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Aims: In many countries, pain is the most common indication for use of antidepressants in older adults. We reviewed the evidence from randomized controlled trials on the efficacy and safety of antidepressants, compared to all alternatives for pain in older adults (aged ≥65 years). Methods: Trials published from inception to 1 February 2024, were retrieved from 13 databases. Two independent reviewers extracted data on study and participant characteristics, primary efficacy (pain scores, converted to 0–100 scale) and harms. Estimates for efficacy were pooled using a random effects model and reported as difference in means and 95% CI. Quality of included trials was assessed using the Cochrane risk of bias tool. Results: Fifteen studies (n = 1369 participants) met the inclusion criteria. The most frequently studied antidepressants were duloxetine and amitriptyline (6/15 studies each). Pain related to knee osteoarthritis was the most studied (6/15 studies). For knee osteoarthritis, antidepressants did not provide a statistically significant effect for the immediate term (0–2 weeks), (−5.6, 95% confidence interval [CI]: −11.5 to 0.3), but duloxetine provided a statistically significant, albeit a very small effect in the intermediate term, (≥6 weeks and <12 months), (−9.1, 95% CI: −11.8 to −6.4). Almost half (7/15) of the studies reported increased withdrawal of participants in the antidepressant treatment group vs. the comparator group due to adverse events. Conclusions: For most chronic painful conditions, the benefits and harms of antidepressant medicines are unclear. This evidence is predominantly from trials with sample sizes of <100, have disclosed industry ties and classified as having unclear or high risk of bias. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome (IBS) is a highly prevalent and debilitating disorder of gut–brain interaction (DGBI) affecting millions globally. It imposes a significant burden on healthcare systems and is a leading cause of workplace absenteeism. IBS is classified into several subtypes based on predominant presenting symptoms, including IBS with constipation (IBS-C) and IBS with diarrhea (IBS-D), with each requiring targeted approaches to treatment. Some treatments, such as psychotherapy, dietary intervention, and medications like tricyclic antidepressants, are nonspecific and recommended for managing IBS symptoms across all subtypes. In contrast, therapies like secretagogues for IBS-C and eluxadoline or rifaximin for IBS-D are subtype-specific. However, many IBS treatments carry conditional recommendations and are based on low-certainty evidence, emphasizing the need for further research to expand the available treatment options. This review compares the latest IBS management guidelines from the American Gastroenterological Association (AGA), American College of Gastroenterology (ACG), British Society of Gastroenterology (BSG), and European Society for Neurogastroenterology and Motility (ESNM). Pharmacologic and non-pharmacologic therapies, including established and emerging interventions, will be explored to provide a comprehensive guide to management. [ABSTRACT FROM AUTHOR]

Background/Objectives: The rising use of antidepressants is linked to oral health risks, including xerostomia, caries, and periodontal disease. Recognizing these risks is essential for improving patient care. To systematically review oral manifestations in patients undergoing antidepressant treatment. Methods: This review follows the PRISMA guidelines and includes observational studies published in the last 21 years. A PICO-based question was developed to select relevant studies, which were assessed for quality using a modified STROBE checklist. Results: A total of 11 studies were analyzed, revealing a consistent association between antidepressant use and the increased risk of xerostomia, caries, and periodontal disease. Additional findings included taste dysfunction and oral bleeding complications. Among the antidepressants, selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) were most commonly associated with xerostomia and caries. However, no significant impact was observed on the chemical composition of saliva or on hemostasis in invasive dental procedures. Conclusions: Antidepressant use may lead to significant oral health issues, notably xerostomia and caries. Further studies are recommended to clarify the influence of specific antidepressants and confounding factors, such as treatment duration, dosage, and hygiene habits, on oral health outcomes. [ABSTRACT FROM AUTHOR]

Peripheral neuropathic pain is common in patients with peripheral nerve injury and can significantly impact both their function and quality of life. There is a wide variety of non‐interventional treatment approaches, including pharmacologic therapy, physical/occupational therapy, modalities (therapeutic, mechanical, thermal, etc.), psychology, and lifestyle modification. First line pharmacologic therapy for peripheral neuropathic pain includes gabapentinoids, tricyclic antidepressants, and serotonin‐norepinephrine reuptake inhibitors. Other classes of medications, such as topical treatments, opioids, and cannabinoids, have more limited usefulness in treatment but remain part of a treatment regimen. Physical and occupational therapy, psychological interventions, and lifestyle medicine are important adjuncts in the treatment and prevention of future peripheral neuropathic pain. The strength of the evidence supporting each intervention varies, with that for pharmacologic intervention being the strongest. A combination of these options tailored to the individual needs of the patient likely will result in the best treatment outcome for peripheral neuropathic pain. [ABSTRACT FROM AUTHOR]

Dibenzocycloheptene antidepressants are tricyclic antidepressants (TCAs) that contain the dibenzocycloheptene moiety in their chemical structures. They are used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Herein, we report the synthesis of a pure tricyclic antidepressant containing dibenzocycloheptene moiety named N-(5H-dibenzo[a,d][7]annulen-5-ylidene)-2-methylpropane-2-sulfinamide (3) in high chemical yield through condensing (R)-tert-butanesulfinamide with a dibenzosuberon ketone. Its structure is elucidated by employing the X-ray technique, NMR spectroscopy characterization, and DFT calculations at the B3LYP/6-31++G(d,p) level of theory. The geometrical parameters are relatively well reproduced, and the optimized and X-ray geometries are relatively well superimposed. The interconnects in the crystalline form of 3 were identified through the analysis of its Hirshfeld surface (HS) and fingerprint plots. The highest interatomic contacts were found between H...H of 58.2% and C.H of 30.6%. Further, the ADMET (absorption, distribution, metabolism, excretion, and toxicity) pharmacokinetics, and physicochemical properties of 3 were determined, which showed that 3 may act as a carbonic Anhydrase I inhibitor. The binding affinity of 3 into the binding site of carbonic Anhydrase I is investigated using a molecular docking study. It forms a stable complex into the binding site of CA I with a binding energy of −7.12 kcal/mol. [ABSTRACT FROM AUTHOR]

As the most common psychiatric symptom, depression represents a subject of high interest for the medical community. Background/Objectives: International guidelines consider selective serotonin reuptake inhibitors (SSRIs) the first-line treatment of depression. Although having better efficacy and tolerability in comparison to tricyclic antidepressants or monoamine oxidase inhibitors, the diversity and potential severity of adverse effects and interactions manifested by SSRIs, combined with the frequency of prescriptions, lead to the necessity of evaluating real-world data. The aim of this study was to identify and evaluate the drug interactions reported in EudraVigilance (EV) for the six SSRIs representatives that are authorized in Europe: fluoxetine (FXT), fluvoxamine (FVM), citalopram (CIT), escitalopram (ESC), paroxetine (PAR) and sertraline (SER). The entire class of SSRIs was examined as a comparator to identify whether one of the representatives was more prone to reporting. Methods: Descriptive analysis and disproportionality analysis were conducted on data extracted from the EV database. Results: A total of 326,450 adverse reactions (ADRs) were reported for the SSRIs group. Approximately a quarter of these (n = 83,201; 25.46%) were reported for SER and 22.37% (n = 73,131) for PAR. Of the total ADRs reported, 2.12% (n = 6925) represent preferred terms related to drug-drug interactions (DDIs): SER (n = 1474; 22.37%), CIT (n = 1272, 19.86), and FXT (n = 1309, 19.83%). Specific ADRs related to inhibitory activity represent 0.98%, and for potentiating activity, 1.89%. Conclusions: Although representing a small value of the total ADRs, DDIs may be related to severe outcomes. Awareness should be raised for this category of ADRs that can be reduced by the joined efforts of physicians and pharmacists. [ABSTRACT FROM AUTHOR]

Amitriptyline is a tricyclic antidepressant commonly used for depressive disorders and is prescribed off-label for several neurological conditions like neuropathic pain, migraines and anxiety. Besides their action on the reuptake of monoaminergic neurotransmitters, tricyclic antidepressants interact with several additional targets that may contribute to either therapeutic or adverse effects. Here, we investigated the effects of amitriptyline on proliferation and autophagy (i.e., an evolutionarily conserved catabolic pathway responsible for the degradation and recycling of cytoplasmic material) in human SH-SY5Y neuroblastoma cell cultures. The dose and time-dependent upregulation of the autophagy marker LC3II and the autophagy receptor p62, with the accumulation of LAMP1 positive compartments, were observed in SH-SY5Y cells exposed to the amitriptyline. These effects were accompanied by reduced cell viability and decreased clonogenic capacity, without a significant induction of apoptosis. Decrease viability and clonogenic activity were still observed in autophagy deficient Atg5−/− MEF and following pre-treatment of SH-SY5Y culture with the autophagy inhibitor chloroquine, suggesting that they were independent from autophagy modulation. Our findings demonstrate that amitriptyline acts on pathways crucial for cell and tissue homeostasis (i.e., autophagy and proliferation) and pose the basis for further studies on the potential therapeutic application of amitriptyline, as well as the consequences of its use for long-term treatments. [ABSTRACT FROM AUTHOR]

Key Points: Question: To what extent do differences in clinician setting explain variability in major depression treatments and outcomes? Findings: In this cohort study derived from electronic health record data, antidepressant prescribing patterns and outcomes varied significantly between prescriber groups. Clinician clusters were significantly associated with clinical outcomes. Meaning: Studies of antidepressant prescribing in real-world settings, and efforts at risk stratification or personalization of care, should include information on treatment setting and other clinician-level factors alongside individual patient characteristics. Importance: While abundant work has examined patient-level differences in antidepressant treatment outcomes, little is known about the extent of clinician-level differences. Understanding these differences may be important in the development of risk models, precision treatment strategies, and more efficient systems of care. Objective: To characterize differences between outpatient clinicians in treatment selection and outcomes for their patients diagnosed with major depressive disorder across academic medical centers, community hospitals, and affiliated clinics. Design, Setting, and Participants: This was a longitudinal cohort study using data derived from electronic health records at 2 large academic medical centers and 6 community hospitals, and their affiliated outpatient networks, in eastern Massachusetts. Participants were deidentified clinicians who billed at least 10 International Classification of Diseases, Ninth Revision (ICD-9) or Tenth Revision (ICD-10) diagnoses of major depressive disorder per year between 2008 and 2022. Data analysis occurred between September 2023 and January 2024. Main Outcomes and Measures: Heterogeneity of prescribing, defined as the number of distinct antidepressants accounting for 75% of prescriptions by a given clinician; proportion of patients who did not return for follow-up after an index prescription; and proportion of patients receiving stable, ongoing antidepressant treatment. Results: Among 11 934 clinicians treating major depressive disorder, unsupervised learning identified 10 distinct clusters on the basis of ICD codes, corresponding to outpatient psychiatry as well as oncology, obstetrics, and primary care. Between these clusters, substantial variability was identified in the proportion of selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, and tricyclic antidepressants prescribed, as well as in the number of distinct antidepressants prescribed. Variability was also detected between clinician clusters in loss to follow-up and achievement of stable treatment, with the former ranging from 27% to 69% and the latter from 22% to 42%. Clinician clusters were significantly associated with treatment outcomes. Conclusions and Relevance: Groups of clinicians treating individuals diagnosed with major depressive disorder exhibit marked differences in prescribing patterns as well as longitudinal patient outcomes defined by electronic health records. Incorporating these group identifiers yielded similar prediction to more complex models incorporating individual codes, suggesting the importance of considering treatment context in efforts at risk stratification. This cohort study investigates differences between outpatient clinicians in treatment selection and outcomes for their patients diagnosed with major depressive disorder across academic medical centers, community hospitals, and affiliated clinics. [ABSTRACT FROM AUTHOR]

Tan Thanh Nguyen,1 Lac Duy Le,1 Thanh Tri Vu,2 Anh Thai Nguyen,1 Duc Binh Doan,1 Duyen Thi Pham,1 Tung Thanh Pham,1 Chuc Ngoc Vu,3 Minh Hoang Nguyen Vo4 1Cardiac Intensive Department, Thu Duc City Hospital, Ho Chi Minh City, Vietnam; 2Board of Directors, Thu Duc City Hospital, Ho Chi Minh City, Vietnam; 3Emergency Department, Thu Duc City Hospital, Ho Chi Minh City, Vietnam; 4Office of Science Management and International Affairs, Thu Duc City Hospital, Ho Chi Minh City, VietnamCorrespondence: Minh Hoang Nguyen Vo, Office of Science Management and International Affairs, Thu Duc City Hospital, No. 29 Phu Chau Street, Tam Phu ward, Thu Duc, Ho Chi Minh City, 700000, Vietnam, Tel +84 389135014, Email minhhoangytcc87@gmail.comIntroduction: Tricyclic antidepressants (TCAs) were once commonly used to treat major depressive disorder (MDD), but are now considered second-line options after SSRIs and SNRIs. Additionally, TCAs are used to treat other conditions such as chronic pain and enuresis in children. Due to their numerous side effects and potential for drug interactions, cases of poisoning and death from TCA overdose, particularly amitriptyline, are on the rise. Therefore, this article revisits the overview and describes the clinical progression regarding blood gases, ECG, and electrolytes of the patient, as well as the use of 4.2% sodium bicarbonate and 2% lidocaine to treat cases of amitriptyline overdose poisoning.Case Presentation: A 49-year-old female patient was admitted to the hospital due to cardiac and respiratory arrest. The patient had a past medical history of untreated cervical cancer and sleep disorders. Prior to admission, the patient had taken about 20 tablets of amitriptyline 25mg and was in a drowsy state with gasping breaths. During transportation to the hospital, the patient experienced cardiac arrest once and was successfully resuscitated, with a total arrest and resuscitation time of approximately 10 minutes.Results: The use of 4.2% Sodium Bicarbonate and 2% Lidocaine, the patient was not used plasma exchange in this case, proved effective in this case. Continuous monitoring of blood gas levels, ECG, and electrolytes was maintained. The patient was able to walk independently and was discharged after 12 days of treatment.Conclusion: The key factor was the healthcare staff’s quick recognition and timely management of TCA poisoning, in this case, amitriptyline.Keywords: tricyclic antidepressants, amitriptyline, cardiac arrhythmia

Osteoporosis, a significant public health concern, affects millions of adult women globally, leading to increased morbidity and fracture risk. Antidepressant use, prevalent in this demographic, is suggested to influence bone mineral density (BMD), yet evidence remains limited across antidepressant classes. We investigated the association between antidepressant use and osteoporosis in a representative sample of adult women in the United States, focusing on different classes of antidepressants and their potential associations with BMD and fracture risk. We conducted a cross-sectional analysis using data from ten cohorts of the National Health and Nutrition Examination Survey (NHANES) spanning 1999–2000 to 2017–2020. The sample included adult women, with data collected on antidepressant use, BMD scores, and reported fractures. Statistical models adjusted for potential confounders such as Major Depressive Disorder (MDD), age, physical activity, and comorbidities. Antidepressant use was associated with a 44 % increase in the odds of osteoporosis. Phenylpiperazines showed the highest association, followed by miscellaneous antidepressants and tricyclic antidepressants (TCAs). Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) also demonstrated significant, though comparatively lower associations. The odds of fractures were elevated by 62 % among antidepressant users, particularly with phenylpiperazines and miscellaneous antidepressants. A dose-response analysis indicated that both the number and duration of antidepressants were associated with increased odds of osteoporosis. Our findings underscore the need for heightened awareness of the adverse effects of antidepressants on bone health, particularly in adult women. Careful consideration is necessary when prescribing these medications, especially in populations at risk for osteoporosis and MDD. • Osteoporosis and fracture risk significantly associated with antidepressant use. • Antidepressant classes affect bone health by varying magnitudes. • Duration of antidepressant use increase osteoporosis risk in adult women. • Concurrent antidepressant use exacerbates osteoporosis in adult women. • Findings urge bone health consideration in antidepressant prescriptions. [ABSTRACT FROM AUTHOR]

Background: Antidepressants have a pivotal role in the treatment of many psychiatric disorders, but there are concerns about long-term use and adverse effects. The objectives of this study were (1) to examine time trends in antidepressant use, (2) to estimate the prevalence of long-term and potential high-risk antidepressant use, and (3) to examine patient characteristics associated with potential deprescribing indications (PDIs) (i.e., simultaneous long-term and potential high-risk antidepressant use). Methods: Repeated population-based cross-sectional study for all 609,299 people aged ≥ 18 years resident in the Tayside or Fife regions of Scotland. The prevalence of antidepressant use was examined on June 30th (index date) of each year from 2012 to 2019, while the prevalence of long-term and potential high-risk use as well as PDIs was assessed and compared on the same dates in 2012 and 2019. Binary logistic regression modeling was used to examine patient characteristics associated with PDIs. Results: Antidepressant use increased by 27% from 12.0 to 15.3% among adult residents between 2012 and 2019. While the proportion of antidepressants users dispensed ≥ 1 antidepressant for > 2 years increased from 54.3 to 61.9% between 2012 and 2019, the proportion of antidepressant users triggering ≥ 1 indicator of potential high-risk use decreased slightly from 37.9 to 34.7%. In 2019, potential high-risk use most commonly related to indicators targeting fall risk (16.0%), cardiovascular risks (14.1%), insomnia (10.6%), and risk of orthostatic hypotension (8.6%). More than 1 in 4 (25.8%) antidepressant users had PDIs. The main risk factors associated with PDIs included increasing age (65–79, adjusted OR 14.12; 95% CI, 13.15–15.17), increasing number of drugs taken concomitantly (≥ 15 drugs, adjusted OR 7.37; 95% CI, 6.71–8.10), use of tricyclic antidepressants (≥ 50 mg) (adjusted OR 5.49; 95% CI, 5.02–6.01), and concomitant use of ≥ 2 antidepressants (adjusted OR 5.52; 95% CI, 5.20–5.85). Conclusions: Long-term and potential high-risk use of antidepressants is widespread, and potential deprescribing indications (PDIs) are increasing, suggesting the need for a critical review of their ongoing use by clinicians. If deemed necessary, future deprescribing interventions may use the criteria applied here for identification of patients with PDIs and for evaluating intervention effectiveness. [ABSTRACT FROM AUTHOR]

There is a paucity of data on the effect of preinjury substance (alcohol, drugs) abuse on the risk of delirium in patients with traumatic brain injury (TBI). This study aimed to assess the incidence of delirium among patients with blunt TBI in association with different substances. We analyzed the 2020 American College of Surgeons–Trauma Quality Improvement Program. We included all adult (≥18 y) patients with blunt TBI who had a recorded substance (drugs and alcohol) screening. Our primary outcome was the incidence of delirium. A total of 72,901 blunt TBI patients were identified. The mean (standard deviation) age was 56 (20) years and 68.0% were males. The median (interquartile range) injury severity score was 17 (10-25). Among the study population, 23.1% tested positive for drugs (Stimulants: 3.0%; Depressants: 2.9%, hallucinogens: 5.1%, Cannabinoids: 13.4%, TCAs: 0.1%), and 22.8% tested positive for Alcohol. Overall, 1856 (2.5%) experienced delirium. On univariate analysis, patients who developed delirium were more likely to have positive drug screening results. On multivariable regression analyses, positive screen tests for isolated stimulants (adjusted odds ratio [aOR]: 1.340, P = 0.018), tricyclic antidepressants (aOR: 3.107, P = 0.019), and cannabinoids (aOR: 1.326, P ≤ 0.001) were independently associated with higher odds of developing delirium. Nearly one-fourth of adult patients with blunt TBI had an initial positive substance screening test. Patients with positive results for isolated stimulants, tricyclic antidepressants, and cannabinoids were at a higher risk of developing delirium, whereas this association was not evident with other drugs and alcohol-positive tests. These findings emphasize the need for early drug screening in TBI patients and close monitoring of patients with positive screening tests. [ABSTRACT FROM AUTHOR]

Introduction and Hypothesis: Despite the high prevalence of fecal incontinence, existing treatment options may be inadequate. Drugs that enhance the tone of the anal sphincter complex could potentially be an effective pharmacological approach. This study investigated the effect of the tricyclic antidepressant imipramine on anal sphincter tone in healthy women, employing anal acoustic reflectometry as the evaluating method. Methods: In a double-blind, randomized, placebo-controlled crossover study, 16 healthy female volunteers were randomized to one of two treatment sequences. The participants attended two study visits separated by at least 7 days' washout. At each visit, they received a single dose of 50 mg imipramine or matching placebo, in alternating order. We assessed the anal opening pressure under the resting state and during voluntary squeezing of the pelvic floor. Measurements were performed pre-dose and 1 h after drug administration, corresponding to the estimated time of peak plasma concentration of imipramine. Results: All participants completed the study. In total, 44% of the participants reported at least one adverse effect, primarily anticholinergic. Compared with placebo, imipramine increased anal opening pressure by 15.2 cmH2O (95% confidence interval [CI] 2.0–28.2 cmH2O, p = 0.03) in the resting state and 15.1 (95% CI 4.2–26.0 cmH2O, p = 0.01) cmH2O during squeezing. Conclusions: The findings indicate that imipramine increases anal sphincter tone in healthy women. However, further research is required to evaluate its clinical impact on individuals with fecal incontinence. This research also demonstrates the effectiveness of using anal acoustic reflectometry for assessing pharmacological effects on anal sphincter function. [ABSTRACT FROM AUTHOR]

Introduction: Tricyclic antidepressants often cause drug-induced QRS complex prolongation in overdose but are now less commonly prescribed. We sought to determine, among a contemporary cohort of patients, the pharmaceuticals independently associated with QRS complex prolongation in acute overdose. Methods: We performed secondary analysis of data from the Toxicology Investigators Consortium (ToxIC) Core Registry. We included adult patients presenting from January 2016 through March 2023 with acute or acute-on-chronic pharmaceutical exposures. The primary outcome was QRS complex prolongation >0.12 s. Secondary outcomes included cardiac arrest, death, ventricular dysrhythmia, intensive care unit admission, initiation of vasopressors, and treatment with sodium bicarbonate. We used a multivariable logistic regression model with QRS complex prolongation as the outcome and individual pharmaceuticals of interest as independent variables. We assessed yearly trends of the contribution of relevant pharmaceuticals to QRS complex prolongation since 2016. Results: Of 11,945 patients in the total cohort (median age 37 years, 6,652 [55.7%] female), 366 (3.1%) developed QRS complex prolongation. Of 9,417 patients included in the model, 290 (3.1%) developed QRS complex prolongation. Amitriptyline, nortriptyline, doxepin, imipramine, noxiptiline, bupropion, flecainide, carvedilol, propranolol, diphenhydramine, and lamotrigine poisonings were independent predictors of QRS complex prolongation. Flecainide poisoning conferred the greatest odds of QRS complex prolongation (OR 574.1; 95% CI: 88.3–12,747). The contribution of tricyclic antidepressants to QRS complex prolongation decreased from 38.8% to 17.6% of all patients with QRS complex prolongation from 2016 to 2022. In 2022, the proportion of QRS complex prolongation from diphenhydramine (20.6%) surpassed that of tricyclic antidepressants. Discussion: This study provides insights into contemporary pharmaceutical poisoning associated with QRS complex prolongation. Tricyclic antidepressants remain clinically relevant exposures but are no longer the most common cause of drug-induced QRS complex prolongation. Conclusions: Bupropion, diphenhydramine, and antidysrhythmics are increasingly common causes of QRS complex prolongation, each associated with numerous severe outcomes in poisoning. Greater safety measures to protect patients from cardiovascular toxicity from these pharmaceuticals are warranted. [ABSTRACT FROM AUTHOR]

Doxepin is an antihistamine and tricyclic antidepressant that binds to the histamine H1 receptor (H1R) with high affinity. Doxepin is an 85:15 mixture of the E‐ and Z‐isomers. The Z‐isomer is well known to be more effective than the E‐isomer, whereas based on the crystal structure of the H1R/doxepin complex, the hydroxyl group of Thr1123.37 is close enough to form a hydrogen bond with the oxygen atom of the E‐isomer. The detailed binding characteristics and reasons for the differences remain unclear. In this study, we analyzed doxepin isomers bound to the receptor following extraction from a purified H1R protein complexed with doxepin. The ratio of the E‐ and Z‐isomers bound to wild‐type (WT) H1R was 55:45, indicating that the Z‐isomer was bound to WT H1R with an approximately 5.2‐fold higher affinity than the E‐isomer. For the T1123.37V mutant, the E/Z ratio was 89:11, indicating that both isomers have similar affinities. Free energy calculations using molecular dynamics (MD) simulations also reproduced the experimental results of the relative binding free energy differences between the isomers for WT and T1123.37V. Furthermore, MD simulations revealed that the hydroxyl group of T1123.37 did not form hydrogen bonds with the E‐isomer, but with the adjacent residues in the binding pocket. Analysis of the receptor‐bound doxepin and MD simulations suggested that the hydroxyl group of T1123.37 contributes to the formation of a chemical environment in the binding pocket, which is slightly more favorable for the Z‐isomer without hydrogen bonding with doxepin. [ABSTRACT FROM AUTHOR]

The open-channel block of N-methyl-D-aspartate receptors (NMDARs) and their calcium-dependent desensitization (CDD) represent conventional mechanisms of glutamatergic synapse regulation. In neurotrauma, neurodegeneration, and neuropathic pain the clinical benefits of cure with memantine, ketamine, Mg2+, and some tricyclic antidepressants are often attributed to NMDAR open-channel block, while possible involvement of NMDAR CDD in the therapy is not well established. Here the effects of selective high-affinity sodium-calcium exchanger (NCX) isoform 1 inhibitor, SEA0400, on NMDA-activated whole-cell currents and their block by amitriptyline, desipramine and clomipramine recorded by patchclamp technique in cortical neurons of primary culture were studied. We demonstrated that in the presence of extracellular Ca2+, 50 nM SEA0400 caused a reversible decrease of the steady-state amplitude of NMDAR currents, whereas loading neurons with BAPTA or the removal of extracellular Ca2+ abolished the effect. The decrease did not exceed 30% of the amplitude and did not depend on membrane voltage. The external Mg2+ block and 50 nM SEA0400 inhibition of currents were additive, suggesting their independent modes of action. In the presence of Ca2+ SEA0400 speeded up the decay of NMDAR currents to the steady state determined by CDD. The measured IC50 value of 27 nM for SEA0400-induced inhibition coincides with that for NCX1. Presumably, SEA0400 effects are induced by an enhancement of NMDAR CDD through the inhibition of Ca2+ extrusion by NCX1. SEA0400, in addition, at nanomolar concentrations could interfere with Ca2+-dependent effect of tricyclic antidepressants. In the presence of 50 nM SEA0400, the IC50s for NMDAR inhibition by amitriptyline and desipramine increased by about 20 folds, as the Ca2+-dependent NMDAR inhibition disappeared. This observation highlights NCX1 involvement in amitriptyline and desipramine effects on NMDARs and unmasks competitive relationships between SEA0400 and these antidepressants. Neither amitriptyline nor desipramine could affect NCX3. The open-channel block of NMDARs by these substances was not affected by SEA0400. In agreement, SEA0400 did not change the IC50 for clomipramine, which acts as a pure NMDAR open-channel blocker. Thus, NCX seems to represent a promising molecular target to treat neurological disorders, because of the ability to modulate NMDARs by decreasing the open probability through the enhancement of their CDD. [ABSTRACT FROM AUTHOR]

AbstractThis review evaluates the use of antidepressants in older patients for the treatment of nonspecific chronic lower back pain (LBP), emphasizing age-related physiological changes and common degenerative conditions in this age group. We conducted a comprehensive search targeting studies on antidepressant use in older patients with LBP. Selective serotonin reuptake inhibitors, while effective for mood regulation, show limited benefits for LBP. Serotonin–norepinephrine reuptake inhibitors, particularly duloxetine, demonstrate potential in managing LBP, though further research is needed to confirm these findings. Tricyclic antidepressants have shown potential for pain relief, with limited evidence for LBP, but have a substantial side effect profile, including cardiotoxicity, weight gain, and severe anticholinergic effects. The evidence for trazodone in the treatment of LBP is limited. When prescribing new medications for older adults, it is crucial to carefully consider the patient’s overall health, potential drug interactions, and sensitivity to side effects, ensuring that the benefits of treatment outweigh the risks. This review underscores the need for further research to understand the long-term effects and benefits of antidepressants in older patients with LBP, aiming to balance pain relief, mood stabilization, and minimized side effects. [ABSTRACT FROM AUTHOR]

Micronutrient deficiencies and excesses are closely related to developing and treating depression. Traditional and effective antidepressants include tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and lithium. There is no consensus on the fluctuation of zinc (Zn2+), magnesium (Mg2+), calcium (Ca2+), copper (Cu2+), iron (Fe2+), and manganese (Mn2+) ion levels in depressed individuals before and after therapy. In order to determine whether there were changes in blood and cerebrospinal fluid (CSF) levels of these ions in depressed patients compared with healthy controls and depressed patients treated with TCAs, SSRIs, or lithium, we applied a systematic review and meta-analysis. Using the Stata 17.0 software, we performed a systematic review and meta-analysis of the changes in ion levels in human samples from healthy controls, depressive patients, and patients treated with TCAs, SSRIs, and lithium, respectively. By searching the PubMed, EMBASE, Google Scholar, Web of Science, China National Knowledge Infrastructure (CNKI), and WAN FANG databases, 75 published analyzable papers were chosen. In the blood, the levels of Zn2+ and Mg2+ in depressed patients had decreased while the Ca2+ and Cu2+ levels had increased compared to healthy controls, Fe2+ and Mn2+ levels have not significantly changed. After treatment with SSRIs, the levels of Zn2+ and Ca2+ in depressed patients increased while Cu2+ levels decreased. Mg2+ and Ca2+ levels were increased in depressed patients after Lithium treatment. The findings of the meta-analysis revealed that micronutrient levels were closely associated with the onset of depression and prompted more research into the underlying mechanisms as well as the pathophysiological and therapeutic implications. [ABSTRACT FROM AUTHOR]

Stimulants, including methylphenidate and amphetamines, are the first-line pharmacological treatment of ADHD in adults. However, in patients who do not respond or poorly tolerate stimulants, non-stimulant medications are usually recommended. The authors provide a narrative review of the literature on non-stimulant treatments for adult ADHD, including controlled and observational clinical studies conducted on adult samples. Atomoxetine has been extensively studied and showed significant efficacy in treating adult ADHD. Issues related to dosing, treatment duration, safety, and use in the case of psychiatric comorbidity are summarized. Among other compounds indicated for ADHD in adults, antidepressants sharing at least a noradrenergic or dopaminergic component, including tricyclic compounds, bupropion, and viloxazine, have shown demonstratable efficacy. Evidence is also available for antihypertensives, particularly guanfacine, as well as memantine, metadoxine, and mood stabilizers, while negative findings have emerged for galantamine, antipsychotics, and cannabinoids. While according to clinical guidelines, atomoxetine may serve as the only second-line option in adults with ADHD, several other nonstimulant compounds may be effectively used in order to personalize treatment based on comorbid conditions and ADHD features. Nevertheless, further research is needed to identify and test more personalized treatment strategies for adults with ADHD. [ABSTRACT FROM AUTHOR]

Mass spectrometry imaging (MSI) is essential for visualizing drug distribution, metabolites, and significant biomolecules in pharmacokinetic studies. This study mainly focuses on imipramine, a tricyclic antidepressant that affects endogenous metabolite concentrations. The aim was to use atmospheric pressure matrix-assisted laser desorption/ionization (AP-MALDI)-MSI combined with different dimensionality reduction methods to examine the distribution and impact of imipramine on endogenous metabolites in the brains of treated wild-type mice. Brain sections from both control and imipramine-treated mice underwent AP-MALDI-MSI. Dimensionality reduction methods, including principal component analysis, multivariate curve resolution, and sparse autoencoder (SAE), were employed to extract valuable information from the MSI data. Only the SAE method identified phosphorylcholine (ChoP) as a potential marker distinguishing between the control and treated mice brains. Additionally, a significant decrease in ChoP accumulation was observed in the cerebellum, hypothalamus, thalamus, midbrain, caudate putamen, and striatum ventral regions of the treated mice brains. The application of dimensionality reduction methods, particularly the SAE method, to the AP-MALDI-MSI data is a novel approach for peak selection in AP-MALDI-MSI data analysis. This study revealed a significant decrease in ChoP in imipramine-treated mice brains. [ABSTRACT FROM AUTHOR]

Objectives: Pharmacotherapy of bipolar depression (BPD) is confronted with major clinical challenges, like limited evidence-based treatment options, regular cases of treatment resistance, and risk of treatment-emergent affective switches. Medical guidelines can support practitioners to make decisions based on current scientific evidence. The objective of this study is to evaluate to what extent recommendations of the 2019 German S3 guidelines "Diagnosis and Treatment of Bipolar Disorders" are reflected in clinical practice in inpatient treatment. Methods: We conducted a descriptive analysis of prescription numbers in 2,627 patients with BPD in a naturalistic inpatient setting analyzing data from the ongoing Bavarian multicenter drug safety project Pharmaco-Epidemiology and Vigilance (Pharmako-EpiVig) from the years 2014-2022. Results: Of the patients, 38% were not administered any drug explicitly recommended for treatment of BPD, that is, quetiapine, lamotrigine, carbamazepine, or olanzapine. Only 6% of the patients received monotherapy with one of those drugs. Of the patients, 34% were administered =4 psychotropic drugs simultaneously. Patients received 912 different therapy regimens of mono or combination therapy with mood stabilizers (MS), atypical antipsychotics (AAP), and antidepressants. Of the patients, 72% received an antidepressant and 6% without concomitant prescription of an AAP or MS. Prescription rates of venlafaxine (21% to 14%) and tricyclic antidepressants (9% to 6%) decreased significantly from the first (2014-2016) to the last (2020-2022) observed time period. Of the patients, 60% received an MS. Prescription rate of valproate (22% to 14%) decreased significantly, while lithium prescription increased significantly (29% to 35%). Of the patients, 71% were administered an AAP. Quetiapine was the most prescribed drug overall (43%). Only two patients were administered a combination of olanzapine and fluoxetine. Conclusion: Our results demonstrate a substantial gap between guideline recommendations and current clinical practice. The remarkable heterogeneity in treatment regimens, with no discernible dominant treatment approach, is in part a reflection of the complexity of bipolar disorder but also substantiates the need of comprehensive recommendations regarding combination therapies. Increase in lithium prescription is an encouraging development due to its unique efficacy in maintenance treatment. To improve the quality of clinical practice guideline implementation, more randomized controlled trials should be conducted in the future to prospectively investigate different implementation strategies. [ABSTRACT FROM AUTHOR]

Background: Nano-structure Lipid Carriers (NLCs) are small spheres extending in scale from 10 to 1000 nanometres comprised of biocompatible and biodegradable lipids. These spheres can encapsulate both hydrophilic and lipophilic drugs, preserving them from degradation and increasing their distribution to the intended place in the body. Imipramine, a tricyclic antidepressant, has been investigated in hamster model at 5-10 mg/kg for experimental leishmaniasis. The goal of this research is to develop Imipramine in a nano-structured lipid carrier formulation for targeting macrophage cells. Materials and Methods: Imipramine-loaded NLCs were created employing Glyceryl Monostearate (GMS) as the solid lipid constituent alongside oleic acid as the liquid lipid, while tween80 acted as the surfactant. The process of hot homogenization was employed to prepare the NLCs. The formulation was optimized using 2³ factorial designs using design expert software. The optimised formulation was further used for the preparation of mannose functionalized imipramine-loaded NLCs. Results: The IMP-NLC opt and M-NLC show a globule size of 348.5±0.81 nm and 459.4±0.28 nm with encapsulation efficiency of 61.6±0.326% and 64.48±0.408%, respectively. The drug release in vitro demonstrates a dual-phase pattern, featuring an early rapid sudden release followed by a gradual and slower release. The surface morphology, drug release kinetics and stability were also used to characterize the prepared NLCs. Conclusion: This study concludes that nanostructured lipid carriers demonstrate considerable encapsulation efficiency, release and stability for further pre-clinical investigation. [ABSTRACT FROM AUTHOR]

This article explores the clinical implications of withdrawal syndromes associated with antidepressant drugs. The author shares their own clinical observations and proposes an oppositional model of tolerance to explain the loss of treatment effectiveness and the occurrence of side effects over time. The article also discusses the phenomenon of withdrawal syndromes during the tapering and discontinuation of antidepressants, emphasizing the need for personalized approaches and the potential for severe and persistent symptoms. The author suggests the use of clonazepam, a medication with neuroprotective properties, to support patients during this phase, and highlights the importance of self-therapy and psychotherapeutic strategies in the discontinuation process. The author calls for further research on the behavioral toxicity of antidepressant medications and emphasizes the importance of individualized treatment approaches. [Extracted from the article]

Irritable bowel syndrome (IBS) is responsive to treatments using central neuromodulators. Central neuromodulators work by enhancing the synaptic transmission of 5-hydroxytryptamine, noradrenalin, and dopamine, achieving a slower regulation or desensitization of their postsynaptic receptors. Central neuromodulators act on receptors along the braingut axis, so they are useful in treating psychiatric comorbidities, modifying gut motility, improving central downregulation of visceral signals, and enhancing neurogenesis in patients with IBS. Choosing a central neuromodulator for treating IBS should be according to the pharmacological properties and predominant symptoms. The first-line treatment for pain management in IBS is using tricyclic antidepressants. An alternative for pain management is the serotonin and noradrenaline reuptake inhibitors. Selective serotonin reuptake inhibitors are useful when symptoms of anxiety and hypervigilance are dominant but are not helpful for treating abdominal pain. The predominant bowel habit is helpful when choosing a neuromodulator to treat IBS; selective serotonin reuptake inhibitors help constipation, not pain, but may cause diarrhea; tricyclic antidepressants help diarrhea but may cause constipation. A clinical response may occur in 6-8 weeks, but long-term treatment (usually 6-12 months) is required after the initial response to prevent relapse. Augmentation therapy may be beneficial when the therapeutic effect of the first agent is incomplete or associated with side effects. It is recommended to reduce the dose of the first agent and add a second complementary treatment. This may include an atypical antipsychotic or brain-gut behavioral treatment. When tapering central neuromodulators, the dose should be reduced slowly over 4 weeks but may take longer when discontinuation effects occur. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Chronic treatment with clomipramine, a tricyclic antidepressant drug, reduces symptoms of obsessive-compulsive disorder (OCD) and can influence the activity of the hypothalamic-pituitary-adrenal axis. However, little is known regarding the effects of acute clomipramine on the immediate expression of stress responses. Serotonergic drugs can elicit surfacing, a behavioral profile potentially related to toxicity in fish, although surfacing has not yet been observed after clomipramine exposure. The present study investigated the impact of acute exposure to clomipramine on basal and stress-induced behaviors in the novel tank test and cortisol levels in mixed-sex, wild-type, adult zebrafish (Danio rerio). The findings show clomipramine-exposed groups (regardless of stress exposure) spent much more time in the top of the novel tank and had significantly less overall motor activity in the behavioral task compared to the fish not exposed to the drug. Then, the dose-dependent effects of acute clomipramine on activity in the surface of the novel tank (top third of the top half) were investigated further. Clomipramine dose-dependently increased surface-dwelling and elicited a dose-dependent hypoactivity in overall motor behavior. There were no statistically significant differences in whole-body cortisol levels in either experiment. Like other serotonin-acting drugs, clomipramine strongly elicited surface-dwelling and depressed motor behavior in adult zebrafish. Additional testing is needed to elucidate whether surfacing represents a toxic state and how serotonin regulates surfacing. [ABSTRACT FROM AUTHOR]

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BACKGROUND: Antidepressants are increasingly used in children for various psychiatric disorders but also for sleep disorders such as insomnia; however, it is currently unknown how many children undergoing polysomnography (PSG) are taking anti-depressants. The aims were: to determine the frequency of use of antidepressants in paediatric patients referred for PSG, to identify the most common antidepressants used, to investigate the reasons for their use, and to analyse the PSG parameters found in children taking antidepressants. METHOD: An observational cross-sectional retrospective chart review of all children undergoing PSG at Seattle Childrens Hospital from 6/14/2020 to 12/8/2022 was carried out. Clinical features (such as diagnosis, especially psychiatric), sleep disorders (such as insomnia and restless sleep), and class of antidepressant used [selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCA), or atypical antidepressants], and PSG parameters were collected for further analysis. RESULTS: Among 3,371 patients who underwent PSG during the study, 367 children were selected who were taking one antidepressant only (154 boys and 213 girls, mean age was 13.7 ± years 3.69). A significantly decreased sleep stage N3 was found in girls, who were older than boys. Children with insomnia had longer sleep latency than children without, but more N3. There was a prolonged rapid eye movement (REM) sleep latency in children with attention-deficit/hyperactivity disorder and children with autism. REM latency was longer and REM percentage smaller in children taking SNRIs. Periodic leg movement index ≥ 5/hour was found in a higher number of children taking SSRIs or SNRIs (24.9%) than in subjects taking TCA or atypical antidepressants (13.3%) (chi-square 5.29, p = 0.013). CONCLUSIONS: Child and adolescent psychiatrists should question about the effects on sleep (both positive and negative) after initiating therapy with antidepressant medications.

Abstract Background Acupuncture showed better improvement than sham acupuncture in reducing attack frequency of tension-type headache (TTH), but its effectiveness relative to first-line drugs for TTH is unknown, which impedes the recommendation of acupuncture for patients who are intolerant to drugs for TTH. We aimed to estimate the relative effectiveness between acupuncture and tricyclic antidepressants (TCAs) through indirect treatment comparison (ITC) meta-analysis. Methods We searched Ovid Medline, Embase, and Cochrane Library from database inception until April 13, 2023. Randomized controlled trials of TCAs or acupuncture in the prevention of TTH in adults were included. The primary outcome was headache frequency. The secondary outcomes were headache intensity, responder rate, and adverse event rate. Bayesian random-effect models were used to perform ITC meta-analysis, and confidence of evidence was evaluated by using the GRADE approach. Results A total of 34 trials involving 4426 participants were included. Acupuncture had similar effect with TCAs in decreasing TTH frequency (amitriptyline: mean difference [MD] -1.29, 95% CI -5.28 to 3.02; amitriptylinoxide: MD -0.05, 95% CI -6.86 to 7.06) and reducing TTH intensity (amitriptyline: MD 2.35, 95% CI -1.20 to 5.78; clomipramine: MD 1.83, 95% CI -4.23 to 8.20). Amitriptyline had a higher rate of adverse events than acupuncture (OR 4.73, 95% CI 1.42 to 14.23). Conclusion Acupuncture had similar effect as TCAs in reducing headache frequency of TTH, and acupuncture had a lower adverse events rate than amitriptyline, as shown by very low certainty of evidence.

AbstractIn epidemiological cohort studies, the relative risk is a key measure to gauge the connection between two treatments or exposures. It quantifies the proportional change in the risk of disease due to the application of a specific treatment. However, the conventional methods for calculating relative risk, available in widely-used software, might yield inaccurate results when applied to correlated binary data from studies conducted over time or in clusters. Recently, various techniques have been proposed to estimate the risk ratio for correlated binary data. However, some methods exhibit a tradeoff between maintaining accurate coverage probability (CP) and ensuring an appropriate interval width or location. This paper introduces a new approach to confidently estimating the risk ratio using a hybrid method. This hybrid method combines two distinct confidence intervals (CIs) derived from single risk rates to establish a unified confidence interval for their ratio. Furthermore, we present a methodology to construct a confidence interval for the risk ratio, which builds upon established methods for correlated binary data. This extension incorporates principles such as the design effect and adequate sample sizes commonly used in representative sample surveys. An extensive simulation study is conducted to evaluate the effectiveness of these proposed methods. The performance of the methods is thoroughly examined in various scenarios. Additionally, the practicality of the proposed methods is showcased through three real-life examples. These examples involve comparing the side effects of low-dose tricyclic antidepressants with a placebo, assessing the efficacy of a treatment group in a teratological experiment, and evaluating the efficiency of active drugs in curing infections during clinical trials. [ABSTRACT FROM AUTHOR]

While antidepressants are frequently used, less is known about contemporary discontinuation patterns, especially across different sociodemographic populations. Patients 16–84 years initiating antidepressants between 2016 and 2019 within a large US health insurer were identified. The association between patient characteristics and time until antidepressant discontinuation was evaluated using adjusted Cox proportional hazard regression. Across 1,365,576 patients, mean time to discontinuation was 168.1 days (SD: 223.6). Men were more likely to discontinue than women (HR: 0.94, 95%CI: 0.94–0.94). Younger patients (16–24 years) were more likely to discontinue than older patients. Patients who were non-White (Asian HR: 1.33, 95%CI: 1.31–1.34; Black HR: 1.27, 95%CI: 1.27–1.28; Hispanic HR: 1.34, 95%:CI 1.34–1.35), with evidence of a substance use disorder (HR: 1.31, 95%CI: 1.27–1.35), or taking tricyclic antidepressants (HR:1.26, 95%CI: 1.25–1.27) were more likely to discontinue. Information on reasons for discontinuation was not available, and wide standard deviations for the primary outcome were reported. The results may not be generalized to non-commercially insured beneficiaries. Discontinuation is common within the first 6 months of treatment but varies across populations, highlighting patients who may benefit from potential intervention. • Most patients discontinued their antidepressants around 6 months post-initiation. • Discontinuation patterns varied across different patient characteristics. • Younger, male, non-White race patients were more likely to discontinue. • Patients with certain diagnoses and drugs were more likely to discontinue. [ABSTRACT FROM AUTHOR]

A method for the determination of amitriptyline, a tricyclic antidepressant, in human urine by immunosensors has been developed using supramolecular systems based on hexamolybdenum cluster complexes. These complexes have electrochemical activity and give a stable analytical signal, which was used in the development of amperometric immunosensors. Luminescence and dynamic light scattering methods were used to demonstrate the formation of a supramolecular system of self-organized hexamolybdenum nanoparticles and chitosan molecules. A composite material based on hexamolybdenum cluster complexes in combination with reduced graphene oxide has been developed. The working range of amitriptyline concentrations to be determined by an amperometric immunosensor was 1 × 10–9–1 × 10–4 M, the limit of determination was at a level of 5 × 10–10 M, and the amitriptyline content of urine samples was at a level of (n – 7) × 10–8 M. A comparison of the results of analysis performed using an amperometric immunosensor and a fluorescence polarization immunoassay showed the absence of significant systematic errors. The ability to determine amitriptyline in biological fluids makes it possible to select an optimal therapeutic dose of the drug, that is, to develop approaches to creating personalized medicine. [ABSTRACT FROM AUTHOR]

Introduction: Chronic pain (CP) and depression/anxiety often coexist, worsening each other's symptoms. Treating this comorbidity is challenging. Tricyclic antidepressants and serotonin noradrenaline reuptake inhibitors are the first-line treatment options for this comorbidity, although sometimes they are not effective and/or well tolerated by patients, and there is little clinical evidence that selective serotonin reuptake inhibitors are useful for controlling CP. The antidepressant vortioxetine, with a multimodal mechanism that may help reduce pain, has proven clinical efficacy in patients with major depressive disorder (MDD). This study investigated vortioxetine's effectiveness for MDD and CP in clinical practice. Methods: This was a 3-month, multicenter, prospective, open-label, non-interventional pharmacoepidemiologic study. Patients (n = 64) with MDD (9-item Patient Health Questionnaire [PHQ-9] score ≥ 15) and CP (visual analogue scale [VAS] score ≥ 4) were treated with vortioxetine for 3 months (initiated with 10 mg/day, with flexible dosing thereafter [5–20 mg/day]). VAS, Clinical Global Impression (CGI), and Patient Global Impression (PGI) scales were used at baseline and at 1 and 3 months. Brief Pain Inventory (BPI), PHQ-9 scale, and Satisfaction with Medicines Questionnaire (SATMED-Q) were used at baseline and at 3 months. Adverse Events (AEs) were recorded. Descriptive statistics, chi-square tests, and Student's t-tests were used for paired data. Results: MDD patients showed a statistically significant improvement in VAS from baseline (mean [standard deviation (SD)]: 7.42 [0.69]) to 1 month (mean [SD]: 6.1 [0.81], P < 0.001) and 3 months (mean [SD]: 5.09 [1.26], P < 0.0001). Similarly, BPI and PHQ-9 scores showed significant improvement from baseline (mean [SD]: 6.20 [0.80] and 16.63 [1.47], respectively) to 3 months (mean [SD]: 4.73 [0.98] and 7.30 [2.60], P < 0.0001, respectively). Patients showed clinical improvement with CGI and PGI scales and reported being satisfied with the treatment in the SATMED-Q. A few mild EAs were registered. Conclusion: Vortioxetine can relieve depressive and pain symptoms, with a good safety profile, in patients with MDD and CP. [ABSTRACT FROM AUTHOR]

BACKGROUND: Functional dyspepsia is a disorder of gut-brain interaction that has the potential to impact aviation performance. Proton pump inhibitors are well-tolerated but are only effective in one half of cases. Second-line treatments, including tricyclic antidepressants, are associated with drowsiness and are not routinely approved for use in aviators. We present a case of a Naval Flight Officer with functional dyspepsia who was successfully treated with amitriptyline and returned to flying status. CASE REPORT: A 23-yr-old male Naval Flight Officer presented with postprandial fullness and epigastric pain. His symptoms were refractory to trials of acid suppression and lifestyle modification. An extensive evaluation by Gastroenterology, including upper endoscopy, did not reveal an organic cause of his symptoms and he was diagnosed with functional dyspepsia. The patient's symptoms resolved with a trial of amitriptyline. Neuropsychological testing demonstrated no medication effect on cognitive performance. A waiver to resume flying duties on amitriptyline was submitted to the Naval Aerospace Medical Institute and was approved. DISCUSSION: We present the second known waiver issued in U.S. Naval aviation history for the use of amitriptyline to treat a gastrointestinal disorder. Amitriptyline is not commonly waived due to the potential for unacceptable cognitive side-effects in the flight environment. However, neuropsychological testing to assess for a possible medication effect on performance can be used to inform an aeromedical disposition and, in this case, allowed for a return to flight status. [ABSTRACT FROM AUTHOR]

Background: Long‐term studies comparing nonresponse to antidepressants for major depressive disorder (MDD) are lacking. Aims: To present systematic population‐based nation‐wide register data on comparative 2‐year non‐response within six antidepressant drug classes and 17 different antidepressants in patients with MDD. Method: The study included all 106,920 patients in Denmark with a first main index diagnosis of MDD at a psychiatric hospital inpatient or outpatient contact and who subsequently had a purchase of an antidepressant in the period from 1995 to 2018. Non‐response to first antidepressant within a 2‐year study period was defined as switch to or add‐on of another antidepressant, antipsychotic medication, lithium, or hospitalization. Analyses emulated a targeted trial in populations standardized according to age, sex, socioeconomic status, and comorbidity with psychiatric and physical disorders. Results: Compared with sertraline, there was no difference for citalopram (RR: 1.00 [95% CI: 0.98–1.02]) but fluoxetine (1.13 [95% CI: 1.10–1.17]), paroxetine (1.06 [95% CI: 1.01–1.10]) and escitalopram (1.22 [95% CI: 1.18–1.25]) were associated with higher risk ratio of non‐responses. Within selective noradrenaline reuptake inhibitors, sertraline outperformed reboxetine; within serotonin‐norepinephrine reuptake inhibitors, venlafaxine outperformed duloxetine; within noradrenergic and specific serotonergic antidepressants, mirtazapine outperformed mianserin and within the class of other antidepressants, sertraline outperformed agomelatine and vortioxetine. Within tricyclic antidepressants, compared to amitriptyline, nortriptyline, dosulepin, and clomipramine had higher non‐response, whereas there was no difference for imipramine. Conclusions: These analyses emulating a randomized trial of "real world" observational register‐based data show that 2‐year long‐term non‐responses to some antidepressants within six different drug classes are increased over others. [ABSTRACT FROM AUTHOR]

To examine the association between depression, the use of antidepressants, and atherosclerotic cardiovascular disease (ASCVD). The South Korean national claims data was used. Among a nationally representative population, 273,656 subjects who had been diagnosed with depression and prescribed antidepressants ("DEP with antidepressants") and 78,851 subjects who had been diagnosed with depression but not prescribed antidepressants ("DEP without antidepressants") were identified to be eligible. Healthy controls (HCs) were 1:1 matched with DEP with antidepressants group for age and sex. We followed up on the occurrence of ASCVD including ischemic heart diseases and ischemic stroke. The risk of ASCVD was increased in the DEP with antidepressants group and decreased in the DEP without antidepressants group compared to HCs. Among those under antidepressants, tricyclic antidepressant users showed the highest risk of ASCVD compared to HCs. Among young adults, the risk of ASCVD was increased in both groups. The risk of ASCVD increased in depression patients taking antidepressants, while it decreased in depression patients not taking antidepressants. However, the relationship showed differences according to drug class and age group. • Depression is a well-known risk factor for atherosclerotic cardiovascular disease. • We examined the risk of ASCVD in depression patients with/without antidepressants. • Depression patients with antidepressants showed an increased risk of ASCVD. • Depression patients without antidepressants showed a decreased risk of ASCVD. • The use of antidepressants, rather than depression, is the risk factor for ASCVD. [ABSTRACT FROM AUTHOR]

Background: Acupuncture showed better improvement than sham acupuncture in reducing attack frequency of tension-type headache (TTH), but its effectiveness relative to first-line drugs for TTH is unknown, which impedes the recommendation of acupuncture for patients who are intolerant to drugs for TTH. We aimed to estimate the relative effectiveness between acupuncture and tricyclic antidepressants (TCAs) through indirect treatment comparison (ITC) meta-analysis. Methods: We searched Ovid Medline, Embase, and Cochrane Library from database inception until April 13, 2023. Randomized controlled trials of TCAs or acupuncture in the prevention of TTH in adults were included. The primary outcome was headache frequency. The secondary outcomes were headache intensity, responder rate, and adverse event rate. Bayesian random-effect models were used to perform ITC meta-analysis, and confidence of evidence was evaluated by using the GRADE approach. Results: A total of 34 trials involving 4426 participants were included. Acupuncture had similar effect with TCAs in decreasing TTH frequency (amitriptyline: mean difference [MD] -1.29, 95% CI -5.28 to 3.02; amitriptylinoxide: MD -0.05, 95% CI -6.86 to 7.06) and reducing TTH intensity (amitriptyline: MD 2.35, 95% CI -1.20 to 5.78; clomipramine: MD 1.83, 95% CI -4.23 to 8.20). Amitriptyline had a higher rate of adverse events than acupuncture (OR 4.73, 95% CI 1.42 to 14.23). Conclusion: Acupuncture had similar effect as TCAs in reducing headache frequency of TTH, and acupuncture had a lower adverse events rate than amitriptyline, as shown by very low certainty of evidence. Highlights: Acupuncture showed better improvement than sham acupuncture in reducing headache frequency of tension-type headache (TTH), but the lack of comparisons between acupuncture and first-line drugs impedes recommendation of acupuncture for TTH. Our indirect treatment comparison meta-analysis found similar effect between acupuncture and tricyclic antidepressants (TCAs) in reducing TTH frequency with very low certainty of evidence. Similar effect between acupuncture and TCAs were also observed in reducing headache intensity with very low certainty of evidence. Acupuncture had a lower rate of adverse events than amitriptyline with very low certainty of evidence. [ABSTRACT FROM AUTHOR]

The International Association for the Study of Pain (IASP) defines pain as an unpleasant emotional experience related to actual or potential tissue damage. It is divided into three groups: nociceptive, neuropathic and psychogenic pain. One of these, neuropathic pain, is different from other frequently reported pain conditions such as headache, back pain and other musculoskeletal pain, which are nociceptive pain types, and reflects both peripheral and central sensitization mechanisms. The management of treatment on patients with neuropathic pain is complex. Stepwise treatment approach is generally recommended in the treatment of neuropathic pain. The first-line treatment includes tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, alpha-2 delta ligand of calcium channels (gabapentin and pregabalin) and topical lidocaine. Opioid analgesics and tramadol are generally recommended for second-line treatment, but may also be recommended for first-line use in certain clinical situations. Third-line treatment includes antiepileptics, antidepressants, mexiletine, N-methyl-D-aspartate receptor antagonists and topical capsaicin. Drug selection should be individualized, considering potential side effects, beneficial or harmful effects, and the need for immediate pain relief. [ABSTRACT FROM AUTHOR]

Hypertonic sodium bicarbonate is advocated for the treatment of sodium channel blocker poisoning, but its efficacy varies amongst different sodium channel blockers. This Commentary addresses common pitfalls and appropriate usage of hypertonic sodium bicarbonate therapy in cardiotoxic drug poisonings. Serum alkalinization is best achieved by the synergistic effect of hypertonic sodium bicarbonate and hyperventilation (PCO2 ∼ 30–35 mmHg [0.47–0.6 kPa]). This reduces the dose of sodium bicarbonate required to achieve serum alkalinization (pH ∼ 7.45–7.55) and avoids adverse effects from excessive doses of hypertonic sodium bicarbonate. Tricyclic antidepressant poisoning responds well to sodium bicarbonate therapy, but many other sodium channel blockers may not. For instance, drugs that block the intercellular gap junctions, such as bupropion, do not respond well to alkalinization. For sodium channel blocker poisonings in which the expected response is unknown, a bolus of 1–2 mmol/kg sodium bicarbonate can be used to assess the response to alkalinization. Hypertonic sodium bicarbonate can cause electrolyte abnormalities such as hypokalaemia and hypocalcaemia, leading to QT interval prolongation and torsade de pointes in poisonings with drugs that have mixed sodium and potassium cardiac channel properties, such as hydroxychloroquine and flecainide. Excessive doses of hypertonic sodium bicarbonate commonly occur if it is administered until the QRS complex duration is < 100 ms. A prolonged QRS complex duration is not specific for sodium channel blocker toxicity. Some sodium channel blockers do not respond, and even when there is a response, it takes a few hours for the QRS complex duration to return completely to normal. In addition, QRS complex prolongation can be due to a rate-dependent bundle branch block. So, no further doses should be given after achieving serum alkalinization (pH ∼ 7.45–7.55). A further strategy to avoid overdosing patients with hypertonic sodium bicarbonate is to set maximum doses. Exceeding 6 mmol/kg is likely to cause hypernatremia, fluid overload, metabolic alkalosis, and cerebral oedema in many patients and potentially be lethal. We propose that hypertonic sodium bicarbonate therapy be used in patients with sodium channel blocker poisoning who have clinically significant toxicities such as seizures, shock (systolic blood pressure < 90 mmHg, mean arterial pressure <65 mmHg) or ventricular dysrhythmia. We recommend initial bolus dosing of hypertonic sodium bicarbonate of 1–2 mmol/kg, which can be repeated if the patient remains unstable, up to a maximum dose of 6 mmol/kg. This is recommended to be administered in conjunction with mechanical ventilation and hyperventilation to achieve serum alkalinization (PCO2∼30–35 mmHg [4-4.7 kPa]) and a pH of ∼7.45–7.55. With repeated bolus doses of hypertonic sodium bicarbonate, it is imperative to monitor and correct potassium and sodium abnormalities and observe changes in serum pH and on the electrocardiogram. Hypertonic sodium bicarbonate is an effective antidote for certain sodium channel blocker poisonings, such as tricyclic antidepressants, and when used in appropriate dosing, it works synergistically with hyperventilation to achieve serum alkalinization and to reduce sodium channel blockade. However, there are many pitfalls that can lead to excessive sodium bicarbonate therapy and severe adverse effects. [ABSTRACT FROM AUTHOR]

Antidepressant drugs play a crucial role in the treatment of mental health disorders, but their efficacy and safety can be compromised by drug degradation. Recent reports point to several drugs found in concentrations ranging from the limit of detection (LOD) to hundreds of ng/L in wastewater plants around the globe; hence, antidepressants can be considered emerging pollutants with potential consequences for human health and wellbeing. Understanding and implementing effective degradation strategies are essential not only to ensure the stability and potency of these medications but also for their safe disposal in line with current environment remediation goals. This review provides an overview of degradation pathways for amitriptyline, a typical tricyclic antidepressant drug, by exploring chemical routes such as oxidation, hydrolysis, and photodegradation. Connex issues such as stability-enhancing approaches through formulation and packaging considerations, regulatory guidelines, and quality control measures are also briefly noted. Specific case studies of amitriptyline degradation pathways forecast the future perspectives and challenges in this field, helping researchers and pharmaceutical manufacturers to provide guidelines for the most effective degradation pathways employed for minimal environmental impact. [ABSTRACT FROM AUTHOR]

Kinetoplastid parasites are "living bridges" in the evolution from prokaryotes to higher eukaryotes. The near-intronless genome of the kinetoplastid Leishmania exhibits polycistronic transcription which can facilitate R-loop formation. Therefore, to prevent such DNA-RNA hybrids, Leishmania has retained prokaryotic-like DNA Topoisomerase IA (LdTOPIA) in the course of evolution. LdTOPIA is an essential enzyme that is expressed ubiquitously and is adapted for the compartmentalized eukaryotic form in harboring functional bipartite nuclear localization signals. Although exhibiting greater homology to mycobacterial TOPIA, LdTOPIA could functionally complement the growth lethality of Escherichia coli TOPIA null GyrB ts strain at non-permissive temperatures. Purified LdTOPIA exhibits Mg2+-dependent relaxation of only negatively supercoiled DNA and preference towards singlestranded DNA substrates. LdTOPIA prevents nuclear R-loops as conditional LdTOPIA downregulated parasites exhibit Rloop formation and thereby parasite killing. The clinically used tricyclic antidepressant, norclomipramine could specifically inhibit LdTOPIA and lead to R-loop formation and parasite elimination. This comprehensive study therefore paves an avenue for drug repurposing against Leishmania. [ABSTRACT FROM AUTHOR]

Background: Burning mouth syndrome (BMS) is a chronic pain disorder characterized by a persistent burning sensation in the oral cavity, affecting quality of life significantly. Pharmacological therapy is commonly employed in the management of BMS, but the comparative efficacy of different pharmaceutical agents remains uncertain. Materials and Methods: This study was conducted involving 80 participants diagnosed with BMS, randomly assigned to two treatment groups: Group A received tricyclic antidepressants (TCAs), while Group B received anticonvulsants. Baseline assessments of pain intensity, oral health-related quality of life, and psychological distress were conducted using standardized measures. Treatment outcomes were evaluated at 3-month and 6-month follow-up visits. Pain intensity was assessed using a visual analog scale (VAS), while oral health-related quality of life and psychological distress were measured using validated questionnaires. Results: Both treatment groups demonstrated significant improvements in pain intensity, oral health-related quality of life, and psychological distress compared to baseline. At the 6-month follow-up, Group A (TCAs) showed a mean reduction of 70% in pain intensity from baseline, whereas Group B (anticonvulsants) exhibited a mean reduction of 65%. The difference in pain reduction between the two groups was not statistically significant (P = 0.35). Both groups also showed similar improvements in oral health-related quality of life and psychological distress measures. Conclusion: TCAs and anticonvulsants are both effective pharmaceutical therapies for managing BMS, resulting in significant improvements in pain intensity, oral health-related quality of life, and psychological distress.

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.

The case report discusses a 29-year-old woman with OCD who experienced a manic episode after abruptly discontinuing sertraline due to concerns about stigma. The patient's symptoms improved with olanzapine and lithium treatment, but she experienced relapses when treatment was disrupted. The report highlights the risks of sudden antidepressant discontinuation and the importance of patient education and careful monitoring by clinicians. The study emphasizes the need for further research in this area to better understand and address these challenges. [Extracted from the article]

Tricyclic antidepressant (TCA) poisoning is one of the conditions that can lead to serious clinical consequences and require urgent medical attention. The clinical presentation of TCA toxicity can range from severe cardiotoxicity to mild antimuscarinic symptoms and signs. The most severe toxicity is to the cardiovascular, central nervous and peripheral nervous system. Sodium bicarbonate therapy is highly effective in treating arrhythmias and improving metabolic acidosis, although there is no known antidote for treatment. This review aims to present current information about the pathophysiology, clinical findings, diagnostic and therapeutic methods and prognosis of TCA poisoning. [ABSTRACT FROM AUTHOR]

Zu den häufigsten Vergiftungen mit Medikamenten gehören Intoxikationen mit Paracetamol, Benzodiazepinen und trizyklischen Antidepressiva. Zur Beurteilung der Schwere der Vergiftung können – neben der Symptomatik der Betroffenen – chemisch-toxikologische Untersuchungen von Urin- und Blutproben wichtige Hinweise geben. Insbesondere bei Paracetamol-Vergiftungen werden auch auf Basis des Substanznachweises Entscheidungen hinsichtlich einer möglichen Antidot-Therapie getroffen. Neben immunchemischen Untersuchungsmethoden kommen für eine eindeutige Identifizierung und Quantifizierung der jeweiligen Wirkstoffe vor allem chromatographische Verfahren zum Einsatz [ABSTRACT FROM AUTHOR]

The use of antidepressants with anticholinergic effects has been associated with an increased risk of dementia. However, the results published are contradictory. The aim of the study is to compare the risk of developing dementia in elderly who were prescribed tricyclic antidepressants (TCA) versus those who were prescribed selective serotonin reuptake inhibitors (SSRIs) and other antidepressants (OA). A prospective population-based cohort study was performed using the Spanish Database for Pharmacoepidemiological Research in Primary Care (BIFAP) data (from 2005 to 2018). The cohort study included 62,928 patients age ≥ 60 without dementia and with antidepressant long-term monotherapy. Patients were divided into exposure antidepressant groups based on ATC system [TCA, SSRIs users and OAs users]. The risk of dementia was calculated by Cox regression models, providing hazard ratios (HR) and 95 % confidence intervals. The Kaplan-Meier model was used for survival analysis. Chi2 test was used as association test. The results showed SSRI users had higher dementia risk than TCA users (HR = 1.864; 95%CI = 1.624–2.140). Moreover, OA users had also significant risk of dementia (HR = 2.103; 95%CI = 1.818–2.431). Several limitations are the variation of the trend in the prescription of antidepressants, the small number of patients that use some antidepressants, the lack of information related to the dose, or socioeconomic characteristics, the use of antidepressant drugs for other indications, or the therapeutic compliance. Our findings showed that older users of SSRI and OA have more risk of developing dementia than TCA elderly users. However, additional studies would be needed. • Antidepressants are associated with neuroprotective effect or cognitive impairment. • Evidence is controversial for long-term antidepressant treatments in older people. • Risk of dementia was higher for SSRI and other antidepressants in elderly users. • Identifying suitable antidepressants is crucial for therapeutic strategies. [ABSTRACT FROM AUTHOR]

Some tricyclic antidepressants (TCAs), including amitriptyline (ATL), clomipramine (CLO), and desipramine (DES), are known to be effective for management of neuropathic pain. It was previously determined that ATL, CLO, and DES are capable of voltage-dependent blocking of NMDA receptors of glutamate (NMDAR), which play a key role in pathogenesis of neuropathic pain. Despite the similar structure of ATL, CLO, and DES, efficacy of their interaction with NMDAR varies significantly. In the study presented here, we applied molecular modeling methods to investigate the mechanism of binding of ATL, CLO, and DES to NMDAR and to identify structural features of the drugs that determine their inhibitory activity against NMDAR. Molecular docking of the studied TCAs into the NMDAR channel was performed. Conformational behavior of the obtained complexes in the lipid bilayer was simulated by the method of molecular dynamics (MD). A single binding site (upper) for the tertiary amines ATL and CLO and two binding sites (upper and lower) for the secondary amine DES were identified inside the NMDAR channel. The upper and lower binding sites are located along the channel axis at different distances from the extracellular side of the plasma membrane. MD simulation revealed that the position of DES in the lower site is stabilized only in the presence of sodium cation inside the NMDAR channel. DES binds more strongly to NMDAR compared to ATL and CLO due to simultaneous interaction of two hydrogen atoms of its cationic group with the asparagine residues of the ion pore of the receptor. This feature may be responsible for the stronger side effects of DES. It has been hypothesized that ATL binds to NMDAR less efficiently compared to DES and CLO due to its lower conformational mobility. The identified features of the structure- and cation-dependent mechanism of interaction between TCAs and NMDAR will help in the further development of effective and safe analgesic therapy. [ABSTRACT FROM AUTHOR]