one of the most common cancers worldwide. Unfortunately, the prognosis of PDAC is rather poor, and for instance, in the USA, over 47,000 people die because of pancreatic cancer annually. Here, we demonstrate that high expression of acid sphingomyelinase in PDAC strongly correlates with long-term survival of patients, as revealed by the analysis of two independent data sources. The positive effects of acid sphingomyelinase expression on long-term survival of PDAC patients were independent of patient demographics as well as tumor grade, lymph node involvement, perineural invasion, tumor stage, lymphovascular invasion, and adjuvant therapy. We also demonstrate that genetic deficiency or pharmacological inhibition of the acid sphingomyelinase promotes tumor growth in an orthotopic mouse model of PDAC. This is mirrored by a poorer pathologic response, as defined by the College of American Pathologists (CAP) score for pancreatic cancer, to neoadjuvant therapy of patients co-treated with functional inhibitors of the acid sphingomyelinase, in particular tricyclic antidepressants and selective serotonin reuptake inhibitors, in a retrospective analysis. Our data indicate expression of the acid sphingomyelinase in PDAC as a prognostic marker for tumor progression. They further suggest that the use of functional inhibitors of the acid sphingomyelinase, at least of tricyclic antidepressants and selective serotonin reuptake inhibitors in patients with PDAC, is contra-indicated. Finally, our data also suggest a potential novel treatment of PDAC patients with recombinant acid sphingomyelinase. Key messages: Pancreatic ductal adenocarcinoma (PDAC) is a common tumor with poor prognosis. Expression of acid sphingomyelinase (ASM) determines outcome of PDAC. Genetic deficiency or pharmacologic inhibition of ASM promotes tumor growth in a mouse model. Inhibition of ASM during neoadjuvant treatment for PDAC correlates with worse pathology. ASM expression is a prognostic marker and potential target in PDAC. [ABSTRACT FROM AUTHOR]

Neuropathic pain is a debilitating condition characterized by abnormal signaling within the nervous system, resulting in persistent and often intense sensations of pain. It can arise from various causes, including traumatic nerve injury, neuropathy, and certain diseases. We present an overview of current and emerging pharmacotherapies for neuropathic pain, focusing on novel drug targets and potential therapeutic agents. Current pharmacotherapies, including tricyclic antidepressants, gabapentinoids, and serotonin norepinephrine re-uptake inhibitors, are discussed, as are emerging treatments, such as ambroxol, cannabidiol, and N-acetyl-L-cysteine. Additionally, the article highlights the need for further research in this field to identify new targets and develop more effective and targeted therapies for neuropathic pain management. [ABSTRACT FROM AUTHOR]

Cyclodextrin-based delivery systems have been intensively used to improve the bioavailability of drugs through the modification of their pharmaceutically relevant properties, such as solubility, distribution and membrane permeation. The present work aimed to disclose the influence of HP-β-CD and SBE-β-CD on the distribution and permeability of nortriptyline hydrochloride (NTT•HCl), a tricyclic antidepressant drug. To this end, the distribution coefficients in the 1-octanol/buffer and n-hexane/buffer model systems and the coefficients of permeability through the cellulose membrane and lipophilic PermeaPad barrier were determined at several cyclodextrin concentrations. The results demonstrated a dramatic decrease in both the distribution and the permeability coefficients as the cyclodextrin concentration rose, with the decrease being more pronounced in SBE-β-CD due to the charge–charge attraction and electrostatic interactions between NTT and SBE-β-CD. It is these interactions that were shown to be responsible for the greater value of the constant of NTT's association with SBE-β-CD than that with HP-β-CD. The findings of this study revealed similar trends in the 1-octanol/buffer 6.8 pH distribution and permeability through the PermeaPad barrier in the presence of CDs. These results were attributed to the determinative role of the distribution coefficient (serving as a descriptor) in permeation through the PermeaPad barrier modeling the lipophilic nature of biological barriers. [ABSTRACT FROM AUTHOR]

Cyclic vomiting syndrome (CVS) is a chronic disorder of gut-brain interaction characterized by recurrent disabling episodes of nausea, vomiting, and abdominal pain. CVS affects both children and adults with a prevalence of approximately 2% in the United States. CVS is more common in female individuals and affects all races. The pathophysiology of CVS is unknown and a combination of genetic, environmental, autonomic, and neurohormonal factors is believed to play a role. CVS is also closely associated with migraine headaches and likely have a shared pathophysiology. The diagnosis of CVS is based on the Rome criteria, andminimal recommended testing includes anupper endoscopy andimaging studies of the abdomen.CVSis frequently associated with anxiety, depression, and autonomic dysfunction. Patients with CVS commonly use cannabis therapeutically for symptom relief. By contrast, cannabinoid hyperemesis syndrome is believed to be a subset of CVS with chronic heavy cannabis use leading to hyperemesis. Due to the recalcitrant nature of the illness, patients often visit the emergency department and are hospitalized for acute CVS flares. Guidelines on themanagement of CVS recommend a biopsychosocial approach. Prophylactic therapy consists of tricyclic antidepressants (amitriptyline), antiepileptics (topiramate), and aprepitant in refractory patients. Abortive therapy consists of triptans, antiemetics (ondansetron), and sedation. Treatment of comorbid conditions is extremely important to improve overall patient outcomes. CVS has a significant negative impact on patients, families, and the healthcare system, and future research to understand its pathophysiology and develop targeted therapies is needed. [ABSTRACT FROM AUTHOR]

In Functional gastrointestinal disorders, there is a paucity of knowledge regarding the fundamental physical and chemical anomalies, thus it can be solely diagnosed by symptomatology. They are triggered by gastrointestinal problems like changes in gut permeability, propulsion, gut flora, immunological response, and central nervous system function. The patient's nonadaptive behaviors, anxiety and concurrent psychiatric disorders all make these symptoms worse and result in long-lasting symptoms that affect the entire gut, such as discomfort, indigestion, and disturbed bowel habits. A biopsychosocial approach to management entails dietary and nutritional adjustments, modifications in lifestyle recommendations, and the use of medicine to address underlying pathophysiology. Functional gastrointestinal disorders are treated with antidepressants, antipsychotics and various medications that target the central nervous system. These drugs are now referred to as neuromodulators. Patients may benefit from using tricyclic antidepressants, selective serotonin reuptake inhibitors, and various central neuromodulators, but there are also risks involved. The different approaches to treat functional gastrointestinal problems are described in this review paper. The various negative effects of central neuromodulators as well as the processes by which they operate, the distinctions between the various classes and types of agents, and how they differ from one another are discussed in this paper. [ABSTRACT FROM AUTHOR]

Changes in the utilization patterns of antidepressants have been noticed worldwide, with tricyclic antidepressants and monoamine oxidase inhibitors being gradually replaced by selective serotonin reuptake inhibitors (SSRI) and newer antidepressants. The aim of this study was to assess drug utilization pattern and conformity with WHO prescribing indicators and 2nd edition of Nigerian Standard Treatment Guidelines (STG) in patients with major depressive disorder. A five-year (1st January 2014 - 31st December 2018) retrospective study of 615 prescriptions of patients with major depressive disorder attending Federal Neuro-Psychiatric Hospital Maiduguri was carried out from March to early April 2019. A data collection form was used to obtain drug information and conformity with WHO prescribing indicators and STG. Data were analysed using SPSS version 20. Results were presented as percentages and mean ± SD. The most common prescribed regimen for the management of depression was amitriptyline (a tricyclic antidepressant), which accounted for 305 (49.6%) prescriptions. These regimens were the least expensive drugs with an average daily cost of - 31.4 ± 9.5. Only few prescriptions contained SSRI as follows: 30 (4.9 %), 15 (2.4%) and 50 (8.1%) of escitalopram, paroxetine and fluoxetine, respectively. Also, 89.4% of the antidepressants prescribed were from the 6th edition of Nigerian National Essential Medicines List, while 88.6 % were from the 2nd edition of the Nigerian STG. In conclusion, the most commonly prescribed antidepressants class were the tricyclics; particularly amitriptyline. This class also had the least average daily cost (approximately - 31.00 for amitriptyline). Almost all of the antidepressants prescribed for these patients conformed to written recommendations in the WHO prescribing indicators and the 2nd edition of Nigerian STG. [ABSTRACT FROM AUTHOR]

Clomipramine, a tricyclic antidepressant used to treat depression and obsessive-compulsive disorder, has been linked to a few cases of acute hepatotoxicity. It is also recognized as a compound that hinders the functioning of mitochondria. Hence, the effects of clomipramine on mitochondria should endanger processes that are somewhat connected to energy metabolism in the liver. For this reason, the primary aim of this study was to examine how the effects of clomipramine on mitochondrial functions manifest in the intact liver. For this purpose, we used the isolated perfused rat liver, but also isolated hepatocytes and isolated mitochondria as experimental systems. According to the findings, clomipramine harmed metabolic processes and the cellular structure of the liver, especially the membrane structure. The considerable decrease in oxygen consumption in perfused livers strongly suggested that the mechanism of clomipramine toxicity involves the disruption of mitochondrial functions. Coherently, it could be observed that clomipramine inhibited both gluconeogenesis and ureagenesis, two processes that rely on ATP production within the mitochondria. Half-maximal inhibitory concentrations for gluconeogenesis and ureagenesis ranged from 36.87 μM to 59.64 μM. The levels of ATP as well as the ATP/ADP and ATP/AMP ratios were reduced, but distinctly, between the livers of fasted and fed rats. The results obtained from experiments conducted on isolated hepatocytes and isolated mitochondria unambiguously confirmed previous propositions about the effects of clomipramine on mitochondrial functions. These findings revealed at least three distinct mechanisms of action, including uncoupling of oxidative phosphorylation, inhibition of the F o F 1 -ATP synthase complex, and inhibition of mitochondrial electron flow. The elevation in activity of cytosolic and mitochondrial enzymes detected in the effluent perfusate from perfused livers, coupled with the increase in aminotransferase release and trypan blue uptake observed in isolated hepatocytes, provided further evidence of the hepatotoxicity of clomipramine. It can be concluded that impaired mitochondrial bioenergetics and cellular damage are important factors underlying the hepatotoxicity of clomipramine and that taking excessive amounts of clomipramine can lead to several risks including decreased ATP production, severe hypoglycemia, and potentially fatal outcomes. [Display omitted] • Mitochondria may be important toxicological targets for clomipramine. • Clomipramine impairs mitochondrial bioenergetics in different ways. • Clomipramine lowers cellular ATP levels and compromises energy-related hepatic metabolism. • Clomipramine is highly capable of causing a substantial reduction in cell viability. • When administered at high doses and for extended periods, clomipramine may harm the liver. [ABSTRACT FROM AUTHOR]

Tricyclic antidepressant is an old and well-established therapeutic agent with a good safety profile, making them an excellent candidate for repurposing. In light of the growing understanding of the importance of nerves in the development and progression of cancer, attention is now being turned to using nerve-targeting drugs for the treatment of cancer, particularly TCAs. However, the specific mechanism by which antidepressants affect the tumor microenvironment of glioblastoma (GBM) is still unclear. Here, we combined bulk RNA sequencing, network pharmacology, single-cell sequencing, molecular docking and molecular dynamics simulation to explore the potential molecular mechanism of imipramine in the treatment of GBM. We first revealed that the imipramine treatment is presumed to target EGFRvIII and neuronal-derived EGFR, which may play a pivotal role in treating GBM by reducing the GABAergic synapse and vesiclemediated release and other processes thereby modulating immune function. The novel pharmacological mechanisms might provide further research directions. [ABSTRACT FROM AUTHOR]

• Tricyclic antidepressants significantly decrease cardiac parasympathetic activity. • Selective serotonin reuptake inhibitors (SSRIs) reduce skin conductance response. • SSRIs have insignificant or inconclusive effects on heart rate variability. • Agomelatine has a beneficial effect on cardiac autonomic regulation. Changes in cardiac autonomic nervous system (ANS) regulation observed in psychiatric disorders may be mitigated by antidepressants. We meta-analyzed and systematically reviewed studies examining antidepressants' effects on ANS outcomes, including heart rate variability (HRV). We conducted a PRISMA/MOOSE-compliant search of PubMed and Scopus until March 28th, 2022. We included randomized placebo-controlled trials (RCTs) and pre-post studies, regardless of diagnosis. We pooled results in random-effects meta-analyses, pooling homogeneous study designs and outcomes. We conducted sensitivity analyses and assessed quality of included studies. Thirty studies could be meta-analyzed. Selective serotonin reuptake inhibitors (SSRIs) were significantly associated with a reduction in the square root of the mean-squared difference between successive R-R intervals (RMSSD) (SMD= -0.48) and skin conductance response (SMD= -0.55) in RCTs and with a significant increase in RMSSD in pre-post studies (SMD=0.27). In pre-post studies, tricyclic antidepressants (TCAs) were associated with a significant decrease in several HRV outcomes while agomelatine was associated with a significant increase in high frequency power (SMD= 0.14). In conclusion, SSRIs reduce skin conductance response but have no or inconclusive effects on other ANS outcomes, depending on study design. TCAs reduce markers of parasympathetic function while agomelatine might have the opposite effect. Studies are needed to investigate the impact of SSRIs on the recovery of cardiac ANS regulation after acute myocardial infarction, and the effects of newer antidepressants. [ABSTRACT FROM AUTHOR]

Some of the most commonly used analgesic drugs in animals are of questionable efficacy or present adverse side effects among the various species of reptiles. Tricyclic antidepressants have been demonstrated to have antinociceptive effects in several animal models of pain and could be a good alternative for use in reptiles. The aim of the study was to investigate the antinociceptive effects of nortriptyline and desipramine hydrochloride in Speke's hinge‐back tortoise. A total of 24 animals weighing 600–1000 g were used for nociceptive tests, i.e., formalin, capsaicin, and hot plate tests. Drugs were administered intracoelomically 30 min before starting the tests. The time spent in nocifensive behavior and the associated observable effects during the tests were recorded. Only the highest dose of 40 mg/kg of nortriptyline hydrochloride caused statistically significant decrease in nocifensive behavior in both the formalin and the capsaicin test. Desipramine hydrochloride at doses of 20 and 40 mg/kg caused statistically significant decrease in nocifensive behavior in the formalin test. Also, desipramine hydrochloride at doses of 15, 20, and 60 mg/kg caused statistically significant decrease in nocifensive behavior in the capsaicin test. None of the doses used for both drugs had any statistically significant effect on nocifensive behavior in the hot plate test. The results show that nortriptyline and desipramine hydrochloride have significant antinociceptive effects in the chemical but not thermal inflammatory pain‐related behavior in the Speke's hinge‐back tortoise. The most common associated side effect following administration of the higher doses of either of the drugs is excessive salivation. [ABSTRACT FROM AUTHOR]

Traditionally prescribed for mood disorders, tricyclic antidepressants (TCAs) have shown promising therapeutic effects on chronic neuralgia and irritable bowel syndrome. However, the mechanism by which these atypical effects manifest is unclear. Among the proposed mechanisms is the well-known pain-related inhibitory G-protein coupled receptor, namely the opioid receptor (OR). Here, we confirmed that TCA indeed stimulates OR and regulates the gating of TRPC4, a downstream signaling of the Gi-pathway. In an ELISA to quantify the amount of intracellular cAMP, a downstream product of OR/Gi-pathway, treatment with amitriptyline (AMI) showed a decrease in [cAMP]i similar to that of the μOR agonist. Next, we explored the binding site of TCA by modeling the previously revealed ligand-bound structure of μOR. A conserved aspartate residue of ORs was predicted to participate in salt bridge interaction with the amine group of TCAs, and in aspartate-to-arginine mutation, AMI did not decrease the FRET-based binding efficiency between the ORs and Gαi2. As an alternative way to monitor the downstream signaling of Gi-pathway, we evaluated the functional activity of TRPC4 channel, as it is well known to be activated by Gαi. TCAs increased the TRPC4 current through ORs, and TCA-evoked TRPC4 activation was abolished by an inhibitor of Gαi2 or its dominant-negative mutant. As expected, TCA-evoked activation of TRPC4 was not observed in the aspartate mutants of OR. Taken together, OR could be proclaimed as a promising target among numerous binding partners of TCA, and TCA-evoked TRPC4 activation may help to explain the nonopioid analgesic effect of TCA. NEW & NOTEWORTHY Endogenous opioid systems modulate pain perception, but concerns about opioid-related substance misuse limit their use. This study has raised TRPC4 channel as a candidate target for alternative analgesics, tricyclic antidepressants (TCAs). TCAs have been shown to bind to and activate opioid receptors (ORs), leading to downstream signaling pathways involving TRPC4. The functional selectivity and biased agonism of TCA towards TRPC4 in dependence on OR may provide a better understanding of its efficacy or side effects. [ABSTRACT FROM AUTHOR]

Background: Electroacupuncture (EA) is a promising therapy for depression. However, a comprehensive review of EA for depression is needed. Methods: We conducted a systematic review and meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA 2020) guidelines to evaluate the efficacy and safety of EA for depression. Potentially relevant trials and reviews were searched in MEDLINE, EMBASE, PsycINFO, and CENTRAL from inception to March 2022. EA alone and combined with other therapy were eligible for inclusion. The severity of depression during and after treatment and the number of adverse events were assessed as outcomes. Risk of bias (ROB) evaluation, subgroup analysis, sensitivity analysis, reporting bias assessment, and GRADE system evaluation were also conducted. Results: Thirty-four trials were included. The overall ROB was medium. Low-quality evidence showed that the efficacy of EA was not less than that of antidepressants [EA + selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs)] and manual acupuncture (MA). EA and EA + SSRIs had better efficacy than SSRIs alone in decreasing the severity of depression during the early treatment. Moderate-quality evidence also showed that EA and EA + SSRIs were safer than SSRIs alone. Sensitivity analysis was mostly not feasible. Major publication bias was unlikely. Conclusion: These results indicate that the efficacy of EA is not less than that of antidepressants and MA. Moreover, EA and EA + SSRI treatments show a more rapid onset and greater safety than SSRIs. More high-quality trials are needed for further confirmation. [ABSTRACT FROM AUTHOR]