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There is urgent need for novel antidepressant treatments that confer therapeutic benefits via engagement with identified mechanistic targets. The objective of the study was to determine whether activation of the classical anti-inflammatory interleukin-6 signaling pathways is associated with the antidepressant effects of whole-body hyperthermia. A 6-week, randomized, double-blind study compared whole-body hyperthermia with a sham condition in a university-based medical center. Medically healthy participants aged 18-65 years who met criteria for major depressive disorder, were free of psychotropic medication use, and had a baseline 17-item Hamilton Depression Rating Scale score ≥ 16 were randomized with 1-to-1 allocation in blocks of 6 to receive whole-body hyperthermia or sham. Of 338 individuals screened, 34 were randomized, 30 received interventions and 26 had ≥ 2 blood draws and depressive symptom assessments. Secondary data analysis examined change in the ratio of IL-6:soluble IL-6 receptor pre-intervention, post-intervention, and at weeks 1 and 4. Hierarchical linear modeling tested whether increased IL-6:soluble IL-6 receptor ratio post-intervention was associated with decreased depressive symptom at weeks 1, 2, 4 and 6 for those randomized to whole-body hyperthermia. Twenty-six individuals were randomized to whole-body hyperthermia [n = 12; 75 % female; age = 37.9 years (SD = 15.3) or sham [n = 14; 57.1 % female; age = 41.1 years (SD = 12.5). When compared to the sham condition, active whole-body hyperthermia only increased the IL-6:soluble IL-6 receptor ratio post-treatment [F(3,72) = 11.73,p < .001], but not pre-intervention or at weeks 1 and 4. Using hierarchical linear modeling, increased IL-6:sIL-6R ratio following whole-body hyperthermia moderated depressive symptoms at weeks 1, 2, 4 and 6, such that increases in the IL-6:soluble IL-6 receptor ratio were associated with decreased depressive symptoms at weeks 1, 2, 4 and 6 for those receiving the active whole-body hyperthermia compared to sham treatment (B = -229.44, t = -3.82,p < .001). Acute activation of classical intereukin-6 signaling might emerge as a heretofore unrecognized novel mechanism that could be harnessed to expand the antidepressant armamentarium.
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Trastorno Depresivo Mayor , Interleucina-6 , Receptores de Interleucina-6 , Transducción de Señal , Humanos , Femenino , Masculino , Interleucina-6/sangre , Adulto , Método Doble Ciego , Persona de Mediana Edad , Transducción de Señal/efectos de los fármacos , Trastorno Depresivo Mayor/terapia , Receptores de Interleucina-6/metabolismo , Hipertermia Inducida/métodos , Adulto Joven , Adolescente , Resultado del Tratamiento , Anciano , Hipertermia , Antidepresivos/uso terapéutico , Antidepresivos/farmacologíaRESUMEN
Evolution has created complex mechanisms to sense environmental danger and protect tissues, with the nervous and immune systems playing pivotal roles. These systems work together, coordinating local and systemic reflexes to restore homeostasis in response to tissue injury and infection. By sharing receptors and ligands, they influence the pathogenesis of various diseases. Recently, a less-explored aspect of neuroimmune communication has emerged: the release of neuropeptides from immune cells and cytokines/chemokines from sensory neurons. This article reviews evidence of this unique neuroimmune interplay and its impact on the development of allergy, inflammation, itch, and pain. We highlight the effects of this neuroimmune signaling on vital processes such as host defense, tissue repair, and inflammation resolution, providing avenues for exploration of the underlying mechanisms and therapeutic potential of this signaling.
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Citocinas , Células Receptoras Sensoriales , Humanos , Transducción de Señal , Inflamación , Neuroinmunomodulación/fisiologíaRESUMEN
Correlations between altered body temperature and depression have been reported in small samples; greater confidence in these associations would provide a rationale for further examining potential mechanisms of depression related to body temperature regulation. We sought to test the hypotheses that greater depression symptom severity is associated with (1) higher body temperature, (2) smaller differences between body temperature when awake versus asleep, and (3) lower diurnal body temperature amplitude. Data collected included both self-reported body temperature (using standard thermometers), wearable sensor-assessed distal body temperature (using an off-the-shelf wearable sensor that collected minute-level physiological data), and self-reported depressive symptoms from > 20,000 participants over the course of ~ 7 months as part of the TemPredict Study. Higher self-reported and wearable sensor-assessed body temperatures when awake were associated with greater depression symptom severity. Lower diurnal body temperature amplitude, computed using wearable sensor-assessed distal body temperature data, tended to be associated with greater depression symptom severity, though this association did not achieve statistical significance. These findings, drawn from a large sample, replicate and expand upon prior data pointing to body temperature alterations as potentially relevant factors in depression etiology and may hold implications for development of novel approaches to the treatment of major depressive disorder.
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Depresión , Trastorno Depresivo Mayor , Humanos , Depresión/terapia , Trastorno Depresivo Mayor/diagnóstico , Temperatura Corporal , Fiebre , AutoinformeRESUMEN
Objective: To evaluate feasibility, acceptability, and preliminary efficacy of heated yoga to treat moderate-to-severe depression.Design: An 8-week randomized controlled trial (RCT) of heated yoga versus waitlist control was conducted from March 2017 to August 2019.Methods: Participants in the yoga condition were asked to attend heated yoga classes at 2 community heated yoga studios at least twice weekly. We assessed acceptability and feasibility using exit interview and attendance data, respectively. The primary intervention efficacy outcome variable was change in the Inventory of Depressive Symptomatology-Clinician Rated (IDS-CR) score from baseline to post-intervention (week 8).Results: We randomized 80 participants and included 65 (mean [± SD] age 32.7 [± 11.7] years; 81.5% female) in the analyses (yoga n = 33, waitlist n = 32). The mean IDS-CR score at baseline was 35.6 (± 7.9) for the full sample, 36.9 (± 8.8) for yoga participants, and 34.4 (± 6.7) for waitlist participants. Participants attended an average of 10.3 (± 7.1) total classes over the 8-week intervention period. Yoga participants had a significantly greater pre- to post-intervention reduction in IDS-CR scores than waitlist participants (Cohen d = 1.04, P < .001). More yoga participants (59.3%; n = 16) than waitlist participants (6.3%; n = 2) evidenced larger treatment responses (IDS-CR ≥ 50% decrease in symptoms). Participants rated the heated yoga and its aftereffects positively in exit interviews.Conclusions: Approximately 1 heated yoga session per week (mean of 10.3 classes over 8 weeks) was associated with significantly greater reduction in depression symptoms than a waitlist control. Participants rated heated yoga positively. Taken together, results suggest feasibility, acceptability, and preliminary efficacy for patients with depression and warrant further research using active control conditions.Trial Registration: ClinicalTrials.gov identifier: NCT02607514.
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Depresión , Yoga , Adulto , Femenino , Humanos , Masculino , Depresión/terapiaRESUMEN
Alzheimer's disease (AD), the most common form of senile dementia, is poised to place an even greater societal and healthcare burden as the population ages. With few treatment options for the symptomatic relief of the disease and its unknown etiopathology, more research into AD is urgently needed. Psychedelic drugs target AD-related psychological pathology and symptoms such as depression. Using microdosing, psychedelic drugs may prove to help combat this devastating disease by eliciting psychiatric benefits via acting through various mechanisms of action such as serotonin and dopamine pathways. Herein, we review the studied benefits of a few psychedelic compounds that may show promise in treating AD and attenuating its related depressive symptoms. We used the listed keywords to search through PubMed for relevant preclinical, clinical research, and review articles. The putative mechanism of action (MOA) for psychedelics is that they act mainly as serotonin receptor agonists and induce potential beneficial effects for treating AD and related depression.
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Enfermedad de Alzheimer , Alucinógenos , Humanos , Alucinógenos/farmacología , Alucinógenos/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Depresión/tratamiento farmacológico , Serotonina , Dietilamida del Ácido Lisérgico/farmacologíaRESUMEN
Inflammation and mitochondrial-dependent oxidative stress are interrelated processes implicated in multiple neuroinflammatory disorders, including Alzheimer's disease (AD) and depression. Exposure to elevated temperature (hyperthermia) is proposed as a non-pharmacological, anti-inflammatory treatment for these disorders; however, the underlying mechanisms are not fully understood. Here we asked if the inflammasome, a protein complex essential for orchestrating the inflammatory response and linked to mitochondrial stress, might be modulated by elevated temperatures. To test this, in preliminary studies, immortalized bone-marrow-derived murine macrophages (iBMM) were primed with inflammatory stimuli, exposed to a range of temperatures (37-41.5 °C), and examined for markers of inflammasome and mitochondrial activity. We found that exposure to mild heat stress (39 °C for 15 min) rapidly inhibited iBMM inflammasome activity. Furthermore, heat exposure led to decreased ASC speck formation and increased numbers of polarized mitochondria. These results suggest that mild hyperthermia inhibits inflammasome activity in the iBMM, limiting potentially harmful inflammation and mitigating mitochondrial stress. Our findings suggest an additional potential mechanism by which hyperthermia may exert its beneficial effects on inflammatory diseases.
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Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Ratones , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Macrófagos/metabolismo , Inflamación/metabolismo , Respuesta al Choque TérmicoRESUMEN
Solid tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems1-5. Whether the neo-innervation of tumours by pain-initiating sensory neurons affects cancer immunosurveillance remains unclear. Here we show that melanoma cells interact with nociceptor neurons, leading to increases in their neurite outgrowth, responsiveness to noxious ligands and neuropeptide release. Calcitonin gene-related peptide (CGRP)-one such nociceptor-produced neuropeptide-directly increases the exhaustion of cytotoxic CD8+ T cells, which limits their capacity to eliminate melanoma. Genetic ablation of the TRPV1 lineage, local pharmacological silencing of nociceptors and antagonism of the CGRP receptor RAMP1 all reduced the exhaustion of tumour-infiltrating leukocytes and decreased the growth of tumours, nearly tripling the survival rate of mice that were inoculated with B16F10 melanoma cells. Conversely, CD8+ T cell exhaustion was rescued in sensory-neuron-depleted mice that were treated with local recombinant CGRP. As compared with wild-type CD8+ T cells, Ramp1-/- CD8+ T cells were protected against exhaustion when co-transplanted into tumour-bearing Rag1-deficient mice. Single-cell RNA sequencing of biopsies from patients with melanoma revealed that intratumoral RAMP1-expressing CD8+ T cells were more exhausted than their RAMP1-negative counterparts, whereas overexpression of RAMP1 correlated with a poorer clinical prognosis. Overall, our results suggest that reducing the release of CGRP from tumour-innervating nociceptors could be a strategy to improve anti-tumour immunity by eliminating the immunomodulatory effects of CGRP on cytotoxic CD8+ T cells.
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Linfocitos T CD8-positivos , Melanoma , Nociceptores , Animales , Ratones , Péptido Relacionado con Gen de Calcitonina/metabolismo , Péptido Relacionado con Gen de Calcitonina/farmacología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Melanoma/inmunología , Melanoma/patología , Nociceptores/fisiología , Células Receptoras Sensoriales/metabolismo , Neuritas/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Tasa de Supervivencia , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Genes RAG-1/genética , Humanos , Biopsia , PronósticoRESUMEN
Background: Transcranial photobiomodulation (t-PBM) with near-infrared (NIR) light might represent a treatment for major depressive disorder (MDD). However, the dosimetry of administered t-PBM varies widely. We tested the efficacy of t-PBM with low irradiance, low energy per session, and low number of sessions in individuals with MDD.Methods: A 2-site, double-blind, sham-controlled study was conducted of adjunct t-PBM NIR (830 nm; continuous wave; 35.8 cm2 treatment area; 54.8 mW/cm2 irradiance; 65.8 J/cm2 fluence, 20 min/session; ~2 W total power; 2.3 kJ total energy per session), delivered to the prefrontal cortex, bilaterally, twice a week for 6 weeks, in subjects diagnosed with MDD per the DSM-IV criteria. Subjects were recruited between August 2016 and May 2018. A sequential parallel comparison design was used: 18 nonresponders to sham in phase 1 (6 weeks) were re-randomized in phase 2. The primary outcome was reduction in depression severity (Hamilton Depression Rating Scale [HDRS-17] and Quick Inventory of Depressive Symptomatology-Clinician Rating [QIDS-C] scores) from baseline. Statistical analyses used R package SPCDAnalyze2, including all subjects with ≥ 1 post-randomization evaluation.Results: Of the 54 subjects recruited, we included 49 MDD subjects in the analysis (71% female, mean ± SD age 40.8 ± 16.1 years). There were no significant differences between t-PBM and sham with respect to the change in HDRS-17 (t = -0.319, P = .751) or QIDS-C (t = -0.499, P = .620) scores. The sham effect was reasonably low.Conclusions: Mostly uncontrolled studies suggest the efficacy of t-PBM for MDD; however, its optimal dose is still to be defined. A minimal dose threshold is likely necessary, similarly to other neuromodulation techniques in MDD (electroconvulsive therapy, transcranial magnetic stimulation). We established a threshold of inefficacy of t-PBM for MDD, based on combined low irradiance, low energy per session, and low number of sessions.Trial Registration: ClinicalTrials.gov identifier: NCT02959307.
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Trastorno Depresivo Mayor , Adulto , Trastorno Depresivo Mayor/terapia , Método Doble Ciego , Euforia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Corteza Prefrontal , Estimulación Magnética Transcraneal/métodos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Some staging models for treatment-resistant depression (TRD) have been developed in the attempt to predict treatment outcome, in particular with electroconvulsive therapy. However, these models have not been tested in predicting clinical outcome of ketamine treatment. We assessed the relationship between patients' classification with different TRD staging models and subsequent nonresponse to acute intravenous ketamine treatment. METHODS: A sample of 120 patients with TRD who received acute ketamine treatment from October 2018 to November 2020 were included. Intravenous ketamine was administered twice weekly for 3 weeks as acute treatment. Generalized linear models were fitted to examine if staging classification at baseline could predict percent change in the 16-item Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16) scale. Potential confounders such as age, sex, and primary diagnosis were included in the models. Other generalized linear models were also fitted with the Bonferroni correction to investigate if other clinical variables of potential relevance could predict percent change in the QIDS-SR16. RESULTS: No TRD staging model proved accurate in predicting depressive improvement after acute ketamine treatment. Clinical variables such as age (F = 6.68, P = 0.01) and history of neuromodulation therapy (F = 5.12, P = 0.03) were negatively associated with subsequent percent improvement in the QIDS-SR16 with acute ketamine treatment. CONCLUSIONS: The efficacy of acute intravenous ketamine treatment was similar in subjects with higher and lower level of treatment resistance, using definitions based on different TRD staging models. Further exploration of ketamine treatment predictors such as age and neuromodulation therapy is warranted.
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Trastorno Depresivo Mayor , Trastorno Depresivo Resistente al Tratamiento , Ketamina , Depresión , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Humanos , Infusiones Intravenosas , Ketamina/uso terapéutico , Resultado del TratamientoRESUMEN
Nociceptors, the high-threshold primary sensory neurons that trigger pain, interact with immune cells in the periphery to modulate innate immune responses. Whether they also participate in adaptive and humoral immunity is, however, not known. In this study, we probed if nociceptors have a role in distinct airway and skin models of allergic inflammation. In both models, the genetic ablation and pharmacological silencing of nociceptors substantially reduced inflammatory cell infiltration to the affected tissue. Moreover, we also found a profound and specific deficit in IgE production in these models of allergic inflammation. Mechanistically, we discovered that the nociceptor-released neuropeptide substance P helped trigger the formation of antibody-secreting cells and their release of IgE. Our findings suggest that nociceptors, in addition to their contributions to innate immunity, play a key role in modulating the adaptive immune response, particularly B cell antibody class switching to IgE.
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Linfocitos B/metabolismo , Cambio de Clase de Inmunoglobulina/genética , Inmunoglobulina E/metabolismo , Nociceptores/metabolismo , HumanosRESUMEN
Prostate cancer is the second leading cause of cancer death in men in the developed world. A more sensitive and specific detection strategy for lethal prostate cancer beyond serum prostate specific antigen (PSA) population screening is urgently needed. Diagnosis by canine olfaction, using dogs trained to detect cancer by smell, has been shown to be both specific and sensitive. While dogs themselves are impractical as scalable diagnostic sensors, machine olfaction for cancer detection is testable. However, studies bridging the divide between clinical diagnostic techniques, artificial intelligence, and molecular analysis remains difficult due to the significant divide between these disciplines. We tested the clinical feasibility of a cross-disciplinary, integrative approach to early prostate cancer biosensing in urine using trained canine olfaction, volatile organic compound (VOC) analysis by gas chromatography-mass spectroscopy (GC-MS) artificial neural network (ANN)-assisted examination, and microbial profiling in a double-blinded pilot study. Two dogs were trained to detect Gleason 9 prostate cancer in urine collected from biopsy-confirmed patients. Biopsy-negative controls were used to assess canine specificity as prostate cancer biodetectors. Urine samples were simultaneously analyzed for their VOC content in headspace via GC-MS and urinary microbiota content via 16S rDNA Illumina sequencing. In addition, the dogs' diagnoses were used to train an ANN to detect significant peaks in the GC-MS data. The canine olfaction system was 71% sensitive and between 70-76% specific at detecting Gleason 9 prostate cancer. We have also confirmed VOC differences by GC-MS and microbiota differences by 16S rDNA sequencing between cancer positive and biopsy-negative controls. Furthermore, the trained ANN identified regions of interest in the GC-MS data, informed by the canine diagnoses. Methodology and feasibility are established to inform larger-scale studies using canine olfaction, urinary VOCs, and urinary microbiota profiling to develop machine olfaction diagnostic tools. Scalable multi-disciplinary tools may then be compared to PSA screening for earlier, non-invasive, more specific and sensitive detection of clinically aggressive prostate cancers in urine samples.
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Biomarcadores de Tumor/orina , Neoplasias de la Próstata/diagnóstico , Olfato , Sistema Urinario/microbiología , Compuestos Orgánicos Volátiles/orina , Animales , Perros , Estudios de Factibilidad , Masculino , Proyectos PilotoRESUMEN
BACKGROUND: Lung nociceptor neurons amplify immune cell activity and mucus metaplasia in response to an inhaled allergen challenge in sensitized mice. OBJECTIVE: We sought to identify the cellular mechanisms by which these sensory neurons are activated subsequent to allergen exposure. METHODS: We used calcium microscopy and electrophysiologic recording to assess whether vagal neurons directly respond to the model allergen ovalbumin (OVA). Next, we generated the first nociceptor-specific FcεR1γ knockdown (TRPV1Cre::FcεR1γfl/fl) mice to assess whether this targeted invalidation would affect the severity of allergic inflammation in response to allergen challenges. RESULTS: Lung-innervating jugular nodose complex ganglion neurons express the high-affinity IgE receptor FcεR1, the levels of which increase in OVA-sensitized mice. FcεR1γ-expressing vagal nociceptor neurons respond directly to OVA complexed with IgE with depolarization, action potential firing, calcium influx, and neuropeptide release. Activation of vagal neurons by IgE-allergen immune complexes, through the release of substance P from their peripheral terminals, directly amplifies TH2 cell influx and polarization in the airways. Allergic airway inflammation is decreased in TRPV1Cre::FcεR1γfl/fl mice and in FcεR1α-/- mice into which bone marrow has been transplanted. Finally, increased in vivo circulating levels of IgE following allergen sensitization enhances the responsiveness of FcεR1 to immune complexes in both mouse jugular nodose complex ganglion neurons and human induced pluripotent stem cell-derived nociceptors. CONCLUSIONS: Allergen sensitization triggers a feedforward inflammatory loop between IgE-producing plasma cells, FcεR1-expressing vagal sensory neurons, and TH2 cells, which helps to both initiate and amplify allergic airway inflammation. These data highlight a novel target for reducing allergy, namely, FcεR1γ expressed by nociceptors.
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Expresión Génica , Hipersensibilidad/inmunología , Hipersensibilidad/metabolismo , Receptores de IgE/genética , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Alérgenos/inmunología , Animales , Calcio/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades/inmunología , Predisposición Genética a la Enfermedad , Hipersensibilidad/genética , Hipersensibilidad/patología , Ratones , Ratones Noqueados , Neuronas/inmunología , Neuronas/metabolismo , Nociceptores/metabolismo , Ovalbúmina/efectos adversos , Ovalbúmina/inmunología , Receptores de IgE/metabolismo , Mucosa Respiratoria/patología , Sustancia P/metabolismo , Nervio VagoRESUMEN
Health disparity related to race/ethnicity has been cited as "the most serious and shameful health care issue of our time"(Peterson et al., 2018). A portion of the now recognized disproportionate impact of the COVID-19 pandemic among Black, Indigenous and People of Color (BIPOC) communities is attributable to social determinants such as socioeconomic status (SES), physical living situation, health care access, and the psychosocial factors associated with socioenvironmental circumstances such as bias, victimization, trauma and toxic stress as well as structural factors that reduce the capacity to practice physical distancing (Agurs-Collins et al., 2019). In this paper, we hypothesize that, prior to the COVID-19 pandemic, disproportionate socio-economic and environmental stressors in the BIPOC population promoted heightened stress-associated neurobiological activity (Stress-NbA). This chronic elevation in Stress-NbA results in down-stream complications of chronic stress including underactivation of anti-viral type I IFN pathway genes. This results in an increase in susceptibility to viral diseases, including coronavirus illnesses. Additionally, Stress-NbA chronically potentiates systemic inflammation (from hematopoietic system activation with myelopoiesis) increasing the prevalence of metabolic syndrome (MetS) and setting the stage for stress-related chronic non-communicable diseases (NCDs). This process was propelled by overactivation of immune cell gene expression in the nuclear factor κ-light-chain-enhancer of activated B cells (NF-kB) activation pathway and underactivation of gene expression in the anti-viral type I interferon (IFN) pathway. The higher prevalence of MetS and NCDs in minority populations turned out to be predictive of the elevated risk they would face in the presence of a highly contagious viral pandemic. The stress-related generation of a chronic non-pathogen associated molecular pattern (non-PAMP) immunoactivation state led to decreased viral immune defense and increased susceptibility to SARS-CoV-2 infection with increased risk of severe illness induced by cytokine storm syndrome (CSS).
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BACKGROUND: Little is known about the long-term outcomes of repeated ketamine infusions for depression. We conducted a retrospective chart review to investigate outcomes of maintenance intravenous ketamine treatment at Massachusetts General Hospital. METHODS: Eighty-five patients with treatment-resistant depression (TRD) who started intravenous ketamine from October 2018 to November 2019 were examined. Symptom severity was evaluated with the 16-item Quick Inventory of Depressive Symptomatology-Self Report scale (QIDS-SR16) at every visit prior to administration. The initial ketamine dose was usually 0.5 mg/kg infused over 40 min. Intravenous ketamine was administered twice-weekly for three weeks in an induction phase, followed by maintenance with a variable administration schedule and dose. Response was defined as a ≥50% reduction in total QIDS-SR16 score from baseline. RESULTS: Forty (47.1%) of the 85 patients who started treatment discontinued during or right after the induction phase; 3 (3.5%) were still on induction at the time of this report, and 42 (49.4%) transitioned to maintenance after completing induction. Among these patients, 14 (16.5%) discontinued during maintenance and 28 (32.9%) continued on maintenance. The mean ketamine dosage during maintenance was 0.91±0.28 mg/kg. Fifteen out of 82 patients (18.3%) responded to induction treatment and 6 (7.3%) remained in responder status at the time of data analysis during maintenance. Three patients discontinued ketamine due to side-effects. CONCLUSIONS: Despite the apparently low response rate in QIDS-SR16 scores and considerable out-of-pocket costs, almost half of real-world outpatients with TRD decided to continue with maintenance ketamine treatment due to perceived significant improvement.
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Trastorno Depresivo Resistente al Tratamiento , Ketamina , Depresión , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Humanos , Infusiones Intravenosas , Ketamina/uso terapéutico , Mantenimiento , Massachusetts , Pacientes Ambulatorios , Estudios Retrospectivos , Resultado del TratamientoAsunto(s)
Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Ketamina/uso terapéutico , Ideación Suicida , Intento de Suicidio , Administración Intranasal , Adulto , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Femenino , Humanos , Ketamina/administración & dosificación , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: While riluzole has been investigated for the treatment of depression, little is known about its longer-term efficacy and optimal treatment duration in treatment-resistant depression (TRD). The objective of this study is to characterize the longer-term outcome of adjunctive riluzole therapy for TRD in an open-label extension of an 8-week acute treatment trial. METHODS: The data from 66 patients with TRD who received adjunctive riluzole in a 12-week open-label extension phase were analyzed. Response rates (⩾50% reduction in the Mongomery-Asberg Depression Rating Scale [MADRS] score), relapse rates (a MADRS score of ⩾22 in patients who had previously achieved response), and adverse events were examined in patients who had achieved response at the end of the acute phase and those who had not. RESULTS: Among acute phase responders, the maintained response rate was 66.7% (8/12) and the relapse rate was 8.3% (1/12). In acute phase non-responders, the response rate was 24.1% (13/54). The most commonly reported adverse event was fatigue (9.1%). Three cases were considered serious adverse events; vomiting (nâ¯=â¯1), shortness of breath (nâ¯=â¯1), and aborted suicide attempt (nâ¯=â¯1). LIMITATIONS: This longer-term study was open-label and uncontrolled. The sample size was relatively small. CONCLUSIONS: Longer-term adjunctive riluzole appears relatively well tolerated and beneficial for maintaining previous response. Additionally, approximately one fourth of patients who did not respond to 8-week antidepressant treatment might respond if treated with riluzole for 12 weeks. Those findings warrant further investigation because adjunctive riluzole could represent an option for treatment of depression when standard antidepressants have failed.
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Antidepresivos/administración & dosificación , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Riluzol/administración & dosificación , Factores de Tiempo , Adulto , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Major depressive disorder topped ischemic heart disease as the number one cause of disability worldwide in 2012, and women have twice the risk of men. Further, the comorbidity of depression and cardiometabolic disorders will be one of the primary causes of disability worldwide by 2020, with women at twice the risk. Thus, understanding the sex-dependent comorbidities has public health consequences worldwide. We propose here that sex differences in MDD-cardiometabolic comorbidity originate, in part, from pathogenic processes initiated in fetal development that involve sex differences in shared pathophysiology between the brain, the vascular system, the CNS control of the heart and associated hormonal, immune, and metabolic physiology. Pathways implicate neurotrophic and angiogenic growth factors, gonadal hormone receptors, and neurotransmitters such as gamma amino butyric acid (GABA) on neuronal and vascular development of HPA axis regions, such as the paraventricular nucleus (PVN), in addition to blood pressure, in part through the renin-angiotensin system, and insulin and glucose metabolism. We show that the same prenatal exposures have consequences for sex differences across multiple organ systems that, in part, share common pathophysiology. Thus, we believe that applying a sex differences lens to understanding shared biologic substrates underlying these comorbidities will provide novel insights into the development of sex-dependent therapeutics. Further, taking a lifespan perspective beginning in fetal development provides the opportunity to target abnormalities early in the natural history of these disorders in a sex-dependent way.
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Enfermedades Cardiovasculares/epidemiología , Trastorno Depresivo Mayor/epidemiología , Enfermedades Metabólicas/epidemiología , Caracteres Sexuales , Estrés Psicológico/fisiopatología , Encéfalo/fisiopatología , Enfermedades Cardiovasculares/fisiopatología , Comorbilidad , Trastorno Depresivo Mayor/fisiopatología , Femenino , Humanos , Sistema Hipotálamo-Hipofisario/fisiopatología , Masculino , Enfermedades Metabólicas/fisiopatología , Sistema Hipófiso-Suprarrenal/fisiopatología , Embarazo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , PrevalenciaRESUMEN
OBJECTIVES: Transcranial photobiomodulation (t-PBM) consists of the delivery of near-infrared (NIR) or red light to the scalp designed to penetrate to subjacent cortical areas of the brain. NIR t-PBM has recently emerged as a potential therapy for brain disorders. This study assessed the efficacy of repeated sessions of NIR t-PBM on sexual dysfunction. METHODS: We performed a secondary analysis of a double-blind clinical trial on t-PBM for major depressive disorder (MDD). Twenty individuals received NIR t-PBM (n = 9) or sham therapy (n = 11) twice a week for 8 weeks. Sexual desire, arousal, and orgasm were assessed using the Systematic Assessment for Treatment-Emergent Effects-Specific Inquiry (SAFTEE-SI). RESULTS: The mean improvement in sexual function (decrease in SAFTEE sex total score) in subjects receiving t-PBM in NIR-mode was significantly greater than in subjects receiving sham-mode in the whole sample (NIR [n = 9] -2.55 ± 1.88 vs. sham [n = 11] -0.45 ± 1.21; z = 2.548, P = 0.011]) and in the completers (NIR [n = 5] -3.4 ± 1.95 vs. sham [n = 7] -0.14 ± 1.21; z = 2.576, P = 0.010]). CONCLUSION: This exploratory study with a small sample size indicates that repeated sessions of NIR t-PBM may be associated with therapeutic effects on sexual dysfunction. The latter appeared unrelated to the antidepressant effect of t-PBM in our cohort. Lasers Surg. Med. 51:127-135, 2019. © 2018 Wiley Periodicals, Inc.