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Ketamine-Induced Brain Changes and Their Modulation by Lamotrigine

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ClinicalTrials.gov Identifier: NCT04156035
Recruitment Status : Recruiting
First Posted : November 7, 2019
Last Update Posted : July 16, 2020
Sponsor:
Collaborator:
Boehringer Ingelheim
Information provided by (Responsible Party):
Simone Grimm, Medical School Berlin

Tracking Information
First Submitted Date  ICMJE October 23, 2019
First Posted Date  ICMJE November 7, 2019
Last Update Posted Date July 16, 2020
Actual Study Start Date  ICMJE March 10, 2020
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 5, 2019)
Functional brain changes induced by emotional and cognitive challenge [ Time Frame: Measurements will occur during (acute) and 24h after (delayed) a single dose of ketamine ]
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 5, 2019)
  • Changes in resting- state functional connectivity in default- mode network (DMN) and affective network (AN) [ Time Frame: Measurements will occur at baseline, during and 24h after a single dose of ketamine ]
    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.
  • Changes in cerebral blood flow in predefined brain regions [ Time Frame: Measurements will occur during and 24h after a single dose of ketamine ]
    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.
  • Association between functional brain changes during emotional and cognitive challenge and ketamine- induced dissociative state [ Time Frame: Measurements will occur during and 24h after a single dose of ketamine ]
    Dissociate state will be investiagted using the Dissoziations-Spannungs-Skala akut (DSS-akut, Stiglmayr et al. 2003).
  • Association between changes in resting- state functional connectivity and ketamine- induced dissociative state [ Time Frame: Measurements will occur during and 24h after a single dose of ketamine ]
    Dissociate state will be investiagted using the Dissoziations-Spannungs-Skala akut (DSS-akut, Stiglmayr et al. 2003).
  • Blood concentration of lamotrigine [ Time Frame: Measurements will occur at baseline as well as 0.30, 1:00, 1:30, 2:55 and 4h following drug administration ]
    Blood samples are taken to determine citrate plasma concentration of Lamotrigine to assess plasma levels during fMRI assessments.
  • Blood concentration of ketamine [ Time Frame: Measurements will occur approx. 40 minutes after commencing ketamine infusion ]
    Blood samples are taken to determine citrate plasma concentration of Ketamine to confirm target exposures (plasma levels) during assessments.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ketamine-Induced Brain Changes and Their Modulation by Lamotrigine
Official Title  ICMJE A Trial to Study Acute and Delayed Effects of a Single Dose of Ketamine on Functional Brain Changes During Emotional/ Cognitive Challenges and at Rest and Their Modulation by Lamotrigine in Healthy Subjects
Brief 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Condition  ICMJE Emotions
Intervention  ICMJE
  • Drug: Lamotrigine
    Orally; 300 mg
  • Drug: Ketamine
    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
  • Drug: Placebo Pretreatment
    Lamotrigine Placebo
  • Drug: Placebo Infusion
    Ketamine Placebo
Study Arms  ICMJE
  • Experimental: Lamotrigine + Ketamine
    Pretreatment with lamotrigine will occur 2 hours before the ketamine infusion
    Interventions:
    • Drug: Lamotrigine
    • Drug: Ketamine
  • Experimental: Placebo + Ketamine
    Pretreatment with placebo will occur 2 hours before the ketamine infusion
    Interventions:
    • Drug: Ketamine
    • Drug: Placebo Pretreatment
  • Placebo Comparator: Placebo + Placebo
    Pretreatment with placebo will occur 2 hours before the placebo infusion
    Interventions:
    • Drug: Placebo Pretreatment
    • Drug: Placebo Infusion
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 5, 2019)
75
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2021
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Main Inclusion Criteria:

  • From 18 to 45 years of age, inclusive
  • Body Mass Index (BMI) between 18.0 and 28.5 kg/m2, inclusive
  • Healthy on the basis of physical examination, medical history, vital signs, clinical laboratory tests, and 12-lead ECG

Main Exclusion Criteria:

  • Clinically relevant allergy or drug hypersensitivity
  • A history of psychiatric or neurologic disorders
  • Alcohol or substance dependence within the last 12 months from screening
  • A positive urine drug screen at any visit
  • MR exclusion criteria, elevated intracranial pressure or glaucoma
  • Hypertonia, cardiac insufficiency, myocardial infarct within last 6 months
  • Liver or renal function disorder
  • Prescription of psychotropic medication within 28 days prior to screening
  • Non-prescription medication, including analgesics and supplements such as vitamins and herbal supplements within 48 hours prior to the baseline visit
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 45 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Simone Grimm, PhD 0049450 ext 517778 simone.grimm@medicalschool-berlin.de
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04156035
Other Study ID Numbers  ICMJE MSB-C001
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Simone Grimm, Medical School Berlin
Study Sponsor  ICMJE Charite University, Berlin, Germany
Collaborators  ICMJE Boehringer Ingelheim
Investigators  ICMJE
Principal Investigator: Simone Grimm, PhD Medical School Berlin
PRS Account Charite University, Berlin, Germany
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP