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Durability of antidepressant response to ketamine: systematic review and meta-analysis
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Resumo: A perturbaĆ§Ć£o depressiva major (PDM) estĆ” a tornar-se cada vez mais prevalente em todo o mundo, e uma fraĆ§Ć£o significativa dos casos sofre tambĆ©m de depressĆ£o resistente ao tratamento (DRT). A cetamina, conhecida hĆ” muito como anestĆ©sico, surgiu como um novo antidepressivo de aĆ§Ć£o rĆ”pida, capaz de proporcionar um alĆvio precoce e robusto dos sintomas. No entanto, as taxas globais de resposta clĆnica e a durabilidade dos efeitos antidepressivos da cetamina ao longo do tempo nĆ£o estĆ£o bem estabelecidas. Foi realizada uma revisĆ£o sistemĆ”tica e meta-anĆ”lise para avaliar a durabilidade dos efeitos terapĆŖuticos da cetamina em adultos com PDM (incluindo DRT) nas fases aguda e de seguimento. Os estudos incluĆram ensaios randomizados controlados e ensaios nĆ£o randomizados controlados publicados sobre cetamina (e escetamina) em adultos (ā„18 anos) com um diagnĆ³stico DSM/ICD de PDM. A extraĆ§Ć£o de dados foi realizada em duplicado. Os resultados foram agrupados por tempo: fase aguda (1ā14 dias), seguimento precoce (15ā55 dias) e seguimento tardio (ā„56 dias). Modelos de efeitos aleatĆ³rios agregaram as proporƧƵes de resposta e remissĆ£o e as alteraƧƵes mĆ©dias padronizadas nas pontuaƧƵes de depressĆ£o (g de Hedges). Um total de 138 estudos (n=6082 doentes) cumpriram os critĆ©rios de inclusĆ£o; 106 (77%) envolveram grupos resistentes ao tratamento. A taxa de resposta clĆnica combinada foi de aproximadamente 50% na fase aguda, aumentou para 59% no seguimento entre 15ā55 dias e foi de 48% aos ā„56 dias. As taxas de remissĆ£o aumentaram de 30% (fase aguda) para 39% (seguimento precoce) e 52% (seguimento tardio). Embora as taxas de resposta combinadas nĆ£o tenham mostrado significĆ¢ncia estatĆstica, as taxas de remissĆ£o nas fases aguda e de seguimento precoce foram estatisticamente significativas. A heterogeneidade foi muito elevada (IĀ² geralmente >80%). A reduĆ§Ć£o mĆ©dia padronizada nos sintomas depressivos foi grande e significativa em todos os momentos (DMP = ā2,15 na fase aguda; ā2,18 no seguimento precoce; ā2,49 no seguimento tardio). Importa notar que, nas anĆ”lises de seguimento tardio, os estudos com ā„6 sessƵes de cetamina mostraram uma taxa de resposta significativamente inferior (36,5%) em comparaĆ§Ć£o com aqueles com <6 sessƵes (58,1%). A cetamina induz um forte efeito antidepressivo, mas o seu efeito sustentado Ć© inconsistente e altamente variĆ”vel. As flutuaƧƵes ao longo do tempo refletem provavelmente a heterogeneidade dos estudos, em vez de tendĆŖncias sistemĆ”ticas. A meta-regressĆ£o nĆ£o identificou indicadores fiĆ”veis de benefĆcio sustentado. Embora alguns pacientes mantenham melhorias durante semanas, os efeitos para alĆ©m de um mĆŖs permanecem incertos. Estudos futuros devem prolongar a duraĆ§Ć£o do seguimento, padronizar os protocolos e explorar indicadores para identificar pacientes com maior probabilidade de resposta. Abordagens combinadas, como a adiĆ§Ć£o de psicoterapia, podem melhorar os resultados. Em conclusĆ£o, a cetamina oferece alĆvio rĆ”pido em pacientes com PDM e DRT, mas o seu benefĆcio sustentado Ć© imprevisĆvel e deve ser interpretado com cautela.
Abstract: Major depressive disorder (MDD) is increasingly prevalent worldwide, and a significant portion of cases are treatment-resistant (TRD). Ketamine, long known as an anesthetic, has emerged as a novel rapid-acting antidepressant capable of producing robust early symptom relief. However, the overall rates of clinical response and the durability of ketamineās antidepressant effects over time are not well established. A systematic review and meta-analysis was conducted to evaluate the durability of ketamineās therapeutic effects in adults with MDD (including TRD) across acute and follow-up phases. Studies included randomized controlled trials and non-randomized controlled trials published of ketamine (and esketamine) in adults (ā„18 years) with a DSM/ICD diagnosis of MDD. Data extraction was performed in duplicate. Outcomes were grouped by time: acute phase (1ā14 days), early follow-up (15ā55 days), and late follow-up (ā„56 days). Random-effects models pooled response and remission proportions and standardized mean changes in depression scores (Hedgesā g). A total of 138 studies (n=6082 patients) met inclusion criteria; 106 (77%) involved treatment-resistant cohorts. The pooled clinical response rate was roughly 50% in the acute phase, rose to 59% in the 15ā55 day follow-up, and was 48% at ā„56 days. Remission rates increased from 30% (acute) to 39% (early follow-up) and 52% (late follow-up). While pooled response rates showed no statistical significance, remission rates at acute and early follow-up were significant, heterogeneity was very high (IĀ² generally >80%). The standardized mean reduction in depressive symptoms was large and significant at all times (SMD = ā2.15 acute; ā2.18 early; ā2.49 late). Notably, in late follow-up analyses, studies with ā„6 ketamine sessions showed significantly lower response (36.5%) than those with <6 sessions (58.1%). Ketamine induces a strong antidepressant effect, but its sustained effect is inconsistent and highly variable. Fluctuations over time likely reflect study heterogeneity rather than systematic trends, and meta-regression identified no reliable predictors of sustained benefit. While some patients maintain improvement for weeks, effects beyond one month remain uncertain. Future studies should extend follow-up duration, standardize protocols, and explore predictors to identify likely responders. Combined approaches, such as adding psychotherapy, may enhance outcomes. In conclusion ketamine offers rapid relief in MDD and TRD patients, but its sustained benefit is unpredictable and should be interpreted with caution.
Abstract: Major depressive disorder (MDD) is increasingly prevalent worldwide, and a significant portion of cases are treatment-resistant (TRD). Ketamine, long known as an anesthetic, has emerged as a novel rapid-acting antidepressant capable of producing robust early symptom relief. However, the overall rates of clinical response and the durability of ketamineās antidepressant effects over time are not well established. A systematic review and meta-analysis was conducted to evaluate the durability of ketamineās therapeutic effects in adults with MDD (including TRD) across acute and follow-up phases. Studies included randomized controlled trials and non-randomized controlled trials published of ketamine (and esketamine) in adults (ā„18 years) with a DSM/ICD diagnosis of MDD. Data extraction was performed in duplicate. Outcomes were grouped by time: acute phase (1ā14 days), early follow-up (15ā55 days), and late follow-up (ā„56 days). Random-effects models pooled response and remission proportions and standardized mean changes in depression scores (Hedgesā g). A total of 138 studies (n=6082 patients) met inclusion criteria; 106 (77%) involved treatment-resistant cohorts. The pooled clinical response rate was roughly 50% in the acute phase, rose to 59% in the 15ā55 day follow-up, and was 48% at ā„56 days. Remission rates increased from 30% (acute) to 39% (early follow-up) and 52% (late follow-up). While pooled response rates showed no statistical significance, remission rates at acute and early follow-up were significant, heterogeneity was very high (IĀ² generally >80%). The standardized mean reduction in depressive symptoms was large and significant at all times (SMD = ā2.15 acute; ā2.18 early; ā2.49 late). Notably, in late follow-up analyses, studies with ā„6 ketamine sessions showed significantly lower response (36.5%) than those with <6 sessions (58.1%). Ketamine induces a strong antidepressant effect, but its sustained effect is inconsistent and highly variable. Fluctuations over time likely reflect study heterogeneity rather than systematic trends, and meta-regression identified no reliable predictors of sustained benefit. While some patients maintain improvement for weeks, effects beyond one month remain uncertain. Future studies should extend follow-up duration, standardize protocols, and explore predictors to identify likely responders. Combined approaches, such as adding psychotherapy, may enhance outcomes. In conclusion ketamine offers rapid relief in MDD and TRD patients, but its sustained benefit is unpredictable and should be interpreted with caution.
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Major depressive disorder Ketamine Meta-Analysis