Effectiveness of Antidepressants in Combination with Psychotherapy.

BACKGROUND: Consensus-guidelines for prescribing antidepressants recommend that clinicians should be vigilant to match antidepressants to patient's medical history but provide no specific advice on which antidepressant is best for a given medical history. AIMS OF THE STUDY: For patients with major depression who are in psychotherapy, this study provides an empirically derived guideline for prescribing antidepressant medications that fit patients' medical history. METHODS: This retrospective, observational, cohort study analyzed a large insurance database of 3,678,082 patients. Data was obtained from healthcare providers in the U.S. between January 1, 2001, and December 31, 2018. These patients had 10,221,145 episodes of antidepressant treatments. This study reports the remission rates for the 14 most commonly prescribed single antidepressants (amitriptyline, bupropion, citalopram, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, mirtazapine, nortriptyline, paroxetine, sertraline, trazodone, and venlafaxine) and a category named "Other" (other antidepressants/combination of antidepressants). The study used robust LASSO regressions to identify factors that affected remission rate and clinicians' selection of antidepressants. The selection bias in observational data was removed through stratification. We organized the data into 16,770 subgroups, of at least 100 cases, using the combination of the largest factors that affected remission and selection bias. This paper reports on 2,467 subgroups of patients who had received psychotherapy. RESULTS: We found large, and statistically significant, differences in remission rates within subgroups of patients. Remission rates for sertraline ranged from 4.5% to 77.86%, for fluoxetine from 2.86% to 77.78%, for venlafaxine from 5.07% to 76.44%, for bupropion from 0.5% to 64.63%, for desvenlafaxine from 1.59% to 75%, for duloxetine from 3.77% to 75%, for paroxetine from 6.48% to 68.79%, for escitalopram from 1.85% to 65%, and for citalopram from 4.67% to 76.23%. Clearly these medications are ideal for patients in some subgroups but not others. If patients are matched to the subgroups, clinicians can prescribe the medication that works best in the subgroup. Some medications (amitriptyline, doxepin, nortriptyline, and trazodone) always had remission rates below 11% and therefore were not suitable as single antidepressant therapy for any of the subgroups. DISCUSSIONS: This study provides an opportunity for clinicians to identify an optimal antidepressant for their patients, before they engage in repeated trials of antidepressants. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: To facilitate the matching of patients to the most effective antidepressants, this study provides access to a free, non-commercial, decision aid at http://MeAgainMeds.com. IMPLICATIONS FOR HEALTH POLICIES:  Policymakers should evaluate how study findings can be made available through fragmented electronic health records at point-of-care. Alternatively, policymakers can put in place an AI system that recommends antidepressants to patients online, at home, and encourages them to bring the recommendation to their clinicians at their next visit. IMPLICATIONS FOR FURTHER RESEARCH:  Future research could investigate (i) the effectiveness of our recommendations in changing clinical practice, (ii) increasing remission of depression symptoms, and (iii) reducing cost of care. These studies need to be prospective but pragmatic. It is unlikely random clinical trials can address the large number of factors that affect remission.

Pharmacological and electronic cigarette interventions for smoking cessation in adults: component network meta-analyses.

BACKGROUND: Tobacco smoking is the leading preventable cause of death and disease worldwide. Stopping smoking can reduce this harm and many people would like to stop. There are a number of medicines licenced to help people quit globally, and e-cigarettes are used for this purpose in many countries. Typically treatments work by reducing cravings to smoke, thus aiding initial abstinence and preventing relapse. More information on comparative effects of these treatments is needed to inform treatment decisions and policies. OBJECTIVES: To investigate the comparative benefits, harms and tolerability of different smoking cessation pharmacotherapies and e-cigarettes, when used to help people stop smoking tobacco. SEARCH METHODS: We identified studies from recent updates of Cochrane Reviews investigating our interventions of interest. We updated the searches for each review using the Cochrane Tobacco Addiction Group (TAG) specialised register to 29 April 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs), cluster-RCTs and factorial RCTs, which measured smoking cessation at six months or longer, recruited adults who smoked combustible cigarettes at enrolment (excluding pregnant people) and randomised them to approved pharmacotherapies and technologies used for smoking cessation worldwide (varenicline, cytisine, nortriptyline, bupropion, nicotine replacement therapy (NRT) and e-cigarettes) versus no pharmacological intervention, placebo (control) or another approved pharmacotherapy. Studies providing co-interventions (e.g. behavioural support) were eligible if the co-intervention was provided equally to study arms. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods for screening, data extraction and risk of bias (RoB) assessment (using the RoB 1 tool). Primary outcome measures were smoking cessation at six months or longer, and the number of people reporting serious adverse events (SAEs). We also measured withdrawals due to treatment. We used Bayesian component network meta-analyses (cNMA) to examine intervention type, delivery mode, dose, duration, timing in relation to quit day and tapering of nicotine dose, using odds ratios (OR) and 95% credibility intervals (CrIs). We calculated an effect estimate for combination NRT using an additive model. We evaluated the influence of population and study characteristics, provision of behavioural support and control arm rates using meta-regression. We evaluated certainty using GRADE. MAIN RESULTS: Of our 332 eligible RCTs, 319 (835 study arms, 157,179 participants) provided sufficient data to be included in our cNMA. Of these, we judged 51 to be at low risk of bias overall, 104 at high risk and 164 at unclear risk, and 118 reported pharmaceutical or e-cigarette/tobacco industry funding. Removing studies at high risk of bias did not change our interpretation of the results. Benefits We found high-certainty evidence that nicotine e-cigarettes (OR 2.37, 95% CrI 1.73 to 3.24; 16 RCTs, 3828 participants), varenicline (OR 2.33, 95% CrI 2.02 to 2.68; 67 RCTs, 16,430 participants) and cytisine (OR 2.21, 95% CrI 1.66 to 2.97; 7 RCTs, 3848 participants) were associated with higher quit rates than control. In absolute terms, this might lead to an additional eight (95% CrI 4 to 13), eight (95% CrI 6 to 10) and seven additional quitters per 100 (95% CrI 4 to 12), respectively. These interventions appeared to be more effective than the other interventions apart from combination NRT (patch and a fast-acting form of NRT), which had a lower point estimate (calculated additive effect) but overlapping 95% CrIs (OR 1.93, 95% CrI 1.61 to 2.34). There was also high-certainty evidence that nicotine patch alone (OR 1.37, 95% CrI 1.20 to 1.56; 105 RCTs, 37,319 participants), fast-acting NRT alone (OR 1.41, 95% CrI 1.29 to 1.55; 120 RCTs, 31,756 participants) and bupropion (OR 1.43, 95% CrI 1.26 to 1.62; 71 RCTs, 14,759 participants) were more effective than control, resulting in two (95% CrI 1 to 3), three (95% CrI 2 to 3) and three (95% CrI 2 to 4) additional quitters per 100 respectively. Nortriptyline is probably associated with higher quit rates than control (OR 1.35, 95% CrI 1.02 to 1.81; 10 RCTs, 1290 participants; moderate-certainty evidence), resulting in two (CrI 0 to 5) additional quitters per 100. Non-nicotine/placebo e-cigarettes (OR 1.16, 95% CrI 0.74 to 1.80; 8 RCTs, 1094 participants; low-certainty evidence), equating to one additional quitter (95% CrI -2 to 5), had point estimates favouring the intervention over control, but CrIs encompassed the potential for no difference and harm. There was low-certainty evidence that tapering the dose of NRT prior to stopping treatment may improve effectiveness; however, 95% CrIs also incorporated the null (OR 1.14, 95% CrI 1.00 to 1.29; 111 RCTs, 33,156 participants). This might lead to an additional one quitter per 100 (95% CrI 0 to 2). Harms There were insufficient data to include nortriptyline and non-nicotine EC in the final SAE model. Overall rates of SAEs for the remaining treatments were low (average 3%). Low-certainty evidence did not show a clear difference in the number of people reporting SAEs for nicotine e-cigarettes, varenicline, cytisine or NRT when compared to no pharmacotherapy/e-cigarettes or placebo. Bupropion may slightly increase rates of SAEs, although the CrI also incorporated no difference (moderate certainty). In absolute terms bupropion may cause one more person in 100 to experience an SAE (95% CrI 0 to 2). AUTHORS' CONCLUSIONS: The most effective interventions were nicotine e-cigarettes, varenicline and cytisine (all high certainty), as well as combination NRT (additive effect, certainty not rated). There was also high-certainty evidence for the effectiveness of nicotine patch, fast-acting NRT and bupropion. Less certain evidence of benefit was present for nortriptyline (moderate certainty), non-nicotine e-cigarettes and tapering of nicotine dose (both low certainty). There was moderate-certainty evidence that bupropion may slightly increase the frequency of SAEs, although there was also the possibility of no increased risk. There was no clear evidence that any other tested interventions increased SAEs. Overall, SAE data were sparse with very low numbers of SAEs, and so further evidence may change our interpretation and certainty. Future studies should report SAEs to strengthen certainty in this outcome. More head-to-head comparisons of the most effective interventions are needed, as are tests of combinations of these. Future work should unify data from behavioural and pharmacological interventions to inform approaches to combined support for smoking cessation.

Effectiveness of Genotype-Specific Tricyclic Antidepressant Dosing in Patients With Major Depressive Disorder: A Randomized Clinical Trial.

Importance: Evidence of the clinical benefit of pharmacogenetics-informed treatment (PIT) with antidepressants is still limited. Especially for tricyclic antidepressants (TCAs), pharmacogenetics may be of interest because therapeutic plasma concentrations are well defined, identification of optimal dosing can be time consuming, and treatment is frequently accompanied by adverse effects. Objective: To determine whether PIT results in faster attainment of therapeutic TCA plasma concentrations compared with usual treatment in patients with unipolar major depressive disorder (MDD). Design, Setting, and Participants: This randomized clinical trial compared PIT with usual treatment among 111 patients at 4 centers in the Netherlands. Patients were treated with the TCAs nortriptyline, clomipramine, or imipramine, with clinical follow-up of 7 weeks. Patients were enrolled from June 1, 2018, to January 1, 2022. At inclusion, patients had unipolar nonpsychotic MDD (with a score of ≥19 on the 17-item Hamilton Rating Scale for Depression [HAMD-17]), were aged 18 to 65 years, and were eligible for TCA treatment. Main exclusion criteria were a bipolar or psychotic disorder, substance use disorder, pregnancy, interacting comedications, and concurrent use of psychotropic medications. Intervention: In the PIT group, the initial TCA dosage was based on CYP2D6 and CYP2C19 genotypes. The control group received usual treatment, which comprised the standard initial TCA dosage. Main Outcomes and Measures: The primary outcome was days until attainment of a therapeutic TCA plasma concentration. Secondary outcomes were severity of depressive symptoms (measured by HAMD-17 scores) and frequency and severity of adverse effects (measured by Frequency, Intensity, and Burden of Side Effects Rating scores). Results: Of 125 patients randomized, 111 (mean [SD] age, 41.7 [13.3] years; 69 [62.2%] female) were included in the analysis; of those, 56 were in the PIT group and 55 were in the control group. The PIT group reached therapeutic concentrations faster than the control group (mean [SD], 17.3 [11.2] vs 22.0 [10.2] days; Kaplan-Meier χ21 = 4.30; P = .04). No significant difference in reduction of depressive symptoms was observed. Linear mixed-model analyses showed that the interaction between group and time differed for the frequency (F6,125 = 4.03; P = .001), severity (F6,114 = 3.10; P = .008), and burden (F6,112 = 2.56; P = .02) of adverse effects, suggesting that adverse effects decreased relatively more for those receiving PIT. Conclusions and Relevance: In this randomized clinical trial, PIT resulted in faster attainment of therapeutic TCA concentrations, with potentially fewer and less severe adverse effects. No effect on depressive symptoms was observed. These findings indicate that pharmacogenetics-informed dosing of TCAs can be safely applied and may be useful in personalizing treatment for patients with MDD. Trial Registration: ClinicalTrials.gov Identifier: NCT03548675.

Clinical characteristics associated with relapse 2 years after electroconvulsive therapy for major depression.

OBJECTIVE: High relapse rates are observed after electroconvulsive therapy (ECT) for major depression. Identifying patients who are at increased risk for relapse to intensify their treatment regimen post-ECT might reduce relapse rates. We aimed to determine clinical characteristics that are associated with relapse within 2 years after successful ECT. METHODS: Patients who remitted to ECT in a randomised controlled trial comparing adjuvant nortriptyline and placebo during a course of bilateral ECT were followed-up prospectively for 1 year with open-label nortriptyline (Dutch Trial Register NTR5579). Second-year follow-up data were collected retrospectively. Thirty-four patients were included in this follow-up cohort. To examine the association between clinical characteristics and the risk of relapse, unadjusted hazard ratios (HRs) were calculated. RESULTS: At 2 years post-ECT, the overall relapse rate was 50%, and the HRs for relapse in patients with psychotic features, a higher severity of depression, and medication resistance prior to ECT were 0.33 (CI 0.12-0.89; p = 0.029), 0.88 (CI 0.80-0.98; p = 0.014), and 4.48 (CI 1.28-15.73, p = 0.019), respectively. No effect was found for age, sex or episode duration on the relapse rate. CONCLUSIONS: Depressed patients with psychotic features, with higher symptom severity and without medication resistance prior to ECT have a significantly decreased risk of relapse after successful ECT. A sustained remission rate of 50% over 2 years in patients with severe major depression who were treated with nortriptyline monotherapy after successful ECT is encouraging.

Antidepressant Augmentation versus Switch in Treatment-Resistant Geriatric Depression.

BACKGROUND: The benefits and risks of augmenting or switching antidepressants in older adults with treatment-resistant depression have not been extensively studied. METHODS: We conducted a two-step, open-label trial involving adults 60 years of age or older with treatment-resistant depression. In step 1, patients were randomly assigned in a 1:1:1 ratio to augmentation of existing antidepressant medication with aripiprazole, augmentation with bupropion, or a switch from existing antidepressant medication to bupropion. Patients who did not benefit from or were ineligible for step 1 were randomly assigned in step 2 in a 1:1 ratio to augmentation with lithium or a switch to nortriptyline. Each step lasted approximately 10 weeks. The primary outcome was the change from baseline in psychological well-being, assessed with the National Institutes of Health Toolbox Positive Affect and General Life Satisfaction subscales (population mean, 50; higher scores indicate greater well-being). A secondary outcome was remission of depression. RESULTS: In step 1, a total of 619 patients were enrolled; 211 were assigned to aripiprazole augmentation, 206 to bupropion augmentation, and 202 to a switch to bupropion. Well-being scores improved by 4.83 points, 4.33 points, and 2.04 points, respectively. The difference between the aripiprazole-augmentation group and the switch-to-bupropion group was 2.79 points (95% CI, 0.56 to 5.02; P = 0.014, with a prespecified threshold P value of 0.017); the between-group differences were not significant for aripiprazole augmentation versus bupropion augmentation or for bupropion augmentation versus a switch to bupropion. Remission occurred in 28.9% of patients in the aripiprazole-augmentation group, 28.2% in the bupropion-augmentation group, and 19.3% in the switch-to-bupropion group. The rate of falls was highest with bupropion augmentation. In step 2, a total of 248 patients were enrolled; 127 were assigned to lithium augmentation and 121 to a switch to nortriptyline. Well-being scores improved by 3.17 points and 2.18 points, respectively (difference, 0.99; 95% CI, -1.92 to 3.91). Remission occurred in 18.9% of patients in the lithium-augmentation group and 21.5% in the switch-to-nortriptyline group; rates of falling were similar in the two groups. CONCLUSIONS: In older adults with treatment-resistant depression, augmentation of existing antidepressants with aripiprazole improved well-being significantly more over 10 weeks than a switch to bupropion and was associated with a numerically higher incidence of remission. Among patients in whom augmentation or a switch to bupropion failed, changes in well-being and the occurrence of remission with lithium augmentation or a switch to nortriptyline were similar. (Funded by the Patient-Centered Outcomes Research Institute; OPTIMUM ClinicalTrials.gov number, NCT02960763.).

Antinociceptive effects of nortriptyline and desipramine hydrochloride in Speke's hinge-back tortoise (Kinixys Spekii).

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

Effect of Information Intervention on Prescribing Practice for Neuropathic Pain in Older Patients: A Nationwide Register-Based Study.

INTRODUCTION: Management of prescription medicines is challenging for older patients due to frail health and the prevalence of multiple chronic conditions. A salient policy challenge of prescribing practices is that all physicians are not well informed about the national clinical guidelines. A feasible policy intervention to mitigate the harms caused by Potentially Inappropriate Medications is to influence the frequency of prescribing and other prescribing attributes of the drugs by providing accurate and up-to-date information about the national clinical guidelines. OBJECTIVES: The objective of this study was to examine the effect of a nationwide information intervention on physicians' prescribing practices and patients' healthcare utilization. METHODS: We used a quasi-experimental research design based on difference-in-differences variation and nationwide register data on prescribers and purchasers of pregabalin, nortriptyline, and amitriptyline combinations in Finland between January 2018 and May 2019. The study included 68,914 patients and 11,432 physicians. RESULTS: We found that the information letter sent to all prescribers of pregabalin, nortriptyline, or amitriptyline combinations to patients aged 75 years or older decreased the probability of prescribing of these medications. The estimated effect of - 3.3 percentage points (95% confidence interval [- 0.041, - 0.024]) corresponds to a 29% reduction compared to the baseline mean of the outcome. The filled quantity, measured in Defined Daily Doses, of pregabalin, nortriptyline, and amitriptyline combinations per month was reduced by 11.7% [- 14.5% to - 8.9%] among patients aged 75 years or older. No effect on patients' healthcare utilization was observed. CONCLUSIONS: Findings of the study suggest that personal information intervention was an effective policy tool for nudging physicians to reduce prescribing of potentially inappropriate medicines, whereas the reduction in prescribing was not accompanied by improvements or adverse effects in patients' health.

Repurposing a tricyclic antidepressant in tumor and metabolism disease treatment through fatty acid uptake inhibition.

Fatty acid uptake is essential for cell physiological function, but detailed mechanisms remain unclear. Here, we generated an acetyl-CoA carboxylases (ACC1/2) double-knockout cell line, which lacked fatty acid biosynthesis and survived on serum fatty acids and was used to screen for fatty acid uptake inhibitors. We identified a Food and Drug Administration-approved tricyclic antidepressant, nortriptyline, that potently blocked fatty acid uptake both in vitro and in vivo. We also characterized underlying mechanisms whereby nortriptyline provoked lysosomes to release protons and induce cell acidification to suppress macropinocytosis, which accounted for fatty acid endocytosis. Furthermore, nortriptyline alone or in combination with ND-646, a selective ACC1/2 inhibitor, significantly repressed tumor growth, lipogenesis, and hepatic steatosis in mice. Therefore, we show that cells actively take up fatty acids through macropinocytosis, and we provide a potential strategy suppressing tumor growth, lipogenesis, and hepatic steatosis through controlling the cellular level of fatty acids.

Antidepressants Trial in Parkinson's Disease (ADepT-PD): protocol for a randomised placebo-controlled trial on the effectiveness of escitalopram and nortriptyline on depressive symptoms in Parkinson's disease.

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.

Rationale and design of a multicenter randomized clinical trial of vestibulodynia: understanding pathophysiology and determining appropriate treatments (vestibulodynia: UPDATe).

BACKGROUND: 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. METHODS: 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. CONCLUSION: 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. ADMINISTRATIVE INFORMATION: 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.

The Effect of Neuromodulatory Drugs on the Intensity of Chronic Pelvic Pain in Women: A Systematic Review.

OBJECTIVE: To evaluate the effect of neuromodulatory drugs on the intensity of chronic pelvic pain (CPP) in women. DATA SOURCES: Searches were carried out in the PubMed, Cochrane Central, Embase, Lilacs, OpenGrey, and Clinical Trials databases. SELECTION OF STUDIES: The searches were carried out by two of the authors, not delimiting publication date or original language. The following descriptors were used: chronic pelvic pain in women OR endometriosis, associated with MESH/ENTREE/DeCS: gabapentinoids, gabapentin, amitriptyline, antidepressant, pregabalin, anticonvulsant, sertraline, duloxetine, nortriptyline, citalopram, imipramine, venlafaxine, neuromodulation drugs, acyclic pelvic pain, serotonin, noradrenaline reuptake inhibitors, and tricyclic antidepressants, with the Boolean operator OR. Case reports and systematic reviews were excluded. DATA COLLECTION: The following data were extracted: author, year of publication, setting, type of study, sample size, intervention details, follow-up time, and results. DATA SYNTHESIS: 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. CONCLUSION: 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.

OBJETIVO: Avaliar o efeito de drogas neuromoduladoras na intensidade da dor pélvica crônica em mulheres. FONTES DE DADOS: 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: chronic pelvic pain in women OR endometriosis, associated with MESH/ENTREE/DeCS: gabapentinoids, gabapentin, amitriptyline, antidepressant, pregabalin, anticonvulsant, sertraline, duloxetine , nortriptyline, citalopram, imipramine, venlafaxine, neuromodulation drugs, acyclic pelvic pain, serotonin, noradrenaline reuptake inhibitors e tricyclic antidepressants, com o operador booleano OR. Relatos de caso e revisões sistemáticas foram excluídos. COLETA DE DADOS: 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.

A secondary analysis of PAIN-CONTRoLS: Pain's impact on sleep, fatigue, and activities of daily living.

INTRODUCTION/AIMS: 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). METHODS: 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. RESULTS: 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. DISCUSSION: 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.

Biomarkers as predictors of treatment response to tricyclic antidepressants in major depressive disorder: A systematic review.

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.

Pharmacovigilance in hospice/palliative care: Net effect of amitriptyline or nortriptyline on neuropathic pain: UTS/IMPACCT Rapid programme international consecutive cohort.

BACKGROUND: Real-world effectiveness of interventions in palliative care need to be systematically quantified to inform patient/clinical decisions. Neuropathic pain is prevalent and difficult to palliate. Tricyclic antidepressants have an established role for some neuropathic pain aetiologies, but this is less clear in palliative care. AIM: To describe the real-world use and outcomes from amitriptyline or nortriptyline for neuropathic pain in palliative care. DESIGN: An international, prospective, consecutive cohort post-marketing/phase IV/pharmacovigilance/quality improvement study of palliative care patients with neuropathic pain where the treating clinician had already made the decision to use a tricyclic antidepressant. Data were entered at set times: baseline, and days 7 and 14. Likert scales graded benefits and harms. SETTING/PARTICIPANTS: Twenty-one sites (inpatient, outpatient, community) participated in six countries between June 2016 and March 2019. Patients had clinician-diagnosed neuropathic pain. RESULTS: One hundred and fifty patients were prescribed amitriptyline (110) or nortriptyline (40) of whom: 85% had cancer; mean age 73.2 years (SD 12.3); mean 0-4 scores for neuropathic pain at baseline were 1.8 (SD 1.0). By day 14, doses of amitriptyline were 57 mg (SD 21) and nortriptyline (48 mg (SD 21). Fifty-two (34.7%) patients had pain improvement by day 14 (amitriptyline (45/110 (43.3%); nortriptyline (7/40 (18.9%)). Thirty-nine (27.7%) had new harms; (amitriptyline 29/104 (27.9%); nortriptyline 10/37 (27.0%); dizziness (n = 23), dry mouth (n = 20), constipation (n = 14), urinary retention (n = 10)). Benefits without harms occurred (amitriptyline (26/104 (25.0%); nortriptyline (4/37 (10.8%)). CONCLUSIONS: Benefits favoured amitriptyline while harms were similar for both medications.

Influence of adjuvant nortriptyline on the efficacy of electroconvulsive therapy: A randomized controlled trial and 1-year follow-up.

OBJECTIVE: There is limited evidence that adding an antidepressant to electroconvulsive therapy (ECT), compared with ECT monotherapy, improves outcomes. We aimed to determine whether the addition of nortriptyline to ECT enhances its efficacy and prevents post-ECT relapse. METHODS: We conducted a randomized, double-blind, placebo-controlled trial (RCT). Patients with major depressive disorder and an indication for ECT received either nortriptyline or placebo during a bilateral ECT course. Outcome measures were mean decrease in Hamilton Rating Scale for Depression (HRSD) score, response, remission, and time to response and remission. Patients who attained remission participated in a 1-year follow-up study with open-label nortriptyline. Outcome measures were relapse and time to relapse. RESULTS: We included 47 patients in the RCT. In the nortriptyline group, 83% showed response, 74% attained remission, and the mean decrease in HRSD score was 21.6 points. In the placebo group these figures were, respectively, 81% (p = 0.945), 73% (p = 0.928) and 20.7 points (p = 0.748). Thirty-one patients participated in the follow-up study. In patients who had received nortriptyline during the RCT, 47% relapsed at a mean of 34.2 weeks. Patients who had received placebo showed similar treatment results. In both study phases, no statistically significant differences between the nortriptyline and the placebo group were found. CONCLUSION: In our sample of severely depressed patients who were often medication resistant and suffering from psychotic depression, the addition of nortriptyline to ECT did not enhance its efficacy or prevent post-ECT relapse. Encouragingly, even in these patients ECT was highly effective and relapse rates were relatively low.

Eficácia e segurança de Duloxetina comparado a outros antidepressivos disponíveis no SUS para o tratamento de depressão maior: revisão rápida de evidências / Effectiveness and safety of Duloxetine compared to other antidepressant agents available in Brazilian Public Health for treatment of major depression: rapid response review of evidence

Tecnologia: Duloxetina e outros antidepressivos disponíveis no Sistema Único de Saúde (amitriptilina, nortriptilina, clomipramina, fluoxetina e bupropiona). Indicação: Tratamento do primeiro episódio depressivo no transtorno de depressão maior em adultos. Pergunta: A duloxetina é mais eficaz e tolerável que a amitriptilina, nortriptilina, clomipramina, fluoxetina e bupropiona para o tratamento do primeiro episódio de depressão maior em adultos? Métodos: Revisão rápida de evidências (overview) de revisões sistemáticas, com levantamento bibliográfico realizado na base de dados PUBMED, utilizando estratégia estruturada de busca. A qualidade metodológica das revisões sistemáticas foi avaliada com AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews). Resultados: Foi selecionada 1 revisão sistemática, que atendia aos critérios de inclusão. Conclusão: Os antidepressivos, comparados ao placebo, tinham maior taxa de resposta, taxa de remissão e taxa de descontinuação devido a efeitos colaterais, no tratamento de curto prazo. Duloxetina tinha taxa de resposta similar a amitriptilina, clomipramina, fluoxetina e bupropiona. Duloxetina e amitriptilina tinham maior taxa de remissão que fluoxetina. Comparando-se as taxas de abandono de tratamento devido a efeitos colaterais, clomipramina era menos seguro, amitriptilina, bupropiona e duloxetina eram parecidos entre si, e fluoxetina era o antidepressivo mais seguro

Technology: Duloxetine and other antidepressants available in the Brazilian Public Health System (amitriptyline, nortriptyline, clomipramine, fluoxetine and bupropion). Indication: Treatment of the first depressive episode in adult major depressive disorder. Question: Is duloxetine more effective and tolerable than amitriptyline, nortriptyline, clomipramine, fluoxetine and bupropion for the treatment of first episode of major depression in adults? Methods: Rapid response review of evidence (overview) from systematic reviews, with a bibliographic search in the PUBMED database, using a structured strategy. The methodological quality of systematic reviews was assessed with AMSTAR-2 (Methodological Quality Assessment of Systematic Reviews). Results: One systematic review was selected, which met the inclusion criteria. Conclusion: In short-term treatment, antidepressants, compared to placebo, had a higher rate of response, rate of remission and rate drop-out due to side effects. Duloxetine had a similar response rate to amitriptyline, clomipramine, fluoxetine and bupropion. Duloxetine and amitriptyline had higher remission rates than fluoxetine. Comparing rates of dropout due to side effects, clomipramine had the worst rates, amitriptyline, bupropion, and duloxetine were similar to each other, and fluoxetine had the better rates

Lisdexanfetamina comparada a Metilfenidato ou antidepressivos no tratamento de TDAH em crianças e adolescentes: revisão rápida de evidências / Lisdexamfetamine compared to Methylphenidate or antidepressants for treatment of ADHD: rapid response review of evidence

Lisdexanfetamina e drogas disponíveis no SUS (metilfenidato, bupropiona, amitriptilina, clomipramina, nortriptilina). Indicação: Transtorno do Déficit de Atenção e Hiperatividade (TDAH) em crianças e adolescentes. Pergunta: Lisdexanfetamina é eficaz e segura para melhoria de sintomática, comparada ao placebo e medicações disponíveis no SUS, no tratamento de crianças e adolescentes com TDAH? Métodos: Revisão rápida de evidências (overview) de revisões sistemáticas, com levantamento bibliográfico realizado na base de dados PUBMED, utilizando estratégia estruturada de busca. A qualidade metodológica das revisões sistemáticas foi avaliada com AMSTAR-2 (A MeaSurement Tool to Assess systematic Reviews). Resultados: Foram selecionadas 3 revisões sistemáticas, que atenderam aos critérios de inclusão. Conclusão: Lisdexanfetamina e metilfenidato são mais eficazes que placebo, e similares entre si, para reduzir sintomas em escalas de avaliação. Lisdexanfetamina e metilfenidato têm risco similar ao placebo de abandono do tratamento devido a efeitos adversos. Bupropiona não é mais eficaz que placebo para alívio sintomático. Lisdexanfetamina tem efeitos adversos de redução do apetite e insônia/ dificuldades do sono. Não foram encontradas evidências na literatura sobre os efeitos terapêuticos de amitriptilina, clomipramina e nortriptilina no tratamento de crianças e adolescentes com TDAH

Lisdexamfetamine and drugs available in the Brazilian Public Health System (BPHS) (methylphenidate, bupropion, amitriptyline, clomipramine, nortriptyline, bupropion). Indication: Children and adolescents with Attention Deficit Hyperactivity Disorder (ADHD). Question: Lisdexamfetamine is effective and safe for symptomatic improvement, compared to placebo and drugs available in the BPHS, for treatment of children and adolescents with ADHD? Methods: Rapid response review of evidence (overview) of systematic reviews, with bibliographic search in the PUBMED database, using a structured strategy. The methodological quality of systematic reviews was assessed with AMSTAR-2 (A MeaSurement Tool to Assess systematic Reviews). Results: 3 systematic reviews met the inclusion criteria and were selected. Conclusion: Lisdexamfetamine and methylphenidate are more effective than placebo, and similar to each other, to reduce symptoms on rating scales. Lisdexamfetamine and methylphenidate are not different from placebo in the risk of treatment discontinuation due to adverse effects. Bupropion is no more effective than placebo for symptomatic relief. Lisdexamfetamine has adverse effects of decreased appetite and insomnia/sleep troubles. No evidence was found in the literature about therapeutic effects of amitriptyline, clomipramine and nortriptyline for treatment of children and adolescents with ADHD

Nortriptyline for pain in knee osteoarthritis: a double-blind randomised controlled trial in New Zealand general practice.

BACKGROUND: Osteoarthritis (OA) of the knee is a common cause of chronic pain. Analgesics that are currently available have limited efficacy and may be poorly tolerated. Tricyclic antidepressants are used as analgesics for other chronic conditions, but they have not been evaluated as analgesics in OA. AIM: To investigate the analgesic efficacy of nortriptyline in people with knee OA. DESIGN AND SETTING: A two-arm, parallel-group, 1:1, double-blind, randomised, placebo-controlled trial in Christchurch, New Zealand. METHOD: Participants were recruited from orthopaedic outpatient clinics, primary care, and through public advertising. Adults with knee OA and a pain score of ≥20 points on the 50-point Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain subscale were randomised to receive either nortriptyline or identical placebo for 14 weeks. The primary outcome was knee pain at 14 weeks measured using the WOMAC pain subscale. Secondary outcomes included: function; stiffness; non-steroidal anti-inflammatory drug, opioid, and/or paracetamol use; each participant's global assessment; and adverse effects at 14 weeks. RESULTS: Of the 205 randomised participants, 201 (98.0%) completed follow-up at 14 weeks. The baseline-adjusted mean WOMAC pain subscale score at week 14 was 6.2 points lower (95% confidence interval = -0.26 to 12.6, P = 0.06) in the nortriptyline arm versus the placebo arm. Differences in secondary outcomes generally favoured the nortriptyline arm, but were small and unlikely to be clinically relevant. However, the following were all more commonly reported by participants taking nortriptyline than those taking a placebo: dry mouth (86.9% versus 51.0%, respectively, P<0.001), constipation (58.6% versus 30.4%, respectively, P<0.001), and sweating (31.3% versus 20.6%, respectively, P = 0.033). CONCLUSION: This study suggests nortriptyline does not significantly reduce pain in people with knee OA. The adverse effect profile was as expected.