Parental acceptance of brain health programs for preschool children: a mixed-methods study exploring barriers, facilitators and future approaches.

Background: Recent research proposes that as much as 40% of dementia risk is amendable. Promoting healthy lifestyle behaviors in early life through educational methods can cultivate habits that may decrease dementia risk in later life. This study explores parental acceptance of brain health programs tailored for preschool children, aiming to identify barriers and facilitators affecting parental and child engagement. Methods: Mixed-methods cross-sectional study. Urban and suburban parents (N = 187, M age = 37.3 SD = 5.53, range = 29) of children aged three to five years across Australia. Parents participated in an online survey containing both open and closed questions exploring their personal views and opinions on brain health programs for their preschool children. Descriptive statistics, multiple linear regression analyses, and thematic analysis were used to explore sociodemographic factors associated with parental program acceptance. Results: Most participants accepted a brain health program with over 98% agreeing a program would be useful for their child(ren). Participants with younger aged children were more likely to exhibit acceptance of a program (ß = -0.209, p = 0.007). Three main categories emerged: dual home and preschool environments, the need for engaging brain health programs that were hands-on and screen-free, and addressing key barriers such as time and financial constraints to support implementation. Conclusion: Participants valued educating their children for a healthy life and viewed brain health programs favorably. This study contributes to early childhood education discussions, offering guidance for future generations' brain health and wellbeing.

Adjunctive Brexpiprazole for Patient Life Engagement in Major Depressive Disorder: A Canadian, Phase 4, Open-Label, Interventional Study: Brexpiprazole d'appoint pour l'engagement dans la vie des patients souffrant de trouble dépressif majeur: une étude interventionnelle canadienne ouverte de phase 4.

OBJECTIVES: To characterize the effects of adjunctive brexpiprazole on patient life engagement and depressive symptoms in patients with major depressive disorder (MDD) using patient-reported outcomes. METHODS: An 8-week, Phase 4, open-label, interventional study was conducted at 15 Canadian trial sites between April 2021 and May 2022. Adult outpatients with MDD (at least moderately severe) and inadequate response to 1-2 antidepressants continued their current antidepressant and received oral adjunctive brexpiprazole 0.5-2 mg/day. Co-primary endpoints were change from baseline to Week 8 in Inventory of Depressive Symptomatology Self-Report (IDS-SR) 10-item Life Engagement subscale score, and IDS-SR 30-item total score. Safety was assessed by standard variables. RESULTS: Of 122 enrolled patients, 120 (98.4%) were treated (mean [SD] dose: 1.2 [0.4] mg/day) and analyzed, and 111 (91.0%) completed the study. Statistically significant least squares mean improvements to Week 8 were observed on IDS-SR10 Life Engagement subscale score (baseline mean [SD]: 16.1 [4.7]; change [95% confidence interval]: -8.11 [-9.34, -6.88]; p < 0.001) and IDS-SR total score (baseline mean [SD]: 41.3 [9.8]; change [95% confidence interval]: -17.38 [-20.08, -14.68]; p < 0.001). Improvements were observed from Week 2, onwards. Treatment-emergent adverse events with incidence ≥5% were fatigue (n = 13, 10.8%), headache (n = 13, 10.8%), insomnia (n = 12, 10.0%), nausea (n = 9, 7.5%), tremor (n = 8, 6.7%), and weight increase (n = 7, 5.8%). Six patients (5.0%) discontinued due to adverse events. Mean (SD) change in body weight from baseline to last visit was +1.9 (3.4) kg. CONCLUSIONS: Using an exploratory patient-reported outcome measure, patients with MDD and inadequate response to antidepressants who received open-label adjunctive brexpiprazole showed early and clinically meaningful improvement in patient life engagement, which should be further assessed in a prospective randomized controlled trial. Patient-rated depressive symptoms (on the validated 30-item IDS-SR) also improved. Adjunctive brexpiprazole was well tolerated, and no new safety signals were observed. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04830215.

Effects of Adjunctive Brexpiprazole on Individual Depressive Symptoms and Functioning in Patients With Major Depressive Disorder and Anxious Distress: Post Hoc Analysis of Three Placebo-Controlled Studies.

PURPOSE/BACKGROUND: Anxiety symptoms in major depressive disorder (MDD) are frequent, and they decrease response to antidepressant treatment (ADT), and affect patient functioning. This post hoc analysis examined the efficacy of adjunctive brexpiprazole on individual depressive symptoms and functioning in patients with MDD with anxious distress. METHODS/PROCEDURES: Data were included from three 6-week, randomized, double-blind, placebo-controlled studies of adjunctive brexpiprazole in patients with MDD and inadequate response to ADTs (ClinicalTrials.gov identifiers: NCT01360645, NCT01360632, NCT02196506). Patients were stratified using proxy criteria for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, anxious distress. Changes in Montgomery-Åsberg Depression Rating Scale item scores and Sheehan Disability Scale mean score from baseline to week 6 were determined for ADT + brexpiprazole (2 and 2-3 mg) versus ADT + placebo. FINDINGS/RESULTS: At baseline, 450 of 746 patients (60.3%, 2 mg analysis) and 670 of 1162 patients (57.7%, 2-3 mg analysis) had anxious distress. In patients with anxious distress, ADT + brexpiprazole 2 mg or 2 to 3 mg showed greater improvements than ADT + placebo (P < 0.05) on the Montgomery-Åsberg Depression Rating Scale items of apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, lassitude, inability to feel, and pessimistic thoughts (Cohen d effect sizes, 0.18-0.44), and on Sheehan Disability Scale mean score (effect sizes, 0.21-0.23). IMPLICATIONS/CONCLUSIONS: Adjunctive brexpiprazole is efficacious in reducing core depressive symptoms, sleep, and appetite, as well as improving functioning, in patients with MDD and anxious distress who have inadequate response to ADTs.

Effects of adjunctive brexpiprazole on patient life engagement in major depressive disorder: Post hoc analysis of Inventory of Depressive Symptomatology Self-Report data.

BACKGROUND: Patient-reported outcomes can capture domains that are meaningful to patients, such as life engagement in major depressive disorder (MDD), which reflects life fulfillment, well-being, and participation in valued and meaningful activities. This analysis investigated the effects of brexpiprazole adjunct to antidepressant treatment (ADT) on patient life engagement over the short and long term, using the 10-item Inventory of Depressive Symptomatology Self-Report (IDS-SR10) Life Engagement subscale. METHODS: Short-term data were pooled from three 6-week, randomized, double-blind studies of ADT + brexpiprazole 2-3 mg/day versus ADT + placebo in adult outpatients with MDD (DSM-IV-TR criteria) and inadequate response to ADTs. Long-term data were from a 26-52-week, open-label extension study of ADT + brexpiprazole 0.5-3 mg/day. RESULTS: Over 6 weeks, ADT + brexpiprazole (n = 579) showed greater improvement in IDS-SR10 Life Engagement subscale score than ADT + placebo (n = 583), with a least squares mean difference of -1.19 (95% confidence limits: -1.78, -0.59; p = 0.0001; Cohen's d effect size: 0.23). Greater improvement for ADT + brexpiprazole versus ADT + placebo (p < 0.05) was also observed on eight life engagement items, with effect sizes ranging from 0.12 to 0.24. In the long-term study, mean (standard deviation) IDS-SR10 Life Engagement subscale score changed by -2.4 (4.9) points to Week 26 (n = 2047), and -3.7 (5.3) points to Week 52 (n = 768), with mean improvements on all ten items. CONCLUSIONS: Beyond its efficacy on depressive symptoms, adjunctive brexpiprazole may improve patient life engagement, thereby helping patients with MDD to achieve personally meaningful functional outcomes.

Online support seeking, co-rumination, and mental health in adolescent girls.

Introduction: Adolescents frequently use informal support seeking to cope with stress and worries. Past research in face-to-face contexts has shown that the relationship between informal support seeking and mental health is influenced by the specific strategy used and the mode through which support is sought. To date, little research has considered the relationship between support seeking online and adolescent mental health. Methods: In this study, structural equation modeling (SEM) examined the mediating role of co-rumination in the relationships between seeking support from friends or online and two measures of mental health: depression and anxiety. Participants were 186 adolescent girls, drawn from four independent girls' schools in Sydney, Australia. Four brief vignettes described common social stressors and participants rated their likelihood of seeking support from close friends and from informal online sources. Co-rumination was measured using a short form of the Co-rumination Questionnaire and depression and anxiety were measured with the youth version of the Depression, Anxiety, and Stress Scale-Youth (DASS-Y). Results: Different patterns of findings were found for support seeking from close friends and support seeking online. First, support seeking from friends was related to lower levels of depression and anxiety while seeking support online was related to higher levels depression and anxiety. Second, co-rumination suppressed the relationship between seeking support from friends and depression, but not online support seeking and depression or anxiety. Discussion: These findings suggest that co-rumination reduces the benefits of seeking support from friends but is unrelated to online support seeking. The findings also confirm the problematic nature of online support seeking for adolescent girls' mental health, particularly in response to social stressors.

Exploring life engagement from the perspective of patients with major depressive disorder: a study using patient interviews.

BACKGROUND: Patient-reported outcomes can measure health aspects that are meaningful to patients, such as 'life engagement' in major depressive disorder (MDD). Expert psychiatrists recently identified ten items from the Inventory of Depressive Symptomatology Self-Report (IDS-SR) that can be used to measure patient life engagement. This study aimed to explore the concept of patient life engagement and provide support for the IDS-SR10 Life Engagement subscale from the patient perspective. METHODS: Semi-structured video interviews were conducted with adults with MDD in the United States. Patients were asked if they ever felt engaged with life, and how this affected their feelings, activities, socializing, and thoughts. Then, patients discussed the ten expert-selected IDS-SR items, and rated the relevance of all 30 items to patient life engagement on a 4-point scale. RESULTS: Patients (N = 20) understood the 'engaged with life' concept and could provide examples from their own lives, such as increased energy/motivation (100%), being more social/spending time with others (85%), being more communicative (80%), and having better mood (75%). Nineteen patients (95%) indicated that all ten IDS-SR10 Life Engagement items were relevant to patient life engagement, and nine of the ten items had a mean score ≥ 3 (moderately relevant). Four additional items (all relating to mood) also scored ≥ 3. CONCLUSIONS: Patients found the concept of life engagement to be important and relatable, and confirmed the IDS-SR10 captures the defining non-mood-related aspects of patient life engagement. This research supports the relevance of patient life engagement as a potential clinical outcome beyond core mood symptoms, and the use of the IDS-SR10 Life Engagement subscale in patient-oriented research.

Efficacy of adjunctive brexpiprazole on symptom clusters of major depressive disorder: A post hoc analysis of four clinical studies.

BACKGROUND: Major depressive disorder (MDD) is a clinically heterogenous condition and its treatment should be individualized according to the presence of particular symptom clusters. The aim of this pooled analysis was to investigate the effects of adjunctive brexpiprazole on different symptom clusters in MDD. METHODS: Data were included from four similarly designed, short-term, randomized, double-blind, placebo-controlled studies of adjunctive brexpiprazole in adults with MDD and inadequate response to 2-4 antidepressant treatments (ADTs), including 1 administered by investigators. Mean changes from baseline and Cohen's d effect sizes (ES) versus placebo were determined for the following Montgomery-Åsberg Depression Rating Scale symptom clusters: core, anhedonia, dysphoria, retardation, vegetative, loss of interest, and lassitude. RESULTS: Over 6 weeks, ADT + brexpiprazole 2 mg (n = 486) showed greater improvement than ADT + placebo (n = 585) for all symptom clusters: core (ES = 0.36; p < 0.0001), anhedonia (ES = 0.43; p < 0.0001), dysphoria (ES = 0.27; p < 0.0001), retardation (ES = 0.32; p < 0.0001), vegetative (ES = 0.29; p < 0.0001), loss of interest (ES = 0.30; p < 0.0001), and lassitude (ES = 0.33; p < 0.0001). Improvements of similar magnitude were observed for ADT + brexpiprazole 2-3 mg (n = 770) versus ADT + placebo (n = 788) (ES = 0.24-0.38; all clusters p < 0.0001). In most cases, improvement over ADT + placebo was observed from Week 1 onwards. LIMITATIONS: Post hoc analysis with no adjunctive active comparator. CONCLUSIONS: Patients receiving adjunctive brexpiprazole versus adjunctive placebo showed improvements across a range of MDD symptom clusters. Improvements appeared early (generally from Week 1) and were maintained over 6 weeks. These data indicate that adjunctive brexpiprazole may benefit multiple subtypes of patient with MDD and inadequate response to ADTs.

What Drives Quality Physical Education? A Systematic Review and Meta-Analysis of Learning and Development Effects From Physical Education-Based Interventions.

Objective: To determine the effects of learning interventions aimed at optimizing the quality of physical education (PE) on psychomotor, cognitive, affective and social learning outcomes in children and adolescents. Design: A systematic review and meta-analysis. Data Sources: After searching PsycInfo, ERIC, and SportDiscus electronic databases, we identified 135 eligible studies published between January 1, 1995 to May 1, 2021. Eligibility Criteria for Selecting Studies: We included randomized controlled trials, quasi-experimental studies, and controlled trials that assessed the effect of a PE-based intervention against one of the four identified learning domains in youth at school (aged 5-18 years). Results: One hundred and thirty five (135) studies with over 42,500 participants and 193 calculated effect sizes were included in the study. The mean effect across all the learning and development outcomes was small to medium (Cohen's d = 0.32, 95% confidence interval [CI] (0.27-0.37). When adjusted for publication bias using the Duval and Tweedie Trim and Fill Method, this mean effect size increased to d = 0.40 (CI = 0.34-0.46). Effect sizes varied significantly based on learning and development outcomes. Interventions that consistently report above or below the mean d = 0.40 effect are identified based on learning outcome. The greatest effects across interventions were witnessed in psychomotor learning outcomes (d = 0.52) followed by affective (d = 0.47), social (d = 0.32), and cognitive (d = 0.17) learning outcomes. A minority (<10%) of PE interventions captured by this systematic review and meta-analysis reported having a negative effect on student learning and development. Conclusion: The interventions with the greatest effects on student learning and development were dependant on the learning domains. Some PE interventions with a pedagogical focus such as games-based approaches, TARGET/Mastery Teaching, and Sport Education were found to be strong investments across multiple domains. The evidence is limited however by consistency in intervention dosage, study design, and data collection instruments. The study received no internal or external funding and was not prospectively registered.

Normal development in Xenopus laevis: A complementary staging table for the skull based on cartilage and bone.

BACKGROUND: Xenopus laevis is a widely used model organism in the fields of genetics and development, and more recently evolution. At present, the most widely used staging table for X. laevis is based primarily on external features and does not describe the corresponding skull development in detail. Here, we describe skull development in X. laevis, complete with labeled figures, for each relevant stage in the most widely used staging table. RESULTS: We find skull development in X. laevis is, for the most part, distinct at each of the previously established stages based on external anatomy. However, variation does exist in the timing of onset of ossification of certain bones in the skull, which results in a range of stages where a skull element first ossifies. The overall sequence of ossification is less variable than the timing of ossification onset. CONCLUSIONS: While events in skull development vary somewhat between specimens, and in comparison, to external events, this staging table is useful in showing both when bones first appear and for documenting the range of temporal variance in X. laevis skull development more accurately than previously done. Furthermore, when only skull data are available, the approximate stage of a specimen can now be determined.

Effects of Brexpiprazole on Functioning in Patients With Schizophrenia: Post Hoc Analysis of Short- and Long-Term Studies.

Objective: To evaluate the short- and long-term effects of brexpiprazole on patient functioning in schizophrenia.Methods: Data were included from three 6-week, randomized, double-blind, placebo-controlled studies (hospitalized patients); a 52-week, randomized, double-blind, placebo-controlled maintenance treatment study (terminated early by the study sponsor based on the positive result of an interim analysis); and two 52-week, open-label extension studies-all in patients with schizophrenia (DSM-IV-TR criteria) and conducted from July 2011-February 2016. Patients allocated to oral brexpiprazole received 2-4 mg/d (short-term studies) or 1-4 mg/d (long-term studies). Functioning was measured using the Personal and Social Performance (PSP) and Global Assessment of Functioning (GAF) scales, with response defined as a PSP/GAF increase of ≥ 10 points and remission as PSP score ≥ 71 or GAF score ≥ 61.Results: Patients receiving brexpiprazole (n = 831) showed greater improvement than those receiving placebo (n = 490) from baseline to week 6 in PSP score (least squares mean difference, 3.20; 95% confidence interval, 1.82-4.58; P < .0001; Cohen d = 0.31) and in all 4 PSP domains. At week 52 of the maintenance study (which had a low completion rate primarily due to the early termination), GAF functional remission was achieved by 65.3% (62/95) of stabilized patients randomized to brexpiprazole and 47.1% (48/102) of stabilized patients randomized to placebo, with a number needed to treat of 6 (95% confidence interval, 4-22; P = .0076). At week 52 of the open-label studies (n = 177), PSP functional response and remission were achieved by 84.2% and 41.8% of patients receiving brexpiprazole, respectively.Conclusions: Although limited by the lack of an active comparator, analyses of this large dataset demonstrate that brexpiprazole treatment is associated with clinically relevant improvement in functioning among patients with schizophrenia, in the short term and long term.Trial Registration: Data used in this post hoc analysis were from studies with ClinicalTrials.gov identifiers: NCT01396421, NCT01393613, NCT01810380, NCT01668797, NCT01397786, and NCT01810783.

Overview of the Neuroprotective Effects of the MAO-Inhibiting Antidepressant Phenelzine.

Phenelzine (PLZ) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. This multifaceted drug has a number of pharmacological and neurochemical effects in addition to inhibition of MAO, and findings on these effects have contributed to a body of evidence indicating that PLZ also has neuroprotective/neurorescue properties. These attributes are reviewed in this paper and include catabolism to the active metabolite ß-phenylethylidenehydrazine (PEH) and effects of PLZ and PEH on the GABA-glutamate balance in brain, sequestration of reactive aldehydes, and inhibition of primary amine oxidase. Also discussed are the encouraging findings of the effects of PLZ in animal models of stroke, spinal cord injury, traumatic brain injury, and multiple sclerosis, as well other actions such as reduction of nitrative stress, reduction of the effects of a toxin on dopaminergic neurons, potential anticonvulsant actions, and effects on brain-derived neurotrophic factor, neural cell adhesion molecules, an anti-apoptotic factor, and brain levels of ornithine and N-acetylamino acids.

The histology of sutures in chicken skulls: Types, conservation, and ontogeny.

Sutures are fibrous joints that occur between bone elements in vertebrate skulls, where they play a variety of roles including facilitating skull growth and function. In addition, a variety of studies examining sutures from diverse perspectives in many taxa have enabled the determination of anatomical homologs. Surprisingly, one important aspect of sutures-histology-remains unknown in the key model organism of the chicken. To fill this gap in our knowledge, we generated histological sections of six different cranial sutures across a range of developmental stages in embryonic chicken. Despite having a skull that is largely co-ossified or fused as an adult, we found that the types, components, and ontogeny of sutures in chicken skulls are very similar to sutures in other vertebrates. We did, however, find a new transient stage in the ontogeny of sutures between endochondral bone elements, in which one element has ossified and one was still cartilaginous. Moreover, to better understand the morphogenetic events at the onset of suture formation, we compared the developmental histology of six sutures with that of the space between the two ossification centers of the frontal-a location expected to be void of suture structures. We found that the mesenchymal cells in sutures condense and form a middle vascular layer. This was not found to be the case in the space between the two ossifications of the frontal, where instead only osteoid occurs.

Development of the chicken skull: A complement to the external staging table of Hamburger and Hamilton.

Embryonic staging tables provide a standard of developmental stages that can be used by individual investigators and provide approximate time points for the study of developmental phenomena. Surprisingly, despite the presence of a plethora of studies on the chicken skull and its role as a model species in developmental research, a staging table of the development of the chicken skull remains lacking. A detailed photographic staging table of the osseous portion of the chicken skull is thus presented here based on cleared and stained HH stages spanning HH 35 (first appearance of skull ossification) to the final stage before hatching (HH 45). This table documents the development of most of the cranial elements in the skull from the start of ossification until the element takes its final shape. The table shows that the elements of the lower jaw and ventral side of the skull begin ossifying before the skull roof and that most elements take roughly 5 days to reach their final shape, whereas others take up to 9 days (e.g., the frontal). The obtained results lead to several hypotheses about chicken skull development and provide a timeframe for future studies on chicken skull development.

Attenuation of the effects of oxidative stress by the MAO-inhibiting antidepressant and carbonyl scavenger phenelzine.

Phenelzine (ß-phenylethylhydrazine) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. It possesses a number of important pharmacological properties which may alter the effects of oxidative stress. After conducting a comprehensive literature search, the authors of this review paper aim to provide an overview and discussion of the mechanisms by which phenelzine may attenuate oxidative stress. It inhibits γ-aminobutyric acid (GABA) transaminase, resulting in elevated brain GABA levels, inhibits both MAO and primary amine oxidase and, due to its hydrazine-containing structure, reacts chemically to sequester a number of reactive aldehydes (e.g. acrolein and 4-hydroxy-2-nonenal) proposed to be implicated in oxidative stress in a number of neurodegenerative disorders. Phenelzine is unusual in that it is both an inhibitor of and a substrate for MAO, the latter action producing at least one active metabolite, ß-phenylethylidenehydrazine (PEH). This metabolite inhibits GABA transaminase, is a very weak inhibitor of MAO but a strong inhibitor of primary amine oxidase, and sequesters aldehydes. Phenelzine may ameliorate the effects of oxidative stress by reducing formation of reactive metabolites (aldehydes, hydrogen peroxide, ammonia/ammonia derivatives) produced by the interaction of MAO with biogenic amines, by sequestering various other reactive aldehydes and by inhibiting primary amine oxidase. In PC12 cells treated with the neurotoxin MPP+, phenelzine has been reported to reduce several adverse effects of MPP+. It has also been reported to reduce lipid peroxidative damage induced in plasma and platelet proteins by peroxynitrite. In animal models, phenelzine has a neuroprotective effect in global ischemia and in cortical impact traumatic brain injury. Recent studies reported in the literature on the possible involvement of acrolein in spinal cord injury and multiple sclerosis indicate that phenelzine can attenuate adverse effects of acrolein in these models. Results from studies in our laboratories on effects of phenelzine and PEH on primary amine oxidase (which catalyzes formation of toxic aldehydes and is overexpressed in Alzheimer's disease), on sequestration of the toxic aldehyde acrolein, and on reduction of acrolein-induced toxicity in mouse cortical neurons are also reported.

Inhibition of p53 attenuates ischemic stress-induced activation of astrocytes.

In cerebral ischemia, studies of cell death have focused primarily on neurons, but recent work indicates that ischemia also causes damage to astrocytes. Activation of astrocytes is a typical brain response to stress stimuli and is evidenced by changes in cellular function and morphology, as well as upregulation of glial fibrillary acidic protein. The tumor-suppressor transcription factor p53 has recently been implicated as a mediator of ischemia-induced neuronal death, but very little is known about its role in the activation or the death of astrocytes. The present study investigated the role of p53 in astrocyte and neuronal toxicity using in-vitro and in-vivo ischemic stroke models. We showed that p53 is activated in ischemic brains and in oxygen-glucose deprivation (OGD)-induced cell death in neurons and astrocytes. Inhibition of p53 activity using either pifithrin-α or small interference RNA interference reduced OGD-induced cell death and pifithrin-α reversed OGD-induced impairment of glutamate uptake in astrocytes, suggesting that p53 might play a key role in mediating neurotoxicity and gliotoxicity in ischemic brain injury. This study shows that p53 is activated in astrocytes during ischemia and that inhibition of the activity of this molecule prevents not only OGD-induced neuronal and astrocytic death but also astrocyte activation and impaired glutamate uptake. These findings suggest that p53 may be a valuable therapeutic target in ischemic brain injury.

Comparison of phenelzine and geometric isomers of its active metabolite, ß-phenylethylidenehydrazine, on rat brain levels of amino acids, biogenic amine neurotransmitters and methylamine.

Phenelzine is a monoamine oxidase (MAO) inhibitor used in treatment of depression and anxiety disorders. It also elevates brain levels of γ-aminobutyric acid (GABA) and inhibits primary amine oxidase (PrAO), an enzyme whose activity and/or expression has been reported to be increased in diabetes mellitus, Alzheimer's disease and cardiovascular disorders. Phenelzine is not only an inhibitor of, but also a substrate for, MAO and it has been suggested that an active metabolite, namely ß-phenylethylidenehydrazine (PEH), is responsible for phenelzine's effects on amino acids. PEH is also a strong inhibitor of PrAO but has weak effects on MAO. PEH has a double bond and can thus exist as (E)- and (Z)-geometric isomers, but to date the two isomers have not been compared with regard to their neurochemical effects. We have investigated the effects of phenelzine, (E)- and (Z)-PEH on rat whole brain levels of amino acids, biogenic amine neurotransmitters and methylamine (an endogenous substrate of PrAO). Under the conditions used in the study, (E)- and (Z)-PEH appear to be equivalent in their neurochemical properties. Both PEH isomers and phenelzine produced marked increases in rat brain levels of GABA and alanine while decreasing brain levels of glutamine. Phenelzine increased brain levels of biogenic amine neurotransmitters (noradrenaline, dopamine and serotonin), whereas neither PEH isomer altered levels of these neurotransmitters to a considerable extent. All three drugs significantly increased rat brain levels of methylamine, with (E)- and (Z)-PEH causing a greater increase than phenelzine. These results are discussed in relation to the possible therapeutic applications of these drugs.

An update on amine oxidase inhibitors: multifaceted drugs.

Although not used as extensively as other antidepressants for the treatment of depression, the monoamine oxidase (MAO) inhibitors continue to hold a niche in psychiatry and to have a relatively broad spectrum with regard to treatment of psychiatric and neurological disorders. Experimental and clinical research on MAO inhibitors has been expanding in the past few years, primarily because of exciting findings indicating that these drugs have neuroprotective properties (often independently of their ability to inhibit MAO). The non-selective and irreversible MAO inhibitors tranylcypromine (TCP) and phenelzine (PLZ) have demonstrated neuroprotective properties in numerous studies targeting elements of apoptotic cascades and neurogenesis. l-Deprenyl and rasagiline, both selective MAO-B inhibitors, are used in the management of Parkinson's disease, but these drugs may be useful in the treatment of other neurodegenerative disorders given that they demonstrate neuroprotective/neurorescue properties in a wide variety of models in vitro and in vivo. Although the focus of studies on the involvement of MAO inhibitors in neuroprotection has been on MAO-B inhibitors, there is a growing body of evidence demonstrating that MAO-A inhibitors may also have neuroprotective properties. In addition to MAO inhibition, PLZ also inhibits primary amine oxidase (PrAO), an enzyme implicated in the etiology of Alzheimer's disease, diabetes and cardiovascular disease. These multifaceted aspects of amine oxidase inhibitors and some of their metabolites are reviewed herein.

The pharmacology and formulation of paliperidone extended release.

Paliperidone, or 9-hydroxyrisperidone (Invega(®), Janssen, Antwerp, Belgium) is the major active metabolite of the atypical antipsychotic risperidone (Risperdal(®), Janssen). It possesses a similar, though not identical, receptor pharmacology to the parent molecule. There are additional differences in terms of its predominant renal metabolism, lower protein binding and decreased inhibition of P-glycoprotein leading to decreased potential for drug-drug interactions. Paliperidone is approved as an extended release (ER) tablet based on an osmotic-controlled release oral Push-Pull™ delivery system (Oral Osmotic System, OROS(®), Alza Corporation) for the treatment of schizophrenia. The ER formulation results in decreased fluctuations in plasma drug levels and allows for once-daily administration with initial tolerability that permits treatment initiation at a clinically effective dose without the need for titration. This achieves therapeutic levels rapidly and simplifies dosing regimens, leading to potentially better adherence and improved outcome. The present review focuses on the clinical implications of the pharmacology and formulation of paliperidone ER.

Monoamine oxidase inhibitors and neuroprotection: a review.

Monoamine oxidase inhibitors have been available for more than 50 years, initially developed as antidepressants but currently used in a variety of psychiatric and neurological conditions. There has been a recent surge of interest in monoamine oxidase inhibitors because of their reported neuroprotective and/or neurorescue properties. Interestingly, it seems that often these properties are independent of their ability to inhibit monoamine oxidase. This review article presents an overview of the neuroprotective/neurorescue properties of these multifaceted drugs and focuses on phenelzine, (-)-deprenyl, rasagiline, ladostigil, tranylcypromine, moclobemide, and clorgyline and their possible neuroprotective mechanisms.

D-serine and schizophrenia: an update.

Considering the lengthy history of pharmacological treatment of schizophrenia, the development of novel antipsychotic agents targeting the glutamatergic system is relatively new. A glutamatergic deficit has been proposed to underlie many of the symptoms typically observed in schizophrenia, particularly the negative and cognitive symptoms (which are less likely to respond to current treatments). D-serine is an important coagonist of the glutamate NMDA receptor, and accumulating evidence suggests that D-serine levels and/or activity may be dysfunctional in schizophrenia and that facilitation of D-serine transmission could provide a significant therapeutic breakthrough, especially where conventional treatments have fallen short. A summary of the relevant animal data, as well as genetic studies and clinical trials examining D-serine as an adjunct to standard antipsychotic therapy, is provided in this article. Together, the evidence suggests that research on the next generation of antipsychotic agents should include studies on increasing brain levels of D-serine or mimicking its action on the NMDA receptor.