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.
Background: Glutamergic system dysfunction has been implicated in the pathophysiology of bipolar depression. This is an update of the 2015 Cochrane Review for the use of glutamate receptor modulators for depression in bipolar disorder. Objectives: 1. To assess the effects of ketamine and other glutamate receptor modulators in alleviating the acute symptoms of depression in people with bipolar disorder.2. To review the acceptability of ketamine and other glutamate receptor modulators in people with bipolar disorder who are experiencing depressive symptoms. 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: RCTs comparing ketamine or other glutamate receptor modulators with other active psychotropic drugs or saline placebo in adults with bipolar depression. Data collection and analysis: Two review authors independently selected studies for inclusion, assessed trial quality and extracted data. Primary outcomes were response rate and adverse events. Secondary outcomes included remission rate, depression severity change scores, suicidality, cognition, quality of life, and dropout rate. The GRADE framework was used to assess the certainty of the evidence. Main results: Ten studies (647 participants) were included in this review (an additional five studies compared to the 2015 review). There were no additional studies added to the comparisons identified in the 2015 Cochrane review on ketamine, memantine and cytidine versus placebo. However, three new comparisons were found: ketamine versus midazolam, N-acetylcysteine versus placebo, and riluzole versus placebo. The glutamate receptor modulators studied were ketamine (three trials), memantine (two), cytidine (one), N-acetylcysteine (three), and riluzole (one). Eight of these studies were placebo-controlled and two-armed. In seven trials the glutamate receptor modulators had been used as add-on drugs to mood stabilisers. Only one trial compared ketamine with an active comparator, midazolam. The treatment period ranged from a single intravenous administration (all ketamine studies), to repeated administration for riluzole, memantine, cytidine, and N-acetylcysteine (with a follow-up of eight weeks, 8 to 12 weeks, 12 weeks, and 16 to 20 weeks, respectively). Six of the studies included sites in the USA, one in Taiwan, one in Denmark, one in Australia, and in one study the location was unclear. All participants had a primary diagnosis of bipolar disorder and were experiencing an acute bipolar depressive episode, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders fourth edition (IV) or fourth edition text revision (IV-TR). Among all glutamate receptor modulators included in this review, only ketamine appeared to be more efficacious than placebo 24 hours after infusion for response rate (odds ratio (OR) 11.61, 95% confidence interval (CI) 1.25 to 107.74; P = 0.03; participants = 33; studies = 2; I² = 0%, low-certainty evidence). Ketamine seemed to be more effective in reducing depression rating scale scores (MD -11.81, 95% CI -20.01 to -3.61; P = 0.005; participants = 32; studies = 2; I2 = 0%, very low-certainty evidence). There was no evidence of ketamine's efficacy in producing remission over placebo at 24 hours (OR 5.16, 95% CI 0.51 to 52.30; P = 0.72; participants = 33; studies = 2; I2 = 0%, very low-certainty evidence). Evidence on response, remission or depression rating scale scores between ketamine and midazolam was uncertain at 24 hours due to very low-certainty evidence (OR 3.20, 95% CI 0.23 to 45.19). In the one trial assessing ketamine and midazolam, there were no dropouts due to adverse effects or for any reason (very low-certainty evidence). Placebo may have been more effective than N-acetylcysteine in reducing depression rating scale scores at three months, although this was based on very low-certainty evidence (MD 1.28, 95% CI 0.24 to 2.31; participants = 58; studies = 2). Very uncertain evidence found no difference in response at three months (OR 0.82, 95% CI 0.32 to 2.14; participants = 69; studies = 2; very low-certainty evidence). No data were available for remission or acceptability. Extremely limited data were available for riluzole vs placebo, finding only very-low certainty evidence of no difference in dropout rates (OR 2.00, 95% CI 0.31 to 12.84; P = 0.46; participants = 19; studies = 1; I2 = 0%). Authors' conclusions: It is difficult to draw reliable conclusions from this review due to the certainty of the evidence being low to very low, and the relatively small amount of data usable for analysis in bipolar disorder, which is considerably less than the information available for unipolar depression. Nevertheless, we found uncertain evidence in favour of a single intravenous dose of ketamine (as add-on therapy to mood stabilisers) over placebo in terms of response rate up to 24 hours, however ketamine did not show any better efficacy for remission in bipolar depression. Even though ketamine has the potential to have a rapid and transient antidepressant effect, the efficacy of a single intravenous dose may be limited. We did not find conclusive evidence on adverse events with ketamine, and there was insufficient evidence to draw meaningful conclusions for the remaining glutamate receptor modulators. However, ketamine's psychotomimetic effects (such as delusions or delirium) may have compromised study blinding in some studies, and so we cannot rule out the potential bias introduced by inadequate blinding procedures. To draw more robust conclusions, further methodologically sound RCTs (with adequate blinding) are needed to explore different modes of administration of ketamine, and to study different methods of sustaining antidepressant response, such as repeated administrations.
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.
OBJETIVO: Los ensayos clínicos demostraron que la ketamina exhibe una eficacia antidepresiva rápida cuando se administra en dosis subanaestéticas. Revisamos la literatura actualmente disponible que investiga la eficacia, las tasas de respuesta y el perfil de seguridad. Métodos: Se incluyeron doce estudios que investigaron la depresión unipolar y siete en la depresión bipolar después de la búsqueda en medline, scopus y web of science. RESULTADOS: Los ensayos aleatorizados, controlados con placebo o en abierto mostraron tasas de respuesta de antidepresivos después de 24 h en las medidas de resultado primarias al 61%. La reducción promedio de la Escala de Depresión de Hamilton (HAM-D) fue de 10,9 puntos, Beck Depression Inventory (BDI) 15,7 puntos y Montgomery-Asberg Depression Rating Scale (MADRS) 20,8 puntos. La ketamina siempre fue superior al placebo. Los efectos secundarios más comunes fueron mareos, visión borrosa, inquietud, náuseas / vómitos y dolor de cabeza, que fueron todos reversibles. Las tasas de recaída oscilaron entre el 60% y el 92%. Para proporcionar información sobre las mejores prácticas a los pacientes, se incluye un formulario de consentimiento para la aplicación y la modificación en el idioma local. Conclusiones. La ketamina constituye una opción terapéutica novedosa, rápida y eficaz para los pacientes que padecen depresión resistente al tratamiento y exhibe efectos anti-suicidas rápidos y significativos. Las nuevas vías de administración podrían servir como alternativa a los regímenes intravenosos para uso potencial en ambientes ambulatorios. Sin embargo, los efectos secundarios a largo plazo no se conocen y la corta duración de la respuesta antidepresiva necesita maneras de prolongar la eficacia de la ketamina.
El componente depresivo es el más prevalente del trastorno bipolar. La ketamina ha mostrado eficacia y rapidez como tratamiento de episodios depresivos. El objetivo del presente trabajo es realizar una revisión sistemática sobre la eficacia y seguridad de la ketamina como tratamiento de la depresión bipolar, y sus tipos de administración. Se obtuvieron 10 artículos relevantes que cumplían con los criterios del estudio: un ensayo clínico, 5 estudios de cohorte y 4 series de casos. La forma de administración utilizada en el 60% de los trabajos fue la infusión intravenosa. La ketamina parece ser un tratamiento seguro y eficaz para la depresión bipolar, aunque la duración de la acción es breve. Los efectos adversos que se observaron se produjeron generalmente en el momento de la infusión y tendieron a desaparecer completamente al cabo de 1-2h. Por tanto, es necesario realizar más estudios para explorar nuevas vías de administración, así como su seguridad y efectos adversos (AU)
El tratamiento de la depresión unipolar con los antidepresivos actualmente disponibles sigue siendo insatisfactorio. El aumento con litio o antipsicóticos de segunda generación es una práctica establecida en los no respondedores a la monoterapia antidepresiva, pero también está asociado con una tasa de falta de respuesta sustancial y con la no tolerancia. Basado en una revisión sistemática de la literatura, incluyendo metaanálisis, ensayos controlados aleatorios (ECA), estudios comparativos no aleatorios y estudios de casos, agentes de aumento fuera de la etiqueta (administrados además de un antidepresivo, sin la aprobación de la FDA para el tratamiento del MDD ) Fueron identificados y evaluados en cuanto a su eficacia utilizando los niveles de evidencia. Los agentes tuvieron que ser añadidos a un régimen antidepresivo existente con el objetivo de lograr una respuesta clínica mejorada a un tratamiento antidepresivo (aumento) o un inicio de efecto más temprano al iniciar el antidepresivo y el agente de aumento simultáneamente (aceleración). Se demostró que cinco sustancias, el modafinilo, la ketamina, el pindolol, la testosterona y el estrógeno (los dos últimos en pacientes con deficiencia hormonal) son clínicamente eficaces en estudios de alta evidencia. Para los seis fármacos, la dexametasona, la mecamilamina, el riluzol, la amantadina, el pramipexol y la yohimbina demostraron claramente la eficacia no fue posible debido a los bajos niveles de evidencia, el tamaño pequeño de la muestra o los resultados discordantes. Para los dos agentes, el metilfenidato y la memantina sólo se pueden encontrar estudios con resultados negativos. En general, la calidad de los diseños de estudio fue baja y los resultados fueron a menudo contradictorios. Sin embargo, el uso de pindolol, ketamina, modafinil, estrógeno y testosterona podría ser una opción para los pacientes deprimidos que no están respondiendo a la monoterapia con antidepresivos o estrategias de aumento establecidas. Otros estudios de alta calidad son necesarios y justificados.
Revista»The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)
BACKGROUND: Several recent trials indicate low-dose ketamine produces rapid antidepressant effects. However, uncertainty remains in several areas: dose response, consistency across patient groups, effects on suicidality, and possible biases arising from crossover trials. METHODS: A systematic search was conducted for relevant randomized trials in Medline, Embase, and PsycINFO databases up to August 2014. The primary endpoints were change in depression scale scores at days 1, 3 and 7, remission, response, suicidality, safety, and tolerability. Data were independently abstracted by 2 reviewers. Where possible, unpublished data were obtained on treatment effects in the first period of crossover trials. RESULTS: Nine trials were identified, including 201 patients (52% female, mean age 46 years). Six trials assessed low-dose ketamine (0.5 mg/kg i.v.) and 3 tested very low-dose ketamine (one trial assessed 50 mg intra-nasal spray, another assessed 0.1–0.4 mg/kg i.v., and another assessed 0.1–0.5 mg/kg i.v., intramuscular, or s.c.). At day 3, the reduction in depression severity score was less marked in the very low-dose trials (<i>P</i> homogeneity < .05) and among bipolar patients. In analyses excluding the second period of crossover trials, response rates at day 7 were increased with ketamine (relative risk 3.4, 95% CI 1.6–7.1, <i>P</i> = .001), as were remission rates (relative risk 2.6, CI 1.2–5.7, <i>P</i> = .02). The absolute benefits were large, with day 7 remission rates of 24% vs 6% (<i>P</i> = .02). Seven trials provided unpublished data on suicidality item scores, which were reduced on days 1 and 3 (both <i>P</i> < .01) but not day 7. CONCLUSION: Low-dose ketamine appears more effective than very low dose. There is substantial heterogeneity in clinical response, with remission among one-fifth of patients at 1 week but most others having benefits that are less durable. Larger, longer term parallel group trials are needed to determine if efficacy can be extended and to further assess safety. (PsycINFO Database Record (c) 2016 APA, all rights reserved)
El trastorno bipolar (BD) tiene un cuadro clínico complejo y variable que se caracteriza por diferentes fases y fases y, como resultado, sus opciones terapéuticas también son complejas ya menudo insatisfactorias. Normalmente, los llamados 'estabilizadores del estado de ánimo' se usan en el tratamiento de BD y en esta clase se incluyen litio y se incluyen antiepilépticos específicos. El presente estudio tuvo como objetivo revisar sistemáticamente la literatura sobre la presencia de ensayos clínicos aleatorios doble ciego de opciones de tratamiento farmacéutico "no convencionales". La presente revisión sistemática utilizó el método PRISMA y buscó en MEDLINE hasta el 1 de enero de 2015 con el uso de palabras clave apropiadas. Con el fin de identificar los ensayos controlados aleatorios-ECA se utilizó una combinación de los términos "bipolar", "maníaco", "manía", "depresión maníaca" y "maníaco-depresiva" con "aleatorizado". También se buscaron páginas web con listas de ensayos, incluyendo http://clinicaltrials.gov y http://www.clinicalstudyresults.org, así como las páginas web oficiales de todas las compañías farmacéuticas con productos comercializados en el tratamiento de BD. También se realizaron búsquedas en las listas de referencias de varios documentos de revisión. El MEDLINE se buscó con la combinación de las palabras «directrices» o «algoritmos» con «manía», «maníaco», «bipolar», «manicodepresivo» o «depresión maníaca» con el fin de identificar los artículos con directrices de tratamiento. También se analizó la lista de referencias de estos artículos. A partir de 3.284 trabajos que fueron inicialmente rastreados, sólo 47 artículos se incluyeron en el presente estudio. De los agentes estudiados en manía aguda, el tamoxifeno es eficaz como monoterapia y como terapia combinada con litio y otros estabilizadores del estado de ánimo, sin embargo su perfil de seguridad es relativamente pobre. El alopurinol manifiesta eficacia en combinación con litio pero no con otros agentes y su perfil de seguridad es satisfactorio. La metoxiprogesterona es eficaz en combinación con estabilizadores del estado de ánimo y su perfil de seguridad es muy bueno. En la depresión bipolar aguda las combinaciones de FEWP con carbamazepina y ketamina, modafinil, pramipexole, pregnenolona y quizá armodafinil con estabilizadores de humor son eficaces. El perfil de seguridad de estas combinaciones es medio. El uso de celecoxib, lisdexamfetamina y memantina tiene datos negativos. En cuanto al tratamiento de mantenimiento, los datos son negativos para la memantina y para la nacetilcisteína. Aunque la mayoría de los datos relativos a la utilidad de los agentes farmacoterapéuticos "no convencionales" en el tratamiento del trastorno bipolar son negativos, es alentador que los agentes que han demostrado ser eficaces probablemente ejercen su efecto terapéutico a través de vías que difieren de lo usual y probablemente diferentes De los considerados clásicamente en la mayoría de los modelos biológicos de la enfermedad bipolar. De esta manera se constituyen nuevos paradigmas y se abren nuevos horizontes en la comprensión de la enfermedad. (PsycINFO Database Record (c) 2017 APA, todos los derechos reservados)
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)
ANTECEDENTES: Existe un creciente interés en los agentes glutamatérgicas en la depresión, especialmente la ketamina, un N-metil-D-aspartato (NMDA) antagonista de los receptores de glutamato. El objetivo fue evaluar la eficacia de la ketamina en los episodios depresivos mayores.
MÉTODO: Se realizaron búsquedas en EMBASE, PsycINFO, CENTRAL, y Medline desde 1962 hasta enero de 2014 para identificar a doble ciego, ensayos controlados aleatorios con ocultamiento de la asignación evaluar la ketamina en los episodios depresivos mayores. La remisión clínica, respuesta y los síntomas depresivos fueron extraídos por dos evaluadores independientes. La medida de resultado primaria fue la remisión clínica a las 24 h, 3 y 7 días después del tratamiento. Los análisis emplearon un modelo de efectos aleatorios.
RESULTADOS: Los datos fueron sintetizados a partir de siete ECA que emplean una infusión intravenosa y un ECA empleando ketamina intranasal, en representación de 73 sujetos en brazos paralelos y 110 sujetos en los diseños cruzados [n = 34 con trastorno bipolar (TB), n = 149 con depresión mayor trastorno (MDD)]. La ketamina se asocia con mayores tasas de remisión clínica relativa al comparador (salinos o midazolam) a las 24 h [OR 7.06, el número necesario a tratar (NNT) = 5], 3 días (OR 3,86; NNT = 6) y 7 días ( OR 4,00; NNT = 6), así como mayores tasas de respuesta clínica a las 24 h (OR 9,10; NNT = 3), 3 días (OR 6,77; NNT = 3), y 7 días (OR 4,87; NNT = 4) . Se observó una diferencia de medias estandarizada de 0,90 a favor de la ketamina a las 24 h basados en puntuaciones de la escala de calificación de depresión, con comparaciones de grupos que revela una mayor eficacia en la depresión unipolar en comparación con la depresión bipolar (1,07 v. 0.68). La ketamina se asoció con efectos psicotomiméticos transitorios, pero no hay psicosis o afectivos interruptores persistentes.
CONCLUSIÓN: Nuestra meta-análisis sugiere que la ketamina sola administraciones son eficaces en el tratamiento rápido de la depresión unipolar y bipolar. Se requiere investigación adicional para determinar los horarios óptimos de dosificación, ruta, horarios de tratamiento, y la potencial eficacia de otros agentes glutamatérgicas.
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.
