Quantitative System Pharmacology (QSP): An Integrative Framework for paradigm change in the treatment of the first-episode schizophrenia.

Despite the lack of progress in the curative treatment of mental illness, especially schizophrenia, the accumulation of neuroscience data over the past decade suggests the re-conceptualization of schizophrenia. With the advent of new biomarkers and cognitive tools, new neuroscience technologies such as functional dynamic connectivity and the identification of subtle clinical features; it is now possible to detect early stages at risk or prodromes of a first psychotic episode. Current concepts reconceptualizes schizophrenia as a neurodevelopmental disorder at early onset, with polygenic risk and only symptomatic treatment for positive symptoms at this time. The use of such technologies in the future suggests new diagnostic and therapeutic options. Next steps include new pharmacological perspectives and potential contributions of new technologies such as quantitative system pharmacology brain computational modeling approach.

Evaluation of symptomatic drug effects in Alzheimer's disease: strategies for prediction of efficacy in humans.

In chronic diseases such as Alzheimer's disease (AD), the arsenal of biomarkers available to determine the effectiveness of symptomatic treatment is very limited. Interpretation of the results provided in literature is cumbersome and it becomes difficult to predict their standardization to a larger patient population. Indeed, cognitive assessment alone does not appear to have sufficient predictive value of drug efficacy in early clinical development of AD treatment. In recent years, research has contributed to the emergence of new tools to assess brain activity relying on innovative technologies of imaging and electrophysiology. However, the relevance of the use of these newer markers in treatment response assessment is waiting for validation. This review shows how the early clinical assessment of symptomatic drugs could benefit from the inclusion of suitable pharmacodynamic markers. This review also emphasizes the importance of re-evaluating a step-by-step strategy in drug development.

[Conceptualisation and validation of the "Emotional State Questionnaire (ESQ)": evaluation of an emotional profile]. / Conceptualisation et validation factorielle d'un questionnaire mesurant le profil émotionnel: Emotional State Questionnaire (ESQ).

OBJECTIVES: The objective of this study is to evaluate the validity of a new self questionnaire: the "ESQ" (Emotional State Questionnaire). BACKGROUND: This novel instrument possesses a number of original attributes: first of all, it is designed to assess a general emotional profile, in opposition to other similar scales which can only be applied to the emotional reactions provoked by specific stimuli. Secondly, this scale is composed of several emotional dimensions. The ESQ has been constructed according to four components: recognition, expression, internal emotional experience and social context. The first three dimensions were selected because of their wide use through behavioral experiments. Indeed, contrary to most scales used in this field, which only assess the emotional experience, we wanted to propose an instrument also able to assess the subject's impression of his own capacities to encode and decode emotions. We hypothesized that these three dimensions could not be dissociated from a fourth dimension, the social context, which therefore also figures in this scale. The emotions explored were the five fundamental emotions indicated by Izard (fear, happiness, sadness, disgust and surprise) to which we added a neutral feeling that we considered as a basic emotion. STUDY DESIGN: To establish this instrument, a first conceptual phase was conducted by a group of experts. These experts all worked in the psychological field. They proposed the scale on the base of their clinical experience and after study of the literature. The scale was then validated in a population of 218 healthy volunteers, aged between 15 and 88 years. Subjects were not included if they presented depression (score above 16 in the Beck Depression Scale) or pathological anxiety (score above 5 in the Spieberger State Anxiety Inventory). The psychometric characteristics tested were: the item analysis, the item-dimension correlation, the factor analysis and the internal consistency reliability. RESULTS: The population studied was equally distributed according to gender (sex ratio: 0.97), the mean age was of 36.2 2 +/- 16.1 years. Acceptability was good with less than 5% of data missing. The analysis of items revealed no floor or ceiling effect and a low correlation between items. Item-dimension correlation ranged from 0.23 to 0.62, with most scores above 0.4. The items were always better correlated to their dimension than to other dimensions, except for one item. The 4 dimensions (recognition, expression, internal emotional experience and social context of emotions) explained 42% of the total variance. Finally, the scale showed good internal consistency with Cronbach coefficients, equal or above 0.84 for the total score, the recognition and the expression dimensions. This coefficient reached 0.77 for the feeling dimension but only 0.58 for the social context dimension. CONCLUSION: All together, results showed satisfactory characteristics in regard of the complexity of the notion measured. However, an important drawback is the lack of an external instrument to assess convergent validity. This instrument can be of great interest in the emotional characterization of healthy volunteers. More-over, if validated in psychiatric populations, this scale could be most useful in psychopathological assessment and also in comparison with behavioral evaluations of emotion.

Multicenter prospective study of children with sickle cell disease: radiographic and psychometric correlation.

After obtaining familial informed consent, between January 1996 and July 1997, 173 children (5 to 15 years old) with sickle cell disease were enrolled in a prospective multicenter study using blood screening, transcranial Doppler ultrasonography (n = 143), cerebral magnetic resonance imaging (n = 144), and neuropsychologic performance evaluation (n = 156) (Wechsler Intelligence tests WISC-III, WIPPSI-R), which were also performed in 76 sibling controls (5 to 15 years old). Among the 173 patients with sickle cell disease (155 homozygous for hemoglobin SS, 8 sickle cell beta0 thalassemia, 3 sickle cell beta+ thalassemia, 7 sickle cell hemoglobin C disease SC), 12 (6.9%) had a history of overt stroke, and the incidence of abnormal transcranial Doppler ultrasonography (defined as mean middle cerebral artery velocity > 200 cm/sec or absent) was 8.4% in the overall study population and 9.6% in patients with homozygous sickle cell anemia The silent stroke rate was 15%. Significantly impaired cognitive functioning was observed in sickle cell disease patients with a history of stroke (Performance IQ and Full Scale IQ), but also in patients with silent strokes (Similarities, Vocabulary, and Verbal Comprehension). However, infarcts on magnetic resonance imaging were not the only factors of cognitive deficit: Verbal IQ, Performance IQ, and Full Scale IQ were strongly impaired in patients with severe chronic anemia (hematocrit < or = 20%) and in those with thrombocytosis (platelets > 500 x 10(9)/L). Multivariate logistic regression analysis showed that abnormal magnetic resonance imaging (odds ratio [OR] = 2.76) (P = .047), hematocrit < or =20% (OR = 5.85) (P = .005), and platelets > 500 x 10(9)/L (OR = 3.99) (P = .004) were independent factors of cognitive deficiency (Full Scale IQ < 75) in sickle cell disease patients. The unfavorable effect of low hematocrit has already been suggested, but this is the first report concerning an effect of thrombocytosis and showing that silent stroke alone is not a factor of cognitive deficit when not associated with low hematocrit or thrombocytosis. The effect of hydroxyurea, which is known to increase hematocrit and decrease platelet count, on cognitive functioning of sickle cell patients should be evaluated prospectively.

Configural and local processing of faces in children with Williams syndrome.

Three experiments investigated face processing in children with Williams syndrome (WS). In Experiment 1, the ability to discriminate different aspects of faces was compared between WS subjects and a group of children individually matched for chronological age (CA-matches) and another group matched for mental age (MA-matches). In Experiments 2 and 3, the ability to process the local and configural aspects of geometrical patterns and faces was assessed within the same groups of subjects. The results indicated that the WSs' overall performance on face recognition was below that of the CA-matches, but similar to that of the MA-matches. This study revealed in addition that the CA- and MA-matches showed a bias toward a configural mode of face and geometrical shape processing, whereas children with WS did not show any bias. These findings suggest that face processing undergoes an abnormal developmental course in WS.