Neurobiology and Target Validation of Novel Therapeutic Agents in Mood Disorders

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This Report involves work collected under protocols 01-M-0254 (NCT00024635 ); 08-M-0196 (NCT00759395); 08-M-0150 (NCT00697268); 14-M-0085 (NCT02122562); 07-M-0021 (NCT00397111); 14-M-0041 (NCT02049385); 07-M-0152 (NCT00472576), 09-M-N230; 15-M-0151 (NCT 02484456), 15-M-0188 (NCT02543983), and 19-M-0107 (NCT03973268). Results this past year: 1. A Randomized trial of the N-Methyl-d-aspartate receptor glycine site antagonist prodrug 4-chlorokynurenine in treatment-resistant depression: Ketamine has rapid-acting antidepressant effects but is associated with psychotomimetic and other adverse effects. A 7-chlorokynurenic acid is a potent and specific glycine site N-methyl-d-aspartate receptor antagonist but crosses the blood-brain barrier inefficiently. Its prodrug, L-4-chlorokynurenine (4-Cl-KYN), exerts acute and sustained antidepressant-like effects in rodents and has no reported psychotomimetic effects in either rodents or healthy volunteers. This study examined whether 4-Cl-KYN has rapid antidepressant effects in individuals with treatment-resistant depression. After a 2-week drug-free period, 19 participants with treatment-resistant depression were randomized to receive daily oral doses of 4-Cl-KYN monotherapy (1080 mg/d for 7 days, then 1440 mg/d for 7 days) or placebo for 14 days in a randomized, placebo-controlled, double-blind, crossover manner. The primary outcome measure was the Hamilton Depression Rating Scale score, assessed at several time points over a 2-week period. Pharmacokinetic measures of 7-chlorokynurenic acid and 4-Cl-KYN and pharmacodynamic assessments were obtained longitudinally and included 1H-magnetic resonance spectroscopy brain glutamate levels, resting-state functional magnetic resonance imaging, and plasma and cerebrospinal fluid measures of kynurenine metabolites and neurotrophic factors. Linear mixed models detected no treatment effects, as assessed by primary and secondary outcome measures. No difference was observed for any of the peripheral or central biological indices or for adverse effects at any time between groups. A 4-Cl-KYN was safe and well-tolerated, with generally minimal associated adverse events. 2. Magnetoencephalographic Correlates of Suicidal Ideation in Major Depression: Defining the neurobiological underpinnings of suicidal ideation (SI) is crucial to improving our understanding of suicide. This study used magnetoencephalographic gamma power as a surrogate marker for population-level excitation-inhibition balance to explore the underlying neurobiology of SI and depression. In addition, effects of pharmacological intervention with ketamine, which has been shown to rapidly reduce SI and depression, were assessed. Data were obtained from 29 drug-free patients with major depressive disorder who participated in an experiment comparing subanesthetic ketamine (0.5 mg/kg) with a placebo saline infusion. Magnetoencephalographic recordings were collected at baseline and after ketamine and placebo infusions. Clinically, patients showed significantly reduced SI and depression after ketamine administration. In addition, distinct regions in the anterior insula were found to be associated with SI compared with depression. In modeling of insula-anterior cingulate connectivity, ketamine lowered the membrane capacitance for superficial pyramidal cells. Finally, connectivity between the insula and anterior cingulate was associated with improvements in depression symptoms. 3. Symptom trajectories in the months before and after a suicide attempt in individuals with bipolar disorder: A STEP-BD study: The suicide crisis is a relatively short-lived psychiatric emergency, with transient symptoms that ebb and flow around the suicide attempt. Understanding the dynamic processes of symptoms before and after suicide attempt may aid future prevention efforts. Data were drawn from the NIMH STEP-BD study, which followed 4,360 patients with bipolar disorder; a subset attempted suicide during the trial (245/4100 or 5.97% of the sample eligible for analysis). This analysis focused on change in suicidal ideation (SI) in the 120 days before and 120 days after suicide attempt; similar analyses were conducted for other depressive symptoms. SI ratings from 216 individuals were analyzed (n = 1,231 total; n = 395 pre-attempt, n = 126 circa-attempt, n = 710 post-attempt) and compared to data from a matched sample of 648 non-attempters. SI worsened in the 120 days pre-attempt but improved afterwards, reaching non-attempter levels by 90 days post-attempt. A similar pattern was found for other depressive symptoms, including depressed mood, loss of interest, guilt, and self-esteem. Pre/post differences in tension/activating symptoms of depression-anxiety, agitation, and irritability-were less pronounced and more time-limited. The suicide crisis is dynamic, and the days before and after suicide attempt may be particularly critical. 4. The kynurenine pathway and bipolar disorder: intersection of the monoaminergic and glutamatergic systems and immune response: Dysfunction in a wide array of systems-including the immune, monoaminergic, and glutamatergic systems-is implicated in the pathophysiology of depression. One potential intersection point for these three systems is the kynurenine (KYN) pathway. This study explored the impact of the prototypic glutamatergic modulator ketamine on the endogenous KYN pathway in individuals with bipolar depression (BD), as well as the relationship between response to ketamine and depression-related behavioral and peripheral inflammatory markers. Thirty-nine participants with treatment-resistant BD received a single ketamine infusion (0.5 mg/kg) over 40 min. KYN pathway analytes-including plasma concentrations of indoleamine 2,3-dioxygenase (IDO), KYN, kynurenic acid (KynA), and quinolinic acid (QA)-were assessed at baseline (pre-infusion), 230 min, day 1, and day 3 post-ketamine. Post-ketamine IDO levels were significantly lower than baseline at all three time points. Conversely, ketamine treatment significantly increased KYN and KynA levels at days 1 and 3 versus baseline. No change in QA levels was observed post-ketamine. A lower post-ketamine ratio of QA/KYN was observed at day 1. In addition, baseline levels of proinflammatory cytokines and behavioral measures predicted KYN pathway changes post ketamine. The results suggest that, in addition to having rapid and sustained antidepressant effects in BD participants, ketamine also impacts key components of the KYN pathway.