Faculty Bibliography

Major depressive disorder (MDD) is a leading cause of disability worldwide, yet current treatment strategies remain limited in their mechanistic diversity. Recent evidence has highlighted a promising novel pharmaceutical target-the KCNQ-type potassium channel-for the treatment of depressive disorders, which may exert a therapeutic effect via functional changes within the brain reward system, including the ventral striatum. The current study assessed the effects of the KCNQ channel opener ezogabine (also known as retigabine) on reward circuitry and clinical symptoms in patients with MDD. Eighteen medication-free individuals with MDD currently in a major depressive episode were enrolled in an open-label study and received ezogabine up to 900 mg/day orally over the course of 10 weeks. Resting-state functional magnetic resonance imaging data were collected at baseline and posttreatment to examine brain reward circuitry. Reward learning was measured using a computerized probabilistic reward task. After treatment with ezogabine, subjects exhibited a significant reduction of depressive symptoms (Montgomery-Asberg Depression Rating Scale score change: -13.7 ± 9.7, p < 0.001, d = 2.08) and anhedonic symptoms (Snaith-Hamilton Pleasure Scale score change: -6.1 ± 5.3, p < 0.001, d = 1.00), which remained significant even after controlling for overall depression severity. Improvement in depression was associated with decreased functional connectivity between the ventral caudate and clusters within the mid-cingulate cortex and posterior cingulate cortex (n = 14, voxel-wise p < 0.005). In addition, a subgroup of patients tested with a probabilistic reward task (n = 9) showed increased reward learning following treatment. These findings highlight the KCNQ-type potassium channel as a promising target for future drug discovery efforts in mood disorders.

OBJECTIVE:Esketamine, the S-enantiomer of ketamine, was recently approved as a rapid-acting intranasal therapy for depression and is currently under development for suicidality. The authors sought to determine the efficacy of adjunctive intranasal esketamine in major depressive disorder (MDD). DATA SOURCES/METHODS:A systematic search of PubMed/MEDLINE was conducted up to January 2019, in addition to abstracts of major psychiatric meetings held since 2010. Searches were conducted by cross-referencing the term intranasal with the term esketamine. Where necessary, authors and/or study sponsors were contacted in order to obtain a copy of the presentation as well as any pertinent study details. STUDY SELECTION/METHODS:241 study abstracts were initially identified and reviewed. Selected studies were randomized, double-blind clinical trials comparing adjunctive intranasal esketamine to adjunctive placebo for MDD. DATA EXTRACTION/METHODS:Data were extracted independently by two of the authors. A random effects model was used to calculate the standardized mean difference (SMD) between esketamine and placebo (intranasal saline) in the Montgomery-Asberg Depression Rating Scale (MADRS) score change from baseline to endpoint, serving as the primary outcome of the study. RESULTS:Five trials with 774 patients were pooled. Adjunctive esketamine was significantly more effective than placebo for MADRS score change, response, and remission (N = 774, SMD = 0.36, 95% CI = 0.24-0.49, P < .0001; response: risk ratio [RR] = 1.40, 95% CI = 1.22-1.61, P < .0001; remission: RR = 1.45, 95% CI = 1.20-1.75, P < .0001). Results remained statistically significant regardless of differences in the study sample, fixed vs new/optimized baseline antidepressants. CONCLUSIONS:Adjunctive intranasal esketamine for patients with MDD who are either treatment-resistant or acutely suicidal appears to be an effective treatment strategy.

Previous studies have suggested that neuropeptide Y (NPY) levels may be altered in patients with major depressive disorder (MDD), post-traumatic stress disorder (PTSD) and chronic stress. We investigated, through systematic review and meta-analysis, whether the mean levels of NPY are significantly different in patients with MDD, PTSD or chronic stress, compared to controls. The main outcome was the pooled standardized mean difference (SMD) with 95% confidence intervals between cases and controls, using the random-effects model. Heterogeneity and publication bias were evaluated. Thirty-five studies met eligibility criteria. Meta-regression determined that medication and sex could explain 27% of the between-study variance. Females and participants currently prescribed psychotropic medications had significantly higher levels of NPY. NPY levels were significantly lower in plasma and cerebrospinal fluid (CSF) in PTSD patients versus controls. Patients with MDD had significantly lower levels of NPY in plasma compared to controls, but not in the CSF. The magnitudes of the decrease in plasma NPY levels were not significantly different between PTSD and MDD. However, chronic stress patients had significantly higher plasma NPY levels compared to controls, PTSD or MDD. Our findings may imply a shared role of NPY in trauma and depression: nevertheless, it is not clear that the association is specific to these disorders. Psychotropic medications may help restore NPY levels. Further controlled studies are needed to better delineate the contribution of confounding variables such as type of depression, body mass index, appetite or sleep architecture.

PURPOSE/BACKGROUND/OBJECTIVE:Major depressive disorder (MDD) and obesity commonly co-occur. We sought to assess the impact of body mass index (BMI) on the acute antidepressant effects of ketamine in patients with treatment-resistant depression. METHODS/PROCEDURES/UNASSIGNED:Post hoc analyses were conducted from a multisite, randomized, double-blind, placebo-controlled trial designed to assess the rapid-onset effects of intravenous ketamine. Patients (n = 99) were randomized to a single dose administration of ketamine 0.1 mg/kg (n = 18), ketamine 0.2 mg/kg (n = 20), ketamine 0.5 mg/kg (n = 22), ketamine 1.0 mg/kg (n = 20), or active placebo, midazolam 0.045 mg/kg (n = 19). Patients were stratified for BMI. For patients randomized to ketamine (n = 80), BMI was assessed as a continuous variable and also categorically (obese, overweight, not obese/overweight [reference]). The primary outcome measure was the change on the 6-item Hamilton Depression Rating Scale 24 hours after treatment. Outcomes at day 3 were also assessed. FINDINGS/RESULTS/UNASSIGNED:The 6-item Hamilton Depression Rating Scale change scores at 24 hours were inversely associated with BMI (-0.28 ± 0.12, P = 0.02). With BMI operationalized categorically, both obese (-4.15 ± 1.41, P = 0.004) and overweight (-1.99 ± 1.14, P = 0.08) categories were inversely related to the 6-item Hamilton Depression Rating Scale change score at 24 hours, statistically significant for the obese category, as compared with the reference group. Similar but weaker findings were observed at 72 hours after infusion. IMPLICATIONS/CONCLUSIONS/UNASSIGNED:Higher BMI and obesity were associated with a more robust acute antidepressant response to ketamine. This may have clinical relevance for a great number of patients who have both MDD and obesity. CLINICAL TRIAL REGISTRATION/BACKGROUND:NCT01920555.

The National Institute of Mental Health (NIMH) 'fast-fail' approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia with a POM study determining whether robust target engagement favorably impacts the brain circuitry hypothesized to mediate clinical effects. Here we report the results from a multicenter, 8-week, double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder (selective KOR antagonist (JNJ-67953964, 10 mg; n = 45) and placebo (n = 44)). JNJ-67953964 significantly increased functional magnetic resonance imaging (fMRI) ventral striatum activation during reward anticipation (primary outcome) as compared to placebo (baseline-adjusted mean: JNJ-67953964, 0.72 (s.d. = 0.67); placebo, 0.33 (s.d. = 0.68); F(1,86) = 5.58, P < 0.01; effect size = 0.58 (95% confidence interval, 0.13-0.99)). JNJ-67953964, generally well tolerated, was not associated with any serious adverse events. This study supports proceeding with assessment of the clinical impact of target engagement and serves as a model for implementing the 'fast-fail' approach.

Obsessive-compulsive disorder (OCD) is highly heterogeneous. While obsessions often involve fear of harm, many patients report uncomfortable sensations and/or urges that drive repetitive behaviors in the absence of a specific fear. Prior work suggests that urges in OCD may be similar to everyday "urges-for-action" (UFA) such as the urge to blink, swallow, or scratch, but very little work has investigated the pathophysiology underlying urges in OCD. In the current study, we used an urge-to-blink approach to model sensory-based urges that could be experimentally elicited and compared across patients and controls using the same task stimuli. OCD patients and controls suppressed eye blinking over a period of 60 s, alternating with free blinking blocks, while brain activity was measured using functional magnetic resonance imaging. OCD patients showed significantly increased activation in several regions during the early phase of eyeblink suppression (first 30 s), including mid-cingulate, insula, striatum, parietal cortex, and occipital cortex, with lingering group differences in parietal and occipital regions during late eyeblink suppression (last 30 s). There were no differences in brain activation during free blinking blocks, and no conditions where OCD patients showed reduced activation compared to controls. In an exploratory analysis of blink counts performed in a subset of subjects, OCD patients were less successful than controls in suppressing blinks. These data indicate that OCD patients exhibit altered brain function and behavior when experiencing and suppressing the urge to blink, raising the possibility that the disorder is associated with a general abnormality in the UFA system that could ultimately be targeted by future treatments.

INTRODUCTION/BACKGROUND:Neuroglial functions may be deteriorated in major depressive disorder (MDD). OBJECTIVE:To evaluate the markers of glial and neuronal cell turnover and to explore their associations with brain metabolites. METHODS:In 10 participants with MDD and 10 healthy controls (HC) we investigated neuronal and glial plasma markers (the neuron-specific enolase, NSE; and S100beta, S100B) and brain metabolites (N-acetyl aspartate, NAA; total choline, Cho; and total creatine, Cr). Blood was collected for NSE and S100B. NAA, Cho, and Cr metabolite levels were measured in the anterior cingulate cortex (ACC) with proton magnetic resonance spectroscopy (1H-MRS) at 3T. RESULTS:NSE and S100B levels were significantly higher in MDD subjects than in HC. The Cr level was significantly higher in MDD subjects than in HC, but the NAA and Cho levels did not differ between groups. NAA/Cr and Cho/Cr ratios were significantly lower in patients with MDD versus HC. S100B was negatively correlated with the Cho levels. CONCLUSIONS:These results provide supporting evidence of neuronal and glial distress in MDD. Neuronal viability appears decreased, whereas glial regenerative activity and energy metabolism in the ACC increase in acute major depressive episode. Since low concentrations of S100B have neuroplastic effects, these changes may indicate a possible compensatory mechanism.

The efficacy of dopamine agonists in treating major depressive disorder has been hypothesized to stem from effects on ventrostriatal dopamine and reward function. However, an important question is whether dopamine agonists are most beneficial for patients with reward-based deficits. This study evaluated whether measures of reward processing and ventrostriatal dopamine function predicted response to the dopamine agonist, pramipexole (ClinicalTrials.gov Identifier: NCT02033369). Individuals with major depressive disorder (n = 26) and healthy controls (n = 26) (mean ± SD age = 26.5 ± 5.9; 50% female) first underwent assessments of reward learning behaviour and ventrostriatal prediction error signalling (measured using functional MRI). 11C-(+)-PHNO PET before and after oral amphetamine was used to assess ventrostriatal dopamine release. The depressed group then received open-label pramipexole treatment for 6 weeks (0.5 mg/day titrated to a maximum daily dose of 2.5 mg). Symptoms were assessed weekly, and reward learning was reassessed post-treatment. At baseline, relative to controls, the depressed group showed lower reward learning (P = 0.02), a trend towards blunted reward-related prediction error signals (P = 0.07), and a trend towards increased amphetamine-induced dopamine release (P = 0.07). Despite symptom improvements following pramipexole (Cohen's d ranging from 0.51 to 2.16 across symptom subscales), reward learning did not change after treatment. At a group level, baseline reward learning (P = 0.001) and prediction error signalling (P = 0.004) were both associated with symptom improvement, albeit in a direction opposite to initial predictions: patients with stronger pretreatment reward learning and reward-related prediction error signalling improved most. Baseline D2/3 receptor availability (P = 0.02) and dopamine release (P = 0.05) also predicted improvements in clinical functioning, with lower D2/3 receptor availability and lower dopamine release predicting greater improvements. Although these findings await replication, they suggest that measures of reward-related mesolimbic dopamine function may hold promise for identifying depressed individuals likely to respond favourably to dopaminergic pharmacotherapy.

Anxiety disorders are the most prevalent psychiatric disorders and a leading cause of disability. While there continues to be expansive research in posttraumatic stress disorder (PTSD), depression and schizophrenia, there is a relative dearth of novel medications under investigation for anxiety disorders. This review's first aim is to summarize current pharmacological treatments (both approved and off-label) for panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and specific phobias (SP), including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), azapirones (e.g., buspirone), mixed antidepressants (e.g., mirtazapine), antipsychotics, antihistamines (e.g., hydroxyzine), alpha- and beta-adrenergic medications (e.g., propranolol, clonidine), and GABAergic medications (benzodiazepines, pregabalin, and gabapentin). Posttraumatic stress disorder and obsessive-compulsive disorder are excluded from this review. Second, we will review novel pharmacotherapeutic agents under investigation for the treatment of anxiety disorders in adults. The pathways and neurotransmitters reviewed include serotonergic agents, glutamate modulators, GABAergic medications, neuropeptides, neurosteroids, alpha- and beta-adrenergic agents, cannabinoids, and natural remedies. The outcome of the review reveals a lack of randomized double-blind placebo- controlled trials for anxiety disorders and few studies comparing novel treatments to existing anxiolytic agents. Although there are some recent randomized controlled trials for novel agents including neuropeptides, glutamatergic agents (such as ketamine and d-cycloserine), and cannabinoids (including cannabidiol) primarily in GAD or SAD, these trials have largely been negative, with only some promise for kava and PH94B (an inhaled neurosteroid). Overall, the progression of current and future psychopharmacology research in anxiety disorders suggests that there needs to be further expansion in research of these novel pathways and larger-scale studies of promising agents with positive results from smaller trials.