Given the high risk of developing drugs for neurodegenerative diseases if post‐phase I decisions to go into efficacy studies were made with quantitative knowledge of an agent's action in brain, the ...risks should be diminished. Furthermore, if biomarkers were compelling, they could be utilized during a lengthy trial as an early measure of futility. What follows is one perspective on the adequacy of current and emerging measures to be applied to such decision making.
A large number of promising candidate disease-modifying treatments for Alzheimer disease (AD) continue to advance into phase II and phase III testing. However, most completed trials have failed to ...demonstrate efficacy, and there is growing concern that methodologic difficulties may contribute to these clinical trial failures. The optimal time to intervene with such treatments is probably in the years prior to the onset of dementia, before the neuropathology has progressed to the advanced stage corresponding to clinical dementia.
An international task force of individuals from academia, industry, nonprofit foundations, and regulatory agencies was convened to discuss optimal trial design in early (predementia) AD.
General consensus was reached on key principles involving the scope of the AD diagnosis, the selection of subjects for trials, outcome measures, and analytical methods.
A consensus has been achieved in support of the testing of candidate treatments in the early (predementia) AD population.
In clinical studies of antidepressants, the Hamilton Depression Rating Scale (HAMD) total score has been the gold standard instrument for establishing and comparing the efficacy of new treatments. ...However, the HAMD is a multidimensional measure, which may reduce its ability to detect differences between treatments, in particular, changes in core symptoms of depression. Two meta-analyses were conducted to compare the responsiveness of the HAMD total score with several published unidimensional subscale scores based upon core symptoms of depression. The first compared the above instrument's ability to detect differences between fluoxetine and placebo across eight studies involving over 1600 patients. The second analysis involved four studies and over 1200 patients randomized to tricyclic antidepressants and placebo. In both meta-analyses, the unidimensional core subscales outperformed the HAMD total score at detecting treatment differences. The implications of this on sample sizes and power for clinical studies will be discussed. In fact, studies based on the observed effect sizes from the core subscales would require approximately one-third less patients than studies based on the HAMD total score. Effect sizes from each individual HAMD item will also be presented to help explain the differences in responsiveness between the scales.
Complexity and lack of standardization have mostly limited the use of event-related potentials (ERPs) and quantitative EEG (QEEG) biomarkers in drug development to small early phase trials. We ...present results from a clinical study on healthy volunteers (HV) and patients with schizophrenia (SZ) that assessed test-retest, group differences, variance, and correlation with functional assessments for ERP and QEEG measures collected at clinical and commercial trial sites with standardized instrumentation and methods, and analyzed through an automated data analysis pipeline.
81 HV and 80 SZ were tested at one of four study sites. Subjects were administered two ERP/EEG testing sessions on separate visits. Sessions included a mismatch negativity paradigm, a 40 Hz auditory steady-state response paradigm, an eyes-closed resting state EEG, and an active auditory oddball paradigm. SZ subjects were also tested on the Brief Assessment of Cognition (BAC), Positive and Negative Syndrome Scale (PANSS), and Virtual Reality Functional Capacity Assessment Tool (VRFCAT).
Standardized ERP/EEG instrumentation and methods ensured few test failures. The automated data analysis pipeline allowed for near real-time analysis with no human intervention. Test-retest reliability was fair-to-excellent for most of the outcome measures. SZ subjects showed significant deficits in ERP and QEEG measures consistent with published academic literature. A subset of ERP and QEEG measures correlated with functional assessments administered to the SZ subjects.
With standardized instrumentation and methods, complex ERP/EEG testing sessions can be reliably performed at clinical and commercial trial sites to produce high-quality data in near real-time.
Converging lines of evidence suggest that the glutamatergic system may play an increasingly important role in the development of novel therapeutics for major depressive disorder (MDD), particularly ...agents associated with rapid antidepressant effects. Diverse glutamatergic modulators targeting N-methyl-D-aspartate receptors have shown efficacy in MDD, but their associated psychotomimetic effects presently preclude their use in larger samples. This small, randomized, double-blind, placebo-controlled, crossover pilot study evaluated the potential antidepressant efficacy and tolerability of an oral formulation of the selective N-methyl-D-aspartate NR2B antagonist MK-0657 in patients with treatment-resistant MDD (TRD). The TRD subjects underwent a 1-week drug-free period and were subsequently randomized to receive either MK-0657 monotherapy (4-8 mg/d) or placebo for 12 days. Because of recruitment challenges and the discontinuation of the compound's development by the manufacturer, only 5 of the planned 21 patients completed both periods of the crossover administration of MK-0657 and placebo. Significant antidepressant effects were observed as early as day 5 in patients receiving MK-0657 compared with those receiving placebo, as assessed by the Hamilton Depression Rating Scale and Beck Depression Inventory; however, no improvement was noted when symptoms were assessed with the Montgomery-Asberg Depression Rating Scale, the primary efficacy measure. No serious or dissociative adverse effects were observed in patients receiving this oral formulation of MK-0657. Despite the small sample size, this pilot study suggests that an oral formulation of the NR2B antagonist MK-0657 may have antidepressant properties in TRD patients. Further studies with larger sample sizes are necessary to confirm these preliminary findings.
To test the hypothesis that excess amyloid deposition is an essential step in the pathophysiology of Alzheimer’s disease appropriate biomarkers are essential in selecting agents that modify amyloid ...formation or clearance. Cerebrospinal fluid concentrations of relevant analytes and PET measures of total brain load have been developed. These are directly applied to testing whether drugs reduce various soluble forms of amyloid as well as whether they enhance elimination of material deposited in brain parenchyma. The ideal profile of a drug that can fully test the amyloid hypothesis can be understood in terms of effects on currently available and future biomarkers. Dose selection for clinical trials should require a quantitative threshold effect on the most relevant biomarker.
The mechanism of action of the novel antidepressant bupropion remains unclear after many years of study. A review of the relevant biochemical, in vivo brain microdialysis, electrophysiologic, ...behavioral, and clinical data clarifies what is known about this unique compound and suggests possible modes of action.
A panel of 11 experts was convened for a conference to discuss bupropion's mechanism of antidepressant activity. Four of the panelists presented current research findings, followed by a discussion.
(1) Biochemical studies suggest down-regulation of postsynaptic beta-adrenoceptors and desensitization of the norepinephrine-stimulated adenylate cyclase in the rat cortex occur only after chronic administration of very high doses of bupropion. (2) In vivo brain microdialysis studies demonstrate that, after chronic administration, there is an enhancement of bupropion-induced increases in extracellular dopamine in the nucleus accumbens. (3) Electrophysiologic data show that with acute dosing, bupropion reduces the firing rates of noradrenergic neurons in the locus ceruleus. The firing rates of dopaminergic neurons are reduced by bupropion in the A9 and A10 areas of the brain, but only at very high doses, and bupropion does not alter the firing rates of serotonergic neurons in the dorsal raphe. (4) Behavioral studies show that the most active metabolite of bupropion, hydroxybupropion (306U73), appears to be responsible for a large part of the compound's effects in animal models of antidepressant activity. (5) Clinical studies indicate that bupropion enhances noradrenergic functional activity as reflected by an increased excretion of the hydroxy metabolite of melatonin, while at the same time producing a presumably compensatory decrease in norepinephrine turnover. In one study, bupropion elevated plasma levels of the dopamine metabolite homovanillic acid in nonresponders, but not in responders.
The mechanism of action of bupropion appears to have an unusual, not fully understood, noradrenergic link. The bupropion metabolite hydroxybupropion probably plays a critical role in bupropion's antidepressant activity, which appears to be predominantly associated with long-term noradrenergic effects. The mild central nervous system activating effects of bupropion appear to be due to weak dopaminergic mechanisms. There is some evidence that dopamine may contribute to bupropion's antidepressant properties. Antidepressant effects of bupropion are not serotonergically mediated.
Introduction This report details the approach taken to providing a dataset allowing for analyses on the performance of recently developed assays of amyloid beta (A beta) peptides in plasma and the ...extent to which they improve the prediction of amyloid positivity. Methods Alzheimer's Disease Neuroimaging Initiative plasma samples with corresponding amyloid positron emission tomography (PET) data were run on six plasma A beta assays. Statistical tests were performed to determine whether the plasma A beta measures significantly improved the area under the receiver operating characteristic curve for predicting amyloid PET status compared to age and apolipoprotein E (APOE) genotype. Results The age and APOE genotype model predicted amyloid status with an area under the curve (AUC) of 0.75. Three assays improved AUCs to 0.81, 0.81, and 0.84 (P < .05, uncorrected for multiple comparisons). Discussion Measurement of A beta in plasma contributes to addressing the amyloid component of the ATN (amyloid/tau/neurodegeneration) framework and could be a first step before or in place of a PET or cerebrospinal fluid screening study. Highlights The Foundation of the National Institutes of Health Biomarkers Consortium evaluated six plasma amyloid beta (A beta) assays using Alzheimer's Disease Neuroimaging Initiative samples. Three assays improved prediction of amyloid status over age and apolipoprotein E (APOE) genotype. Plasma A beta 42/40 predicted amyloid positron emission tomography status better than A beta 42 or A beta 40 alone.
Minimum therapeutic doses of paroxetine and citalopram produce 80% occupancy for the serotonin (5-HT) transporter (5-HTT). The authors used (11)CDASB positron emission tomography to measure ...occupancies of three other selective serotonin reuptake inhibitors (SSRIs) at minimum therapeutic doses. The relationship between dose and occupancy was also investigated.
Striatal 5-HTT binding potential was measured in 77 subjects before and after 4 weeks of medication administration. Binding potential is proportional to the density of receptors not blocked by medication. Subjects received citalopram, fluoxetine, sertraline, paroxetine, or extended-release venlafaxine. Healthy subjects received subtherapeutic doses; subjects with mood and anxiety disorders received therapeutic doses. Percent reduction in 5-HTT binding potential for each medication and dose was calculated. To obtain test-retest data, binding potential was measured before and after 4 weeks in six additional healthy subjects.
Substantial occupancy occurred at subtherapeutic doses for all SSRIs. Compared to test-retest data, each drug at the minimum therapeutic dose had a significant effect on striatal 5-HTT binding potential. Mean occupancy at this dose was 76%-85%. At higher plasma SSRI concentrations, 5-HTT occupancy tended to increase above 80%. For each drug, as the dose (or plasma level) increased, occupancy increased nonlinearly, with a plateau for higher doses.
At tolerable doses, SSRIs have increasing occupancy with increasing plasma concentration or dose. Occupancy of 80% across five SSRIs occurs at minimum therapeutic doses. This suggests that 80% 5-HTT blockade is important for therapeutic effect. Occupancy should be measured during development of antidepressant compounds targeting the 5-HTT.
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