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1.
J Zoo Wildl Med ; 50(4): 1005-1007, 2020 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-31926537

RESUMEN

At times severe, and occasionally fatal, aggression plays an intrinsic role in chimpanzee behavior and social dynamics, particularly among male chimpanzees in both managed and free-ranging troops. At the Los Angeles Zoo, one adult male's natural aggressive behavior developed into unmanageable violence during a period of social and emotional instability consequent to the lack of an established alpha male in the colony. The severity and duration of resulting attacks on a subdominant member of the community, despite environmental and behavioral modification, indicated the need for psychopharmaceutical intervention. Prior treatment of this animal with haloperidol and gabapentin had produced undesirable side effects. Administration of citalopram hydrobromide, a selective serotonin reuptake inhibitor, successfully reduced both the intensity and duration of this male chimpanzee's attacks upon a conspecific animal with minimal observable side effects or adverse behavioral changes.


Asunto(s)
Agresión/efectos de los fármacos , Citalopram/farmacología , Pan troglodytes , Inhibidores de la Captación de Serotonina/farmacología , Animales , Masculino
2.
Life Sci ; 245: 117307, 2020 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-31954746

RESUMEN

AIM: To investigate whether a chronic 5-HT reuptake inhibitor (i.e. Fluoxetine-FLX) exposure in young adult rats overfed during suckling period would modulate interscapular brown adipose tissue (iBAT) mitochondria and browning agents in white adipose tissue (WAT). METHODS: Male Wistar rats were assigned into either a normofed group (n = 9 per group) or an overfed group (n = 3 per group) induced by litter size reduction at postnatal day 3 (PND3). Pharmacological manipulation was carried out between PND39 and PND59 and groups were assigned accordingly: Normofed + vehicle solution - NaCl 0.9% (NV group), normofed + FLX solution - 10 mg/kg b.w. (NF group), overfed + vehicle (OV group) and overfed + FLX (OF group). We evaluated mitochondrial oxygen consumption and reactive species (RS) production, oxidative stress analyses (MDA concentration, carbonyl content, REDOX state [GSH/GSSG], global oxy score) in the iBAT, gene (leptin, Ucp1, Sirt1, Pgc1α and Prdm16) and protein (UCP1) expression in the iBAT and epididymal WAT (eWAT). KEY FINDINGS: OV group increased body weight gain, Lee index and oxidative stress in the iBAT. Both FLX-treated groups showed less weight gain compared to their controls. OF group showed different leptin expression in the WAT and iBAT; increased functional UCP1 content and mitochondrial activity with less oxidative stress in the iBAT and upregulation of browning genes in eWAT (Pgc1α, Prdm16 and Ucp1). CONCLUSION: Altogether our findings indicated that FLX treatment in young adult overfed animals improved the iBAT mitochondrial function, reduced oxidative stress and induced transcriptional activation of browning agents in white adipose tissue.


Asunto(s)
Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Blanco/efectos de los fármacos , Fluoxetina/farmacología , Mitocondrias/efectos de los fármacos , Hipernutrición/metabolismo , Inhibidores de la Captación de Serotonina/farmacología , Animales , Peso Corporal/efectos de los fármacos , Masculino , Consumo de Oxígeno/efectos de los fármacos , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteína Desacopladora 1/metabolismo
3.
Chemosphere ; 238: 124587, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31425864

RESUMEN

Pharmaceuticals are emerging as environmentally problematic compounds. As they are often not appropriately removed by sewage treatment plants, pharmaceutical compounds end up in surface water environments worldwide at concentrations in the ng to µg L-1 range. There is a need to further explore single compound and mixture effects using e.g. in vivo test model systems. We have investigated, for the first time, behavioral effects in larval zebrafish (Danio rerio) exposed to a binary mixture of an antidepressant drug (citalopram) and a synthetic opioid (tramadol). Citalopram and tramadol have a similar mode of action (serotonin reuptake inhibition) and are known to produce drug-drug interactional effects resulting in serotonin syndrome (SS) in humans. Zebrafish embryo-larvae were exposed to citalopram, tramadol and 1:1 binary mixture from fertilization until 144 h post-fertilization. No effects on heart rate, spontaneous tail coiling, or death/malformations were observed in any treatment at tested concentrations. Behavior (hypoactivity in dark periods) was on the other hand affected, with lowest observed effect concentrations (LOECs) of 373 µg L-1 for citalopram, 320 µg L-1 for tramadol, and 473 µg L-1 for the 1:1 mixture. Behavioral EC50 was calculated to be 471 µg L-1 for citalopram, 411 µg L-1 for tramadol, and 713 µg L-1 for the 1:1 mixture. The results of this study conclude that tramadol and citalopram produce hypoactivity in 144 hpf zebrafish larvae. Further, a 1:1 binary mixture of the two caused the same response, albeit at a higher concentration, possibly due to SS.


Asunto(s)
Analgésicos Opioides/farmacología , Citalopram/farmacología , Inhibidores de la Captación de Serotonina/farmacología , Tramadol/farmacología , Contaminantes Químicos del Agua/farmacología , Pez Cebra/embriología , Animales , Embrión no Mamífero/efectos de los fármacos , Larva/efectos de los fármacos
4.
Pharm Res ; 37(1): 7, 2019 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-31845095

RESUMEN

PURPOSE: Antidepressants like the serotonin reuptake inhibitors (SRIs) are often used concomitantly with tamoxifen (e.g. for treatment of depression). This may lead to an additional prolongation of the QTc-interval, with an increased risk of cardiac side effects. Therefore we investigated whether there is a drug-drug interaction between tamoxifen and SRIs resulting in a prolonged QTc-interval. METHODS: Electrocardiograms (ECGs) of 100 patients were collected at steady state tamoxifen treatment, with or without concomitant SRI co-medication. QTc-interval was manually measured and calculated using the Fridericia formula. Primary outcome was difference in QTc-interval between tamoxifen monotherapy and tamoxifen concomitantly with an SRI. RESULTS: The mean QTc-interval was 12.4 ms longer when tamoxifen was given concomitantly with an SRI (95% CI:1.8-23.1 ms; P = 0.023). Prolongation of the QTc-interval was particularly pronounced for paroxetine (17.2 ms; 95%CI:1.4-33.0 ms; P = 0.04), escitalopram (12.5 ms; 95%CI:4.4-20.6 ms; P < 0.01) and citalopram (20.7 ms; 95%CI:0.7-40.7 ms; P = 0.047), where other agents like venlafaxine did not seem to prolong the QTc-interval. None of the patients had a QTc-interval of >500 ms. CONCLUSIONS: Concomitant use of tamoxifen and SRIs resulted in a significantly higher mean QTc-interval, which was especially the case for paroxetine, escitalopram and citalopram. When concomitant administration with an SRI is warranted venlafaxine is preferred.


Asunto(s)
Antidepresivos de Segunda Generación/farmacología , Antineoplásicos Hormonales/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/fisiopatología , Inhibidores de la Captación de Serotonina/efectos adversos , Tamoxifeno/efectos adversos , Anciano , Antidepresivos de Segunda Generación/efectos adversos , Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/complicaciones , Citalopram/farmacología , Femenino , Humanos , Síndrome de QT Prolongado/inducido químicamente , Persona de Mediana Edad , Inhibidores de la Captación de Serotonina/farmacología , Tamoxifeno/farmacología
5.
Anticancer Res ; 39(11): 6155-6163, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31704843

RESUMEN

BACKGROUND/AIM: Fluoxetine, an antidepressant, has cytotoxic effects on several cancer cell lines, while paclitaxel is an antineoplastic agent for various cancers. The aim of this study was to evaluate whether fluoxetine enhances the cytotoxic effect of paclitaxel in gastric adenocarcinoma cells and determine the mechanism of cell death. MATERIALS AND METHODS: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to examine cell viability and perform cell cycle analysis. Annexin V propidium iodide (PI) staining, 4',6-diamidino-2-phenylindole (DAPI) staining, caspase-3/7 assay, and western blot analysis were performed for determining cell death. RESULTS: Fluoxetine enhanced the anti-proliferative effect of paclitaxel. Fluoxetine-paclitaxel combination caused G2/M arrest and increased events in the sub G0/G1 phase in a time and dose-dependent manner, indicating apoptotic cell death. Combination treatment caused an increase in early apoptotic and late apoptotic cell death compared to single treatment alone. CONCLUSION: Fluoxetine enhanced the antiproliferation effect of paclitaxel in gastric adenocarcinoma AGS cells and the combination caused cell death by triggering apoptosis and necroptosis.


Asunto(s)
Apoptosis/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , Fluoxetina/farmacología , Necrosis , Paclitaxel/farmacología , Neoplasias Gástricas/patología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Antineoplásicos Fitogénicos/farmacología , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Inhibidores de la Captación de Serotonina/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Células Tumorales Cultivadas
6.
Eur J Med Chem ; 183: 111736, 2019 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-31586817

RESUMEN

A series of novel 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives were synthesised and evaluated for their 5-HT1A/D2/5-HT2A/5-HT6/5-HT7 receptor affinity and serotonin reuptake inhibition. Most of the evaluated compounds displayed high affinities for 5-HT1A receptors (e.g., 4cKi = 2.3 nM, 4lKi = 3.2 nM). The antidepressant activity of the selected compounds was screened in vivo using the forced swim test (FST). The results indicate that compound MW005 (agonist of the pre- and postsynaptic 5-HT1A receptor) exhibited promising affinities for the 5-HT1A/SERT/D2/5-HT6/5-HT7 receptors and showed an antidepressant-like activity in the FST model.


Asunto(s)
Antidepresivos , Indoles , Pirrolidinonas , Animales , Antidepresivos/síntesis química , Antidepresivos/farmacología , Células CHO , Cricetulus , Células HEK293 , Humanos , Indoles/síntesis química , Indoles/farmacología , Masculino , Ratones , Pirrolidinonas/síntesis química , Pirrolidinonas/farmacología , Receptores de Serotonina/metabolismo , Inhibidores de la Captación de Serotonina/síntesis química , Inhibidores de la Captación de Serotonina/metabolismo , Inhibidores de la Captación de Serotonina/farmacología
7.
BMC Neurol ; 19(1): 237, 2019 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-31615444

RESUMEN

BACKGROUND: The anterior cingulate cortex (ACC) is a key structure of the pain processing network. Several structural and functional alterations of this brain area have been found in migraine. In addition, altered serotonergic neurotransmission has been repeatedly implicated in the pathophysiology of migraine, although the exact mechanism is not known. Thus, our aim was to investigate the relationship between acute increase of brain serotonin (5-HT) level and the activation changes of the ACC using pharmacological challenge MRI (phMRI) in migraine patients and healthy controls. METHODS: Twenty-seven pain-free healthy controls and six migraine without aura patients participated in the study. All participant attended to two phMRI sessions during which intravenous citalopram, a selective serotonin reuptake inhibitor (SSRI), or placebo (normal saline) was administered. We used region of interest analysis of ACC to compere the citalopram evoked activation changes of this area between patients and healthy participants. RESULTS: Significant difference in ACC activation was found between control and patient groups in the right pregenual ACC (pgACC) during and after citalopram infusion compared to placebo. The extracted time-series showed that pgACC activation increased in migraine patients compared to controls, especially in the first 8-10 min of citalopram infusion. CONCLUSIONS: Our results demonstrate that a small increase in 5-HT levels can lead to increased phMRI signal in the pregenual part of the ACC that is involved in processing emotional aspects of pain. This increased sensitivity of the pgACC to increased 5-HT in migraine may contribute to recurring headache attacks and increased stress-sensitivity in migraine.


Asunto(s)
Giro del Cíngulo/metabolismo , Giro del Cíngulo/fisiopatología , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/fisiopatología , Serotonina/metabolismo , Adulto , Mapeo Encefálico/métodos , Citalopram/farmacología , Método Doble Ciego , Femenino , Giro del Cíngulo/efectos de los fármacos , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Inhibidores de la Captación de Serotonina/farmacología
8.
J Steroid Biochem Mol Biol ; 195: 105470, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31509772

RESUMEN

Serotonin reuptake inhibitors (SRIs) are currently the main molecules prescribed to pregnant women that suffer from depression. Placental cells are exposed to SRIs via maternal blood, and we have previously shown that SRIs alter feto-placental steroidogenesis in an in vitro co-culture model. More specifically, serotonin (5-HT) regulates the estrogen biosynthetic enzyme aromatase (cytochrome P450 19; CYP19), which is disrupted by fluoxetine and its active metabolite norfluoxetine in BeWo choriocarcinoma cells. Based on molecular simulations, the present study illustrates that the SRIs fluoxetine, norfluoxetine, paroxetine, sertraline, citalopram and venlafaxine exhibit binding affinity for the active-site pocket of CYP19, suggesting potential competitive inhibition. Using BeWo cells and primary villous trophoblast cells isolated from normal term placentas, we compared the effects of the SRIs on CYP19 activity. We observed that paroxetine and sertraline induce aromatase activity in BeWo cells, while venlafaxine, fluoxetine, paroxetine and sertraline decrease aromatase activity in primary villous trophoblast. The effects of paroxetine and sertraline in primary villous trophoblasts were observed at the lower doses tested. We also showed that 5-HT and the 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) induced CYP19 activity. An increase in phosphorylation of serine and tyrosine and a decrease in threonine phosphorylation of CYP19 was also associated with DOI treatment. Our results contribute to better understanding how 5-HT and SRIs interact with CYP19 and may affect estrogen production. Moreover, this study suggests that alteration of placental 5-HT levels due to depression and/or SRI treatment during pregnancy may be associated with disruption of placental estrogen production.


Asunto(s)
Aromatasa/metabolismo , Placenta/efectos de los fármacos , Inhibidores de la Captación de Serotonina/farmacología , Serotonina/farmacología , Células Cultivadas , Citalopram/farmacología , Femenino , Fluoxetina/análogos & derivados , Fluoxetina/farmacología , Humanos , Simulación del Acoplamiento Molecular , Paroxetina/farmacología , Placenta/metabolismo , Embarazo , Sertralina/farmacología , Trofoblastos/efectos de los fármacos , Trofoblastos/metabolismo , Clorhidrato de Venlafaxina/farmacología
9.
Zebrafish ; 16(5): 443-450, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31436486

RESUMEN

The two-factor theory predicts that the acquisition of avoidance responses is dependent on fear reduction; as such, drugs that reduce or increase fear or anxiety states should alter inhibitory avoidance (IA) acquisition. The present experiment used white spaces as aversive unconditioned stimuli in IA in zebrafish. Adult zebrafishes were tested in three experiments: validation of white compartment as aversive in IA; open field test; and effect of antidepressant (fluoxetine, imipramine) and anxiolytic (diazepam, clonazepam). The data show the effectiveness of the white compartment as an aversive stimulus in IA. Antidepressant fluoxetine did not alter and imipramine impairs avoidance acquisition in higher doses. Imipramine also produced a sedative effect in lower doses. Anxiolytic and stimulant drugs facilitated learning at doses which did not impair locomotion, suggesting that pharmacological manipulation of other factors in addition to fear/anxiety can impact aversive learning in zebrafish.


Asunto(s)
Antidepresivos Tricíclicos/farmacología , Reacción de Prevención/efectos de los fármacos , Fluoxetina/farmacología , Imipramina/farmacología , Inhibidores de la Captación de Serotonina/farmacología , Animales , Antidepresivos Tricíclicos/administración & dosificación , Femenino , Fluoxetina/administración & dosificación , Imipramina/administración & dosificación , Masculino , Aprendizaje por Laberinto , Inhibidores de la Captación de Serotonina/administración & dosificación , Pez Cebra/fisiología
10.
Artículo en Inglés | MEDLINE | ID: mdl-31422163

RESUMEN

Paraoxonase-I (PON1) is a calcium-dependent hydrolytic enzyme, plays an important role in most antioxidant properties related to high-density lipoprotein (HDL). Antidepressant drugs are commonly employed in treatment of mood disorders and anxiety treatment. In this study, human serum PON1 was purified using simple reproducible procedures and the effects of some antidepressant drugs on its activity were determined. It was found that mirtazapine, aripiprazole, escitalopram, and risperidone exhibited potential inhibitory properties on the purified PON1 activity with IC50 values in the range of 115.50-231.00 µM and Ki values in the range of 41.66 ±â€¯4.27 µM-276.36 ±â€¯35.28 µM. Both risperidone and escitalopram inhibited PON1 activity competitively, while both aripiprazole and mirtazapine inhibited PON1 activity non-competitively. Chlorpromazine did not affect PON1 activity. Usage of drugs with significant biological activity may be hazardous in some cases.


Asunto(s)
Antidepresivos/farmacología , Arildialquilfosfatasa , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos/farmacología , Inhibidores de la Captación de Serotonina/farmacología , Arildialquilfosfatasa/química , Arildialquilfosfatasa/aislamiento & purificación , Humanos , Cinética
11.
Transl Psychiatry ; 9(1): 173, 2019 07 04.
Artículo en Inglés | MEDLINE | ID: mdl-31273200

RESUMEN

Metabolomics provides valuable tools for the study of drug effects, unraveling the mechanism of action and variation in response due to treatment. In this study we used electrochemistry-based targeted metabolomics to gain insights into the mechanisms of action of escitalopram/citalopram focusing on a set of 31 metabolites from neurotransmitter-related pathways. Overall, 290 unipolar patients with major depressive disorder were profiled at baseline, after 4 and 8 weeks of drug treatment. The 17-item Hamilton Depression Rating Scale (HRSD17) scores gauged depressive symptom severity. More significant metabolic changes were found after 8 weeks than 4 weeks post baseline. Within the tryptophan pathway, we noted significant reductions in serotonin (5HT) and increases in indoles that are known to be influenced by human gut microbial cometabolism. 5HT, 5-hydroxyindoleacetate (5HIAA), and the ratio of 5HIAA/5HT showed significant correlations to temporal changes in HRSD17 scores. In the tyrosine pathway, changes were observed in the end products of the catecholamines, 3-methoxy-4-hydroxyphenylethyleneglycol and vinylmandelic acid. Furthermore, two phenolic acids, 4-hydroxyphenylacetic acid and 4-hydroxybenzoic acid, produced through noncanconical pathways, were increased with drug exposure. In the purine pathway, significant reductions in hypoxanthine and xanthine levels were observed. Examination of metabolite interactions through differential partial correlation networks revealed changes in guanosine-homogentisic acid and methionine-tyrosine interactions associated with HRSD17. Genetic association studies using the ratios of these interacting pairs of metabolites highlighted two genetic loci harboring genes previously linked to depression, neurotransmission, or neurodegeneration. Overall, exposure to escitalopram/citalopram results in shifts in metabolism through noncanonical pathways, which suggest possible roles for the gut microbiome, oxidative stress, and inflammation-related mechanisms.


Asunto(s)
Citalopram/farmacología , Trastorno Depresivo Mayor/tratamiento farmacológico , Metaboloma/efectos de los fármacos , Inhibidores de la Captación de Serotonina/farmacología , Transducción de Señal/efectos de los fármacos , Adulto , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/fisiopatología , Femenino , Estudios de Seguimiento , Microbioma Gastrointestinal/efectos de los fármacos , Humanos , Masculino , Metabolómica , Persona de Mediana Edad , Índice de Severidad de la Enfermedad
12.
Expert Opin Drug Metab Toxicol ; 15(8): 619-631, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31271537

RESUMEN

Introduction: The comorbidity between obsessive-compulsive disorder (OCD) and bipolar disorders (BDs) is a frequent and severe condition characterized by a chronic course, high suicidal risk and tendency towards chronicity and treatment non-response. It represents a real challenge to psychiatrists, while requiring a careful and appropriate therapeutic management consisting in the combination of serotonergic antidepressants (ADs), such as serotonin reuptake inhibitors (SRIs), with mood stabilizers. This combination, like any other, raises the problems related to drug interactions that may lead to pharmacokinetic and pharmacodynamic changes, resulting in the modification of the pharmacologic effect and safety profile of a given compound. Areas covered: The aim of the present paper was to review the literature on the pharmacokinetic and pharmacodynamic changes resulting from the interactions of the different drugs prescribed in the OCD-BD comorbidity. Expert opinion: The literature data on pharmacokinetic and pharmacodynamic changes due to interactions of drugs commonly prescribed in the treatment of the OCD-BD comorbidity are extremely limited, and the information is inferred by findings gathered in psychiatric patients suffering from other disorders. This represents a gap in psychopharmacology that should be filled by specific studies on this important topic.


Asunto(s)
Trastorno Bipolar/tratamiento farmacológico , Trastorno Obsesivo Compulsivo/tratamiento farmacológico , Antimaníacos/administración & dosificación , Antimaníacos/farmacocinética , Antimaníacos/farmacología , Antipsicóticos/administración & dosificación , Antipsicóticos/farmacocinética , Antipsicóticos/farmacología , Trastorno Bipolar/complicaciones , Interacciones de Drogas , Humanos , Trastorno Obsesivo Compulsivo/complicaciones , Inhibidores de la Captación de Serotonina/administración & dosificación , Inhibidores de la Captación de Serotonina/farmacocinética , Inhibidores de la Captación de Serotonina/farmacología
13.
Expert Opin Pharmacother ; 20(15): 1837-1845, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31355688

RESUMEN

Introduction: Although postnatal depression is now well recognized, there is also a risk of depressive symptoms during perimenopause. The mechanisms underlying perimenopausal depression are still poorly understood; however, there are available treatment options. Areas covered: This review describes: the current pharmacotherapeutic approaches for perimenopausal depression, their strengths and weakness, and provides recommendations on how current treatment can be improved in the future. An electronic search identified specific guidelines for the treatment of perimenopausal depression released in 2018, as well as recent clinical studies on the subject. Expert opinion: The 2018 guidelines recommend selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) as front-line medications for perimenopausal depression, but SSRIs and SNRIs are not always effective. The efficacy of estrogen in perimenopausal depression is well documented, but estrogen is not FDA-approved to treat mood disturbances in perimenopausal women. Clinical practice guidelines currently recommend to restrict hormone therapy to the symptomatic treatment of menopause (not for the prevention of chronic diseases). Research with new estrogenic compounds is under way to improve their benefit/risk ratio in perimenopausal depression.


Asunto(s)
Depresión/tratamiento farmacológico , Perimenopausia/psicología , Inhibidores de la Captación de Serotonina/uso terapéutico , Depresión/patología , Femenino , Humanos , Inhibidores de la Captación de Serotonina/farmacología
14.
Expert Opin Pharmacother ; 20(16): 1961-1970, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31355689

RESUMEN

Introduction: Given our improved understanding of the role of central sensitization (CS) in many patients with chronic pain, it seems rational to account for CS during treatment. Areas covered: First, the treatment rationale based on the complex mechanisms underlying CS in patients having chronic pain is presented. Second, emphasis is given to explaining the concept of CS when providing treatment, as well as why patients and clinicians should focus on long-term rather than short-term treatment effects. Third, possible pharmacological and non-pharmacological treatment options are discussed. Expert opinion: Centrally acting drugs such as tricyclic compounds, serotonin-norepinephrine reuptake inhibitors, and α2δ ligands each target mechanisms that are often dysfunctional in patients having chronic pain and CS, but decades of clinical practice and clinical trials have not resulted in satisfactory outcomes. This comes as no surprise; CS comprises complex psycho-neuro-immunological interactions, while each of the tested drugs targets one or two of those mechanisms from a purely biomedical viewpoint. Clinicians willing to take CS into account should design an individually tailored multimodal treatment plan comprising pain neuroscience education, cognition-targeted exercise therapy, sleep management, stress management, and/or dietary intervention.


Asunto(s)
Dolor Crónico/tratamiento farmacológico , Inhibidores de la Captación de Serotonina/uso terapéutico , Analgésicos Opioides/farmacología , Analgésicos Opioides/uso terapéutico , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Sensibilización del Sistema Nervioso Central/efectos de los fármacos , Dolor Crónico/metabolismo , Dolor Crónico/patología , Humanos , Inhibidores de la Captación de Serotonina/farmacología
16.
Endocrinology ; 160(9): 2137-2142, 2019 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-31305910

RESUMEN

Owing to the prevalence of depression during childbearing, mothers can be prescribed multiple antidepressants; however, little is known about the risk and consequences to the offspring or subsequent generations. Fluoxetine (FLX) is usually the first-line of pharmacological treatment for affective disorders in pregnant women, with venlafaxine (VEN) used as secondary treatment. Given that FLX and VEN readily cross the placenta, a fetus from a treated pregnant woman is potentially at risk of the endocrine disruptive effects of these chemicals. Pharmaceutical agents, including FLX and VEN, reach aquatic ecosystems through sewage release; thus, fish could also be inadvertently affected. We report the results from a 6-day FLX exposure during early zebrafish development to an environmentally relevant level (0.54 µg/L in water) and a concentration detected in the cord blood of FLX-treated pregnant women (54 µg/L in water). The FLX exposure reduced the stress response (arithmetic difference between the stress-induced and unstressed whole-body cortisol levels) in the adult female and male zebrafish, an effect that persisted for four generations. To model the possibility of a second antidepressant exposure, filial generation 4 was exposed to VEN (5 µg/L). We found that FLX exposure sensitized these descendants to VEN. VEN treatment further suppressed cortisol production in females and decreased spawning rates in adult pairs. This is an important demonstration that in an animal model, a brief ancestral exposure of great-great-grandparents to the selective serotonin reuptake inhibitor FLX will shape the physiological responses of future generations to the serotonin and norepinephrine reuptake inhibitor VEN.


Asunto(s)
Fluoxetina/farmacología , Hidrocortisona/biosíntesis , Inhibidores de la Captación de Serotonina/farmacología , Clorhidrato de Venlafaxina/farmacología , Pez Cebra/fisiología , Animales , Femenino , Masculino , Exposición Materna/efectos adversos
17.
Neuroimage ; 199: 143-152, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31112788

RESUMEN

Disruption of cholinergic and serotonergic neurotransmitter systems is associated with cognitive, emotional and behavioural symptoms of Alzheimer's disease (AD). To investigate the responsiveness of these systems in AD we measured the effects of a single-dose of the selective serotonin reuptake inhibitor citalopram and acetylcholinesterase inhibitor galantamine in 12 patients with AD and 12 age-matched controls on functional brain connectivity with resting state functional magnetic resonance imaging. In this randomized, double blind, placebo-controlled crossover study, functional magnetic resonance images were repeatedly obtained before and after dosing, resulting in a dataset of 432 scans. Connectivity maps of ten functional networks were extracted using a dual regression method and drug vs. placebo effects were compared between groups with a multivariate analysis with signals coming from cerebrospinal fluid and white matter as covariates at the subject level, and baseline and heart rate measurements as confound regressors in the higher-level analysis (at p < 0.05, corrected). A galantamine induced difference between groups was observed for the cerebellar network. Connectivity within the cerebellar network and between this network and the thalamus decreased after galantamine vs. placebo in AD patients, but not in controls. For citalopram, voxelwise network connectivity did not show significant group × treatment interaction effects. However, we found default mode network connectivity with the precuneus and posterior cingulate cortex to be increased in AD patients, which could not be detected within the control group. Further, in contrast to the AD patients, control subjects showed a consistent reduction in mean connectivity with all networks after administration of citalopram. Since AD has previously been characterized by reduced connectivity between the default mode network and the precuneus and posterior cingulate cortex, the effects of citalopram on the default mode network suggest a restoring potential of selective serotonin reuptake inhibitors in AD. The results of this study also confirm a change in cerebellar connections in AD, which is possibly related to cholinergic decline.


Asunto(s)
Enfermedad de Alzheimer , Cerebelo/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Conectoma , Red Nerviosa/efectos de los fármacos , Inhibidores de la Captación de Serotonina/farmacología , Tálamo/efectos de los fármacos , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Cerebelo/diagnóstico por imagen , Cerebelo/fisiología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/fisiología , Citalopram/farmacología , Estudios Cruzados , Método Doble Ciego , Femenino , Galantamina/farmacología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/fisiología , Tálamo/diagnóstico por imagen , Tálamo/fisiología
18.
Expert Opin Pharmacother ; 20(11): 1341-1349, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31046480

RESUMEN

INTRODUCTION: Insomnia in Major Depressive Disorder (MDD) is highly prevalent and associated with increased suffering and functional impairment. Effective, evidence-based treatments for insomnia in MDD are an unmet need in clinical practice. AREAS COVERED: Herein, the authors provide a review of the clinical correlates, putative neurobiological mechanisms and treatment options for the management of insomnia in individuals with MDD. EXPERT OPINION: Sleep disturbances in MDD should be recognized as at least one of the following: (1) a domain of depressive psychopathology; (2) a consequence of rhythm disruptions; (3) a manifestation of comorbidities of sleep disturbances; (4) a manifestation of the influence of sex hormones in the brain in MDD; (5) a general medical comorbidity; and (6) a side effect of antidepressant medications. Assessment of insomnia in clinical practices is routinely performed with the use of non-structured interviews. Other methods such as standardized questionnaires and sleep diaries, along with complementary methods such as actigraphy and polysomnography are more scarcely applied. Smartphones and personal devices offer a promising strategy with the use of passive, long lasting, and ecologically valid assessments despite the lack of studies specifically targeting insomnia in individuals with MDD. New therapeutic approaches are essential, including novel targets such as orexins/hypocretins and the endocannabinoid system.


Asunto(s)
Antidepresivos/efectos adversos , Trastorno Depresivo Mayor/patología , Inhibidores de la Captación de Serotonina/uso terapéutico , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Ritmo Circadiano/efectos de los fármacos , Trastorno Depresivo Mayor/complicaciones , Trastorno Depresivo Mayor/tratamiento farmacológico , Práctica Clínica Basada en la Evidencia , Humanos , Orexinas/antagonistas & inhibidores , Orexinas/metabolismo , Inhibidores de la Captación de Serotonina/farmacología , Trastornos del Inicio y del Mantenimiento del Sueño/etiología
19.
Int J Mol Sci ; 20(8)2019 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-31018568

RESUMEN

Despite numerous studies on major depressive disorder (MDD) susceptibility, the precise underlying molecular mechanism has not been elucidated which restricts the development of etiology-based disease-modifying drug. Major depressive disorder treatment is still symptomatic and is the leading cause of (~30%) failure of the current antidepressant therapy. Here we comprehended the probable genes and pathways commonly associated with antidepressant response and MDD. A systematic review was conducted, and candidate genes/pathways associated with antidepressant response and MDD were identified using an integrative genetics approach. Initially, single nucleotide polymorphisms (SNPs)/genes found to be significantly associated with antidepressant response were systematically reviewed and retrieved from the candidate studies and genome-wide association studies (GWAS). Also, significant variations concerning MDD susceptibility were extracted from GWAS only. We found 245 (Set A) and 800 (Set B) significantly associated genes with antidepressant response and MDD, respectively. Further, gene set enrichment analysis revealed the top five co-occurring molecular pathways (p ≤ 0.05) among the two sets of genes: Cushing syndrome, Axon guidance, cAMP signaling pathway, Insulin secretion, and Glutamatergic synapse, wherein all show a very close relation to synaptic plasticity. Integrative analyses of candidate gene and genome-wide association studies would enable us to investigate the putative targets for the development of disease etiology-based antidepressant that might be more promising than current ones.


Asunto(s)
Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/genética , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Inhibidores de la Captación de Serotonina/uso terapéutico , Antidepresivos/farmacología , AMP Cíclico/metabolismo , Trastorno Depresivo Mayor/metabolismo , Estudio de Asociación del Genoma Completo , Genómica/métodos , Humanos , Inhibidores de la Captación de Serotonina/farmacología , Transducción de Señal/efectos de los fármacos , Flujo de Trabajo
20.
Expert Opin Pharmacother ; 20(9): 1091-1107, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31002267

RESUMEN

INTRODUCTION: Frontotemporal dementia (FTD) is a heterogeneous clinical entity that includes several disorders characterized by different cellular mechanisms. Distinctive clinical features in FTD include behavioral, affective, and cognitive symptoms. Unfortunately, little progress has been made over the past 20 years in terms of the development of effective disease-modifying drugs with the currently available symptomatic treatments having limited clinical utility. AREAS COVERED: This article reviews the principal pharmacological intervention studies for FTD. These are predominantly randomized clinical trials and include symptomatic treatments and potential disease-modifying drugs. EXPERT OPINION: There is insufficient evidence on effective treatments for FTD and studies with better methodological backgrounds are needed. Most studies reporting therapeutic benefits were conducted with selective serotonin reuptake inhibitors, while anti-dementia drugs have been ineffective in FTD. Since the underlying pathology of FTD mostly consists of abnormal tau protein or TDP-43 aggregates, treatments are being developed to interfere with their aggregation process or with the clearance of these proteins. Furthermore, disease-modifying treatments remain years away as demonstrated by the recent negative Phase III findings of a tau aggregation inhibitor (LMTM) for treating the behavioral variant of FTD. The results from current ongoing Phase I/II trials will hopefully give light to future treatment options.


Asunto(s)
Demencia Frontotemporal/tratamiento farmacológico , Demencia Frontotemporal/terapia , Inhibidores de la Captación de Serotonina/uso terapéutico , Demencia Frontotemporal/patología , Humanos , Fenotipo , Inhibidores de la Captación de Serotonina/farmacología
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