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. Fine-tuning neural excitation/inhibition for tailored ketamine use in treatment-resistant depression. Ketamine has been shown to rapidly reduce depressive symptoms in patients with treatment-resistant major depressive disorder (TRD). Although its mechanisms of action are not fully understood, changes in cortical excitation/inhibition (E/I) following ketamine administration are well documented in animal models and could represent a potential biomarker of treatment response. Here, we analyze neuromagnetic virtual electrode time series collected from the primary somatosensory cortex in 18 unmedicated patients with TRD and in an equal number of age-matched healthy controls during a somatosensory 'airpuff' stimulation task. We demonstrate that the Poincar diagram offers classification capability for TRD patients, in that the further the patients' coordinates were shifted (by virtue of ketamine) toward the stable (top-left) quadrant of the Poincar diagram, the more their depressive symptoms improved. The same relationship was not observed by virtue of a placebo effect-thereby verifying the drug-specific nature of the results. We show that the shift in neural dynamics required for symptom improvement necessitates an increase in both excitatory and inhibitory coupling. We present accompanying MATLAB code made available in a public repository, thereby allowing for future studies to assess individually tailored treatments of TRD. 2. Ketamine and attentional bias toward emotional faces: dynamic causal modeling of magnetoencephalographic connectivity in treatment-resistant depression. Ketamine rapidly reduces depressive symptoms in individuals with treatment-resistant major depressive disorder and bipolar disorder. This double-blind, crossover, placebo-controlled study analyzed data from 19 drug-free individuals with TRD and 15 healthy volunteers who received a single intravenous infusion of ketamine (0.5 mg/kg) as well as an intravenous infusion of saline placebo. Magnetoencephalographic recordings were collected prior to the first infusion and 6-9 h after both drug and placebo infusions. Ketamine administration led to faster gamma aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) transmission in the early visual cortex, faster NMDA transmission in the fusiform cortex, and slower NMDA transmission in the amygdala. Ketamine administration also led to direct and indirect changes in local inhibition in the early visual cortex and inferior frontal gyrus and to indirect increases in cortical excitability within the amygdala. Finally, reductions in depressive symptoms in TRD participants post-ketamine were associated with faster -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) transmission and increases in gain control of spiny stellate cells in the early visual cortex. These findings provide additional support for the GABA and NMDA inhibition and disinhibition hypotheses of depression and support the role of AMPA throughput in ketamine's antidepressant effects. 3. Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability. Ketamine, a racemic mixture of (S)-ketamine and (R)-ketamine enantiomers, has been used as an anesthetic, analgesic and more recently, as an antidepressant. However, ketamine has known abuse liability (the tendency of a drug to be used in non-medical situations due to its psychoactive effects), which raises concerns for its therapeutic use. (S)-ketamine was recently approved by the United States' FDA for treatment-resistant depression. Recent studies showed that (R)-ketamine has greater efficacy than (S)-ketamine in preclinical models of depression, but its clinical antidepressant efficacy has not been established. The behavioral effects of racemic ketamine have been studied extensively in preclinical models predictive of abuse liability in humans (self-administration and conditioned place preference CPP). In contrast, the behavioral effects of each enantiomer in these models are unknown. We show here that in the intravenous drug self-administration model, the gold standard procedure to assess potential abuse liability of drugs in humans, rats self-administered (S)-ketamine but not (R)-ketamine. Subanesthetic, antidepressant-like doses of (S)-ketamine, but not of (R)-ketamine, induced locomotor activity (in an opioid receptor-dependent manner), induced psychomotor sensitization, induced CPP in mice, and selectively increased metabolic activity and dopamine tone in medial prefrontal cortex (mPFC) of rats. Pharmacological screening across thousands of human proteins and at biological targets known to interact with ketamine yielded divergent binding and functional enantiomer profiles, including selective mu and kappa opioid receptor activation by (S)-ketamine in mPFC. Our results demonstrate divergence in the pharmacological, functional, and behavioral effects of ketamine enantiomers, and suggest that racemic ketamine's abuse liability in humans is primarily due to the pharmacological effects of its (S)-enantiomer. 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 6 month follow-up ratings. In total, over 900 HCWs completed ratings related to COVID exposure, distress, resilience and mental health symptoms including PTSD.