title: Benefits and harms of low and high second-generation antipsychotics doses for bipolar depression: A meta-analysis.
abstract: The aim of this systematic review and meta-analysis was testing whether low versus high doses of second-generation antipsychotics (SGAs) are associated with different clinical benefits and harms for the acute treatment of bipolar depression. We included clinical trials comparing different doses of the same SGA monotherapy for bipolar depression. SGAs defined daily doses were used to define high and low doses. Clinical benefit outcomes included improvement, response and remission rates on Montgomery-Asberg Depression Rating Scale. Clinical harm outcomes included all-cause and adverse effect-related discontinuation rates. Data from seven clinical trials testing high and low doses of quetiapine (4 trials), cariprazine, lurasidone, and ziprasidone (1 trial each), showed no differences between lower and higher doses of selected SGAs on improvement, response and remission rates, without significant heterogeneity across studies (I2= 0%). Subgroup analyses based on single SGAs confirmed the clinical benefit comparability between low and high doses. However, clinical harm favorable differences for low doses on all-cause (p = 0.01) and adverse effects-related discontinuation (p = 0.001) were found. In sum, this meta-analysis showed that, although no benefits were found in terms of symptoms improvement, response and remission rates, there were clear disadvantages in prescribing higher rather than lower doses of selected SGAs. The uniform methodological strength of studies increases confidence in our findings. These data need to be integrated with individual patient characteristics (e.g., clinical urgency and adverse effect sensitivity) to optimize management of acute bipolar depression.
authors.affiliation: Department of Medicine and Surgery, University of Milano Bicocca, Milano, Italy. Electronic address: f.bartoli@campus.unimib.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bartoli
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford School of Medicine, Stanford, CA, USA; Department of Psychiatry, University of Milan, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Dell'Osso
authors.affiliation: Department of Medicine and Surgery, University of Milano Bicocca, Milano, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Crocamo
authors.affiliation: Department of Psychiatry, University of Naples SUN, Naples, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fiorillo
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford School of Medicine, Stanford, CA, USA.
authors.forename: Terence A
authors.initials: TA
authors.lastname: Ketter
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford School of Medicine, Stanford, CA, USA; VA Palo Alto Health Care System, Palo Alto, CA, USA.
authors.forename: Trisha
authors.initials: T
authors.lastname: Suppes
authors.affiliation: Department of Medicine and Surgery, University of Milano Bicocca, Milano, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Clerici
authors.affiliation: Department of Medicine and Surgery, University of Milano Bicocca, Milano, Italy; Division of Psychiatry, University College London, London, UK.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Carrà
mesh_terms: D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D006801:Humans
chemical_list: D014150:Antipsychotic Agents
keywords: Antipsychotics; Bipolar disorder; Meta-analysis; Psychopharmacology