A comparative analysis between site-based and centralized ratings and patient self-ratings in a clinical trial of Major Depressive Disorder.

We compared scores from three different ratings methods in a clinical trial of patients with Major Depressive Disorder (MDD). The Quick Inventory of Depressive Symptoms (QIDS-SR16) was compared to site-based clinician and centralized (site-independent) ratings of the Inventory of Depressive Symptoms (IDSc30). An extracted QIDSc16 was used for a matched comparison with the QIDS-SR16. Patient self-ratings were more depressed at baseline than either site-based ratings (p = 0.131) or centralized ratings (p = 0.005), but significantly less depressed at the end of double-blind treatment than either site-based (p = 0.006) or centralized ratings (p = 0.014), and after 12 weeks (site-based ratings: p = 0.048; centralized ratings: p = 0.004). The matched comparisons with patient self-ratings revealed ICC of r = 0.55 (site-based raters) and r = 0.49 (centralized raters) at baseline. After baseline, the correlations between the two different clinician ratings and patient self-ratings improved to r-values between 0.78 and 0.89. At the end of double-blind treatment, site-based raters separated the combination treatment from placebo on the IDSc30 (p = 0.030) whereas neither centralized ratings nor patient self-ratings achieved statistical significance. Alternatively, patient self-ratings separated the combination treatment from buspirone (p = 0.030) whereas neither clinician rating method achieved significance. A "dual" scoring concordance range reduced the placebo response rate and increased the drug effect between the combination treatment and placebo. These findings reveal scoring variability between each of the three ratings methods and challenge the reliability of any single method to accurately assess symptom severity scores, particularly at baseline. The use of "dual" scoring criteria may help to confirm symptom severity scores and improve ratings precision, particularly prior to enrolling subjects into CNS trials.

An exploratory study of combination buspirone and melatonin SR in major depressive disorder (MDD): a possible role for neurogenesis in drug discovery.

We used in vitro neurogenesis-based human neural stem cell (hNSCs) assays and rodent in vivo behavioral assays to identify potential novel antidepressants. A combination of buspirone and melatonin displayed antidepressant activity in these assays whereas neither buspirone nor melatonin alone showed any antidepressant-like profile. After evaluating numerous combination ratios, we determined that low dose buspirone 15 mg combined with melatonin-SR 3 mg yielded optimal antidepressant efficacy in our pre-clinical platform. The low dose of buspirone suggested that antidepressant efficacy might be achieved with only minimal adverse event liability. Based on these data, we conducted an exploratory 6-week, multi-center, double-blind, randomized, placebo- and comparator-controlled study of the combination of buspirone and melatonin in subjects with acute Major Depressive Disorder (MDD). The combination treatment revealed a significant antidepressant response in subjects with MDD on several measures (Clinical Global Impression of Severity and Improvement, Inventory of Depressive Symptomatology) compared to either placebo or buspirone 15 mg monotherapy. These preliminary findings have clinical implications and suggest that a platform of pre-clinical neurogenesis matched with confirmatory behavioral assays may be useful as a drug discovery strategy.

Whole organism high-content screening by label-free, image-based Bayesian classification for parasitic diseases.

Sole reliance on one drug, Praziquantel, for treatment and control of schistosomiasis raises concerns about development of widespread resistance, prompting renewed interest in the discovery of new anthelmintics. To discover new leads we designed an automated label-free, high content-based, high throughput screen (HTS) to assess drug-induced effects on in vitro cultured larvae (schistosomula) using bright-field imaging. Automatic image analysis and Bayesian prediction models define morphological damage, hit/non-hit prediction and larval phenotype characterization. Motility was also assessed from time-lapse images. In screening a 10,041 compound library the HTS correctly detected 99.8% of the hits scored visually. A proportion of these larval hits were also active in an adult worm ex-vivo screen and are the subject of ongoing studies. The method allows, for the first time, screening of large compound collections against schistosomes and the methods are adaptable to other whole organism and cell-based screening by morphology and motility phenotyping.

Differential distribution of voltage-gated calcium channel alpha-2 delta (alpha2delta) subunit mRNA-containing cells in the rat central nervous system and the dorsal root ganglia.

Voltage-gated calcium channels (VGCCs) play an essential role in controlling neurotransmitter release, neuronal excitability, and gene expression in the nervous system. The distribution of cells that contain mRNAs encoding the auxiliary alpha2delta-1, alpha2delta-2, and alpha2delta-3 subunits of the VGCCs in the central nervous system (CNS) and the dorsal root ganglia (DRG) was examined in rats by using in situ hybridization. Specific labeling of alpha2delta-1, alpha2delta-2, and alpha2delta-3 mRNAs appeared to be largely confined to neurons and was widely, although differentially, distributed in the brain, the spinal cord, and the DRG. Importantly, alpha2delta-2 mRNA was found to be expressed in interneurons in the cortex, the hippocampus, the striatum, and in regions that contain dense cholinergic neurons. Our results suggest that different alpha2delta subunits may exert distinctive functions in the CNS. The alpha2delta-1 subunit mRNA is localized in brain regions known to be involved in cortical processing, learning and memory, defensive behavior, neuroendocrine secretion, autonomic activation, primary sensory transmission, and general arousal. The alpha2delta-2 subunit mRNA is present in brain regions known to modulate the overall activities of the cortex, the hippocampus, and the thalamus. The alpha2delta-2 subunit is also found in brain regions known to be involved in olfaction, somatic motor control, fluid homeostasis, ingestive and defensive behaviors, neuroendocrine functions, and circadian rhythm. In addition to being localized in brain regions that express alpha2delta-1 and alpha2delta-2 subunit mRNAs, alpha2delta-3 subunit mRNA is highly expressed in regions involved in auditory information processing and somatic movement.

Cyclohexenyl- and dehydropiperidinyl-alkynyl pyridines as potent metabotropic glutamate subtype 5 (mGlu5) receptor antagonists.

Structure-activity relationship studies leading to the discovery of novel mGlu5 receptor antagonists are described. These compounds show high in vitro potency, have good in vivo receptor occupancy, and a reasonable intravenous pharmacokinetic profile.

Identification of metabotropic glutamate receptor antagonists using an automated high-throughput screening system.

Antagonists to the human metabotropic glutamate receptor subtype 5a(mGluR(5a)) have been implicated as potential therapeutics for the treatment of a variety of nervous system disorders, including pain, anxiety, and Parkinson's disease. To discover novel antagonists to the mGluR(5a), a functional assay measuring agonist-induced intracellular calcium release was developed. The assay was used for the high-throughput screening of a large collection of compounds in single wells using a fully automated robotic platform. Primary high-throughput screening hits were subjected to a combination of data analysis and counterscreening assays to identify several compounds with both efficacy and selectivity for the metabotropic glutamate receptor target.