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.

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