Neural connectivity moderators and mechanisms of ketamine treatment among treatment-resistant depressed patients: a randomized controlled trial

BACKGROUND: Intravenous (IV) ketamine has emerged as a rapid and effective treatment for TRD. However, the specific neural mechanisms of ketamine's effects in humans remains unclear. Although neuroplasticity is implicated as a mechanism of action in animal models, relatively few randomized controlled trials (RCTs) in TRD patients have examined ketamine's impact on functional connectivity, a posited functional marker of neuroplasticity-particularly in the context of a mood-induction paradigm (termed miFC). METHODS: 152 adults with TRD (63% female; 37% male) were randomly allocated to receive a single infusion of ketamine or saline in a 2:1 ratio. We examined changes in connectivity (from baseline to 24-h post-infusion) that differed by treatment, and whether clinical treatment response at 24-h post-infusion was uniquely related (among patients allocated to ketamine relative to saline) to (1) pre-treatment connectivity and (2) changes in connectivity. We examined both miFC and rsFC, using prefrontal cortex and limbic seed regions. We also conducted a multiverse analysis to examine findings most robust against analytic decisions. FINDINGS: Across both miFC and rsFC, ketamine was associated with greater in prefrontal/limbic connectivity compared to saline, and lower baseline connectivity of limbic and prefrontal regions predicted greater treatment response in patients receiving ketamine. Greater connectivity increases in participants receiving ketamine was uniquely related to greater treatment response. In addition, certain findings were identified as being reproducible against different analytic decisions in multiverse analyses. INTERPRETATION: Our findings identify specific neural connectivity patterns impacted by ketamine and were uniquely related to outcomes following ketamine (relative to saline). These findings generally support prominent neuroplasticity models of ketamine's therapeutic efficacy. These findings lay new groundwork for understanding how to enhance and optimize ketamine treatments and develop novel rapid-acting treatments for depression. FUNDING: This research was supported by NIH grant R01MH113857 and by the Clinical and Translational Sciences Institute at the University of Pittsburgh (UL1-TR-001857).