Clinical trials are the backbone of medical scientific research. However, this experimental strategy has some drawbacks. We focused on two issues: (a) The internal validity ensured by clinical trial procedures does not necessarily allow for generalization of efficacy results to causal claims about effectiveness in the population. (b) Statistical significance does not imply clinical or practical significance; p-values should be supplemented with effect size (ES) estimators and an interpretation of the magnitude of the effects found. We conducted a systematic review (from 2000 to 2020) on Scopus, PubMed, and four ProQuest databases, including PsycINFO. We searched for experimental studies with significant effects of pharmacological treatments on depressive symptoms, measured with a specific scale for depression. We assessed the claims of effectiveness, and reporting and interpreting of effect sizes in a small, unbiased sample of clinical trials (n = 10). Only 30% of the studies acknowledged that efficacy does not necessarily translate to effectiveness. Only 20% reported ES indices, and only 40% interpreted the magnitude of their findings. We encourage reflection on the applicability of results derived from clinical trials about the efficacy of antidepressant treatments, which often influence daily clinical decision-making. Comparing experimental results of antidepressants with supplementary observational studies can provide clinicians with greater flexibility in prescribing medication based on patient characteristics. Furthermore, the ES of a treatment should be considered, as treatments with a small effect may be worthwhile in certain circumstances, while treatments with a large effect may be justified despite additional costs or complications. Therefore, researchers are encouraged to report and interpret ES and explicitly discuss the suitability of their sample for the clinical population to which the antidepressant treatment will be applied.
BACKGROUND: Many studies have recently been conducted to assess the antidepressant efficacy of glutamate modification in mood disorders. This is an update of a review first published in 2015 focusing on the use of glutamate receptor modulators in unipolar depression.
OBJECTIVES: To assess the effects - and review the acceptability and tolerability - of ketamine and other glutamate receptor modulators in alleviating the acute symptoms of depression in people with unipolar major depressive disorder.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Embase and PsycINFO all years to July 2020. We did not apply any restrictions to date, language or publication status.
SELECTION CRITERIA: Double- or single-blinded randomised controlled trials (RCTs) comparing ketamine, memantine, esketamine or other glutamate receptor modulators with placebo (pill or saline infusion), other active psychotropic drugs, or electroconvulsive therapy (ECT) in adults with unipolar major depression.
DATA COLLECTION AND ANALYSIS: Three review authors independently identified studies, assessed trial quality and extracted data. The primary outcomes were response rate (50% reduction on a standardised rating scale) and adverse events. We decided a priori to measure the efficacy outcomes at different time points and run sensitivity/subgroup analyses. Risk of bias was assessed using the Cochrane tool, and certainty of the evidence was assessed using GRADE.
MAIN RESULTS: Thirty-one new studies were identified for inclusion in this updated review. Overall, we included 64 studies (5299 participants) on ketamine (31 trials), esketamine (9), memantine (5), lanicemine (4), D-cycloserine (2), Org26576 (2), riluzole (2), atomoxetine (1), basimglurant (1), citicoline (1), CP-101,606 (1), decoglurant (1), MK-0657 (1), N-acetylcysteine (1), rapastinel (1), and sarcosine (1). Forty-eight studies were placebo-controlled, and 48 were two-arm studies. The majority of trials defined an inclusion criterion for the severity of depressive symptoms at baseline: 29 at least moderate depression; 17 severe depression; and five mild-to-moderate depression. Nineteen studies recruited only patients with treatment-resistant depression, defined as inadequate response to at least two antidepressants. The majority of studies investigating ketamine administered as a single dose, whilst all of the included esketamine studies used a multiple dose regimen (most frequently twice a week for four weeks). Most studies looking at ketamine used intravenous administration, whilst the majority of esketamine trials used intranasal routes. The evidence suggests that ketamine may result in an increase in response and remission compared with placebo at 24 hours odds ratio (OR) 3.94, 95% confidence interval (CI) 1.54 to 10.10; n = 185, studies = 7, very low-certainty evidence). Ketamine may reduce depression rating scale scores over placebo at 24 hours, but the evidence is very uncertain (standardised mean difference (SMD) -0.87, 95% CI -1.26 to -0.48; n = 231, studies = 8, very low-certainty evidence). There was no difference in the number of participants assigned to ketamine or placebo who dropped out for any reason (OR 1.25, 95% CI 0.19 to 8.28; n = 201, studies = 6, very low-certainty evidence). When compared with midazolam, the evidence showed that ketamine increases remission rates at 24 hours (OR 2.21, 95% CI 0.67 to 7.32; n = 122,studies = 2, low-certainty evidence). The evidence is very uncertain about the response efficacy of ketamine at 24 hours in comparison with midazolam, and its ability to reduce depression rating scale scores at the same time point (OR 2.48, 95% CI 1.00 to 6.18; n = 296, studies = 4,very low-certainty evidence). There was no difference in the number of participants who dropped out of studies for any reason between ketamine and placebo (OR 0.33, 95% CI 0.05 to 2.09; n = 72, studies = 1, low-certainty evidence). Esketamine treatment likely results in a large increase in participants achieving remission at 24 hours compared with placebo (OR 2.74, 95% CI 1.71 to 4.40; n = 894, studies = 5, moderate-certainty evidence). Esketamine probably results in decreases in depression rating scale scores at 24 hours compared with placebo (SMD -0.31, 95% CI -0.45 to -0.17; n = 824, studies = 4, moderate-certainty evidence). Our findings show that esketamine increased response rates, although this evidence is uncertain (OR 2.11, 95% CI 1.20 to 3.68; n = 1071, studies = 5, low-certainty evidence). There was no evidence that participants assigned to esketamine treatment dropped out of trials more frequently than those assigned to placebo for any reason (OR 1.58, 95% CI 0.92 to 2.73; n = 773, studies = 4,moderate-certainty evidence). We found very little evidence for the remaining glutamate receptor modulators. We rated the risk of bias as low or unclear for most domains, though lack of detail regarding masking of treatment in the studies reduced our certainty in the effect for all outcomes.
AUTHORS' CONCLUSIONS: Our findings show that ketamine and esketamine may be more efficacious than placebo at 24 hours. How these findings translate into clinical practice, however, is not entirely clear. The evidence for use of the remaining glutamate receptor modulators is limited as very few trials were included in the meta-analyses for each comparison and the majority of comparisons included only one study. Long term non-inferiority RCTs comparing repeated ketamine and esketamine, and rigorous real-world monitoring are needed to establish comprehensive data on safety and efficacy.
OBJECTIVE: Suicide is a public health crisis with limited treatment options. The authors conducted a systematic review and individual participant data meta-analysis examining the effects of a single dose of ketamine on suicidal ideation.
METHOD: Individual participant data were obtained from 10 of 11 identified comparison intervention studies that used either saline or midazolam as a control treatment. The analysis included only participants who had suicidal ideation at baseline (N=167). A one-stage, individual participant data, meta-analytic procedure was employed using a mixed-effects, multilevel, general linear model. The primary outcome measures were the suicide items from clinician-administered (the Montgomery-Åsberg Depression Rating Scale [MADRS] or the Hamilton Depression Rating Scale [HAM-D]) and self-report scales (the Quick Inventory of Depressive Symptomatology-Self Report [QIDS-SR] or the Beck Depression Inventory [BDI]), obtained for up to 1 week after ketamine administration.
RESULTS: Ketamine rapidly (within 1 day) reduced suicidal ideation significantly on both the clinician-administered and self-report outcome measures. Effect sizes were moderate to large (Cohen's d=0.48-0.85) at all time points after dosing. A sensitivity analysis demonstrated that compared with control treatments, ketamine had significant benefits on the individual suicide items of the MADRS, the HAM-D, and the QIDS-SR but not the BDI. Ketamine's effect on suicidal ideation remained significant after adjusting for concurrent changes in severity of depressive symptoms.
CONCLUSIONS: Ketamine rapidly reduced suicidal thoughts, within 1 day and for up to 1 week in depressed patients with suicidal ideation. Ketamine's effects on suicidal ideation were partially independent of its effects on mood, although subsequent trials in transdiagnostic samples are required to confirm that ketamine exerts a specific effect on suicidal ideation. Additional research on ketamine's long-term safety and its efficacy in reducing suicide risk is needed before clinical implementation.
Antecedentes: Los psicoestimulantes son frecuentemente prescritos fuera de la etiqueta para adultos con trastorno depresivo mayor o trastorno bipolar. El uso frecuente y creciente de estimulantes en los trastornos del estado de ánimo merece una evaluación cuidadosa de la eficacia de esta clase de agentes. En este sentido, se pretende estimar la eficacia de los psicoestimulantes en adultos con depresión unipolar o bipolar. MÉTODOS: La base de datos de PubMed / Medline se realizó desde el inicio hasta el 16 de enero de 2016 para ensayos clínicos aleatorios, controlados con placebo, que investigaron la eficacia antidepresiva de los psicoestimulantes en el tratamiento de adultos con depresión unipolar o bipolar. RESULTADOS: Los psicoestimulantes se asociaron con una mejoría estadísticamente significativa en los síntomas depresivos en el trastorno depresivo mayor (OR = 1,41; IC del 95%, 1,13 - 1,78, P = 0,003). Los resultados de eficacia difirieron entre los psicoestimulantes evaluados como una función de las tasas de respuesta: ar / modafinil (OR, 1,47; IC del 95%, 1,20-1,81; P = 0,0002); Dextroanfetamina (OR, 7,11; IC del 95%, 1,09 - 46,44; P = 0,04); Lisdexamfetamina dimesilato (OR, 1,21; IC del 95%, 0,94 - 1,56; P = ns); Metilfenidato (OR, 1,49; IC del 95%, 0,88 - 2,54; P = ns). Los resultados de eficacia también difirieron entre los agentes utilizados como terapia adyuvante (OR, 1,39; IC del 95%: 1,19-1,64) o monoterapia (OR, 2,25; IC del 95%: 0,67-7,52). CONCLUSIONES: Los psicoestimulantes no están suficientemente estudiados como adyuvantes o monoterapia en adultos con trastornos del estado de ánimo. La mayoría de los estudios publicados tienen limitaciones metodológicas significativas (por ejemplo, muestras heterogéneas, medidas dependientes, tipo / dosis del agente). Además de las mejoras en los factores metodológicos, una hipótesis comprobable es que los psicoestimulantes pueden ser probados más apropiadamente en dominios selectos de la psicopatología (por ejemplo, el procesamiento emocional cognitivo), más que como antidepresivos de "amplio espectro".
Los antagonistas del receptor de N-metil-D-aspartato de ketamina y no ketamina (antagonistas NMDAR) demostraron recientemente eficacia antidepresiva para el tratamiento de la depresión refractaria, pero el tamaño del efecto, las trayectorias y los posibles efectos de clase no están claros. MÉTODO: Se realizaron búsquedas en PubMed / PsycINFO / Web of Science / clinicaltrials.gov hasta el 25 de agosto de 2015. Ensayos controlados aleatorios (ECAs) de grupos paralelos o cruzados comparando la infusión intravenosa única de ketamina o un antagonista NMDAR no ketamínico versus placebo / Pseudo-placebo en pacientes con trastorno depresivo mayor (MDD) y / o depresión bipolar (BD) se incluyeron en los análisis. Los coeficientes de riesgo de cobertura y riesgo y sus intervalos de confianza (IC) del 95% se calcularon utilizando un modelo de efectos aleatorios. El resultado primario fue el cambio de síntomas depresivos. Los resultados secundarios incluyeron respuesta, remisión, descontinuación de todas las causas y efectos adversos. Se realizaron metaanálisis un total de 14 ECA (nueve estudios de ketamina: n = 234, cinco estudios con antagonistas NMDAR no ketamínicos: n = 354, MDD = 554, BD = 34), con una duración de 10,0 ± 8,8 días. La ketamina redujo significativamente la depresión significativamente más que el placebo / pseudo-placebo, comenzando a los 40 min, alcanzando un máximo en el día 1 (g de Hedges = -1,00, IC del 95%: -1,28 a -0,73, p <0,001) . Los antagonistas NMDAR no ketamínicos fueron superiores al placebo sólo en los días 5-8 (g de Hedges = -0,37, IC del 95%: -0,66 a -0,09, p = 0,01). Comparado con placebo / pseudo-placebo, la ketamina condujo a una respuesta significativamente mayor (40 min al día 7) y la remisión (80 min a los días 3-5). Los antagonistas NMDAR no ketamínicos lograron una mayor respuesta al día 2 y los días 3-5. La interrupción de todas las causas fue similar entre ketamina (p = 0,34) o antagonistas NMDAR no ketamínicos (p = 0,94) y placebo. Aunque algunos efectos adversos fueron más comunes con los antagonistas de ketamina / NMDAR que con el placebo, estos fueron transitorios y clínicamente insignificantes. CONCLUSIONES: Una única infusión de ketamina, pero menos de antagonistas NMDAR no ketamínicos, tiene una eficacia ultra rápida para MDD y BD, con una duración de hasta 1 semana. El desarrollo de antagonistas de NMDAR administrados repetidamente de fácil administración, sin riesgo de toxicidad cerebral, es de importancia crítica. (PsycINFO Database Record (c) 2016 APA, todos los derechos reservados)
OBJETIVO: Los autores realizaron una revisión sistemática y meta-análisis de ketamina y otros antagonistas de los receptores N-metil-D-aspartato (NMDA) en el tratamiento de la depresión mayor.
Se realizaron búsquedas en MEDLINE, PsycINFO y otras bases de datos para controlado con placebo, doble ciego, ensayos clínicos aleatorios de antagonistas de NMDA en el tratamiento de la depresión: método. Los resultados primarios fueron las tasas de respuesta al tratamiento y la remisión transitoria de los síntomas. Los resultados secundarios incluyeron el cambio en la gravedad de la depresión de los síntomas y la frecuencia y gravedad de los efectos disociativos y psicotomiméticas. Los resultados para cada antagonista de NMDA se combinaron en los metanálisis, la presentación de informes odds ratios para los resultados dicotómicos y diferencias de medias estandarizadas para los resultados continuos.
RESULTADOS: La ketamina (siete ensayos que abarca 147 participantes tratados con ketamina) producen una rápida, pero transitoria, el efecto antidepresivo, con odds ratios para la respuesta transitoria y la remisión de los síntomas a las 24 horas equivale a 9,87 (4,37 a 22,29) y 14,47 (2,67-78,49) , respectivamente, acompañados de breves efectos psicotomiméticas y disociativos. El aumento de la TEC ketamina (cinco ensayos que abarcan 89 participantes tratados con ketamina) redujo significativamente los síntomas depresivos después del tratamiento inicial (Hedges g = 0,933), pero no en la conclusión del curso de la TEC. Otros antagonistas de NMDA no lograron demostrar la eficacia consistentemente; Sin embargo, dos agonistas parciales en el sitio NMDA coagonista, d-cicloserina y rapastinel, reducen significativamente los síntomas depresivos y sin efectos psicotomiméticas o disociativos.
Conclusiones: La eficacia antidepresiva de la ketamina, y quizás D-cicloserina y rapastinel, es prometedor para futuras estrategias de glutamato-modulación; Sin embargo, la ineficacia de otros antagonistas de NMDA sugiere que todas las futuras avances dependerán de mejorar nuestra comprensión del mecanismo de ketamina de acción. La fugacidad de beneficio terapéutico de la ketamina, junto con su potencial para el abuso y la neurotoxicidad, sugieren que su uso en las órdenes de ajuste clínico precaución.
A survey of medical literature suggests that for patients with depression who have not responded to other augmentation strategies, psychostimulants may offer improvements in mood, energy, and concentration.
Depression is a common condition that significantly impairs social and occupational functioning. Many patients do not respond to first-line pharmacotherapies and are considered to have treatment-resistant depression (TRD). These patients may benefit from augmentation of their antidepressant to reduce depression. Multiple medications have demonstrated various degrees of efficacy for augmentation, including psychostimulants. This article reviews studies of psychostimulants as augmentation agents for TRD and discusses risks, offers advice, and makes recommendations for clinicians who prescribe stimulants.
Depression is a burdening disease state where up to 30% of individuals do not respond to first-line treatment. Adjunctive use of psychostimulants has been investigated for the treatment of depression in patient populations, including those with treatment-resistant depression or terminal illness. The purpose of this paper is to present a review of the literature on the efficacy of using methylphenidate to manage depression.A search was conducted in PubMed, Ovid/MEDLINE, and PsychINFO using the following key words: psychostimulants, stimulants, methylphenidate, alternative therapy, depression, and major depressive disorder. All reports included were published before June 30, 2015.For this review 10 reports, including randomized controlled, case series, and retrospective chart review studies, were identified and assessed. Patient populations studied included patients with treatment-resistant depression, patients with terminal illness, geriatric patients, and patients with miscellaneous indications, such as history of stroke and human immunodeficiency virus (HIV), or acquired immune deficiency syndrome (AIDS). For treatment-resistant depression, treatment differences for fatigue and apathy in favor of methylphenidate were found, but no difference was found for response rates in depression. Additionally, in palliative care and hospice patients, methylphenidate was found to improve fatigue and depressive symptoms. Patients with other conditions (poststroke and HIV patients) achieved some relief of depressive symptoms.The efficacy data for methylphenidate in depression are limited, with inconsistent results in specific patient populations that limit external validity. At this time, it should not be recommended as first-line treatment in depression. Future research should be developed focusing on long-term safety and efficacy in nonspecialized patient populations.
OBJETIVO: Los médicos a menudo consideran que el uso fuera de etiqueta de estimulantes o alternativas estimulantes como los antidepresivos complementarios. Los autores revisaron la literatura disponible sobre la eficacia de estos agentes para el tratamiento de la depresión unipolar y bipolar refractario.
FUENTES DE INFORMACIÓN: PubMed, MEDLINE, y la literatura en idioma Inglés relevante de 1988-2013 se realizaron búsquedas. Palabras clave eran dopaminérgico, estimulante, aumento, tratamiento de la depresión refractaria, dextroanfetamina, metilfenidato, modafinilo, atomoxetina, y la seguridad cardiovascular.
SELECCIÓN DE ESTUDIOS: Se incluyeron todos los ensayos controlados aleatorios (ECA) publicados durante este período de tiempo. Cuando ECA no estaban disponibles, se resumieron estudios abiertos.
EXTRACCIÓN DE DATOS: Los datos sobre la eficacia de los estimulantes y alternativas estimulantes como aumento de tratamiento para la depresión unipolar y bipolar fueron extraídos.
RESULTADOS: Tres estudios abiertos mostraron resultados positivos para los estimulantes dopaminérgicos, y, aunque 2 ECA mostraron resultados negativos, un ECA reciente reveló resultados positivos para lisdexanfetamina como un agente coadyuvante. Hasta la fecha, los estimulantes dopaminérgicos no se han probado en la depresión bipolar ECA. Cuatro ECA completado sugirieron que el modafinilo / armodafinilo eran beneficiosos como auxiliares de tratamiento para la depresión unipolar y bipolar, con tasas muy bajas de interruptor de estado de ánimo en la depresión bipolar. Un estudio se detuvo antes de tiempo debido a las preocupaciones de seguridad de un mayor riesgo de suicidio.
CONCLUSIONES: El modafinil y armodafinil se recomiendan complementos de tratamiento para la depresión unipolar y bipolar refractario. Hasta hace poco, datos de ECA sobre estimulantes dopaminérgicos fueron demasiado limitados como para justificar su uso como complemento del tratamiento de primera línea. Sin embargo, los resultados prometedores de 1 ECA reciente lisdexanfetamina, cuando se considera en el contexto del efecto deletéreo de la depresión subsindrómica, sugieren la consideración de medicamentos dopaminérgicos en la depresión unipolar o bipolar resistente al tratamiento cuando modafinilo es un costo prohibitivo o contraindicación.
Clinical trials are the backbone of medical scientific research. However, this experimental strategy has some drawbacks. We focused on two issues: (a) The internal validity ensured by clinical trial procedures does not necessarily allow for generalization of efficacy results to causal claims about effectiveness in the population. (b) Statistical significance does not imply clinical or practical significance; p-values should be supplemented with effect size (ES) estimators and an interpretation of the magnitude of the effects found. We conducted a systematic review (from 2000 to 2020) on Scopus, PubMed, and four ProQuest databases, including PsycINFO. We searched for experimental studies with significant effects of pharmacological treatments on depressive symptoms, measured with a specific scale for depression. We assessed the claims of effectiveness, and reporting and interpreting of effect sizes in a small, unbiased sample of clinical trials (n = 10). Only 30% of the studies acknowledged that efficacy does not necessarily translate to effectiveness. Only 20% reported ES indices, and only 40% interpreted the magnitude of their findings. We encourage reflection on the applicability of results derived from clinical trials about the efficacy of antidepressant treatments, which often influence daily clinical decision-making. Comparing experimental results of antidepressants with supplementary observational studies can provide clinicians with greater flexibility in prescribing medication based on patient characteristics. Furthermore, the ES of a treatment should be considered, as treatments with a small effect may be worthwhile in certain circumstances, while treatments with a large effect may be justified despite additional costs or complications. Therefore, researchers are encouraged to report and interpret ES and explicitly discuss the suitability of their sample for the clinical population to which the antidepressant treatment will be applied.
Pregunta de la revisión sistemática»Revisión sistemática de intervenciones
