Abstract
Ketamine produces a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown. In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27). We hypothesized that responders to therapy would demonstrate response-dependent connectivity changes while all subjects would show treatment-dependent connectivity changes. Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8). Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change. A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe.ClinicalTrials.gov: Treatment Resistant Depression (Pilot), NCT01179009.
Highlights
Until recently, approved antidepressant medications have primarily targeted the brain monoamine systems
The first is that a single, prolonged, high-dose infusion may offer more persistent antidepressant effect than brief ketamine bolus
The response rate at 2 weeks post-infusion (52%, 11/21) is similar to the response rate that has been reported at 4 weeks with recurrent twice-weekly intranasal esketamine of 50–55% in ketamine-naive treatment-resistant depression patients (Fedgchin et al 2019)
Summary
Until recently, approved antidepressant medications have primarily targeted the brain monoamine systems (i.e., those involving serotonin, dopamine, norepinephrine). Monoaminergic antidepressant medications work slowly and require compliance, and, in many cases, are either not tolerated or not sufficient to produce remission of symptoms. Clinical trials of ketamine for chronic pain have reported that prolonged ketamine infusions over 4–14 days provide sustained relief of symptoms for as long as 8 months (Webster and Walker 2006; Sigtermans et al 2009; Schwartzman et al 2009; Niesters et al 2014). This raises the question of whether a longer infusion paradigm might produce more durable antidepressant effects
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