Ketamine-Induced Brain Changes and Their Modulation by Lamotrigine
Condition: Emotions
Study type: Interventional

Summary: 
      This study is firstly designed to investigate acute and delayed effects of a single dose of
      ketamine on functional brain changes during emotional and cognitive challenges and at rest.
      Secondly, it aims to investigate whether functional brain changes after ketamine require
      increased glutamatergic signaling and will accordingly be modulated after pretreatment with
      lamotrigine.
    

Detailed description: 
      Despite the rapid antidepressant effects of ketamine, its increasing use as an AD and the
      recent (2019) FDA approval of ketamine nasal spray as medication for treatment-resistant
      depression, the exact neurobiological mechanisms underlying its effects remain unclear.

      There are numerous reasons, why so far there has been no coherent explanatory framework. Most
      previous studies focused on investigating a single domain such as functional connectivity
      (e.g. Deakin et al., 2008; Scheidegger et al., 2012), functional brain changes to either
      cognitive (e.g. Honey et al., 2005; Driessen et al., 2013) or emotional challenge (e.g.
      Scheidegger & Grimm et al., 2016; Reed et al., 2019), perfusion (e.g. Pollack et al., 2015),
      magnetic fields (Salvadore et al., 2010) or neurotransmitter concentrations (e.g. Abdallah et
      al., 2018). Small sample sizes of as little as 8 subjects, the lack of a control group, the
      limited number of timepoints for measurement of the above-mentioned parameters, and the
      failure to modulate glutamatergic signalling after ketamine further limit the informative
      value of previous findings. What is therefore urgently needed in order to better understand
      the mechanisms of ketamine, is a study that combines neuroimaging in several modalities,
      investigates acute as well as delayed effects of ketamine and applies an approach to modulate
      glutamatergic signaling after ketamine.

      Accordingly, this study is designed to investigate acute and delayed effects of a single dose
      of ketamine on functional brain changes during emotional and cognitive challenge and at rest
      as well as to investigate the functional significance of increased glutamatergic signalling
      after ketamine. Measurement of functional brain changes will occur during (acute) and 24 hrs.
      after a single dose of ketamine, as differential effects are hypothesized. To modulate
      glutamatergic signaling after ketamine, a lamotrigine pretreatment protocol will be used. It
      is hypothesized that functional brain changes previously linked to ketamine require increased
      glutamatergic signaling and will be attenuated by pretreatment with lamotrigine. To test
      these hypotheses, we will implement a randomized, placebo-controlled, parallel-group design
      with 3 treatment conditions (lamotrigine + ketamine, placebo + ketamine, placebo + placebo).
      All subjects will undergo two scanning sessions (acute + post 24 hrs.). In order to include
      baseline values as covariates in the analyses, imaging will begin 10 minutes before infusion
      of ketamine/placebo. Pretreatment with lamotrigine or matching placebo will occur 2 hours
      before the ketamine/placebo infusion. Blood samples will be taken at 0:30, 1:00, 1:30, 2:55
      and 4 hours following oral drug administration to determine the plasma pharmacokinetics of
      lamotrigine, and at 40 minutes after commencing ketamine infusion to confirm target ketamine
      plasma levels.
    

Intervention name(s): Lamotrigine; Ketamine; Placebo Pretreatment; Placebo Infusion
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Orally; 300 mg; Intravenously; 0.12 mg/kg during the first minute followed by a continuous infusion of approximately 0.31 mg/kg/h over approx. 40 min; Lamotrigine Placebo; Ketamine Placebo
Intervention MeSH terms: Lamotrigine; Ketamine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science