OBJECTIVE:To evaluate the efficacy and safety of retigabine 600, 900, and 1,200 mg/day administered three times daily as adjunctive therapy in patients with partial-onset seizures. METHODS:A multicenter, randomized, double-blind, placebo-controlled trial was performed. After an 8-week baseline phase, patients were randomized to a 16-week double-blind treatment period (8-week forced titration and 8-week maintenance) followed by either tapering or entry into an open-label extension study. Primary efficacy was the percentage change from baseline in monthly seizure frequency and compared across treatment arms. Secondary efficacy comparisons included the proportion of patients experiencing >/=50% reduction in seizure frequency (responder rate), emergence of new seizure types, and physician assessment of global clinical improvement. Safety/tolerability assessments included adverse events (AEs), physical and neurologic examinations, and clinical laboratory evaluations. Efficacy analyses were performed on the intent-to-treat population. RESULTS:Of the 399 randomized patients, 279 (69.9%) completed the double-blind treatment period. The median percent change in monthly total partial seizure frequency from baseline was -23% for 600 mg/day, -29% for 900 mg/day, and -35% for 1,200 mg/day vs -13% for placebo (p < 0.001 for overall difference across all treatment arms). Responder rates for retigabine were 23% for 600 mg/day, 32% for 900 mg/day (p = 0.021), and 33% for 1,200 mg/day (p = 0.016), vs 16% for placebo. The most common treatment-emergent AEs were somnolence, dizziness, confusion, speech disorder, vertigo, tremor, amnesia, abnormal thinking, abnormal gait, paresthesia, and diplopia. CONCLUSION:Adjunctive therapy with retigabine is well tolerated and reduces the frequency of partial-onset seizures in a dose-dependent manner.

This review summarizes those studies, completed over the last 15 years, which compare the clinical benefit of the two most commonly used dopamine agonists, pergolide and bromocriptine. In these studies, both drugs were evaluated as adjunctive therapy to levodopa for the treatment of Parkinson's disease (PD). Ten studies are analyzed and the affect of pergolide and bromocriptine on PD compared. Although variation in study design and disease rating scales prevents the opportunity for a true meta-analysis, this review analyses the outcome of each individual study to assess the benefit of pergolide over bromocriptine. Pergolide improves patients' activities-of-daily-living and their clinical PD symptoms over bromocriptine. Additionally, a large percentage of patients who do not respond to bromocriptine, or whose PD symptoms worsened, improved on pergolide. Furthermore, patients who are adequately treated with bromocriptine experienced additional improvement with pergolide therapy. In summary, pergolide provided benefits to PD patients over bromocriptine in nine studies and was equivalent in the tenth. The benefits associated with pergolide may be partly due to the action of pergolide on dopamine D-1 and D-2 receptors (bromocriptine is associated with the D-2 agonism). In conclusion, in the majority of completed studies to date, pergolide provided greater improvement to the clinical signs and symptoms of PD than bromocriptine.

ResumenAntecedentes:La selectividad clínica de los antidepresivos con especificidad farmacológica se sigue debatiendo todavía.Método:En el ensayo abierto presentado más adelante, se compararon los efectos de la fluoxetina, un inhibidor selectivo de la recaptación de la serotonina (SSRI), a través de dos grupos de pacientes internos depresivos que contrastaban en su expresión de síntomas (agitados/ansiosos frente a pacientes con retardo/embotamiento afectivo). Dieciséis pacientes (8 en cada grupo) fueron incluidos en el período de tratamiento de 4 semanas y sometidos a una valoración semanal. Se evaluó la depresión global, el retardo, el embotamiento emocional, la agitación, la ansiedad y el perfil de estado de ánimo.Resultados:Se observaron mejorías significativas de las puntuaciones en la HDRS y la MADRS en ambos grupos. Aunque no se encontró interacción grupo tratamiento en las puntuaciones globales de depresión, se observó un efecto diferencial sobre la ansiedad, la agitación, la irritabilidad y la labilidad emocional según el grupo.Discusión:Estos resultados preliminares apoyan la hipótesis de que el efecto de la fluoxetina sobre las dimensiones clínicas positivas podría llevar a un efecto diferencial en los pacientes con agitación/ansiedad, comparados con los pacientes con retardo/embotamiento afectivo.

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Background: Clinical selectivity of antidepressants with pharmacological specificity still remains under debate. Method: In the open trial presented below, the effects of fluoxetine, a selective serotonin re-uptake inhibitor (SSRI), were compared across two groups of depressive inpatients contrasted on their symptomatological expression (agitated/anxious versus retarded/blunted affect). Sixteen patients (8 in each groups) were included in the 4-weeks treatment period and submitted to a weekly-based evaluation. Global depression, retardation, emotional blunting, agitation, anxiety and mood profile were assessed. Results: Significant improvements of the HDRS and MADRS scores were observed in both groups. Although no group x treatment interaction was found on the global scores of depression, a differential effect according to the group was observed on anxiety, agitation, irritability and emotional lability. Discussion: These preliminary results support the hypothesis that the effect of fluoxetine on positive clinical dimensions could lead to a differential effect in patients with agitation/anxiety when compared with patients with retardation/blunted affect.

The availability of new drugs for Alzheimer's disease, with different pharmacological profiles, leads to a redefinition the relevant methodology for developing drugs in this indication, including the inclusion/exclusion criteria, the duration of the studies, and therefore, the relevant guidelines. This nas the purpose of the Giens Round-table devoted to the new methodology for drug development in Alzheimer disease.

To determine the respective contribution of the subcortical structures and the prefrontal cortex in behavioural adaptation, we applied the delayed response paradigm, considered as a functional marker of the dorsolateral region of the prefrontal cortex, to patients with striatal dysfunction: Parkinson's disease (n = 27), progressive supranuclear palsy (n = 20); to patients with prefrontal lesions (n = 10) and to normal control subjects (n = 24). The performance of each group was compared in four experiments: a delayed response task in which the correct answer was previously indicated by an explicit cue (externally guided task); delayed alternation and non-alternation tasks coupled with a delayed reversal task in which the patient had to discover the rule by himself in the absence of explicit cues (internally driven tasks). All groups of patients showed a short-term spatial representational memory deficit in the externally guided situation. Patients with striatal dysfunction showed difficulties in re-engaging attention on a new programme and in maintaining it. However, they did not express the spontaneous tendency to alternate nor the severe difficulties in disengaging from a previous pattern of response demonstrated by patients with prefrontal lesions. These results validate the concept of a striato-frontal functional system in humans and suggest the existence of two different levels of behavioural organization: elaboration of new programmes of behaviour in association with inhibition of previously established ones, that might be under frontal lobe control; maintenance of the new programme until the action has been accomplished and automatization for a routine utilization, that might be under control of the striatum.

Cortical activation during arithmetic calculation (silent subtraction by sevens) was compared to that observed during a control condition for which subjects were required to count forward by ones. Nine normal subjects underwent 1.5-T functional magnetic resonance imaging while performing these tasks. All subjects showed bilateral premotor, posterior parietal, and prefrontal cortex activation during serial calculation. There was a large degree of individual variation in activation outside of these areas. These results confirm the role of posterior parietal cortex in arithmetic calculation and implicate other regions, including prefrontal cortex.

REGIONAL cerebral blood flow was measured with positron emission tomography in seven normal volunteers while they performed various script event verification tasks. The left frontal lobe, left anterior cingulate and the anterior part of the left superior temporal gyrus were more activated in the script event membership and action categorization conditions, whereas the right frontal lobe, left superior temporal gyrus and the middle temporal gyrus bilaterally were more activated in the script event temporal order verification condition. These results indicate that the temporal ordering of script events and determining whether an event belongs to a particular script or action category are processed by distinctive distributed neuronal networks.

This round table discussion was devoted to describing the present status of clinical trials in the hospital setting, analysing common difficulties in conducting quality clinical research, and proposing realistic solutions to solve or attenuate those difficulties. This analysis was performed on five critical topics: personnel, laboratory tests and investigations, drug supplies, source documents and investigator's procedures.

To identify alterations in elementary cognitive operations according to dimensions of depression, two stages of information processing, namely the response choice and the motor preparation stages, were explored using an event-related potential paradigm in two subgroups of depressed patients (retarded and blunted affect versus anxious-agitated and impulsive) compared to controls. Two results are common to all depressed patients: a slow encoding of stimuli (P1 wave) and a prolonged processing of stimulus-response compatibility (after P3b). This is compensated by a global velocity increase in stimulus evaluation or decision making (P3b) in anxious-agitated patients or, on the contrary, cumulated with its velocity decrease in retarded-blunted-affect patients. Such results could provide an explanation for the massive retardation observed in blunted-affect patients, contrary to anxious-agitated patients, whose normal reaction times may come from a very high energetical involvement at the P3b level. Results as a whole suggest that impairments in blunted-affect patients concern effort mechanisms, whereas those in anxious-agitated patients concern perceptual processes.

WE STUDIED 12 normal volunteers who were asked to imagine and plan their behavior in emotional and nonemotional situations while their regional cerebral blood flow was measured with positron emission tomography. The dorsolateral prefrontal and posterior temporal cortex were more activated during the nonemotional situation whereas the medial prefrontal cortex and anterior temporal cortex were more activated during the emotional situation. These results demonstrate that distinctive regions of the prefrontal and temporal cortex used to imagine and plan behavior are activated during the expression of emotional and non-emotional plans.

1. Current research uses a variety of traditional validation methods in order to test the clinical expression of biological models in psychiatry. The application of these methods has resulted in a paradoxical situation which requires the definition of new objectives in biological and pharmacoclinical research: the biological specificity of new psychotropic drugs does not assume any congruence between their pharmacological and their therapeutic effects, but raises the question of the relationship between biological systems and clinical symptomatology. The dimensional description of psychopathological disorders may be more appropriate to biological studies in psychiatry. 2. A study was undertaken on a population of twenty-one in-patients fulfilling the DSM III-R criteria for major depressive episode. They were divided into two groups on the basis of contrasting clinical dimensions: anxious-agitation and impulsiveness versus retardation and affective blunting. 3. Significant clinical differences between the two groups on mood profiles were echoed by contrasts in event-related potentials during a go-nogo task: only anxious agitated and impulsive patients developed an abnormal cortical activity, as measured by contingent negative variation (CNV), in the nogo condition. 4. This paper suggests how a paradigm with control of motor action leads to specify premotor activation abnormalities in the agitated impulsive depression subtype.

Several theorists have drawn a distinction between automatic and attentional or controlled processing. Hasher and Zacks (1979), were the very first to argue that effortful processes are reduced under conditions of stress including depression. They suggested that, in these conditions, no such deficit occurs in automatic processing. Then, Weingartner and co-workers provided some experiments which seemed to support such an interpretation of the cognitive dysfunction in depressed patients. However, some recent data do not fit with this well admitted theoretical framework. The purpose of our article is to try to clarify this issue both from a theoretical and from a methodological point of view. First, we make a critical review of the most recent results in three fields of experimentation related to the "automatic versus controlled" topic: 1) The classical neuropsychology of memory which manipulates the level of effort required to perform the tasks. Confusion arises when theories at the process level are tested with reference to data collected at the task level. The transparency assumption could be false: Impairment in an effort-demanding task could be due to a defect in automatic processes and it is possible to hypothesize that the more automatic processes are deficient, the more controlled processes are saturated and the effort demanding task impaired. The emergence of controlled processes could depend on the level of automaticity and the regulation of automatic processes could be determinant for the ability of the subject to make associations. 2) The recent studies on implicit memory in depression.(ABSTRACT TRUNCATED AT 250 WORDS)

Several theorists have drawn a distinction between automatic and attentional or controlled processing. Hasher and Zacks (1979), were the very first to argue that effortful processes are reduced under conditions of stress including depression. They suggested that, in these conditions, no such deficit occurs in automatic processing. Then, Weingartner and co-workers provided some experiments which seemed to support such an interpretation of the cognitive dysfunction in depressed patients. However, some recent data do not fit with this well admitted theoretical framework. The purpose of our article is to try to clarify this issue both from a theoretical and from a methodological point of view. First, we make a critical review of the most recent results in three fields of experimentation related to the "automatic versus controlled" topic: 1) The classical neuropsychology of memory which manipulates the level of effort required to perform the tasks. Confusion arises when theories at the process level are tested with reference to data collected at the task level. The transparency assumption could be false: Impairment in an effort-demanding task could be due to a defect in automatic processes and it is possible to hypothesize that the more automatic processes are deficient, the more are saturated and the effort demanding task impaired. The emergence of controlled processes could depend on the level of automaticity and the regulation of automatic processes could be determinant for the ability of the subject to make associations. 2) The recent studies on implicit memory in depression. Four studies showed intact priming in depressives, but one study showed results contrary to the conclusion that implicit memory is intact in depression. Furthermore, available data in this domain concern only perceptual implicit tasks but not conceptual tasks which are supposed to be more likely impaired in mood disorders. Conclusion that implicit memory remains intact in depression would be prematurely generalized. 3) Attentional studies. Very few studies exist in comparison to the clinical complaints of patients which report problems with attention. Results in Stroop tasks studies confirmed that attentional processes are impaired in depression, but failed to explain the mechanism of this deficit. As far as we know, only three studies used the event-related potential methodology with attentional paradigms. Despite some discrepancy in the results, this tool seems to be very powerful in the study of the cognitive processes in psychiatric disorders. The second part of our article is the presentation of experimental data which directly challenge the assumption that automatic processes are intact in depressed patients. We examined automatic versus controlled processes in sixteen depressed patients (DSM III-R major depressive episode), analysing the event related potentials (ERPs) in a go-nogo paradigm. The patients were selected according to their clinical subtype - anxious, agitated and impulsive versus retarded and blunted affect - assuming that these two opposite dimensions of the depressive mood would rely on different physiopathological mechanisms. Results showed that the P3a component, which indexes automatic cognitive processes, was dramatically decreased in patients with clinical deficit, suggesting that failure in stimulus evaluation is related to this symptomatology. These data accord with previous ERP results in depression. However, taking into account the sub-types of depression and the sub-components of the P300, a new hypothesis could be discussed: From an energetical point of view, the cognitive strategy of these patients with deficit was different of that of the anxious-impulsive patients, even if both sub-groups were "major depressive episode" diagnosed. Then, some deficit symptoms, like emotional blunting, involving behavioral and cognitive defects, could be a physiological response to the handicap. Finally, we propose a physiopathological interpretation of our results in terms of a functional frontal de-afferentation in depressed patients with clinical deficit. Such an interpretation, supported by the P300 literature on frontal patients, sub-cortical dementia and pharmacological studies with neuroleptics, could explain the decrease of the P300 amplitude in several pathological processes such as schizophrenia or dementia. From this point of view, the P300 could index some non-specific adaptive processes. Hence, some aspects of cognitive functioning could be part of a vulnerability factor whereas others would reflect the pathological process itself.