An interventional study of Lamotrigine and Ketamine in Emotions, sponsored by Charite University, Berlin, Germany. Completed at 1 site in Germany. Open to participants aged 18 Years to 45 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2021-03-29.
Sponsored by Charite University, Berlin, Germany · Not applicable, Interventional, and Basic science
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.
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.
Charite University, Berlin, Germany is the lead sponsor of 836 studies on the registry; 129 are open to participants now.
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Main Inclusion Criteria:
Main Exclusion Criteria:
Pretreatment with lamotrigine will occur 2 hours before the ketamine infusion
Drug: Lamotrigine · Drug: Ketamine
Pretreatment with placebo will occur 2 hours before the ketamine infusion
Drug: Ketamine · Drug: Placebo Pretreatment
Pretreatment with placebo will occur 2 hours before the placebo infusion
Drug: Placebo Pretreatment · Drug: Placebo Infusion
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
Functional brain changes induced by emotional and cognitive challenge
The primary endpoints of efficacy are the functional brain changes induced by emotional and cognitive challenge during ketamine infusion as compared to placebo and to the responses during ketamine infusion after Lamotrigine pretreatment during and after (post 24 hrs.) in following brain regions (bilateral): * Amygdala * Hippocampus * Dorsolateral Prefrontal Cortex * Anterior cingulate Cortex * Insula
Time frame: Measurements will occur during (acute) and 24h after (delayed) a single dose of ketamine
Changes in resting- state functional connectivity in default- mode network (DMN) and affective network (AN)
Changes in resting- state functional connectivity in default- mode network (DMN) and affective network (AN) in the following brain regions (bilateral): Amygdala, Hippocampus, Dorsolateral Prefrontal Cortex, Anterior cingulate Cortex and Insula. During the resting state scan, During this scan, subjects are asked to relax and to keep their eyes open.
Time frame: Measurements will occur at baseline, during and 24h after a single dose of ketamine
Changes in cerebral blood flow in predefined brain regions
Changes in cerebral blood flow (ASL) in in the following brain regions (bilateral): Amygdala, Hippocampus, Dorsolateral Prefrontal Cortex, Anterior cingulate Cortex and Insula. During ASL, subjects engage in no special task, but are asked to close their eyes and relax. ASL provides quantitative parametric images of tissue perfusion.
Time frame: Measurements will occur during and 24h after a single dose of ketamine
Association between functional brain changes during emotional and cognitive challenge and ketamine- induced dissociative state
Dissociate state will be investiagted using the Dissoziations-Spannungs-Skala akut (DSS-akut, Stiglmayr et al. 2003).
Time frame: Measurements will occur during and 24h after a single dose of ketamine
Association between changes in resting- state functional connectivity and ketamine- induced dissociative state
Dissociate state will be investiagted using the Dissoziations-Spannungs-Skala akut (DSS-akut, Stiglmayr et al. 2003).
Time frame: Measurements will occur during and 24h after a single dose of ketamine
Blood concentration of lamotrigine
Blood samples are taken to determine citrate plasma concentration of Lamotrigine to assess plasma levels during fMRI assessments.
Time frame: Measurements will occur at baseline as well as 0.30, 1:00, 1:30, 2:55 and 4h following drug administration
Blood concentration of ketamine
Blood samples are taken to determine citrate plasma concentration of Ketamine to confirm target exposures (plasma levels) during assessments.
Time frame: Measurements will occur approx. 40 minutes after commencing ketamine infusion
Plan to share: No
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Charite University, Berlin, Germany