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Limited data are available to establish evidence-based management protocols for vestibulodynia (VBD), a chronic vulvar pain condition that affects approximately 14 million women in the U.S. For the purposes of the study, our group subdivided VBD subtypes that may benefit from different types of treatment: 1) VBD peripheral (VBD-p), characterized by pain localized to the vulvar vestibule and 2) VBD central (VBD-c), characterized by VBD alongside one or more other chronic overlapping pain conditions (e.g. irritable bowel syndrome, temporomandibular disorder, and fibromyalgia syndrome) that affect remote body regions. Here, we describe the rationale and design of an NIH-funded multicenter clinical trial comparing the effectiveness of topical and/or systemic medication for alleviating pain and normalizing pain- relevant biomarkers among women with VBD-p and VBD-c. Participants will be randomly assigned to one of four parallel arms: peripheral treatment with 5% lidocaine + 0.5 mg/ml 0.02% oestradiol compound cream + oral placebo pill, 2) central treatment with the tricyclic antidepressant nortriptyline + placebo cream, 3) combined peripheral cream and central pill treatments, or 4) placebo cream and placebo pill. The treatment phase will last 16 weeks, with outcome measures and biomarkers assessed at 4 time points (0, 8, 16, and 24 weeks). First, we will compare the efficacy of treatments in alleviating pain using standardized tampon insertion with a numeric rating scale and self-reported pain on the short form McGill Pain Questionnaire. Next, we will compare the efficacy of treatments in improving perceived physical, mental, and sexual health using standardized questionnaires. Finally, we will measure cytokines and microRNAs in local vaginal and circulating blood samples using multiplex assays and RNA sequencing, and determine the ability of these biomarkers to predict treatment response. This is the first multicenter randomized controlled trial to evaluate the efficacy of peripherally and centrally acting medications currently used in clinical practice for treating unique VBD subtypes based on distinct clinical and biological signatures. Vestibulodynia UPDATe is a multi-centre, two-by-two factorial designed randomized, double-blind, placebo-controlled trial registered at clinical trials.gov (NCT03844412). This work is supported by the R01 HD096331 awarded to Drs. Nackley, Rapkin, Geller and Carey by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).Key messagesPeripheral lidocaine and oestradiol and centrally-targeted nortriptyline medications are used for the treatment of pain in women with VBD, but there is a lack of data from well-powered RCTs.This two-by-two factorial RCT will test the efficacy of these medications in VBD subtypes characterized by distinct clinical characteristics and biomarker profiles.We hope that results will provide clinicians with scientific evidence of therapeutic efficacy in distinct VBD subtypes in an effort to direct and optimize treatment approaches. Peripheral lidocaine and oestradiol and centrally-targeted nortriptyline medications are used for the treatment of pain in women with VBD, but there is a lack of data from well-powered RCTs. This two-by-two factorial RCT will test the efficacy of these medications in VBD subtypes characterized by distinct clinical characteristics and biomarker profiles. We hope that results will provide clinicians with scientific evidence of therapeutic efficacy in distinct VBD subtypes in an effort to direct and optimize treatment approaches.

The effect of LC mobile phase composition and flow rate (2–50 µL/min) on mobility behavior in vacuum differential mobility spectrometry (vDMS) was investigated for electrosprayed isobaric antidepressant drugs (AD); amitriptyline, maprotiline, venlafaxine; and structurally related antidepressants nortriptyline, imipramine, and desipramine. While at 2 µL/min, no difference in compensation voltage was observed with methanol and acetonitrile, at 50 µL/min, acetonitrile used for LC elution of analytes enabled the selectivity of the mobility separation to be improved. An accurate and sensitive method could be developed for the quantification of six AD drugs in human plasma using trap/elute micro-LC setup hyphenated to vDMS with mass spectrometric detection in the selected ion monitoring mode. The assay was found to be linear over three orders of magnitude, and the limit of quantification was of 25 ng/mL for all analytes. The LC-vDMS-SIM/MS method was compared to a LC-MRM/MS method, and in both cases, inter-assay precisions were lower than 12.5 and accuracies were in the range 91.5–110%, but with a four times reduced analysis time (2 min) for the LC-vDMS-SIM/MS method. This work illustrates that with vDMS, the LC mobile phase composition can be used to tune the ion mobility separation and to improve assay selectivity without additional hardware. Graphical abstract

Peripheral neuropathies commonly affect quality of life of patients due to pain, sleep disturbances, and fatigue, although trials have not adequately explored these domains of care. The aim of this study was to assess the impact of nortriptyline, duloxetine, pregabalin, and mexiletine on pain, sleep, and fatigue in patients diagnosed with cryptogenic sensory polyneuropathy (CSPN).We implemented a Bayesian adaptive design to perform a 12-wk multisite, randomized, prospective, open-label comparative effectiveness study in 402 CSPN patients. Participants received either nortriptyline (n = 134), duloxetine (n = 126), pregabalin (n = 73), or mexiletine (n = 69). At prespecified analysis timepoints, secondary outcomes, Patient Reported Outcomes Measurement Information System (PROMIS) surveys including Short Form (SF)-12, pain interference, fatigue, and sleep disturbance, were collected.Mexiletine had the highest quit rate (58%) due to gastrointestinal side effects, while nortriptyline (38%) and duloxetine (38%) had the lowest quit rates. If tolerated for the full 12 wk of the study, mexiletine had the highest probability (90%) of positive outcomes for improvements in pain interference and fatigue. There was no significant difference among the medications for sleep disturbance or SF-12 scores. Adverse events and lack of efficacy were the two most common reasons for cessation of therapy.Physicians caring for patients with CSPN should consider mexiletine to address pain and fatigue, although nortriptyline and duloxetine are better medications to trial first since they are better tolerated. Future research should compare other commonly used medications for CSPN to determine evidence-based treatment strategies.

With the thought and strong hope of uniqueness and challenging characteristic highlights and importance of nanofibrous mats (NFMs) along with cyclodextrins (CDs) that having a significant opportunity, chances and handling a vital role in hostile to bacterial activities. For the most part, CDs are utilized to upgrade the antibacterial activity through the improvement of solubility, stability, and etc., to any molecule which can bring inside the CDs cavity

Amitriptyline is an established drug in managing depression and neuropathic pain. Body exposure to amitriptyline and its by-products is influenced by enzymes activities, which are subject to genetic variation, whereas other medications in a patient’s treatment regimen may alter drug breakdown. To study these implications, genetic testing was conducted in 33 outpatients on amitriptyline therapy, alongside measurement of drug concentrations in blood and consideration of any co-administered medications. Breakdown of amitriptyline to nortriptyline was associated with the genetically determined status of patients. Subjects at high risk of having their rate for further breakdown delayed by other drugs had higher blood levels than expected in normal cases. A proportion of variation observed in blood drug concentrations across individuals with same genetic results could be explained by actions of drugs received concurrently. Supportive evidence is provided on the integration of drug interaction information with insights from genetic testing for patient-tailored pharmacotherapy that attempts to mitigate the possibility of missing an intended benefit or the risk of adverse events due to altered blood levels.

Migraine ranked as the eighth cause of disability worldwide. Statins with anti-inflammatory and vasodilatory endothelial effects have been introduced as an option for the prevention of migraine-type headaches. The current study aimed to assess the efficacy and tolerability of atorvastatin for the prevention of migraine in adults.This prospective, triple-blind, randomized controlled clinical trial was performed in adult migraineurs from mid-July 2019 to late-April 2020. Patients were randomly assigned to receive atorvastatin or placebo in combination with nortriptyline for 24-weeks. The frequency of headache was the primary outcome, and intensity of the headache and quality of life (QOL) were the secondary outcomes for this study.With 34 patients in each arm, 68 patients with migraines based on the International Headache Society (IHS) criteria were enrolled in the study. At week 24, patients in the atorvastatin group experienced significantly fewer migraine attacks than the placebo group (P-value = 0.004). Moreover, there were significant differences between the two groups in QOL at follow-up intervals of 14 (P-value = 0.001) and 24 (P-value0.001) weeks. However, no significant difference was observed in the intensity of headache was observed in both groups (P-value0.05). The most common adverse effects in intervention and control groups were constipation and insomnia, respectively.In patients with migraine, prophylaxis with atorvastatin significantly improved the frequency of headache and QOL over 24 weeks compared with placebo with no effect on the intensity of headache. Statins seem to be a potential promising drug for prophylaxis of migraine headaches.

A solid phase extraction-based (SPE) procedure for simultaneous preconcentration of five tricyclic antidepressants (TCAs), amitriptyline hydrochloride (AMT), nortriptyline hydrochloride (NOR), doxepin hydrochloride (DOX), imipramine hydrochloride (IMI), and clomipramine hydrochloride (CLO) from water samples with determination by HPLC-DAD is proposed. Polymers were characterized by FT-IR, SEM, and thermogravimetric analysis. SPE-based methods were carried out by the preconcentration of 320.0 mL of TCAs at pH 7.0 (buffered with 0.01 mol L

BACKGROUND: Interpatient variability in cytochrome P450 2D6 (CYP2D6) enzyme activity alters the serum concentrations of most psychotropics, which often have narrow therapeutic indices. Therefore, preemptive knowledge of CYP2D6 activity is desired. However, accessible indicators for deficient CYP2D6 activity are necessary because genotyping all patients prescribed CYP2D6 metabolized drugs is often not feasible or cost-effective. METHODS: In this study, the predictive value of the ratio between a CYP2D6 substrate and its metabolite, known as the metabolic ratio (MR), the dose-corrected serum concentration of substrate (CDR), and the dose-corrected sum concentration of substrate and metabolite (Sum CDR) of venlafaxine, risperidone, aripiprazole, and nortriptyline were determined to predict the CYP2D6 poor metabolizer (PM) phenotype. The area-under-the-receiver operator characteristic curve, as well as the sensitivity, specificity, and positive and negative predictive values of the optimal thresholds, were calculated. RESULTS: Although the MR, CDR, and Sum CDR all predicted the CYP2D6 PM phenotype, the predictive value of the MR was most robust for venlafaxine and aripiprazole, and the Sum CDR was inferior for all 3 psychotropics. MRs of venlafaxine, risperidone, and aripiprazole, and CDR of nortriptyline showed an area-under-the-receiver operator characteristics (95% confidence interval) of 97.2% (94.7%-99.6%), 93.0% (88.8%-97.2%), 97.8% (95.4%-100.0%), and 85.6% (78.0%-93.1%), respectively. Thresholds of the log(MR) of ≥0.1 for venlafaxine, ≥0.0 for risperidone, and ≥1.5 for aripiprazole, and log(CDR) ≥0.5 for nortriptyline produced >92% sensitivity and >64% specificity. CONCLUSIONS: If therapeutic drug monitoring is available, the thresholds presented here could serve as a diagnostic tool for the CYP2D6 PM phenotype of psychiatric patients prescribed the aforementioned psychotropic medications.

Smoking is highly prevalent in the psychiatric population, and hospital admittance usually results in partial or complete smoking cessation. Tobacco use is known to affect the metabolism of certain psychoactive drugs, but whether smoking influences the plasma concentration of tricyclic antidepressants (TCAs) remains unclear. This article investigates the possible effect of smoking on the plasma concentration of TCAs. A systematic review of the literature available on PubMed and EMBASE as of October 2020 was carried out using PRISMA guidelines. Studies reporting plasma concentrations of any TCA in both a smoking and a non-smoking group were included and compared. Ten eligible studies were identified and included. In the eight studies investigating the effect of smoking on amitriptyline and/or nortriptyline, five studies found no significant effect. Two studies investigating the effect of smoking on imipramine found a significant effect, and one study investigating the effect of smoking on doxepin found no significant effect. The majority of studies included in this review were influenced by small study populations and other methodical issues. The effect of smoking on the plasma concentration of TCAs is still not entirely clear. There is a possibility that smoking affects the distribution of TCA metabolites, but this is probably not of clinical importance.

Background Depressive symptoms are common in patients with Parkinson’s disease and depression is a significant predictor of functional impairment, reduced quality of life and general well-being in Parkinson's disease. Despite the high prevalence of depression, evidence on the effectiveness and tolerability of antidepressants in this population is limited. The primary aim of this trial is to establish the clinical and cost effectiveness of escitalopram and nortriptyline for the treatment of depression in Parkinson’s disease. Methods This is a multi-centre, double-blind, randomised placebo-controlled trial in 408 people with Parkinson’s disease with subsyndromal depression, major depressive disorder or persistent depressive disorder and a Beck Depression Inventory-II (BDI-II) score of 14 or above. Participants will be randomised into one of three groups, receiving either escitalopram, nortriptyline or placebo for 12 months. Trial participation is face-to-face, hybrid or remote. The primary outcome measure is the BDI-II score following 8 weeks of treatment. Secondary outcomes will be collected at baseline, 8, 26 and 52 weeks and following withdrawal, including severity of anxiety and depression scores as well as Parkinson’s disease motor severity, and ratings of non-motor symptoms, cognitive function, health-related quality of life, levodopa-equivalence dose, changes in medication, overall clinical effectiveness, capability, health and social care resource use, carer health-related quality of life, adverse effects and number of dropouts. Discussion This trial aims to determine the effectiveness of escitalopram and nortriptyline for reducing depressive symptoms in Parkinson’s disease over 8 weeks, to provide information on the effect of these medications on anxiety and other non-motor symptoms in PD and on impact on patients and caregivers, and to examine their effect on change in motor severity. Trial registration ClinicalTrials.gov Identifier: NCT03652870 Date of registration – 29th August 2018

Graphene is a two-dimensional material with unique physical and chemical properties, whose excellent biocompatibility has also attracted widespread attention in the field of biosensing and medical detection. Graphene provides a novel solution for dramatically improving the sensitivity of terahertz metasurface sensors, since the electrical conductivity can be modified by contact with biomolecules. In this paper, a metal-graphene hybrid metasurface is proposed and demonstrated for high-sensitive nortriptyline sensing based on the plasmon-induced transparency (PIT) resonances. The π-π stacks between nortriptyline and graphene lead to an increase in the Fermi level of graphene and a decrease in the conductivity, thus enhancing the PIT resonance. Experimental results show that the peak-to-peak amplitude magnitude of the PIT window is enhanced up to 3.4-fold with 1 ng nortriptyline analyte, and the minimum detection limit is extended down to 0.1 ng. But no significant change is observed from the samples without graphene as a comparative experiment, which demonstrates that the presence of graphene greatly enhances the bonding to the drug molecules and improves the sensing sensitivity. This metasurface sensor has the advantages of high sensitivity, fast detection speed, label-free and steady properties, which has potential applications in the fields of trace molecular sensing and disease diagnosis.

The cognitive adverse effects (AEs) of electroconvulsive therapy (ECT) limit the wider use of the treatment. These AEs can be attenuated by changing the way ECT is administered; however, such changes may reduce the response rate, the speed of response, or both. A recent systematic review and meta-analysis identified more than a dozen pharmacologic interventions in 26 randomized controlled trials (RCTs) that sought to reduce ECT-induced cognitive AEs. Because of large differences across RCTs, only a few outcomes for a few interventions could be pooled in meta-analysis, and most pooled analyses included only 2-3 RCTs. Important findings were that acetylcholinesterase inhibitors, ketamine, memantine, and liothyronine were associated with improved global cognitive functioning at 1-14 days post-ECT. Anti-inflammatory treatments and opioid receptor antagonists were not associated with improvement in general cognitive outcome at 1-14 days post-ECT. Meta-analysis was not possible for the remaining interventions, including piracetam, melatonin, pemoline, nortriptyline, herbal agents, drugs acting on the cortisol pathway, opioid receptor antagonists, l-tryptophan, vasopressin analogs, calcium channel blockers, and others; in individual RCTs, some of these interventions attenuated some cognitive measures as some time points after ECT. Regrettably, none of the RCTs examined clinically meaningful outcomes such as subjective cognitive impairment, impairments in daily life, and persistent autobiographical memory deficits. Future research should study such clinically meaningful outcomes (rather than laboratory tests), using pharmacologic interventions, perhaps in combination, for ECT procedures that are associated with higher cognitive AE burden. A risk is that whatever attenuates ECT-induced cognitive AEs may also attenuate ECT-related therapeutic benefits.

To evaluate the effect of neuromodulatory drugs on the intensity of chronic pelvic pain (CPP) in women. Searches were carried out in the PubMed, Cochrane Central, Embase, Lilacs, OpenGrey, and Clinical Trials databases. The searches were carried out by two of the authors, not delimiting publication date or original language. The following descriptors were used: The following data were extracted: author, year of publication, setting, type of study, sample size, intervention details, follow-up time, and results. A total of 218 articles were found, with 79 being excluded because they were repeated, leaving 139 articles for analysis: 90 were excluded in the analysis of the titles, 37 after reading the abstract, and 4 after reading the articles in full, and 1 could not be found, therefore, leaving 7 articles that were included in the review. Most of the studies analyzed have shown pain improvement with the help of neuromodulators for chronic pain. However, no improvement was found in the study with the highest statistical power. There is still not enough evidence that neuromodulatory drugs reduce the intensity of pain in women with CPP. Avaliar o efeito de drogas neuromoduladoras na intensidade da dor pélvica crônica em mulheres. As buscas foram realizadas nas bases de dados PubMed, Cochrane Central, Embase, Lilacs, OpenGrey e Clinical Trials. SELEçãO DOS ESTUDOS:: As buscas foram realizadas por dois dos autores, não delimitando data de publicação ou idioma de publicação. Foram usados os seguintes descritores: Foram extraídos os seguintes dados: autor, ano de publicação, local de origem, tipo de estudo, tamanho da amostra, detalhes da intervenção, tempo de seguimento e resultados. SíNTESE DOS DADOS:: Foram encontrados 218 artigos, sendo 79 deles excluídos por serem repetidos, restando 139 artigos para análise, dos quais 90 foram excluídos na análise dos títulos, 37 após a leitura do resumo e 4 após a leitura dos artigos na íntegra, e 1 não foi encontrado, restando, então, 7 artigos que foram incluídos na revisão. CONCLUSãO:: A maioria dos estudos analisados mostrou melhora da dor crônica com auxílio de neuromoduladores. No entanto, nenhuma melhora foi encontrada no artigo com maior poder estatístico. Ainda não há evidências suficientes de que drogas neuromoduladoras reduzam a intensidade da dor pélvica crônica em mulheres.

Sturge–Weber syndrome (SWS) is a neurocutaneous disorder characterized by vascular malformations affecting skin, eyes and leptomeninges of the brain, which can lead to glaucoma, seizures and intellectual disability. The discovery of a disease-causing somatic missense mutation in the GNAQ gene, encoding an alpha chain of heterotrimeric G-proteins, has initiated efforts to understand how G-proteins contribute to SWS pathogenesis. The mutation is predominantly detected in endothelial cells and is currently believed to affect downstream MAPK signalling. In this study of six Norwegian patients with classical SWS, we aimed to identify somatic mutations through deep sequencing of DNA from skin biopsies. Surprisingly, one patient was negative for the GNAQ mutation, but instead harbored a somatic mutation in GNB2 (NM_005273.3:c.232A>G, p.Lys78Glu), which encodes a beta chain of the same G-protein complex. The positions of the mutant amino acids in the G-protein are essential for complex reassembly. Therefore, failure of reassembly and continuous signalling is a likely consequence of both mutations. Ectopic expression of mutant proteins in endothelial cells revealed that expression of either mutant reduced cellular proliferation, yet regulated MAPK signalling differently, suggesting that dysregulated MAPK signalling cannot fully explain the SWS phenotype. Instead, both mutants reduced synthesis of Yes-associated protein (YAP), a transcriptional co-activator of the Hippo signalling pathway, suggesting a key role for this pathway in the vascular pathogenesis of SWS. The discovery of the GNB2 mutation sheds novel light on the pathogenesis of SWS and suggests that future research on targets of treatment should be directed towards the YAP, rather than the MAPK, signalling pathway.

Objective: Aim of the present study was to compare the effects of pregabalin and nortriptyline on sleep and quality of life in patients of postherpetic neuralgia (PHN). Methods: The present study was conducted in 48 patients of PHN attending the outpatient department (OPD) of Dermatology, Government Medical College Jammu. Based on inclusion/exclusion criteria patients were randomized into two treatment groups. One group received pregabalin 150 mg/day and the other group was treated with nortriptyline 25 mg/day. The patients were followed up to eight weeks and assessed for Sleep (Medical Outcomes Study sleep scale) and quality of life (Euro QOL-5D-5L score). Clinicians Global Impression of Change (CGIC) score and Patient Global Impression of Change (PGIC) score were used to evaluate overall clinical improvement. Results: Both drugs significantly improved all parameters studied (p

Background Testicular torsion is a pathological condition which needs emergency surgical intervention. However, after surgical reperfusion, oxidative stress factors cause to germ cell apoptosis. The study was planned to evaluate the efficacy of simultaneous use of Cyclosporine A (CsA) and Nortriptyline (Nort) to repair testicular damages in an experimental torsion/detorsion (T/D) rat model. Methods Male rats (n = 112) were allocated into 7 groups 16 each in; (Group 1); Control group, (Group 2); T/D group, (Group 3–4); CsA 1 and 5 mg/kg, (Group 5–6); Nort 2 and 10 mg/kg and (Group 7); concurrent group, CsA (1 mg/kg) + Nort (2 mg/kg). Right uni-lateral torsion was inducted by twisting testis 720 degrees in the clockwise direction for 1 h. For short-term and mid-term studies, lipid peroxidation, antioxidant enzyme activities, caspase-3 level, histopathological changes and germ cell apoptosis were evaluated. Moreover, in long-term investigation, semen analysis was performed. Results After T/D induction, testis abnormalities both functional and structural were appeared. Pre- and post-treatment with CsA and Nort, separately, reduced MDA and caspase-3 levels, normalized antioxidant levels, ameliorate tissue injury and improved sperm criteria. Conclusion The antioxidant and anti-apoptotic characteristics of CsA and Nort and their protective effects have been shown in our study. Concurrent administration of CsA and Nort in selected low-dose indicated a significant positive effect as compared to the individual drug interventions on the reversal of T/D induced oxidative stress in short-term, apoptosis, and histologic changes in mid-term, as well as semen criteria in the long-term appraisal.

Fluphenazine HCl (FLU) is an anxiolytic, while Nortriptyline HCl (NOR) is an anti-depressant. They are co-formulated together to treat depression and schizophrenia. Perphenazine (PER) and dibenzosuberone (DBZ) are the pharmacopeial impurities of FLU and NOR, respectively. Four spectrophotometric and multivariate chemometric methods were developed to determine the two drugs together or in presence of their two impurities in their bulk and pharmaceutical formulation. Method (A) is the triple divisor-ratio derivative (TDR) method, where the zero order spectrum of each component was divided by a mixture of the other 3 components, then the peak amplitudes of the first derivative spectra of FLU, NOR and DBZ were measured at 265, 245.4 and 283.2 nm, respectively. Method (B) is the double divisor-ratio difference-dual wavelength (DD-RD-DW) method, in which each component spectrum mixture was divided by a binary mixture of 2 of the interfering components. In the resulting ratio spectra, the amplitude difference is calculated between 2 wavelengths at which the third interfering component has zero difference. Methods (C and D) are the principle component analysis (PCA) and partial least squares (PLS) models. Methods (A and B) failed to quantify PER (FLU impurity), while (C and D) succeeded to quantify all components. The four methods have been applied for the prediction of the FLU and NOR in their pharmaceutical formulation with good accuracy and precision. The proposed methods have been validated according to the ICH guidelines and the results were within the acceptable limits.

Tinnitus can vary widely with regard to pitch, loudness, description of sound, special localization, and temporal pattern. Tinnitus is sometimes the first sign of hearing loss in older people. It also can be a side effect of various medications (antibiotics, cancer drugs, quinine medications, antidepressants, aspirin) If the condition is left unattended for a prolonged period, it can also lead to psychological problems. Extensive reviews of randomized clinical trials have revealed that only nortriptyline, amitriptyline, alprazolam, clonazepam, and oxazepam are more beneficial than placebo. Keywords: Tinnitus, Sytematic review, Hearing impairment, Antidepressants, Benzodiazepines.

Background: Depressive disorders are amongst the most prevailing causes of morbidity and disability in the Indian population. Choosing suitable antidepressants for a particular patient is an imperative decision. Aim: To study the drug utilization of antidepressantdrugs and their adverse drug reaction in the department of psychiatry of a tertiary care hospital. Materials and Methods: It was an observational, prospective study conducted for a duration of 18 months, i.e., from February 2018 to July 2019. The first six months were for recruitment of patients and 12 months were for follow up and data compilation. The prescriptions of every alternate patient were collected on a twice-weekly basis. Results: In our study, 21–30 years of age group accounted for majority (31.98%) of all depressive disorders. Males (52.28%) were found to be more affected than females. SSRIs (73.26%) were most frequently prescribed, followed by TCA (20%) and SNRI (6.33%). The average number of drugs per prescription was 2.49. The most commonly reported ADR was insomnia (21.23%). ADRs were more commonly found with nortriptyline; a tricyclic antidepressant drug. PDD/DDD values of most of the drugs were close to one. Conclusions: Through this study, we found that SSRIs were the most commonly prescribed group of antidepressants because of their better efficacy, safety, tolerability, and fewer side effects as compared to TCAs. PDD/DDD ratio signifies that the drugs were neither under-utilized nor over-utilized. Since no prescription had more than five drugs; we can say that polypharmacy was avoided. Keywords: Depressive disorders, Defined Daily Dose, Prescribed Daily Dose, Polypharmacy, Psychiatry.

Background Antidepressants are recommended for the treatment of chronic musculoskeletal pain; however, target serum concentrations based on therapeutic drug monitoring (TDM) have not been established. Therefore, the authors analyzed routine care TDM data of antidepressants in patients with chronic pain with and without depression in terms of treatment outcomes in an interdisciplinary multimodal pain treatment (IMPT) program. Methods Patients with chronic musculoskeletal pain and TDM for amitriptyline (n = 45) or duloxetine (n = 30) were retrospectively included. The German pain questionnaire for pain intensity and the Depression Anxiety Stress scale were applied at T0 and at the end of the IMPT program (T1). A relief of pain intensity score ≥2 was considered as a positive outcome. Comorbid depression was diagnosed based on ICD-10 criteria. Serum concentrations of antidepressants were measured for routine clinical care TDM. Results After IMPT, stress improved in all subgroups, and depressive symptoms improved only in the duloxetine group. Overall, 40% and 27% of patients in the amitriptyline and duloxetine subgroup, respectively, were responders in terms of maximum pain score relief. Responders with comorbid depression were treated with a dose that led to a 1.7-fold higher serum concentration of the active moiety of amitriptyline (amitriptyline + nortriptyline) compared with nonresponders. Similarly, a 2.3-fold higher serum concentration was observed in depressed responders than in nondepressed responders (at minimum 131.5 ng/mL). Conclusions Dosing of antidepressants for chronic pain relief should specifically take comorbid depression into account. TDM may provide better outcomes of pain relief in an IMPT setting in patients with comorbid depression.

Introduction: An antidepressant nortriptyline potentiates glucocorticoid (GC) action with synergistic suppression of inflammatory mediator release, but the precise molecular mechanism is unknown. Materials and methods: Peripheral blood cells from patients with chronic obstructive pulmonary disease (COPD) (n = 21) were incubated with nortriptyline (1 μM or 10 μM), budesonide (10 nM), or their combinations, followed by stimulation with phorbol myristate acetate (PMA) and ionomycin. Cytokine production, glucocorticoid receptor β (GRβ), histone deacetylase 2 (HDAC2) and histone H4 acetylation of K8 (HAT) expression, p65 NF-kB and p38 mi­togen-activated protein kinase (p38 MAPK) phosphorylation in NK (CD3-CD56+) and NKT-like (CD3+CD56+) cells were analyzed by flow cytometry. Results: We observed that nortriptyline (10 μM) significantly attenuated the effects of PMA/ionomycin on the synthe­sis of interferon γ (IFNγ), interleukin 4 (IL-4), and IL-8, expression of GRβ and HAT, as well as p65 NF-kB and p38 MAPK phosphorylation in NK and NKT-like cells, whereas nortriptyline (1 μM) only inhibited IL-4 production by NK and NKT-like cells. Discussion: The combination of nortriptyline (10 μM) and budesonide decreased IFNγ, tumor necrosis factor α, IL-4, IL-8, and GRβ expression, as well as phosphorylated p38 MAPK and p65 NF-κB levels by NK and NKT-like cells above that of budesonide alone. Furthermore, the same association of drugs enhanced HDAC2 expression in NK and NKT-like cells. Conclusion: Collectively, our results show that nortriptyline might enhance GC function through modulation of HAT, HDAC2, GRβ, phospho-p38 MAPK expression. These data provide a strong rationale for combining nortriptyline with budesonide to treat COPD.

Objective: To determine the effectiveness of nortriptyline and tolerability of side effects in the treatment of neurogenic cough. Secondary goal is to evaluate the association between laryngeal asymmetry and clinical response to nortriptyline. Study Design: Retrospective case series. Materials and Methods: Consecutive patients diagnosed with neurogenic cough at a quaternary care specialty hospital from 2001 to 2020 were identified. Subjects Results: Forty-two patients met inclusion and exclusion criteria, 7 males and 35 females with an average age of 56.5 (±13.1) years. There were 26/36 (72.2%) responders and 10/36 (27.8%) non-responders; 6 patients stopped nortriptyline due to side effects and were not included in the response comparison. Laryngeal asymmetry was present in 36/42 (85.7%) patients. No factors related to laryngeal asymmetry were significantly different between responders and non-responders. Medication tolerance was observed in 3/42 (7.1%) patients. Side effects were reported in 16/42 (38.1%) patients. The most common side effects were sedation 9/42 (21.4%) and xerostomia 3/42 (7.1%). Conclusion: Nortriptyline is effective for treating neurogenic cough with 72% of patients reporting improvement in cough. Evidence of laryngeal asymmetry was not associated with better treatment response. Although 38% experienced side effects, the majority of patients continued nortriptyline despite side effects. Level of Evidence: 4

Background and Aim: Headache is the most common cause of referral to a physician. Two approaches of the migraine treatment include: treat the acute attacks and prevent future attacks. In this regard, the aim of this study was to investigate the effect of three drugs lutiracetam, sodium valproate and nortriptyline in the control of migraine headaches in patients with migraine in Birjand Neurology Clinic. Materials and Methods: This study is a quasi-experimental study. According to the physician, 120 migraine patients were divided into one of three groups: Lutiracetam with a daily dose of 250 mg, sodium valproate 500 mg and nortriptyline 25 mg for 4 weeks. Patientschr('39') information was collected through a questionnaire. Then the data were analyzed by SPSS) Version 16) software by using chi-square, paired t-test, and ANOVA. Results: 120 patients were divided into three groups of 40 patients. The mean age of the subjects was 33±11 years, 53.3% of them were female and 46.7% of them were male. In total, 46.7% of patients had severe headache before taking these three drugs. None of them had severe headache after taking the drug and 77.5% of them had mild headache. Lutiracetam group showed the greatest decrease in headache intensity. (P=0.01). Conclusion: Levetiracetam appears to be more effective than the other two drugs, especially sodium valproate, in reducing different degrees of headache.

Objectives To evaluate the treatment outcomes of medication therapies in patients with burning mouth syndrome (BMS) and to identify the clinical characteristics that may affect the efficacy of prescribed medications. Methods This is a retrospective study of 769 patients with oral burning sensations. Of these patients, 420 patients diagnosed as the primary BMS received an "Initial Approach" that involved a detailed explanation about its etiopathophysiology, self-care instruction, and use of an oral lubricant. Neuropathic medications were prescribed for 277 patients who did not respond to the initial approach. Clinical characteristics, prescribed medications, and changes in intensity of oral symptoms were reviewed. Results Clonazepam was administered as the first-line medication. Alpha-lipoic acid (ALA), gabapentin, and nortriptyline were commonly administered in combination with clonazepam. More than two-thirds of the patients reported a marked improvement in oral symptoms after treatments with combination of neuropathic medications and ALA. The efficacies of the initial approach and clonazepam had significant positive associations with the initial intensity of oral symptoms and significant negative associations with depression. Conclusions Clonazepam therapy in combination with appropriate medications was effective for managing patients with BMS. The initial intensity of oral symptoms and psychological status were significantly associated with treatment outcomes.

PURPOSE: Neuropathic corneal pain (NCP) is a recently acknowledged disease entity. However, there is no consensus in potential treatment strategies, particularly in patients with a centralized component of pain. This study aims to assess the efficacy and tolerability of the tricyclic antidepressant, nortriptyline, among NCP patients. METHODS: Patients with clinically diagnosed NCP and a centralized component of pain, treated with oral nortriptyline, who had recorded pain scores as assessed by the ocular pain assessment survey at the first and last visit were included. Patients were excluded if they had any other ocular pathology that might result in pain or had less than 4 weeks of nortriptyline use. Demographics, time between visits, concomitant medications, systemic and ocular comorbidities, duration of NCP, side effects, ocular pain scores, and quality of life (QoL) assessment were recorded. RESULTS: Thirty patients with a mean age of 53.1±18.5 were included. Male to female ratio was 8:22. Mean ocular pain in the past 24 hours improved from 5.7±2.1 to 3.6±2.1 after 10.5±9.1 months (p

Single-crystal X-ray diffraction and DFT calculation have been carried out for an atomic-level understanding of β-cyclodextrin (β-CD) inclusion complexation with 2 tricyclic antidepressants (TCAs), desipramine and imipramine. X-ray analysis discloses that the A–C-rings are buried in the β-CD cavity and the side chain is mostly outside the cavity, nearby the O2–H/O3–H side. Hence, the inclusion structures of both complexes are stabilized by host–guest C5–H∙∙∙π interaction and N5′–H∙∙∙O5/O6 H-bonds of twofold-screw-symmetry-related molecules, which are similar to those of the reported complexes of nortriptyline and amitriptyline. The DFT full-geometry optimization in the gas phase reveals an alternative inclusion scenario with the TCA side chain that is embedded in the β-CD cavity and stabilized by intermolecular O6–H∙∙∙N5’ H-bond and O2–H/O3–H∙∙∙π interactions. The β-CD encapsulation of the TCA side chain is more energetically stable by 10.76 and 4.70 kcal mol−1 than that of the aromatic moiety for the respective complexes of DPM and IPM, based on the relative stabilization energies (ΔΔEstb). This suggests the existence of the bimodal β-CD–TCA inclusion complexes as spectroscopically observed in solution, thus explaining the controversy in the inclusion mode and the improvement of TCA therapeutic effect by CD encapsulation.

The degradation behavior of eight tricyclic antidepressants (TCAs; amitriptyline, amoxapine (AMX), imipramine, clomipramine, desipramine, doxepin, dothiepin, and nortriptyline) in artificial gastric juice was investigated to estimate their pharmacokinetics in the stomach. As a result, among the eight TCAs, only AMX was degraded in artificial gastric juice. The degradation was a pseudo first-order reaction; activation energy (Ea) was 88.70 kJ/mol and activation entropy (ΔS) was -80.73 J/K·mol. On the other hand, the recovery experiment revealed that the degradation product did not revert to AMX and accordingly, this reaction was considered to be irreversible. In the AMX degradation experiment, peaks considered to be degradation products A (I) and B (II) were detected at retention times of around 3 min and 30 min in LC/UV measurements, respectively. Structural analysis revealed that compound (I) was [2-(2-aminophenoxy)-5-chlorophenyl]-piperazin-1-yl-methanone, a new compound, and compound (II) was 2-chlorodibenzo[b,f][1,4]oxazepin-11(10H)-one. As for the degradation behavior, it was estimated that AMX was degraded into (II) via (I), i.e., (II) was the final product. The results are expected to be useful in clinical chemistry and forensic science, including the estimation of drugs to be used at the time of judicial dissection and suspected drug addiction.

Parotid gland plays the most critical role in saliva secretion in the oral cavity. Parotid gland injuries due to facial trauma can cause various complications such as formation of a fistula or sialocele. Thus, such saliva-related complications can interfere with wound healing and increase the risk of infection. Several previous studies have discussed the treatment of fistula or sialocele. Nonetheless, prevention of such complications is of utmost importance. We present a case of parotid gland injury due to trauma to the cheeks that was surgically treated, with early postoperative management involving oral administration of nortriptyline and closed drainage, without complications.

Purpose This study compares the pharmacokinetic and safety profiles between a new generic and a branded reference formulation of amitriptyline hydrochloride tablets, and assesses the bioequivalence of the two products in healthy Chinese volunteers to obtain sufficient evidence for the marketing approval of the generic drug. Materials and methods A randomized, open-label, two-period crossover study (clinicaltrials.gov, NCT03646526) was conducted under both fasting and fed conditions in healthy Chinese volunteers (24 subjects/condition). Eligible subjects randomly received a single 25 mg dose of either the test or the reference formulation, followed by a 3-week washout period. Blood samples were collected until 144 h following administration. The pharmacokinetic parameters were acquired based on the concentration-time profiles, including the areas under the plasma concentration-time curve (AUC0-t, AUC0-∞), the peak plasma concentration (Cmax), the time to achieve Cmax (Tmax), and the elimination half-life (t1/2). The geometric mean ratios (GMRs) and the corresponding 90% confidence intervals (CIs) of amitriptyline were acquired for bioequivalence analysis, and values of these parameters for nortriptyline were used for comparison of therapeutic outcomes. Safety assessments included laboratory tests, physical examination, vital signs, and incidence of adverse events (AEs). Results The values of t1/2 and Tmax for amitriptyline were not significantly different between the test and reference products under both fasting and fed conditions (P > 0.05). The GMRs of Cmax, AUC0-t, and AUC0-∞ between the two products, and corresponding 90% CIs, were all within the range of 80% to 125% under both fasting and fed conditions. The test and reference products were well tolerated and did not elicit serious adverse events. Conclusion This study demonstrated that the generic and reference products were well tolerated by the subjects and bioequivalent, according to the rate and extent of the drug absorption.

ObjectiveGiven the lack of evidence on patients with medically refractory vestibular migraine, this study aimed to identify factors associated with pharmacotherapy failure and progression to botulinum toxin injection in vestibular migraine.MethodsA retrospective cohort study was conducted on definite vestibular migraine patients from September 2015 to July 2019 who completed the Dizziness Handicap Inventory at least six weeks apart..ResultsThe study comprised 47 patients (mean age = 50.2 ± 15.8 years), with a mean follow-up time of 6.0 ± 6.0 months. The mean pre-treatment Dizziness Handicap Inventory score was 57.5 ± 23.5, with a mean reduction of 17.3 ± 25.2 (p < 0.001) at last follow up. Oscillopsia (r = 0.458, p = 0.007), failure of first medication (r = 0.518, p = 0.001) and pre-treatment Dizziness Handicap Inventory question 15 (an emotional domain question) score (r = 0.364, p = 0.019) were the only variables significantly correlated with progression to botulinum toxin injection.ConclusionMotion hypersensitivity, failure of first medication, and fear of social stigmatisation suggest a decreased treatment response. These symptoms may require more aggressive treatment at an earlier stage.

Background: Gastric ulcer is among the most serious stomach disorder universally. Several effective drugs are employed in the management of this disease, although there have been adverse effects in some cases. The aim of this study was to investigate the effect of nortriptyline to protect against gastric lesions, induced by indomethacin or cold-stress in rats. Methods: Gastric lesions were induced by oral indomethacin (30 mg/kg) or cold-shock at 2-4°C. Animals were pre-treated with 5, 10 or 20 mg/kg nortriptyline. After 4hr of exposure to indomethacin or cold shock, the stomach was removed for histological examinations and the levels of enzymatic and non-enzymatic oxidative stress markers were determined in the tissue samples. Results: The results showed that nortriptyline at 20 mg/kg significantly restored the activity of the oxidative stress markers, such as Superoxide Dismutase (SOD) and Catalase (CAT) enzymes. It also decreased the tissue Malondialdehyde (MDA) concentration. In addition, nortriptyline at 20 mg/kg, ameliorated the gastric tissue damages caused by indomethacin or the cold shock. Conclusion: The results suggest that improvement in gastric mucosal lesions can be mediated by nortriptyline pretreatment, which is likely due to its antioxidant property.

OBJECTIVE: To describe the usage patterns of antidepressants with published CYP2D6- and CYP2C19-based prescribing guidelines among depressed primary care patients and estimate the proportion of patients taking antidepressants not recommended for them based on their CYP2C19 and CYP2D6 genotype-predicted metabolizer status. METHODS: Medication use and pharmacogenetic testing results were collected on 128 primary care patients enrolled in a 10-year depression cohort study. At each 12-month interval, we calculated the proportion of patients that: (1) reported use of one or more of the 13 antidepressant medications (i.e. amitriptyline, citalopram, escitalopram, clomipramine, desipramine, doxepin, fluvoxamine, imipramine, nortriptyline, paroxetine, sertraline, trimipramine, venlafaxine) with published CYP2D6- and CYP2C19-based prescribing guidelines, (2) were taking an antidepressant that was not recommended for them based on their CYP2C19 and CYP2D6 genotype-predicted metabolizer phenotype, and (3) switched medications from the previous 12-month interval. RESULTS: The annual proportion of individuals taking an antidepressant with a CYP2D6- and CYP2C19-based prescribing guidelines ranged from 45 to 84%. The proportion of participants that used an antidepressant that was not recommended for them, based on available CYP2D6 and CYP2C19 metabolizer phenotype, ranged from 18 to 29% and these individuals tended to switch medications more frequently (10%) compared to their counterparts taking medication aligned with their metabolizer phenotype (6%). CONCLUSION: One-quarter of primary care patients used an antidepressant that was not recommended for them based on CYP2D6- and CYP2C19-based prescribing guidelines and switching medications tended to be more common in this group. Studies to determine the impact of CYP2D6 and CYP2C19 genotyping on reducing gene-antidepressant mismatches are warranted.

A simple and cheap all-in-one concept for at-line coupling of hollow fiber liquid-phase microextraction (HF-LPME) to commercial capillary electrophoresis (CE) is demonstrated, which enables the direct analysis of complex samples. A disposable microextraction device compatible with injection systems of Agilent CE instruments is proposed, which consists of a short segment of a porous HF attached to a tapered polypropylene holder. The holder maintains a constant position of the HF in a CE vial during extraction and simultaneously guides the injection end of a separation capillary into the HF lumen for automated CE injection and analysis. In a typical analytical procedure, the HF is impregnated with a water-immiscible solvent, its lumen is filled with 5 μL of an aqueous acceptor solution, and the microextraction device is placed in a 2 mL glass CE vial containing 550 μL of a donor solution. The vial is agitated at 750 rpm for 10 min, and the resulting acceptor solution is injected directly from the HF lumen into the commercial CE. No additional manual handling is required, except for the transfer of the CE vial to the CE autosampler. Multiple complex samples can be simultaneously pretreated in a multiple-well plate format, thus significantly reducing the total analysis time. Suitability of the analytical method is demonstrated by the direct determination of model basic drugs (nortriptyline, haloperidol, loperamide, and papaverine) in physiological solutions, urine, and dried blood spot (DBS) samples. Repeatability of the method is better than 12.8% (%RSD), extraction recoveries range between 34 and 76%, and enrichment factors are 37-84. The method is linear in a range of 2 orders of magnitude (

An LC–MS-MS method for the determination of 14 benzodiazepines (BZDs) (alprazolam, α-hydroxyalprazolam, clonazepam, bromazepam, diazepam, nordiazepam, lorazepam, lormetazepam, oxazepam, flunitrazepam, 7-aminoflunitrazepam, triazolam, midazolam and zolpidem) and 15 antidepressants (ADs) (amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, norclomipramine, fluoxetine, norfluoxetine, sertraline, norsertraline, paroxetine, venlafaxine, desmethylvenlafaxine, citalopram and desmethylcitalopram) in meconium was developed and validated. Meconium samples (0.25 ± 0.02 g) were homogenized in methanol and subjected to mixed-mode cation exchange solid-phase extraction. Chromatographic separation was performed in reversed phase, with a gradient of 0.1% formic acid in 2 mM ammonium formate and acetonitrile. Two different chromatographic gradient methods were employed, one for the separation of ADs and another for BZDs. Analytes were monitored by tandem mass spectrometry employing electrospray positive mode in MRM mode (2 transitions per compound). Method validation included: linearity [n = 5, limit of quantification (LOQ) to 400 ng/g], limits of detection (n = 6, 1–20 ng/g), LOQ (n = 9, 5–20 ng/g), selectivity (no endogenous or exogenous interferences), accuracy (n = 15, 90.6–111.5%), imprecision (n = 15, 0–14.6%), matrix effect (n = 10, −73 to 194.9%), extraction efficiency (n = 6, 35.9–91.2%), process efficiency (n = 6, 20.1–188.2%), stability 72 h in the autosampler (n = 3, −8.5 to 9%) and freeze/thaw stability (n = 3, −1.2 to −47%). The method was applied to four meconium specimens, which were analyzed with and without hydrolysis (enzymatic and alkaline). The authentic meconium samples tested positive for alprazolam, α-hydroxyalprazolam, clonazepam, diazepam, nordiazepam, fluoxetine, norfluoxetine, clomipramine and norclomipramine. Therefore, the present LC–MS-MS method allows a high throughput determination of the most common BZDs and ADs in meconium, which could be useful in clinical and forensic settings.

Neurobiological underpinnings of treatment-resistant depression, a debilitating condition associated with significant functional impairment, have not been elucidated. Consequently, the aim of this study was to use animal models of response and resistance to antidepressant treatment, in an attempt to identify differences in associated transcriptional responses. Flinders Sensitive Line rats were subjected to maternal separation (MS) and chronically treated with Escitalopram or Nortriptyline. Antidepressants reduced immobility time in the forced swim test in non-MS rats, while lack of antidepressant behavioural response was observed in MS animals. We developed a novel bioinformatic algorithm that enabled identification of transcriptional signatures in hippocampus and pre-frontal cortex that discriminate vehicle- and antidepressant-treated subjects in both MS and non-MS rats. Functional annotation analysis showed that in antidepressant-responder rats the most enriched pathways included IQGAPs activation, toll-like receptor trafficking, energy metabolism, and regulation of endopeptidase activity. The analysis of interacting proteins implicated synaptic vesicles and neurotransmitter release, ubiquitin regulation, cytoskeleton organisation and carbohydrate metabolism. In contrast, in treatment-resistant MS rats, main expression changes were revealed in ribosomal proteins, inflammatory responses, transcriptional/epigenetic regulation, and small GTPases. Susceptibility signature shared Rtn1, Zdhhc5, Igsf6, and Sim1 genes with the latest depression GWAS meta-analysis, while antidepressant resistance signature shared Ctnnd1, Rbms3, Atp1a3, and Pla2r1 genes. In conclusion, this study demonstrated that distinct transcriptional signatures are associated with behavioural response or non-response to antidepressant treatment. The identification of genes involved in antidepressant response will increase the comprehension of the neurobiological underpinnings of treatment-resistant depression, thus contributing to identification of novel therapeutic targets.

Amitriptyline is prescribed for treating the symptoms of neuroinflammatory disorders including neuropathic pain and fibromyalgia. As amitriptyline has evidence of modulating the neuroimmune interface; the effects of amitriptyline treatment on T-cell phenotype and function were examined in vitro. Peripheral blood mononuclear cells(PBMCs) were isolated and treated with amitriptyline, nortriptyline and a combination of both drugs. Toxicity for T-cells was assessed by Annexin V/Propidium Iodide staining. Activation status and cytokine expression by T-cells post treatment was assessed by flow cytometry. The levels of secreted cytokines, chemokines and neurotrophins were measured by ELISA in the supernatants. There was no significant increase in T-cell death following 24 or 48 h compared to controls. There were significantly lower frequencies of CD8+ T-cells after treatment with amitriptyline, nortriptyline and a combination of both compared to a Vehicle Control(VC)(p

Introduction Drug-induced QT prolongation is associated with higher cardiovascular mortality. Material and methods We conducted a protocol-based comprehensive review of antidepressant-induced QT prolongation in people with mental disorders. Results Based on findings from 47 published randomized controlled trials (RCTs), 3 unpublished RCTs, 14 observational studies, 662 case reports of torsades de pointes, and 168 cases of QT prolongation, we conclude that all antidepressants should be used only with licensed doses, and that all patients receiving antidepressants require monitoring of QT prolongation and clinical symptoms of cardiac arrhythmias. Large observational studies suggest increased mortality associated with all antidepressants (RR = 1.62, 95% CI: 1.60-1.63, number of adults: 1,716,552), high doses of tricyclic antidepressants (OR = 2.11, 85% CI 1.10-4.22), selective serotonin reuptake inhibitors (OR = 2.78, 95% CI: 1.24-6.24), venlafaxine (OR = 3.73, 95% CI: 1.33-10.45, number of adults: 4,040), and nortriptyline (OR = 4.60, 95% CI: 1.20-18.40, number of adults: 5,298). Conclusions Evidence regarding the risk of QT prolongation in children is sparse.

Contains fulltext : 251161.pdf (Publisher’s version ) (Open Access) Tricyclic antidepressants (TCAs) are frequently prescribed in case of non-response to first-line antidepressants in Major Depressive Disorder (MDD). Treatment of MDD often entails a trial-and-error process of finding a suitable antidepressant and its appropriate dose. Nowadays, a shift is seen towards a more personalized treatment strategy in MDD to increase treatment efficacy. One of these strategies involves the use of biomarkers for the prediction of antidepressant treatment response. We aimed to summarize biomarkers for prediction of TCA specific (i.e. per agent, not for the TCA as a drug class) treatment response in unipolar nonpsychotic MDD. We performed a systematic search in PubMed and MEDLINE. After full-text screening, 36 papers were included. Seven genetic biomarkers were identified for nortriptyline treatment response. For desipramine, we identified two biomarkers; one genetic and one nongenetic. Three nongenetic biomarkers were identified for imipramine. None of these biomarkers were replicated. Quality assessment demonstrated that biomarker studies vary in endpoint definitions and frequently lack power calculations. None of the biomarkers can be confirmed as a predictor for TCA treatment response. Despite the necessity for TCA treatment optimization, biomarker studies reporting drug-specific results for TCAs are limited and adequate replication studies are lacking. Moreover, biomarker studies generally use small sample sizes. To move forward, larger cohorts, pooled data or biomarkers combined with other clinical characteristics should be used to improve predictive power.

A 66-year-old man with no headache history presented with a new daily and persistent headache that began acutely 1 year ago without any clear provoking features. The pain was mild, constant holocephalic pressure with associated photophobia and phonophobia. He denied nausea/vomiting or migraine aura–like symptoms. Previously failed preventive migraine medications included onabotulinumtoxinA injections, nortriptyline, gabapentin, and metoprolol. The patient's neurologic examination including funduscopic evaluation was normal.

Background Many clinical toxicology laboratories receive urine specimens in urine cups that contain point of care (POC) drug testing strips. We conducted this study to evaluate the effect on the stability of commonly measured drugs in the clinical toxicology laboratory when urine is exposed to POC urine drug testing cups. Methods Drug free urine was spiked with 85 drugs that were measured by a validated liquid chromatography mass spectrometry (LCMS) method after exposure to POC urine drug testing cups at ambient and 2–6 °C temperatures. Alterations ≥20% were defined as significant changes in the drugs concentration. Results Concentrations of amitriptyline, cyclobenzaprine, fentanyl, fluoxetine, flunitrazepam, nortriptyline, paroxetine, and sertraline were significantly reduced when urine specimens were stored inside POC urine drug testing cups for 24 h at ambient temperature. Storage of urine in urine chemistry dipsticks reduced the concentration of several drugs. When spiked urine was exposed to an increasing number of POC urine drug testing strips, the concentrations of some drugs were reduced in a dose-dependent manner. The drugs that were absorbed by POC urine drug testing strips were partially back extracted from the strips. Conclusion Exposure of urine specimens to POC urine drug testing strips reduces the concentration of several drugs measured by LCMS method.

Background: Little is known whether cholesterol levels affect depression treatment outcomes. We aimed to study the association between baseline and changes in blood cholesterol levels with drug-specific antidepressant response and long-term prognosis in patients with major depressive disorder (MDD). Methods: From the Danish site of the GENDEP trial, we included patients with MDD randomized to escitalopram or nortriptyline treatment. Total and free cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and depression severity using the Montgomery-Åsberg Depression rating scale (MADRS) were measured at baseline and after 26 weeks of treatment initiation. By linkage with nationwide registers, we analyzed psychiatric and cardiometabolic hospital contacts during the five years after the trial. We assessed the association of cholesterol levels with a) depression severity using linear and mixed effects regression analyses; and b) the register-based outcomes using Cox regression analyses. Results: Among 78 patients (mean age 38 years, 74% women, mean MADRS score 28 [SD=4.5]), baseline cholesterol levels were not correlated with antidepressant response. Among 58 patients with measurements at week 0 and 26, cholesterol levels significantly increased in both treatment groups. Only in patients using escitalopram did the increase in total and free cholesterol and LDL correlate with improved antidepressant response. Baseline or changes in cholesterol were not associated with 5-year outcomes. Limitations: Secondary analyses on a rather small sample. Conclusion: This study provides clinical insight into potential drug-specific associations between increases in cholesterol levels and antidepressant response to escitalopram but not nortriptyline.

Objectives: Antidepressants and anticonvulsants are most commonly prescribed in postherpetic neuralgia (PHN). The aim of the present study was to compare the efficacy and safety of pregabalin and nortriptyline in patients of PHN. Methods: The present study was conducted in 48 patients of PHN attending outpatient department of Dermatology, GMC Jammu. After obtaining written consent, the enrolled patients were randomized into two groups, one group was given pregabalin 150 mg orally per day, and other group was treated with nortriptyline 25 mg orally per day and were followed up to 8 weeks. Patients were assessed on numerical rating scale (NRS), Leeds assessment of neuropathic symptoms and signs (LANSS). Safety of the drugs was monitored by adverse drug reactions (ADRs). Results: All patients were over 57 years and thoracic dermatome was most affected. Both drugs significantly reduced NRS and LANSS (p

Objective Pain in Parkinson disease (PD) is complex as this symptom can be multifactorial in origin because deficits in dopaminergic but also other neurotransmitters are involved. Pain and depression are increasingly recognized to have clinical importance for the quality of life of people living with PD. This systematic review aims to summarize the existing evidence on the potential benefit of using prescribed antidepressants for decreasing or controlling pain associated with PD. Methods PubMed databases were searched for relevant studies using keywords and our exclusion/inclusion criteria and targeting only randomized placebo-controlled trials for antidepressants in PD. Results After screening 108 articles, only 3 focused articles were analyzed. Two of the included studies reported were on nortriptyline and paroxetine antidepressants. Unfortunately, included studies did not align in their outcome measures and did not directly compare the drug groups against each other or the placebo. Therefore, the complex nature of the unaligned outcome measures is inadequate for interpreting the efficacy of antidepressants in treating pain symptoms in PD. The third study focused solely on observing the effects of duloxetine but showed no favorable effects of this drug on pain. Conclusions Prospective studies with a direct comparison of antidepressants and placebo should be conducted, focusing on pain-related scales and questions to understand further the role of antidepressants in treating pain in PD.

Steroid unresponsiveness is a significant problem in the management of chronic obstructive pulmonary disease (COPD). The tricyclic antidepressant nortriptyline has been reported to reverse corticosteroid resistance induced by oxidative stress. This study examined the potential synergistic anti-inflammatory effects of nortriptyline and corticosteroids in T lymphocytes from patients with COPD and the molecular mechanisms underlying their action. Peripheral blood mononuclear cells (PBMCs) or whole blood cells from COPD patients were incubated with budesonide, nortriptyline, or their combinations and stimulated with phytohaemagglutinin (PHA) or phorbol myristate acetate (PMA) plus ionomycin. The release of interleukin 4 (IL-4), IL-5, IL-8 and other mediators from PBMCs was measured by ELISA. Intracellular pro-inflammatory cytokines, glucocorticoid receptor (GR) and its isoform GRβ, histone deacetylase 2 (HDAC2), phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) and p65 nuclear factor-κ (p65 NF-κB) were determined in CD4+ and CD8+ T cells using flow cytometry. Nortriptyline 10 μM decreased PHA-induced release of cytokines: IL-4, IL-5, IL-13, IL-17A, IL-33, macrophage migration inhibitory factor and thymic stromal lymphopoietin (TSLP). This drug alone also reduced the percentage of IL-4, IL-8, interferon gamma (IFNγ) positive CD4+ T cells and IL-4, IL-8 expressing CD8+ T cells stimulated with PMA/ionomycin, whereas nortriptyline 1 μM had less pronounced effect. The combination of budesonide 10 nM with nortriptyline 10 μM was more potent at suppressing IL-4, IL-5, IL-8, IL-13, IL-17A, TSLP secretion from PBMCs, as well as IL-4, IL-8, IFNγ, GRβ expression by CD4+ and CD8+ T cells when compared with single budesonide treatment. The association of budesonide 10 nM and Nt (1 μM to 10 μM) effectively decreased p38 MAPK and p65 NF-κB phosphorylation and increased HDAC2 expression in both CD4+ and CD8+ T cells. In conclusion, nortriptyline alone demonstrates anti-inflammatory effects on blood T lymphocytes from COPD patients. Nortriptyline may also potentiate the effects of glucocorticoids and overcome corticosteroid insensitivity.

Amitriptyline and its metabolite, Nortriptyline are commonly used tricyclic antidepressant (TCA) drugs that are electrochemically active. In this work, the performance characteristics of a plasticized PVC membrane-coated glassy carbon (GC) electrode are described for the voltammetric quantification of Amitriptyline and Nortriptyline in whole blood. The highly lipophilic Amitriptyline and Nortriptyline preferentially partition into the plasticized PVC membrane where the free drug is oxidized on the GC electrode. The concentrations of the drugs in the membrane are orders of magnitude larger than in the sample solution, resulting in superb limit of detection (LOD) of the membrane-coated voltammetric sensor: 3 nmol/L for Amitriptyline and 20 nmol/L for Nortriptyline. Conversely, hydrophilic components of the sample solution, e.g., proteins, the protein-bound fraction of the drugs, and electrochemically active small molecules are blocked from entering the membrane, which provides exceptional selectivity for the membrane-coated sensor and feasibility for the measurements of Amitriptyline in whole blood. In this work, the concentrations of Amitriptyline and Nortriptyline were determined in whole blood using the sensor and the results of our analysis were compared to the results of the standard HPLC-MS method. Based on our experience, the one-step voltammetric methods with the membrane-coated sensor may become a real alternative to the significantly more complex HPLC-MS analysis.

Author(s): Goshtasbi, Khodayar; Chua, Janice T; Risbud, Adwight; Sarna, Brooke; Jamshidi, Shahrnaz; Abouzari, Mehdi; Djalilian, Hamid R | Abstract: ObjectivesTo describe a cohort of patients presenting with long-term sudden sensorineural hearing loss (SSNHL) treated with prophylactic migraine and intratympanic steroid therapy.MethodsPatients presenting to a neurotology clinic at least 6 weeks from SSNHL onset were included. All patients received migraine prophylactic medication (nortriptyline, topiramate, and/or verapamil) and lifestyle changes for at least 6 weeks, as well as intratympanic steroid injections, if appropriate.ResultsTwenty-one patients (43% female) with a mean age of 64 ± 11 years who presented 9 ± 8 months (median = 5) from symptom onset were included. Posttreatment hearing thresholds were significantly improved compared with pretreatment thresholds at 500 Hz (49 ± 19 dB versus 55 ± 20 dB, p = 0.01), 1000 Hz (52 ± 19 dB versus 57 ± 21 dB, p = 0.03), low-frequency pure-tone average (53 ± 15 dB versus 57 ± 17 dB, p = 0.01), and speech-frequency pure-tone average (57 ± 13 dB versus 60 ± 15 dB, p = 0.02). Posttreatment word-recognition-score (WRS) and speech-recognition-threshold (SRT) were also significantly improved (45 ± 28% versus 70 ± 28% and 57 ± 18 dB versus 50 ± 16 dB, respectively, both p l 0.01). Notably, ≥15% improvement in WRS and ≥10 dB improvement in SRT was observed in 13 (68%) and 8 (40%) patients, respectively. Of the 11 patients who presented with initial l 50% WRS, 8 (73%) had improved posttreatment g50% WRS with an average improvement of 39 ± 9%.ConclusionsMigraine medications in addition to intratympanic steroid injections significantly improved SRT and hearing frequencies in 40% and 29% of SSNHL patients, respectively, while significant WRS recovery was observed in most (68%) patients. This suggests SSNHL may be an otologic migraine phenomenon, which may be at least partially reversible even after the traditional 30-day postonset window.

Antidepressant drugs elicit different behavioral and neurochemical responses with age. In fact, the use of antidepressants during adolescence is associated with an increased risk of suicidal thinking, being the best pharmacological treatment during this critical period a matter of constant debate in terms of its risk-benefit outcome. In this regard, the present study compared the effects of nortriptyline (3–10 mg/kg, 7 days) on regulating different aspects of affective-like behavior by screening adolescent and adult Sprague-Dawley rats through several consecutive tests (forced-swim, open field, sucrose preference). Brains were later collected to evaluate hippocampal neurogenesis and mBDNF protein content as potential molecular correlates of the observed behavioral responses. The main results in adolescent rats showed that nortriptyline induced dose-dependent opposite effects: while 3 mg/kg decreased immobility and increased mBDNF (indicative of an antidepressant-like response), 10 mg/kg decreased exploratory time in the open field and mBDNF (suggestive of an anxiogenic-like response). These effects were not associated with changes in neurogenesis regulation. In adult rats, nortriptyline failed to modulate affective-like behavior or the neuroplasticity markers evaluated at the doses tested. In conclusion, clear behavioral and neurochemical differences were observed between adolescent and adult rats in response to nortriptyline treatment. Interestingly, while nortriptyline displayed an antidepressant-like potential at the lowest dose examined in adolescence, a higher dose shifted these results towards a negative outcome, thus reinforcing the need to extreme caution when considering this treatment for our younger population.