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2.
Medicine (Baltimore) ; 103(11): e37612, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38489675

RESUMO

Lipid emulsion has been shown to effectively relieve refractory cardiovascular collapse resulting from toxic levels of nonlocal anesthetics. The goal of this study was to examine the effect of lipid emulsions on neuropsychiatric drug-induced toxicity using relevant case reports of human patients, with a particular focus on the Glasgow Coma Scale (GCS) score and corrected QT interval, to analyze drugs that frequently require lipid emulsion treatment. The following keywords were used to retrieve relevant case reports from PubMed: "antidepressant or antipsychotic drug or amitriptyline or bupropion or citalopram or desipramine or dosulepin or dothiepin or doxepin or escitalopram or fluoxetine or haloperidol or olanzapine or phenothiazine or quetiapine or risperidone or trazodone" and "lipid emulsion or Intralipid." Lipid emulsion treatment reversed the corrected QT interval prolongation and decreases in Glasgow Coma Scale scores caused by toxic doses of neuropsychiatric drugs, especially lipid-soluble drugs such as amitriptyline, trazodone, quetiapine, lamotrigine, and citalopram. The log P (octanol/water partition coefficient) of the group which required more than 3 lipid emulsion treatments was higher than that that of the group which required less than 3 lipid emulsion treatments. The main rationale to administer lipid emulsion as an adjuvant was as follows: hemodynamic depression intractable to supportive treatment (88.3%) > lipophilic drugs (8.3%) > suspected overdose or no spontaneous breathing (1.6%). Adjuvant lipid emulsion treatment contributed to the recovery of 98.30% of patients with neuropsychiatric drug-induced toxicity. However, further analyses using many case reports are needed to clarify the effects of lipid emulsion resuscitation.


Assuntos
Dotiepina , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Trazodona , Humanos , Fumarato de Quetiapina , Amitriptilina , Citalopram , Emulsões Gordurosas Intravenosas/uso terapêutico
4.
Ann Intern Med ; 177(2): JC15, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38315998

RESUMO

SOURCE CITATION: Ford AC, Wright-Hughes A, Alderson SL, et al; ATLANTIS trialists. Amitriptyline at low-dose and titrated for irritable bowel syndrome as second-line treatment in primary care (ATLANTIS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023;402:1773-1785. 37858323.


Assuntos
Síndrome do Intestino Irritável , Humanos , Amitriptilina/uso terapêutico , Método Duplo-Cego , Síndrome do Intestino Irritável/tratamento farmacológico , Síndrome do Intestino Irritável/diagnóstico , Atenção Primária à Saúde , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase III como Assunto
5.
Handb Clin Neurol ; 199: 67-86, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38307673

RESUMO

Migraine headache is highly prevalent and the most common neurologic disorder, affecting one billion people worldwide. It is also the most disabling condition in people under 50, with a huge impact on working ability, family, and social life. Access to effective preventive medication is important and may be considered if the patient has 6 or more migraine days per month, ineffective abortive agents, or disability on 2 or more days per month. Propranolol, metoprolol, candesartan, topiramate, divalproex, lisinopril, amitriptyline, and venlafaxine have the strongest evidence to support for use. Flunarizine and pizotifen may also be effective. Selection of preventive treatments is based on individual characteristics, comorbid conditions, efficacy, contraindications, side effects, cost, compliance, and drug. An adequate trial of migraine prophylaxis is usually 2 months at the target dose, and it is always important to re-evaluate indication for prophylactic use after a period of time.


Assuntos
Transtornos de Enxaqueca , Humanos , Administração Oral , Amitriptilina/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/prevenção & controle , Propranolol/uso terapêutico , Ácido Valproico/uso terapêutico
6.
Environ Sci Pollut Res Int ; 31(13): 19649-19657, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38363510

RESUMO

The uptake, translocation, and metabolization of four widely used drugs, amitriptyline, orphenadrine, lidocaine, and tramadol, were investigated in a laboratory study. Cress (Lepidium sativum L.) and pea (Pisum sativum L.) were employed as model plants. These plants were grown in tap water containing the selected pharmaceuticals at concentrations ranging from 0.010 to 10 mg L-1, whereby the latter concentration was employed for the (tentative) identification of drug-related metabolites formed within the plant. Thereby, mainly phase I metabolites were detected. Time-resolved uptake studies, with sampling after 1, 2, 4, 8, and 16 days, revealed that all four pharmaceuticals were taken up by the roots and further relocated to plant stem and leaves. Also in these studies, the corresponding phase I metabolites could be detected, and their translocation from root to stem (pea only) and finally leaves could be investigated.


Assuntos
Brassicaceae , Tramadol , Amitriptilina/metabolismo , Orfenadrina/metabolismo , Lidocaína/metabolismo , Plantas/metabolismo , Verduras , Preparações Farmacêuticas/metabolismo , Raízes de Plantas/metabolismo
7.
Psychiatry Res ; 334: 115764, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38350291

RESUMO

Sleep disturbances in posttraumatic stress disorder (PTSD) are a potential target for improving PTSD severity with pharmacotherapy. TNX-102 SL is a bedtime sublingual formulation of cyclobenzaprine with potent binding and antagonist activity at 5-HT2A, α1-adrenergic, H1 histaminergic, and M1 muscarinic receptors, which play roles in the pharmacological management of sleep disturbances. This Phase 3 trial evaluated the efficacy and safety of TNX-102 SL in patients with military-related PTSD. Early and sustained improvements in sleep were associated with TNX-102 SL treatment by PROMIS Sleep Disturbance scale and Clinician Administered PTSD Scale (CAPS-5) "sleep disturbance" item, establishing a sleep quality benefit. Primary analysis comparing change from baseline in CAPS-5 total severity between TNX-102 SL and placebo at week 12 was not significant; however, week 4 was associated with an improvement. Secondary analyses showed TNX-102 SL treatment was associated with benefits on the Clinician Global Impression of Improvement at week 4 and the Patient Global Impression of Change at week 12. Time since trauma exposure was a discriminator of CAPS-5 treatment response in the subgroup ≤ 9 years since the index event. This study provides preliminary evidence that TNX-102 SL is well-tolerated and may promote recovery from PTSD by addressing sleep-related symptoms.


Assuntos
Amitriptilina/análogos & derivados , Militares , Transtornos de Estresse Pós-Traumáticos , Humanos , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Sono , Resultado do Tratamento , Método Duplo-Cego
8.
Pharmacopsychiatry ; 57(2): 69-77, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38354747

RESUMO

INTRODUCTION: CYP2D6 and CYP2C19 functional status as defined by genotype is modulated by phenoconversion (PC) due to pharmacokinetic interactions. As of today, there is no data on the effect size of PC for CYP2C19 functional status. The primary aim of this study was to investigate the impact of PC on CYP2C19 functional status. METHODS: Two patient cohorts (total n=316; 44.2±15.4 years) were investigated for the functional enzyme status of CYP2C19 applying two different correction methods (PCBousman, PCHahn&Roll) as well as serum concentration and metabolite-to-parent ratio of venlafaxine, amitriptyline, mirtazapine, sertraline, escitalopram, risperidone, and quetiapine. RESULTS: There was a decrease in the number of normal metabolizers of CYP2C19 and an increase in the number of poor metabolizers. When controlled for age, sex, and, in the case of amitriptyline, venlafaxine, and risperidone, CYP2D6 functional enzyme status, an association was observed between the CYP2C19 phenotype/functional enzyme status and serum concentration of amitriptyline, sertraline, and escitalopram. DISCUSSION: PC of CYP2C19 changes phenotypes but does not improve correlations with serum concentrations. However, only a limited number of patients received perturbators of CYP2C19. Studies with large numbers of patients are still lacking, and thus, it cannot be decided if there are minor differences and which method of correction to use. For the time being, PC is relevant in individual patients treated with CYP2C19-affecting drugs, for example, esomeprazole. To ensure adequate serum concentrations in these patients, this study suggests the use of therapeutic drug monitoring.


Assuntos
Amitriptilina , Citocromo P-450 CYP2D6 , Humanos , Citocromo P-450 CYP2D6/genética , Cloridrato de Venlafaxina , Farmacogenética , Sertralina , Risperidona , Escitalopram , Citocromo P-450 CYP2C19/genética , Genótipo
9.
Environ Toxicol Pharmacol ; 106: 104372, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38244879

RESUMO

Interaction of nanoplastics (NPls) with other environmental contaminants could affect their uptake by the organisms and their toxicity. Thus, the present study aims to investigate the polystyrene NPls (44 nm) interaction with the antidepressant amitriptyline (AMI) and its toxicity to Danio rerio embryos. A similar toxicological profile for NPls + AMI exposure was found for most of the evaluated endpoints, comparing with AMI single exposure, showing that the presence of NPls did not modulate the AMI toxicity. However, the behavioral assessment showed a different pattern with hypoactivity for the NPls + AMI exposure (NPls - hyperactivity; AMI - no effect). Interaction effects between NPls and AMI were also found in the protein contents (antagonism) and in the total glutathione content (synergism). This study highlights the complexity and unpredictability of NPls interaction with pharmaceuticals, important for an accurate environmental risk assessment and for the developing of effective strategies and interventions against plastic pollution.


Assuntos
Amitriptilina , Poluentes Químicos da Água , Animais , Amitriptilina/toxicidade , Peixe-Zebra/metabolismo , Microplásticos/toxicidade , Poluentes Químicos da Água/toxicidade , Poluentes Químicos da Água/metabolismo , Poliestirenos/toxicidade
10.
J Psychiatr Res ; 170: 375-386, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38215648

RESUMO

Clinical and preclinical studies suggest that hippocampal astrocyte dysfunction is involved in the pathophysiology of depression; however, the underlying molecular mechanisms remain unclear. Here, we attempted to identify the hippocampal astrocytic transcripts associated with antidepressant effects in a mouse model of depression. We used a chronic corticosterone-induced mouse model of depression to assess the behavioral effects of amitriptyline, a tricyclic antidepressant. Hippocampal astrocytes were isolated using fluorescence-activated cell sorting, and RNA sequencing was performed to evaluate the transcriptional profiles associated with depressive effects and antidepressant responses. Depression model mice exhibited typical depression-like behaviors that improved after amitriptyline treatment; the depression group mice also had significantly reduced GFAP-positive astrocyte numbers in hippocampal subfields. Comprehensive transcriptome analysis of hippocampal astrocytes showed opposing responses to amitriptyline in depression group and control mice, suggesting the importance of using the depression model. Transcription factor 7 like 2 (TCF7L2) was the only upstream regulator gene altered in depression model mice and restored in amitriptyline-treated depression model mice. In fact, TCF7L2 expression was significantly decreased in the depression group. The level of TCF7L2 long non-coding RNA, which controls mRNA expression of the TCF7L2 gene, was also significantly decreased in this group and recovered after amitriptyline treatment. The Gene Ontology biological processes associated with astrocytic TCF7L2 included proliferation, differentiation, and cytokine production. We identified TCF7L2 as a gene associated with depression- and antidepressant-like behaviors in response to amitriptyline in hippocampal astrocytes. Our findings could provide valuable insights into the mechanism of astrocyte-mediated antidepressant effects.


Assuntos
Amitriptilina , Astrócitos , Camundongos , Animais , Amitriptilina/farmacologia , Amitriptilina/metabolismo , Astrócitos/metabolismo , Depressão/tratamento farmacológico , Antidepressivos/farmacologia , Hipocampo , Modelos Animais de Doenças
11.
Clin Neuropharmacol ; 47(2): 33-36, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38285063

RESUMO

OBJECTIVE: Burning mouth syndrome (BMS) is an intractable chronic pain disorder characterized by a burning sensation without organic abnormalities in the oral mucosa. Amitriptyline may be effective for BMS or, conversely, may exacerbate pain. QTc is necessary for monitoring psychotropic adverse effects, but it is not known if it is a predictor of efficacy for BMS. We investigated the efficacy of amitriptyline in BMS and its effect on QTc. METHODS: Visual analog scale and electrocardiogram were examined before and 1 month after treatment in 51 consecutive patients diagnosed with BMS according to the International Classification of Headache Disorders, Third Edition (ICHD-3), criteria and treated with amitriptyline. RESULTS: There were 26 amitriptyline responders and 25 nonresponders, with no differences in age, sex, and amitriptyline dosage. Amitriptyline responders showed little change in QTc, whereas nonresponders showed a trend toward significantly shorter QTc. Changes in visual analog scale correlated statistically significantly with changes in QTc (Spearman rank correlation coefficient: 0384; P = 0.0054). The degree of pain tended to worsen with QTc shortening. CONCLUSION: Amitriptyline provides analgesia in about half of BMS patients, but some BMS patients have worse pain with amitriptyline. Not only do changes in the QTc detect amitriptyline adverse effects with prolongation, but also, conversely, its shortening predicts amitriptyline ineffectiveness.


Assuntos
Amitriptilina , Síndrome da Ardência Bucal , Humanos , Amitriptilina/efeitos adversos , Manejo da Dor , Dor/induzido quimicamente , Eletrocardiografia
12.
Neurotherapeutics ; 21(1): e00296, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38241158

RESUMO

While loss-of-function (LoF) variants in KCNQ2 are associated with a spectrum of neonatal-onset epilepsies, gain-of-function (GoF) variants cause a more complex phenotype that precludes neonatal-onset epilepsy. In the present work, the clinical features of three patients carrying a de novo KCNQ2 Y141N (n â€‹= â€‹1) or G239S variant (n â€‹= â€‹2) respectively, are described. All three patients had a mild global developmental delay, with prominent language deficits, and strong activation of interictal epileptic activity during sleep. Epileptic seizures were not reported. The absence of neonatal seizures suggested a GoF effect and prompted functional testing of the variants. In vitro whole-cell patch-clamp electrophysiological experiments in Chinese Hamster Ovary cells transiently-transfected with the cDNAs encoding Kv7.2 subunits carrying the Y141N or G239S variants in homomeric or heteromeric configurations with Kv7.2 subunits, revealed that currents from channels incorporating mutant subunits displayed increased current densities and hyperpolarizing shifts of about 10 â€‹mV in activation gating; both these functional features are consistent with an in vitro GoF phenotype. The antidepressant drug amitriptyline induced a reversible and concentration-dependent inhibition of current carried by Kv7.2 Y141N and G239S mutant channels. Based on in vitro results, amitriptyline was prescribed in one patient (G239S), prompting a significant improvement in motor, verbal, social, sensory and adaptive behavior skillsduring the two-year-treatment period. Thus, our results suggest that KCNQ2 GoF variants Y141N and G239S cause a mild DD with prominent language deficits in the absence of neonatal seizures and that treatment with the Kv7 channel blocker amitriptyline might represent a potential targeted treatment for patients with KCNQ2 GoF variants.


Assuntos
Amitriptilina , Epilepsia , Recém-Nascido , Cricetinae , Animais , Humanos , Cricetulus , Células CHO , Mutação com Ganho de Função , Fenótipo , Convulsões , Canal de Potássio KCNQ2/genética
13.
Medicine (Baltimore) ; 103(1): e36790, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38181253

RESUMO

There are studies on the effect of low-dose amitriptyline on pain control, but there is a lack of studies on the use of amitriptyline for chronic pain and the factors associated with the prescription of traditional doses. We used a national sample cohort of patients aged ≥ 18 years who were prescribed amitriptyline along with chronic pain, without psychiatric disorders, between 2002 to 2015. We categorized the prescriptions into 2 groups according to the daily dose: low doses (≤25 mg) and traditional doses (>25 mg). Multivariable logistic regression models were used to identify factors associated with traditional dose prescriptions. Among 177,769 prescriptions for amitriptyline, 15,119 (8.5%) were prescribed for chronic pain. The prevalence of prescriptions and proportion of traditional doses of amitriptyline tended to decrease during the study period. Male sex (odds ratio [OR] 1.09, 95% confidence interval [CI] 1.05-1.13); age 65-80 years (OR 1.12, 95% CI 1.08-1.16), especially ≥ 80 years (OR 1.55, 95% CI 1.45-1.65); headaches (OR 1.18, 95% CI 1.10-1.27), receiving medical aids (OR 2.58, 95% CI 2.46-2.71); and being prescribed benzodiazepines or zolpidem concomitantly (OR 1.10, 95% CI 1.06-1.15) were significantly associated with traditional dose prescriptions of amitriptyline. Although traditional dose prescriptions of amitriptyline have been declining, close monitoring is still required in the presence of the above-mentioned factors.


Assuntos
Amitriptilina , Dor Crônica , Humanos , Masculino , Estudos Transversais , Amitriptilina/uso terapêutico , Dor Crônica/tratamento farmacológico , Benzodiazepinas , Cefaleia
14.
Am J Psychiatry ; 181(1): 47-56, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37849303

RESUMO

OBJECTIVE: The authors investigated the clinical outcomes of commonly used antidepressants among older adults who initiated first-time antidepressants for depression by analyzing the 1-year risk of selected clinically relevant outcomes. METHODS: This cohort study used nationwide Danish registry data and included all older adults who redeemed a first-time (since 1995) antidepressant prescription with an indication of depression between 2006 and 2017. Only the 10 most frequently redeemed antidepressants were included in the analyses. Outcomes included discontinuation, switching, augmentation, psychiatric hospital contacts, suicide attempt or self-harm, fall-related injuries, cardiovascular events, and all-cause mortality. Incidence rate ratios (IRRs) and 95% confidence intervals were estimated using Poisson regression models, controlling for potential confounders. RESULTS: The study sample included 93,883 older adults (mean age, 78.0 years, SD=7.5 years; 56% female). The most frequently prescribed antidepressants were selective serotonin reuptake inhibitors (citalopram, 47.04%; escitalopram, 11.81%; fluoxetine, 0.55%; paroxetine, 0.52%; sertraline, 11.17%), serotonin-norepinephrine reuptake inhibitors (duloxetine, 0.71%; venlafaxine, 1.54%), a tricyclic antidepressant (amitriptyline, 1.86%), and two atypical antidepressants (mianserin, 1.93%; mirtazapine, 22.87%). Compared with users of sertraline (the reference drug in this analysis, as Danish guidelines recommend it as the first-choice treatment for depression), users of most of the other nine antidepressants had a significantly higher risk of discontinuation (e.g., mirtazapine: IRR=1.55, 95% CI=1.50-1.61; venlafaxine: IRR=1.22, 95% CI=1.12-1.32), switching (amitriptyline: IRR=1.45, 95% CI=1.15-1.81; venlafaxine: IRR=1.47, 95% CI=1.20-1.80), augmentation, cardiovascular events, and mortality. Overall, mirtazapine and venlafaxine users had the most adverse outcomes compared with sertraline users. These results remained consistent in analyses stratified by sex and age (≤75 years vs. >75 years). CONCLUSIONS: This real-world evidence suggests that clinical outcomes may vary among initiators of commonly used antidepressants in older adults, which may inform benefit-risk evaluation at treatment initiation, and highlights the importance of careful selection of antidepressant treatment.


Assuntos
Doenças Cardiovasculares , Sertralina , Feminino , Humanos , Idoso , Masculino , Cloridrato de Venlafaxina , Sertralina/uso terapêutico , Depressão/tratamento farmacológico , Estudos de Coortes , Mirtazapina/uso terapêutico , Amitriptilina , Antidepressivos/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina , Dinamarca/epidemiologia
15.
Neurogastroenterol Motil ; 36(1): e14705, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37953495

RESUMO

BACKGROUND: Amitriptyline (AT) is recommended as first-line prophylactic therapy in patients with cyclic vomiting syndrome (CVS). However, significant side effects limit its use and dosing is based on trial and error. Though the Clinical Pharmacogenetic Implementation Consortium (CPIC) Guidelines recommend dosing for AT based on CY2D6 and CYP2C19 genotype profile, this is not followed in clinical practice. METHODS: This pilot study determined CYP2C19 and CYP2D6 genotypes and ascertained its association with adverse drug reactions (ADRs), clinical response, and serum concentration of AT and nortriptyline in a well-characterized cohort of adults with CVS. KEY RESULTS: Of 46 subjects with CVS, age 33 ± 12 years, 61% female, 85% Caucasian, a third (33%) had normal CYP2C19 metabolizer status, while 4% were poor, and 43% were ultrarapid metabolizers. Most (61%) had normal CYP2D6 genotype while 9% were poor and 2% were ultra-rapid metabolizers. There was no statistically significant association between genotype and ADRs, clinical response or serum drug concentration. There was a trend towards significance between genotype and clinical response, with 64% of responders having normal CYP2D6 metabolism versus 36% of nonresponders (p = 0.06). ADRs were encountered in 46% of patients with 28% discontinuing the medication as a result. CONCLUSIONS AND INFERENCES: A subset of patients with CVS have dysfunctional alleles of CYP2C19 and CYP2D6. Larger prospective studies to evaluate the clinical impact of pharmacogenomic testing in CVS are needed. This has the potential to optimize clinical management, predict ADRs and allow for personalized therapy.


Assuntos
Citocromo P-450 CYP2D6 , Testes Farmacogenômicos , Adulto , Humanos , Feminino , Adulto Jovem , Pessoa de Meia-Idade , Masculino , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Estudos Prospectivos , Citocromo P-450 CYP2C19/genética , Projetos Piloto , Amitriptilina , Genótipo
16.
J Investig Med ; 72(2): 171-177, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37997432

RESUMO

As more states legalize cannabinoid products for recreational use and medicinal purposes, the prevalence of cannabinoid hyperemesis syndrome has become increasingly common. Yet, it remains unrecognized to many healthcare providers along with the most efficacious treatments. Cannabinoid hyperemesis syndrome most often presents with episodic vomiting secondary to chronic daily cannabis use over several months to years. Patients often complain of nausea and abdominal pain that is improved by taking hot showers or baths. Symptoms are alleviated with the cessation of cannabis use over a period of 6-12 months. Treatment for acute attacks often consists of parenteral benzodiazepines in the inpatient setting. Long-term management and prevention of further attacks are aided by tricyclic antidepressants such as amitriptyline with a dose range of 50-200 mg/d. Once a patient is in remission, amitriptyline can be tapered slowly. As cannabis becomes more widely available and accepted in the continental United States, so must education on the diagnosis of cannabinoid hyperemesis syndrome and treatment strategies.


Assuntos
Cannabis , Humanos , Cannabis/efeitos adversos , Prevalência , Amitriptilina , Vômito/induzido quimicamente , Vômito/epidemiologia , Vômito/terapia
18.
J Am Geriatr Soc ; 72(1): 91-101, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37933734

RESUMO

BACKGROUND: The growth of oral muscle relaxant prescriptions among older adults in the United States is concerning due to the drugs' adverse sedative effects. Baclofen is a gamma-aminobutyric acid agonist muscle relaxant that is associated with encephalopathy. We characterized the risk of fall and fracture associated with oral baclofen against other muscle relaxants (tizanidine or cyclobenzaprine) in older adults. METHODS: We designed a new-user, active-comparator study using tertiary health system data from Geisinger Health, Pennsylvania (January 2005 through December 2018). Older adults (aged ≥65 years) newly treated with baclofen, tizanidine, or cyclobenzaprine were included. Propensity score-based inverse probability of treatment weighting (IPTW) was used to balance the treatment groups on 58 baseline characteristics. Fine-Gray competing risk regression was used to estimate the risk of fall and fracture. RESULTS: The study cohort comprised of 2205 new baclofen users, 1103 new tizanidine users, and 9708 new cyclobenzaprine users. During a median follow-up of 100 days, baclofen was associated with a higher risk of fall compared to tizanidine (IPTW incidence rate, 108.4 vs. 61.9 per 1000 person-years; subdistribution hazard ratio [SHR], 1.68 [95% CI, 1.20-2.36]). The risk of fall associated with baclofen was comparable to cyclobenzaprine (SHR, 1.17 [95% CI, 0.93-1.47]) with a median follow-up of 106 days. The risk of fracture was similar among patients treated with baclofen versus tizanidine (SHR, 0.85 [95% CI, 0.63-1.14]) or cyclobenzaprine (SHR, 0.85 [95% CI, 0.67-1.07]). CONCLUSIONS: The risk of fall associated with baclofen was greater than tizanidine, but not compared to cyclobenzaprine in older adults. The risk of fracture was comparable among the older users of baclofen, tizanidine, and cyclobenzaprine. Our findings may inform risk-benefit considerations in the increasingly common clinical encounters where oral muscle relaxants are prescribed.


Assuntos
Amitriptilina/análogos & derivados , Fraturas Ósseas , Relaxantes Musculares Centrais , Humanos , Idoso , Baclofeno/efeitos adversos , Relaxantes Musculares Centrais/efeitos adversos , Acidentes por Quedas , Estudos de Coortes , Fraturas Ósseas/induzido quimicamente
19.
Neuropsychopharmacology ; 49(3): 561-572, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37673966

RESUMO

Prototypic antidepressants, such as tricyclic/tetracyclic antidepressants (TCAs), have multiple pharmacological properties and have been considered to be more effective than newer antidepressants, such as selective serotonin reuptake inhibitors, in treating severe depression. However, the clinical contribution of non-monoaminergic effects of TCAs remains elusive. In this study, we discovered that amitriptyline, a typical TCA, directly binds to the lysophosphatidic acid receptor 1 (LPAR1), a G protein-coupled receptor, and activates downstream G protein signaling, while exerting a little effect on ß-arrestin recruitment. This suggests that amitriptyline acts as a G protein-biased agonist of LPAR1. This biased agonism was specific to TCAs and was not observed with other antidepressants. LPAR1 was found to be involved in the behavioral effects of amitriptyline. Notably, long-term infusion of mouse hippocampus with the potent G protein-biased LPAR agonist OMPT, but not the non-biased agonist LPA, induced antidepressant-like behavior, indicating that G protein-biased agonism might be necessary for the antidepressant-like effects. Furthermore, RNA-seq analysis revealed that LPA and OMPT have opposite patterns of gene expression changes in the hippocampus. Pathway analysis indicated that long-term treatment with OMPT activated LPAR1 downstream signaling (Rho and MAPK), whereas LPA suppressed LPAR1 signaling. Our findings provide insights into the mechanisms underlying the non-monoaminergic antidepressant effects of TCAs and identify the G protein-biased agonism of LPAR1 as a promising target for the development of novel antidepressants.


Assuntos
Amitriptilina , Depressão , Camundongos , Animais , Amitriptilina/farmacologia , Depressão/tratamento farmacológico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Antidepressivos Tricíclicos , Proteínas de Ligação ao GTP
20.
Curr Neuropharmacol ; 22(4): 749-805, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37533247

RESUMO

Antidepressants are a commonly used, easily accessible, and overall safe treatment option for post-traumatic stress disorder (PTSD). The present review aims to evaluate the efficacy and safety of antidepressants in treating sleep disturbances in patients with PTSD. PubMed and the Cochrane Library were searched (July 2022) for systematic reviews and meta-analyses on the treatment of PTSD. Moreover, PubMed and ClinicalTrials.gov were searched for individual trials investigating the antidepressant treatment of PTSD (up to September 2022), and reference lists of all possibly relevant identified studies were screened. Sleep-related outcomes, i.e., total sleep time, sleep quality, dreams/ nightmares, insomnia, and somnolence, were extracted independently by at least two reviewers. Metaanalytic evaluations were performed wherever possible. 39 randomised controlled trials (RCTs) were identified; data from pooled analyses, reviews, and observational studies were used for antidepressants with a weak evidence base or when their findings were deemed important. Overall, scarce data exist on the effects of antidepressants on sleep outcomes among patients with PTSD. Some evidence may support the use of amitriptyline, nefazodone, paroxetine, and sertraline for improving sleep in patients with PTSD. Τhere was a meta-analytical trend indicating improvement of nightmares with fluoxetine, less insomnia with amitriptyline and more with brofaromine, as well as more somnolence with paroxetine vs. placebo, respectively. However, data from more than 1 RCT with a considerable number of patients were only available for paroxetine. Evidence is insufficient to draw safe conclusions. More and better-designed RCTs, with consistent reporting of sleep-related outcomes, are needed.


Assuntos
Distúrbios do Início e da Manutenção do Sono , Transtornos de Estresse Pós-Traumáticos , Humanos , Transtornos de Estresse Pós-Traumáticos/complicações , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Paroxetina/efeitos adversos , Amitriptilina/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Sonolência , Revisões Sistemáticas como Assunto , Antidepressivos/uso terapêutico
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