Neuropharmacologic Imaging and Biomarker Assessments of Response to Acute and Repeated-Dosed Ketamine Infusions in Major Depressive Disorder

Objective The current protocol has a two-fold purpose. In the pharmacodynamic imaging phase, we will investigate the neuropharmacodynamics of acute intravenous ketamine administration in patients with major depressive disorder (MDD) and healthy volunteers (HV) using functional MRI (fMRI) and electrophysiological modalities \[electroencephalography (EEG) and magnetoencephalography (MEG)\]. We will also investigate if specific signatures from functional neuroimaging, transcranial magnetic stimulation (TMS) associated evoked potentials (TMS-EP), sleep EEG (S-EEG), and psychophysiologic responses can be used to classify specific subpopulations of patients with MDD; preliminary findings from such an approach may be important in forging further studies identifying those who will respond to ketamine infusions. In the repeat-dosing phase, we will expand upon our previous findings of the immediate efficacy of glutamatergic modulators by investigating the safety and efficacy of repeated dose administrations of ketamine in MDD patients. We will include all MDD patients regardless of antidepressant response to single infusions of ketamine to allow for potential identification of patients who are able to attain and/or maintain a response over a series of infusions. To reduce any potential biases due to partial blinding, all patients will be randomized into groups to receive ketamine at either 0.5 mg/kg or 0.1 mg/kg (an active comparator). Study Population The study consists of 50 patients with treatment-resistant MDD between 18 and 65 years old and 50 age/gender matched HVs. Within the MDD group, 25 patients will be enrolled into each group in the repeat-dosing phase. An addition 50 HVs will participate in the Ketamine Metabolites Substudy. Study Design This study is a Phase I Clinical Trial that comprises four phases. Phase I includes screening, medication taper (patients, as needed), medication-free period (patients), and baseline assessments, including optional TMS-EP, S-EEG, the None, Predictive, Unpredictive (NPU)-threat test, non-brain imaging cognitive tasks, and blood samples for plasma neurochemicals and peripheral blood biomarkers. In Phase II, all subjects (patients with MDD and HVs) will receive an alternating series of placebo and ketamine infusions, once per week, for a total of 4 infusions (2 ketamine, 2 placebo). Concurrently with each infusion, subjects will be administered either resting-state fMRI with simultaneous EEG, or resting state MEG recording, thus each subject receives fMRI+EEG and MEG for both a placebo and ketamine infusion. Participants may also undergo optional sEEG, non-brain imaging cognitive tasks, TMS-EP, and NPU. Phase III involves MDD patients whose depression symptoms relapsed after the final infusion in Phase II. Patients whose symptoms did not relapse may receive an additional one-week washout prior to participating in Phase III. Subjects will be randomized to receive ketamine at 0.5 or 0.1 mg/kg twice weekly for 4 weeks (total of 8 infusions). Participants may undergo optional fMRI, S-EEG, MEG, non-brain imaging cognitive tasks, TMS-EP, pupillometry, and NPU at time points between infusions. Clinical rating scales will assess depression symptomology and blood will be drawn for pharmacokinetics testing and biomarker analyses. Phase IV includes patients who completed Phase III and who are responders. These patients will be followed up for an additional 4 weeks, or until relapse (whichever comes first), to determine durability of response. The final study day will include rating scales, medical evaluations, blood tests, and an additional sMRI to assess structural changes that may have occurred due to repeated ketamine infusions. The protocol includes a substudy evaluating ketamine metabolites in healthy volunteers (Ketamine Metabolites Substudy). Only HVs will be enrolled in this substudy. Subjects will undergo a single infusion of ketamine concurrently with serial peripheral blood collection. Some participants may also undergo serial CSF collection during the ketamine infusion. Clinical rating scales, cognitive tasks, MEG, S-EEG, CSF and/or blood draws for pharmacokinetics testing and biomarker analyses will be done. Outcome Measures The primary outcome measure of Phase II is the pharmacodynamic fMRI and MEG responses to ketamine compared to placebo. Secondary outcome measures include the difference in Montgomery-Asberg Depression Rating Scale (MADRS) score from baseline to 24 hours between the placebo and ketamine infusion, correlations between an antidepressant response and TMS-EP, S-EEG, neuroimaging, cognitive, and NPU measures. In Phase II, the HVs acts as another level of control to identify a potential neuropharmacodynamic signature associated with an antidepressant response to ketamine. The primary outcome measure for Phase III is the difference or change in MADRS from baseline to the end of 4 weeks of twice-weekly infusions. Secondary outcome measures include cognitive, TMS-EP, S-EEG, and NPU-threat test measures. The primary outcome measure for the Ketamine Metabolites Substudy are the levels of ketamine metabolites in CSF and peripheral blood. Other outcome measures for both Phase II and III include clinical rating scales, neurocognitive tests, ketamine levels, plasma neurochemicals, and peripheral blood biomarkers. Additional outcomes in Phase III are baseline and post-repeated dose infusion MRI scans, and neurocognitive test results. Rating scales are the outcomes measures of Phase IV. Subjects will continue Phase IV for 4 weeks or until relapse (whichever comes first). Additional outcomes for the Ketamine Metabolites Substudy are metabolite levels and clinical rating scales