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We therefore conducted a systematic review of trials of ketamine in patients with treatment-resistant depression to evaluate antidepressant efficacy, suicidality, safety, and tolerability. Potential biases from crossover designs, such as carryover of treatment effect into the second treatment period, can be addressed by restricting analyses to the first treatment period but often requires unpublished data. One other key issue is the extent of bias resulting from the use of a crossover design in all but one previous trial.

OвЂ™Keefe, unpublished data) evaluated lower doses of ketamine than previously tested, providing an opportunity to compare treatment efficacy and tolerability of different doses. Three very recently reported trials ( Lai et al., 2014 Lapidus et al., 2014) (C. Since then, several more trials have been published ( Zarate et al., 2006 Diazgranados et al., 2010a Zarate et al., 2012 Murrough et al., 2013 Sos et al., 2013), but existing reports and reviews ( aan het Rot et al., 2010 Aan Het Rot et al., 2012 Katalinic et al., 2013 Brittner et al., 2014 Caddy et al., 2014 McGirr et al., 2014) do not easily allow a direct comparison of how treatment effects persist in the days following treatment, given differences in graphical and tabular reporting methods and outcome scales. Ketamine appeared to improve specific depressive symptoms such as sadness, suicidality, and helplessness, rather than induce a nonspecific mood-elevating effect.

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In 2000 a small crossover trial suggested that a single subanaesthetic dose of ketamine could provide a large antidepressant benefit, starting within a few hours and lasting for at least several days ( Berman et al., 2000). This presents a major clinical challenge, especially for patients who have not responded fully to existing therapy or if symptoms include suicidality.

Aside from electro-convulsive therapy (ECT), there are no widely used treatments that provide large or rapid benefits for patients suffering from severe depression ( Martinowich et al., 2013).

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