RESUMO
Adolescent stress (AS) has been associated with higher vulnerability to psychiatric disorders such as schizophrenia, depression, or drug dependence. Moreover, the alteration of brain catecholamine (CAT) transmission in the medial prefrontal cortex (mPFC) has been found to play a major role in the etiology of psychiatric disturbances. We investigated the effect of adolescent stress on CAT transmission in the mPFC of freely moving adult rats because of the importance of this area in the etiology of psychiatric disorders, and because CAT transmission is the target of a relevant group of drugs used in the therapy of depression and psychosis. We assessed basal dopamine (DA) and norepinephrine (NE) extracellular concentrations (output) by brain microdialysis in in the mPFC of adult rats that were exposed to chronic mild stress in adolescence. To ascertain the role of an altered release or reuptake, we stimulated DA and NE output by administering either different doses of amphetamine (0.5 and 1.0 mg / kg s.c.), which by a complex mechanism determines a dose dependent increase in the CAT output, or reboxetine (10 mg/kg i.p.), a selective NE reuptake inhibitor. The results showed the following: (i) basal DA output in AS rats was lower than in controls, while no difference in basal NE output was observed; (ii) amphetamine, dose dependently, stimulated DA and NE output to a greater extent in AS rats than in controls; (iii) reboxetine stimulated NE output to a greater extent in AS rats than in controls, while no difference in stimulated DA output was observed between the two groups. These results show that AS determines enduring effects on DA and NE transmission in the mPFC and might lead to the occurrence of psychiatric disorders or increase the vulnerability to drug addiction.
Assuntos
Dopamina , Norepinefrina , Córtex Pré-Frontal , Estresse Psicológico , Animais , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Dopamina/metabolismo , Masculino , Norepinefrina/metabolismo , Ratos , Estresse Psicológico/metabolismo , Microdiálise , Anfetamina/farmacologia , Reboxetina/farmacologia , Morfolinas/farmacologia , Ratos Wistar , Relação Dose-Resposta a Droga , Inibidores da Captação Adrenérgica/farmacologiaRESUMO
BACKGROUND: A panic attack is a discrete period of fear or anxiety that has a rapid onset and reaches a peak within 10 minutes. The main symptoms involve bodily systems, such as racing heart, chest pain, sweating, shaking, dizziness, flushing, churning stomach, faintness and breathlessness. Other recognised panic attack symptoms involve fearful cognitions, such as the fear of collapse, going mad or dying, and derealisation (the sensation that the world is unreal). Panic disorder is common in the general population with a prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions, including antidepressants and benzodiazepines. OBJECTIVES: To compare, via network meta-analysis, individual drugs (antidepressants and benzodiazepines) or placebo in terms of efficacy and acceptability in the acute treatment of panic disorder, with or without agoraphobia. To rank individual active drugs for panic disorder (antidepressants, benzodiazepines and placebo) according to their effectiveness and acceptability. To rank drug classes for panic disorder (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), mono-amine oxidase inhibitors (MAOIs) and benzodiazepines (BDZs) and placebo) according to their effectiveness and acceptability. To explore heterogeneity and inconsistency between direct and indirect evidence in a network meta-analysis. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Specialised Register, CENTRAL, CDSR, MEDLINE, Ovid Embase and PsycINFO to 26 May 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of people aged 18 years or older of either sex and any ethnicity with clinically diagnosed panic disorder, with or without agoraphobia. We included trials that compared the effectiveness of antidepressants and benzodiazepines with each other or with a placebo. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles/abstracts and full texts, extracted data and assessed risk of bias. We analysed dichotomous data and continuous data as risk ratios (RRs), mean differences (MD) or standardised mean differences (SMD): response to treatment (i.e. substantial improvement from baseline as defined by the original investigators: dichotomous outcome), total number of dropouts due to any reason (as a proxy measure of treatment acceptability: dichotomous outcome), remission (i.e. satisfactory end state as defined by global judgement of the original investigators: dichotomous outcome), panic symptom scales and global judgement (continuous outcome), frequency of panic attacks (as recorded, for example, by a panic diary; continuous outcome), agoraphobia (dichotomous outcome). We assessed the certainty of evidence using threshold analyses. MAIN RESULTS: Overall, we included 70 trials in this review. Sample sizes ranged between 5 and 445 participants in each arm, and the total sample size per study ranged from 10 to 1168. Thirty-five studies included sample sizes of over 100 participants. There is evidence from 48 RCTs (N = 10,118) that most medications are more effective in the response outcome than placebo. In particular, diazepam, alprazolam, clonazepam, paroxetine, venlafaxine, clomipramine, fluoxetine and adinazolam showed the strongest effect, with diazepam, alprazolam and clonazepam ranking as the most effective. We found heterogeneity in most of the comparisons, but our threshold analyses suggest that this is unlikely to impact the findings of the network meta-analysis. Results from 64 RCTs (N = 12,310) suggest that most medications are associated with either a reduced or similar risk of dropouts to placebo. Alprazolam and diazepam were associated with a lower dropout rate compared to placebo and were ranked as the most tolerated of all the medications examined. Thirty-two RCTs (N = 8569) were included in the remission outcome. Most medications were more effective than placebo, namely desipramine, fluoxetine, clonazepam, diazepam, fluvoxamine, imipramine, venlafaxine and paroxetine, and their effects were clinically meaningful. Amongst these medications, desipramine and alprazolam were ranked highest. Thirty-five RCTs (N = 8826) are included in the continuous outcome reduction in panic scale scores. Brofaromine, clonazepam and reboxetine had the strongest reductions in panic symptoms compared to placebo, but results were based on either one trial or very small trials. Forty-one RCTs (N = 7853) are included in the frequency of panic attack outcome. Only clonazepam and alprazolam showed a strong reduction in the frequency of panic attacks compared to placebo, and were ranked highest. Twenty-six RCTs (N = 7044) provided data for agoraphobia. The strongest reductions in agoraphobia symptoms were found for citalopram, reboxetine, escitalopram, clomipramine and diazepam, compared to placebo. For the pooled intervention classes, we examined the two primary outcomes (response and dropout). The classes of medication were: SSRIs, SNRIs, TCAs, MAOIs and BDZs. For the response outcome, all classes of medications examined were more effective than placebo. TCAs as a class ranked as the most effective, followed by BDZs and MAOIs. SSRIs as a class ranked fifth on average, while SNRIs were ranked lowest. When we compared classes of medication with each other for the response outcome, we found no difference between classes. Comparisons between MAOIs and TCAs and between BDZs and TCAs also suggested no differences between these medications, but the results were imprecise. For the dropout outcome, BDZs were the only class associated with a lower dropout compared to placebo and were ranked first in terms of tolerability. The other classes did not show any difference in dropouts compared to placebo. In terms of ranking, TCAs are on average second to BDZs, followed by SNRIs, then by SSRIs and lastly by MAOIs. BDZs were associated with lower dropout rates compared to SSRIs, SNRIs and TCAs. The quality of the studies comparing antidepressants with placebo was moderate, while the quality of the studies comparing BDZs with placebo and antidepressants was low. AUTHORS' CONCLUSIONS: In terms of efficacy, SSRIs, SNRIs (venlafaxine), TCAs, MAOIs and BDZs may be effective, with little difference between classes. However, it is important to note that the reliability of these findings may be limited due to the overall low quality of the studies, with all having unclear or high risk of bias across multiple domains. Within classes, some differences emerged. For example, amongst the SSRIs paroxetine and fluoxetine seem to have stronger evidence of efficacy than sertraline. Benzodiazepines appear to have a small but significant advantage in terms of tolerability (incidence of dropouts) over other classes.
Assuntos
Transtorno de Pânico , Inibidores da Recaptação de Serotonina e Norepinefrina , Adulto , Humanos , Transtorno de Pânico/tratamento farmacológico , Transtorno de Pânico/complicações , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Paroxetina/uso terapêutico , Fluoxetina/uso terapêutico , Cloridrato de Venlafaxina/uso terapêutico , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico , Alprazolam/uso terapêutico , Clomipramina/uso terapêutico , Reboxetina/uso terapêutico , Clonazepam/uso terapêutico , Desipramina/uso terapêutico , Metanálise em Rede , Antidepressivos/uso terapêutico , Antidepressivos Tricíclicos/uso terapêutico , Benzodiazepinas/uso terapêutico , Diazepam/uso terapêuticoRESUMO
OBJECTIVES: Reboxetine is a potent and selective norepinephrine reuptake inhibitor that was effective in combination with citalopram for resistant obsessive-compulsive disorder (OCD). This study aims to assess its effectiveness and tolerability in combination with fluoxetine in treating OCD. METHODS: In this 2-center, placebo-controlled, and double-blind, randomized clinical trial, 76 patients with OCD were assigned into 2 parallel groups to receive fluoxetine (up to 80 mg/d) plus placebo (F + P) or fluoxetine (up to 80 mg/d) plus reboxetine (F + R) (10 mg twice daily) for 10 weeks. Participants were assessed with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at baseline and weeks 5 and 10. RESULTS: A total of 76 patients completed the trial. There was no significant difference between the 2 groups in baseline Y-BOCS scores. General linear model repeated-measures showed significant effects on time × treatment interaction on total Y-BOCS ( F = 6.33, df = 1.42, P = 0.006) and obsession subscale scores ( F = 10.39, df = 1.48, P < 0.001), and insignificance on compulsion subscale scores ( F = 1.86, df = 1.24, P = 0.173). Reboxetine combination therapy demonstrated a higher partial and complete treatment response rate ( P < 0.01) according to the Y-BOCS total scores. There was no significant difference between the 2 groups in the frequency of adverse effects. CONCLUSIONS: Reboxetine combination therapy with fluoxetine can effectively improve symptoms in patients with OCD in a short period of treatment. However, further studies with larger sample sizes and longer follow-up periods are needed to confirm these findings.This trial was registered with the Iranian Registry of Clinical Trials ( www.irct.ir ; No IRCT20090117001556N129).
Assuntos
Fluoxetina , Transtorno Obsessivo-Compulsivo , Reboxetina , Humanos , Método Duplo-Cego , Quimioterapia Combinada , Fluoxetina/uso terapêutico , Irã (Geográfico) , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Reboxetina/uso terapêutico , Resultado do TratamentoRESUMO
Foraging theory prescribes when optimal foragers should leave the current option for more rewarding alternatives. Actual foragers often exploit options longer than prescribed by the theory, but it is unclear how this foraging suboptimality arises. We investigated whether the upregulation of cholinergic, noradrenergic, and dopaminergic systems increases foraging optimality. In a double-blind, between-subject design, participants (N = 160) received placebo, the nicotinic acetylcholine receptor agonist nicotine, a noradrenaline reuptake inhibitor reboxetine, or a preferential dopamine reuptake inhibitor methylphenidate, and played the role of a farmer who collected milk from patches with different yield. Across all groups, participants on average overharvested. While methylphenidate had no effects on this bias, nicotine, and to some extent also reboxetine, significantly reduced deviation from foraging optimality, which resulted in better performance compared to placebo. Concurring with amplified goal-directedness and excluding heuristic explanations, nicotine independently also improved trial initiation and time perception. Our findings elucidate the neurochemical basis of behavioral flexibility and decision optimality and open unique perspectives on psychiatric disorders affecting these functions.
Assuntos
Acetilcolina , Metilfenidato , Humanos , Nicotina/farmacologia , Norepinefrina , Reboxetina , Método Duplo-CegoRESUMO
About 30% of major depression disorder patients fail to achieve remission, hence being diagnosed with treatment-resistant major depression (TRD). Opium had been largely used effectively to treat depression for centuries, but when other medications were introduced, its use was discounted due to addiction and other hazards. In a series of previous studies, we evaluated the antinociceptive effects of eight antidepressant medications and their interaction with the opioid system. Mice were tested with a hotplate or tail-flick after being injected with different doses of mianserin, mirtazapine, trazodone, venlafaxine, reboxetine, moclobemide, fluoxetine, or fluvoxamine to determine the effect of each drug in eliciting antinociception. When naloxone inhibited the antinociceptive effect, we further examined the effect of the specific opioid antagonists of each antidepressant drug. Mianserin and mirtazapine (separately) induced dose-dependent antinociception, each one yielding a biphasic dose-response curve, and they were antagonized by naloxone. Trazodone and venlafaxine (separately) induced a dose-dependent antinociceptive effect, antagonized by naloxone. Reboxetine induced a weak antinociceptive effect with no significant opioid involvement, while moclobemide, fluoxetine, and fluvoxamine had no opioid-involved antinociceptive effects. Controlled clinical studies are needed to establish the efficacy of the augmentation of opiate antidepressants in persons with treatment-resistant depression and the optimal dosage of drugs prescribed.
Assuntos
Analgésicos Opioides , Trazodona , Animais , Camundongos , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Mianserina/farmacologia , Mianserina/uso terapêutico , Cloridrato de Venlafaxina/farmacologia , Cloridrato de Venlafaxina/uso terapêutico , Fluvoxamina , Mirtazapina/farmacologia , Mirtazapina/uso terapêutico , Fluoxetina , Reboxetina , Moclobemida , Depressão , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Naloxona/farmacologia , Naloxona/uso terapêutico , Relação Dose-Resposta a DrogaRESUMO
Previous research reported an age-related decline in brain norepinephrine transporter (NET) using (S, S)-[11C]O-methylreboxetine ([11C]MRB) as a radiotracer. Studies with the same tracer have been mixed in regard to differences related to body mass index (BMI). Here, we investigated potential age-, BMI-, and gender-related differences in brain NET availability using [11C]MRB, the most selective available radiotracer. Forty-three healthy participants (20 females, 23 males; age range 18-49 years), including 12 individuals with normal/lean weight, 15 with overweight, and 16 with obesity were scanned with [11C]MRB using a positron emission tomography (PET) high-resolution research tomograph (HRRT). We evaluated binding potential (BPND ) in brain regions with high NET availability using multilinear reference tissue model 2 (MRTM2) with the occipital cortex as a reference region. Brain regions were delineated with a defined anatomic template applied to subjects' structural MR scans. We found a negative association between age and NET availability in the locus coeruleus, raphe nucleus, and hypothalamus, with a 17%, 19%, and 14% decrease per decade, respectively, in each region. No gender or BMI relationships with NET availability were observed. Our findings suggest an age-related decline, but no BMI- or gender-related differences, in NET availability in healthy adults.
Assuntos
Morfolinas , Proteínas da Membrana Plasmática de Transporte de Norepinefrina , Masculino , Adulto , Feminino , Humanos , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Reboxetina/metabolismo , Morfolinas/metabolismo , Índice de Massa Corporal , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Tomografia por Emissão de Pósitrons/métodosRESUMO
STUDY OBJECTIVES: Although recent investigations combining noradrenergic and antimuscarinic drugs have shown promising short-term results to treat obstructive sleep apnea (OSA), the mid-term effect and optimal dosage remain uncertain. The present study aimed to evaluate the effect of 1 week of 5 mg oxybutynin and 6 mg reboxetine (oxy-reb) on OSA versus placebo. METHODS: We performed a randomized, placebo-controlled, double-blind, crossover trial comparing the effect of 1 week of oxy-reb versus 1 week of placebo on OSA severity. At-home polysomnography was performed at baseline and after each week of intervention. RESULTS: Fifteen participants (male 66.7%) aged 59 [44-62] years (median [interquartile range]) with a mean body mass index of 33.1 ± 6.6 kg/m2 were included. No significant difference in apnea-hypopnea index (AHI) was observed between conditions (estimated marginal means [95% confidence interval] at baseline: 39.7 [28.5-55.3]; oxy-reb: 34.5 [22.7-52.3]; placebo: 37.9 [27.1-52.9]; p = 0.652), but oxy-reb improved average oxygen desaturation (p = 0.016) and hypoxic burden (p = 0.011) and lowered sleep efficiency (p = 0.019) and rapid eye movement sleep (p = 0.002). Moreover, participants reported reduced sleep quality during the week of oxy-reb compared to the week of placebo (4.7 [3.5; 5.9] vs. 6.5 [5.5; 7.5] on a 0-10 visual analogic scale, respectively; p = 0.001). No significant differences in sleepiness, vigilance, and fatigue were observed. No serious adverse events occurred. CONCLUSIONS: Administration of oxybutynin 5 mg and reboxetine 6 mg did not improve OSA severity assessed by AHI, but did alter sleep architecture and sleep quality. Reduced average oxygen desaturation and hypoxic burden were also observed. CLINICAL TRIAL: ClinicalTrials.gov, https://clinicaltrials.gov, NCT04394143.
Assuntos
Apneia Obstrutiva do Sono , Humanos , Masculino , Reboxetina , Estudos Cross-Over , Apneia Obstrutiva do Sono/tratamento farmacológico , Oxigênio , Método Duplo-CegoRESUMO
The combination of noradrenergic (reboxetine) plus antimuscarinic (oxybutynin) drugs (reb-oxy) reduced obstructive sleep apnea (OSA) severity but no data are available on its effects on cardiac autonomic modulation. We sought to evaluate the impact of 1-week reb-oxy treatment on cardiovascular autonomic control in OSA patients. OSA patients were randomized to a double-blind, crossover trial comparing 4 mg reboxetine plus 5 mg oxybutynin to a placebo for OSA treatment. Heart rate (HR) variability (HRV), ambulatory blood pressure (BP) monitoring (ABPM) over 24 h baseline and after treatment were performed. Baroreflex sensitivity was tested over beat-to-beat BP recordings. 16 subjects with (median [interquartile range]) age 57 [51-61] years and body mass index 30 [26-36]kg/m2 completed the study. The median nocturnal HR was 65 [60-69] bpm at baseline and increased to 69 [64-77] bpm on reb-oxy vs 66 [59-70] bpm on placebo (p = 0.02). The mean 24 h HR from ABPM was not different among treatment groups. Reb-oxy administration was not associated with any modification in HRV or BP. Reb-oxy increased the baroreflex sensitivity and did not induce orthostatic hypotension. In conclusion, administration of reb-oxy did not induce clinically relevant sympathetic overactivity over 1-week and, together with a reduction in OSA severity, it improved the baroreflex function.
Assuntos
Monitorização Ambulatorial da Pressão Arterial , Apneia Obstrutiva do Sono , Humanos , Pessoa de Meia-Idade , Reboxetina/uso terapêutico , Sistema Nervoso Autônomo , Frequência Cardíaca/fisiologiaRESUMO
ABSTRACT: Descending control of nociception (DCN; also known as conditioned pain modulation [CPM], the behavioral correlate of diffuse noxious inhibitory controls) is the phenomenon whereby pain inhibits pain in another part of the body and is the subject of increasing study because it may represent a biomarker of chronic pain. We recently discovered that pain modulation on the application of a DCN paradigm involving low-intensity test stimuli occurs in the direction of hyperalgesia in healthy mice and rats, whereas the use of high-intensity stimuli produces analgesia. To elucidate the physiological mechanisms underlying hyperalgesic DCN, we administered agonists and antagonists of norepinephrine (NE) and serotonin (5-HT) receptors, key neurochemical players in the production of analgesic DCN. We find that 3 different monoamine reuptake inhibitors-the NE-selective reboxetine, the 5-HT-selective fluoxetine, and the dual NE/5-HT agonist duloxetine-all abolish hyperalgesic DCN when administered into the spinal cord (but not systemically), with no effect on heat or mechanical pain sensitivity. The reversal by reboxetine of hyperalgesic DCN is mediated by α 2 -adrenergic receptors (ie, blocked by atipamezole), and the fluoxetine reversal is mediated by 5-HT 7 receptors (ie, blocked by SB269970). By contrast, analgesic DCN was found to be reversed by atipamezole and SB269970 themselves, with no effect of reboxetine or fluoxetine. Thus, hyperalgesic DCN seems to be the neurochemical opposite to analgesic DCN. These data further validate and help elucidate a preclinical paradigm that mimics dysfunctional CPM and thus may form the basis of translational experiments that aim to reveal preventative pharmacological strategies for individuals predisposed to persistent pain.
Assuntos
Dor Crônica , Hiperalgesia , Ratos , Camundongos , Animais , Hiperalgesia/tratamento farmacológico , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Serotonina , Reboxetina , Nociceptividade , Ratos Sprague-Dawley , Analgésicos , Norepinefrina/fisiologiaRESUMO
BACKGROUND: Norepinephrine transporter inhibitors that can alter the level of neurotransmitter in the brain are used to treat neurological disorders. However, a number of studies have reported their limited significance as a result of their slow onset of action and moderate efficacy. OBJECTIVES: To determine the effects of norepinephrine reuptake inhibitors (NRIs), reboxetine and atomoxetine on schizophrenia and attention deficit hyperactivity disorder (ADHD). MATERIAL AND METHODS: Relevant articles published between 2000 and 2022 were searched in the MEDLINE, CINAHL (via Ebsco), Web of Science and Scopus databases. Among the various NRIs, studies concerning the 2 potent drugs - reboxetine and atomoxetine - were selected for analysis. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were estimated, along with the exploration of heterogeneity and publication bias, using RevMan software. RESULTS: A total of 14 eligible studies with a combined sample size of 970 patients were included. Using a random effects model, an OR of 0.55 (0.32-0.94), a Tau2 value of 0.23, a ÷2 value of 12.31, 8 degrees of freedom (df), an I2 of 35%, a Z value of 2.19, and a p-value of 0.03 were recorded for reboxetine. Atomoxetine had an OR of 0.35 (0.13-0.97), a Tau2 value of 0.58, a ÷2 value of 7.31, 4 df, an I2 of 45%, a Z value of 1.53, and a p-value of 0.04. All results were statistically significant with a low risk of publication bias, as was evident from the p-values >0.05 derived from the Egger's test and the Begg's test. These drugs provided comparable changes to control drugs in Hamilton Depression Rating Scale (HAM-D) scores, Positive and Negative Syndrome Scale (PANSS) scores and ADHD ratings. This confirms the efficacy of reboxetine for the treatment of schizophrenia and atomoxetine for the treatment of ADHD. CONCLUSION: The present meta-analysis suggests that NRIs are efficacious and therefore they are potential candidate drugs for the treatment of schizophrenia and ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Esquizofrenia , Humanos , Cloridrato de Atomoxetina/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Reboxetina/uso terapêutico , Esquizofrenia/tratamento farmacológico , Inibidores da Captação Adrenérgica/uso terapêutico , Norepinefrina/uso terapêutico , Resultado do TratamentoRESUMO
STUDY OBJECTIVES: Recent findings indicate that noradrenergic and muscarinic processes are crucial for pharyngeal muscle control during sleep. However, to date, reductions in obstructive sleep apnea (OSA) severity have only been detected when noradrenergic agents are combined with an antimuscarinic. Accordingly, this study aimed to determine if reboxetine alone and combined with oxybutynin reduces OSA severity. The pathophysiological mechanisms underpinning the effects of these agents were also investigated via endotyping analysis. METHODS: Sixteen people (6 women) with OSA completed 3 polysomnograms (â¼1-week washout) according to a double-blind, placebo-controlled, three-way crossover design across 2 sites. Single doses of 4 mg reboxetine, placebo, or 4 mg reboxetine + 5 mg oxybutynin were administered before sleep (order randomized). RESULTS: Reboxetine reduced the apnea-hypopnea index (primary outcome) by 5.4 (95% confidence interval -10.4 to -0.3) events/h, P = .03 (-24 ± 27% in men; -0.7 ± 32% in women). Oxybutynin did not cause additional reductions in apnea-hypopnea index. Reboxetine alone reduced the 4% oxygen desaturation index by (mean ± standard deviation) 5.2 ± 7.2 events/h and reboxetine+oxybutynin by 5.1 ± 10.6 events/h vs placebo, P = .02. Nadir oxygen saturation also increased by 7 ± 11% with reboxetine and 5 ± 9% with reboxetine+oxybutynin vs placebo, P = .01. Mechanistically, reboxetine and reboxetine+oxybutynin improved pharyngeal collapsibility and respiratory control (loop gain). Larger reductions in apnea-hypopnea index with reboxetine in men were associated with higher baseline loop gain. CONCLUSIONS: These findings show the first evidence that reboxetine alone reduces OSA severity. The data provide novel insight into the role of norepinephrine reuptake inhibitors on upper airway stability during sleep and are important to inform future pharmacotherapy development for OSA. CLINICAL TRIAL REGISTRATION: Registry: Australian New Zealand Clinical Trials Registry; Name: Reboxetine and Combination Therapy with AD128 in Sleep Apnoea Trial: A Double-Blind, 3-Way Cross-Over Study; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374614&isReview=true; Identifier: ACTRN12620000662965. CITATION: Altree TJ, Aishah A, Loffler KA, Grunstein RR, Eckert DJ. The norepinephrine reuptake inhibitor reboxetine alone reduces obstructive sleep apnea severity: a double-blind, placebo-controlled, randomized crossover trial. J Clin Sleep Med. 2023;19(1):85-96.
Assuntos
Apneia Obstrutiva do Sono , Masculino , Humanos , Feminino , Estudos Cross-Over , Reboxetina/uso terapêutico , Austrália , Apneia Obstrutiva do Sono/terapia , Método Duplo-CegoRESUMO
The NMDA antagonist ketamine demonstrated a fast antidepressant activity in treatment-resistant depression. Pre-clinical studies suggest that de novo synthesis of the brain-derived neurotrophic factor (BDNF) in the PFC might be involved in the rapid antidepressant action of ketamine. Applying a genetic model of impaired glutamate release, this study aims to further identify the molecular mechanisms that could modulate antidepressant action and resistance to treatment. To that end, mice knocked-down for the vesicular glutamate transporter 1 (VGLUT1+/-) were used. We analyzed anhedonia and helpless behavior as well as the expression of the proteins linked to glutamate transmission in the PFC of mice treated with ketamine or the reference antidepressant reboxetine. Moreover, we analyzed the acute effects of ketamine in VGLUT1+/- mice pretreated with chronic reboxetine or those that received a PFC rescue expression of VGLUT1. Chronic reboxetine rescued the depressive-like phenotype of the VGLUT1+/- mice. In addition, it enhanced the expression of the proteins linked to the AMPA signaling pathway as well as the immature form of BDNF (pro-BDNF). Unlike WT mice, ketamine had no effect on anhedonia or pro-BDNF expression in VGLUT1+/- mice; it also failed to decrease phosphorylated eukaryote elongation factor 2 (p-eEF2). Nevertheless, we found that reboxetine administered as pretreatment or PFC overexpression of VGLUT1 did rescue the antidepressant-like activity of acute ketamine in the mice. Our results strongly suggest that not only do PFC VGLUT1 levels modulate the rapid-antidepressant action of ketamine, but also highlight a possible mechanism for antidepressant resistance in some patients.
Assuntos
Ketamina , Proteína Vesicular 1 de Transporte de Glutamato , Animais , Camundongos , Anedonia , Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/metabolismo , Modelos Animais de Doenças , Ácido Glutâmico/metabolismo , Ketamina/farmacologia , Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Reboxetina/farmacologia , Proteína Vesicular 1 de Transporte de Glutamato/metabolismoRESUMO
A systematic review and random-effects model network meta-analysis were conducted to compare the efficacy, acceptability, tolerability, and safety of antidepressants to treat adults with major depressive disorder (MDD) in the maintenance phase. This study searched the PubMed, Cochrane Library, and Embase databases and included only double-blind, randomized, placebo-controlled trials with an enrichment design: patients were stabilized on the antidepressant of interest during the open-label study and then randomized to receive the same antidepressant or placebo. The outcomes were the 6-month relapse rate (primary outcome, efficacy), all-cause discontinuation (acceptability), discontinuation due to adverse events (tolerability), and the incidence of individual adverse events. The risk ratio with a 95% credible interval was calculated. The meta-analysis comprised 34 studies (n = 9384, mean age = 43.80 years, and %females = 68.10%) on 20 antidepressants (agomelatine, amitriptyline, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, tianeptine, venlafaxine, vilazodone, and vortioxetine) and a placebo. In terms of the 6-month relapse rate, amitriptyline, citalopram, desvenlafaxine, duloxetine, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, tianeptine, venlafaxine, and vortioxetine outperformed placebo. Compared to placebo, desvenlafaxine, paroxetine, sertraline, venlafaxine, and vortioxetine had lower all-cause discontinuation; however, sertraline had a higher discontinuation rate due to adverse events. Compared to placebo, venlafaxine was associated with a lower incidence of dizziness, while desvenlafaxine, sertraline, and vortioxetine were associated with a higher incidence of nausea/vomiting. In conclusion, desvenlafaxine, paroxetine, venlafaxine, and vortioxetine had reasonable efficacy, acceptability, and tolerability in the treatment of adults with stable MDD.
Assuntos
Transtorno Depressivo Maior , Feminino , Humanos , Adulto , Transtorno Depressivo Maior/tratamento farmacológico , Cloridrato de Duloxetina/uso terapêutico , Sertralina/uso terapêutico , Citalopram/uso terapêutico , Cloridrato de Venlafaxina/uso terapêutico , Vortioxetina/uso terapêutico , Fluoxetina/uso terapêutico , Paroxetina/uso terapêutico , Mirtazapina/uso terapêutico , Amitriptilina/uso terapêutico , Succinato de Desvenlafaxina/uso terapêutico , Fluvoxamina/uso terapêutico , Reboxetina/uso terapêutico , Metanálise em Rede , Antidepressivos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Antipsychotic-induced weight gain is an extremely common problem in people with schizophrenia and is associated with increased morbidity and mortality. Adjunctive pharmacological interventions may be necessary to help manage antipsychotic-induced weight gain. This review splits and updates a previous Cochrane Review that focused on both pharmacological and behavioural approaches to this problem. OBJECTIVES: To determine the effectiveness of pharmacological interventions for preventing antipsychotic-induced weight gain in people with schizophrenia. SEARCH METHODS: The Cochrane Schizophrenia Information Specialist searched Cochrane Schizophrenia's Register of Trials on 10 February 2021. There are no language, date, document type, or publication status limitations for inclusion of records in the register. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) that examined any adjunctive pharmacological intervention for preventing weight gain in people with schizophrenia or schizophrenia-like illnesses who use antipsychotic medications. DATA COLLECTION AND ANALYSIS: At least two review authors independently extracted data and assessed the quality of included studies. For continuous outcomes, we combined mean differences (MD) in endpoint and change data in the analysis. For dichotomous outcomes, we calculated risk ratios (RR). We assessed risk of bias for included studies and used GRADE to judge certainty of evidence and create summary of findings tables. The primary outcomes for this review were clinically important change in weight, clinically important change in body mass index (BMI), leaving the study early, compliance with treatment, and frequency of nausea. The included studies rarely reported these outcomes, so, post hoc, we added two new outcomes, average endpoint/change in weight and average endpoint/change in BMI. MAIN RESULTS: Seventeen RCTs, with a total of 1388 participants, met the inclusion criteria for the review. Five studies investigated metformin, three topiramate, three H2 antagonists, three monoamine modulators, and one each investigated monoamine modulators plus betahistine, melatonin and samidorphan. The comparator in all studies was placebo or no treatment (i.e. standard care alone). We synthesised all studies in a quantitative meta-analysis. Most studies inadequately reported their methods of allocation concealment and blinding of participants and personnel. The resulting risk of bias and often small sample sizes limited the overall certainty of the evidence. Only one reboxetine study reported the primary outcome, number of participants with clinically important change in weight. Fewer people in the treatment condition experienced weight gains of more than 5% and more than 7% of their bodyweight than those in the placebo group (> 5% weight gain RR 0.27, 95% confidence interval (CI) 0.11 to 0.65; 1 study, 43 participants; > 7% weight gain RR 0.24, 95% CI 0.07 to 0.83; 1 study, 43 participants; very low-certainty evidence). No studies reported the primary outcomes, 'clinically important change in BMI', or 'compliance with treatment'. However, several studies reported 'average endpoint/change in body weight' or 'average endpoint/change in BMI'. Metformin may be effective in preventing weight gain (MD -4.03 kg, 95% CI -5.78 to -2.28; 4 studies, 131 participants; low-certainty evidence); and BMI increase (MD -1.63 kg/m2, 95% CI -2.96 to -0.29; 5 studies, 227 participants; low-certainty evidence). Other agents that may be slightly effective in preventing weight gain include H2 antagonists such as nizatidine, famotidine and ranitidine (MD -1.32 kg, 95% CI -2.09 to -0.56; 3 studies, 248 participants; low-certainty evidence) and monoamine modulators such as reboxetine and fluoxetine (weight: MD -1.89 kg, 95% CI -3.31 to -0.47; 3 studies, 103 participants; low-certainty evidence; BMI: MD -0.66 kg/m2, 95% CI -1.05 to -0.26; 3 studies, 103 participants; low-certainty evidence). Topiramate did not appear effective in preventing weight gain (MD -4.82 kg, 95% CI -9.99 to 0.35; 3 studies, 168 participants; very low-certainty evidence). For all agents, there was no difference between groups in terms of individuals leaving the study or reports of nausea. However, the results of these outcomes are uncertain given the very low-certainty evidence. AUTHORS' CONCLUSIONS: There is low-certainty evidence to suggest that metformin may be effective in preventing weight gain. Interpretation of this result and those for other agents, is limited by the small number of studies, small sample size, and short study duration. In future, we need studies that are adequately powered and with longer treatment durations to further evaluate the efficacy and safety of interventions for managing weight gain.
Assuntos
Antipsicóticos , Melatonina , Metformina , Esquizofrenia , Antipsicóticos/efeitos adversos , beta-Histina/uso terapêutico , Famotidina/uso terapêutico , Fluoxetina/uso terapêutico , Humanos , Melatonina/uso terapêutico , Metformina/uso terapêutico , Náusea/tratamento farmacológico , Nizatidina/uso terapêutico , Ranitidina/uso terapêutico , Reboxetina/uso terapêutico , Esquizofrenia/tratamento farmacológico , Esquizofrenia/prevenção & controle , Topiramato/uso terapêutico , Aumento de PesoRESUMO
Traumatic brain injury (TBI) is a significant public health concern, with the majority of injuries being mild. Many TBI victims experience chronic pain. Unfortunately, the mechanisms underlying pain after TBI are poorly understood. Here we examined the contribution of spinal monoamine signaling to dysfunctional descending pain modulation after TBI. For these studies we used a well-characterized concussive model of mild TBI. Measurements included mechanical allodynia, the efficacy of diffuse noxious inhibitory control (DNIC) endogenous pain control pathways and lumber norepinephrine and serotonin levels. We observed that DNIC is strongly reduced in both male and female mice after mild TBI for at least 12 weeks. In naïve mice, DNIC was mediated through α2 adrenoceptors, but sensitivity to α2 adrenoceptor agonists was reduced after TBI, and reboxetine failed to restore DNIC in these mice. The intrathecal injection of ondansetron showed that loss of DNIC was not due to excess serotonergic signaling through 5-HT3 receptors. On the other hand, the serotonin-norepinephrine reuptake inhibitor, duloxetine and the serotonin selective reuptake inhibitor escitalopram both effectively restored DNIC after TBI in both male and female mice. Therefore, enhancing serotonergic signaling as opposed to noradrenergic signaling alone may be an effective pain treatment strategy after TBI.
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Concussão Encefálica , Lesões Encefálicas Traumáticas , Dor Crônica , Aminas , Animais , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/tratamento farmacológico , Cloridrato de Duloxetina/farmacologia , Feminino , Masculino , Camundongos , Norepinefrina , Ondansetron , Reboxetina , Receptores Adrenérgicos , Serotonina , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêuticoRESUMO
An efficient, simple, and concise organocatalyzed protecting-group-free synthetic approach to the stereoisomers of the antidepressant drug reboxetine and its implementation toward the asymmetric synthesis of (S,S)-reboxetine and (S,R)-reboxetine from commercially available trans-cinnamaldehyde are described. The synthesis features organocatalytic Jørgensen asymmetric epoxidation, epoxide migration, and Mitsunobu inversion as key steps.
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Antidepressivos , Morfolinas , Reboxetina , EstereoisomerismoRESUMO
AIMS: Urethral closure function is essential for urinary continence in women and decreased urethral pressure is associated with stress urinary incontinence (SUI). For decades, the effects of serotonergic drugs on central neural control of urethral closure have been investigated and discussed. Epidemiological studies suggest that the use of selective serotonin reuptake inhibitors (SSRIs), such as citalopram, is associated with SUI. However, the literature findings are conflicting. This study aimed to evaluate citalopram's effect on opening urethral pressure (OUP) in healthy women. METHODS: We conducted a randomized, double-blind, placebo- and active-controlled crossover study in 24 healthy women. On three study days, which were separated by 8 days of washout, the subjects received single doses of either 40 mg citalopram (and placeboreboxetine ), 8 mg reboxetine (and placebocitalopram ), or two placebos. Study drugs were administered at a 1-h interval due to a difference in estimated time to peak plasma concentration (tmax ). We measured OUP with urethral pressure reflectometry under both resting and squeezing conditions of the pelvic floor at estimated tmax for both study drugs (one timepoint). RESULTS: Compared to placebo, citalopram increased OUP by 6.6 cmH2 0 (95% confidence interval [CI] 0.04-13.1, p = 0.048) in resting condition. In squeezing condition, OUP increased by 7.1 cmH2 0 (95% CI: 1.3-12.9, p = 0.01). Reboxetine increased OUP by 30.0 cmH2 0 in resting condition compared to placebo (95% CI: 23.5-36.5, p < 0.001), and 27.0 cmH2 0 (95% CI: 21.2-32.8, p < 0.001) in squeezing condition. CONCLUSION: Citalopram increased OUP slightly compared to placebo suggesting that SSRI treatment does not induce or aggravate SUI.
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Citalopram , Incontinência Urinária por Estresse , Citalopram/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Reboxetina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Uretra , Incontinência Urinária por Estresse/tratamento farmacológicoRESUMO
Pain perception is decreased by shifting attentional focus away from a threatening event. This attentional analgesia engages parallel descending control pathways from anterior cingulate (ACC) to locus coeruleus, and ACC to periaqueductal grey (PAG) - rostral ventromedial medulla (RVM), indicating possible roles for noradrenergic or opioidergic neuromodulators. To determine which pathway modulates nociceptive activity in humans, we used simultaneous whole brain-spinal cord pharmacological-fMRI (N = 39) across three sessions. Noxious thermal forearm stimulation generated somatotopic-activation of dorsal horn (DH) whose activity correlated with pain report and mirrored attentional pain modulation. Activity in an adjacent cluster reported the interaction between task and noxious stimulus. Effective connectivity analysis revealed that ACC interacts with PAG and RVM to modulate spinal cord activity. Blocking endogenous opioids with Naltrexone impairs attentional analgesia and disrupts RVM-spinal and ACC-PAG connectivity. Noradrenergic augmentation with Reboxetine did not alter attentional analgesia. Cognitive pain modulation involves opioidergic ACC-PAG-RVM descending control which suppresses spinal nociceptive activity.
Assuntos
Tronco Encefálico/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Temperatura Alta , Imageamento por Ressonância Magnética/métodos , Percepção da Dor/efeitos dos fármacos , Medula Espinal/diagnóstico por imagem , Adolescente , Adulto , Analgésicos Opioides/administração & dosagem , Encéfalo/efeitos dos fármacos , Tronco Encefálico/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naltrexona/administração & dosagem , Dor/tratamento farmacológico , Medição da Dor , Reboxetina/administração & dosagem , Medula Espinal/efeitos dos fármacos , Adulto JovemRESUMO
Vocal deficits and anxiety are common, co-occurring, and interacting signs of Parkinson Disease (PD) that have a devastating impact on quality of life. Both manifest early in the disease process. Unlike hallmark motor signs of PD, neither respond adequately to dopamine replacement therapies, suggesting that their disease-specific mechanisms are at least partially extra-dopaminergic. Because noradrenergic dysfunction is also a defining feature of PD, especially early in the disease progression, drug therapies targeting norepinephrine are being trialed for treatment of motor and non-motor impairments in PD. Research assessing the effects of noradrenergic manipulation on anxiety and vocal impairment in PD, however, is sparse. In this pre-clinical study, we quantified the influence of pharmacologic manipulation of norepinephrine on vocal impairment and anxiety in Pink1-/- rats, a translational model of PD that demonstrates both vocal deficits and anxiety. Ultrasonic vocalization acoustics, anxiety behavior, and limb motor activity were tested twice for each rat: after injection of saline and after one of three drugs. We hypothesized that norepinephrine reuptake inhibitors (atomoxetine and reboxetine) and a ß receptor antagonist (propranolol) would decrease vocal impairment and anxiety compared to saline, without affecting spontaneous motor activity. Our results demonstrated that atomoxetine and reboxetine decreased anxiety behavior. Atomoxetine also modulated ultrasonic vocalization acoustics, including an increase in vocal intensity, which is almost always reduced in animal models and patients with PD. Propranolol did not affect anxiety or vocalization. Drug condition did not influence spontaneous motor activity. These studies demonstrate relationships among vocal impairment, anxiety, and noradrenergic systems in the Pink1-/- rat model of PD.
Assuntos
Ansiedade , Norepinefrina/farmacologia , Doença de Parkinson/fisiopatologia , Vocalização Animal/efeitos dos fármacos , Inibidores da Captação Adrenérgica/farmacologia , Animais , Cloridrato de Atomoxetina/farmacologia , Modelos Animais de Doenças , Humanos , Masculino , Proteínas Quinases/genética , Ratos , Ratos Long-Evans , Reboxetina/farmacologiaRESUMO
Reboxetine, the first selective norepinephrine (NA) reuptake inhibitor used in the treatment of depression, mainly acts by binding to the NA transporter and blocking reuptake of extracellular NA. Recently, some other pharmacological targets beyond the NA transporter are being demonstrated for reboxetine. Peroxisome proliferator activated receptor α (PPARα) is a member of the nuclear hormone receptor family of ligand-dependent transcription factors. Previous reports have demonstrated the role of hippocampal PPARα in the pathophysiology of depression. Here we assume that hippocampal PPARα may participate in the antidepressant mechanism of reboxetine. Therefore, the chronic social defeat stress (CSDS) model of depression, various behavioral tests, the western blotting and adenovirus associated virus (AAV)-mediated genetic knockdown methods were used together in the present study. Our results showed that repeated reboxetine treatment markedly restored the decreasing effects of CSDS on the expression of hippocampal PPARα, brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP response element binding protein (pCREB). Pharmacological blockade of PPARα notably prevented the antidepressant-like effects of reboxetine in the CSDS model. Furthermore, genetic knockdown of hippocampal PPARα also fully abolished the antidepressant-like effects of reboxetine in the CSDS model. Taken together, promoting the hippocampal PPARα expression participates in the antidepressant mechanism of reboxetine.