Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD.

Metabotropic glutamate receptor-2 positive allosteric modulator, JNJ-40411813 (ADX71149), was characterised for clinical effects in healthy volunteers in two phase-1 studies. In study 1, healthy men received 50-, 100-, 150- or 225 mg and women received 100 mg JNJ-40411813 (n=6, each cohort) or placebo (n=2, each cohort) twice daily for seven days; smoking men (n=30) received placebo twice daily on days 1-7, 100 mg JNJ-40411813 (n=20) or placebo (n=10) on days 8-14. In study 2, healthy men received intravenous 0.005 mg/kg S(+) ketamine over 60 min at 3 (n=24; cohort 1), 12 h (n=8; cohort 3), and 24 h (n=8; cohort 2) after a single oral dose of 500 mg JNJ-40411813 or placebo. The pharmacokinetics and effects of JNJ-40411813 on cognition and subjective awareness were evaluated. Plasma JNJ-40411813 exposure was dose-dependent, t max ranged from 3-4 h and t 1/2 19.4-34.2 h across the dose levels. JNJ-40411813 significantly (p=0.02) reduced continuity of attention score (150 mg dose) and ameliorated smoking withdrawal-induced changes in power of attention and quality of episodic memory versus placebo. A modest reduction in alertness was observed at 150-225 mg doses, JNJ-40411813 (500 mg) reduced S(+) ketamine-induced negative symptoms by approximately 43% and 30% in cohorts 1 and 3, respectively. JNJ-40411813 was generally well-tolerated.

Nasal obstruction, also referred to as congestion, blockage or stuffiness, is a crucial symptom in allergic rhinitis (AR) and may affect sleep as well as quality of life. Early- and late-phase-allergic reactions both contribute to nasal obstruction, although it primarily represents a major symptom in the chronic allergic reaction. A complex network of inflammatory and neurogenic phenomena relates to chronic nasal obstruction, including the subepithelial accumulation of inflammatory cells, particularly mast cells and eosinophils, and the release of neuropeptides. Nasal obstruction is a difficult-to-treat symptom. Vasoconstrictors (decongestants) and intranasal corticosteroids, due to their anti-inflammatory properties, have mainly been used for relieving the nasal passages from the congested mucosa. However, there is accumulating evidence recently that the latest-generation potent antihistamines have decongestant properties in AR. This paper aims to review the pathophysiologic background of nasal obstruction and the evidence for an antihistamine, levocetirizine, in relieving nasal congestion. A meta-analysis on the early and late effects of levocetirizine on nasal obstruction under artificial and natural allergen exposure conditions is presented, demonstrating convincingly that levocetirizine shows a consistent effect on nasal obstruction as early as over the first 2 h and sustained over 6 weeks.

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SUMMARYPurpose: To determine whether levetiracetam (LEV) affects plasma concentrations of carbamazepine, valproic acid, topiramate, and lamotrigine in children with epilepsy. Methods: The potential for interaction of LEV with other antiepileptic drugs (AEDs) was assessed using plasma drug levels obtained in a randomized placebo-controlled phase III trial of adjunctive LEV in children receiving one or two concomitant AEDs. Multiple plasma AED levels at baseline and during adjunctive treatment with LEV or placebo were compared by repeated measures analysis of covariance and mean concentration ratios (treatment/baseline) were estimated with their 90% confidence intervals (CI). Results: The study population included 187 children receiving any concomitant AED alone or in combination. The geometric mean concentrations at baseline and during LEV treatment were carbamazepine 8.4 µg/ml versus 8.1 µg/ml (coefficient of variation, CV = 30%; n = 35); valproic acid 83.8 versus 82.5 µg/ml (CV = 38%; n = 23); topiramate 7.3 versus 7.2 µg/ml (CV = 82%; n = 28); lamotrigine 8.2 versus 7.7 µg/ml (CV = 62%; n = 22). For each AED, the mean concentration ratios (LEV/baseline) and their 90% CIs showed that AED concentrations were unaffected by concomitant LEV administration. No differences were observed between LEV and placebo. Conclusions: LEV does not affect plasma concentrations of carbamazepine, valproic acid, topiramate, or lamotrigine in children with epilepsy.