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The use of first-line drugs in clinical practice for attention deficit hyperactivity disorder (ADHD) is limited by their adverse effects. Many novel monoamine reuptake inhibitors (MRIs) with better safety profiles and comparable efficacy are also being tried for ADHD. This network meta-analysis (NMA) has evaluated the efficacy and safety of MRIs in ADHD. The data was extracted from 31 relevant clinical trials after a literature search on MEDLINE/PubMed, Embase, Scopus, Cochrane databases, and clinical trial registries. Quality assessment was performed using the risk of bias assessment tool (RoB2) by Cochrane Collaboration, and the random-effects model was used to estimate the effect size. Standardised mean difference (SMD) and 95% credible interval(95%CrI) were reported for the reduction in ADHD rating scale score. Network geometry was visualised, and node splitting was done for the closed triangles. Meta-regression was done for the duration of therapy. PRISMA-NMA guidelines were followed in selecting, analyzing, and reporting findings. The drugs showing significant reduction on the ADHD rating scale as compared to placebo are bupropion (SMD: 0.33; 95%CrI: 0.60,-0.059), dasotraline(SMD: 0.49; 95%CrI: 0.82,-0.16), venlafaxine(SMD: 0.71; 95%CrI: 1.3,-0.15), viloxazine(SMD: 0.45; 95%CrI: 0.77,-0.12). Other drugs (centanafadine, duloxetine, edivoxetine, reboxetine, tipepidine, vortioxetine) were no better than placebo in reducing symptom severity of ADHD. The efficacy of none of the drugs was found to be significantly different as compared to methylphenidate. Among all, duloxetine (OR:15; 95%CrI:1.8130) showed significantly more treatment-emergent adverse events than methylphenidate. In conclusion, venlafaxine, viloxazine, and bupropion are the most efficacious MRIs for ADHD symptom reduction as compared to placebo with high certainty of evidence.
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Trastorno por Déficit de Atención con Hiperactividad , Teorema de Bayes , Metaanálisis en Red , Humanos , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Inhibidores de la Captación de Neurotransmisores/farmacología , Inhibidores de la Captación de Neurotransmisores/administración & dosificación , Inhibidores de la Captación de Neurotransmisores/efectos adversos , Evaluación de Resultado en la Atención de SaludRESUMEN
INTRODUCTION: Adrenergic neurotransmitter reuptake inhibitors are gaining attention in treatment for attention-deficit hyperactivity disorder (ADHD). Due to their effects on norepinephrine, dopamine, and serotonin neurotransmission, they benefit both ADHD and comorbid disorders and have some other advantages including longer duration of action and fewer adverse effects compared to stimulants. There is continued interest in these agents with novel mechanisms of action in treatment of ADHD. AREAS COVERED: The authors conducted a PubMed literature search using the following key words: 'ADHD' AND 'adrenergic reuptake inhibitors' OR 'nonstimulants' OR 'atomoxetine' OR 'Viloxazine' OR 'Dasotraline' OR 'Centanafadine' OR 'PDC-1421' OR 'Reboxetine' OR 'Edivoxetine' OR 'Bupropion' OR 'Venlafaxine' OR 'Duloxetine.' They reviewed FDA fact sheets of available medications for safety/tolerability studies and reviewed published clinical studies of these medications for treatment of ADHD. EXPERT OPINION: Adrenergic neurotransmitter reuptake inhibitors fit the diverse needs of children and adolescents with ADHD with 1) poor tolerability to stimulants (e.g. due to growth suppression, insomnia, rebound irritability, co-morbid depression, anxiety and tic disorders, substance abuse or diversion concerns), 2) cardiac risks, and/or 3) need for extended duration of action. Their differences in receptor affinities and modulating effects support the unique benefits of individual agents.
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Trastorno por Déficit de Atención con Hiperactividad , Humanos , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Niño , Adolescente , Inhibidores de Captación Adrenérgica/uso terapéutico , Inhibidores de Captación Adrenérgica/farmacología , Inhibidores de Captación Adrenérgica/efectos adversos , Estimulantes del Sistema Nervioso Central/uso terapéutico , Estimulantes del Sistema Nervioso Central/efectos adversos , Estimulantes del Sistema Nervioso Central/farmacología , Animales , Inhibidores de la Captación de Neurotransmisores/uso terapéutico , Inhibidores de la Captación de Neurotransmisores/farmacología , Inhibidores de la Captación de Neurotransmisores/efectos adversosRESUMEN
Previous studies showed a prominent role of the medial prefrontal cortex (mPFC), especially the prelimbic (PL) and infralimbic (IL) subregions, in behavioral and physiological responses to stressful stimuli. Nevertheless, the local neurochemical mechanisms involved are not completely understood. In this sense, previous studies identified cholinergic terminals within the mPFC, and stressful stimuli increased local acetylcholine release. Despite these pieces of evidence, the specific role of cholinergic neurotransmission in different subregions of the mPFC controlling the cardiovascular responses to stress has never been systematically evaluated. Therefore, the purpose of this study was to investigate the involvement of cholinergic neurotransmission present within PL and IL in cardiovascular responses to an acute session of restraint stress in rats. For this, rats received bilateral microinjection of the choline uptake inhibitor hemicholinium-3 before exposure to restraint stress. The arterial pressure and heart rate (HR) increases and the decrease in tail skin temperature as an indirect measurement of sympathetically-mediated cutaneous vasoconstriction were recorded throughout the restraint stress session. The results showed that the depletion of acetylcholine within the PL caused by local microinjection of hemicholinium-3 decreased the tachycardia to restraint stress, but without affecting the pressor response and the drop in tail skin temperature. Conversely, IL treatment with hemicholinium-3 decreased the restraint-evoked pressor response and the sympathetically-mediated cutaneous vasoconstriction without interfering with the HR response. Taken together, these results indicate functional differences of cholinergic neurotransmission within the PL and IL in control of cardiovascular and autonomic responses to stressful stimuli.
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Acetilcolina/fisiología , Sistema Nervioso Autónomo/fisiología , Presión Sanguínea/fisiología , Colinérgicos/farmacología , Frecuencia Cardíaca/fisiología , Inhibidores de la Captación de Neurotransmisores/farmacología , Corteza Prefrontal/fisiología , Estrés Psicológico/fisiopatología , Transmisión Sináptica/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Hemicolinio 3/farmacología , Corteza Prefrontal/efectos de los fármacos , Ratas , Restricción FísicaRESUMEN
Background: Depression is a common morbidity after traumatic brain injury. This network meta-analysis investigated the efficacy and tolerability of pharmacologic and nonpharmacologic interventions for depression after traumatic brain injury. Methods: We extracted randomized controlled trials examining pharmacologic or nonpharmacologic interventions with placebo- or active-controlled designs from PubMed, the Cochrane Library and ScienceDirect, from inception to October 30, 2018. We based study selection and extraction of a predefined list of variables on the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines, and conducted meta-analysis procedures using random effects modelling. Primary outcomes were changes in depressive symptom severity after pharmacologic or nonpharmacologic treatment; the secondary outcome was tolerability, reflected in overall patient dropout rates. Results: Our analysis of 27 randomized controlled trials (10 pharmacologic, total n = 483, mean age = 37.9 yr; 17 nonpharmacologic, total n = 1083, mean age = 38.0 yr) showed that methylphenidate had significantly superior efficacy compared to placebo or control (standardized mean difference -0.91, 95% confidence interval [CI] -1.49 to -0.33). Sertraline was associated with significantly lower tolerability (i.e., a higher dropout rate) compared to placebo or control (odds ratio 2.65, 95% CI 1.27 to 5.54). No nonpharmacologic treatment was more effective than the others, and we found no significant differences in tolerability (i.e., dropout rates) among the nonpharmacologic treatments. Limitations: Heterogeneity in participant characteristics (e.g., comorbidities), study designs (e.g., trial duration) and psychopathology assessment tools, as well as small trial numbers for some treatment arms, could have been confounders. Conclusion: The present network meta-analysis suggests that methylphenidate might be the best pharmacologic intervention for depressive symptoms related to traumatic brain injury. None of the nonpharmacologic interventions was associated with better improvement in depressive symptoms than the others or than control conditions. None of the pharmacologic or nonpharmacologic treatments had inferior tolerability compared to placebo or controls except for sertraline, which had significantly lower tolerability than placebo.
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Lesiones Traumáticas del Encéfalo/complicaciones , Depresión/terapia , Trastorno Depresivo Mayor/terapia , Metilfenidato/farmacología , Inhibidores de la Captación de Neurotransmisores/farmacología , Psicoterapia , Depresión/etiología , Trastorno Depresivo Mayor/etiología , Humanos , Metaanálisis en RedRESUMEN
In our screening program for new biologically active secondary metabolites, nine new polycyclic polyprenyled acylphloroglucinols, hyperscabins D-L, together with three known compounds, were obtained from the aerial parts of Hypericum scabrum. The chemical structures of 1-9 were characterized by extensive spectroscopic analyses, nuclear magnetic resonance calculation with DP4+ probability analysis, and the electronic circular dichroism spectra were calculated. Compound 1 was an unusual prenylated acylphloroglucinol decorated with a 5-oxaspiro [4,5] deca-1,9-dione skeleton. Compound 2 was a newly identified spirocyclic polyprenylated acylphloroglucinol possessing a rare 5,5-spiroketal segment. Compounds 3, 8, and 10 (10 µM) exhibited pronounced hepatoprotective activity against d-galactosamine-induced WB-F344 cell damage in vitro assays. All test compounds (1, 3, and 7-12) demonstrated potential inhibitory effects at 10 µM against noradrenalinet ([3H]-NE) reuptake in rat brain synaptosome.
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Antidepresivos/farmacología , Hemiterpenos/farmacología , Hypericum/química , Floroglucinol/análogos & derivados , Floroglucinol/farmacología , Sustancias Protectoras/farmacología , Animales , Antidepresivos/síntesis química , Antidepresivos/aislamiento & purificación , Línea Celular , Hemiterpenos/síntesis química , Hemiterpenos/aislamiento & purificación , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/aislamiento & purificación , Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/metabolismo , Floroglucinol/aislamiento & purificación , Componentes Aéreos de las Plantas/química , Sustancias Protectoras/síntesis química , Sustancias Protectoras/aislamiento & purificación , Ratas , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismoRESUMEN
Frontocortical NMDA receptors are pivotal in regulating cognition and mood, are hypofunctional in schizophrenia, and may contribute to autistic spectrum disorders. Despite extensive interest in agents potentiating activity at the co-agonist glycine modulatory site, few comparative functional studies exist. This study systematically compared the actions of the glycine reuptake inhibitors, sarcosine (40-200 mg/kg) and ORG24598 (0.63-5 mg/kg), the agonists, glycine (40-800 mg/kg), and D-serine (10-160 mg/kg) and the partial agonists, S18841 (2.5 mg/kg s.c.) and D-cycloserine (2.5-40 mg/kg) that all dose-dependently prevented scopolamine disruption of social recognition in adult rats. Over similar dose ranges, they also prevented a delay-induced impairment of novel object recognition (NOR). Glycine reuptake inhibitors specifically elevated glycine but not D-serine levels in rat prefrontal cortical (PFC) microdialysates, while glycine and D-serine markedly increased levels of glycine and D-serine, respectively. D-Cycloserine slightly elevated D-serine levels. Conversely, S18841 exerted no influence on glycine, D-serine, other amino acids, monamines, or acetylcholine. Reversal of NOR deficits by systemic S18841 was prevented by the NMDA receptor antagonist, CPP (20 mg/kg), and the glycine modulatory site antagonist, L701,324 (10 mg/kg). S18841 blocked deficits in NOR following microinjection into the PFC (2.5-10 µg/side) but not the striatum. Finally, in rats socially isolated from weaning (a neurodevelopmental model of schizophrenia), S18841 (2.5 and 10 mg/kg s.c.) reversed impairment of NOR and contextual fear-motivated learning without altering isolation-induced hyperactivity. In conclusion, despite contrasting neurochemical profiles, partial glycine site agonists and glycine reuptake inhibitors exhibit comparable pro-cognitive effects in rats of potential relevance to treatment of schizophrenia and other brain disorders where cognitive performance is impaired.
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Trastornos del Conocimiento/tratamiento farmacológico , Cognición/efectos de los fármacos , Glicinérgicos/farmacología , Glicina/metabolismo , Memoria a Corto Plazo/efectos de los fármacos , Inhibidores de la Captación de Neurotransmisores/farmacología , Nootrópicos/farmacología , Aminoácidos/análisis , Animales , Trastorno del Espectro Autista/tratamiento farmacológico , Cicloserina/farmacología , Relación Dosis-Respuesta a Droga , Reacción Cataléptica de Congelación/efectos de los fármacos , Glicina/agonistas , Glicina/análogos & derivados , Glicina/farmacología , Masculino , Actividad Motora/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Wistar , Receptores de Glicina/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/fisiología , Reconocimiento en Psicología/efectos de los fármacos , Sarcosina/farmacología , Esquizofrenia/tratamiento farmacológico , Escopolamina/antagonistas & inhibidores , Serina/farmacología , Conducta SocialRESUMEN
BACKGROUND: Catecholamines are important for cognitive control and the ability to adapt behavior (e.g., after response errors). A prominent drug that modulates the catecholaminergic system is methylphenidate. On the basis of theoretical consideration, we propose that the effects of methylphenidate on behavioral adaptation depend on prior learning experience. METHODS: In a double-blind, randomized, placebo-controlled crossover study design, we examined the effect of methylphenidate (0.25 mg/kg) on post error behavioral adaptation processes in a group of n = 43 healthy young adults. Behavioral adaptation processes were examined in a working memory, modulated response selection task. The focus of the analysis was on order effects within the crossover study design to evaluate effects of prior learning/task experience. RESULTS: The effect of methylphenidate/placebo on post-error behavioral adaptation processes reverses depending on prior task experience. When there was no prior experience with the task, methylphenidate increased post-error slowing and thus intensified behavioral adaptation processes. However, when there was prior task experience, (i.e., when the placebo session was conducted first in the crossover design), methylphenidate even decreased post-error slowing and behavioral adaptation. Effect sizes were large and the power of the observed effects was higher than 95%. CONCLUSIONS: The data suggest that catecholaminergic effects on cognitive control functions vary as a function of prior learning/task experience. The data establish a close link between learning/task familiarization and catecholaminergic effects for executive functions, which has not yet been studied, to our knowledge, but is of considerable clinical relevance. Theoretical implications are discussed.
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Adaptación Psicológica/efectos de los fármacos , Función Ejecutiva/efectos de los fármacos , Metilfenidato/farmacología , Inhibidores de la Captación de Neurotransmisores/farmacología , Práctica Psicológica , Desempeño Psicomotor/efectos de los fármacos , Reconocimiento en Psicología , Adulto , Estudios Cruzados , Dopamina/fisiología , Método Doble Ciego , Femenino , Humanos , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Norepinefrina/fisiología , Adulto JovenRESUMEN
Ketamine significantly increases the locomotor activity of rodents, however this effect varies according to the sex and age of the animal being tested. To determine the role monoamine systems play in ketamine's locomotor activating effects: (a) male and female preweanling, adolescent, and adult rats were pretreated with vehicle or the monoamine depleting agent reserpine (1 or 5â¯mg/kg), and (b) the behavioral actions of ketamine (20 or 40â¯mg/kg) were then compared to d-amphetamine (2â¯mg/kg) and cocaine (10 or 15â¯mg/kg). The ability of reserpine to deplete dorsal striatal dopamine (DA) and serotonin (5-HT) in male and female rats was determined using HPLC. Ketamine caused substantial increases in the locomotion of preweanling rats and older female rats (adolescents and adults), but had only small stimulatory effects on adolescent and adult male rats. When compared to cocaine and d-amphetamine, ketamine was especially sensitive to the locomotor-inhibiting effects of monoamine depletion. Ketamine-induced locomotion is at least partially mediated by monoamine systems, since depleting DA and 5-HT levels by 87-96% significantly attenuated the locomotor activating effects of ketamine in male and female rats from all three age groups. When administered to reserpine-pretreated rats, ketamine produced a different pattern of behavioral effects than either psychostimulant, suggesting that ketamine does not stimulate locomotor activity via actions at the presynaptic terminal. Instead, our results are consistent with the hypothesis that ketamine increases locomotor activity through a down-stream mechanism, possibly involving ascending DA and/or 5-HT projection neurons.
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Conducta Animal/efectos de los fármacos , Monoaminas Biogénicas/metabolismo , Antagonistas de Aminoácidos Excitadores/farmacología , Ketamina/farmacología , Locomoción/efectos de los fármacos , Inhibidores de la Captación de Neurotransmisores/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Transmisión Sináptica/efectos de los fármacos , Inhibidores de Captación Adrenérgica/farmacología , Factores de Edad , Animales , Cocaína/farmacología , Dextroanfetamina/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Interacciones Farmacológicas , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Femenino , Ketamina/administración & dosificación , Masculino , Inhibidores de la Captación de Neurotransmisores/administración & dosificación , Ratas , Ratas Sprague-Dawley , Reserpina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Caracteres SexualesRESUMEN
Psychostimulants are highly effective cognitive-enhancing therapeutics yet have a significant potential for abuse and addiction. While psychostimulants likely exert their rewarding and addictive properties through dopamine transporter (DAT) inhibition, the mechanisms of their procognitive effects are less certain. By one prevalent view, psychostimulants exert their procognitive effects exclusively through norepinephrine transporter (NET) inhibition, however increasing evidence suggests that DAT also plays a critical role in their cognitive-enhancing properties, including long-term memory enhancement. The present experiments test the hypothesis that combined strong NET and weak DAT inhibition will mimic the fear memory-enhancing but not the addiction-related effects of psychostimulants in mice. We examined the effects of the high affinity NET inhibitors atomoxetine or nisoxetine and the low affinity DAT inhibitor bupropion, either alone or in combination, on short- and long-term memory of Pavlovian fear conditioning. We also examined the addiction-related effects of combined strong NET and weak DAT inhibition using conditioned place preference and a locomotor activity test. While atomoxetine or nisoxetine alone enhanced short-term fear memory, the addition of bupropion was required to significantly enhance long-term fear memory. Additionally, combined atomoxetine and bupropion did not produce substantial motor stimulation or place preference. These findings suggest that combining strong NET and weak DAT inhibition could lead to the development of a highly effective cognitive enhancer that lacks the potential for addiction.
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Clorhidrato de Atomoxetina/farmacología , Conducta Animal/efectos de los fármacos , Bupropión/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Condicionamiento Clásico/efectos de los fármacos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Miedo/efectos de los fármacos , Fluoxetina/análogos & derivados , Memoria a Largo Plazo/efectos de los fármacos , Inhibidores de la Captación de Neurotransmisores/farmacología , Nootrópicos/farmacología , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Animales , Clorhidrato de Atomoxetina/administración & dosificación , Bupropión/administración & dosificación , Estimulantes del Sistema Nervioso Central/administración & dosificación , Quimioterapia Combinada , Femenino , Fluoxetina/administración & dosificación , Fluoxetina/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Inhibidores de la Captación de Neurotransmisores/administración & dosificación , Nootrópicos/administración & dosificaciónRESUMEN
SMe1EC2M3 is a pyridoindole derivative related to the neuroleptic drug carbidine. Based on the structural similarities of SMe1EC2M3 and known serotonin (5-HT), norepinephrine, and dopamine reuptake inhibitors, we hypothesized that this compound may also have triple reuptake inhibition efficacy and an antidepressant-like effect. PreADMET and Dragon software was used for in silico prediction of pharmacokinetics and pharmacodynamics of SMe1EC2M3. Forced swim test was used to evaluate its antidepressant-like effects. Extracellular in vivo electrophysiology was used to assess 5-HT, norepinephrine, and dopamine reuptake inhibition efficacy of SMe1EC2M3. PreADMET predicted reasonable intestinal absorption, plasma protein binding, and blood-brain permeability for SMe1EC2M3. Dragon forecasted its efficiency as an antidepressant. Using behavioral measurements, it was found that SMe1EC2M3 decreased immobility time and increase swimming time during the forced swim test (FST). Electrophysiological investigations showed that SMe1EC2M3 dose-dependently suppressed the excitability of 5-HT neurons of the dorsal raphe nucleus (DRN), norepinephrine neurons of the locus coeruleus (LC), and dopamine neurons of the ventral tegmental area (VTA). The SMe1EC2M3-induced suppression of 5-HT, norepinephrine, and dopamine neurons was reversed by the antagonists of serotonin-1A (5-HT1A; WAY100135), α-2 adrenergic (α2, yohimbine), and dopamine-2 receptors (D2, haloperidol), respectively. We conclude that SMe1EC2M3 is prospective triple 5-HT, norepinephrine, and dopamine reuptake inhibitor with antidepressant-like properties, however future studies should be performed to complete the pharmacological profiling of this compound.
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Antidepresivos , Fenómenos Electrofisiológicos/efectos de los fármacos , Neuronas/metabolismo , Inhibidores de la Captación de Neurotransmisores , Transmisión Sináptica/efectos de los fármacos , Animales , Antidepresivos/química , Antidepresivos/farmacocinética , Antidepresivos/farmacología , Masculino , Inhibidores de la Captación de Neurotransmisores/química , Inhibidores de la Captación de Neurotransmisores/farmacocinética , Inhibidores de la Captación de Neurotransmisores/farmacología , Ratas , Ratas WistarRESUMEN
Significant unmet needs exist for development of better pharmacotherapeutic agents for major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) as the current drugs are inadequate. Our goal in this study is to investigate behavioral pharmacological characterization of a novel triple reuptake inhibitor (TRI) D-578 which exhibits nanomolar potency at all three monoamine transporters (Ki; 16.2. 16.2, 3.23â¯nM, and 29.6, 20.6, 6.10â¯nM for the rat brain and cloned human dopamine, serotonin and norepinephrine transporters, respectively) and exhibited little to no affinity for other off-target CNS receptors. In a rat forced swim test, compound D-578 upon oral administration displayed high efficacy and not stimulating in locomotor behavior. The effects of D-578 and paroxetine were next evaluated in a rat model for traumatic stress exposure - the single prolonged stress (SPS) model - which has been shown to have construct, predictive, and behavioral validity in modeling aspects of PTSD. Our results show that SPS had no effect on the acquisition of conditioned fear, but impaired extinction learning and extinction retention of fear behavior compared to sham treatment. D-578, but not paroxetine, attenuated the extinction and extinction-retention deficit induced by SPS. These findings suggest that D-578 has greater efficacy in normalizing traumatic stress-induced extinction-retention learning in a model for PTSD compared to paroxetine. Overall these results suggest that D-578, in addition to producing a robust and efficacious antidepressant effect, may attenuate maladaptive retention of fearful memories and support further testing of this agent for the pharmacotherapy of depression and PTSD.
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Antidepresivos/farmacología , Trastorno Depresivo Mayor/tratamiento farmacológico , Inhibidores de la Captación de Neurotransmisores/farmacología , Trastornos por Estrés Postraumático/tratamiento farmacológico , Estrés Psicológico/complicaciones , Administración Oral , Animales , Antidepresivos/uso terapéutico , Técnicas de Observación Conductual , Conducta Animal/efectos de los fármacos , Trastorno Depresivo Mayor/etiología , Trastorno Depresivo Mayor/psicología , Modelos Animales de Enfermedad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Inhibidores de la Captación de Neurotransmisores/uso terapéutico , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Ratas , Retención en Psicología/efectos de los fármacos , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Trastornos por Estrés Postraumático/etiología , Trastornos por Estrés Postraumático/psicología , Estrés Psicológico/psicologíaRESUMEN
INTRODUCTION: A 'holy grail' of treatment options for attention-deficit hyperactivity disorder (ADHD) has been an agent with low abuse potential and peak-trough clinical effects, providing sustained therapeutic benefits throughout the day. One such agent, dasotraline, a dopamine and norepinephrine reuptake inhibitor agent, was recently reviewed by the FDA. Areas covered: The authors completed a timely drug review using a PubMed literature search using words 'Dasotraline, ADHD' 'stimulant, abuse' 'atomoxetine, ADHD.' FDA fact sheets of available medications were reviewed for comparison of safety and tolerability data. The authors reviewed preclinical, efficacy, and safety trials of dasotraline in ADHD: two phase 1, one phase 2, and several phase 3 trials have established efficacy in reducing ADHD symptoms. Expert opinion: Due to its stable plasma concentrations with once-daily dosing, dasotraline could have sustained treatment benefits for ADHD, with low abuse potential and a stable therapeutic response over a 24-h period.
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1-Naftilamina/análogos & derivados , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Inhibidores de la Captación de Neurotransmisores/farmacología , 1-Naftilamina/farmacocinética , 1-Naftilamina/farmacología , Humanos , Inhibidores de la Captación de Neurotransmisores/farmacocinéticaRESUMEN
OBJECTIVE: To evaluate the efficacy and tolerability of pharmacotherapy in pediatric anxiety disorders using network meta-analysis. DATA SOURCES: PubMed, Cochrane Database, Web of Science, PsycNET, and ClinicalTrials.gov were searched for double-blind, controlled pharmacotherapy trials in youth with anxiety disorders from 1966 to September 2017. DATA SELECTION: All double-blind, placebo-controlled trials of pharmacotherapy in the treatment of pediatric patients with generalized, social, and/or separation anxiety disorders were included. DATA EXTRACTION: We extracted demographic, symptom severity, global improvement, discontinuation, and suicidality data. Risk of bias was assessed with the Cochrane risk-of-bias tool, and a network meta-analysis comparing the efficacy and tolerability of medications and medication classes was performed using the gemtc package (R). RESULTS: We identified 20 citations (22 RCTs, 24 treatment arms) with 2,623 patients. Selective serotonin reuptake inhibitors (SSRIs) were the only class that was superior in reducing anxiety (standardized mean difference: 5.2; credible interval [CrI]: [2.8 to 8.8]) and in likelihood of treatment response compared to placebo (odds ratio [OR]: 4.6; CrI: [3.1 to 7.5]). Serotonin-norepinephrine reuptake inhibitor (SNRI) and α2 agonist treatment were associated with more frequent treatment response compared to placebo. The likelihood of treatment response was greater for SSRIs compared to SNRIs (OR: 1.9; CrI: [1.1 to 3.5]). All-cause discontinuation and treatment-emergent suicidality significantly differed among medications but not medication class. CONCLUSIONS: Although multiple medications reduce anxiety in children and adolescents, treatment response, tolerability, and treatment-emergent suicidality differ among these medications and medication classes. Determining whether efficacy and tolerability differences represent true differences (or reflect differences in trial design) requires additional head-to-head medication trials and-to exclude the impact of missing treatment interventions-requires trials of medications that successfully treat anxiety in adults but that have not been evaluated in youth.
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Trastornos de Ansiedad/tratamiento farmacológico , Inhibidores de la Captación de Neurotransmisores/farmacología , Niño , Humanos , Metaanálisis en Red , Resultado del TratamientoRESUMEN
The degeneration in the locus coeruleus associated with Alzheimer's disease suggests an involvement of the noradrenergic system in the disease pathogenesis. The role of depleted norepinephrine was tested in adult and aged rhesus macaques to develop a potential model for testing Alzheimer's disease interventions. Monkeys were injected with the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) or vehicle at 0, 3, and 6 months; brains were harvested at 9 months. Reduced norepinephrine in the locus coeruleus was accompanied by decreased dopamine ß-hydroxylase staining and increased amyloid-ß load in the aged group, and the proportion of potentially toxic amyloid-ß42 peptide was increased. Immunohistochemistry revealed no effects on microglia or astrocytes. DSP4 treatment altered amyloid processing, but these changes were not associated with the induction of chronic neuroinflammation. These findings suggest norepinephrine deregulation is an essential component of a nonhuman primate model of Alzheimer's disease, but further refinement is necessary.
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Péptidos beta-Amiloides/metabolismo , Bencilaminas/farmacología , Locus Coeruleus/metabolismo , Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/metabolismo , Fragmentos de Péptidos/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Precursor de Proteína beta-Amiloide/antagonistas & inhibidores , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Femenino , Locus Coeruleus/efectos de los fármacos , Macaca mulatta , Norepinefrina/antagonistas & inhibidores , Fragmentos de Péptidos/antagonistas & inhibidores , Distribución AleatoriaRESUMEN
Reserpine treatment in rodents has been shown to induce depression-like behaviors that mimic monoamine dysfunction implicated in the development of depression. Herein, we aimed to demonstrate the antidepressant-like activities of scopolamine, the muscarinic receptor antagonist, in a reserpine-induced mouse model. Mice were injected with 1.5â¯mg/kg (i.p.) of reserpine for 10 days, and the depression-like state was confirmed via the open field test (OFT) and forced swimming test (FST). Then, the mice were treated with scopolamine (25⯵g/kg, i.p.) or saline for 3 days. Ten days of reserpine treatment resulted in a significant decrease in locomotor activity and an increase in immobility time in the OFT and FST, respectively, indicating that ten days of reserpine administration significantly induced depression-like behaviors in mice. However, scopolamine rapidly ameliorated the increase in immobility time in the FST and had no effect on locomotor activity in the OFT. In addition, the reserpine-induced decreases in serotonin transporter (5-HTT), brain-derived neurotrophic factor (BDNF) and tryptophan hydroxylase 1 (TPH1) in mouse hippocampus and prefrontal cortex (PFC) were significantly reversed by scopolamine. Our study provides evidence that scopolamine rapidly attenuates reserpine-induced depression in mice partially by regulating 5-HTT, BDNF and TPH1 in the hippocampus and PFC of mice.
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Conducta Animal/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/efectos de los fármacos , Depresión/inducido químicamente , Depresión/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Antagonistas Muscarínicos/farmacología , Inhibidores de la Captación de Neurotransmisores/farmacología , Corteza Prefrontal/efectos de los fármacos , Reserpina/farmacología , Escopolamina/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/efectos de los fármacos , Triptófano Hidroxilasa/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos ICR , Antagonistas Muscarínicos/administración & dosificación , Inhibidores de la Captación de Neurotransmisores/administración & dosificación , Reserpina/administración & dosificación , Escopolamina/administración & dosificación , Regulación hacia ArribaRESUMEN
Acute exposure to stress induces significant behavioural changes, while repeated exposure to the same stressor leads to the development of tolerance to stress. The development of tolerance appears to involve the serotonergic projections from the Median Raphe Nucleus (MnRN) to the dorsal Hippocampus (dH), since rats with lesions of this pathway does not develop tolerance to stress. Previous data from our laboratory showed that treatment with imipramine, a serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor, lead to the development of tolerance. However, it remains to be elucidated whether such tolerance involves the participation of the noradrenergic system, apart from the serotonergic projections. Therefore, the aim of this work was to investigate the behavioural and neurochemical effects of chronic treatment with desipramine (NA reuptake inhibitor) or fluoxetine (5-HT reuptake inhibitor) in chronically stressed rats with lesions of the serotonergic neurons of the MnRN. Male Wistar rats with or without lesion in the MnRN were submitted or not to acute (2â¯h) or chronic restraint (2â¯h/seven days) stress and tested in the elevated pus maze (EPM). Treatment with fluoxetine, desipramine (10â¯mg/kg) or saline was performed twice daily (12-12â¯h interval), for 7 consecutive days. EPM test was conducted 24â¯h after the treatment. Fluoxetine attenuated the anxiogenic-induced effect of lesion in chronically restrained rats, without changing serotonin and noradrenaline levels in the hippocampus of lesioned rats. A similar profile was also observed after treatment with desipramine. These results suggest that both the serotonergic and the noradrenergic systems are involved in the development of tolerance to chronic stress. Additionally, the integrity of the serotonergic pathway of the MnRN-dH is not essential for the anxiolytic-like effects of these drugs.
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Núcleo Dorsal del Rafe/citología , Núcleo Dorsal del Rafe/lesiones , Norepinefrina/metabolismo , Neuronas Serotoninérgicas/fisiología , Serotonina/metabolismo , Estrés Psicológico , 5,7-Dihidroxitriptamina/farmacología , Análisis de Varianza , Animales , Desipramina/farmacología , Modelos Animales de Enfermedad , Tolerancia a Medicamentos , Fluoxetina/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Inhibidores de la Captación de Neurotransmisores/farmacología , Ratas , Ratas Wistar , Serotoninérgicos/farmacología , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Estrés Psicológico/patologíaRESUMEN
The ability to selectively perceive and flexibly attend to relevant sensory signals in the environment is essential for action control. Whereas neuromodulation of sensory or attentional processing is often investigated, neuromodulation of interactive effects between perception and attention, that is, high attentional control demand when the relevant sensory information is perceptually less salient than the irrelevant one, is not well understood. To fill this gap, this pharmacological-electroencephalogram (EEG) study applied an intensity-modulated, focused-attention dichotic listening paradigm together with temporal EEG signal decomposition and source localization analyses. We used a double-blind MPH/placebo crossover design to delineate the effects of methylphenidate (MPH)-a dopamine/norepinephrine transporter blocker-on the resolution of perceptual-attentional conflicts, when perceptual saliency and attentional focus favor opposing ears, in healthy young adults. We show that MPH increased behavioral performance specifically in the condition with the most pronounced conflict between perceptual saliency and attentional focus. On the neurophysiological level, MPH effects in line with the behavioral data were observed after accounting for intraindividual variability in the signal. More specifically, MPH did not show an effect on stimulus-related processes but modulated the onset latency of processes between stimulus evaluation and responding. These modulations were further shown to be associated with activation differences in the temporoparietal junction (BA40) and the superior parietal cortex (BA7) and may reflect neuronal gain modulation principles. The findings provide mechanistic insights into the role of modulated dopamine/norepinephrine transmitter systems for the interactions between perception and attention.
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Atención/efectos de los fármacos , Percepción Auditiva/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Conflicto Psicológico , Electroencefalografía/métodos , Potenciales Evocados/fisiología , Metilfenidato/farmacología , Inhibidores de la Captación de Neurotransmisores/farmacología , Desempeño Psicomotor/efectos de los fármacos , Adulto , Estudios Cruzados , Inhibidores de Captación de Dopamina/farmacología , Método Doble Ciego , Femenino , Humanos , Masculino , Metilfenidato/administración & dosificación , Inhibidores de la Captación de Neurotransmisores/administración & dosificación , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Adulto JovenRESUMEN
The prefrontal cortex (PFC) plays an important role in several forms of cost-benefit decision making. Its contributions to decision making under risk of explicit punishment, however, are not well understood. A rat model was used to investigate the role of the medial PFC (mPFC) and its monoaminergic innervation in a Risky Decision-making Task (RDT), in which rats chose between a small, "safe" food reward and a large, "risky" food reward accompanied by varying probabilities of mild footshock punishment. Inactivation of mPFC increased choice of the large, risky reward when the punishment probability increased across the session ("ascending RDT"), but decreased choice of the large, risky reward when the punishment probability decreased across the session ("descending RDT"). In contrast, enhancement of monoamine availability via intra-mPFC amphetamine reduced choice of the large, risky reward only in the descending RDT. Systemic administration of amphetamine reduced choice of the large, risky reward in both the ascending and descending RDT; however, this reduction was not attenuated by concurrent mPFC inactivation, indicating that mPFC is not a critical locus of amphetamine's effects on risk taking. These findings suggest that mPFC plays an important role in adapting choice behavior in response to shifting risk contingencies, but not necessarily in risk-taking behavior per se.
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Toma de Decisiones/fisiología , Corteza Prefrontal/fisiología , Castigo , Asunción de Riesgos , Anfetamina/farmacología , Animales , Monoaminas Biogénicas/metabolismo , Toma de Decisiones/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Conducta Alimentaria/fisiología , Conducta Alimentaria/psicología , Masculino , Inhibidores de la Captación de Neurotransmisores/farmacología , Corteza Prefrontal/efectos de los fármacos , Psicotrópicos/farmacología , Ratas Long-EvansRESUMEN
Rational drug design method has been used to generate 4-arylpiperazine carboxamides in an effort to develop safer, more potent and effective monoamine neurotransmitters reuptake inhibitors. Out of twenty-seven synthesized compounds, compound 9 displayed potent monoamine neurotransmitter reuptake inhibitory activity against HEK cells transfected with hSERT or hNET. A Surflex-Dock docking model of 9 was also studied.