RESUMEN
Chronic treatment with clomipramine, a tricyclic antidepressant drug, reduces symptoms of obsessive-compulsive disorder (OCD) and can influence the activity of the hypothalamic-pituitary-adrenal axis. However, little is known regarding the effects of acute clomipramine on the immediate expression of stress responses. Serotonergic drugs can elicit surfacing, a behavioral profile potentially related to toxicity in fish, although surfacing has not yet been observed after clomipramine exposure. The present study investigated the impact of acute exposure to clomipramine on basal and stress-induced behaviors in the novel tank test and cortisol levels in mixed-sex, wild-type, adult zebrafish (Danio rerio). The findings show clomipramine-exposed groups (regardless of stress exposure) spent much more time in the top of the novel tank and had significantly less overall motor activity in the behavioral task compared to the fish not exposed to the drug. Then, the dose-dependent effects of acute clomipramine on activity in the surface of the novel tank (top third of the top half) were investigated further. Clomipramine dose-dependently increased surface-dwelling and elicited a dose-dependent hypoactivity in overall motor behavior. There were no statistically significant differences in whole-body cortisol levels in either experiment. Like other serotonin-acting drugs, clomipramine strongly elicited surface-dwelling and depressed motor behavior in adult zebrafish. Additional testing is needed to elucidate whether surfacing represents a toxic state and how serotonin regulates surfacing.
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Conducta Animal , Clomipramina , Relación Dosis-Respuesta a Droga , Hidrocortisona , Pez Cebra , Animales , Clomipramina/farmacología , Clomipramina/administración & dosificación , Conducta Animal/efectos de los fármacos , Hidrocortisona/metabolismo , Masculino , Femenino , Antidepresivos Tricíclicos/farmacología , Antidepresivos Tricíclicos/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificaciónRESUMEN
The studyFord AC, Wright-Hughes A, Alderson SL, et al. Amitriptyline at low-dose and titrated for irritable bowel syndrome as second-line treatment in primary care (ATLANTIS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2023;402:1773-85.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/irritable-bowel-syndrome-low-dose-antidepressant-improves-symptoms/.
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Amitriptilina , Síndrome del Colon Irritable , Síndrome del Colon Irritable/tratamiento farmacológico , Humanos , Amitriptilina/administración & dosificación , Amitriptilina/uso terapéutico , Método Doble Ciego , Antidepresivos/uso terapéutico , Antidepresivos/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Antidepresivos Tricíclicos/administración & dosificación , Antidepresivos Tricíclicos/uso terapéutico , Resultado del Tratamiento , Ensayos Clínicos Fase III como AsuntoRESUMEN
Stepwise covariate modeling (SCM) has a high computational burden and can select the wrong covariates. Machine learning (ML) has been proposed as a screening tool to improve the efficiency of covariate selection, but little is known about how to apply ML on actual clinical data. First, we simulated datasets based on clinical data to compare the performance of various ML and traditional pharmacometrics (PMX) techniques with and without accounting for highly-correlated covariates. This simulation step identified the ML algorithm and the number of top covariates to select when using the actual clinical data. A previously developed desipramine population-pharmacokinetic model was used to simulate virtual subjects. Fifteen covariates were considered with four having an effect included. Based on the F1 score (an accuracy measure), ridge regression was the most accurate ML technique on 200 simulated datasets (F1 score = 0.475 ± 0.231), a performance which almost doubled when highly-correlated covariates were accounted for (F1 score = 0.860 ± 0.158). These performances were better than forwards selection with SCM (F1 score = 0.251 ± 0.274 and 0.499 ± 0.381 without/with correlations respectively). In terms of computational cost, ridge regression (0.42 ± 0.07 seconds/simulated dataset, 1 thread) was ~20,000 times faster than SCM (2.30 ± 2.29 hours, 15 threads). On the clinical dataset, prescreening with the selected ML algorithm reduced SCM runtime by 42.86% (from 1.75 to 1.00 days) and produced the same final model as SCM only. In conclusion, we have demonstrated that accounting for highly-correlated covariates improves ML prescreening accuracy. The choice of ML method and the proportion of important covariates (unknown a priori) can be guided by simulations.
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Desipramina , Aprendizaje Automático , Humanos , Desipramina/farmacocinética , Simulación por Computador , Antidepresivos Tricíclicos/farmacocinética , Antidepresivos Tricíclicos/administración & dosificación , Algoritmos , Modelos BiológicosRESUMEN
OBJECTIVE: We aim to develop a personalized dosing tool for tricyclic antidepressants (TCAs) that integrates CYP2D6 and CYP2C19 gene variants and their effects while also considering the polypharmacy effect. METHODS: The study first adopted a scoring system that assigns weights to each genetic variant. A formula was then developed to compute the effect of both genes' variants on drug dosing. The output of the formula was assessed by a comparison with the clinical pharmacogenetics implementation consortium recommendation. The study also accounts for the effect of the co-administration of inhibitors and inducers on drug metabolism. Accordingly, a user-friendly tool, Clinical Dosing Tool ver.2, was created to assist clinicians in dosing patients on TCAs. RESULTS: The study provides a comprehensive list of all alleles with corresponding activity values and phenotypes for both enzymes. The tool calculated an updated area under the curve ratio that utilizes the effects of both enzymes' variants for dose adjustment. The tool provided a more accurate individualized dosing that also integrates the polypharmacy effect. CONCLUSION: To the best of our knowledge, the literature misses such a tool that provides a numerical adjusted dose based on continuous numerical activity scores for the considered patients' alleles and phenoconversion.
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Antidepresivos Tricíclicos , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2D6 , Medicina de Precisión , Humanos , Antidepresivos Tricíclicos/administración & dosificación , Antidepresivos Tricíclicos/farmacocinética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Medicina de Precisión/métodos , Alelos , Relación Dosis-Respuesta a Droga , PolifarmaciaRESUMEN
PURPOSE: The present study aimed to elucidate the transport properties of imipramine and paroxetine, which are the antidepressants, across the blood-brain barrier (BBB) in rats. METHODS: In vivo influx and efflux transport of imipramine and paroxetine across the BBB were tested using integration plot analysis and a combination of brain efflux index and brain slice uptake studies, respectively. Conditionally immortalized rat brain capillary endothelial cells, TR-BBB13 cells, were utilized to characterize imipramine and paroxetine transport at the BBB in vitro. RESULTS: The in vivo influx clearance of [3H]imipramine and [3H]paroxetine in rats was determined to be 0.322 mL/(min·g brain) and 0.313 mL/(min·g brain), respectively. The efflux clearance of [3H]imipramine and [3H]paroxetine was 0.380 mL/(min·g brain) and 0.126 mL/(min·g brain), respectively. These results suggest that the net flux of paroxetine, but not imipramine, at the BBB in vivo was dominated by transport to the brain from the circulating blood. The uptake of imipramine and paroxetine by TR-BBB13 cells exhibited time- and temperature-dependence and one-saturable kinetics with a Km of 37.6 µM and 89.2 µM, respectively. In vitro uptake analyses of extracellular ion dependency and the effect of substrates/inhibitors for organic cation transporters and transport systems revealed minor contributions to known transporters and transport systems and the difference in transport properties in the BBB between imipramine and paroxetine. CONCLUSIONS: Our study showed the comprehensive outcomes of imipramine and paroxetine transport at the BBB, implying that molecular mechanism(s) distinct from previously reported transporters and transport systems are involved in the transport.
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Antidepresivos de Segunda Generación/metabolismo , Antidepresivos Tricíclicos/metabolismo , Barrera Hematoencefálica/metabolismo , Imipramina/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Paroxetina/metabolismo , Animales , Antidepresivos de Segunda Generación/administración & dosificación , Antidepresivos Tricíclicos/administración & dosificación , Transporte Biológico , Línea Celular , Imipramina/administración & dosificación , Inyecciones Intravenosas , Cinética , Masculino , Modelos Biológicos , Paroxetina/administración & dosificación , Permeabilidad , Ratas WistarRESUMEN
BACKGROUND: Increased traumatic brain injury (TBI) risk was found in patients with bipolar disorder (BPD). Whether the medications for BPD and dosage moderate the risk of TBI is not clear. AIM: This study aimed to determine whether an association exists between BPD and TBI and whether the prescription of psychotropics moderates TBI risk. METHODS: A total of 5606 individuals who had received diagnoses of BPD between January 1, 1997 and December 31, 2013 and 56,060 matched controls without BPD were identified from Taiwan's National Health Insurance Research Database. Cases and controls were followed until the date of TBI diagnosis. RESULTS: BPD was associated with a high risk of TBI (adjusted hazard ratio (aHR): 1.85; 95% CI: 1.62-2.11). Patients with BPD, with or without a history of psychiatric hospitalization, had increased risks of TBI (aHR: 1.94, 95% CI: 1.57-2.4 and aHR: 1.82, 95% CI: 1.55-2.1, respectively). The prescription of typical antipsychotics (0 < defined daily dose (DDD) < 28: hazard ratio (HR) = 1.52, 95% CI: 1.19-1.94; ⩾28 DDD: HR = 1.54, 95% CI: 1.15-2.06) and tricyclic antidepressants (TCAs) (0 < DDD < 28: HR = 1.73, 95% CI: 1.26-2.39; ⩾28 DDD: HR = 1.52, 95% CI: 1.02-2.25) was associated with higher TBI risk. Patients receiving higher doses of benzodiazepines (BZDs) (cumulative dose ⩾28 DDD) had a higher TBI risk (HR = 1.53, 95% CI: 1.13-2.06). CONCLUSION: Patients with BPD have a higher risk of TBI. The use of typical antipsychotics, TCAs, or high-dose BZDs increases the risk of TBI in BPD.
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Antipsicóticos/administración & dosificación , Trastorno Bipolar/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antidepresivos Tricíclicos/administración & dosificación , Antidepresivos Tricíclicos/efectos adversos , Antipsicóticos/efectos adversos , Benzodiazepinas/administración & dosificación , Benzodiazepinas/efectos adversos , Trastorno Bipolar/complicaciones , Lesiones Traumáticas del Encéfalo/etiología , Estudios de Casos y Controles , Estudios de Cohortes , Bases de Datos Factuales , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Riesgo , Taiwán , Adulto JovenRESUMEN
We have previously shown that histamine (2-(1H-imidazol-4-yl)ethanamine) exerted concentration-dependent positive inotropic effects (PIE) or positive chronotropic effects (PCE) on isolated left and right atria, respectively, of transgenic (H2R-TG) mice that overexpress the human H2 histamine receptor (H2R) in the heart; however, the effects were not seen in their wild-type (WT) littermates. Amitriptyline, which is still a highly prescribed antidepressant drug, was reported to act as antagonist on H2Rs. Here, we wanted to determine whether the histamine effects in H2R-TG were antagonized by amitriptyline. Contractile studies were performed on isolated left and right atrial preparations, isolated perfused hearts from H2R-TG and WT mice and human atrial preparations. Amitriptyline shifted the concentration-dependent PIE of histamine (1 nM-10 µM) to higher concentrations (rightward shift) in left atrial preparations from H2R-TG. Similarly, in isolated perfused hearts from H2R-TG and WT mice, histamine increased the contractile parameters and the phosphorylation state of phospholamban (PLB) at serine 16 in the H2R-TG mice, but not in the WT mice. However, the increases in contractility and PLB phosphorylation were attenuated by the addition of amitriptyline in perfused hearts from H2R-TG. In isolated electrically stimulated human atria, the PIE of histamine that was applied in increasing concentrations from 1 nM to 10 µM was reduced by 10-µM amitriptyline. In summary, we present functional evidence that amitriptyline also acts as an antagonist of contractility at H2Rs in H2R-TG mouse hearts and in the human heart which might in part explain the side effects of amitriptyline.
Asunto(s)
Amitriptilina/farmacología , Atrios Cardíacos/efectos de los fármacos , Antagonistas de los Receptores H2 de la Histamina/farmacología , Receptores Histamínicos H2/efectos de los fármacos , Amitriptilina/administración & dosificación , Animales , Antidepresivos Tricíclicos/administración & dosificación , Antidepresivos Tricíclicos/farmacología , Relación Dosis-Respuesta a Droga , Atrios Cardíacos/metabolismo , Histamina/administración & dosificación , Histamina/metabolismo , Antagonistas de los Receptores H2 de la Histamina/administración & dosificación , Humanos , Ratones , Ratones Transgénicos , Contracción Miocárdica/efectos de los fármacos , Receptores Histamínicos H2/metabolismo , Especificidad de la EspecieRESUMEN
A significant clinical issue encountered after a successful acute major depressive disorder (MDD) treatment is the relapse of depressive symptoms. Although continuing maintenance therapy with antidepressants is generally recommended, there is no established protocol on whether or not it is necessary to prescribe the antidepressant used to achieve remission. In this meta-analysis, the risk of relapse and treatment failure when either continuing with the same drug used to achieved remission or switching to a placebo was assessed in several clinically significant subgroups. The pooled odds ratio (OR) (±95% confidence intervals (CI)) was calculated using a random effects model. Across 40 studies (n = 8890), the relapse rate was significantly lower in the antidepressant group than the placebo group by about 20% (OR = 0.38, CI: 0.33-0.43, p < 0.00001; 20.9% vs 39.7%). The difference in the relapse rate between the antidepressant and placebo groups was greater for tricyclics (25.3%; OR = 0.30, CI: 0.17-0.50, p < 0.00001), SSRIs (21.8%; OR = 0.33, CI: 0.28-0.38, p < 0.00001), and other newer agents (16.0%; OR = 0.44, CI: 0.36-0.54, p < 0.00001) in that order, while the effect size of acceptability was greater for SSRIs than for other antidepressants. A flexible dose schedule (OR = 0.30, CI: 0.23-0.48, p < 0.00001) had a greater effect size than a fixed dose (OR = 0.41, CI: 0.36-0.48, p < 0.00001) in comparison to placebo. Even in studies assigned after continuous treatment for more than 6 months after remission, the continued use of antidepressants had a lower relapse rate than the use of a placebo (OR = 0.40, CI: 0.29-0.55, p < 0.00001; 20.2% vs 37.2%). The difference in relapse rate was similar from a maintenance period of 6 months (OR = 0.41, CI: 0.35-0.48, p < 0.00001; 19.6% vs 37.6%) to over 1 year (OR = 0.35, CI: 0.29-0.41, p < 0.00001; 19.9% vs 39.8%). The all-cause dropout of antidepressant and placebo groups was 43% and 58%, respectively, (OR = 0.47, CI: 0.40-0.55, p < 0.00001). The tolerability rate was ~4% for both groups. The rate of relapse (OR = 0.32, CI: 0.18-0.64, p = 0.0010, 41.0% vs 66.7%) and all-cause dropout among adolescents was higher than in adults. To prevent relapse and treatment failure, maintenance therapy, and careful attention for at least 6 months after remission is recommended. SSRIs are well-balanced agents, and flexible dose adjustments are more effective for relapse prevention.
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Antidepresivos/administración & dosificación , Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Inducción de Remisión , Antidepresivos Tricíclicos/administración & dosificación , Antidepresivos Tricíclicos/uso terapéutico , Ensayos Clínicos Controlados como Asunto , Depresión/tratamiento farmacológico , Humanos , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéuticoRESUMEN
Discovery of the rapid antidepressant effect of ketamine has been considered one of the most important advances in major depressive disorder treatment. Several studies report a significant benefit to patients that lasts up to 19 days after treatment. However, concerns arise from the long-term use of ketamine, thus a safe and effective strategy for maintaining its antidepressant effect is still necessary. To this end, our work assessed the effects of imipramine and fluoxetine after repeated ketamine treatment in male mice. Ketamine (30 mg/kg/day for 14 days) induced an anti-immobility effect in the forced swimming (FS) paradigm, detected 1 and 3 days after treatment. Seven days after the last ketamine injection, mice received imipramine (20 mg/kg) or fluoxetine (30 mg/kg). Imipramine and fluoxetine did not change mice's immobility time, regardless of the pre-treatment (saline or ketamine). Since both drugs' anti-immobility effect was demonstrated in the classical FS test, we can assume that repeated exposure to intermittent stress inhibited the antidepressant drugs' anti-immobility effects. Moreover, pre-exposure to ketamine did not counteract stress-induced changes in mice response to antidepressants. Since exposure to forced swim and i.p. injections are stressful to rodents, each stressor's contribution to the blunted response to antidepressants was investigated. Our data demonstrated that both stressors (FS and i.p. injections) influenced the reported effect. In summary, our results showed that exposure to intermittent repeated stress inhibited the anti-immobility effect of imipramine and fluoxetine in mice and corroborated findings demonstrating that exposure to stress can blunt patients' response to antidepressants.
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Antidepresivos de Segunda Generación/administración & dosificación , Antidepresivos Tricíclicos/administración & dosificación , Fluoxetina/administración & dosificación , Imipramina/administración & dosificación , Ketamina/administración & dosificación , Estrés Psicológico/psicología , Animales , Conducta Animal/efectos de los fármacos , Masculino , RatonesAsunto(s)
Amitriptilina/administración & dosificación , Amitriptilina/efectos adversos , Muerte Encefálica/diagnóstico , Sobredosis de Droga , Adulto , Antidepresivos Tricíclicos/administración & dosificación , Antidepresivos Tricíclicos/efectos adversos , Diagnóstico Diferencial , Femenino , HumanosRESUMEN
Chronic pain syndromes cost the US healthcare system over $600 billion per year. A subtype of chronic pain is neuropathic pain (NP), which is defined as "pain caused by a lesion or disease of the somatosensory system," according to the International Association for the Study of Pain (IASP). The pathophysiology of neuropathic pain is very complex, and more research needs to be done to find the exact mechanism. Patients that have preexisting conditions such as cancer and diabetes are at high-risk of developing NP. Many NP patients are misdiagnosed and receive delayed treatment due to a lack of a standardized classification system that allows clinicians to identify, understand, and utilize pain management in these patients. Medications like tricyclic antidepressants, serotonin-norepinephrine reuptake Inhibitor (SNRIs), and gabapentinoids are first-line treatments followed by opioids, cannabinoids, and other drugs. There are limited studies on the treatment of NP.
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Anticonvulsivantes/administración & dosificación , Antidepresivos Tricíclicos/administración & dosificación , Dolor Crónico/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Manejo del Dolor/métodos , Inhibidores de Captación de Serotonina y Norepinefrina/administración & dosificación , Dolor Crónico/diagnóstico , Dolor Crónico/fisiopatología , Gabapentina/administración & dosificación , Humanos , Neuralgia/diagnóstico , Neuralgia/fisiopatologíaRESUMEN
Zinc (Zn) was found to enhance the antidepressant efficacy of imipramine (IMI) in human depression and animal tests/models of depression. However, the underlying mechanism for this effect remains unknown. We measured the effect of intragastric (p.o.) combined administration of IMI (60 mg/kg) and Zn (40 mg Zn/kg) in the forced swim test (FST) in mice. The effect of Zn + IMI on serum, brain, and intestinal Zn concentrations; Zn transporter (ZnT, ZIP) protein levels in the intestine and ZnT in the brain; including BDNF (brain-derived neurotrophic factor) and CREB (cAMP response element-binding protein) protein levels in the brain were evaluated. Finally, the effect of IMI on Zn permeability was measured in vitro in colon epithelial Caco-2 cells. The co-administration of IMI and Zn induced antidepressant-like activity in the FST in mice compared to controls and Zn or IMI given alone. This effect correlated with increased BDNF and the ratio of pCREB/CREB protein levels in the prefrontal cortex (PFC) compared to the control group. Zn + IMI co-treatment increased Zn concentrations in the serum and brain compared to the control group. However, in serum, co-administration of IMI and Zn decreased Zn concentration compared to Zn alone treatment. Also, there was a reduction in the Zn-induced enhancement of ZnT1 protein level in the small intestine. Zn + IMI also induced an increase in the ZnT4 protein level in the PFC compared to the control group and normalized the Zn-induced decrease in the ZnT1 protein level in the hippocampus (Hp). The in vitro studies revealed enhanced Zn permeability (observed as the increased transfer of Zn through the intestinal cell membrane) after IMI treatment. Our data indicate that IMI enhances Zn transfer through the intestinal tract and influences the redistribution of Zn between the blood and brain. These mechanisms might explain the enhanced antidepressant efficacy of combined IMI/Zn treatment observed in the FST in mice.
Asunto(s)
Antidepresivos Tricíclicos/farmacología , Encéfalo/metabolismo , Imipramina/farmacología , Zinc/metabolismo , Zinc/farmacología , Administración Oral , Animales , Antidepresivos Tricíclicos/administración & dosificación , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Células CACO-2 , Proteínas Portadoras/metabolismo , Proteínas de Transporte de Catión/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Sinergismo Farmacológico , Tracto Gastrointestinal/metabolismo , Humanos , Imipramina/administración & dosificación , Masculino , Ratones , Zinc/administración & dosificación , Zinc/sangreRESUMEN
The risk of colorectal cancer associated to antidepressant use remains unclear. The purpose of this meta-analysis was to investigate the risk of colorectal cancer associated to antidepressant use.Medline, Embase, Web of Science, and Cochrane Database were accessed from the dates of their establishment to October 2018, to collect study of antidepressant use and colorectal cancer morbidity and mortality. Then a meta-analysis was conducted using Stata 12.0 software.A total of 11 publications involving 109,506 participants were included. The meta-analysis showed that antidepressant use was not associated with colorectal cancer morbidity (relevant risk (RR): 0.97; 95% confidence interval (CI): 0.94-1.01) and mortality (RR: 1.08; 95% CI: 0.99-1.17). Subgroup analysis showed selective serotonin reuptake inhibitor (RR: 0.99; 95% CI: 0.96-1.03) or serotonin norepinephrine reuptake inhibitor (RR: 1.04; 95% CI: 0.86-1.26) were not associated with colorectal cancer risk; however, TCA was associated with colorectal cancer risk decrement (RR: 0.92; 95% CI: 0.87-0.98). Furthermore, the results also showed that antidepressant use was not associated with colorectal cancer risk in Europe and North America (RR: 0.97; 95% CI: 0.92-1.02) and Asia (RR: 1.00; 95% CI: 0.95-1.26). Additionally, a dose-response showed per 1 year of duration of antidepressant use incremental increase was not associated with colorectal cancer risk (RR: 0.96; 95% CI: 0.87-1.09).Evidence suggests that antidepressant use was not associated with colorectal cancer morbidity and mortality. The cumulative duration of antidepressant use did not utilized played critical roles.
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Antidepresivos/administración & dosificación , Antidepresivos/efectos adversos , Neoplasias Colorrectales/epidemiología , Trastorno Depresivo/tratamiento farmacológico , Antidepresivos Tricíclicos/administración & dosificación , Antidepresivos Tricíclicos/efectos adversos , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/psicología , Relación Dosis-Respuesta a Droga , Humanos , Factores de Riesgo , Inhibidores de Captación de Serotonina y Norepinefrina/administración & dosificación , Inhibidores de Captación de Serotonina y Norepinefrina/efectos adversosRESUMEN
Deficient learning and memory are well-established pathophysiologic features of depression, however, mechanisms of the enhanced learning of aversive experiences associated with this disorder are poorly understood. Currently, neurobiological mechanisms of enhanced retention of aversive memories during depression, and, in particular, their relation to neuroinflammation are unclear. As the association between major depressive disorder and inflammation has been recognized for some time, we aimed to address whether neuroinflammatory changes are involved in enhanced learning of adversity in a depressive state. To study this question, we used a recently described mouse model of enhanced contextual conditioning of aversive memories, the modified forced swim model (modFST). In this model, the classic two-day forced swim is followed by an additional delayed session on Day 5, where increased floating behaviour and upregulated glycogen synthase kinase-3 (GSK-3) are context-dependent. Here, increased time spent floating on Day 5, a parameter of enhanced learning of the adverse context, was accompanied by hypercorticosteronemia, increased gene expression of GSK-3α, GSK-3ß, c-Fos, cyclooxygenase-1 (COX-1) and pro-inflammatory cytokines interleukin-1 beta (IL-1ß), tumor necrosis factor (TNF), and elevated concentrations of protein carbonyl, a marker of oxidative stress, in the prefrontal cortex and hippocampus. There were significant correlations between cytokine levels and GSK-3ß gene expression. Two-week administration of compounds with antidepressant properties, imipramine (7 mg/kg/day) or thiamine (vitamin B1; 200 mg/kg/day) ameliorated most of the modFST-induced changes. Thus, enhanced learning of adverse memories is associated with pro-inflammatory changes that should be considered for optimizing pharmacotherapy of depression associated with enhanced learning of aversive memories.
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Antidepresivos Tricíclicos/administración & dosificación , Encéfalo/metabolismo , Depresión/metabolismo , Encefalitis/metabolismo , Imipramina/administración & dosificación , Aprendizaje/fisiología , Memoria/fisiología , Animales , Encéfalo/efectos de los fármacos , Depresión/complicaciones , Depresión/prevención & control , Modelos Animales de Enfermedad , Encefalitis/etiología , Encefalitis/prevención & control , Mediadores de Inflamación/metabolismo , Masculino , Ratones Endogámicos C57BLRESUMEN
The purpose of this study was to evaluate the pharmacokinetics of oral amitriptyline in horses. Oral amitriptyline (1 mg/kg) was administered to six horses. Blood samples were collected from jugular and lateral thoracic vein at predetermined times from 0 to 24 hr after administration. Plasma concentrations were determined by high-performance liquid chromatography and analyzed using noncompartmental methods. Pharmacodynamic parameters including heart rate, respiration rate, and intestinal motility were evaluated, and electrocardiographic examinations were performed in all subjects. The mean maximum plasma concentration (Cmax ) of amitriptyline was 30.7 ng/ml, time to maximum plasma concentration (Tmax ) 1-2 hr, elimination half-life (t1/2 ) 17.2 hr, area under plasma concentration-time curve (AUC) 487.4 ng ml-1 hr-1 , apparent clearance (Cl/F) 2.6 L hr-1 kg-1 , and apparent volume of distribution (Vd/F) 60.1 L/kg. Jugular vein sampling overestimated the amount of amitriptyline absorbed and should not be used to study uptake following oral administration. Heart rate and intestinal motility showed significant variation (p < .05). Electrocardiography did not provide conclusive results. Further studies are required to discern if multiple dose treatment would take the drug to steady state as expected, consequently increasing plasma concentrations.
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Amitriptilina/farmacocinética , Antidepresivos Tricíclicos/farmacocinética , Caballos/metabolismo , Administración Oral , Amitriptilina/administración & dosificación , Amitriptilina/sangre , Animales , Antidepresivos Tricíclicos/administración & dosificación , Antidepresivos Tricíclicos/sangre , Área Bajo la Curva , Femenino , Semivida , Caballos/sangre , MasculinoRESUMEN
Tianeptine is an atypical mu-opioid receptor agonist. It is available as an antidepressant outside the United States, but it is also classified as a controlled substance in many other countries. It is not approved by the United States Food and Drug Administration for the treatment of depression but it can be obtained online without a prescription. The case described in this article involved a patient who developed symptoms of psychosis on supratherapeutic doses of tianeptine, highlighting the importance of inquiring into all supplements taken by patients when conducting an initial psychiatric evaluation.
Asunto(s)
Antidepresivos Tricíclicos , Trastornos Psicóticos/tratamiento farmacológico , Tiazepinas , Adulto , Antidepresivos Tricíclicos/administración & dosificación , Antidepresivos Tricíclicos/efectos adversos , Antipsicóticos/uso terapéutico , Deluciones/etiología , Femenino , Humanos , Palmitato de Paliperidona/uso terapéutico , Receptores Opioides mu/agonistas , Tiazepinas/administración & dosificación , Tiazepinas/efectos adversos , Estados UnidosRESUMEN
OBJECTIVE: To analyse the use, indications and potential risks of tricyclic antidepressants (TCAs), using a technological system of clinical alerts at the time of prescription. METHODS: Observational, descriptive, retrospective study on a population covered by a Colombian health insurance plan with an average of 2,333,582 members/month. The information was generated in the PBM (Pharmacy Benefit Management) MC21 Colombia technological platform. RESULTS: Of the total members, 368,298 (16%) patients/month on average were prescribed medicines; 3,640 (1%) were prescribed TCAs: 2,573 amitriptyline (70%) and 1.062 imipramine (29%); 817 (22.5%) were over 65 years of age. The median daily dose of amitriptyline and imipramine was 25 mg. A total of 17,153 alerts were reported: 8,685 (51%) for drug-drug interactions, 7,354 (43%) for drug-age interactions and 543 (3%) for duplicate therapy. CONCLUSIONS: Risks were identified in the prescription of tricyclic antidepressants, especially in the over-65 population, where these drugs are used in particular for the management of neuropathic pain. The clinical alert system at the time of medicinal product formulation can make an important contribution to the prevention of potential adverse events associated with the use of medicinal products.
Asunto(s)
Antidepresivos Tricíclicos/administración & dosificación , Sistemas de Entrada de Órdenes Médicas , Pautas de la Práctica en Medicina/estadística & datos numéricos , Adolescente , Adulto , Factores de Edad , Anciano , Amitriptilina/administración & dosificación , Antidepresivos Tricíclicos/efectos adversos , Niño , Preescolar , Colombia , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Humanos , Imipramina/administración & dosificación , Lactante , Internet , Persona de Mediana Edad , Neuralgia/tratamiento farmacológico , Pautas de la Práctica en Medicina/normas , Estudios Retrospectivos , Adulto JovenRESUMEN
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<0.001). The frequencies of naive CD8+CD45RA+ cells were significantly lower after amitriptyline, nortriptyline and a combination of both (p<0001). The frequencies of CD27+CD4+(p<0.05) and CD27+CD8+(p<0.01) T-cells were also significantly lower following combination drug treatment. Significantly lower frequencies of IFN-γ-producing CD8+ T-cells were observed with all treatment combinations(p<0.05) and frequencies of IL-17-producing CD4+ and CD8+ T-cells were significantly lower following amitriptyline treatment (p<0.05). Frequencies of Natural Killer T-cells were significantly higher following treatment with nortriptyline (p<0.05). Significantly higher levels of IL-16 (p<0.001) and lower levels of TNF-ß (p<0.05) were observed in supernatants. This data indicates that both amitriptyline and nortriptyline modulate the phenotype and function of T-cells and this may have clinical relevance in the pathologies of its off-label applications.
Asunto(s)
Amitriptilina/administración & dosificación , Antidepresivos Tricíclicos/administración & dosificación , Leucocitos Mononucleares/efectos de los fármacos , Nortriptilina/administración & dosificación , Fenotipo , Linfocitos T/efectos de los fármacos , Adulto , Anciano , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/fisiología , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Citocinas/fisiología , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Femenino , Humanos , Leucocitos Mononucleares/fisiología , Masculino , Persona de Mediana Edad , Linfocitos T/fisiologíaRESUMEN
Background and objectives: Oxidative stress and inflammation have been implicated in the etiology of irritable bowel syndrome (IBS), a common gastrointestinal functional disease. This study aimed to further characterize the contention-stress rat model by exploring a possible correlation between oxidative stress markers measured in brain tissues with behavioral components of the aforementioned model. Thus, it is hereby proposed a possible IBS animal model relevant to pharmacological and complementary medicine studies. Materials and Methods: Wild-type male Wistar rats (n = 5/group) were chronically exposed to 6-hour/day contention, consisting of isolating the animals in small, vital space-granting plastic devices, for seven consecutive days. Following contention exposure, temporal lobes were extracted and subjected to biochemical analyses to assess oxidative stress-status parameters. Results: Our results show increased brain oxidative stress in contention-stress rat model: decreased superoxide dismutase and glutathione peroxidase activities and increased malondialdehyde production in the IBS group, as compared to the control group. Furthermore, the biochemical ratios which are used to evaluate the effectiveness of an antioxidant system on oxidative stress could be described in this model. Conclusions: The correlations between the behavioral patterns and biochemical oxidative stress features could suggest that this may be a complex model, which can successfully mimic IBS symptomatology further providing evidence of a strong connection between the digestive system, enteric nervous system, and the central nervous system.
Asunto(s)
Antidepresivos Tricíclicos/farmacología , Antioxidantes/farmacología , Encéfalo/metabolismo , Síndrome del Colon Irritable/metabolismo , Nortriptilina/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Antidepresivos Tricíclicos/administración & dosificación , Antidepresivos Tricíclicos/uso terapéutico , Biomarcadores/metabolismo , Glutatión Peroxidasa/metabolismo , Humanos , Síndrome del Colon Irritable/tratamiento farmacológico , Peroxidación de Lípido/efectos de los fármacos , Masculino , Malondialdehído/metabolismo , Modelos Animales , Nortriptilina/administración & dosificación , Nortriptilina/uso terapéutico , Estrés Oxidativo/fisiología , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismoRESUMEN
PURPOSE/BACKGROUND: We examined the relative safety and effectiveness of adding a monoamine oxidase inhibitor (MAOI) to a failed tricyclic antidepressant (TCA) trial versus adding a TCA to a failed MAOI trial or adding a TCA to a failed TCA trial in treatment-resistant depression. METHODS/PROCEDURES: Data were retrospectively harvested from approximately 2500 treatment charts of subjects with treatment-resistant depression who attended a university mood disorders clinic between 1983 and 2015. Hierarchical linear modeling was used to examine the effectiveness of treatment condition on outcome. Relative adverse event profiles were also examined. FINDINGS/RESULTS: Eighty-four treatment outcome observations were made from 54 subjects who received combination therapy: TCA plus TCA (n = 22), TCA plus MAOI (n = 44), and MAOI plus TCA (n = 18). Treatment condition predicted a poorer (albeit not statistically significant) outcome for TCA plus TCA compared with TCA plus MAOI, or MAOI plus TCA therapy (P = 0.098). Specific adverse events occurred with significantly greater frequency between treatment groups; that is, impotence was more frequent with TCA plus MAOI therapy; headaches and insomnia were more frequent with MAOI plus TCA therapy; and constipation was more frequent with TCA plus TCA therapy. There were no reported or observed hypertensive or serotonergic events. IMPLICATIONS/CONCLUSIONS: In contrast to conventional wisdom that combined TCA and MAOI therapy should be avoided, the judicious use of this combination may be relatively safe and effective compared with combined TCA plus TCA therapy. However, sample sizes were limited, and the analysis was nonrandomized and retrospective.