Are the cognitive effects of atypical antipsychotics influenced by their affinity to 5HT-2A receptors?

It is well documented that atypical antipsychotics have an influence on cognitive function in patients with schizophrenia, although the neurochemical basis for this effect is not well understood. One suggestion is that the effects are exerted through action on 5HT-2A receptors, which leads to changes in the level of dopamine in the prefrontal cortex. The following study explored this hypothesis by comparing the cognitive effects of the atypical antipsychotics which have a high affinity for 5HT-2A receptors, with those that have little or no affinity to these receptors. Forty-four patients with a DSM-IV diagnosis of schizophrenia were recruited within 6 weeks of starting one of the atypical antipsychotics: clozapine, olanzapine, risperidone, quetiapine, or amisulpride. The patients were divided into two groups according to the 5HT-2A affinity of the individual medications (high 5HT-2A affinity--clozapine, olanzapine, risperidone vs. low 5HT-2A affinity--quetiapine, amisulpride). Patients were tested on a broad range of neuropsychological measures after 9 months and 18 months of treatment. The high 5HT-2A affinity group showed a decrement in performance on tests of visual recognition memory and planning ability. In contrast, the low-5HT-2A affinity group showed improvements on these measures in addition to others. The 5HT-2A affinity of the atypical antipsychotics is an important determinant of their cognitive effects.     

What are the effects of prolonged seizures in the brain?

Convulsive status epilepticus is the most common neurological emergency in children and is associated with significant morbidity and mortality. The morbidities include later development of epilepsy, cognitive impairment, and psychiatric impairments. There has been a long‐standing hypothesis that these outcomes are, at least in part, a function of brain injury induced by the status epilepticus. There is evidence from animal models and prospective human studies that the hippocampus may be injured during febrile status epilepticus although this pathophysiological sequence remains uncommon. Potential mechanisms include excitotoxicity, ischaemia, and inflammation. Neuroprotective drugs reduce brain injury but have little impact on epileptogenesis or cognitive impairments. Anti‐inflammatory treatments have given mixed results to date. Broad‐spectrum anti‐inflammatory agents, such as steroids, are potentially harmful, whereas prevention of leucocyte diapedesis across the blood brain barrier appears to have a positive outcome. Therefore, more studies dissecting the inflammatory process are required to establish the most effective strategies for translation into clinical practice. In addition to neuronal loss, cognitive impairments are related to neuronal re‐organisation and disruption of neural networks underpinning cognition. Further understanding of these mechanisms may lead to novel therapies that prevent brain injury, but also therapies that may improve outcomes even if injury has occurred.     

Are the cognitive functions of children with Down syndrome related to their participation?

Aim  There is a lack of investigation into the functional developmental profile of children with Down syndrome. On the basis of current international health paradigms, the purpose of this study was to assess the developmental profile of these children.
Method  Sixty children (33 males, 27 females) with Down syndrome (age range 6–16y; mean age 9y 3mo, SD 28.8mo), who had received standard, holistic, early intervention, were assessed. Of these, 42 (70%) had congenital anomalies, 12 had severe congenital heart defects. Participants were assessed on measures of cognitive function (Beery–Buktenica Developmental Test of Visual–Motor Integration; Stanford–Binet Intelligence Scale) and participation (Vineland Adaptive Behaviour Scales).
Results  No difference was found on any measure on the basis of severity of congenital anomaly. Results showed improvements in age-related body function and correlations between specific body functions and participation. No decline in IQ was found with age, and significant correlations between IQ and all other measures were noted. Although sex differences were found in the body functions of short-term memory and motor function, no difference in measures of activity performance and participation was found.
Interpretation  Our findings emphasize the need for paediatric Down syndrome intervention to encourage improved body functions while emphasizing the acquisition of functional skills that enable enhanced participation in age-appropriate activities.     

Monoamine oxidase inhibitory activity in tobacco particulate matter: Are harman and norharman the only physiologically relevant inhibitors?

Monoamine oxidase inhibition is significant in smokers, but it is still unclear how the inhibition that is seen in the brains and bodies of smokers is brought about. Our aim was to test the contribution of the harman and norharman in tobacco smoke to MAO-A inhibition from tobacco smoke preparations, as part of a re-examination of harman and norharman as the cause of the inhibition of MAO-A inhibition in the brain.Tobacco smoke particulate matter and cigarette smoke particulate matter were prepared and the amounts of harman and norharman measured. The results were compared with the total monoamine oxidase-A inhibitory activity.At a nicotine concentration of 0.6 μM (a “physiological” concentration in blood) the total monoamine oxidase-A inhibitory activity measured in these samples was sufficient to inhibit the enzyme by approximately 10%. Of this inhibitory activity, only a small proportion of the total was found to be due to harman and norharman.These results show that harman and norharman provide only a moderate contribution to the total monoamine oxidase-A inhibitory activity of tobacco smoke, perhaps under 10%. This suggests that other inhibitors (either known or unknown) may be more significant contributors to total inhibitory activity than has yet been established, and deserve closer examination.     

It’s in the eye of the beholder: selective attention to drink properties during tasting influences brain activation in gustatory and reward regions

Statements regarding pleasantness, taste intensity or caloric content on a food label may influence the attention consumers pay to such characteristics during consumption. There is little research on the effects of selective attention on taste perception and associated brain activation in regular drinks. The aim of this study was to investigate the effect of selective attention on hedonics, intensity and caloric content on brain responses during tasting drinks. Using functional MRI brain responses of 27 women were measured while they paid attention to the intensity, pleasantness or caloric content of fruit juice, tomato juice and water. Brain activation during tasting largely overlapped between the three selective attention conditions and was found in the rolandic operculum, insula and overlying frontal operculum, striatum, amygdala, thalamus, anterior cingulate cortex and middle orbitofrontal cortex (OFC). Brain activation was higher during selective attention to taste intensity compared to calories in the right middle OFC and during selective attention to pleasantness compared to intensity in the right putamen, right ACC and bilateral middle insula. Intensity ratings correlated with brain activation during selective attention to taste intensity in the anterior insula and lateral OFC. Our data suggest that not only the anterior insula but also the middle and lateral OFC are involved in evaluating taste intensity. Furthermore, selective attention to pleasantness engaged regions associated with food reward. Overall, our results indicate that selective attention to food properties can alter the activation of gustatory and reward regions. This may underlie effects of food labels on the consumption experience of consumers.     

Is psychoanalytic theory relevant to the psychology of women?

This article reviews the literature addressing the relevance of psychoanalytic theory to the psychology of women and offers a possible rapprochement between these divergent perspectives. This rapprochement is accomplished first by defining "psychoanalytic theory" and "the psychology of women" in line with current scholarship, then by comparing and contrasting these definitions in an item-by-item analysis. The basic tenets of modern psychoanalytic theory emerge as highly relevant to the understanding of the psychology of women, despite the fact that particular "brands" of psychoanalytic theory may not demonstrate this same compatibility.     

Choice of endpoints in antiplatelet trials: which outcomes are most relevant to stroke patients?

The relative efficacies of different antiplatelet agents for stroke prevention are unclear because of differences in clinical trial design, a lack of direct comparisons between individual agents, and differences in the choice of primary endpoints. Individual endpoints in a clinical trial are often combined into a single primary endpoint cluster. Theoretically, a combined endpoint may reduce the sample size required to demonstrate significant benefits of an effective therapy. However, unless all components of a composite endpoint are affected in the same direction and to a similar degree, their inclusion may not provide the anticipated increase in statistical power. In fact, the use of a combined endpoint may lead to an underestimate of therapeutic benefits when patients at high risk for one particular endpoint are studied. For patients with stroke or TIA, the single outcome of stroke is particularly important because these patients have a higher risk of recurrent stroke than any other vascular outcome during the initial years after a stroke. Because of the low incidence of myocardial infarction (MI) in stroke trials, the inclusion of MI in the primary endpoint will usually have minimal influence on trial outcome, and antiplatelet therapy has not been shown to be beneficial in preventing nonvascular death. Chance variations in the incidence of MI or death may detract from the benefit of the agent for stroke prevention when it is included in a combined endpoint. The benefit of antiplatelet therapies for patients with recent cerebrovascular events is determined most accurately if stroke alone is chosen as the primary endpoint.     

Postnatal exposure to the β-adrenoceptor agonist clenbuterol has regionally selective direct and long-term effects on rat brain β-adrenoceptors and monoamine metabolism

The effects of chronic postnatal β₂-adrenoceptor activation on the maturation of the rat brain noradrenergic system have been studied. For that purpose, rat pups have been treated twice daily during the first 10 days of life β with the β₂-agonist clenbuterol-HCl (2.5 mg/kg s.c.), and the effects on the β-adrenoceptor number and monoamine metabolism have been determined directly after the treatment and in adulthood. On postnatal day 10, 90 min after the last clenbuterol injection 4.5 μg/g of the drug was present in the brain. At the end of the treatment the β-receptor binding had decreased in the cerebellum (35%), but not in the frontal cortex or mesolimbic system. Clenbuterol significantly increased the steady-state brain levels of noradrenaline (NA) in the striatum 90 min after the last injection, whereas the levels in the frontal cortex, meso-limbic system, medulla pons and cerebellum were unaffected. The NA metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), had significantly increased in the frontal cortex and striatum. The serotonergic (5-HT) and dopaminergic (DA) system were not altered. In general, no long-lasting effects on β-adrenoceptor number and affinity or monoamine metabolism were measurable, except for the frontal cortex which showed a sustained increase of MHPG, a decrease of 5-HT and an increase of 5-HIAA/5-HT on PN 60. In conclusion, chronic postnatal activation of β₂-adrenoceptors by clenbuterol treatment selectively causes changes in the setting of the neurochemical parameters investigated in the frontal cortex.     

Effects of aging and β-amyloid on the properties of brain synaptic and mitochondrial membranes

Summary. The effects of aging and of different amyloid β-peptides (Aβ) on the properties of purified synaptosomal plasma and mitochondrial membranes were studied using different fluorescent dyes. Aging led to opposite membrane alterations in both mouse brain fractions. Cholesterol levels were significantly enhanced in synaptosomal plasma membranes (SPM) from aged mice only. Flexibility of membrane fatty acids was decreased in synaptosomal plasma and mitochondrial membranes, mobility of pyrene was enhanced, but in SPM only. With regard to acyl chain flexibility in aged brain membranes, both membrane preparations were less sensitive to Aβ. By contrast, effects of Aβ on the mobility of pyrene were not reduced for aged synaptic membranes, but even seemed to be enhanced in the case of aged mitochondrial membranes. The data presented significantly enhance our understanding of the mechanism of the Aβ's disordering effects on synaptosomal membranes that are also detectable for mitochondrial membranes and show for the first time that Aβ effects are modified by brain aging. This is of special interest since membrane alterations and in particular modifications of membrane cholesterol were recently linked to Alzheimer's Disease. Received October 6, 2000; accepted April 2, 2001     

Are effects of emotion in single words non-lexical? Evidence from event-related brain potentials

Emotional meaning impacts word processing. However, it is unclear, at which functional locus this influence occurs and whether and how it depends on word class. These questions were addressed by recording event-related potentials (ERPs) in a lexical decision task with written adjectives, verbs, and nouns of positive, negative, and neutral emotional valence. In addition, word frequency (high vs. low) was manipulated. The early posterior negativity (EPN) in ERPs started earlier for emotional nouns and adjectives than for verbs. Depending on word class, EPN onsets coincided with or followed the lexicality effects. Main ERP effects of emotion overlapped with effects of word frequency between 300 and 550 ms but interacted with them only after 500 ms. These results indicate that in all three word classes examined, emotional evaluation as represented by the EPN has a post-lexical locus, starting already after a minimum of lexical access.     

Are gender differences important for the clinical effects of antidepressants?

OBJECTIVE: Gender differences in antidepressant treatment response, side effects, dropout rates, and plasma concentrations were examined in patients with major and predominantly melancholic depression. METHOD: The study included a subgroup of 292 inpatients (96 men, 196 women) from three Danish double-blind, randomized, controlled trials. All patients completed a 5-week treatment period and fulfilled the DSM-III or DSM-III-R criteria for major depression. Clomipramine (150 mg/day) was the reference treatment, and comparable treatments were citalopram (40 mg/day), paroxetine (30 mg/day), and moclobemide (400 mg/day). Assessments were performed by using the 17-item Hamilton Depression Rating Scale and the Udvalg for Kliniske Unders?gelser Side Effect Rating Scale. In a subgroup of 110 patients, weekly measurements of clomipramine plasma concentrations were obtained. Nonparametric statistical tests and multiple linear and logistic regression models were used for statistical evaluations. RESULTS: Both genders had similar remission rates (Hamilton depression scale score <8) when treated with clomipramine and had significantly higher remission rates with clomipramine than with the comparable treatments. The plasma concentrations of clomipramine were significantly higher for female than for male patients. No gender differences were found in posttreatment Hamilton depression scale scores, nor did the therapeutic effects of treatment depend on gender. Rates of dropout and side effects were similar for men and women. No relationship between plasma concentrations, gender, and therapeutic outcome was found. CONCLUSIONS: In a group of patients with major and predominantly melancholic depression, differentiation according to gender was not important in treatment with common antidepressants. Women appeared to have higher plasma concentrations of tricyclic antidepressants than men. The consequences of this difference for clinical effects are unclear. Gender-specific recommendations for dosing of tricyclic antidepressants may be considered.