RESUMO
This column is the third in a 3-part series describing cases in which general medical knowledge, including psychiatric and clinical pharmacology, was instrumental in determining whether dereliction was the direct cause of damages in a malpractice suit. This case illustrates how not taking into account the following variables can result in a false-positive diagnosis of a lethal serotonin syndrome: (a) the time course of treatment, (b) the time course of symptoms, (c) the difference between antemortem plasma and postmortem whole-blood levels of highly protein bound and highly lipophilic drugs. The case also illustrates how taking those 3 variables into account led to the conclusion that there was no dereliction in the care of the patient that was the direct cause of his death, and hence, there was no medical malpractice.
Assuntos
Inibidores Seletivos de Recaptação de Serotonina , Síndrome da Serotonina , Sertralina , Humanos , Síndrome da Serotonina/diagnóstico , Síndrome da Serotonina/sangue , Síndrome da Serotonina/induzido quimicamente , Masculino , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Reações Falso-Positivas , Adulto , Pessoa de Meia-IdadeRESUMO
Reversible cerebral vasoconstriction syndrome (RCVS) represents a group of conditions that show reversible multifocal narrowing or constriction of the cerebral arteries that supply blood to the brain. The initial manifestation of RCVS often includes a "thunderclap" headache that is sudden, severe, and often disabling. Stimulants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and antipsychotics with serotonergic activity can alter the cerebral arterial tone, trigger vasoconstriction, and place patients at risk of a cerebrovascular accident. Thus, psychiatric medications are commonly discontinued on admission for RCVS, and psychiatry is often consulted for input on acute medication management and longitudinal treatment options. Currently, there is a dearth of literature on managing psychiatric medications in RCVS, resulting in variable practice patterns that place patients at risk of withdrawal, decompensation, and relapse. In this article, we provide a case example and aim to consolidate the limited data surrounding the management of psychiatric illness with comorbid RCVS in our discussion. There is a clear concern about worsening and even potentially lethal consequences due to serotonin or stimulant-induced vasospasm both during an acute episode and in long-term management of RCVS. We discuss the underlying pathophysiologic mechanisms proposed for serotonergic-, noradrenergic-, and dopaminergic-induced cerebral vasospasm and how this correlates with the clinical management of patients on psychiatric medications. These data will then be organized to create a risks versus benefits outline to equip psychiatrists to make decisions about when to stop and when to restart psychiatric medications in the setting of RCVS.
Assuntos
Vasoespasmo Intracraniano , Humanos , Vasoespasmo Intracraniano/induzido quimicamente , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Transtornos da Cefaleia Primários/induzido quimicamente , Feminino , Serotoninérgicos/efeitos adversos , Serotoninérgicos/farmacologia , Serotoninérgicos/administração & dosagem , AdultoRESUMO
There is little evidence for psychopharmacotherapy in pica. A few studies reported some benefit from the use of SSRIs, atypical antipsychotics and methylphenidate. That said, evidence to deploy these agents remains, at large, flimsy. Here, despite scarcity, we review available literature and draw some generalities that can inform decision-making on clinical grounds.
Assuntos
Antipsicóticos , Pica , Humanos , Pica/tratamento farmacológico , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacologia , Metilfenidato/administração & dosagem , Metilfenidato/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagemRESUMO
Major depressive disorder (MDD) is a mental health disorder associated with cognitive impairment, dysregulated appetite, fatigue, insomnia or hypersomnia, and severe mood changes that significantly impact the ability of the affected individual to perform day-to-day tasks, leading to suicide in the worst-case scenario. As MDD is becoming more prevalent, affecting roughly 300 million individuals worldwide, its treatment has become a major point of interest. Antidepressants acting as selective serotonin reuptake inhibitors (SSRIs) are currently used as the first line of treatment for MDD. Other antidepressants currently used for the treatment of MDD include the serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs). However, although effective in alleviating symptoms of MDD, most antidepressants require weeks or even months of regular administration prior to eliciting a rational clinical effect. Owing to the strong evidence showing a relationship between neural plasticity, neurogenesis, and MDD, researchers have also looked at the possibility of using treatment modalities that target these processes in an attempt to improve clinical outcome. The overarching aim of this chapter is to highlight the role of neural plasticity and neurogenesis in the pathophysiology of MDD and discuss the most recently studied treatment strategies that target these processes by presenting supporting evidence from both animal and human studies.
Assuntos
Antidepressivos , Transtorno Depressivo Maior , Neurogênese , Plasticidade Neuronal , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Neurogênese/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Antidepressivos/uso terapêutico , Antidepressivos/farmacologia , Animais , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
Postprandial dyslipidemia is commonly present in people with type 2 diabetes and obesity and is characterized by overproduction of apolipoprotein B48-containing chylomicron particles from the intestine. Peripheral serotonin is emerging as a regulator of energy homeostasis with profound implications for obesity; however, its role in dietary fat absorption and chylomicron production is unknown. Chylomicron production was assessed in Syrian golden hamsters by administering an olive oil gavage and IP poloxamer to inhibit lipoprotein clearance. Administration of serotonin or selective serotonin reuptake inhibitor, fluoxetine, increased postprandial plasma triglyceride (TG) and TG-rich lipoproteins. Conversely, inhibiting serotonin synthesis pharmacologically by p-chlorophenylalanine (PCPA) led to a reduction in both the size and number of TG-rich lipoprotein particles, resulting in lower plasma TG and apolipoprotein B48 levels. The effects of PCPA occurred independently of gastric emptying and vagal afferent signaling. Inhibiting serotonin synthesis by PCPA led to increased TG within the intestinal lumen and elevated levels of TG and cholesterol in the stool when exposed to a high-fat/high-cholesterol diet. These findings imply compromised fat absorption, as evidenced by reduced lipase activity in the duodenum and lower levels of serum bile acids, which are indicative of intestinal bile acids. During the postprandial state, mRNA levels for serotonin receptors (5-HTRs) were upregulated in the proximal intestine. Administration of cisapride, a 5-HT4 receptor agonist, alleviated reductions in postprandial lipemia caused by serotonin synthesis inhibition, indicating that serotonin controls dietary fat absorption and chylomicron secretion via 5-HT4 receptor.
Assuntos
Quilomícrons , Gorduras na Dieta , Mesocricetus , Receptores 5-HT4 de Serotonina , Serotonina , Triglicerídeos , Animais , Masculino , Quilomícrons/metabolismo , Serotonina/metabolismo , Receptores 5-HT4 de Serotonina/metabolismo , Gorduras na Dieta/farmacologia , Triglicerídeos/metabolismo , Triglicerídeos/sangue , Cricetinae , Fenclonina/farmacologia , Absorção Intestinal/efeitos dos fármacos , Fluoxetina/farmacologia , Período Pós-Prandial/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
When an organism encounters a pathogen, the host innate immune system activates to defend against pathogen colonization and toxic xenobiotics produced. C. elegans employ multiple defense systems to ensure survival when exposed to Pseudomonas aeruginosa including activation of the cytoprotective transcription factor SKN-1/NRF2. Although wildtype C. elegans quickly learn to avoid pathogens, here we describe a peculiar apathy-like behavior towards PA14 in animals with constitutive activation of SKN-1, whereby animals choose not to leave and continue to feed on the pathogen even when a non-pathogenic and healthspan-promoting food option is available. Although lacking the urgency to escape the infectious environment, animals with constitutive SKN-1 activity are not oblivious to the presence of the pathogen and display the typical pathogen-induced intestinal distension and eventual demise. SKN-1 activation, specifically in neurons and intestinal tissues, orchestrates a unique transcriptional program which leads to defects in serotonin signaling that is required from both neurons and non-neuronal tissues. Serotonin depletion from SKN-1 activation limits pathogen defenses capacity, drives the pathogen-associated apathy behaviors and induces a synthetic sensitivity to selective serotonin reuptake inhibitors. Taken together, our work reveals interesting insights into how animals perceive environmental pathogens and subsequently alter behavior and cellular programs to promote survival.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Proteínas de Ligação a DNA , Pseudomonas aeruginosa , Serotonina , Fatores de Transcrição , Animais , Caenorhabditis elegans/microbiologia , Caenorhabditis elegans/imunologia , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Pseudomonas aeruginosa/fisiologia , Pseudomonas aeruginosa/patogenicidade , Serotonina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Neurônios/metabolismo , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/metabolismo , Infecções por Pseudomonas/microbiologia , Imunidade Inata , Transdução de Sinais , Apatia/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
Purpose: To investigate the neuroplasticity hypothesis of depression by measuring brain-derived neurotrophic factor (BDNF) levels in plasma astrocyte-derived extracellular vesicles (ADEVs) and to evaluate their potential as biomarkers for depression compared with plasma BDNF levels. Patients and Methods: Thirty-five patients with major depressive disorder (MDD) and 35 matched healthy controls (HCs) were enrolled. Plasma ADEVs were isolated using a combination of ultracentrifugation and immunoaffinity capture. Isolated ADEVs were validated using transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. BDNF levels were quantified in both ADEVs and plasma. ALG-2-interacting protein X (Alix) and cluster of differentiation 81 (CD81) levels, two established extracellular vesicle markers, were measured in ADEVs. Results: After false discovery rate correction, patients with MDD exhibited higher CD81 levels (P FDR = 0.040) and lower BDNF levels (P FDR = 0.043) in ADEVs than HCs at baseline. BDNF levels in ADEVs normalized to CD81 (P FDR = 0.002) and Alix (P FDR = 0.040) remained consistent with this finding. Following four weeks of selective serotonin reuptake inhibitor treatment (n=10), CD81 levels in ADEVs decreased (P FDR = 0.046), while BDNF levels normalized to CD81 increased (P FDR = 0.022). BDNF levels in ADEVs were more stable than in plasma. Exploratory analysis revealed no correlation between BDNF levels in ADEVs and plasma (ρ=0.117, P = 0.334). Conclusion: This study provides human in vivo evidence supporting the neuroplasticity hypothesis of depression by demonstrating altered BDNF levels in ADEVs. ADEVs may be more suitable for developing biomarkers of depression than plasma-derived biomarkers.
Assuntos
Astrócitos , Biomarcadores , Fator Neurotrófico Derivado do Encéfalo , Transtorno Depressivo Maior , Vesículas Extracelulares , Plasticidade Neuronal , Humanos , Fator Neurotrófico Derivado do Encéfalo/sangue , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/química , Masculino , Feminino , Plasticidade Neuronal/fisiologia , Adulto , Pessoa de Meia-Idade , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/metabolismo , Biomarcadores/sangue , Astrócitos/metabolismo , Tetraspanina 28/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Estudos de Casos e Controles , Proteínas de Ligação ao Cálcio , Proteínas de Ciclo Celular , Complexos Endossomais de Distribuição Requeridos para TransporteRESUMO
BACKGROUND: Selective Serotonin Reuptake Inhibitors (SSRIs) represent a diverse class of medications widely prescribed for depression and anxiety. Despite their common use, there is an absence of large-scale, real-world evidence capturing the heterogeneity in their effects on individuals. This study addresses this gap by utilizing naturalistic search data to explore the varied impact of six different SSRIs on user behavior. METHODS: The study sample included â¼508 thousand Bing users with searches for one of six SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) from April-December 2022, comprising 510 million queries. Cox proportional hazard models were employed to examine 30 topics (e.g., shopping, tourism, health) and 195 health symptoms (e.g., anxiety, weight gain, impotence), using each SSRI as a reference. We assessed the relative hazard ratios between drugs and, where feasible, ranked the SSRIs based on their observed effects. We used Cox proportional hazard models in order to account for both the likelihood of users searching for a particular topic or symptom and the associated time to that search. The temporal aspect aided in distinguishing between potential symptoms of the disorder, short-term medication side effects, and later appearing side effects. RESULTS: Differences were found in search behaviors associated with each SSRI. E.g., fluvoxamine was associated with a significantly higher likelihood of searching weight gain compared to all other SSRIs (HRs 1.85-2.93). Searches following citalopram were associated with significantly higher rates of later impotence queries compared to all other SSRIs (HRs 5.11-7.76), except fluvoxamine. Fluvoxamine was associated with a significantly higher rate of health related searches than all other SSRIs (HRs 2.11-2.36). CONCLUSIONS: Our study reveals new insights into the varying SSRI impacts, suggesting distinct symptom profiles. This novel use of large-scale, naturalistic search data contributes to pharmacovigilance efforts, enhancing our understanding of intra-class variation among SSRIs, potentially uncovering previously unidentified drug effects.
Assuntos
Citalopram , Fluvoxamina , Inibidores Seletivos de Recaptação de Serotonina , Humanos , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Fluvoxamina/efeitos adversos , Fluvoxamina/farmacologia , Citalopram/efeitos adversos , Masculino , Adulto , Feminino , Antidepressivos/efeitos adversos , Fluoxetina/efeitos adversos , Modelos de Riscos Proporcionais , Paroxetina/efeitos adversos , Escitalopram/farmacologia , Escitalopram/administração & dosagem , Sertralina/efeitos adversos , Depressão/tratamento farmacológicoRESUMO
The main hurdles with current therapies for major depressive disorder (MDD) include lack of efficacy, therapeutic latency, and adverse drug reactions. Add-on therapy to conventional antidepressants may result in better therapeutic outcomes to overcome these obstacles. Sarcosine (N-methyl glycine), an endogenous amino acid that acts by modulating the NMDA receptor, is available as a dietary supplement. So, the present study was planned to evaluate the efficacy and safety of add-on sarcosine to SSRIs in MDD. In the present randomized, double-blind clinical trial (NCT04975100), 60 eligible participants with MDD were randomly assigned to either the test group (SSRI + sarcosine) or the control group (SSRI + placebo). Clinical and biochemical parameters like MADRS, CGI, serum BDNF, and serum glycine were assessed at baseline and eight weeks. The mean reduction in MADRS score was significant in both the control (-8.7, 95% CI: -11.0 to -6.4, p < 0.001) and the test group (-13.3, 95% CI: -14.9 to -11.7, p < 0.001), but the change in the test group was significantly greater (-4.6, 95% CI: -7.5 to -1.7, p = 0.003). The test group had a significantly higher response rate (p = 0.007) and remission rate (p = 0.038) compared to the control group. There was a significant increase in serum BDNF in both groups; however, the change in the test group was significantly higher than in the control group (p = 0.041). Similarly, the test group had a significantly higher increase in serum glycine than the control group (p < 0.001). Sarcosine may be considered an efficacious and safe add-on therapy to standard SSRIs in the management of MDD. ClinicalTrial.gov IdentifierNCT04975100.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Transtorno Depressivo Maior , Quimioterapia Combinada , Sarcosina , Inibidores Seletivos de Recaptação de Serotonina , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/sangue , Masculino , Feminino , Adulto , Sarcosina/farmacologia , Sarcosina/sangue , Sarcosina/administração & dosagem , Método Duplo-Cego , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Pessoa de Meia-Idade , Fator Neurotrófico Derivado do Encéfalo/sangue , Adulto Jovem , Avaliação de Resultados em Cuidados de Saúde , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Antidepressivos/farmacologiaRESUMO
BACKGROUND: Fluoxetine is present in breast milk, yet it is unclear to what extent it, or its active metabolite, norfluoxetine, reaches the brain of the infant and what the effects of such exposure on neurobiological processes are. We therefore aimed to quantify the concentration of passively administered fluoxetine and norfluoxetine in the whole brains of exposed Flinders sensitive line (FSL) offspring and establish their influence on serotonergic function and redox status. METHODS: Adult FSL dams received fluoxetine (10 mg/kg/day), or placebo for fourteen days, beginning on postpartum day 04. Offspring were passively exposed to fluoxetine until postnatal day 18 and euthanized on postnatal day 22. Whole brain fluoxetine, norfluoxetine, serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and reduced (GSH) and oxidized glutathione (GSSG) concentrations were measured via liquid chromatography-mass spectrometry (LC-MS) analysis. RESULTS: Whole-brain serotonin and 5-hydroxyindoleacetic acid concentrations, and serotonin turnover (5-HIAA/5-HT) were comparable between strains. Treatment-naïve FSL rats had lower GSH and higher GSSG whole-brain concentrations, relative to FRL controls, and an overall decreased GSH/GSSG ratio. Passively administered fluoxetine resulted in undetectable whole-brain concentrations, while norfluoxetine averaged 41.28 ± 6.47 ng/g. Serotonin turnover of FSL rats was unaffected by passively administered fluoxetine, while redox status (GSH/GSSG) was decreased. CONCLUSION: Our findings confirm that passively administered fluoxetine reaches the infant brain in the form of norfluoxetine and may manipulate processes of oxidative stress regulation. Further studies into the long-term bio-behavioural effects are however needed to effectively inform breast feeding mothers on the safety of antidepressant-use.
Assuntos
Encéfalo , Fluoxetina , Inibidores Seletivos de Recaptação de Serotonina , Serotonina , Animais , Fluoxetina/análogos & derivados , Fluoxetina/farmacologia , Serotonina/metabolismo , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Feminino , Ratos , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Masculino , Gravidez , Glutationa/metabolismoRESUMO
The role of serotonin in human behaviour is informed by approaches which allow in vivo modification of synaptic serotonin. However, characterising the effects of increased serotonin signalling in human models of behaviour is challenging given the limitations of available experimental probes, notably selective serotonin reuptake inhibitors. Here we use a now-accessible approach to directly increase synaptic serotonin in humans (a selective serotonin releasing agent) and examine its influence on domains of behaviour historically considered core functions of serotonin. Computational techniques, including reinforcement learning and drift diffusion modelling, explain participant behaviour at baseline and after week-long intervention. Reinforcement learning models reveal that increasing synaptic serotonin reduces sensitivity for outcomes in aversive contexts. Furthermore, increasing synaptic serotonin enhances behavioural inhibition, and shifts bias towards impulse control during exposure to aversive emotional probes. These effects are seen in the context of overall improvements in memory for neutral verbal information. Our findings highlight the direct effects of increasing synaptic serotonin on human behaviour, underlining its role in guiding decision-making within aversive and more neutral contexts, and offering implications for longstanding theories of central serotonin function.
Assuntos
Serotonina , Humanos , Serotonina/metabolismo , Masculino , Feminino , Adulto , Adulto Jovem , Reforço Psicológico , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Emoções/fisiologia , Inibição Psicológica , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Aprendizagem/fisiologia , Tomada de Decisões/fisiologia , Memória/fisiologia , Memória/efeitos dos fármacosRESUMO
Obsessive-compulsive disorder (OCD) is a chronic mental disease that affects approximately 2% of the population. Obsessions and compulsions are troublesome for patients and may disturb their everyday activities. The pathogenesis of this disease is still not fully elucidated, but dysfunctions of serotonin-, dopamine- and glutamate-mediated neurotransmission together with early maladaptive schemas seem of importance. Pharmacological treatment includes drugs affecting the serotoninergic, dopaminergic, and glutamatergic systems, such as selective serotonin reuptake inhibitors (SSRIs). Providing that up to 40% of patients with OCD are resistant to the currently available medications, there is a need for novel and effective therapies. Recent discoveries suggest that psilocybin, a non-physically addictive psychoactive substance, may ameliorate disease symptoms. When used in appropriate doses and under strict clinical control, psilocybin appears as a valuable treatment for OCD. This narrative article provides a thorough overview of OCD's etiology, current treatment options, and the emerging evidence supporting psilocybin's efficacy in managing OCD symptoms.
Assuntos
Alucinógenos , Transtorno Obsessivo-Compulsivo , Psilocibina , Humanos , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Psilocibina/uso terapêutico , Psilocibina/farmacologia , Alucinógenos/uso terapêutico , Alucinógenos/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , AnimaisRESUMO
BACKGROUND: Borderline personality disorder (BPD) is a severe mental illness, with high rates of co-morbid depression and suicidality. Despite the importance of optimizing treatment in BPD, little is known about how neural processes relate to individual treatment response. This study examines how baseline regional brain blood oxygen level dependent (BOLD) activation during a functional magnetic resonance imaging (fMRI) task of emotion regulation is related to treatment response following a six-month randomized clinical trial of Dialectical Behavior Therapy (DBT) or Selective Serotonin Reuptake Inhibitor (SSRI) treatment. METHODS: Unmedicated females with BPD (N = 37), with recent suicidal behavior or self-injury, underwent an fMRI task in which negative personal memories were presented and they were asked to distance (i.e., downregulate their emotional response) or immerse (i.e., experience emotions freely). Patients were then randomized to DBT (N = 16) or SSRI (N = 21) treatment, with baseline and post-treatment depression and BPD severity assessed. RESULTS: BOLD activity in prefrontal cortex, anterior cingulate, and insula was associated with distancing. Baseline BOLD during distancing in dorsolateral, ventrolateral, and orbital prefrontal cortex (dlPFC, vlPFC, OFC) differentially predicted depression response across treatment groups, with higher activity predicting better response in the SSRI group, and lower activity predicting better response in the DBT group. LIMITATIONS: All female samples. DISCUSSION: Findings indicate that greater prefrontal engagement during emotion regulation may predict more antidepressant benefit from SSRIs, whereas lower engagement may predict better response to DBT. These results suggest different mechanisms of action for SSRI and DBT treatment, and this may allow fMRI to guide individualized treatment selection.
Assuntos
Transtorno da Personalidade Borderline , Regulação Emocional , Imageamento por Ressonância Magnética , Córtex Pré-Frontal , Inibidores Seletivos de Recaptação de Serotonina , Humanos , Transtorno da Personalidade Borderline/fisiopatologia , Transtorno da Personalidade Borderline/terapia , Transtorno da Personalidade Borderline/tratamento farmacológico , Transtorno da Personalidade Borderline/diagnóstico por imagem , Feminino , Regulação Emocional/fisiologia , Córtex Pré-Frontal/fisiopatologia , Córtex Pré-Frontal/diagnóstico por imagem , Adulto , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Terapia do Comportamento Dialético , Adulto Jovem , Resultado do Tratamento , Giro do Cíngulo/fisiopatologia , Giro do Cíngulo/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/fisiopatologia , Emoções/fisiologia , Comportamento Autodestrutivo/fisiopatologia , Comportamento Autodestrutivo/terapiaRESUMO
Previous studies have suggested a role for selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac®) in the treatment of dizziness and inner ear vestibular dysfunction. The potential mechanism of action within the vestibular system remains unclear; however, fluoxetine has been reported to block certain types of K+ channel in other systems. Here, we investigated the direct actions of fluoxetine on membrane currents in presynaptic hair cells and postsynaptic calyx afferents of the gerbil peripheral vestibular system using whole cell patch clamp recordings in crista slices. We explored differences in K+ currents in peripheral zone (PZ) and central zone (CZ) calyces of the crista and their response to fluoxetine application. Outward K+ currents in PZ calyces showed greater inactivation at depolarized membrane potentials compared to CZ calyces. The application of 100 µM fluoxetine notably reduced K+ currents in calyx terminals within both zones of the crista, and the remaining currents exhibited distinct traits. In PZ cells, fluoxetine inhibited a non-inactivating K+ current and revealed a rapidly activating and inactivating K+ current, which was sensitive to blocking by 4-aminopyridine. This was in contrast to CZ calyces, where low-voltage-activated and non-inactivating K+ currents persisted following application of 100 µM fluoxetine. Additionally, marked inhibition of transient inward Na+ currents by fluoxetine was observed in calyces from both crista zones. Different concentrations of fluoxetine were tested, and the EC50 values were found to be 40 µM and 32 µM for K+ and Na+ currents, respectively. In contrast, 100 µM fluoxetine had no impact on voltage-dependent K+ currents in mechanosensory type I and type II vestibular hair cells. In summary, micromolar concentrations of fluoxetine are expected to strongly reduce both Na+ and K+ conductance in afferent neurons of the peripheral vestibular system in vivo. This would lead to inhibition of action potential firing in vestibular sensory neurons and has therapeutic implications for disorders of balance.
Assuntos
Fluoxetina , Gerbillinae , Fluoxetina/farmacologia , Animais , Potenciais da Membrana/efeitos dos fármacos , Vestíbulo do Labirinto/efeitos dos fármacos , Vestíbulo do Labirinto/metabolismo , Técnicas de Patch-Clamp , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Canais de Potássio/metabolismo , Masculino , Células Ciliadas Vestibulares/efeitos dos fármacos , Células Ciliadas Vestibulares/metabolismoRESUMO
BACKGROUND: There are limited data regarding gamma-aminobutyric acid (GABA) allosteric modulator sleep-aid medications in persons with depression, insomnia, and suicidal ideation (SI). AIMS: This secondary analysis examined the relationship of age to insomnia and the impact of age on the treatment of insomnia with zolpidem extended-release (zolpidem-ER) in depressed suicidal patients. A prior report found that the addition of zolpidem-ER promoted significantly superior reductions in global severity of insomnia in depressed outpatients with insomnia and SI over 8 weeks, but here we report the differences among early, middle, and late insomnia. METHODS: This secondary analysis examined the three early, middle, and late insomnia items of the Hamilton Rating Scale for Depression (HRSD) and their relationship to age and responsiveness to treatment with zolpidem-ER. One hundred and three patients with major depression, SI, and insomnia received open-label serotonin reuptake inhibitors and were randomly allocated 1:1 to receive zolpidem-ER or placebo at bedtime. Results: Older age at baseline was associated with worse middle and late insomnia, but not with early insomnia. Subsequent treatment with zolpidem-ER produced superior improvement in early and middle insomnia, but not late insomnia. CONCLUSIONS: These findings are consistent with the known age-related advancement of sleep timing in the general population and depressed outpatients and with the expected effects of a short half-life GABA allosteric modulator sleep aid. By implication, prescribers of pharmacologic treatment of insomnia in depressed patients should consider an alternative to zolpidem-ER when late insomnia is a concern.Trial registration number: ClinicalTrials.gov Identifier: NCT01689909.
Assuntos
Preparações de Ação Retardada , Transtorno Depressivo Maior , Piridinas , Medicamentos Indutores do Sono , Distúrbios do Início e da Manutenção do Sono , Ideação Suicida , Zolpidem , Humanos , Zolpidem/administração & dosagem , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Feminino , Adulto , Piridinas/farmacologia , Piridinas/administração & dosagem , Medicamentos Indutores do Sono/administração & dosagem , Medicamentos Indutores do Sono/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Fatores Etários , Idoso , Pacientes Ambulatoriais , Escalas de Graduação Psiquiátrica , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Sono/efeitos dos fármacos , Adulto JovemRESUMO
Fluoxetine, being a selective serotonin uptake inhibitor, has been broadly used to modulate the neurotransmission of serotonin in the central nervous system. Fluoxetine performs a number of crucial central nervous system-related tasks, including neuroprotective effects against microglial neurotoxicity and protecting oxidative cell damage produced by stress in a variety of stress-related unfavourable health disorders. Studies have shown that the drug (fluoxetine) also has analgesic and anti-inflammatory characteristics in addition to its other basic benefits. Furthermore, existing treatment approaches (NSAIDs, DMARDs, corticosteroids and other immunosuppressants) for RA have limited effects on chronic immunological models. These facts served as the basis for carrying out a study on fluoxetine to explore its therapeutics in a chronic inflammatory rat model called Freund's complete adjuvant (FCA)-induced arthritis. The therapeutic effect of the fluoxetine in FCA-induced arthritic rats was assessed by paw volume, paw diameter, arthritic index and body weight at specific days through the experiment of 28 days. These findings were further co-investigated by haematological, biochemical parameters and radiographic imaging at the end of experiment. Furthermore, the modulatory effects on gene expression (NF-κB, PGE2, COX2, INF-γ, IL-4 and IL-10) and antioxidant properties were gritty using qRT-PCR and ELISA kits, respectively, in experimental arthritic rats. Fluoxetine at 10, 20 and 40 mg/kg doses reduced (p < 0.001) the serum concentration of C-reactive protein and rheumatoid factor as well as suppressed the expression of PGE2, NF-kB, COX2 and INF-γ when compared to arthritic control. Moreover, fluoxetine (at higher doses) caused significant rise of IL-4 and IL-10. These findings supported the anti-inflammatory and antioxidant potential of fluoxetine in chronic inflammatory model and endorsed it for clinical trials.
Assuntos
Anti-Inflamatórios , Antioxidantes , Artrite Experimental , Reposicionamento de Medicamentos , Fluoxetina , Adjuvante de Freund , Inflamação , Fluoxetina/farmacologia , Animais , Ratos , Antioxidantes/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Reposicionamento de Medicamentos/métodos , Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Expressão Gênica/efeitos dos fármacos , Ratos Wistar , Modelos Animais de Doenças , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are commonly prescribed to women during pregnancy and breastfeeding despite posing a risk of adverse cognitive outcomes and affective disorders for the child. The consequences of SSRI-induced excess of 5-HT during development for the brain neuromodulatory 5-HT system remain largely unexplored. In this study, an SSRI - fluoxetine (FLX) - was administered to C57BL/6 J mouse dams during pregnancy and lactation to assess its effects on the offspring. We found that maternal FLX decreased field potentials, impaired long-term potentiation, facilitated long-term depression and tended to increase the density of 5-HTergic fibers in the medial prefrontal cortex (mPFC) of female but not male adolescent offspring. These effects were accompanied by deteriorated performance in the temporal order memory task and reduced sucrose preference with no change in marble burying behavior in FLX-exposed female offspring. We also found that maternal FLX reduced the axodendritic tree complexity of 5-HT dorsal raphe nucleus (DRN) neurons in female but not male offspring, with no changes in the excitability of DRN neurons of either sex. While no effects of maternal FLX on inhibitory postsynaptic currents (sIPSCs) in DRN neurons were found, we observed a significant influence of FLX exposure on kinetics of spontaneous excitatory postsynaptic currents (sEPSCs) in DRN neurons. Finally, we report that no changes in field potentials and synaptic plasticity were evident in the mPFC of the offspring after maternal exposure during pregnancy and lactation to a new antidepressant, vortioxetine. These findings show that in contrast to the mPFC, long-term consequences of maternal FLX exposure on the structure and function of DRN 5-HT neurons are mild and suggest a sex-dependent, distinct sensitivity of cortical and brainstem neurons to FLX exposure in early life. Vortioxetine appears to exert fewer side effects with regards to the mPFC when compared with FLX.
Assuntos
Núcleo Dorsal da Rafe , Fluoxetina , Camundongos Endogâmicos C57BL , Plasticidade Neuronal , Córtex Pré-Frontal , Efeitos Tardios da Exposição Pré-Natal , Inibidores Seletivos de Recaptação de Serotonina , Transmissão Sináptica , Animais , Fluoxetina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Feminino , Camundongos , Núcleo Dorsal da Rafe/efeitos dos fármacos , Núcleo Dorsal da Rafe/metabolismo , Gravidez , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Neurônios/efeitos dos fármacos , Serotonina/metabolismo , Potenciação de Longa Duração/efeitos dos fármacosRESUMO
BACKGROUND: Major depressive disorder (MDD) affects multiple functional neural networks. Neuroimaging studies using resting-state functional connectivity (FC) have focused on the amygdala but did not assess changes in connectivity between the left and right amygdala. The current study aimed to examine the inter-hemispheric functional connectivity (homotopic FC, HoFC) between different amygdalar sub-regions in patients with MDD compared to healthy controls, and to examine whether amygdalar sub-regions' HoFC also predicts response to Serotonin Selective Reuptake Inhibitors (SSRIs). METHOD: Sixty-seven patients with MDD and 64 matched healthy controls were recruited. An MRI scan focusing on resting state fMRI and clinical and cognitive evaluations were performed. An atlas seed-based approach was used to identify the lateral and medial sub-regions of the amygdala. HoFC of these sub-regions was compared between groups and correlated with severity of depression, and emotional processing performance. Baseline HoFC levels were used to predict response to SSRIs after 2 months of treatment. RESULTS: Patients with MDD demonstrated decreased inter-hemispheric FC in the medial (F3,120 = 4.11, p = 0.008, η2 = 0.096) but not in the lateral (F3,119 = 0.29, p = 0.82, η2 = 0.008) amygdala compared with healthy controls. The inter-hemispheric FC of the medial sub-region correlated with symptoms severity (r = -0.33, p < 0.001) and emotional processing performance (r = 0.38, p < 0.001). Moreover, it predicted treatment response to SSRIs 65.4 % of the cases. LIMITATIONS: The current study did not address FC changes in MDD biotypes. In addition, structural connectivity was not examined. CONCLUSIONS: Using a unique perspective of the amygdalar distinct areas elucidated differential inter-hemispheric FC patterns in MDD patients, emphasizing the role of interhemispheric communication in depression.
Assuntos
Tonsila do Cerebelo , Transtorno Depressivo Maior , Imageamento por Ressonância Magnética , Inibidores Seletivos de Recaptação de Serotonina , Humanos , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/diagnóstico por imagem , Tonsila do Cerebelo/fisiopatologia , Tonsila do Cerebelo/diagnóstico por imagem , Masculino , Feminino , Adulto , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Pessoa de Meia-Idade , Biomarcadores , Estudos de Casos e Controles , Vias Neurais/fisiopatologia , Emoções/fisiologia , Rede Nervosa/fisiopatologia , Rede Nervosa/diagnóstico por imagemRESUMO
No study has determined the minimal effective dose of trazodone required to induce behavioral changes and its safety profile in rabbits. Therefore, this study aimed to determine the minimal effective dose of trazodone to improve compliance to handling, and to evaluate associated changes in motor activity, physiological and arterial blood gas parameters. Eight intact female New Zealand White rabbits (2-month-old; 1.66 ± 0.12 kg) were included in this prospective, blinded, randomized cross-over study. After a 10-day acclimation, rabbits randomly received placebo or trazodone 10, 20 or 30 mg/kg orally (PLAC, TRAZ10, TRAZ20, TRAZ30) with a 1-week wash-out period. Compliance scoring (dynamic interactive visual analog scale; DIVAS), activity levels measured with accelerometry (T0-T600), physiological parameters (temperature, heart, and respiratory rates), and arterial blood gas parameters (up to T240) were evaluated. Compliance scores, accelerometry, physiological and arterial blood gas parameters and hypoxemia prevalence (PaO2 <60 mmHg) were analyzed using linear mixed models and Chi-squared tests, respectively (P<0.05). When compared with PLAC, DIVAS scores were significantly higher at T80-120, T40-120 and T120-200 in TRAZ10, TRAZ20 and TRAZ30 post-administration, respectively. When compared with baseline, DIVAS scores were significantly higher from T80-160, T40-240 and T80-200 in TRAZ10, TRAZ20 and TRAZ30, respectively. All other parameters were not significantly different. In TRAZ30, hypoxemia was observed in 2/8 rabbits (P=0.104). In conclusion, oral trazodone improved rabbit compliance at all studied dosages, especially 20 mg/kg improved rabbit compliance without decreasing motor activity or causing hypoxemia.
Assuntos
Estudos Cross-Over , Trazodona , Animais , Coelhos , Feminino , Trazodona/administração & dosagem , Trazodona/farmacologia , Administração Oral , Estudos Prospectivos , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Gasometria/veterinária , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
BACKGROUND: The understanding of mechanisms underlying non-response to antidepressants is limited. The latest data highlights the role of insulin resistance (IR) in major depressive disorder (MDD) pathophysiology, presentation, and treatment efficacy. This work aimed to assess IR in MDD and explore the relationships between IR, MDD presentation and non-response to selective serotonin and noradrenaline reuptake inhibitors (SNRI). METHODS: 67 MDD individuals: 36 responsive (MDD T[+]), 31 non-responsive (MDD T[-]) to SNRI and 30 healthy controls were recruited. The treatment response criteria were: Clinical Global Impression Scale-Improvement score of 1 or 2 after ≥ 8 weeks of treatment. Participants were assessed by physician and self-report tools measuring depression, anhedonia, anxiety, bipolarity, sleep quality. Blood samples were collected to assess fasting glucose and insulin levels and calculate HOMA-IR (homeostasis model assessment of insulin resistance). RESULTS: MDD T[-] vs. MDD T[+] had significantly higher body mass index, insulin levels, and HOMA-IR. MDD T[-] presented higher levels of depressed mood, appetite/weight changes, loss of interest, energy, overall depressive symptoms, and sleep impairment; some evaluations suggested higher anhedonia and anxiety in MDD T[-] vs. MDD T[+]. Insulin and IR were weakly but significantly correlated with the severity of psychomotor symptoms, energy level, thoughts of death/suicide, self-criticism, appetite/weight, depressed mood symptoms, sleep problems. IR was weakly but significantly correlated with anhedonia. CONCLUSION: IR appears to be linked to depressive symptoms characteristic of the "metabolic" MDD subtype, such as psychomotor changes, energy level, anhedonia, sleep problems, appetite/weight changes, state and trait anxiety, sleep quality, and non-response to SNRI.