BACKGROUND:Mismatch negativity (MMN) is a component of the auditory event-related potential (ERP) that is elicited during a passive oddball paradigm where task-irrelevant infrequent deviants are presented in a stream of more frequent standard stimuli. MMN is believed to index a preattentive stage of auditory information processing closely linked to NMDA receptor (NMDAR) function. Ketamine is thought to act primarily as an NMDAR antagonist, has been used in clinical trials to model the symptoms of schizophrenia, and is increasingly being used in the clinic to treat depression. Various studies have reported that ketamine reduces MMN amplitude, which in turn may reflect reduced function of NMDAR-mediated neurotransmission. Nonetheless, there is growing evidence showing MMN amplitude either having high variability or, paradoxically, moving in the opposite direction after ketamine in different individuals. METHODS:We analyzed results from 3 independent ERP studies to test the hypothesis of a crossover interaction (disordinal drug effect) between the duration-deviant MMN amplitude at baseline (without ketamine) and the direction and magnitude of the ketamine effect. To rule out regression to the mean (RTM), a statistical phenomenon that may also partially explain this crossover interaction, we separately estimated RTM using a drug-free test-retest study. RESULTS:Our results are the first to statistically demonstrate the existence of a disordinal drug response to ketamine, where the direction and magnitude of ketamine-induced changes in MMN amplitude can be predicted by baseline MMN amplitude. CONCLUSIONS:These new insights may contribute to novel precision medicine approaches in the treatment of central nervous system disorders.

BACKGROUND:Diagnostic criteria for apathy in neurocognitive disorders (DCA-NCD) have recently been updated. OBJECTIVES:We investigated whether validated scales measuring apathy severity capture the three dimensions of the DCA-NCD (diminished initiative, diminished interest, diminished emotional expression). MEASUREMENTS:Degree of mapping ("not at all", "weakly", or "strongly") between items on two commonly used apathy scales, the Neuropsychiatric Inventory-Clinician (NPI-C) apathy and Apathy Evaluation Scale (AES), with the DCA-NCD overall and its 3 dimensions was evaluated by survey. DESIGN:Survey participants, either experts (n = 12, DCA-NCD authors) or scientific community members (n = 19), rated mapping for each item and mean scores were calculated. Interrater reliability between expert and scientific community members was assessed using Cohen's kappa. RESULTS:According to experts, 9 of 11 (81.8%) NPI-C apathy items and 6 of 18 (33.3%) AES items mapped strongly onto the DCA-NCD overall. For the scientific community group, 10 of 11 (90.9%) NPI-C apathy items and 7 of 18 (38.8%) AES items mapped strongly onto the DCA-NCD overall. The overall mean mapping scores were higher for the NPI-C apathy compared to the AES for both expert (t (11) = 3.13, p = .01) and scientific community (t (17) = 3.77, p = .002) groups. There was moderate agreement between the two groups on overall mapping for the NPI-C apathy (kappa= 0.74 (0.57, 1.00)) and AES (kappa= 0.63 (0.35, 1.00)). CONCLUSIONS:More NPI-C apathy than AES items mapped strongly and uniquely onto the DCA-NCD and its dimensions. The NPI-C apathy may better capture the DCA-NCD and its dimensions compared with the AES.

Traditionally, Phase 1 clinical trials were largely conducted in healthy normal volunteers and focused on collection of safety, tolerability, and pharmacokinetic data. However, in the CNS therapeutic area, with more drugs failing in later phase development, Phase 1 trials have undergone an evolution that includes incorporation of novel approaches involving novel study designs, inclusion of biomarkers, and early inclusion of patients to improve the pharmacologic understanding of novel CNS-active compounds early in clinical development with the hope of improving success in later phase pivotal trials. In this chapter, the authors will discuss the changing landscape of Phase 1 clinical trials in CNS, including novel trial methodology, inclusion of pharmacodynamic biomarkers, and experimental medicine approaches to inform early decision-making in clinical development.

INTRODUCTION:Apathy is common in neurocognitive disorders (NCD) but NCD-specific diagnostic criteria are needed.METHODS:The International Society for CNS Clinical Trials Methodology Apathy Work Group convened an expert group and sought input from academia, health-care, industry, and regulatory bodies. A modified Delphi methodology was followed, and included an extensive literature review, two surveys, and two meetings at international conferences, culminating in a consensus meeting in 2019.RESULTS:The final criteria reached consensus with more than 80% agreement on all parts and included: limited to people with NCD; symptoms persistent or frequently recurrent over at least 4 weeks, a change from the patient's usual behavior, and including one of the following: diminished initiative, diminished interest, or diminished emotional expression/responsiveness; causing significant functional impairment and not exclusively explained by other etiologies.DISCUSSION:These criteria provide a framework for defining apathy as a unique clinical construct in NCD for diagnosis and further research.

NV-5138 (or SPN-820) is a novel small molecule activator of the mechanistic target of rapamycin complex 1 (mTORC1) currently under development for use in treatment- resistant depression. This phase I study evaluated the safety, tolerability, and pharmacodynamics (as measured by quantitative electroencephalography, qEEG) of two sequential oral doses of NV-5138 in healthy adult males. Twenty-five participants were randomly assigned to double-blind treatment with a single dose of placebo or 2400 mg NV-5138 on Day 1, and a second dose of the same treatment on Day 3. The two doses of NV-5138 were safe and well tolerated, with no deaths, serious adverse events, or discontinuations due to adverse events. Spectral band amplitudes, derived frequency measures, and magnitude squared coherences were computed from qEEG recordings during resting state eyes-open and eyes-closed conditions at multiple timepoints. In the NV-5138 group only, significant changes in qEEG measures occurred at 1 hour post-dose on both days (near NV-5138 T max ), including decreases in low-frequency band amplitudes (theta) and increases in high-frequency EEG band amplitudes (high beta and gamma). These effects were mirrored by a decrease in the theta/beta ratio, a measure negatively associated with arousal and cognitive processing capability. Significantly increased high beta and gamma band coherences were also detected at several specific electrode pairs in both eyes-open and eye-closed conditions. NV-5138 actively modulated functional brain parameters consistent with positive effects on mood, cognition, and arousal. These results indicate that qEEG measures may be useful biomarkers of NV-5138 target engagement and related changes in neural activity.

Athira Pharma, Inc. is developing a new class of blood‐brain barrier (BBB)‐penetrant small molecule drugs aimed at activating the neurotrophic system HGF/MET to promote multiple neurorestorative processes, with the potential to ultimately improve brain function. ATH‐1017 is the lead clinical candidate for the treatment of Alzheimer’s disease (AD). Electroencephalogram (EEG) plays a growing role in facilitating dose exploration of investigational agents like ATH‐1017 by demonstrating brain penetration and target engagement, helping to accelerate CNS drug development.

Introduction: Many patients with major depressive disorder (MDD) do not achieve remission with their first antidepressant (AD), resulting in a high burden due to treatment failure. Vortioxetine is a valid treatment option for patients with MDD only partially responding to their first AD. Characterization of vortioxetine's potential benefits versus other approved treatments is important. Areas covered: The cost-effectiveness of vortioxetine, including cognitive outcomes, was modeled in comparison with levomilnacipran and vilazodone for patients switched to these medications after inadequate responses to a first AD. Expert opinion: Vortioxetine was associated with incremental quality-adjusted life-year (QALY) gains versus levomilnacipran (0.008) or vilazodone (0.009). Vortioxetine was dominant versus levomilnacipran and cost-effective versus vilazodone (incremental cost-effectiveness ratio [ICER],33,829 USD/QALY). In sensitivity analyses using residual cognitive dysfunction rates (vortioxetine, 49%; levomilnacipran, 58%, and vilazodone, 64%), incremental QALY gains for vortioxetine versus levomilnacipran (0.0085) or vilazodone (0.0109) were found. Vortioxetine remained dominant versus levomilnacipran and cost-effective versus vilazodone (ICER, 27,633 USD/QALY). ICER reduction was found with cognition outcomes inclusion. This model provides additional support for considering vortioxetine for patients requiring a switch of MDD treatments, although its conclusions are limited by the data available for inclusion. Additional research and real-world trials are needed to confirm the findings.

Efforts to identify fluid biomarkers of Parkinson’s disease (PD) have intensified in the last decade. As the role of inflammation in PD pathophysiology becomes increasingly recognized, investigators aim to define inflammatory signatures to help elucidate underlying mechanisms of disease pathogenesis and aid in identification of patients with inflammatory endophenotypes that could benefit from immunomodulatory interventions. However, discordant results in the literature and a lack of information regarding the stability of inflammatory factors over a 24-h period have hampered progress.

AZD3293 (LY3314814) is a promising new potentially disease-modifying BACE1 (β-secretase) inhibitor in Phase III clinical development for the treatment of Alzheimer's disease. Reported here are the first two Phase I studies: (1) a single ascending dose study evaluating doses of 1-750 mg with a food-effect component (n = 72), and (2) a 2-week multiple ascending dose study evaluating doses of 15 or 50 mg once daily (QD) or 70 mg once weekly (QW) in elderly subjects (Part 1, n = 31), and 15, 50, or 150 mg QD in patients with mild to moderate Alzheimer's disease (Part 2, n = 16). AZD3293 was generally well tolerated up to the highest doses given. No notable food effects were observed. PK following multiple doses (Part 2) were tmax of 1 to 3 h and mean t1/2 of 16 to 21 h across the 15 to 150 mg dose range. For single doses of ≥5 mg, a ≥70% reduction was observed in mean plasma Aβ40 and Aβ42 concentrations, with prolonged suppression for up to 3 weeks at the highest dose level studied. Following multiple doses, robust reductions in plasma (≥64% at 15 mg and ≥78% at ≥50 mg) and cerebrospinal fluid (≥51% at 15 mg and ≥76% at ≥50 mg) Aβ peptides were seen, including prolonged suppression even with a QW dosing regimen. AZD3293 is the only BACE1 inhibitor for which prolonged suppression of plasma Aβ with a QW dosing schedule has been reported. Two Phase III studies of AZD3293 (AMARANTH, NCT02245737; and DAYBREAK-ALZ, NCT02783573) are now ongoing.

CSF IFNγ and serum IL-8 positively correlated with UPDRS components at baseline in PD subjects. (PDF 563 kb)

β-Amyloid (Aβ) peptides are thought to be critically involved in the etiology of Alzheimer’s disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of Aβ, and BACE1 inhibition is thus an attractive target for the treatment of AD. We show that verubecestat (MK-8931) is a potent, selective, structurally unique BACE1 inhibitor that reduced plasma, cerebrospinal fluid (CSF), and brain concentrations of Aβ40, Aβ42, and sAPPβ (a direct product of BACE1 enzymatic activity) after acute and chronic administration to rats and monkeys. Chronic treatment of rats and monkeys with verubecestat achieved exposures >40-fold higher than those being tested in clinical trials in AD patients yet did not elicit many of the adverse effects previously attributed to BACE inhibition, such as reduced nerve myelination, neurodegeneration, altered glucose homeostasis, or hepatotoxicity. Fur hypopigmentation was observed in rabbits and mice but not in monkeys. Single and multiple doses were generally well tolerated and produced reductions in Aβ40, Aβ42, and sAPPβ in the CSF of both healthy human subjects and AD patients. The human data were fit to an amyloid pathway model that provided insight into the Aβ pools affected by BACE1 inhibition and guided the choice of doses for subsequent clinical trials.

Correction to: Molecular Psychiatry advance online publication, 8 December 2015; doi:10.1038/mp.2015.178 Following publication of this paper, the authors noticed that Figures 5a and b contained the same image. In addition, there was a typo in Table 3 at #703. The correct figure and table appear here.

LY3202626 is a small molecule non-selective BACE1 inhibitor. In dogs, LY3202626 is highly potent, producing dose-dependent reductions in CSF and plasma Aβ concentrations. The initial human study (I7X-EW-LLCA, clinicaltrials.gov identifier NCT02323334) described herein was a single and multiple ascending dose trial, in 4 parts, to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of LY3202626 in healthy subjects (HS) and patients with Alzheimer’s disease (AD). In Part A, HS received placebo or LY3202626 (0.1 to 45 mg) as single doses. Part B evaluated CSF PK/PD in HS by serial sampling after single dose placebo or LY3202626 (1.6 to 26 mg) administration. In Part C, HS received daily doses of placebo or LY3002626 (1 to 26 mg) for 14 days. In Part D, patients with AD received daily doses of 6 mg for 14 days. In Parts C and D, CSF was obtained by lumbar puncture at baseline and 24 hrs after last dose. Plasma and CSF LY3202626 concentrations were measured by LC/MS/MS. Plasma and CSF Aβ1-40 and Aβ1-42 were measured by immunoassay. PK/PD was assessed after single doses and at steady state. Adverse events, vital signs, ECG, clinical laboratories, neurological and eye exams were assessed throughout the study and for up to 42 days after the last dose to characterize safety and tolerability. LY3202626 was well tolerated by HS (n=92) and AD patients (n=2) at all doses. In HS, maximum plasma LY3202626 concentrations (Cmax) were observed approximately 3 hrs post-dose. The terminal half-life was around 21 hrs, and PK was generally dose proportional. LY3202626 appeared to freely penetrate the blood brain barrier, with CSF Cmax approximately 6 hrs post-dose. Plasma steady-state was achieved within 8 to 10 days. Following single doses, LY3202626 produced dose-dependent reductions in plasma and CSF Aβ1-40 and Aβ1-42. At steady-state, Aβ1-40 in CSF was reduced by approximately 50%, 75%, and >90% at daily doses of 1, 6, or 26 mg, respectively. LY3202626 is a well-tolerated, potent, low dose, freely CNS penetrant BACE inhibitor. These data support further clinical development of LY3202626.

Hypofunction of NMDA receptors has been implicated in neuropsychiatric disorders including schizophrenia. NMDA receptor neurotransmission can be enhanced through inhibition of glycine reuptake by the glycine transporter type 1 (GlyT1).

We wanted to examine tolerability and efficacy of NSI-189, a benzylpiperizine-aminiopyridine neurogenic compound for treating major depressive disorder (MDD). This was a Phase 1B, double blind, randomized, placebo controlled, multiple-dose study with three cohorts. The first cohort received 40 mg q.d. ( n =6) or placebo ( n =2), the second cohort 40 mg b.i.d. ( n =6) or placebo ( n =2), and the third cohort 40 mg t.i.d. ( n =6) or placebo ( n =2). Twenty-four patients with MDD were recruited, with the diagnosis and severity confirmed through remote interviews. Eligible patients received NSI-189 or placebo for 28 days in an inpatient setting with assessments for safety, pharmacokinetics (PK) and efficacy. Outpatient follow-up visits were conducted until day 84 (±3). NSI-189 was relatively well tolerated at all doses, with no serious adverse effects. NSI-189 area under the curve increased in a dose-related and nearly proportional manner across the three cohorts, with a half-life of 17.4–20.5 h. The exploratory efficacy measurements, including Symptoms Of Depression Questionnaire (SDQ), Montgomery-Asberg Depression Scale (MADRS), Clinical Global Impressions—Improvement (CGI-I), and The Massachusetts General Hospital (MGH) Cognitive and Physical Functioning Questionnaire (CPFQ) showed a promising reduction in depressive and cognitive symptoms across all measures for NSI-189, with significant improvement in the SDQ and CPFQ, and a medium to large effect size for all measures. These improvements persisted during the follow-up phase. In summary, NSI-189 shows potential as a treatment for MDD in an early phase study. The main limitation of this preliminary study was the small sample size of each cohort.

BACE1 is a key protease controlling the formation of amyloid β, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid β lowering in nonclinical animal models. Similar potent and persistent amyloid β lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.

Vortioxetine, a novel antidepressant exhibiting a multimodal mechanism of action, was approved for the treatment of adults with major depressive disorder (MDD). This extension study of a recently published meta-analysis (Llorca et al. Curr Med Res Opin 2014;30(12):2589-606) compares the efficacy and tolerability of vortioxetine with seven commonly used antidepressants marketed in the US. Indirect comparisons using meta-regression, an extension of random-effects meta-analysis, were performed using data from 54 double-blind, placebo-controlled Phase 3 pivotal studies identified in a systematic review (N= 18,312 patients). To ensure study comparability, only experimental drug and placebo arms were included in primary analyses. Study-level standardized effect sizes were regressed on active treatment to compare efficacy and tolerability of vortioxetine with branded (levomilnacipran, vilazodone, desvenlafaxine) and generic (duloxetine, escitalopram, sertraline, venlafaxine) antidepressants. Efficacy was defined as change from baseline on the Montgomery-Asberg Depression Scale or Hamilton Depression Rating Scale after 2 months (6-12 weeks) of treatment. Tolerability was defined as the withdrawal rate due to any adverse event. Standardized mean differences for vortioxetine compared with the selected antidepressants (negative estimates favor vortioxetine) were: duloxetine, 0.10 (95% confidence interval [CI]: -0.12, 0.32); escitalopram, -0.04 (95% CI: -0.32, 0.24); sertraline, -0.02 (95% CI: -0.39, 0.34); venlafaxine, 0.14 (95% CI: -0.11, 0.39); levomilnacipran, -0.05 (95% CI: -0.28, 0.19); vilazodone, -0.23 (95% CI: -0.53, 0.06); and desvenlafaxine, 0.04 (95% CI: -0.16, 0.23). Significantly lower withdrawal rates were observed for vortioxetine versus sertraline, venlafaxine, and desvenlafaxine (all P<0.05). No statistically significant difference in withdrawal rates was observed between vortioxetine and duloxetine, escitalopram, levomilnacipran, or vilazodone. These findings show that vortioxetine offers a comparable combination of efficacy and tolerability in MDD to other antidepressants marketed in the US.