The effect of mirtazapine augmentation of clozapine in the treatment of negative symptoms of schizophrenia: a double-blind, placebo-controlled study

The development of therapeutic strategies to effectively treat negative symptoms remains one of the primary goals in the treatment of schizophrenia. Mirtazapine is the first of a new class of dual action compounds, the noradrenergic and specific serotonergic antidepressants (NaSSa), whose activity is related to the enhancement of noradrenergic and serotonergic transmission by a presynaptic alpha2 antagonism and postsynaptic 5-HT2 and 5-HT3 antagonism, respectively. This study was a 8-week double-blind, randomized, placebo-controlled trial of 30 mg adjunctive mirtazapine to clozapine therapy in 24 patients with DSM-IV schizophrenia. The main finding at the end of the trial was a significant reduction on the Scale for the Assessment of Negative Symptoms (SANS) total scores in the mirtazapine group compared to placebo (P<0.01) with a significant improvement on the SANS subscales avolition/apathy and anhedonia/asociality. The Brief Psychiatric Rating Scale total score at week 8 showed superiority of mirtazapine over placebo. These findings suggest a potential role for mirtazapine as an augmentation strategy in the treatment of negative symptoms of schizophrenia.     

Healthcare Workers’ (HCWs) attitudes towards mandatory influenza vaccination: A systematic review and meta-analysis

Influenza is a disease responsible for thousands of deaths every year. Although healthcare workers (HCWs) represent a way of contagion for patients, vaccination coverage among them is low. Mandatory vaccination has been proposed, but controversies remain. This systematic review and meta-analysis aimed to assess the acceptance of mandatory vaccination by HCWs, and to investigate associated characteristics. MEDLINE, Scopus, Embase, PsycInfo, CINAHL and Web of Science were used to search for studies assessing the topic. PRISMA statements were followed. Of the 13,457 univocal records found, 52 studies were included in the systematic review and 40 in the meta-analysis. The pooled proportion of HCWs accepting the policy was of 61% (95% CI: 53%- 68%) but with great heterogeneity between continents (from 54% in Europe to 69% in Asia) and in different professionals (from 40% in nurses to 80% in students). Vaccinated HCWs agreed more frequently with mandatory vaccination than non-vaccinated ones. More studies that consider mandatory vaccination acceptance as the main outcome are needed, but the results of this study confirm that in some settings the majority of HCWs favour mandatory vaccination. This, combined with effects that a flu epidemic could have if overlapped to pandemics with similar symptoms, requires renewed considerations on mandatory vaccination.     

Social Media and Mental Health Among Early Adolescents in Sweden: A Longitudinal Study With 2-Year Follow-Up (KUPOL Study)

PurposeThe aim of this study is to assess the longitudinal associations between the frequency of social media use and symptoms of mental ill-health among Swedish adolescents.MethodsData came from KUPOL, a Swedish school-based longitudinal cohort accrued in 101 participating schools in 8 regions of Sweden. The study sample consisted of 3,501 adolescents in grade 8 (14–15 years, 51.5%, n = 1,765 girls) followed for 2 consecutive years. Daily social media use was measured as weighted average of self-reported use in weekdays and weekend days. Mental health was measured with the Strength and Difficulties Questionnaire (SDQ). A Random-Intercept Cross-Lagged Panel Model was applied to distinguish between-person from within-person associations between social media use and symptoms of mental ill-health.ResultsMedian SDQ score at baseline was 9 (interquartile range [IQR] 6–14). Median social media use was 1.7 hours at baseline (interquartile range .6–3.0) and increased over the 3-year period. Adolescents with more social media use also reported higher SDQ scores, B (95% confidence interval [CI]) = 2.40 (2.03–2.77). On a within-person level, no cross-lagged associations were found between changes in social media use and subsequent changes in symptoms of mental ill-health after 1 year, B (95% CI) = .02 (?.12 to .16) or vice versa B (95% CI) = .00 (?.02 to .02). Weak cross-sectional associations were found between changes in social media use and concurrent changes in symptoms of mental ill-health, B (95% CI) = .24 (.00–.48).ConclusionsAdolescents with higher use of social media report more symptoms of mental health problems, but there is no evidence for a longitudinal association between increased use and mental health problems. This suggests that social media may be rather an indicator than a risk factor for symptoms of mental ill-health.     

2-[(4-phenylpiperazin-1-yl)methyl]imidazo(di)azines as selective D4-ligands. Induction of penile erection by 2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]imidazo[1,2-a]pyridine (PIP3EA), a potent and selective D4 partial agonist

A series of novel 2-[(4-phenylpiperazin-1-yl)methyl]imidazoazines and aza-analogues were prepared and screened at selected dopamine, serotonin, and adrenergic receptor subtypes. 2-Substituted imidazopyridines and pyridazines presented high affinities and selectivities for D4 dopamine receptors. Whereas functional experiments indicated neutral antagonists or weak partial agonist effects for most of the target compounds, the 2-methoxyphenyl substituted 2-piperazinylmethylimidazopyridine 3c (PIP3EA) displayed substantial agonist efficacy in mitogenesis experiments and GTPgammaS binding tests, resulting in EC50 values of 3.0 (46%) and 4.5 nM (57%), respectively. Our D4 agonist 3c induced penile erection in vivo when administered to rats. This effect was inhibited by L-745,870 a D4 selective antagonist, confirming the mechanistic pathway.     

The cannabinoid receptor antagonist SR-141716A induces penile erection in male rats: involvement of paraventricular glutamic acid and nitric oxide

The cannabinoid CB1 receptor antagonist SR141716A (0.5, 1 and 2 microg) induces penile erection when injected into the paraventricular nucleus of male rats. The pro-erectile effect of SR 141716A occurs concomitantly with an increase in the concentration of NO2- and NO3- in the paraventricular dialysate obtained by means of intracerebral microdialysis. Both penile erection and NO2- increase induced by SR 141716A were reduced by the prior injection into the PVN of the cannabinoid CB1 agonists WIN 55,212-2 (5 microg) or HU 210 (5 microg), given into the paraventricular nucleus at doses unable to induce penile erection or to modify NO2- concentration. SR 141716A responses were also reduced by nitro-L-arginine methylester (20 microg), a non-selective NO synthase inhibitor, S-methyl-L-thiocitrulline (20 microg), a selective neuronal NO synthase inhibitor, the excitatory amino acid NMDA receptor antagonist dizocilpine ((+)MK 801) (1 microg), or the GABAA receptor agonist muscimol (0.2 microg) injected into the PVN 15 min before SR 141716A. In contrast, the inducible NO synthase inhibitor L-N(6)-(1-iminoethyl)lysine (20 microg), the GABAB receptor agonist baclofen (0.2 microg), the mixed dopamine receptor antagonist cis-flupenthixol (10 microg), and the oxytocin receptor antagonist d(CH2)5Tyr(Me)-Orn8 -vasotocin (1 microg), were ineffective. Despite its inability to reduce penile erection and NO2- increase induced by SR 141716A when injected into the PVN, d(CH2)5Tyr(Me)-Orn8 -vasotocin (1 microg) reduced almost completely penile erection without reducing paraventricular NO2- increase when injected into the lateral ventricles 15 min before SR 141716A. The present results show that SR 141716 induces penile erection by a mechanism (possibly activation of excitatory amino acid neurotransmission), which causes the activation of neuronal NO synthase in paraventricular oxytocinergic neurons mediating penile erection.     

School and family participation in a longitudinal study of tobacco use: some methodological notes

School-based recruitment of youth for a research purpose is problematic, as one has to deal with multiple ethical and practical constraints. This study reports on predictors of schools' and families' participation in a longitudinal study of tobacco use among 11-year-old children. School size, but not tobacco policy, was linked to participation. High parental education and average social status in the residence area were associated with parental consent. Given the social background, prevalence of parental tobacco use was close to the expected. Compliance of responsible adults in youth research cannot be predicted on the basis of simple behavioural models.     

Identification of 5-arylidene-4-thiazolidinone derivatives endowed with dual activity as aldose reductase inhibitors and antioxidant agents for the treatment of diabetic complications

In continuing the search for more effective 5-arylidene-4-thiazolidinones as aldose reductase inhibitors, a new set of suitably substituted compounds (4, 5 and 8) was explored. Acetic acids 5, particularly 5a and 5h, proved to be interesting inhibitors of the enzyme as well as excellent antioxidant agents that are potentially able to counteract the oxidative stress associated with both diabetic complications as well as other pathologies. Molecular docking experiments supported SAR studies.     

Design and development of 2,3-benzodiazepine (CFM) noncompetitive AMPA receptor antagonists

2,3-Benzodiazepines represent a class of heterocyclic compounds that interact with AMPA-type glutamate receptors in a noncompetitive manner. These compounds have attracted great interest for their pharmacological effects against acute and chronic neurodegenerative diseases, such as ischemia and epilepsy. We synthesized a large number of 2,3-benzodiazepine derivatives, which showed anticonvulsant properties in different seizure models and a noncompetitive blockade of AMPA receptor. This article will briefly mention our work in this field and the main SAR considerations.     

Smooth blood pressure control obtained with extended-release felodipine in elderly patients with hypertension: evaluation by 24-hour ambulatory blood pressure monitoring

OBJECTIVE: To assess, by smoothness index (SI), distribution of the antihypertensive effect of extended-release (ER) felodipine over 24 hours in elderly patients with hypertension. METHODS: After a 4-week washout phase, 35 elderly patients (mean age 69 +/- 4 years) with mild-to-moderate hypertension received 2 weeks' treatment with ER felodipine 5mg once daily. The dosage of ER felodipine was doubled to 10 mg/day and given for a further 2 weeks in non-responders (sitting clinic blood pressure > 140/90mm Hg). The study had an open-label design with no placebo control. After each period, clinic and ambulatory blood pressures were measured. Trough-to-peak (T/P) ratio was computed by dividing the blood pressure (BP) change at trough (22 to 24 hours after drug intake) by the change at peak (2 adjacent hours with a maximal BP reduction between the second and eighth hour after drug intake). SI was calculated as the ratio between the average of the 24, hourly, treatment-induced BP changes and its standard deviation. RESULTS: After the initial 2-week treatment period, clinic and 24-hour ambulatory BP values were higher in non-responders (145 +/- 11/87 +/- 8 and 135 +/- 17/80 +/- 6mm Hg, respectively) than in responders (133 +/- 6/81 +/- 3 and 130 +/- 9/77 +/- 7mm Hg). In non-responders, clinic and 24-hour BP values were lowered after a further 2 weeks of treatment with ER felodipine 10 mg/day (128 +/- 11/78 +/- 6 and 128 +/- 12/75 +/- 5mm Hg). SI was high in responders (0.8 +/- 0.8/0.7 +/- 0.7 for systolic/diastolic BP) and low in non-responders (0.5 +/- 0.6/0.3 +/- 0.6) during the first 2-week treatment period. It increased in non-responders after an additional 2 weeks of treatment with ER felodipine 10 mg/day (1.0 +/- 0.8/0.7 +/- 0.6). Median T/P ratios were 0.73 and 0.61 (systolic BP and diastolic BP) in responders and 0.41 and 0.61 in non-responders after 2 weeks of treatment. At variance with SI, T/P ratios did not increase in non-responders after doubling the dosage of ER felodipine (0.34 and 0.18). ER felodipine did not increase 24-hour heart rate. A total of nine adverse events were recorded in six patients (17%), but no patients withdrew from the study. CONCLUSION: ER felodipine 5 to 10 mg/day smoothly and safely reduces 24-hour ambulatory BP in elderly patients with hypertension.