Cognitive Impairment and Diminished Neural Responses Constitute a Biomarker Signature of Negative Symptoms in Psychosis.

The treatment of negative symptoms (NS) in psychosis represents an urgent unmet medical need given the significant functional impairment it contributes to psychosis syndromes. The lack of progress in treating NS is impacted by the lack of known pathophysiology or associated quantitative biomarkers, which could provide tools for research. This current analysis investigated potential associations between NS and an extensive battery of behavioral and brain-based biomarkers in 932 psychosis probands from the B-SNIP database. The current analyses examined associations between PANSS-defined NS and (1) cognition, (2) pro-/anti-saccades, (3) evoked and resting-state electroencephalography (EEG), (4) resting-state fMRI, and (5) tractography. Canonical correlation analyses yielded symptom-biomarker constructs separately for each biomarker modality. Biomarker modalities were integrated using canonical discriminant analysis to summarize the symptom-biomarker relationships into a "biomarker signature" for NS. Finally, distinct biomarker profiles for 2 NS domains ("diminished expression" vs "avolition/apathy") were computed using step-wise linear regression. NS were associated with cognitive impairment, diminished EEG response amplitudes, deviant resting-state activity, and oculomotor abnormalities. While a connection between NS and poor cognition has been established, association to neurophysiology is novel, suggesting directions for future mechanistic studies. Each biomarker modality was related to NS in distinct and complex ways, giving NS a rich, interconnected fingerprint and suggesting that any one biomarker modality may not adequately capture the full spectrum of symptomology.

Binding of the D3-preferring antipsychotic candidate F17464 to dopamine D3 and D2 receptors: a PET study in healthy subjects with [11C]-(+)-PHNO.

RATIONALE: F17464, a dopamine D3 receptor antagonist with relatively high D3 selectivity (70 fold vs D2 in vitro), exhibits an antipsychotic profile in preclinical studies, and therapeutic efficacy was demonstrated in a randomized placebo-controlled clinical trial in patients with schizophrenia (Bitter et al. Neuropsychopharmacology 44(11):1917-1924, 2019). OBJECTIVE: This open-label study in healthy male subjects aimed at characterizing F17464 binding to D3/D2 receptors and the time course of receptor occupancy using positron emission tomography (PET) imaging with a D3-preferring tracer, [11C]-(+)-PHNO. METHODS: PET scans were performed at baseline and following a single 30 mg or 15 mg dose of F17464 (3 subjects/dose), and blood samples were collected for pharmacokinetic analysis. Receptor occupancy was calculated based upon reduction in binding potential of the tracer following F17464 administration. The relationship between plasma F17464 concentration and D3/D2 receptor occupancy was modeled and the plasma concentration corresponding to 50% receptor occupancy (EC50) calculated. RESULTS: Both doses of F17464 robustly blocked [11C]-(+)-PHNO D3 receptor binding, with substantial occupancy from 1 h post-administration, which increased at 6-9 h (89-98% and 79-87% for the 30 mg and 15 mg groups, respectively) and remained detectable at 22 h. In contrast, D2 binding was only modestly blocked at all time points (< 18%). F17464 exhibited a combination of rapid peripheral kinetics and hysteresis (persistence of binding 22 h post-dose despite low plasma concentration). The best estimate of the EC50 was 19 ng ml-1 (~ 40 nM). CONCLUSION: Overall, F17464 was strongly D3-selective in healthy volunteers, a unique profile for an antipsychotic candidate drug.

Randomized, double-blind, placebo-controlled study of F17464, a preferential D3 antagonist, in the treatment of acute exacerbation of schizophrenia.

F17464, a highly potent preferential D3 antagonist, is a novel compound in development for schizophrenia treatment. This phase II, double-blind, randomized, placebo-controlled, parallel-group study in five European countries evaluated the efficacy and safety of F17464, 20 mg twice daily, versus placebo over 6 weeks in patients with acute exacerbation of schizophrenia. Change from baseline to Day 43 of the Positive and Negative Syndrome Scale (PANSS) total score was the primary outcome. The data from 134 randomized patients (67 per group) were analyzed (efficacy/safety). Using analysis of covariance (ANCOVA) after last observation carried forward (LOCF) imputation (primary analysis), the PANSS total score reduction was statistically significantly greater for F17464 than placebo treated subjects at endpoint (p = 0.014); using ANCOVA with Multiple Imputation (MI) method, the between-group difference was in favor of F17464 but did not reach statistical significance. Differences in PANSS positive and general psychopathology subscale score, Marder positive factor score, PANSS response, and PANSS resolution criteria were also statistically significant in favor of F17464 (p values < 0.05) using the LOCF method, with similar results as for the primary analysis using the MI method. Treatment-related adverse events (AEs) were reported in 49.3% and 46.3% of patients on F17464 and placebo, respectively. The most common AEs in F17464 group: insomnia, agitation, and increased triglycerides; worsening of schizophrenia/drug ineffective was less frequent in F17464. Interestingly, no weight gain, no extrapyramidal disorder except rare akathisia were observed under F17464. This 6-week trial demonstrated therapeutic efficacy of 40 mg/day F17464 in improving symptoms of acute exacerbation of schizophrenia with a favorable safety profile.

Efficacy and safety of a new 5% minoxidil formulation in male androgenetic alopecia: A randomized, placebo-controlled, double-blind, noninferiority study.

BACKGROUND: Androgenetic alopecia (AGA) is the most common cause of hair loss in men. Topical minoxidil solutions can help to treat AGA but have to be applied continuously to be effective. OBJECTIVES: A new minoxidil formulation with improved cosmetic characteristics (DC0120, Pierre-Fabre Dermatologie) was tested for noninferiority vs a comparator minoxidil product (ALOSTIL® , Johnson & Johnson) in stimulating hair growth in men with AGA. METHODS: Two 10 cm2 areas on the scalp of each subject were randomized to receive DC0120, the comparator, or one of their corresponding vehicles, applied twice per day for 16 weeks. Nonvellus target area hair count (TAHC) was measured within treatment areas at baseline (day 1) and after 8 and 16 weeks by digital phototrichogram. RESULTS: Two hundred and twenty subjects were included and randomized, of which 210 completed the study. The mean change in nonvellus TAHC between baseline and week 16 was +22.0 hairs/cm2 (95% CI: 18.1; 25.9) in the DC0120 group and +20.5 hairs/cm2 (95% CI: 16.6; 24.4) in the comparator group. The adjusted mean difference in TAHC changes between the two treatments was +1.5 hairs/cm2 (95% CI -2.3; 5.2), with the lower 95% confidence interval above the noninferiority threshold of -7 hairs/cm2 . This indicated that DC0120 was noninferior to the comparator. Both minoxidil treatments also increased nonvellus TAHC compared to vehicle groups at 8 and 16 weeks. No new safety signals were observed. CONCLUSIONS: DC0120 was as safe and effective as a similar marketed minoxidil product for stimulating hair growth in men with AGA.

Randomized trial of the efficacy and safety of a new oral spray for drug-induced xerostomia.

The aim of this study was to evaluate the efficacy, safety, and tolerability of three formulations of DC161 oral spray, a saliva substitute, and a comparator in relieving drug-induced xerostomia. This was an open-label, randomized, 4-period, cross-over study in adult subjects with drug-induced xerostomia and documented hyposalivation. During each of the four 1-day periods, one product (one of three DC161 formulations or the comparator) was applied at T0 and then at T4h (before a meal). Mouth dryness and related symptoms were evaluated by the subject on a 100-mm visual analog scale. The primary efficacy criterion was the area under the curve of the dry mouth evaluation (baseline to T4h) after the first application. The oral mucosa was examined by a dental specialist; tolerability and product acceptability were assessed by the subject. Twenty-four subjects were randomized and completed the study. Despite large variability in data among the products, the selected aqueous formulation - DC161-DP0292 - reduced the intensity of dryness of mouth at least as well as the comparator; DC161-DP0292 provided a fast relief and a long-lasting effect on mouth dryness. Both products improved other symptoms such as swallowing and speaking, even when applied just prior to a meal. DC161-DP0292 was well tolerated and rated by subjects as providing a slightly higher acceptability of taste/aftertaste, texture, and lubricating effect than the comparator. No clinically relevant signs were reported for any product following the oral examination. DC161-DP0292 provides fast and long-acting symptomatic relief and is a relevant new treatment for drug-induced xerostomia.

Adjunctive levetiracetam in children, adolescents, and adults with primary generalized seizures: open-label, noncomparative, multicenter, long-term follow-up study.

PURPOSE: To evaluate the long-term efficacy and tolerability of adjunctive levetiracetam (LEV) in patients with uncontrolled idiopathic generalized epilepsy (IGE). METHODS: This phase III, open-label, long-term, follow-up study (N167; NCT00150748) enrolled patients (4 to <65 years) with primary generalized seizures (tonic-clonic, myoclonic, absence). Patients received adjunctive LEV at individualized doses (1,000-4,000 mg/day; 20-80 mg/kg/day for children/adolescents weighing <50 kg). Efficacy results are reported for all seizure types [intention-to-treat (ITT) population, N = 217] and subpopulations with tonic-clonic (n = 152), myoclonic (n = 121), and/or absence (n = 70) seizures at baseline. KEY FINDINGS: One hundred twenty-five (57.6%) of 217 patients were still receiving treatment at the end of the study. Mean (standard deviation, SD) LEV dose was 2,917.5 (562.9) mg/day. Median (Q1-Q3) exposure to LEV was 2.1 (1.5-2.8) years, and the maximum duration was 4.6 years. Most patients were taking one (124/217, 57.1%) or ≥2 (92/217, 42.4%) concomitant antiepileptic drugs (AEDs). Seizure freedom of ≥6 months (all seizure types; primary efficacy end point) was achieved by 122 (56.2%) of 217 patients, and 49 (22.6%) of 217 patients had complete seizure freedom. Seizure freedom of ≥6 months from tonic-clonic, myoclonic, and absence seizures was achieved by 95 (62.5%) of 152, 75 (62.0%) of 121, and 44 (62.9%) of 70 patients, respectively. Mean (SD) maximum seizure freedom duration was 371.7 (352.4) days. At least one treatment-emergent adverse event (TEAE) was reported by 165 (76%) of 217 patients; most TEAEs were mild/moderate in severity, with no indication of an increased incidence over time. Seventeen (7.8%) of 217 patients discontinued medication because of TEAEs. The most common psychiatric TEAEs were depression (16/217, 7.4%), insomnia (9/217, 4.1%), nervousness (8/217, 3.7%), and anxiety (7/217, 3.2%). SIGNIFICANCE: Adjunctive LEV (range 1,000-4,000 mg/day) demonstrated efficacy as a long-term treatment for primary generalized seizures in children, adolescents, and adults with IGE, and was well tolerated.

Efficacy and safety of levetiracetam as adjunctive therapy in adult patients with uncontrolled partial epilepsy: the Asia SKATE II Study.

This study evaluated the safety and efficacy of levetiracetam as adjunctive therapy for partial seizures in everyday clinical practice in Asian populations. Patients aged > or =16 years (N=251) with inadequately controlled partial epilepsy were recruited from 29 centers across Asia. Levetiracetam was added to existing antiepileptic medication for 16 weeks at a starting dose of 500 or 1000 mg/day and titrated to a maximum of 3000 mg/day according to clinical response. The study completion rate was 86.9%. Adverse events were reported by 73.3% of patients and were generally mild, leading to treatment withdrawal in only 7.2%. The most common adverse events were somnolence (30.3%) and dizziness (14.7%). Compared with pretreatment baseline, 44.0% of patients had a > or =50% reduction in seizure frequency, with a median reduction of 46.4%, and 17.7% became seizure free during the treatment period. Levetiracetam was well tolerated and efficacious as adjunctive therapy for partial epilepsy in clinical practice among Asian populations.

Clinical pharmacology of levetiracetam for the treatment of epilepsy.

Levetiracetam is an antiepileptic drug that is mainly indicated for the adjunctive treatment of partial-onset seizures in adults and children and of myoclonic and primary generalized tonic-clonic seizures in patients with idiopathic generalized epilepsy. In Europe, levetiracetam is also indicated as monotherapy for partial-onset seizures in patients with newly diagnosed epilepsy. Synaptic vesicle protein 2A is the primary molecular target for its anticonvulsive effect but additional mechanisms may also contribute. Recent clinical and pharmacokinetic developments for levetiracetam are reviewed in specific populations, including the effects of age, pregnancy, birth and lactation, pediatric development, and ethnic origin. The population pharmacokinetics of levetiracetam and drug-drug interactions have been explored across large adult and pediatric populations. The exposure-response relationship has also been characterized in adults and children through nonlinear mixed-effects modeling. Finally, new formulations including intravenous infusion and extended-release once-daily tablets have been compared with immediate-release tablets and oral solution, and can be used interchangeably.

Efficacy and safety of levetiracetam as adjunctive treatment of refractory partial seizures in a multicentre open-label single-arm trial in Korean patients.

This prospective, open-label study evaluated the efficacy and safety of adjunctive levetiracetam (LEV) in Korean adults with uncontrolled partial epilepsy. Study patients had to have an average of at least 1 and not more than 14 partial seizures per month (averaged over a 3-month historical baseline) despite the use of one or two AEDs. Patients initially received LEV 1000 mg/day (administered bid) and could increase to 2000 mg/day after 2 weeks, and to 3000 mg/day after another 2 weeks, to obtain adequate seizure control. During the 12-week maintenance period, the dose of LEV could be increased or decreased once if seizure control was insufficient or tolerability warranted, respectively. Seizure count and adverse events (AEs) were recorded by patients. Global evaluation scale (GES) and quality of life (QOLIE-31) were also evaluated. A total of 100 patients were enrolled and 92 patients completed the study. The median percent reduction in weekly seizure frequency over the treatment period was 43.2%. The >or=50% and >or=75% responder rates were 45.4% and 36.1%, respectively. Seizure freedom throughout the 16-week treatment period was observed in 17 patients. On investigator's GES, 81 patients were considered improved, with 41 patients showing marked improvement. Most QOLIE-31 scales improved significantly. Treatment-emergent AEs were reported in 59 patients. Three most common AEs were somnolence (36%), dizziness (12%), and headache (8%). Adjunctive LEV therapy was effective and well-tolerated in Korean adults with refractory partial epilepsy.