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1.
Psychopharmacology (Berl) ; 237(7): 1909-1915, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32529266

RESUMO

RATIONALE: Depression is a major mental disorder affecting millions of people worldwide. Serotonin and norepinephrine reuptake inhibitors (SNRIs) are one of the antidepressant drugs prescribed for depression treatment. OBJECTIVE AND METHOD: There are many contradiction studies about the adverse effect and genotoxicity of SNRIs. So here, based on the guidelines proposed at the PRISMA statement, we performed a quantitative systematic review by searching international electronic databases (PubMed, Scopus, Embase, and Web of Science) for published documents on SSNRIs and their genotoxicity effects. RESULTS: The database searches retrieved 336 records, 18 of which met the inclusion criteria. Evaluation of the selected articles showed that a total of 9 articles were appropriate for final review. Most of these studies (78%) reported positive results for the genotoxicity of SNRIs CONCLUSION: Finally, we can conclude that these drugs have the potential to damage DNA.


Assuntos
Antidepressivos/efeitos adversos , Dano ao DNA/efeitos dos fármacos , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/genética , Inibidores da Recaptação de Serotonina e Norepinefrina/efeitos adversos , Antidepressivos/farmacologia , Dano ao DNA/fisiologia , Transtorno Depressivo/metabolismo , Humanos , Norepinefrina/antagonistas & inibidores , Norepinefrina/genética , Norepinefrina/metabolismo , Serotonina/genética , Serotonina/metabolismo , Inibidores de Captação de Serotonina/efeitos adversos , Inibidores de Captação de Serotonina/farmacologia , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia
2.
Nat Commun ; 11(1): 2335, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393738

RESUMO

Selective serotonin reuptake inhibitors (SSRIs) constitute a first-line antidepressant intervention, though the precise cognitive and computational mechanisms that explain treatment response remain elusive. Using week-long SSRI treatment in healthy volunteer participants, we show serotonin enhances the impact of experimentally induced positive affect on learning of novel, and reconsolidation of previously learned, reward associations. Computational modelling indicated these effects are best accounted for by a boost in subjective reward perception during learning, following a positive, but not negative, mood induction. Thus, instead of influencing affect or reward sensitivity directly, SSRIs might amplify an interaction between the two, giving rise to a delayed mood response. We suggest this modulation of affect-learning dynamics may explain the evolution of a gradual mood improvement seen with these agents and provides a novel candidate mechanism for the unfolding of serotonin's antidepressant effects over time.


Assuntos
Afeto/efeitos dos fármacos , Serotonina/farmacologia , Adulto , Feminino , Humanos , Aprendizagem/efeitos dos fármacos , Masculino , Recompensa , Inibidores de Captação de Serotonina/farmacologia , Análise e Desempenho de Tarefas , Adulto Jovem
3.
Nat Commun ; 11(1): 1491, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32198394

RESUMO

The serotonin transporter (SERT) terminates serotonin signaling by rapid presynaptic reuptake. SERT activity is modulated by antidepressants, e.g., S-citalopram and imipramine, to alleviate symptoms of depression and anxiety. SERT crystal structures reveal two S-citalopram binding pockets in the central binding (S1) site and the extracellular vestibule (S2 site). In this study, our combined in vitro and in silico analysis indicates that the bound S-citalopram or imipramine in S1 is allosterically coupled to the ligand binding to S2 through altering protein conformations. Remarkably, SERT inhibitor Lu AF60097, the first high-affinity S2-ligand reported and characterized here, allosterically couples the ligand binding to S1 through a similar mechanism. The SERT inhibition by Lu AF60097 is demonstrated by the potentiated imipramine binding and increased hippocampal serotonin level in rats. Together, we reveal a S1-S2 coupling mechanism that will facilitate rational design of high-affinity SERT allosteric inhibitors.


Assuntos
Sítio Alostérico/efeitos dos fármacos , Citalopram/farmacologia , Imipramina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Regulação Alostérica/efeitos dos fármacos , Sítio Alostérico/genética , Animais , Antidepressivos/farmacologia , Citalopram/química , Desenvolvimento de Medicamentos , Engenharia Genética , Imipramina/química , Ligantes , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Conformação Proteica , Ratos , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
4.
Psychopharmacology (Berl) ; 237(6): 1681-1689, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32125484

RESUMO

RATIONALE: A variety of neural systems are involved in drug addiction, and some of these systems are shared across different addictive drugs. We have found several different types of drug treatments that successfully reduce nicotine self-administration. OBJECTIVES: The current set of studies is the first in a series to determine if drug treatments that have been found to significantly reduce nicotine self-administration would reduce opiate self-administration. METHODS: Amitifadine, a triple reuptake inhibitor of dopamine, norepinephrine, and serotonin, was assessed in female Sprague-Dawley rats to determine whether it significantly reduces remifentanil self-administration with either acute or chronic treatment. RESULTS: Acutely, amitifadine doses of 5, 10, and 20 mg/kg each significantly reduced remifentanil self-administration. In a chronic study, repeated treatment with 10 mg/kg of amitifadine continued to reduce remifentanil self-administration, even after the cessation of treatment. However, amitifadine was not found to attenuate the rise in remifentanil self-administration with continued access. This study and our earlier one showed that the 10 mg/kg amitifadine dose did not significantly affect food motivated responding. Amitifadine did not attenuate remifentanil-induced antinociception as measured on the hot plate test but extended and maintained antinociceptive effects. CONCLUSIONS: These studies show the promise of amitifadine as a treatment for countering opiate self-administration for adjunctive use with opioids for analgesia. Further studies are needed to determine the possible efficacy of amitifadine for combating opiate addiction or preventing it in humans during adjunctive use with opioids for chronic pain.


Assuntos
Analgésicos Opioides/administração & dosagem , Compostos Aza/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Inibidores da Captação de Dopamina/uso terapêutico , Norepinefrina/antagonistas & inibidores , Remifentanil/administração & dosagem , Inibidores de Captação de Serotonina/uso terapêutico , Animais , Compostos Aza/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Motivação/efeitos dos fármacos , Motivação/fisiologia , Nicotina/administração & dosagem , Norepinefrina/metabolismo , Dor/tratamento farmacológico , Dor/metabolismo , Ratos , Ratos Sprague-Dawley , Autoadministração , Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Estereoisomerismo
6.
J Zoo Wildl Med ; 50(4): 1005-1007, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31926537

RESUMO

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.


Assuntos
Agressão/efeitos dos fármacos , Citalopram/farmacologia , Pan troglodytes , Inibidores de Captação de Serotonina/farmacologia , Animais , Masculino
7.
Life Sci ; 245: 117307, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31954746

RESUMO

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.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Fluoxetina/farmacologia , Mitocôndrias/efeitos dos fármacos , Hipernutrição/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Masculino , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Proteína Desacopladora 1/metabolismo
8.
Psychopharmacology (Berl) ; 237(3): 627-638, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31927606

RESUMO

RATIONALE: Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by intrusive obsessive thoughts and/or compulsive behaviors. Currently, serotonin reuptake inhibitors (SRIs) provide the only pharmacological monotherapy for OCD, but response rates are insufficient. Ketamine, a noncompetitive NMDA receptor antagonist, was reported to have rapid, sustained therapeutic effects in OCD patients. However, the mechanisms remain unknown. OBJECTIVES: Here, we aimed to provide a platform for investigating mechanisms underlying anti-OCD effects of ketamine treatment by assessing whether ketamine pretreatment could alleviate 5-HT1B receptor (5-HT1BR)-induced OCD-like behavior in mice. METHODS: We assessed whether acute ketamine (0, 3, 10, 30 mg/kg), administered at two pretreatment time points (30 min, 24 h), would modulate 5-HT1BR-induced OCD-like behavior in mice. Behavioral measures were perseverative hyperlocomotion in the open field and deficits in prepulse inhibition (PPI) induced by acute pharmacological 5-HT1BR challenge. RESULTS: Three milligrams per kilogram of ketamine reduced 5-HT1BR-induced perseverative hyperlocomotion, but not PPI deficits, 24 h postinjection. In contrast, higher doses of ketamine were either ineffective (10 mg/kg) or exacerbated (30 mg/kg) 5-HT1BR-induced perseverative hyperlocomotion 30 min postinjection. At 24 h postinjection, 30 mg/kg ketamine reduced perseverative hyperlocomotion across all groups. CONCLUSIONS: Our results suggest that the 5-HT1BR-induced model of OCD-like behavior is sensitive to a low dose of ketamine, a potential fast-acting anti-OCD treatment, and may provide a tool for studying mechanisms underlying the rapid therapeutic effects of ketamine in OCD patients.


Assuntos
Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Ketamina/uso terapêutico , Transtorno Obsessivo-Compulsivo/induzido quimicamente , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Agonistas do Receptor 5-HT1 de Serotonina/toxicidade , Animais , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Ketamina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Transtorno Obsessivo-Compulsivo/psicologia , Inibição Pré-Pulso/efeitos dos fármacos , Inibição Pré-Pulso/fisiologia , Distribuição Aleatória , Inibidores de Captação de Serotonina/farmacologia , Inibidores de Captação de Serotonina/uso terapêutico , Fatores de Tempo
9.
Psychopharmacology (Berl) ; 237(5): 1281-1290, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31965254

RESUMO

RATIONALE: Some mood disorders, such as major depressive disorder, are more prevalent in women than in men. However, historically preclinical studies in rodents have a lower inclusion rate of females than males, possibly due to the fact that behavior can be affected by the estrous cycle. Several studies have demonstrated that chronic antidepressant treatment can decrease anxiety-associated behaviors and increase adult hippocampal neurogenesis in male rodents. OBJECTIVE: Very few studies have looked at the effects of antidepressants on behavior and neurogenesis across the estrous cycle in naturally cycling female rodents. METHODS: Here, we analyze the effects of chronic treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine (Prozac) on behavior and adult hippocampal neurogenesis in naturally cycling C57BL/6J females across all four phases of the estrous cycle. RESULTS: In naturally cycling C57BL/6J females, fluoxetine decreases negative valence behaviors associated with anxiety in the elevated plus maze and novelty-suppressed feeding task, reduces immobility time in forced swim test, and increases adult hippocampal neurogenesis. Interestingly, the effects of fluoxetine on several negative valence behavior and adult hippocampal neurogenesis measures were mainly found within the estrus and diestrus phases of the estrous cycle. CONCLUSIONS: Taken together, these data are the first to illustrate the effects of fluoxetine on behavior and adult hippocampal neurogenesis across all four phases of the murine estrous cycle.


Assuntos
Ciclo Estral/efeitos dos fármacos , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Inibidores de Captação de Serotonina/farmacologia , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Depressão/tratamento farmacológico , Depressão/psicologia , Ciclo Estral/fisiologia , Feminino , Fluoxetina/uso terapêutico , Hipocampo/citologia , Hipocampo/fisiologia , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/fisiologia , Inibidores de Captação de Serotonina/uso terapêutico
10.
Psychopharmacology (Berl) ; 237(1): 127-136, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31473777

RESUMO

RATIONALE: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most commonly used drugs for the treatment of depression. Studies have shown that chronic treatment with SSRIs and SNRIs produces a protective effect against oxidative stress. Thioredoxin (Trx) is an antioxidant protein that reverses protein cysteine oxidation and facilitates scavenging reactive oxygen species. OBJECTIVES: The current study is to determine whether the SSRI fluoxetine and the SNRI venlafaxine regulate Trx and protect neuronal cells against protein cysteine oxidation. METHODS: HT22 mouse hippocampal cells were incubated with fluoxetine or venlafaxine for 5 days. Protein levels of Trx, Trx reductase (TrxR), and Trx-interacting protein (Txnip) were measured by immunoblotting analysis. Trx and TrxR activities were analyzed by spectrophotometric method. Protein cysteine sulfenylation was measured by dimedone-conjugation assay, while nitrosylation was measured by biotin-switch assay. RESULTS: We found that treatment with fluoxetine or venlafaxine for 5 days increased Trx and TrxR protein levels but produced no effect on Txnip protein levels. These treatments also increased Trx and TrxR activities. Although treatment with fluoxetine or venlafaxine alone had no effect on sulfenylated and nitrosylated protein levels, both drugs inhibited H2O2-increased sulfenylated protein levels and nitric oxide donor nitrosoglutathione-increased nitrosylated protein levels. Stress increases risk of depression. We also found that treatment with fluoxetine or venlafaxine for 5 days inhibited stress hormone corticosterone-increased total sulfenylated and nitrosylated protein levels. CONCLUSIONS: Our findings suggest that chronic treatment with antidepressants may upregulate Trx, subsequently inhibiting protein sulfenylation and nitrosylation, which may contribute to the protective effect of antidepressants against oxidative stress. Our findings also indicate that thioredoxin is a potential therapeutic target for the treatment of depression.


Assuntos
Fluoxetina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Tiorredoxinas/metabolismo , Regulação para Cima/efeitos dos fármacos , Cloridrato de Venlafaxina/farmacologia , Animais , Antidepressivos/farmacologia , Proteínas de Transporte/metabolismo , Linhagem Celular , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Tiorredoxina Dissulfeto Redutase/metabolismo
11.
Synapse ; 74(1): e22130, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31449695

RESUMO

Due to the prevalence of depression in women, female rats may be a better models for antidepressant research than males. In male rats, fluoxetine inhibited the serotonin (5-hydroxytryptamine, 5-HT) transporter (SERT) which is reducing the immobility time in the repeated forced swimming test (rFST). The performance of female rats in this test is unknown. In this study, responses of male and female rats in the rFST under chronic treatment with fluoxetine and the function of SERT in their brains were examined. Wistar rats received oral fluoxetine (females: 0, 1, 2.5, or 5 mg kg-1  day-1 ; males: 0 or 2.5 mg kg-1  day-1 ; in sucrose 10%, 1.5 ml/rat) 1 hr before the test daily for 12 days over the course of the rFST. rFST consisted of a 15 min pretest followed by 5 min sessions of swimming at 1 (test), 7 (retest 1), and 14 (retest 2) days later. SERT functioning was assessed by ex vivo assays of the frontal cortex and hippocampus of rats. Fluoxetine reduced immobility time of males in the rFST while it failed to do so in females. In vitro treatment with fluoxetine inhibited the uptake of 5-HT of both sexes similarly, while in vivo chronic administration of fluoxetine failed to do so. In summary, rats responded to the chronic treatment with fluoxetine in a sexually dimorphic fashion during the rFST despite the functioning of SERT in their brains remaining equally unchanged. Hence, our data suggest that sexually dimorphic responses to fluoxetine in rFST may be unrelated to the function of SERT in rat brains.


Assuntos
Fluoxetina/farmacologia , Lobo Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Feminino , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Masculino , Ratos , Ratos Wistar , Fatores Sexuais , Natação
12.
Chemosphere ; 238: 124587, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31425864

RESUMO

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.


Assuntos
Analgésicos Opioides/farmacologia , Citalopram/farmacologia , Inibidores de Captação de Serotonina/farmacologia , Tramadol/farmacologia , Poluentes Químicos da Água/farmacologia , Peixe-Zebra/embriologia , Animais , Embrião não Mamífero/efeitos dos fármacos , Larva/efeitos dos fármacos
13.
Pharmacol Rev ; 72(1): 80-151, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31826934

RESUMO

This review evaluates current knowledge about obsessive-compulsive disorder (OCD), with the goal of providing a roadmap for future directions in research on the psychopharmacology of the disorder. It first addresses issues in the description and diagnosis of OCD, including the structure, measurement, and appropriate description of the disorder and issues of differential diagnosis. Current pharmacotherapies for OCD are then reviewed, including monotherapy with serotonin reuptake inhibitors and augmentation with antipsychotic medication and with psychologic treatment. Neuromodulatory therapies for OCD are also described, including psychosurgery, deep brain stimulation, and noninvasive brain stimulation. Psychotherapies for OCD are then reviewed, focusing on behavior therapy, including exposure and response prevention and cognitive therapy, and the efficacy of these interventions is discussed, touching on issues such as the timing of sessions, the adjunctive role of pharmacotherapy, and the underlying mechanisms. Next, current research on the neurobiology of OCD is examined, including work probing the role of various neurotransmitters and other endogenous processes and etiology as clues to the neurobiological fault that may underlie OCD. A new perspective on preclinical research is advanced, using the Research Domain Criteria to propose an adaptationist viewpoint that regards OCD as the dysfunction of a normal motivational system. A systems-design approach introduces the security motivation system (SMS) theory of OCD as a framework for research. Finally, a new perspective on psychopharmacological research for OCD is advanced, exploring three approaches: boosting infrastructure facilities of the brain, facilitating psychotherapeutic relearning, and targeting specific pathways of the SMS network to fix deficient SMS shut-down processes. SIGNIFICANCE STATEMENT: A significant proportion of patients with obsessive-compulsive disorder (OCD) do not achieve remission with current treatments, indicating the need for innovations in psychopharmacology for the disorder. OCD may be conceptualized as the dysfunction of a normal, special motivation system that evolved to manage the prospect of potential danger. This perspective, together with a wide-ranging review of the literature, suggests novel directions for psychopharmacological research, including boosting support systems of the brain, facilitating relearning that occurs in psychotherapy, and targeting specific pathways in the brain that provide deficient stopping processes in OCD.


Assuntos
Antipsicóticos/uso terapêutico , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/psicologia , Inibidores de Captação de Serotonina/uso terapêutico , Animais , Antipsicóticos/farmacologia , Estimulação Encefálica Profunda , Humanos , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/terapia , Psicofarmacologia , Psicoterapia/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores de Captação de Serotonina/farmacologia
15.
Pharm Res ; 37(1): 7, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31845095

RESUMO

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.


Assuntos
Antidepressivos de Segunda Geração/farmacologia , Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/fisiopatologia , Inibidores de Captação de Serotonina/efeitos adversos , Tamoxifeno/efeitos adversos , Idoso , Antidepressivos de Segunda Geração/efeitos adversos , Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/complicações , Citalopram/farmacologia , Feminino , Humanos , Síndrome do QT Longo/induzido quimicamente , Pessoa de Meia-Idade , Inibidores de Captação de Serotonina/farmacologia , Tamoxifeno/farmacologia
16.
Psychiatry Res ; 282: 112637, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31690461

RESUMO

The goal of this study was to summarize evidence from head-to-head randomized trials for treatment of posttraumatic stress disorder (PTSD) in adults comparing trauma-focused psychotherapies and selective serotonin reuptake inhibitors (SSRIs) or serotonin/norepinephrine reuptake inhibitors (SNRIs) in a systematic review and meta-analysis. We conducted a search of multiple databases to identify trials comparing a trauma-focused psychotherapy (cognitive behavioral therapy, prolonged exposure, cognitive therapy, cognitive processing therapy or eye movement desensitization and reprocessing) to an SSRI or SNRI. Cochrane Risk of Bias 2.0 was used to assess risk of bias; high risk of bias trials were included only in sensitivity analyses. PTSD symptom reduction was the primary outcome. Four trials met inclusion criteria. Random effects meta-analysis of the two trials that were not high risk of bias showed no difference in PTSD symptom reduction, but a wide confidence interval, including effects favoring psychotherapy and effects favoring medication. Heterogeneity was high. Inclusion of the two high risk of bias trials did not change substantive conclusions. There is insufficient evidence to determine whether SSRIs or trauma-focused psychotherapies are more effective for PTSD symptom reduction among adults with PTSD.


Assuntos
Terapia Cognitivo-Comportamental , Pesquisa Comparativa da Efetividade , Dessensibilização Psicológica , Avaliação de Resultados em Cuidados de Saúde , Trauma Psicológico/terapia , Inibidores de Captação de Serotonina/farmacologia , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia , Transtornos de Estresse Pós-Traumáticos/terapia , Adulto , Humanos , Trauma Psicológico/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico
17.
Psychiatry Res ; 282: 112613, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31669837

RESUMO

BACKGROUND: While there is sufficient evidence that Crocus Sativus L. (saffron) improves symptoms of depression in young and middle-aged adults, research on older people are missing. The purpose of the double-blind, randomized intervention study was to compare the effect of saffron and sertraline on MDD among a sample of older people. METHODS: A total of 50 older out-patients with MDD (mean age = =65 years; 70% males) were randomly assigned either to the saffron condition (60 mg/d) or to the sertraline condition (100 mg/day) for six consecutive weeks. Experts employed the Hamilton Depression Rating Scale (HDRS) to rate participants' degree of depression. Timepoints were baseline, week 2, week 4 and week 6, the end of the study. RESULTS: Symptoms of depression decreased over time, with no advantages or disadvantages for the saffron or sertraline condition. CONCLUSION: The pattern of results suggests that both saffron and sertraline have the potential to significantly decrease symptoms of depression. The results are clinically relevant, because major depressive disorders in older people is a health concern. The results are further relevant, because saffron appears to be a powerful antidepressant for older people, who might be more reluctant to the use of synthetic drugs.


Assuntos
Antidepressivos/farmacologia , Crocus , Transtorno Depressivo Maior/tratamento farmacológico , Fitoterapia , Extratos Vegetais/farmacologia , Inibidores de Captação de Serotonina/farmacologia , Sertralina/farmacologia , Idoso , Antidepressivos/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/administração & dosagem , Inibidores de Captação de Serotonina/administração & dosagem , Sertralina/administração & dosagem , Resultado do Tratamento
18.
Anticancer Res ; 39(11): 6155-6163, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704843

RESUMO

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.


Assuntos
Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Fluoxetina/farmacologia , Necrose , Paclitaxel/farmacologia , Neoplasias Gástricas/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Antineoplásicos Fitogênicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Inibidores de Captação de Serotonina/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Células Tumorais Cultivadas
19.
BMC Neurol ; 19(1): 237, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615444

RESUMO

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.


Assuntos
Giro do Cíngulo/metabolismo , Giro do Cíngulo/fisiopatologia , Transtornos de Enxaqueca/metabolismo , Transtornos de Enxaqueca/fisiopatologia , Serotonina/metabolismo , Adulto , Mapeamento Encefálico/métodos , Citalopram/farmacologia , Método Duplo-Cego , Feminino , Giro do Cíngulo/efeitos dos fármacos , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Inibidores de Captação de Serotonina/farmacologia
20.
Expert Opin Ther Targets ; 23(10): 883-891, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31637934

RESUMO

Introduction: In line with the monoamine hypothesis of major depressive disorder (MDD), the clinical efficacy of the selective serotonin reuptake inhibitor fluoxetine has classically been ascribed to central serotonin enhancing properties. Current research described disturbances in brain energy metabolism in MDD. Additionally, fluoxetine showed beneficial effects in neuropsychiatric disorders associated with central energy imbalance. Areas covered: The effect of in vitro fluoxetine exposure on cellular glucose uptake and cerebral glucose transporter function was assessed in human peripheral blood mononuclear cells (PBMC) and murine neuroblastoma N2a cells. Fluoxetine augmented glucose uptake, measured by utilizing the radionuclide-labled glucose analog [18]F-fluorodeoxyglucose, in PBMC without affecting glucose transporter protein content. Analysis of protein palmitoylation using the acyl-biotinyl exchange method revealed GLUT3 to be palmitoylated in PBMC and N2a cells, while palmitoylation of GLUT1 was detected only in N2a cells. Treatment with fluoxetine significantly increased palmitoylation of GLUT3 in PBMC and strongly induced palmitoylation of GLUT1 in PBMC and N2a cells. Expert opinion: Our findings suggest a novel mechanism exerted by fluoxetine targeting glucose metabolism by regulating glucose transporter palmitoylation. Thus, fluoxetine might evoke its therapeutic effects in neuropsychiatric diseases characterized by disturbances in central energy metabolism at least partly by improving cerebral glucose uptake.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Fluoxetina/farmacologia , Glucose/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Adulto , Animais , Proteínas Facilitadoras de Transporte de Glucose/efeitos dos fármacos , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Lipoilação/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Neuroblastoma/metabolismo
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