Glutamatergic Modulators for Rapid and Sustained Antidepressant Effect

National Institute Of Mental Health

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Abstract

Our results indicate that the glutamatergic system is involved in the mechanism of action of rapid antidepressant response. In addition, this system may be a feasible target for developing treatments that have rapid and robust efficacy in individuals who have treatment-resistant depression and suicidal thoughts. We found that the glutamatergic modulator ketamine resulted in rapid, robust and relatively sustained antidepressant, antisuicidal, and antianhedonic effects. Response with ketamine occurred within 2 hours and lasted approximately 1 week. Study: (Biomarkers of rapid response in major depressive disorder): protocols 04-M-0222 (NCT00088699), 17-M-0060 (NCT03065335), and 19-M-0107 (NCT 03973268). OBJECTIVE: To identify the neural correlates and cellular and molecular targets of rapid antidepressant response to the NMDA antagonist ketamine in subjects with major depressive disorder. Aims are 1) to examine the antisuicidal effects of ketamine, and 2) to examine correlates of antidepressant response to ketamine in both major depressive disorder and bipolar disorder and include these data/outcome measures: clinical (e.g., family history), imaging (magnetic resonance imaging/spectroscopy), electrophysiological (magnetoencephalography MEG, electroencephalography EEG), neuropsychological, and biochemical (e.g., genetics, microRNA, BDNF, metabolomics), 3) To demonstrate more robust neuropharmacodynamic effects measured by neuropharmacodynamic imaging (fMRI+EEG and MEG) of ketamine 0.5 mg/kg as compared to placebo administered over 40 minutes, and 4) To understand the involvement of AMPA receptors in ketamine's antidepressant response. Secondary aims: To determine if increases in synaptic plasticity, using electrophysiological measures in response to TMS and in association with sleep (i.e., slow wave sleep EEG activity) are associated with better antidepressant response. Results in the past year: 1. Magnetoencephalography biomarkers of suicide attempt history and antidepressant response to ketamine in treatment-resistant major depression. This study examined magnetoencephalographic (MEG) correlates of suicidal ideation (SI) and suicide attempt history in patients with treatment-resistant major depression (TRD) at baseline and following subanesthetic-dose ketamine infusion. Twenty-nine drug-free patients with TRD participated in a crossover randomized trial of ketamine. MEG data were collected during an attentional dot probe task with emotional face stimuli at baseline and several hours post-ketamine infusion. Synthetic aperture magnetometry was used to project source power in the theta, alpha, beta, and gamma frequencies for angry-neutral, happy-neutral, and neutral-neutral face pairings during a one-second peristimulus period. Ketamine significantly reduced SI and depression across the sample. Post-ketamine, attempters had improved accuracy and non-attempters had reduced accuracy on the task. SI was positively associated with gamma power in regions of the frontal and parietal cortices across groups. In an extended amygdala-hippocampal region, attempters differed significantly in their emotional reactivity to angry versus happy faces as indexed by theta power differences, irrespective of drug. Ketamine significantly reduced the association between alpha power and SI for angry compared with happy faces in a fronto-insular/anterior cingulate region important for regulating sensory attentiveness. The findings highlight key differences in band-limited power between attempters and non-attempters and reinforce previous findings that ketamine has distinct response properties in patients with a suicide history. 2. Transcriptional Activation, Deactivation and Rebound Patterns in Cortex, Hippocampus and Amygdala in Response to Ketamine Infusion in Rats. In this molecular-pharmacological investigation in the rat, we used short- and longer-term infusions of high dose ketamine to stimulate neuronal transcription processes. We hypothesized that a progressively stronger modulation of neuronal gene networks would occur over time in cortical and limbic pathways. A continuous intravenous administration paradigm for ketamine was developed in rat consisting of short (1 h) and long duration (10 h, and 10 h + 24 h recovery) infusions of anesthetic concentrations to activate or inhibit gene transcription. Transcription was measured by RNA-Seq in three brain regions: frontal cortex, hippocampus, and amygdala. Induction of a shared transcriptional regulatory network occurred within 1 h in all three brain regions consisting of (a) genes involved in stimulus-transcription factor coupling that are induced during altered synaptic activity (immediate early genes, IEGs, such as c-Fos, 9-12) and (b) the Nrf2 oxidative stress-antioxidant response pathway downstream from glutamate signaling per brain region. By 10 h of infusion, the acute results were further reinforced and consisted of more and stronger gene alterations reflecting a sustained and accentuated ketamine modulation of regional excitation and plasticity. After 24 h recovery, we observed overshoot of transcriptional processes rather than a smooth return to homeostasis suggesting an oscillation of plasticity occurs during the transition to a new phase of neuronal regulation. These data elucidate critical molecular regulatory actions during and downstream of ketamine administration that may contribute to the unique drug actions of this anesthetic agent. These molecular investigations point to pathways linked to therapeutically useful attributes of ketamine. 3. Comparative metabolomic analysis in plasma and cerebrospinal fluid of humans and in plasma and brain of mice following antidepressant-dose ketamine administration. Preclinical studies found that (2 R,6 R;2 S,6 S)-hydroxynorketamine (HNK), a major circulating metabolite of ketamine, elicits antidepressant effects similar to those of ketamine. To help determine how (2 R,6 R)-HNK contributes to ketamine's mechanism of action, an exploratory, targeted, metabolomic analysis was carried out on plasma and CSF of nine healthy volunteers receiving a 40-minute ketamine infusion (0.5 mg/kg). Ketamine and (2 R,6 R)-HNK both affected multiple pathways associated with inflammatory conditions. In addition, several changes were unique to either the healthy human volunteers and/or the mouse arm of the study, indicating that different pathways may be differentially involved in ketamine's effects in mice and humans. Mechanisms of action found to consistently underlie the effects of ketamine and/or (2 R,6 R)-HNK across both the human metabolome in plasma and CSF and the mouse arm of the study included LAT1, IDO1, NAD+, the nitric oxide (NO) signaling pathway, and sphingolipid rheostat. 4. The Mental Health Impact of COVID-19 Pandemic on Healthcare Workers Protocol (P205022: PI: Zarate, Carlos) completed initial baseline data collection and one month follow-up, and will re-contact participants for 2 month follow-up ratings. In total, over 900 HCWs completed ratings related to COVID exposure, distress, resilience and mental health symptoms including PTSD.