Michele Fornaro1, André F Carvalho2, Andrea Fusco3, Annalisa Anastasia4, Marco Solmi5, Michael Berk6, Kang Sim7, Eduard Vieta8, Andrea de Bartolomeis9. 1. Federico II University, Section of Psychiatry, Department of Neuroscience, Reproductive Sciences and Dentistry, Naples, Italy; Polyedra Research Team, Teramo, Italy. Electronic address: dott.fornaro@gmail.com. 2. Department of Psychiatry, University of Toronto; and Centre for Addiction & Mental Health (CAMH), Canada. 3. Italian National Healthcare System, Naples, Italy. 4. Polyedra Research Team, Teramo, Italy. 5. Neuroscience Department, Psychiatry Unit, University of Padua; Psychiatry Unit, Azienda Ospedaliera di Padova, Padua Hospital, Italy. 6. Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Geelong, VIC, Australia; Orygen, The Centre of Excellence in Youth Mental Health, the Department of Psychiatry and the Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Australia. 7. West Region, Institute of Mental Health, Singapore. 8. Department of Psychiatry and Psychology, Hospital Clinic, Bipolar Unit, Institute of Neuroscience, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain. 9. Federico II University, Section of Psychiatry, Department of Neuroscience, Reproductive Sciences and Dentistry, Naples, Italy.
Abstract
BACKGROUND: The definitions of treatment-resistant bipolar disorder (TRBD) have varied across studies. Additionally, its management is clinically challenging. An updated synthesis and appraisal of the available evidence is needed. METHODS: A systematic search of major electronic databases from inception up to May 25th, 2020, was conducted to identify randomized controlled trials (RCTs) of pharmacological and non-pharmacological interventions for the management of TRBD. When sufficient evidence was available, a meta-analysis was conducted. RESULTS: Seventeen studies (n = 928 patients) were included in the qualitative synthesis. Fourteen studies (n = 803) assessed treatment-resistant acute bipolar depression (TRBD-De), including five neuromodulatory and nine pharmacological trials. Rapid- vs. standard up-titration of clozapine showed promising efficacy for TRBD mania, without significant adverse events. Electroconvulsive therapy (ECT) was confirmed to be similarly effective for TRBD-De as for treatment-resistant unipolar depression: odd ratio, OR = 0.919 (95%C.I. = 0.44-1.917), I2 = 13.98, p = .822. TRBD-De patients exposed to ketamine at day one post-infusion had high odds of response: OR = 10.682 (95%C.I. = 2.142-53.272), I2 = 0, p = <.005. The pooled drop-out rate in the ketamine trials was 21.2%. Additional evidence is warranted to confirm the potential efficacy of pramipexole or stimulants for TRBD-De. LIMITATIONS: Publication/measurement bias; exploratory nature of the meta-analyses for interventions that included participants solely with TRBD-De. CONCLUSIONS: Overall, a few interventions are available for TRBD, including pramipexole, ECT, and clozapine, among others. Larger and better-designed trials for TRBD are warranted and should be based on more uniform operational definitions. PROSPERO registration number: CRD42018114567.
BACKGROUND: The definitions of treatment-resistant bipolar disorder (TRBD) have varied across studies. Additionally, its management is clinically challenging. An updated synthesis and appraisal of the available evidence is needed. METHODS: A systematic search of major electronic databases from inception up to May 25th, 2020, was conducted to identify randomized controlled trials (RCTs) of pharmacological and non-pharmacological interventions for the management of TRBD. When sufficient evidence was available, a meta-analysis was conducted. RESULTS: Seventeen studies (n = 928 patients) were included in the qualitative synthesis. Fourteen studies (n = 803) assessed treatment-resistant acute bipolar depression (TRBD-De), including five neuromodulatory and nine pharmacological trials. Rapid- vs. standard up-titration of clozapine showed promising efficacy for TRBD mania, without significant adverse events. Electroconvulsive therapy (ECT) was confirmed to be similarly effective for TRBD-De as for treatment-resistant unipolar depression: odd ratio, OR = 0.919 (95%C.I. = 0.44-1.917), I2 = 13.98, p = .822. TRBD-De patients exposed to ketamine at day one post-infusion had high odds of response: OR = 10.682 (95%C.I. = 2.142-53.272), I2 = 0, p = <.005. The pooled drop-out rate in the ketamine trials was 21.2%. Additional evidence is warranted to confirm the potential efficacy of pramipexole or stimulants for TRBD-De. LIMITATIONS: Publication/measurement bias; exploratory nature of the meta-analyses for interventions that included participants solely with TRBD-De. CONCLUSIONS: Overall, a few interventions are available for TRBD, including pramipexole, ECT, and clozapine, among others. Larger and better-designed trials for TRBD are warranted and should be based on more uniform operational definitions. PROSPERO registration number: CRD42018114567.
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