ASP0367, or bocidelpar sulfate, is an orally administered small molecule that potently and selectively modulates peroxisome proliferator–activated receptor δ (PPARδ) to address mitochondrial dysfunction occurring in diseases including primary mitochondrial myopathy and Duchenne muscular dystrophy. The objectives of this first‐in‐human trial were to evaluate the safety/tolerability, pharmacokinetics, and pharmacodynamics of ASP0367 in healthy participants.

Aberrant glutamate neurotransmission, and in particular dysfunction of the N-methyl-d-aspartate receptor (NMDAR), has been implicated in psychiatric disorders and represents a novel therapeutic target. Low-dose administration of the NMDA antagonist ketamine in healthy volunteers elicits a strong blood oxygenation level dependent (BOLD) imaging signal that can be attenuated by pretreatment with single, therapeutically effective doses of marketed medicines interacting with the glutamate system.

AIMS:The safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of single and multiple doses of a novel mGlu2 agonist were assessed in healthy males.METHODS:In two, Phase 1 investigator- and subject-blind, placebo-controlled studies, oral doses of prodrug LY2979165 were evaluated: single doses (20-150 mg, N = 30) and multiple once-daily (QD) doses (20-400 mg; N = 84), using a titration regimen. The plasma and urine PK of LY2979165 and active moiety, 2812223, were measured. Cerebrospinal fluid (CSF) was collected to determine PK and neurotransmitter levels. Safety parameters were assessed throughout.RESULTS:Nausea and vomiting were dose limiting following single doses; dose titration allowed higher doses to be tested over 14 days. The most common adverse events related to LY2979165 were dizziness, vomiting, nausea, somnolence and headache. The plasma PK of 2812223 were approximately linear with minimal accumulation with QD dosing. Conversion of LY2979165 to 2812223 was extensive, with minimal LY2979165 measurable in plasma. There was no effect of food on the PK of LY2979165 and 2812223. After 60 mg LY2979165 single-dose, 2812223 exposure in CSF was approximately 2-6% and plasma exposure and peak concentrations were approximately four-fold higher than the mGlu2 agonist in vitro EC50 value. No consistent effects were observed on CSF neurotransmitter levels.CONCLUSIONS:Oral doses of LY2979165 up to 60 mg as a single dose and up to 400 mg given as multiple QD doses, using a titration regimen, were well tolerated with linear PK. Overall, these data support further clinical evaluation of LY2979165.

Background: Selective kappa opioid receptor antagonism is a promising experimental strategy for the treatment of depression. The kappa opioid receptor antagonist, LY2456302, exhibits similar to 30-fold higher affinity for kappa opioid receptors over mu opioid receptors, which is the next closest identified pharmacology.Methods: Here, we determined kappa opioid receptor pharmacological selectivity of LY2456302 by assessing mu opioid receptor antagonism using translational pupillometry in rats and humans.Results: In rats, morphine-induced mydriasis was completely blocked by the nonselective opioid receptor antagonist naloxone (3 mg/kg, which produced 90% mu opioid receptor occupancy), while 100 and 300 mg/kg LY2456302 (which produced 56% and 87% mu opioid receptor occupancy, respectively) only partially blocked morphine-induced mydriasis. In humans, fentanyl-induced miosis was completely blocked by 50 mg naltrexone, and LY2456302 dose-dependently blocked miosis at 25 and 60 mg (minimal-to-no blockade at 4-10 mg).Conclusions: We demonstrate, for the first time, the use of translational pupillometry in the context of receptor occupancy to identify a clinical dose of LY2456302 achieving maximal kappa opioid receptor occupancy without evidence of significant mu receptor antagonism.

Accumulating evidence indicates that selective antagonism of kappa opioid receptors may provide therapeutic benefit in the treatment of major depressive disorder, anxiety disorders, and substance use disorders. LY2456302 is a high-affinity, selective kappa opioid antagonist that demonstrates >30-fold functional selectivity over mu and delta opioid receptors. The safety, tolerability, and pharmacokinetics (PK) of LY2456302 were investigated following single oral doses (2-60mg), multiple oral doses (2, 10, and 35mg), and when co-administered with ethanol. Plasma concentrations of LY2456302 were measured by liquid chromatography-tandem mass spectrometry method. Safety analyses were conducted on all enrolled subjects. LY2456302 doses were well-tolerated with no clinically significant findings. No safety concerns were seen on co-administration with ethanol. No evidence for an interaction between LY2456302 and ethanol on cognitive-motor performance was detected. LY2456302 displayed rapid oral absorption and a terminal half-life of approximately 30-40hours. Plasma exposure of LY2456302 increased proportionally with increasing doses and reached steady state after 6-8 days of once-daily dosing. Steady-state PK of LY2456302 were not affected by coadministration of a single dose of ethanol. No clinically important changes in maximum concentration (Cmax) or AUC of ethanol (in the presence of LY2456302) were observed.

OBJECTIVE The purpose of this study was to assess the clinical outcomes from an open label study of edivoxetine, a selective norepinephrine reuptake inhibitor, in pediatric patients with attention-deficit/hyperactivity disorder (ADHD). METHODS This was a multi-cohort open-label study of edivoxetine consisting of a single-dose administration period (Part 1) and an open-label once daily (QD) dose long-term period (Part 2). Adolescents ages 12-17 years and children ages 6-11 years were enrolled in Part 1 and continued to Part 2 where they received 0.05 to 0.3 mg/kg edivoxetine QD for ≤12 months. Safety was assessed by adverse events, vital signs, weight, electrocardiograms, and laboratory tests. In Part 2, Attention-Deficit/Hyperactivity Disorder Rating Scale-Version IV-Parent Reported: Investigator Scored (ADHDRS-IV) and Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) scores were determined. RESULTS Fifty-three patients enrolled in Part 1, and 49 continued to Part 2 with a mean exposure duration of 22 weeks. The 31 patients completing Part 2 then entered another long-term open-label study. One serious adverse event of mania was reported; all other treatment-emergent adverse events were mild or moderate in severity. Nausea, decreased appetite, somnolence, increased blood pressure, and upper respiratory tract infection were most frequently reported (three events each). No clinically relevant changes were noted in the laboratory parameters. ADHDRS-IV total score, inattention and hyperactivity/impulsivity subscores, and CGI-ADHD-S scores were statistically significantly improved at endpoint compared with baseline. CONCLUSIONS This study provides preliminary evidence to suggest that edivoxetine at doses ≤0.3 mg/kg/day is safe and may improve ADHD symptoms in pediatric patients. These results require confirmation in larger, double-blind, placebo-controlled trials.

The normalization of excessive glutamatergic neurotransmission through the activation of metabotropic glutamate 2 (mGlu2) receptors may have therapeutic potential in a variety of psychiatric disorders, including anxiety/depression and schizophrenia. Here, we characterize the pharmacological properties of N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (THIIC), a structurally novel, potent, and selective allosteric potentiator of human and rat mGlu2 receptors (EC(50) = 23 and 13 nM, respectively). THIIC produced anxiolytic-like efficacy in the rat stress-induced hyperthermia assay and the mouse stress-induced elevation of cerebellar cGMP and marble-burying assays. THIIC also produced robust activity in three assays that detect antidepressant-like activity, including the mouse forced-swim test, the rat differential reinforcement of low rate 72-s assay, and the rat dominant-submissive test, with a maximal response similar to that of imipramine. Effects of THIIC in the forced-swim test and marble burying were deleted in mGlu2 receptor null mice. Analysis of sleep electroencephalogram (EEG) showed that THIIC had a sleep-promoting profile with increased non-rapid eye movement (REM) and decreased REM sleep. THIIC also decreased the dark phase increase in extracellular histamine in the medial prefrontal cortex and decreased levels of the histamine metabolite tele-methylhistamine (t-MeHA) in rat cerebrospinal fluid. Collectively, these results indicate that the novel mGlu2-positive allosteric modulator THIIC has robust activity in models used to predict anxiolytic/antidepressant efficacy, substantiating, at least with this molecule, differentiation in the biological impact of mGlu2 potentiation versus mGlu2/3 orthosteric agonism. In addition, we provide evidence that sleep EEG and CSF t-MeHA might function as viable biomarker approaches to facilitate the translational development of THIIC and other mGlu2 potentiators.

AIM:To determine the potential of cortisol secretion, in response to a physiological stressor, as a biomarker for centrally active compounds targeting the hypothalamic-pituitary-adrenocortical (HPA) axis.METHODS:Cortisol response to hypoglycaemia was measured in 26 healthy males in two stages: firstly to derive an algorithm for individualized, graded insulin infusion rates to achieve defined hypoglycaemic targets over 3 h and secondly to determine the inter- and intra-subject variability of cortisol response to hypoglycaemia over two identical periods by measuring the maximum (t(max) ), time to maximum (C(max) ) response and cortisol area under the response curve (AUC).RESULTS:Hypoglycaemia induced a consistent cortisol response starting at approximately 1 h, corresponding to blood glucose concentrations of approximately 3.3 mmol l⁻¹, and peaking approximately 3 h after the start of infusion. The inter- and intra-subject coefficients of variation (CVs) of cortisol response were approximately 19 and 19% (AUC), 15 and 19 % (C(max) ) and 10 and 14% (t(max) ), respectively. The intra-subject CVs for the ratio of maximum cortisol response to baseline concentration and rate of initial cortisol response between study days were more variable (32.8% and 59.0%, respectively). The blood glucose-cortisol response model derived from the study was predictive of the individual observed cortisol responses, and estimated a blood glucose EC(50) associated with onset of the cortisol response of 3.3 mmol l⁻¹.CONCLUSIONS:Gradual hypoglycaemia is an effective, reproducible and well-tolerated method of stimulating a cortisol response and may therefore be useful in assessing the neuroendocrine response to HPA axis inhibitors, such as corticotropin-releasing hormone-1 (CRH-1) antagonists.

Objective: The present work examined suicide-related events in acute, double-blind, and placebo- or active comparator-controlled trials with atomoxetine. Method: Fourteen trials in pediatric patients were included. Potential events were identified in the adverse events database using a text-string search. Potential suicide-related events were categorized according to U.S. Food and Drug Administration-defined codes using blinded patient summaries. The meta-analyses used the Mantel-Haenszel incidence difference and Mantel-Haenszel risk ratio methods. Results: No patient in atomoxetine attention-deficit/hyperactivity disorder (ADHD) trials committed suicide. The frequency of suicidal ideation was 0.37% (5/1357) in pediatric patients taking atomoxetine versus 0% (0/851) for the placebo group; Mantel-Haenszel incidence difference of 0.46 (95% confidence interval 0.09-0.83; p = .016) and Mantel-Haenszel risk ratio of 2.92 (95% confidence interval 0.63-13.57; p = .172). Frequencies of suicide-related events in pediatric patients with ADHD did not differ between methylphenidate and atomoxetine treatments (Mantel-Haenszel incidence difference of -0.12 (95% confidence interval -0.62 to 0.38; p = .649). The number needed to harm in pediatric patients for an additional suicide-related event is 227 compared to the number needed to treat of five to achieve remission of ADHD symptoms. Conclusions: Although uncommon, suicidal ideation was significantly more frequent in pediatric ADHD patients treated with atomoxetine compared to those treated with placebo. Retrospective analysis has limitations in ascertaining intent.

ABSTRACTBackgroundThe association between treatment-emergent suicidality as an adverse event and fluoxetine treatment was examined using a fluoxetine double-blind placebo-controlled database of clinical trials for indications other than major depressive disorder.MethodThe database consisted of 53 trials for 16 different indications (14 psychiatric, two non-psychiatric). Within each study, patient adverse event reports and narratives were searched extensively for treatment-emergent thoughts and behaviors associated with suicide. The incidence of adverse events was classified using Food and Drug Administration (FDA) codes for completed suicide, preparatory acts, suicidal ideation and the summary category of ‘all suicidality.’ The risk difference and risk ratios between fluoxetine and placebo treatment arms were compared using Mantel–Haenszel methods.ResultsWithin this large database, patients were randomly assigned to receive treatment with either fluoxetine (n=7066) or placebo (n=4382). Treatment groups did not differ in their risk for the emergence of suicidality for any FDA code; the risk ratio for ‘all suicidality’ was 0·82 (p=0·406), and there were no completed suicides in either group. Analyses based on treatment indication (bulimia, obsessive-compulsive disorder, other psychiatric and non-psychiatric illness) also showed no significant difference in risk between treatment groups. When examined by age categories (18–24, 25–30, 31–65, and ⩾65 years), fluoxetine and placebo treatments did not result in significant risk difference for the emergence of suicidality.ConclusionsThe risk of treatment-emergent suicidality does not appear to be associated with fluoxetine treatment for adults with various non-MDD conditions.

This meta-analysis assessed aggression and/or hostility-related events in children and adolescents treated with fluoxetine (n = 376) compared with placebo (n = 255). Aggression and/or hostility-related events were identified in 2.1% of fluoxetine versus 3.1% of placebo-treated patients (p = 0.588). This analysis fails to support an association between fluoxetine treatment and increased risk of aggression and/or hostility-related events in children and adolescents compared with placebo.

Background: We systematically examined potential aggression/hostility-related events in a meta-analysis of acute clinical trials of atomoxetine for attention-deficit/hyperactivity disorder (ADHD).Methods: Pediatric patients from 14 trials of atomoxetine were subdivided into a placebo-controlled (atomoxetine n = 1308, placebo n = 806) or active comparator databases (atomoxetine n = 566, methylphenidate n = 472). A third database comprised adult patients from placebo-controlled studies (atomoxetine n = 541, placebo n = 405). A computerized search of adverse events and comments identified patients with potential aggression/hostility events. Mantel-Haenszel incidence differences (MHID) were calculated.Results: In the placebo-controlled database, we observed 21 atomoxetine and 9 placebo patients with reported aggression/hostility events, MHID of .6% (95% confidence interval [Cl]: -.4,1.7). In the active comparator database, there were seven events in atomoxetine and four in methylphenidate patients, MHID = .2% (95% CI: -1.0,11.3). In the adult database, there were no events in 0 atomoxetine and one placebo patient, MHID = -.3% (95% CI: -.8,.2).Conclusions: Aggression/hostility-related events occurred in less than 2% of patients and were more frequent in pediatric patients treated with atomoxetine versus placebo (risk ratio of 1.33; not statistically significant). The risk of aggression/hostility events was similar inpatients treated with atomoxetine or methylphenidate.

Selective serotonin reuptake inhibitor treatments have been suggested by some to induce emergence of suicidality (ideation and behaviors). The objective of this study was to assess suicidality emergence by adverse event and rating scale data in the largest available, adult, major depression, double-blind, placebo-controlled, fluoxetine trial database (18 trials). Adverse event reports and comments for patients (fluoxetine, n = 2200; placebo, n = 1551) were searched for suicide-related events that were then classified into Food and Drug Administration categories. For 16 trials, suicidality was also examined by Hamilton Depression Scale item 3 (suicide) scores, and these data were analyzed along with the combination of event-based data and scale-based data. Comparisons between treatments were made for various estimates of worsening (risk) and improvement (benefit) of suicidality. Fluoxetine treatment did not result in greater worsening but was associated with greater improvement and faster resolution of ideation (P ≤ 0.05 vs placebo). Data sources were differentially sensitive in detecting changes in suicidal ideation and behaviors. Fluoxetine treatment led to greater benefit rather than risk for suicidality.

Rationale. Extrapyramidal symptoms (EPS) are common with conventional antipsychotics. Clozapine and other novel antipsychotic substances with lower in vitro affinity for dopamine-2 (D2) receptors have a lower propensity to induce EPS.