RESUMO
BACKGROUND: Antidepressants are used to treat acute depression in patients with bipolar I disorder, but their effect as maintenance treatment after the remission of depression has not been well studied. METHODS: We conducted a multisite, double-blind, randomized, placebo-controlled trial of maintenance of treatment with adjunctive escitalopram or bupropion XL as compared with discontinuation of antidepressant therapy in patients with bipolar I disorder who had recently had remission of a depressive episode. Patients were randomly assigned in a 1:1 ratio to continue treatment with antidepressants for 52 weeks after remission or to switch to placebo at 8 weeks. The primary outcome, assessed in a time-to-event analysis, was any mood episode, as defined by scores on scales measuring symptoms of hypomania or mania, depression, suicidality, and mood-episode severity; additional treatment or hospitalization for mood symptoms; or attempted or completed suicide. Key secondary outcomes included the time to an episode of mania or hypomania or depression. RESULTS: Of 209 patients with bipolar I disorder who participated in an open-label treatment phase, 150 who had remission of depression were enrolled in the double-blind phase in addition to 27 patients who were enrolled directly. A total of 90 patients were assigned to continue treatment with the prescribed antidepressant for 52 weeks (52-week group) and 87 were assigned to switch to placebo at 8 weeks (8-week group). The trial was stopped before full recruitment was reached owing to slow recruitment and funding limitations. At 52 weeks, 28 of the patients in the 52-week group (31%) and 40 in the 8-week group (46%) had a primary-outcome event. The hazard ratio for time to any mood episode in the 52-week group relative to the 8-week group was 0.68 (95% confidence interval [CI], 0.43 to 1.10; P = 0.12 by log-rank test). A total of 11 patients in the 52-week group (12%) as compared with 5 patients in the 8-week group (6%) had mania or hypomania (hazard ratio, 2.28; 95% CI, 0.86 to 6.08), and 15 patients (17%) as compared with 35 patients (40%) had recurrence of depression (hazard ratio, 0.43; 95% CI, 0.25 to 0.75). The incidence of adverse events was similar in the two groups. CONCLUSIONS: In a trial involving patients with bipolar I disorder and a recently remitted depressive episode, adjunctive treatment with escitalopram or bupropion XL that continued for 52 weeks did not show a significant benefit as compared with treatment for 8 weeks in preventing relapse of any mood episode. The trial was stopped early owing to slow recruitment and funding limitations. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00958633.).
Assuntos
Transtorno Bipolar , Humanos , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/diagnóstico , Mania , Bupropiona/efeitos adversos , Depressão , Escitalopram , Canadá , Recidiva Local de Neoplasia/tratamento farmacológico , Antidepressivos/efeitos adversos , Método Duplo-Cego , Resultado do TratamentoRESUMO
Individuals with a history of early-life stress (ELS) tend to have an altered course of depression and lower treatment response rates. Research suggests that ELS alters brain development, but the molecular changes in the brain following ELS that may mediate altered antidepressant response have not been systematically studied. Sex and gender also impact the risk of depression and treatment response. Here, we leveraged existing RNA sequencing datasets from 1) blood samples from depressed female- and male-identifying patients treated with escitalopram or desvenlafaxine and assessed for treatment response or failure; 2) the nucleus accumbens (NAc) of female and male mice exposed to ELS and/or adult stress; and 3) the NAc of mice after adult stress, antidepressant treatment with imipramine or ketamine, and assessed for treatment response or failure. We find that transcriptomic signatures of adult stress after a history of ELS correspond with transcriptomic signatures of treatment nonresponse, across species and multiple classes of antidepressants. Transcriptomic correspondence with treatment outcome was stronger among females and weaker among males. We next pharmacologically tested these predictions in our mouse model of early-life and adult social defeat stress and treatment with either chronic escitalopram or acute ketamine. Among female mice, the strongest predictor of behavior was an interaction between ELS and ketamine treatment. Among males, however, early experience and treatment were poor predictors of behavior, mirroring our bioinformatic predictions. These studies provide neurobiological evidence for molecular adaptations in the brain related to sex and ELS that contribute to antidepressant treatment response.
Assuntos
Experiências Adversas da Infância , Ketamina , Humanos , Masculino , Feminino , Camundongos , Animais , Depressão/tratamento farmacológico , Depressão/genética , Escitalopram , Ketamina/farmacologia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Resultado do Tratamento , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/genéticaRESUMO
Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed treatment for individuals experiencing major depressive disorder. The therapeutic mechanisms that take place before, during, or after SSRIs bind the serotonin transporter (SERT) are poorly understood, partially because no studies exist on the cellular and subcellular pharmacokinetic properties of SSRIs in living cells. We studied escitalopram and fluoxetine using new intensity-based, drug-sensing fluorescent reporters targeted to the plasma membrane, cytoplasm, or endoplasmic reticulum (ER) of cultured neurons and mammalian cell lines. We also used chemical detection of drug within cells and phospholipid membranes. The drugs attain equilibrium in neuronal cytoplasm and ER at approximately the same concentration as the externally applied solution, with time constants of a few s (escitalopram) or 200-300 s (fluoxetine). Simultaneously, the drugs accumulate within lipid membranes by ≥18-fold (escitalopram) or 180-fold (fluoxetine), and possibly by much larger factors. Both drugs leave cytoplasm, lumen, and membranes just as quickly during washout. We synthesized membrane-impermeant quaternary amine derivatives of the two SSRIs. The quaternary derivatives are substantially excluded from membrane, cytoplasm, and ER for >2.4 h. They inhibit SERT transport-associated currents sixfold or 11-fold less potently than the SSRIs (escitalopram or fluoxetine derivative, respectively), providing useful probes for distinguishing compartmentalized SSRI effects. Although our measurements are orders of magnitude faster than the therapeutic lag of SSRIs, these data suggest that SSRI-SERT interactions within organelles or membranes may play roles during either the therapeutic effects or the antidepressant discontinuation syndrome.SIGNIFICANCE STATEMENT Selective serotonin reuptake inhibitors stabilize mood in several disorders. In general, these drugs bind to SERT, which clears serotonin from CNS and peripheral tissues. SERT ligands are effective and relatively safe; primary care practitioners often prescribe them. However, they have several side effects and require 2-6 weeks of continuous administration until they act effectively. How they work remains perplexing, contrasting with earlier assumptions that the therapeutic mechanism involves SERT inhibition followed by increased extracellular serotonin levels. This study establishes that two SERT ligands, fluoxetine and escitalopram, enter neurons within minutes, while simultaneously accumulating in many membranes. Such knowledge will motivate future research, hopefully revealing where and how SERT ligands engage their therapeutic target(s).
Assuntos
Transtorno Depressivo Maior , Inibidores Seletivos de Recaptação de Serotonina , Animais , Humanos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Fluoxetina/farmacologia , Escitalopram , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Retículo Endoplasmático/metabolismo , Citalopram/farmacologia , MamíferosRESUMO
BACKGROUND: Major depressive disorder (MDD) is commonly treated with selective serotonin reuptake inhibitors (SSRIs). SSRIs inhibit the serotonin transporter (5-HTT), but the downstream antidepressant mechanism of action of these drugs is poorly understood. The serotonin 1B (5-HT1B) receptor is functionally linked to 5-HTT and 5-HT1B receptor binding and 5-HT1B receptor mRNA is reduced in the raphe nuclei after SSRI administration in primates and rodents, respectively. The effect of SSRI treatment on 5-HT1B receptor binding in patients with MDD has not been examined previously. This positron emission tomography (PET) study aimed to quantify brain 5-HT1B receptor binding changes in vivo after SSRI treatment for MDD in relation to treatment effect. METHODS: Eight unmedicated patients with moderate to severe MDD underwent PET with the 5-HT1B receptor radioligand [11C]AZ10419369 before and after 3 to 4 weeks of treatment with the SSRI escitalopram 10 mg daily. Depression severity was assessed at time of PET and after 6 to 7 weeks of treatment with the Montgomery-Åsberg Depression Rating Scale. RESULTS: We observed a significant reduction in [11C]AZ10419369 binding in a dorsal brainstem (DBS) region containing the median and dorsal raphe nuclei after escitalopram treatment (P = .036). Change in DBS [11C]AZ10419369 binding correlated with Montgomery-Åsberg Depression Rating Scale reduction after 3-4 (r = 0.78, P = .021) and 6-7 (r = 0.94, P < .001) weeks' treatment. CONCLUSIONS: Our findings align with the previously reported reduction of 5-HT1B receptor binding in the raphe nuclei after SSRI administration and support future studies testing change in DBS 5-HT1B receptor binding as an SSRI treatment response marker.
Assuntos
Transtorno Depressivo Maior , Escitalopram , Tomografia por Emissão de Pósitrons , Receptor 5-HT1B de Serotonina , Inibidores Seletivos de Recaptação de Serotonina , Receptor 5-HT1B de Serotonina/metabolismo , Masculino , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/diagnóstico por imagem , Adulto , Feminino , Pessoa de Meia-Idade , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Escitalopram/farmacologia , Escitalopram/metabolismo , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Resultado do Tratamento , Piperazinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Adulto Jovem , Citalopram/farmacologia , Benzopiranos , MorfolinasRESUMO
BACKGROUND: Psilocybin Therapy (PT) is being increasingly studied as a psychiatric intervention. Personality relates to mental health and can be used to probe the nature of PT's therapeutic action. METHODS: In a phase 2, double-blind, randomized, active comparator controlled trial involving patients with moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, over a core 6-week trial period. Five-Factor model personality domains, Big Five Aspect Scale Openness aspects, Absorption, and Impulsivity were measured at Baseline, Week 6, and Month 6 follow-up. RESULTS: PT was associated with decreases in neuroticism (B = -0.63), introversion (B = -0.38), disagreeableness (B = -0.47), impulsivity (B = -0.40), and increases in absorption (B = 0.32), conscientiousness (B = 0.30), and openness (B = 0.23) at week 6, with neuroticism (B = -0.47) and disagreeableness (B = -0.41) remaining decreased at month 6. Escitalopram Treatment (ET) was associated with decreases in neuroticism (B = -0.38), disagreeableness (B = -0.26), impulsivity (B = -0.35), and increases in openness (B = 0.28) at week 6, with neuroticism (B = -0.46) remaining decreased at month 6. No significant between-condition differences were observed. CONCLUSIONS: Personality changes across both conditions were in a direction consistent with improved mental health. With the possible exception of trait absorption, there were no compelling between-condition differences warranting conclusions regarding a selective action of PT (v. ET) on personality; however, post-ET changes in personality were significantly moderated by pre-trial positive expectancy for escitalopram, whereas expectancy did not moderate response to PT.
Assuntos
Transtorno Depressivo Maior , Psilocibina , Humanos , Psilocibina/farmacologia , Psilocibina/uso terapêutico , Escitalopram , Transtorno Depressivo Maior/tratamento farmacológico , Depressão , Personalidade , NeuroticismoRESUMO
BACKGROUND: To investigate the association between pre-trial expectancy, suggestibility, and response to treatment in a trial of escitalopram and investigational drug, COMP360, psilocybin, in the treatment of major depressive disorder (ClinicalTrials.gov registration: NCT03429075). METHODS: We used data (n = 55) from our recent double-blind, parallel-group, randomized head-to-head comparison trial of escitalopram and investigational drug, COMP360, psilocybin. Mixed linear models were used to investigate the association between pre-treatment efficacy-related expectations, as well as baseline trait suggestibility and absorption, and therapeutic response to both escitalopram and COMP360 psilocybin. RESULTS: Patients had significantly higher expectancy for psilocybin relative to escitalopram; however, expectancy for escitalopram was associated with improved therapeutic outcomes to escitalopram, expectancy for psilocybin was not predictive of response to psilocybin. Separately, we found that pre-treatment trait suggestibility was associated with therapeutic response in the psilocybin arm, but not in the escitalopram arm. CONCLUSIONS: Overall, our results suggest that psychedelic therapy may be less vulnerable to expectancy biases than previously suspected. The relationship between baseline trait suggestibility and response to psilocybin therapy implies that highly suggestible individuals may be primed for response to this treatment.
Assuntos
Transtorno Depressivo Maior , Escitalopram , Psilocibina , Sugestão , Humanos , Psilocibina/farmacologia , Psilocibina/administração & dosagem , Psilocibina/uso terapêutico , Masculino , Adulto , Feminino , Transtorno Depressivo Maior/tratamento farmacológico , Método Duplo-Cego , Pessoa de Meia-Idade , Escitalopram/farmacologia , Alucinógenos/farmacologia , Alucinógenos/administração & dosagem , Antecipação Psicológica/efeitos dos fármacos , Resultado do Tratamento , Citalopram/uso terapêutico , Citalopram/farmacologia , Citalopram/administração & dosagemRESUMO
Selective serotonin reuptake inhibitors (SSRIs) are widely used for treating neuropsychiatric disorders. However, the exact mechanism of action and why effects can take several weeks to manifest is not clear. The hypothesis of neuroplasticity is supported by preclinical studies, but the evidence in humans is limited. Here, we investigate the effects of the SSRI escitalopram on presynaptic density as a proxy for synaptic plasticity. In a double-blind placebo-controlled study (NCT04239339), 32 healthy participants with no history of psychiatric or cognitive disorders were randomized to receive daily oral dosing of either 20 mg escitalopram (n = 17) or a placebo (n = 15). After an intervention period of 3-5 weeks, participants underwent a [11C]UCB-J PET scan (29 with full arterial input function) to quantify synaptic vesicle glycoprotein 2A (SV2A) density in the hippocampus and the neocortex. Whereas we find no statistically significant group difference in SV2A binding after an average of 29 (range: 24-38) days of intervention, our secondary analyses show a time-dependent effect of escitalopram on cerebral SV2A binding with positive associations between [11C]UCB-J binding and duration of escitalopram intervention. Our findings suggest that brain synaptic plasticity evolves over 3-5 weeks in healthy humans following daily intake of escitalopram. This is the first in vivo evidence to support the hypothesis of neuroplasticity as a mechanism of action for SSRIs in humans and it offers a plausible biological explanation for the delayed treatment response commonly observed in patients treated with SSRIs. While replication is warranted, these results have important implications for the design of future clinical studies investigating the neurobiological effects of SSRIs.
Assuntos
Disfunção Cognitiva , Inibidores Seletivos de Recaptação de Serotonina , Humanos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Escitalopram , Encéfalo , Sinapses , Disfunção Cognitiva/tratamento farmacológico , Citalopram/farmacologia , Citalopram/uso terapêuticoRESUMO
BACKGROUND: Major depressive disorder is common in people with asthma. Yet, few studies have evaluated depression treatment in those with asthma. OBJECTIVE: To explore the relationship between antidepressant use, depressive symptoms, and asthma control, pooled data from 3 randomized trials of either citalopram or escitalopram were assessed. METHODS: Linear fixed effects and binary logistic regression analyses were conducted with between-subject covariates including treatment group, (original) study, and demographics. The within-subject effect of visit, and a treatment group-visit (between-within) interaction effect, were also evaluated. Analyses were repeated in a high asthma exacerbation subgroup having at least 3 oral corticosteroid bursts in the previous 12 months. Outcomes included the Hamilton rating scale for depression (HAM-D17), the 7-item asthma control questionnaire (ACQ), and oral corticosteroid use (yes or no). RESULTS: In the pooled sample (n = 255), the antidepressant treatment group exhibited lower HAM-D17 overall (P ≤ .001) and a lower likelihood for oral corticosteroid use (P ≤ .001) relative to the placebo group. In the high-exacerbation subgroup (n = 96), treatment group participants had lower overall asthma control questionnaire (P = .004) and HAM-D17 scores (P ≤ .001), and a lower likelihood of oral corticosteroid use (P = .003), relative to placebo participants. All treatment group interaction effects were not significant. CONCLUSION: Citalopram or escitalopram exhibited efficacy in reducing depressive symptoms and the need for rescue oral corticosteroids in patients with asthma and major depressive disorder. Future work should determine whether selective serotonin reuptake inhibitors are effective at improving asthma outcomes in those with asthma who are not depressed. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00621946 and NCT01324700 (one study was conducted before ClinicalTrials.gov requirements).
Assuntos
Asma , Citalopram , Transtorno Depressivo Maior , Escitalopram , Humanos , Corticosteroides/uso terapêutico , Antidepressivos/uso terapêutico , Asma/tratamento farmacológico , Citalopram/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Escitalopram/uso terapêutico , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: To assess the pharmacokinetic correlates of reported adverse drug reactions (ADRs) under antidepressant treatment with escitalopram (ESC) using a large therapeutic drug monitoring database. METHODS: A large naturalistic sample of inpatients and outpatients prescribed ESC was analyzed. ADRs were classified using the Udvalg for Kliniske Undersogelser side effect rating scale. We compared ESC-treated patients with (n = 35) and without ADRs (n = 273) using ESC plasma concentrations as the primary outcome. We also compared ADR rates in the 2 groups based on 2 cut-off ESC levels reflecting the recommended upper thresholds of the therapeutic reference range of 80 ng/mL, suggested by the consensus therapeutic drug monitoring guidelines, and 40 ng/mL, based on recent meta-analysis data. The effects of age, sex, smoking, daily ESC dose, plasma concentrations, and concentrations corrected for daily dose were included in a binary logistic regression model to predict ADRs. RESULTS: No differences in clinical, demographic, or pharmacokinetic parameters were observed between patients with and without ADRs ( P > 0.05). Patients with ESC-related ADRs were more frequently diagnosed with psychotic disorders than those without (25% vs. 7.1%, P = 0.004). None of the variables was associated with ADR risk. Overall, ADR rates were not significantly different in patients above versus below thresholds of ESC concentrations (ESC concentrations >40 [n = 59] vs. ≤40 ng/mL [n = 249] and >80 [n = 8] vs. ≤80 ng/mL [n = 300]; P = 0.56 and P = 1.0, respectively). CONCLUSIONS: No distinct pharmacokinetic patterns underlying ESC-associated ADRs were observed. Further studies with more specific assessments of ADRs in larger cohorts are required to better identify potential underlying patterns.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Transtornos Psicóticos , Humanos , Escitalopram , Transtornos Psicóticos/tratamento farmacológico , Monitoramento de Medicamentos , Pacientes AmbulatoriaisRESUMO
OBJECTIVE: To evaluate the therapeutic efficacy and safety of agomelatine for treating the sleep and mood disorders in epilepsy patients. METHODS: Retrospective data were derived from 113 epilepsy patients for at least 8 weeks. All the subjects were divided into two groups, one was treated with agomelatine, the other was treated with escitalopram. Their depression and anxiety states were assessed by Hamilton Depression (HAMD) and Hamilton Anxiety (HAMA) Scales. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI). RESULTS: The HAMA, HAMD and PSQI scores in both groups significantly declined after the treatments with agomelatine and escitalopram. However, the agomelatine group exhibited greater improvement in terms of HAMA and PSQI scores compared to the escitalopram group. No severe adverse events were observed in agomelatine group. SIGNIFICANCE: Agomelatine performed better in HAMA and PSQI scores compared to escitalopram, where no significant increase in seizure frequency or side effects were observed. Possibly, agomelatine presents a promising therapeutic option for treating the sleep or mood disorders in epilepsy patients.
Assuntos
Transtorno Depressivo Maior , Epilepsia , Humanos , Estudos Retrospectivos , Escitalopram , Resultado do Tratamento , Sono , Transtornos do Humor/etiologia , Transtornos do Humor/induzido quimicamente , Acetamidas/efeitos adversos , Epilepsia/complicações , Epilepsia/tratamento farmacológico , Epilepsia/induzido quimicamenteRESUMO
PURPOSE: The aim of this study was to examine the age of onset for increased dose-adjusted serum concentrations (C/D ratio) of common antidepressant drugs and to explore the potential association with sex and CYP2C19/CYP2D6 genotype. METHODS: Serum concentrations and prescribed daily doses for citalopram, escitalopram, sertraline, venlafaxine and mirtazapine, and CYP genotypes, were obtained from a therapeutic drug monitoring (TDM) service. Segmented linear regression analysis was used to examine the relationship between age and antidepressant log C/D ratio in (i) all individuals, (ii) men and women, and (iii) CYP2D6/CYP2C19 normal metabolizers (NMs) and CYP2D6/CYP2C19 intermediate or poor metabolizers (IMs/PMs). RESULTS: A total of 34,777 individuals were included in the study; CYP genotype was available for 21.3%. An increase in C/D ratio started at 44â55 years of age. Thereafter, the increase progressed more rapidly for citalopram and escitalopram than for venlafaxine and mirtazapine. A doubled C/D ratio was estimated to occur at 79 (citalopram), 81 (escitalopram), 86 (venlafaxine), and 90 years (mirtazapine). For sertraline, only modest changes in C/D ratio were observed. For escitalopram and venlafaxine, the observed increase in C/D ratio started earlier in women than in men. The results regarding CYP genotype were inconclusive. CONCLUSION: The age-related increase in C/D ratio starts in middle-aged adults and progresses up to more than twofold higher C/D ratio in the oldest old. Sertraline seems to be less prone to age-related changes in C/D ratio than the other antidepressants.
Assuntos
Citalopram , Sertralina , Adulto , Masculino , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Feminino , Humanos , Sertralina/uso terapêutico , Cloridrato de Venlafaxina , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Mirtazapina , Escitalopram , Idade de Início , Antidepressivos/uso terapêutico , GenótipoRESUMO
Brain-derived neurotrophic factor (BDNF) dysfunction is one of the most important mechanisms underlying depression. It seems that selective serotonin reuptake inhibitors (SSRIs) improve depression via affecting BDNF level. In this systematic review, for the first time, we aimed to review the effect of three SSRIs including fluoxetine, escitalopram, and sertraline, on both depression and BDNF level in preclinical and clinical studies. PubMed electronic database was searched, and 193 articles were included in this study. After reviewing all manuscripts, only one important difference was found: subjects. We found that SSRIs induce different effects in animals vs. humans. Preclinical studies showed many controversial effects, while human studies showed only two effects: improvement of depression, with or without the improvement of BDNF. However, most studies used chronic SSRIs treatment, while acute SSRIs were not effectively used and evaluated. In conclusion, it seems that SSRIs are reliable antidepressants, and the improvement effect of SSRIs on depression is not dependent to BDNF level (at least in human studies).
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Depressão , Fluoxetina , Inibidores Seletivos de Recaptação de Serotonina , Sertralina , Humanos , Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Sertralina/farmacologia , Sertralina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Fluoxetina/farmacologia , Animais , Depressão/tratamento farmacológico , Escitalopram/farmacologia , Escitalopram/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/uso terapêuticoRESUMO
There exists little empirical evidence helping clinicians to select the most effective treatment for individual patients with persistent depressive disorder (PDD). This study identifies and characterizes subgroups of patients with PDD who are likely to benefit more from an acute treatment with psychotherapy than from pharmacotherapy and vice versa. Non-medicated outpatients with PDD were randomized to eight weeks of acute treatment with the Cognitive Behavioral Analysis System of Psychotherapy (CBASP; n = 29) or escitalopram plus clinical management (ESC/CM; n = 31). We combined several baseline variables to one composite moderator and identified two subgroups of patients: for 56.0%, ESC/CM was associated with a greater reduction in depression severity than CBASP, for the remaining 44.0%, it was the other way around. Patients likely to benefit more from ESC/CM were more often female, had higher rates of moderate-to-severe childhood trauma, more adverse life events and more previous suicide attempts. Patients likely to benefit more from CBASP were older, had more often an early illness onset and more previous treatments with antidepressants. Symptomatic response, remission, and reductions in symptom severity occurred more often in those patients treated with their likely more effective treatment condition. The findings suggest that the baseline phenotype of patients with PDD moderates their benefit from acute treatment with CBASP relative to ESC/CM. Once confirmed in an independent sample, these results could serve to guide the choice between primarily psychotherapeutic or pharmacological treatments for outpatients with PDD.
Assuntos
Terapia Cognitivo-Comportamental , Transtorno Depressivo , Humanos , Feminino , Escitalopram , Terapia Cognitivo-Comportamental/métodos , Pacientes Ambulatoriais , Transtorno Depressivo/terapia , Psicoterapia/métodos , Doença CrônicaRESUMO
OBJECTIVES: This study aims to evaluate the safety and efficacy of escitalopram and sertraline in post-stroke depression (PSD) patients, to provide more reliable therapeutics for cardiovascular and psychiatric clinical practice. METHODS: We recruited 60 patients (aged 40-89 years old) with an ICD-10 diagnosis of PSD, who were then randomly assigned to two groups and treated with flexible doses of escitalopram (10 to 20 mg/day, n = 30) or sertraline (50 to 200 mg/day, n = 30) for consecutive 8 weeks, respectively. The 24-item Hamilton Depression Rating Scale (HAMD-24), the 14-item Hamilton Anxiety Rating Scale (HAMA-14), the Treatment Emergent Symptom Scale (TESS), the Montreal Cognitive Assessment Scale (MOCA), and the Activity of Daily Living scale (ADL) were used to assess patients before, during, and after treatment for depression, anxiety, adverse effects, cognitive function, and daily living activities. Repeated measures ANOVA, the Mann-Whitney U test, the chi-square test (χ2), or Fisher's exact test was employed to assess baseline demographics, response rate, adverse effects rate, and changes in other clinical variables. RESULTS: Significant reduction in HAMD-24 and HAMA-14 scores was evaluated at baseline, as well as 1, 3, 4, 6, and 8 weeks of drug intervention (p < 0.01). There was a significant group difference in post-treatment HAMD-24 scores (p < 0.05), but no difference was observed in HAMA-14 scores (p > 0.05). Further analysis showed a significant variance in the HAMD-24 scores between the two groups at the end of the first week (p < 0.01). The incidence of adverse effects in both patient groups was mild, but there was a statistically significant difference between the two groups (p < 0.05). The improvement in cognitive function and the recovery of daily living abilities were comparable between both groups (p > 0.05). CONCLUSION: Escitalopram and sertraline showed comparable efficacy for anxiety symptoms, cognitive function, and daily living abilities in PSD patients. In addition, escitalopram was more appropriate for alleviating depressive symptoms. To validate the conclusion, trials with a larger sample size are in demand in the future. The registration number is ChiCTR1800017373.
Assuntos
Atividades Cotidianas , Escitalopram , Sertralina , Acidente Vascular Cerebral , Humanos , Sertralina/uso terapêutico , Sertralina/efeitos adversos , Masculino , Idoso , Feminino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Adulto , Idoso de 80 Anos ou mais , Escitalopram/uso terapêutico , Escitalopram/efeitos adversos , Depressão/tratamento farmacológico , Depressão/etiologia , Resultado do Tratamento , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Escalas de Graduação Psiquiátrica , Antidepressivos/uso terapêutico , Antidepressivos/efeitos adversos , Citalopram/uso terapêutico , Citalopram/efeitos adversosRESUMO
OBJECTIVE: The purpose of this study was to investigate the effects of escitalopram on the peripheral expression of hypothalamic-pituitary-adrenal (HPA) axis-related genes (FKBP51, HSP90, NR3C1 and POMC) and HPA-axis hormones in patients with panic disorder (PD). METHODS: Seventy-seven patients with PD were treated with escitalopram for 12 weeks. All participants were assessed for the severity of panic symptoms using the Panic Disorder Severity Scale (PDSS). The expression of HPA-axis genes was measured using real-time quantitative fluorescent PCR, and ACTH and cortisol levels were measured using chemiluminescence at baseline and after 12 weeks of treatment. RESULTS: At baseline, patients with PD had elevated levels of ACTH and cortisol, and FKBP51 expression in comparison to healthy controls (all p < 0.01). Correlation analysis revealed that FKBP51 expression levels were significantly positively related to cortisol levels and the severity of PD (all p < 0.01). Furthermore, baseline ACTH and cortisol levels, and FKBP51 expression levels were significantly reduced after 12 weeks of treatment, and the change in the PDSS score from baseline to post-treatment was significantly and positively related to the change in cortisol (p < 0.01). CONCLUSIONS: The results suggest that PD may be associated with elevated levels of ACTH and cortisol, and FKBP51 expression, and that all three biomarkers are substantially decreased in patients who have received escitalopram treatment.
Assuntos
Transtorno de Pânico , Humanos , Transtorno de Pânico/tratamento farmacológico , Transtorno de Pânico/genética , Transtorno de Pânico/diagnóstico , Hormônio Adrenocorticotrópico/metabolismo , Hormônio Adrenocorticotrópico/farmacologia , Hidrocortisona/metabolismo , Escitalopram , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , RNA MensageiroRESUMO
Alzheimer's disease (AD) is accompanied by behavioral and psychological symptoms of dementia (BPSD), which is often alleviated by treatment with psychotropic drugs, such as antidepressants, hypnotics, and anxiolytics. If these drugs also inhibit acetylcholinesterase (AChE) activity, they may contribute to the suppression of AD progression by increasing brain acetylcholine concentrations. We tested the potential inhibitory effects of 31 antidepressants, 21 hypnotics, and 12 anxiolytics on recombinant human AChE (rhAChE) activity. At a concentration of 10-4 M, 22 antidepressants, 19 hypnotics, and 11 anxiolytics inhibited rhAChE activity by <20%, whereas nine antidepressants (clomipramine, amoxapine, setiptiline, nefazodone, paroxetine, sertraline, citalopram, escitalopram, and mirtazapine), two hypnotics (triazolam and brotizolam), and one anxiolytic (buspirone) inhibited rhAChE activity by ≥20%. Brotizolam (≥10-6 M) exhibited stronger inhibition of rhAChE activity than the other drugs, with its pIC50 value being 4.57 ± 0.02. The pIC50 values of the other drugs were <4, and they showed inhibitory activities toward rhAChE at the following concentrations: ≥3 × 10-6 M (sertraline and buspirone), ≥10-5 M (amoxapine, nefazodone, paroxetine, citalopram, escitalopram, mirtazapine, and triazolam), and ≥3 × 10-5 M (clomipramine and setiptiline). Among these drugs, only nefazodone inhibited rhAChE activity within the blood concentration range achievable at clinical doses. Therefore, nefazodone may not only improve the depressive symptoms of BPSD through its antidepressant actions but also slow the progression of cognitive symptoms of AD through its AChE inhibitory actions.
Assuntos
Amoxapina , Ansiolíticos , Triazolam , Humanos , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Acetilcolinesterase , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/uso terapêutico , Sertralina , Clomipramina , Mirtazapina , Paroxetina , Citalopram , Escitalopram , Buspirona , Antidepressivos/farmacologia , Antidepressivos/uso terapêuticoRESUMO
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 , GenótipoRESUMO
OBJECTIVE: To examine the long-term safety and tolerability of off-label high-dose serotonin reuptake inhibitors (OLHD-SRIs) in the treatment of obsessive-compulsive disorder (OCD). METHODS: A retrospective longitudinal study was performed on 105 randomly selected outpatients diagnosed with OCD and were treated with OLHD-SRIs for at least 6 months. Patients received sertraline >200 mg/day, escitalopram >20 mg/day, fluvoxamine >300 mg/day, and fluoxetine >60 mg/day, combined with exposure and response prevention therapy. Patients were divided into three dosing groups: sertraline equivalent dose (SED) ≤ 200 mg/day (n = 26, 24.7%), 201-400 mg/day (n = 51, 48.5%) and 401-650 mg/day (n = 28, 26.6%). Safety and tolerability were assessed with an electrocardiogram, blood biochemistry, complete blood count, and side-effects monitoring. RESULTS: SED ranged from 100 to 650 mg/day and the mean duration of OLHD-SRI treatment was 20.8 months. The most common side-effects reported were sexual dysfunction (n = 36, 34%), weight gain (n = 28, 27%), sedation (n = 27, 26%), hyperhidrosis (n = 20, 19%), and tremor (n = 11, 10%). Abnormal ECG was documented in one patient, and another patient experienced a first-time seizure, whereas elevated liver enzymes were seen in 4.8% of the sample (n = 5). None of the patients had serotonin syndrome or drug-induced liver injury. Side-effects did not differ among the three dosing groups. CONCLUSION: OLHD-SRIs appear to be safe and well tolerated in OCD patients in SED ≤ 650 mg/day doses and the side-effects did not differ between the three dosing groups.
Assuntos
Fluvoxamina , Transtorno Obsessivo-Compulsivo , Uso Off-Label , Inibidores Seletivos de Recaptação de Serotonina , Sertralina , Humanos , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Feminino , Adulto , Masculino , Estudos Retrospectivos , Fluvoxamina/uso terapêutico , Fluvoxamina/administração & dosagem , Fluvoxamina/efeitos adversos , Sertralina/uso terapêutico , Sertralina/administração & dosagem , Sertralina/efeitos adversos , Pessoa de Meia-Idade , Estudos Longitudinais , Fluoxetina/uso terapêutico , Fluoxetina/administração & dosagem , Fluoxetina/efeitos adversos , Escitalopram/uso terapêutico , Escitalopram/administração & dosagem , Adulto Jovem , Resultado do Tratamento , Relação Dose-Resposta a DrogaRESUMO
OBJECTIVES: Treatment-emergent sexual dysfunction is frequently reported by individuals with major depressive disorder (MDD) on antidepressants, which negatively impacts treatment adherence and efficacy. We investigated the association of polymorphisms in pharmacokinetic genes encoding cytochrome-P450 drug-metabolizing enzymes, CYP2C19 and CYP2D6, and the transmembrane efflux pump, P-glycoprotein (i.e., ABCB1), on treatment-emergent changes in sexual function (SF) and sexual satisfaction (SS) in the Canadian Biomarker Integration Network in Depression 1 (CAN-BIND-1) sample. METHODS: A total of 178 adults with MDD received treatment with escitalopram (ESC) from weeks 0-8 (Phase I). At week 8, nonresponders were augmented with aripiprazole (ARI) (i.e., ESC + ARI, n = 91), while responders continued ESC (i.e., ESC-Only, n = 80) from weeks 8-16 (Phase II). SF and SS were evaluated using the sex effects (SexFX) scale at weeks 0, 8, and 16. We assessed the primary outcomes, SF and SS change for weeks 0-8 and 8-16, using repeated measures mixed-effects models. RESULTS: In ESC-Only, CYP2C19 intermediate metabolizer (IM) + poor metabolizers (PMs) showed treatment-related improvements in sexual arousal, a subdomain of SF, from weeks 8-16, relative to CYP2C19 normal metabolizers (NMs) who showed a decline, F(2,54) = 8.00, p < 0.001, q = 0.048. Specifically, CYP2C19 IM + PMs reported less difficulty with having and sustaining vaginal lubrication in females and erection in males, compared to NMs. Furthermore, ESC-Only females with higher concentrations of ESC metabolite, S-desmethylcitalopram (S-DCT), and S-DCT/ESC ratio in serum demonstrated more decline in SF (r = -0.42, p = 0.004, q = 0.034) and SS (r = -0.43, p = 0.003, q = 0.034), respectively, which was not observed in males. ESC-Only females also demonstrated a trend for a correlation between S-DCT and sexual arousal change in the same direction (r = -0.39, p = 0.009, q = 0.052). CONCLUSIONS: CYP2C19 metabolizer phenotypes may be influencing changes in sexual arousal related to ESC monotherapy. Thus, preemptive genotyping of CYP2C19 may help to guide selection of treatment that circumvents selective serotonin reuptake inhibitor-related sexual dysfunction thereby improving outcomes for patients. Additionally, further research is warranted to clarify the role of S-DCT in the mechanisms underlying ESC-related changes in SF and SS. This CAN-BIND-1 study was registered on clinicaltrials.gov (Identifier: NCT01655706) on 27 July 2012.
Assuntos
Citocromo P-450 CYP2D6 , Transtorno Depressivo Maior , Adulto , Masculino , Feminino , Humanos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Aripiprazol/efeitos adversos , Escitalopram , Citalopram/efeitos adversos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Depressão , Canadá , Biomarcadores , Subfamília B de Transportador de Cassetes de Ligação de ATPRESUMO
Treatment-resistant depression (TRD) poses significant therapeutic challenges despite available interventions. Escitalopram (ESC) is a highly selective antidepressant. This study aimed to compare ESC alone and ESC combined with modified electroconvulsive therapy (MECT) or high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) in TRD patients. Ninety participants were randomized into ESC alone, ESC + MECT, and ESC + HF-rTMS groups. Notable differences were observed in Hamilton Depression Rating Scale (HDRS-17) scores at 12 weeks among ESC (14.37), ESC + MECT (10.27), and ESC + HF-rTMS (10.77) groups (P = 0.006). In terms of overall quality of life (QoL) evaluated using the World Health Organization Quality of Life Questionnaire (WHOQOL-BREF) at 12 weeks, the ESC, ESC + MECT, and ESC + HF-rTMS groups scored 2, 3, and 3.5, respectively. ESC + MECT/HF-rTMS groups showed reduced depressive symptoms compared to the ESC group, accompanied by higher overall QoL scores and increased satisfaction with health. Patients receiving ESC + MECT demonstrated no significant alterations in short-term memory and orientation, as measured by the Montreal Cognitive Assessment (MoCA), before and after treatment. Moreover, a decline in language was observed compared to baseline (12 weeks: median 2, IQR 2-3; baseline: median 1, IQR 1-3; P = 0.022). The positive impact of ESC with HF-rTMS on cognitive function was evidenced by improvements in all domines MoCA.Combining ESC with MECT or HF-rTMS exhibited enhanced effectiveness in alleviating depressive symptoms and enhancing QoL compared to ESC monotherapy. Specifically, the ESC + HF-rTMS combination displayed potential as a comprehensive treatment strategy for TRD, addressing both emotional and cognitive aspects.