Social phobia is a common disorder associated with significant psychosocial impairment, representing a substantial public health problem largely determined by the high prevalence, and the lifelong chronicity. Social phobia starts in early childhood or adolescence and is often comorbid with depression, other anxiety disorders, alcohol and substance abuse or eating disorders. This cascade of comorbidity, usually secondary to social phobia, increases the disability associated with the condition. The possibility that social phobia may be a trigger for later developing comorbid disorders directs attention to the need for early effective treatment as a preventive measure. The most recent drug class to be investigated for the psychopharmacological treatment of social phobia is the SSRI group for which there is growing support. The other drug classes that have been evaluated are monoamine oxidase inhibitors (MAOIs), benzodiazepines, and beta-blockers. The SSRIs represent a new and attractive therapeutic choice for patients with generalized social phobia. Recently the first, large scale, placebo-controlled study to assess the efficacy of drug treatment in generalized social phobia has been completed with paroxetine. Paroxetine was more effective in reducing the symptoms than placebo and was well tolerated. Many now regard SSRIs as the drugs of choice in social phobia because of their effectiveness and because they avoid the problems of treatment with benzodiazepines or classical MAOIs.

This revision of the 2005 British Association for Psychopharmacology guidelines for the evidence-based pharmacological treatment of anxiety disorders provides an update on key steps in diagnosis and clinical management, including recognition, acute treatment, longer-term treatment, combination treatment, and further approaches for patients who have not responded to first-line interventions. A consensus meeting involving international experts in anxiety disorders reviewed the main subject areas and considered the strength of supporting evidence and its clinical implications. The guidelines are based on available evidence, were constructed after extensive feedback from participants, and are presented as recommendations to aid clinical decision-making in primary, secondary and tertiary medical care. They may also serve as a source of information for patients, their carers, and medicines management and formulary committees.

Tardive dyskinesia (TD), a movement disorder produced by long-term treatment with a classical antipsychotic drug, is generally considered to be a disorder of dopamine (DA) systems, since classical antipsychotics are potent DA D2 receptor blockers. Also, acute DA D1 agonist treatment of rats is known to produce vacuous chewing movements (VCMs), a behavioral feature resembling the oral dyskinesia that is so prominent in most instances of TD. In this paper we outline a series of studies in a new animal model of TD in which DA D1 receptor supersensitivity was produced by neonatal 6-hydroxydopamine (6-OHDA)-induced destruction of nigrostriatal DA fibers. In rats so-lesioned 5-HT receptor supersensitivity is additionally produced, and in fact 5-HT receptor antagonists attenuate enhanced DA D16-lesioned rats treated with haloperidol for one year, there is a 2-fold increase in numbers of VCMs (versus intact rats treated with haloperidol); and this high frequency of VCMs persists for more than 6 months after discontinuing haloperidol treatment. During this stage, 5-HT2 receptor antagonists, but not DA D1 receptor antagonists, attenuate the incidence of VCMs. This series of findings implicates the 5-HT neuronal phenotype in TD, and promotes 5-HT2 receptor antagonists, more specifically 5-HT2C receptor antagonists, as a rational treatment approach for TD in humans.

Les erreurs innées du métabolisme sont des maladies héréditaires pouvant affecter, entre autres, la synthèse et le transport des neurotransmetteurs. Le diagnostic de ces pathologies repose essentiellement sur l’analyse par chromatographie d’un fluide biologique [plasma, urine, liquide céphalorachidien (LCR)]. L’objectif de cette thèse était de développer des méthodes simples et rapides pour le diagnostique des troubles de la neurotransmission. Dans un premier temps, nous avons développé et validé le dosage simultané, en moins de 10 minutes, des métabolites de la dopamine, de la sérotonine et de la tétrahydrobioptérine (BH4) par chromatographie liquide ultra-haute pression (UHPLC) couplée à une détection séquentielle électrochimique et fluorimétrique. Cette méthode a été appliquée à l’analyse de 1372 échantillons de LCR, permettant ainsi d’établir les valeurs fréquentes de la population française. Afin de transposer la méthode précédente en UHPLC couplée à la spectrométrie de masse (MS), nous avons étudié les mécanismes d’auto- et d’électro- oxydation de la BH4, par mobilité ionique différentielle couplée à la MS haute résolution (résonance cyclonique ionique FTICR) et à la photodissociation Infra-rouge. Ce travail nous a permis d’isoler et de caractériser pour la première fois la qBH2, intermédiaire réactionnel fugace de la BH4, impliqué dans le mécanisme d’action de cette dernière. La méthode UHPLC-MS/MS développée, permet en outre le dosage simultané du 5-Méthyl-tétrahydrofolate. / Inborn errors of metabolism are inherited diseases that can alter the synthesis and transport of neurotransmitters. The diagnosis of these conditions is currently based on the chromatographic analysis of a biological fluid [plasma, urine, cerebrospinal fluid (CSF)]. The aim of this thesis was to develop simple and rapid methods for the diagnosis of neurotransmitter disorders. Firstly, we developed and validated the simultaneous determination of dopamine, serotonin, and tetrahydrobiopterin (BH4) metabolites by ultrahigh pressure liquid chromatography (UHPLC) coupled to sequential electrochemical and fluorimetric detection. This method was applied to the analysis of 1372 CSF samples, thus establishing the frequent ranges of the French population. In order to transpose the previous method into UHPLC coupled to mass spectrometry (MS), we studied the mechanisms of auto- and electro- oxidation of BH4, by Differential Ion Mobility coupled to high resolution MS (FTICR) in conjunction with Infra-Red photo-dissociation. This work allowed us to isolate and characterize qBH2, the transient reaction intermediate of BH4, involved in the mechanism of action of the latter. The proposed UHPLC-MS/MS method also allows the simultaneous determination of 5-methyltetrahydrofolate.

Selective Serotonin Reuptake Inhibitors and Bone mineral Density in a Population of U.S. Premenopausal Women May 2011 M.S., UNIVERSITY of Massachusetts Amherst Directed by: Professor Elizabeth R. Bertone-Johnson Low bone mineral density (BMD) in post-menopausal women is a risk factor for bone fractures and osteoporosis development. Prior studies in post-menopausal women have shown the use of antidepressant medications, specifically selective serotonin reuptake inhibitors (SSRIs) to be inversely related to BMD. However, the association has not been studied in pre-menopausal women. Current SSRI use is widespread with 8% of U.S. women age 18-44 reporting use. We evaluated the association between SSRIs and BMD and bone mineral content (BMC) cross-sectionally using data from the University of Massachusetts Vitamin D Status Study. SSRI use, diet, and lifestyle factors were assessed by questionnaire. BMD and BMC were measured using dual-energy x-ray absorptiometry (DEXA). The study included 256 women aged 18-30 (mean=21.6 years, SD=4.3 years). In this population, SSRI use was 5%, BMD values ranged from 0.97-1.38 g/cm2 (mean 1.16, SD 0.08), and BMC values ranged from 1833g to 3682g (mean 2541.5, SD=349.2). After adjustment for age, body mass index, and physical activity, mean BMD in the 13 users of SSRIs was 1.15g/cm2 (SD=0.06) compared to 1.16g/cm2 (SD=0.77) in the 243 non-users (p =0.66). After the same adjustments, mean BMC in the 13 users was 2467.1g (SD=285.0) compared to 2547.6g (SD=352.6) in the 243 non-users (p=0.94). Our findings do not support an inverse association between SSRI use and BMD or BMC. However, given the prevalence of SSRI use in young women and the potential for adverse effects on bone health, further study of this association is warranted.

No description available.

Abstract: To study potential biochemical correlates of dopamine (DA) and serotonin receptor supersensitivity, rats were lesioned at 3 days after birth with 6‐hydroxydopamine (6‐OHDA; 67 µg in each lateral ventricle; desipramine pretreatment, 20 mg/kg i.p., 1 h) and then sensitized with the DA D1 agonist, SKF 38393 HCl (3.0 mg/kg i.p. per day) either ontogenetically (daily, for 28 consecutive days from birth) and/or in adulthood (four weekly injections, 6–9 weeks from birth). Controls received vehicle in place of 6‐OHDA or SKF 38393. Enhanced locomotor responses were observed after SKF 38393 at 6 weeks, only in rats that received SKF 38393 + 6‐OHDA in ontogeny. Locomotor responses were further enhanced in this group after the last of four weekly SKF 38393 injections at the 9th week. These weekly SKF 38393 treatments also produced enhanced responses in 6‐OHDA rats that did not receive SKF 38393 in ontogeny. When striata were studied at 11 weeks, the percentages of high and low affinity DA D1 binding sites were not altered. Basal as well as DA‐, NaF‐, and forskolin‐stimulated adenylyl cyclase activities also were not changed. Dot blot analysis showed that there was a reduction of mRNA levels for DA D1, but not serotonin1C, receptors in the 6‐OHDA groups. However, SKF 38393 at 6–9 weeks eliminated this alteration. Based on these findings it can be proposed that supersensitization may be a consequence of altered neuronal cross talk rather than an imbalance of receptor elements per se.

Anelosimus studiosus is a socially polyphenic spider. Individuals can be classified as social/tolerant or solitary/aggressive. These behavioral differences are associated with considerable variation in social structure. Here, we begin to examine the physiological differences that may underlie the behavioral dimorphism in this species and possible implications for the evolution of sociality. Octopamine is a neurotransmitter that has been found to elevate aggression in invertebrates. Serotonin has been shown, in some cases, to interact antagonistically with octopamine. We used High Pressure Liquid Chromatography with Electrochemical Detection to quantify levels of these neurochemicals among adult females from social (multi-female) and solitary (single-female) webs in east Tennessee. A subset of spiders was scored for individual social tendency. We found that higher octopamine levels are associated with a greater degree of aggression and intolerance, both at the individual level and the population level, while higher levels of serotonin are found in multi-female colonies and social individuals.

No description available.

Doctoral thesis assessing the effects of one-week of escitalopram administration on healthy humans during sequence motor learning training. Published in 3 research articles.