Case studies documenting fewer than three participants were excluded. Study selection Using the stated search strategy 11,138 reports were identified. The search and process of identification is summarized in Figure 2. In total, 26 studies were ultimately identified

as fulfilling criteria, with a total of 629 participants. Figure 2. Flow diagram demonstrating the process of inclusion of studies for review. Data extraction In order to collate relevant information from each article the following data were extracted from each: characteristics of participants (age, gender, length of illness, Inhibitors,research,lifescience,medical length of current episode, method of diagnosis); trial inclusion and exclusion criteria; type of intervention (type, dose, duration, design); response criteria; type of outcome measure (depression scale, response rates, remission rates, follow up). Several different and quite diverse themes emerged during the data

extraction and the sample was thus divided into the following three categories to allow better clarification and interpretation of results: ketamine only; ketamine plus Inhibitors,research,lifescience,medical a second drug; ketamine and electroconvulsive therapy (ECT) or surgery. Data analysis For each of the subcategories of theme identified a table is presented with Inhibitors,research,lifescience,medical the characteristics of the included studies. Hamilton depression scale ratings data from the five studies with control groups [Berman et al. 2000; DiazGranados et al. 2010b; Valentine et al. 2011; Zarate et al. 2006, 2012] were subjected to two cross-study meta-analyses using OpenMeta[Analyst], Brown Education software (see http://www.cebm.brown.edu/open_meta). For the first

meta-analysis, the effects of ketamine versus placebo on depressive ratings Inhibitors,research,lifescience,medical were assessed at baseline, for the second 60–80 minutes Pim inhibitor post-infusion, and for the third 210–230 minutes post-infusion. Given that the included studies did not coherently Inhibitors,research,lifescience,medical report the means and standard deviations for each group at each time point, values were read off the available graphs in each paper. Ketamine only Studies with no control group There were 11 studies that administered ketamine to all participants with no control aminophylline condition: their characteristics are detailed in Table 1 and results are given in Table 2. Six studies evaluated single-dose ketamine administration on depressive symptoms, three multiple-dose schedules and two primarily evaluated changes to suicidal ideation. Trial size varied from 11 to 33 participants, and recorded follow up from 230 minutes to 83 days post-ketamine administration. A total of 206 participants, all with major depressive episodes (MDEs; diagnosed using DSM), completed these trials, and all were undertaken within the past 5 years. Ketamine was administered at 0.5 mg/kg in all trials except one [Larkin and Beautrais, 2011]. All studies adopted the Montgomery–Asberg Depression Rating Scale (MADRS) as the primary outcome measure: response was defined as ≥50% reduction in scores throughout, and remission a score of < 10.