Teses / dissertações sobre o tema "Psychopharmacology"

Thesis (DPhil)--Stellenbosch University, 2008.
ENGLISH ABSTRACT: The use of psychiatric medication is an important part of modern medical and psychiatric practice. Clinical psychopharmacology raises a broad range of philosophical issues, including metaphysical, epistemological, and moral questions. This dissertation attempts to provide a conceptual framework for addressing several of these questions, and for formulating a conceptual basis for psychiatry in general and clinical psychopharmacology in particular. The dissertation begins by heuristically contrasting two broad approaches towards a range of questions in the philosophy of science, language, and medicine. A classical position takes an essentialist and objective view of categories while a critical position emphasizes that categories are often metaphoric and subjective. A synthetic or integrated position might be possible, in which radial categories are often based on metaphoric extensions of basic-level sensorimotor-affective experience, and are embodied in the brain-mind and in social practices. Rather than attempt to defend an integrated position in purely conceptual terms, the dissertation supports this view of categories using data from the cognitive-affective sciences. An important category for philosophy of medicine is disorder, and the dissertation argues that certain universal considerations explain agreement about prototypical disorders. Extensions of disorder metaphors are theory-driven and valueladen, and although disagreement about atypical conditions is likely, reasonable debate is possible. The dissertation then considers several conceptual questions, namely the nature of psychotropics, of emotion, and of the self. In each case, a classical position which attempts an essentialist definition is contrasted with a critical position which emphasizes that these constructs are socially constructed and crucially subjective. Cognitiveaffective data is then employed to support an integrative position which emphasizes the embodiment of complex brain-mind phenomena in the brain-mind and in social practices. Explanatory questions considered are how best to explain pharmacotherapy and psychotherapy, how to account for placebo responses, and the relevance of evolutionary explanations of disorder. It is argued that a functionalist account fails to explain psychopharmacological phenomena, including pharmacotherapy and placebo effects. Instead, an account which emphasizes how psychobiological mechanisms produce complex brain-mind phenomena is needed. Evolutionary explanations add to this account, but cannot by themselves differentiate disorder from non-disorder. Ethical questions include the question of whether psychiatric disorders should be treated, whether such disorders should be treated with psychotropics, and whether psychotropics should be used to enhance. The cognitive-affective sciences support the treatment of typical disorders. In more atypical cases, pharmacotherapy, psychotherapy, and non-medical interventions should be considered on an individual basis. As technologies expand, considerations about the value of accepting fate versus the value of attempting to improve life by a range of methods, will need to be weighed carefully. In summary, this dissertation puts forward a philosophy of psychopharmacology which argues that psychiatry practice can be viewed, naturalistically, as based on the natural and human sciences. At the same time, good psychiatric practice involves an engagement with the complex realities of the human condition, including a consideration of individuals’ suffering. Good psychopharmacological practice requires integrating the objective and the subjective, considering both explanation and understanding, and providing a balanced view of the good and bad of psychotropics that avoids both unrealistic optimism and undue pessimism.
AFRIKAANSE OPSOMMING: Die gebruik van psigiatriese medikasie maak belangrike deel uit van moderne mediese en psigiatriese praktyk. Psigofarmakologie bring wye reeks filosofiese kwessies ter sprake, met inbegrip van metafisiese, epistemologiese, en morele vrae. Hierdie proefskrif poog om konseptuele raamwerk te verskaf ten einde verskeie van hierdie vrae die hoof te bied, en na die formulering van konseptuele basis vir psigiatrie in die algemeen en kliniese psigofarmakologie in die besonder om te sien. Die proefskrif begin deur twee algemene benaderings ten opsigte van reeks vrae in die filosofie van wetenskap, taal en geneeskunde te kontrasteer. Klassieke posisie huldig essensialistiese en objektiewe siening van kategorieë, terwyl kritiese posisie klem daarop lê dat kategorieë dikwels metafories en subjektief is. Sintetiese of geïntegreerde posisie is dalk moontlik, met radiale kategorieë wat dikwels op metaforiese uitbreidings van konsepte op basiese vlak sensorimotor-affektiewe ervaring gebaseer word, en in die bewussyn-brein en in sosiale gebruike vergestalt word. Eerder as om te probeer om geïntegreerde posisie in suiwer konseptuele terme te verdedig, steun die proefskrif hierdie siening van kategorieë met behulp van data uit die kognitiewe-affektiewe wetenskappe. Belangrike kategorie vir die filosofie van geneeskunde is steuring, en die proefskrif voer aan dat sekere universele oorwegings ’n verklaring bied vir ooreenstemming ten opsigte van prototipiese steurings. Uitbreidings van die steuring metafoor is teoriegedrewe en waardebelaai, en alhoewel daar waarskynlik meningsverskil omtrent atipiese toestande kan voorkom, is redelike bespreking haalbaar. Die proefskrif neem dan verskeie konseptuele vrae in aanmerking, naamlik die aard van psigotropika, van emosie, en van die self. In elke geval word klassieke posisie wat essensialistiese definisie aandurf, gekontrasteer met kritiese posisie wat beklemtoon dat hierdie konstrukte sosiaal gekonstrueer en besonder subjektief is. Kognitiewe-affektiewe data word dan aangewend om integratiewe posisie te handhaaf wat die vergestalting van komplekse bewussyn-brein fenomene in die bewyssyn-brein en in sosiale praktyke beklemtoon. Verklarende vrae het aandag geskenk aan die beste wyse om farmakoterapie en psigoterapie te verklaar, aan die wyse waarop placebo-reaksies verklaar kan word, en aan die rol van proksimale en evolusionêre verklarings. Daar word aangevoer dat funksionalistiese verklaring nie daarin slaag om psigofarmakologiese verskynsels, met inbegrip van farmakoterapie en placebo-effekte, te verklaar nie. In plaas daarvan word verklaring wat beklemtoon hoe psigobiologiese meganisme komplekse fenomene kan laat ontstaan, benodig. Evolusionêre verklarings dra tot hierdie verklaring by, maar kan nie op sigself steuring van niesteuring onderskei nie. Etiese vrae sluit die vraag in of psigiatriese steurings behandel moet word, of sodanige steurings met psigotropika behandel moet word, en of psigotropika gebruik moet word om te verhoog. Die kognitief-affektiewe wetenskappe ondersteun die behandeling van tipiese steuringe. In meer atipiese gevalle moet farmakoterapie, psigoterapie, en nie-mediese intervensies op individuele basis oorweeg word. Algaande tegnologieë uitbrei, moet ons oorwegings van die waarde van lotsaanvaarding sowel as die waarde van ’n poging om ’n mens se lewe te verbeter, versigtig in ag neem. Ter opsomming, hierdie proefskrif stel filosofie van psigofarmakologie voor wat aanvoer dat psigiatriese praktyk naturalisties verstaan kan word, soos gebaseer op die natuur- en geesteswetenskappe. Terselfdetyd, behels goeie psigofarmakologiese praktyk ‘n verwantskap met die komplekse werklikhede van die menslike kondisie. Dit vereis ‘n omvattende oorweeging van en omgang met individuele pasiënte se lyding. Goeie psigofarmakologiese praktyk integreer die “objektiewe” en die “subjektiewe” aspekte van die menslike bestaan, streef na sowel verklaring en verstaan, verskaf ‘n gebalanseerde perspektief oor die goed en die sleg van psigiatriese medikasies, en middel tussen onrealistiese optimisme en buitensporige pessimisme.

This thesis is an interdisciplinary project in experimental social psychology, psychopharmacology, neuroscience, and neuroethics. The role of emotion in higher order psychological processes – social and moral judgments – was investigated. Specifically the role of noradrenergic mediated emotional arousal was researched. Behavioural studies demonstrated that acute beta adrenergic blockade with propranolol led to a reduction in negative implicit racial associations and also a modification of moral decision making. These findings suggest that basic affective processes might be causally relevant for higher order evaluations. However, enhancement with the noradrenergic potentiating agent reboxetine did not show effects opposite to those of propranolol on racial attitudes or moral judgments, which might indicate that emotional arousal, specific to beta-adrenoceptors might be involved in the effects of propranolol. Further a pharmacological fMRI study demonstrated that the activation pattern in brain regions commonly associated with intergroup bias -- such as the amygdala, insula, dorsolateral prefrontal cortex, and fusiform gyrus -- was affected by propranolol, and that the effect in the amygdala was correlated with implicit racial bias. Taken together the research suggests that automatic emotional arousal plays a role in higher order psychological processes, such as moral and social judgments, which aids the understanding of the underlying neurobiology of such processes. Finally, the ethical implications – such as the prospect of pharmacological moral enhancement – are discussed. The findings also suggest that the moral and social effects of already widely used psychotropic medications should be subject to further empirical and ethical investigation.

Over recent years, the rapid proliferation of novel psychoactive substances has presented significant challenges to health professionals, regulators, and forensic scientists alike. Synthetic cannabinoids comprise an increasingly prevalent and diverse class of compounds that are used by many people around the world for recreational purposes. These compounds tend to produce psychoactive effects similar to, but stronger than, those of the prototypical cannabis-derived receptor agonist ∆9-tetrahydrocannabinol. The majority of modern synthetic cannabinoids have never been systematically assessed for their effects in humans, meaning that their psychopharmacological and toxicological effects remain largely uncharacterised. Unfortunately, but perhaps not surprisingly, these compounds are implicated in scores of toxic and fatal episodes worldwide. This thesis presents a series of studies aimed at building new knowledge regarding the behavioural and physiological effects of specific synthetic cannabinoids, their potency and metabolism, their long-term effects on cognitive function and brain neurochemistry, and analytical techniques that may be useful in the development of agonist substitution therapies to assist with synthetic cannabinoid withdrawal. The results obtained in this thesis and the wider literature are combined to identify in vivo structure-activity and structure-metabolism relationships for a wide variety of synthetic cannabinoids. These relationships may prove useful for the prediction of the psychopharmacological properties and metabolic pathways of future novel synthetic cannabinoids, reducing the burden involved in testing large numbers of novel compounds individually. Based on rodent assays, long-lasting cognitive impairments and subtle biochemical modulations are predicted in chronic synthetic cannabinoid users. Finally, analytical techniques for evaluating and monitoring agonist replacement therapy for synthetic cannabinoid withdrawal are established.

C’est à partir de l’idée des «paradigmes» en psychiatrie, formulée par le psychiatre G. Lantéri-Laura, que nous proposons la thèse du paradigme actuel de la psychiatrie, celui qui prédominerait dans la nosologie, la clinique, l’épidémiologie, la théorie et les traitements du champ psy. Suivant la thèse et la présentation de Lantéri-Laura des trois premiers paradigmes qu’il identifie, nous formulons, par hypothèse, l’existence d’un «Quatrième paradigme», qui est tributaire de l’apparition du premier médicament psychotrope, de la psychopharmacologie et de ce que nous appelons le «dispositif pharmaceutique». Ces nouveaux éléments et dispositifs auront des conséquences dans la clinique et le diagnostic, et dans la nosologie et la critériologie actuelles de tout le champ de la psychopathologie. Même si un champ du savoir psychiatrique préexiste à ce dispositif, c’est ce dernier qui va faire basculer ce champ, le transformer, redessiner ses contours et déclencher la rupture avec les éléments établis précédemment par la psychiatrie classique et la psychanalyse. Ce remaniement produira de nouvelles conceptions des «troubles»: il s’agit de ce que nous dénommerons des «troubles pharmaco-modifiés» et des «troubles pharmaco-déduits» ou «nouveaux syndromes». En outre, ces dispositifs modifieront à tout jamais la manière dont on conçoit les psychothérapies et les divers traitements inclus dans la praxis du champ «psy». Le dispositif pharmaceutique et la brèche ouverte par le médicament vont aussi remanier et permettre la parution de nouvelles formes des psychothérapies. L’incidence de la médecine des preuves sur la psychothérapie et la naissance depuis une vingtaine d’années des thérapies appuyées sur des épreuves empiriques (majoritairement thérapies cognitivo-comportementales), auront comme conséquence l’entrée d’un courant de pensée psychothérapeutique propre au Quatrième paradigme
According to the idea of Ŗparadigmsŗ in psychiatry, formulated by psychiatrist G. Lantéri-Laura we propose the thesis of the current Ŗparadigmŗ of psychiatry, which predominates in the nosology, the clinics, the epidemiology, the theory and the treatments of the psychological field. Following the thesis and the presentation of Lantéri-Laura of the first three paradigms he identifies, we formulate, by hypothesis, the existence of a ŖFourth paradigmŗ, which is a result of the appearance of the first psychotropic drug, of psychopharmacology and of what we call the Ŗpharmaceutical apparatus.ŗ These new components and devices will have consequences in the clinical diagnosis, the nosology and the current criteria in all the field of psychopathology. Even if a field of psychiatric knowledge pre-exists this apparatus, it is the latter that will shake up this field, transform it, reshape its contours and trigger the rupture with the elements previously established by classical psychiatry and psychoanalysis. This overhaul will produce new types of Ŗdisordersŗ: this is what we will call Ŗpharmaco-modified disordersŗ and Ŗpharmaco-derived disordersŗ or Ŗnew syndromesŗ. Moreover, these apparatuses will change forever how one conceives psychotherapy and the various treatments included in the praxis of the psychological field. The Ŗpharmaceutical apparatusŗ and the breach opened by the drug will also redesign and allow the emergence of new forms of psychotherapy. The incidence of evidence-based medicine on psychotherapy and the rise in the last twenty years of empirically supported therapy (mainly cognitive behavior therapies) will result in the entry of a school of psychotherapeutic thought that belongs to the ŖFourth paradigm

Dissertation (DSc)-- Stellenbosch University, 2008.
ENGLISH ABSTRACT: The overall aim of these studies was to investigate selected aspects of psychopathology, neurobiological abnormalities and treatment in schizophrenia. The following topics were researched: 1. Psychopathology: We explored the symptom structure of schizophrenia by means of principal components and factor analysis in two separate samples. a. The first study investigated the nature of symptoms in patients with a first-episode of schizophrenia, in a large cohort of patients who were participating in a multinational clinical trial. We compared our findings with similar analyses previously conducted in multi-episode schizophrenia patients. b. We then assessed the influence of culture on the symptom structure of schizophrenia by conducting a principal components and factor analysis of the symptom ratings in a large sample of South African Xhosa patients with schizophrenia, and comparing the results with those in other parts of the world. c. We investigated the occurrence of co-morbid depressive and anxiety symptoms, and their demographic and clinical correlates. The sample for this study comprised acutely psychotic patients who were participants in clinical drug trials conducted at our centre. d. To explore the relationships between obsessive-compulsive disorder and schizophrenia, we conducted a review of the relevant literature. 2. Neurobiological abnormalities: a. We performed a series of studies to investigate disorders of water homeostasis and vasopressin secretion in schizophrenia. To test the hypothesis that acutely psychotic patients have disordered regulation of water homeostasis, we applied a dynamic suppression test - a water loading test, with assessment of excretory capacity (including arginine vasopressin assay) in acutely psychotic patients. To evaluate whether a subset of patients with schizophrenia and co-morbid disordered water homeostasis sustained cerebral damage as a consequence of water intoxication we did the following experiment: We identified a cohort of subjects with schizophrenia and disordered water homeostasis and compared them with patients with schizophrenia without disordered water homeostasis in terms of cerebral ventricular size and cognitive function. To assess the prevalence of disordered water homeostasis in a long-term inpatient sample of psychiatric patients we conducted serum sodium screening tests. Those subjects with dilutional hyponatraemia were then further investigated for dysregulation of water homeostatic mechanisms. b. We studied neurological soft signs in a sample of subjects with first-episode schizophrenia followed up over a two year period. We investigated their occurrence, relationships to psychiatric symptoms and medication effects, their temporal stability and their outcome correlates. We also investigated their potential to predict outcome in schizophrenia 3. Treatment aspects A great deal of our work has focussed on the pharmacological treatment of schizophrenia. The following aspects of treatment are included in this thesis: a. Treatment effects on psychiatric symptoms: i. To assess the effects of ethnicity on treatment outcome in schizophrenia we compared the acute response to antipsychotic treatment in 3 ethnic groups, namely blacks, coloureds and whites. We included patients in this analysis who had participated in clinical trials in our department as well as the Department of Psychiatry in the University of the Free Sate. Patients had been treated under blinded conditions over a 6-week period. ii. After discussions with the late Dr David Horrobin, who had pioneered possible applications of the omega-3 fatty acids in the treatment of various psychiatric disorders, we became interested in further investigating the potential of this group of compounds as an affordable adjunct to treating schizophrenia. We assessed the antipsychotic potential of the omega-3 fatty acid, ethyl-eicosapentaenoic-acid (e-EPA) supplementation versus placebo supplementation in a small sample of subjects with schizophrenia who had been only partially responsive to antipsychotic treatment previously. We also conducted a review of the literature to evaluate the evidence for efficacy for the omega-3 fatty acids in schizophrenia according to published studies. b. Treatment effects on neurological abnormalities: i. In a single-blinded controlled study we compared a new generation antipsychotic to a conventional antipsychotic in the treatment of tardive dyskinesia (TD). This was a long-term (1 yr) study in patients with chronic schizophrenia and established tardive dyskinesia. ii. We also assessed the effect of omega-3 fatty acid (e-EPA) supplementation in treating TD. This was conducted in a larger sample (n=84) of patients with chronic schizophrenia and established TD. The blinded, placebo-controlled phase was 12 weeks. This was followed by an open-label extension for 40 weeks. c. Conventional versus new generation antipsychotic agents. Several evidence-based literature reviews of the efficacy and tolerability of the new generation of antipsychotics compared to the conventional agents were conducted. Some multinational, randomised, controlled clinical trials in which the author was principal investigator, are included in this thesis. Also, studies addressing patients with partial treatment refractoriness are included, as well as studies of the effects of antipsychotics on depressive symptoms, body mass and glycaemic control. Finally, we have included a pharmacoeconomic study comparing a conventional antipsychotic (haloperidol) with a new generation antipsychotic (quetiapine) in partially refractory patients in a South African setting. Findings and conclusions: 1. Psychopathology: Our studies demonstrated that the factor structure for the symptoms of schizophrenia is replicable across samples, and is not greatly influenced by ethnic and cultural factors. However, changes in the factor structures do occur over time. There are symptom domains that are present in first-episode schizophrenia but disappear as a distinct entity as the illness becomes chronic. Particularly, a motor component is evident in untreated patients, but disappears after initiation of treatment. We found that depression and anxiety are common co-morbid symptoms in schizophrenia, and have important clinical and outcome correlates. Depressive symptoms in the acute psychotic phase of schizophrenia are associated with a favourable prognosis and diminish as the symptoms of psychosis improve in response to antipsychotic treatment. However, persistent depressive symptoms are associated with a poorer prognosis, and require additional therapeutic intervention. 2. Neurobiological abnormalities: We investigated the occurrence of disordered water regulation in a population of psychiatric inpatients, and conducted further investigations on those identified, in order to establish mechanisms involved. Polydipsia and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) were found to occur in a subset of patients with schizophrenia, and are associated with acute psychosis, as well as with some psychotropic medications. These patients are characterised by more severe cognitive impairment and evidence of cerebral atrophy. The condition can become life-threatening in the presence of other factors impeding water excretion, particularly thiazide diuretics. Neurological soft signs were investigated in a sample of patients with a first-episode of schizophrenia. These soft signs appear to be trait-like (present early in the illness, and stable over time), except for a motor sequencing factor. Patients performing poorly on this latter group of tests have a longer duration of untreated psychosis, and are at significant risk for developing TD. 3. Treatment aspects: Our studies suggest that there are important ethnic differences in antipsychotic treatment response, but that these differences could be explained by a number of environmental and biological factors. As was found with many studies worldwide, we found that the new generation antipsychotics have important efficacy and safety advantages over their predecessors. Risperidone was as effective as haloperidol in first-episode psychosis, but with a more favourable side-effect profile in terms of reduced extrapyramidal symptoms. Quetiapine treatment in partially refractory patients resulted in more responders compared to haloperidol, and fewer extrapyramidal symptoms. However, evidence of a different side-effect profile is emerging. Of particular concern is the finding that some of the new antispychotics cause weight gain, glucose intolerance and dyslipidaemias. We found that one novel antipsychotic, quetiapine, was not associated with significantly more weight gain or disordered glucose metabolism that a conventional agent, haloperidol. The omega-3 fatty acids, particularly EPA may have a role in the treatment of various psychiatric disorders. Our studies provided mixed results – the first found a significant beneficial effect on psychotic symptoms and dyskinesia scores for EPA supplementation, while the second failed to demonstrate a beneficial effect on TD or psychotic symptoms. We explored the early treatment response in first-episode psychosis and found, unlike that reported in multi-episode patients, some patients took a long time to respond. We also found that early treatment response was a significant predictor of later remission, as was duration of untreated psychosis, educational level and baseline excitement factor scores. Finally, our pharmacoeconomic study conducted for South African circumstances in patients with a partial response to conventional antipsychotic treatment showed cost-neutrality or cost-benefits for quetiapine compared with haloperidol treatment for direct costs.
AFRIKAANSE OPSOMMING: Die oorkoepelende doel van hierdie studies was om geselekteerde aspekte van psigopatologie, neurobiologiese abnormaliteite en behandeling in skisofrenie te ondersoek. Die volgende onderwerpe is nagevors: 4. Psigopatologie: Ons het die simptoomstruktuur van skisofrenie ondersoek deur middel van hoofkomponent- en faktoranalise in twee aparte steekproewe. a. Die eerste studie het die aard van simptome in pasiënte, met ʼn eerste-episode van skisofrenie, ondersoek in ʼn groot kohort van pasiënte wat deelgeneem het aan ʼn multi-nasionale kliniese proefneming. Ons het ons bevindinge vergelyk met soortgelyke analises wat voorheen gedoen is in multi-eposode skisofrenie pasiënte. b. Hierna het ons die invloed van kultuur op die simptoom struktuur van skisofrenie geassesseer deur ʼn hoofkomponent- en faktoranalise van die simptoomtellings uit te voer in ʼn groot steekproef van Suid-Afrikaanse Xhosa pasiënte met skisofrenie en die resultate te vergelyk met bevindinge in ander dele van die wêreld. c. Ons het die voorkoms van ko-morbiede depressiewe en angssimptome ondersoek, asook hul demografiese en kliniese korrelate. Die steekproef vir hierdie studie het bestaan uit akute psigotiese pasiënte wat deelnemers was in ʼn kliniese geneesmiddel proef wat uitgevoer is by ons sentrum. d. Om die verband tussen obsessief-kompulsiewe steurnis en skisofrenie te verken, het ons ʼn oorsig van die relevante literatuur gedoen. 5. Neurobiologiese abnormaliteite: a. Ons het ʼn reeks studies uitgevoer om steurnisse in water homeostase en vasopressien sekresie in skisofrenie te ondersoek. Om die hipotese dat akute psigotiese pasiënte versteurde regulering van water homeostase het te ondersoek, het ons ʼn dinamiese onderdrukkingstoets toegepas – ʼn water ladingstoets, met assessering van ekskresiekapasiteit (insluitend arginien vasopressien essai) in akute psigotiese pasiënte. Om te evalueer of ʼn onderafdeling van skisofrenie pasiënte met ko-morbiede versteurde water homeostase serebrale skade opgedoen het as gevolg van water intoksikasie, het ons die volgende eksperiment uitgevoer: Ons het ʼn kohort deelnemers met skisofrenie en versteurde water homeostase geïdentifiseer en hulle vergelyk met skisofrenie pasiënte sonder versteurde water homeostase in terme van serebrale ventrikulêre grootte en kognitiewe funksionering. Om die voorkoms van versteurde water homeostase in ʼn langtermyn binne-pasiënt steekproef van psigiatriese pasiënte te bepaal, het ons serum natrium siftingstoetse uitgevoer. Deelnemers met hiponatremie is hierna verder ondersoek vir disregulering van water homeostatiese meganismes. b. Ons het neurologiese sagte tekens in ʼn steekproef van deelnemers met eersteepisode skisofrenie bestudeer en opgevolg oor ʼn twee jaar tydperk. Ons het hulle voorkoms, verwantskappe met psigiatriese simptome en medikasie effekte, hulle temporale stabiliteit en hul uitkoms korrelate ondersoek. Ons het ook hulle potensiaal om die uitkoms in skisofrenie te voorspel, ondersoek. 6. Behandelings aspekte ʼn Groot meerderheid van ons werk het gefokus op die farmakologiese behandeling van skisofrenie. Die volgende aspekte van behandeling is ingesluit in hierdie tesis: a. Behandelingseffekte op psigiatriese simptome: i. Om die effek van etnisiteit op behandelingsuitkoms in skisofrenie te assesseer, het ons die akute respons op anti-psigotiese behandeling in 3 etniese groepe vergelyk, naamlik swart, gekleurd, en wit. Ons het pasiënte wat deelgeneem het aan kliniese proefnemings in ons departement sowel as die Departement Psigiatrie van die Universiteit van die Vrystaan ingesluit in hierdie analise. Pasiënte is behadel onder geblinde toestande oor ʼn tydperk van 6 weke. ii. Na besprekings met wyle Dr David Horrobin, wie die moontlike toepassings van omega-3 vetsure in die behandeling van verskeie psigiatreise steurnisse gepionier het, het ons begin belangstel in verdere ondersoek na die potensiaal van hierdie groep samestellings as ʼn bekostigbare toevoeging in die behandeling van skisofrenie. Ons het die anti-psigotiese potensiaal van die omega-3 vetsuur, etieleikosapentanoësuur (e-EPA) supplementasie versus plasebo supplementasie ondersoek in ʼn klein steekproef van deelnemers met skisofrenie wat slegs gedeeltelik responsief was op anti-psigotiese behandeling in die verlede. Ons het ook ʼn literatuuroorsig gedoen om die bewyse vir die effektiwiteit vir die omega-3 vetsure in skisofrenie te evalueer volgens gepubliseerde studies. b. Behandelingseffekte op neurologiese abnormaliteite: i. In ʼn enkelblinde kontrole studie het ons ʼn nuwe generasie anti-psigotiese medikasie vergelyk met ʼn konvensionele anti-psigotiese medikasie in die behandeling van tardiewe diskinesie (TD). Hierdie was ʼn langtermyn (1- jaar) studie in pasiënte met chroniese skisofrenie en vasgestelde TD. ii. Ons het ook die effek van omega-3 vetsuur (e-EPA) suplementasie geassesseer in die behandeling van TD. Dit was gedoen in ʼn groter steekproef (n=84) van pasiënte met chroniese skisofrenie en vasgestelde TD. Die blinde, placebo kontrole fase was 12 weke. Dit is gevolg deur ʼn nie-geblinde ekstensie vir 40 weke. c. Konvensionele versus nuwe generasie anti-psigotiese agente. Verskeie bewys-gebaseerde literatuuroorsigte oor die effektiwiteit en toleransie van die nuwe generasie anti-psigotiese agente in vergelyking met die konvensionele agente, is gedoen. Sommige multi-nasionale, ewekansige, kontole kliniese proefnemings waarin die outeur die hoofnavorser was, is ingesluit in hierdie tesis. Verder, studies wat die pasiënte met gedeeltelike behandelingsweerstandigheid aanspreek, is ingesluit, sowel as studies oor die effekte van anti-psigotiese agente op depressiewe simptome, liggaamsmassa en glisemiese kontrole. Laastens, het ons a farmakoekonomiese studie ingesluit wat die konvensionele anti-psigotiese behandeling (haloperidol) met ʼn nuwe generasie anti-psigotiese behandeling (quetiapien) in gedeeltelik weerstandige pasiënte in ʼn Suid-Afrikaanse ligging vergelyk. Bevindinge en gevolgtrekkings: 4. Psigopatologie: Ons studies het gedemonstreer dat die faktor struktuur vir die simptome van skisofrenie herhaalbaar is oor steekproewe, en dat dit nie grootliks beïnvloed word deur etnisiteit en kulturele faktore nie. Veranderinge vind egter in die faktor strukture wel plaas met verloop van tyd. Daar is simptoom domeine wat teenwoordig is in eerste-episode skisofrenie, maar verdwyn as ʼn afsonderlike entiteit soos wat die toestand chronies word. Spesifiek, ʼn motoriese komponent is duidelik in onbehandelde pasiënte, maar verdwyn na die aanvang van behandeling. Ons het gevind dat depressie en angs algemene ko-morbiede simptome in skisofrenie is en het belangrike kliniese en uitkoms korrelate. Depressiewe simptome in die akute psigotiese fase van skisofrenie word geassosieer met ʼn gunstige prognose en verminder soos wat die simptome van psigose verbeter in repons op anti-psigotiese behandeling. Egter, volgehoue depressiewe simptome word geassosieer met ʼn swakker prognose en benodig addisionele terepeutiese intervensie. 5. Neurobiologiese abnormaliteite: Ons het die voorkoms van versteurde water regulering ondersoek in ʼn populasie van psigiatriese binne-pasiënte en verdere ondersoek ingestel op dié wie geïdentifiseer is, om die betrokke meganismes vas te stel. Polidipsie en en die sindroom van onvoldoende antidiuretiese hormoon sekresie (SIADH) is gevind om voor te kom in ʼn onderafdeling van pasiënte met skisofrenie, en word geassosieer met akute psigose sowel as met somige psigotropiese medikasie. Hierdie pasiënte word gekenmerk deur meer ernstige kognitiewe beperking en bewyse van serebrale atrofie. Die toestand kan lewensbedreigend raak in die teenwoordigheid van ander faktore wat water ekskresie hinder, veral tiasied diuretikums. Neurologiese sagte tekens is ondersoek in ʼn steekproef van pasiënte met eerste-episode skisofrenie. Hierdie sagte tekens blyk om kenmerkend (teenwoordig vroeg in die siekte, en stabiel oor tyd) te wees, behalwe vir ʼn motoriese volgorde faktor. Pasiënte wat swak vaar op die laasgenoemde groep toetse, het ʼn langer durasie van onbehandelde psigose, en het ʼn beduidende risko om TD te ontwikkel. 6. Behandeling aspekte: Ons studies stel voor dat daar ʼn belangrigke etniese verskil is in anti-psigotiese behandelingsrespons, maar dat hierdie verskille verduidelik kan word deur ʼn aantal omgewings- en biologiese faktore. Soos wat gevind was vir verskeie studies wêreldwyd, het ons gevind dat die nuwe generasie anti-psigotiese agente belangrike effektiwiteit- en veiligheidsvoordele het bo hulle voorgangers. Risperidoon was net so effektief as haloperidol in eerste-episode psigose, maar met ʼn meer gunstige newe-effkte profiel in terme van verminderde ekstrapirimidale simptome. Quetiapien behandeling in veral refraktêre pasiënte het gelei tot meer respondeerders vergeleke met haloperidol, en minder ekstra pirimidale simptome. Alhoewel, bewyse van ʼn verskillende newe-effekte profiel is besig om na vore te kom. Van spesifieke belang is die bevinding dat sommige van die nuwe anti-psigotiese agente gewigstoename, glukose intoleransie en dyslipidemie veroorsaak. Ons het gevind dat een nuwe anti-psigotiese agent, quetiapien, nie geassosieer was met enige beduidende meer gewigstoename of versteurde glukose metabolisme as ʼn konvensionele agent, haloperidol, nie. Die omega-3 vetsure, spesifiek EPA mag moontlik ʼn rol in die behandeling van verskeie psigiatriese versteurings hê. Ons studies het gemengde resultate voorsien – die eerste het ʼn beduidende voordelige effek op psigotiese simptome en diskinesie tellings vir EPA supplementasie gevind, terwyl die tweede nie ʼn voordelige effek op TD of psigotiese simptome gevind het nie. Ons het die vroeë behandelingsrespons ondersoek in eersteepisode pasiënte en het gevind, in teenstelling met dit wat gerapporteer word in multi-episode pasiënte, dat sommige pasiënte ʼn lang tyd geneem het om te reaggeer. Ons het ook gevind dat vroeë behandelingsrespons ʼn beduidende voorspeller was van latere remissie, so ook die durasie van onbehandelde psigose, opvoedingspeil, en basisvlak opwindings-faktor tellings. Laastens het ons farma-ekonomiese studie, wat uitgevoer is vir Suid-Afrikaanse omstandighede in pasiënte met ʼn gedeeltelike repons op konvensionele anti-psigotiese behandeling, koste-neutraliteit of koste-voordele aangetoon vir quetiapien vergeleke met haloperidol behandeling vir direkte onkostes.

The study used a non-invasive technique, the Tilt Aftereffect (TAE) test, to investigate the visual changes influenced by dopamine (DA) in schizophrenia. One-third of forty five schizophrenic patients could not complete the TAE test and this group was found to have impaired sustained attention and to have different demographic and clinical characteristics from the schizophrenic patients who could complete the TAE test. TAE changes were found only in response to DA changes brought about by altering neuroleptic levels, e.g. 'before' compared with 'after' a depot injection. These changes were only found when gratings of 2 c/d were used and not for 10 c/d. No illness or drug effect was found using the TAE test. A similarity in the pattern of change over time was found for the TAE test using 2 c/d gratings and the peak spatial frequency (SF) from the Contrast Sensitivity (CS) test in response to changes in levels of DA. A decrease in DA caused a shift of the CS peak to lower SFs, with a decrease in sensitivity for mid to high SFs (3 - 10 c/d) and an increase in sensitivity for low SFs (0.5, 1 c/d). The findings suggest that both the TAE and CS tests are influenced by DA and that lateral inhibition alone cannot explain the production of the TAE since the influence of the orientation of the adapting gratings on the size of the TAE indicates that an adaptation process is involved. It is suggested that the transient system, which is sensitive to low spatial and high temporal frequencies, may be selectively affected by DA changes.

Interval timing behaviour refers to the ability of animals and humans to adapt their behaviour to temporal regularities in their environments. Two important classes of interval timing behaviour are temporal discrimination (discriminating between the durations of external events) and temporal differentiation (behavioural adaptation during an ongoing interval). It has been known for many years that drugs that affect central dopaminergic function can alter both forms of timing behaviour. More recently, evidence has been accumulated which shows that manipulation of central 5-hydroxytryptaminergic (5-HTergic) function can also influence interval timing behaviour. The experiments described in this thesis examined the effects of drugs acting at some subtypes of 5-HT receptors on temporal discrimination and temporal differentiation in the rat. Chapter 1 contains a review of the relevant literature. First, the anatomy, biochemistry and receptor pharmacology of the 5-HTergic system is outlined, and a selective review of the role of 5-HT in some behaviours relevant to this project is presented. This is followed by an overview of the behavioural methodology that has been used to study timing behaviour in animals, and an account of the major theories of timing behaviour. Finally, the behavioural pharmacology of timing behaviour is reviewed. Chapters 2-7 describe a series of experiments examining the effects of drugs acting at 5-HT1A, 5-HT2A/2C, and 5-HT3 receptors on temporal discrimination and temporal differentiation. Experiment 1 examined the effect of the 5-HT3 receptor agonist m-chlorophenylbiguanide (m-CPBG) and the non-selective agonist quipazine on temporal discrimination performance in the discrete-trials psychophysical procedure. Quipazine produced a dose-dependent disruption of temporal discrimination, consisting of a rightward displacement and flattening of the fitted psychometric function, reflected in a significant increase in the values of the indifference point T50 and the Weber fraction. m-CPBG had no significant effect on either T50 or the Weber fraction. The effects of quipazine were completely abolished by the 5-HT2A receptor antagonist ketanserin, but not by the 5-HT3 receptor antagonist topanyl 3,5-dichlorobenzoate (MDL-72222), indicating that the effect of quipazine was mediated by 5-HT 2A, and not 5-HT 3 receptors. In experiment 2, the effects of quipazine and m-CPBG were examined on temporal differentiation performance in the free-operant psychophysical procedure. Quipazine dose-dependently displaced the psychometric function to the left, reducing the value of T50, and significantly increased the Weber fraction. m-CPBG had no effect on the parameters of the function. The effects of quipazine were reversed by co-administration of ketanserin, but not by co-administration of MD L-72222. These results suggest that while 5-HT 2A receptor stimulation has a robust influence on temporal differentiation, 5-HT3 receptor stimulation does not. Experiment 3 further examined the effect of 5-HT2A receptor stimulation on temporal discrimination. The 5-HT 2A/2C receptor agonist 2,5- dimethoxy-4-iodoamphetamine (DOI) increased the Weber fraction and tended to increase T50. Ketanserin and the highly selective 5-HT2A receptor antagonist (± )2,3-dimethoxyphenyl-1-(2-( 4-piperidine )-methanol) (MDL-I00907) fully antagonized the effects of DOI The results indicate that DOI disrupts temporal discrimination via stimulation of 5-HT2A receptors. Experiment 4 examined whether intra-striatal injection of DOI would affect temporal discrimination, and whether the effect of systemically administered DOI on temporal discrimination would be blocked either by MDL-100907 or by 8-( 5 -(2, 4-dimethoxy-5 -( trifluoromethylphenylsulphonamido )phenyl-5-oxopentyl)-1 ,3,8- riazaspiro( 4.5)decane-2,4-dione RS- 102221: a selective 5-HT2C receptor antagonist), administered directly into the dorsal striatum. Intra-striatal injection of DOI did not affect temporal discrimination. Systemically administered DOI disrupted temporal discrimination; this effect was not attenuated by intra-striatal injection of MDL-100907 or RS102221, suggesting that the 5-HT2 receptors that mediate DOI's effect on temporal discrimination are not located in the dorsal striatum. Experiments 5 and 6 examined the effects of intra-striatally administered DOI, MDL-100907 and RS-102221 on temporal differentiation. In experiment 5, systemic injection of DOI significantly reduced T50. This effect was antagonized by systemically administered MDL-100907. In experiment 6, intra-striatally administered DOI had no significant effect on T50 or the Weber fraction. Intra-striatal injections of MDL-100907 and RS-102221 did not alter temporal differentiation, and failed to reverse the effects of systemically administered DOI. The results suggest that the 5-HT2 receptor population responsible for DOI’s effect on temporal differentiation is not located in the dorsal striatum. Experiment 7 examined the effect of a 5-HT1A and a 5-HT2A receptor agonist on another widely-used temporal differentiation schedule, the fixed interval peak procedure. The 5-HT1A receptor agonist 8-hydroxy-2-( di-n-propylamino) tetralin (8-0H-DPAT) and the 5-HT2A/2C receptor agonist DOI had similar effects on performance: both agonists displaced the peak function to the left and reduced the peak time, tpeak. The effect of 8-0H-DPAT was antagonized by the selective 5-HT1A receptor antagonist N-[2-( 4-[2-methoxyphenyl]- 1-piperazinyl)ethyl]-N-2-pyridinylcyclohexane-carboxamide (WAY- 100635), and the effect of DOI by the 5-HT2A receptor antagonist ketanserin, respectively. These results, taken together with previous findings with the free-operant psychophysical procedure, suggest that 5-HT1A and 5-HT2A receptors mediate similar effects on temporal differentiation. The final chapter (Chapter 8) summarizes the findings from the project, and discusses their implications for the putative role of 5-HT in interval timing and for current theoretical accounts of timing. It is argued that current models of timing behaviour that assume the existence of a unitary 'pacemaker-driven' internal clock may have difficulty accommodating the finding that the same drug can have qualitatively different effects on temporal discrimination and temporal differentiation. Some possible directions for future research in this area are also discussed.

In 2019, the Italian Supreme Court established that hemp, for non-medical use, cannot be commercialized for human use, when the “psychotropic effect” of the product or its “offensiveness” can be demonstrated. The first chapter of this work reports a review of the European and Italian legislation on hemp cultivation, as well as the hemp production chain and commercial activities. The second chapter reports the pharmacological aspects and the psychoactive effects of light cannabis, along with pharmacokinetics of the main Cannabis compounds: Δ9-tetrahydrocannabinol (Δ9-THC), Cannabidiol (CBD) and Cannabinol (CBN). The aim of the experimental study, reported in the third chapter, is to assess Δ9-THC and CBD blood concentrations after smoking “light cannabis”, and its effects on vigilance, cognitive and motor skills. Eighteen young adults consumed three light cannabis cigarettes with a percentage of 0.41% of Δ9-THC and of 12.41% of CBD. Blood samples were collected before the experiment (t0) and after pre-defined time-lapses. Five performance tasks and a subjective scale were employed for measuring cognitive and psychomotor performances the day before the experiment (TT0) and after the third cigarette (TT1). Mean (SD) concentrations (ng/ml) were between 1.0(0.8) in t1 and 0.3(0.3) in t5 for Δ9-THC; and 10.5(10.3) in t1 and 5.7(5.7) in t5 for CBD. No significant differences were observed between TT0 and TT1 for all performed psychomotor performance task. Δ9-THC and CBD concentrations showed a high inter-subject variability, and the average concentrations were lower than those previously reported. Toxicological results showed a decrease of Δ9-THC and CBD after the third light cannabis cigarette, and a Δ9-THC /CBD ratio always < 1 was observed. This value might be useful in discriminating light cannabis versus illegal/medical cannabis consumption. The lack of impairment observed in our participants can be interpreted as a consequence of the very low concentrations in the blood.
Nel 2019, una sentenza della Suprema Corte di Cassazione ha stabilito che la canapa, al di fuori degli usi medici, non può essere commercializzata se destinata al consumo umano, qualora sia dimostrata la "capacità drogante" del prodotto. Il primo capitolo dell’elaborato di tesi riporta una revisione della legislazione Italiana ed Europea sulla coltivazione della canapa e sulla catena produttiva e di commercio. Il secondo capitolo presenta gli aspetti farmacologici dei principali composti della canapa, il Δ9-tetraidrocannabinolo(Δ9-THC), il Cannabidiolo(CBD) ed il Cannabinolo(CBN). Il terzo capitolo riporta lo studio sperimentale, il cui scopo è quello di studiare la farmacocinetica e le proprietà psicotrope della cosiddetta "cannabis light". Diciotto giovani adulti hanno consumato in condizioni sperimentali tre sigarette contenenti cannabis light, con una percentuale di Δ9-THC dello 0.41% e di CBD del 12.41%. Sono stati raccolti ed analizzati campioni ematici prima dell'esperimento (t0) e dopo periodi di tempo predefiniti. Cinque test di performance psicomotori sono stati somministrati il giorno prima dell'esperimento (TT0) e dopo la terza sigaretta (TT1). Le concentrazioni medie (Dev.st.) in ng/ml rilevate erano comprese tra 1.0(0.8) in t1 e 0.3(0.3) in t5 per il Δ9-THC; e tra 10.5(10.3) in t1 e 5.7(5.7) in t5 per il CBD. Non sono state osservate differenze significative tra i risultati dei test psicomotori tra TT0 e TT1. Il Δ9-THC ed il CBD hanno mostrato un'ampia variabilità inter-individuale, e le concentrazioni medie osservate nel presente studio si sono rilevate inferiori a quelle già riportate su popolazioni ridotte. E’ stata osservata una riduzione della concentrazione di entrambi i composti dopo la terza sigaretta, ed un rapporto Δ9-THC/CBD sempre inferiore a 1. Questo valore potrebbe essere utilizzato per discriminare tra utilizzo di cannabis light e cannabis con elevata percentuale di Δ9-THC. La mancanza di impairment psicomotorio potrebbe essere interpretata come una conseguenza delle basse concentrazioni ematiche.

Antipsychotic drugs are the mainstay of treatment for psychotic disorders according to the Standard Treatment Guidelines (2012). However, these drugs are associated with multiple severe adverse drug reactions. In order to limit the effect of adverse drug reactions on patient care, documentation is necessary. Documentation of adverse drug reactions entails recording the reaction experienced, as well as supplementary information. Proper documentation can prevent future occurrences of the same or similar adverse drug reactions. The aim of this study was to determine the effects of an educational intervention targeting increasing documentation of the adverse effects of antipsychotic drugs. The objectives of the study were: to determine the pre-intervention extent and frequency of documentation of antipsychotic-related adverse drug reactions in the patient medical record; to implement an intervention aimed at educating the relevant healthcare professionals, focusing on the adverse drug reactions of antipsychotic drugs and how to record or document these reactions; to assess the post-intervention extent and frequency of documentation of antipsychotic-related adverse drug reactions in the patient medical record; and to assess the attitude of healthcare providers towards the documentation of antipsychotic related adverse drug reactions before and after the intervention.

Cognitive impairments are a common feature of neurological and neuropsychiatric disorders, as well as of substance-abuse disorders. The impairments seen in these disorders can be caused by disruptions to common neural substrates, and therefore pharmacological agents can be repositioned from use in neuropsychiatric to neurological disorders, and vice versa. Together, these disorders have been estimated to comprise 13% of the global burden of disease. Indeed, an individual’s ability to successfully perform everyday activities can be limited by deficits in crucial cognitive functions such as attention, response inhibition, planning and working memory. Frontal-striatal networks in the brain have been shown to underlie these vital functions, which are modulated by neurotransmitters including acetylcholine, dopamine, and noradrenaline. Importantly, these functions are susceptible to pharmacological intervention with drugs such as physostigmine, modafinil, and atomoxetine. In order to explore the nature of a variety of forms of cognitive impairment, which were diverse in severity from mild to more severe, studies were carried out on amateur boxers and sleep-deprived doctors, as well as on patients with subarachnoid haemorrhage (SAH) and on patients with Parkinson’s disease (PD). Quantification of cognitive impairment is the crucial first step in determining which neural networks are involved, and thus which pharmacological agents would be suitable candidates for treatment. A longitudinal study was carried out using a comprehensive battery of well-validated cognitive tasks, in order to quantify the change in cognitive ability in healthy individuals who participated in amateur boxing. Subtle cognitive impairments, which were related to structural changes, were documented. Using existing understanding of pharmacological agents, novel treatments for cognitive impairments were explored in relation to sleep-deprived doctors, as well as to PD and SAH patients. A novel treatment for specific cognitive problems in PD was investigated: atomoxetine, a noradrenaline reuptake inhibitor. A double-blind placebo-controlled study revealed that atomoxetine may be a candidate for treatment of response inhibition impairments seen in PD. This finding is important as noradrenergic treatments are not currently used in PD, despite degeneration in the locus coeruleus, the main cortical source of noradrenaline. Another novel treatment explored was modafinil, a drug that has also been shown to modulate the noradrenergic system, as well as the dopaminergic system. Modafinil is currently licensed for use in narcolepsy and shift work sleep disorder. It was found that modafinil remediates task set-switching impairments and reduces impulsivity in sleep-deprived doctors. Furthermore, it was shown that modafinil might be a potential treatment for cognitive impairments found in neurological patients with SAH. In contrast to this, physostigmine, a cholinesterase inhibitor, did not seem to alter the cognitive symptoms investigated. To summarise, this thesis aims to quantify cognitive impairment in a range of groups, and to explore the potential use of existing pharmacological agents that could be repurposed to treat cognitive impairments in novel ways.

Previous work on the unconditioned effects of amphetamine in rats has examined qualitative changes in behaviours which become stereotyped and quantitative changes in locomotion. Stereotyped behaviours have been adopted as a model of raised caudate-putameri function whilst locomotion has been adopted as a model of raised mesolimbic dopamine function. These models have been used to study drugs which are effective in the treatment of schizophrenia. Only locomotion is reliably antagonised by all classes of antipsychotic drugs, although it has been hypothesised that, under some doses of amphetamine, locomotion may also become stereotyped. The Lyon-Robbins hypothesis of the behavioural effects of amphetamine predicts competition between the output of the mesolimbic and caudate-putamen, and would predict that stereotyped locomotion represents a 'blending' of mesolimbic and caudate-putamen behavioural output. An experiment was conducted to test the Lyon-Robbins hypothesis using contrast-based image analysis to determine the spatio-temporal characteristics of open-field locomotion. A further four experiments examined the effects of a classic antipsychotic (haloperidol), the atypical antipsychotics (clozapine and sulpiride) and a putative antipsychotic (a 5-HT3 antagonist, ondansetron) on open-field locomotor routes taken by rats following treatment with 3.5mg/kg amphetamine. Measures of stereotyped locomotion derived from image analysis were supported by a novel form of behavioural analysis based on multi-dimensional scaling which provided an integrated analysis of behavioural change following drug treatment. Haloperidol blocked locomotion and stereotyped behaviours including stereotyped locomotion, whereas clozapine, sulpiride and ondansetron blocked locomotion but not stereotyped locomotion and in some cases increased stereotyped behaviours. This suggests that stereotyped locomotion represents synergistic functioning of both mesolimbic and caudate-putamen systems, when the output from the caudate-putamen is insufficient to over-ride that of the mesolimbic system. Antagonism of a 5-HT3 enhancement of mesolimbic locomotor activity by ondansetron allowed latent 5-HT and dopamine mediated behaviours to be expressed. This effectively mimicked a leftwards shift of the amphetamine dose response curve, hypothesised as amplification of the caudate-putamen output. These findings lend support to the Lyon-Robbins hypothesis of the behavioural effects of amphetamine.

Dans son analyse de la démarche de socialisation des enfants, Émile Durkheim met en garde contre « toute action positive destinée à imprimer une orientation déterminée à l’esprit de la jeunesse ». Notre thèse explore les déclinaisons contemporaines de ces « actions positives » qui émanent de l’État et de différents éléments de la société, et qui, en modifiant le fonctionnement cérébral, entendent orienter le comportement d’enfants non malades vers davantage d’attention et moins d’impulsivité. Cette orientation recouvre un enjeu politique : la réduction des inégalités dans les capacités cérébrales, qui tendent à devenir des inégalités majeures dans la société de performance contemporaine. Notre objet de recherche est constitué par les nouveaux pouvoirs exercés par les adultes sur les enfants, au moyen de techniques biomédicales nouvelles, en particulier par des substances chimiques : les médicaments psychostimulants. Les moyens biomédicaux s’exercent directement sur le fonctionnement cérébral, de manière intrusive, sans la médiation du langage et de la communication, et posent de ce fait des nouvelles questions liées à leur puissance d’action. Ce travail se donne pour objectif de contribuer à une théorie de la justice cognitive pour les enfants. Les nouvelles significations des inégalités d’attention dans les apprentissages, les enjeux sociaux de ces inégalités dans une société de performance et les nouvelles possibilités d’intervention biomédicales sur le fonctionnement cérébral des enfants convergent vers de nouvelles formes dans l’économie psychique des enfants. Il semble possible d’interpréter ces nouvelles forces à l’œuvre comme s’inspirant d’un principe de justice. Le débat autour d’une justice cognitive reflète alors le caractère ressenti comme insupportable socialement des inégalités d’attention et le caractère ressenti comme inévitable de la réponse pharmacologique qui lui est associée. Le recours à la théorie d’une justice cognitive implique, pour l’analyse des pratiques de prescription massives de Ritaline, de se situer au-delà du paradigme habituel de contrôle social et de contrôle des comportements par la médicalisation de la société
The analysis of children’s socialization process made by Emile Durkheim warns us against any actions intended to have an impact on the orientation of the young spirits. Our thesis explores the contemporary range of these positive actions issued from the state as well as from different parts of society. Those ones, by modifying the proper cerebral functioning, are guiding the behaviour of non-ill toward more attention and less impulsivness. This subject has a significant political concern: the reduction of cerebral inequal capacities which tend to become more and more important in our contemporary performance oriented society. Our research investigates new powers exerciced by adults on children, through the use of modern biomedical techniques, and particuly through psychostimulant pharmaceuticals. Biomedical tools directly reach the functioning brain, in an intrusive way, without the intermediate of either language or communication, which therefore arises new questions about their power of action. The aim of this study is to contribute to a theory of a cognitive justice for children. The new meanings of the inequalities of focus in learning, the social issues of these inequalities in a performance society and the new possibilities of biomedical intervention on the functioning brain converge towards new forms in psychic economy of children. It seems possible to interpret those new forces in action through a principle of justice. The debate around a cognitive justice reflects the unbearable social aspect of the disparities in attention capacity and the hypothetically unavoidable pharmacological answers associated to it. The solution of the theory of cognitive justice involves, for the pratical analysis of the massive instruction of Ritaline, to be situated beyond the usual paradigm of social control and behavioural control through society’s medicalization

These British Association for Psychopharmacology guidelines cover the range and aims of treatment for anxiety disorders. They are based explicitly on the available evidence and are presented as recommendations to aid clinical decision making in primary and secondary medical care. They may also serve as a source of information for patients and their carers. The recommendations are presented together with a more detailed review of the available evidence. A consensus meeting involving experts in anxiety disorders reviewed the main subject areas and considered the strength of evidence and its clinical implications. The guidelines were constructed after extensive feedback from participants and interested parties. The strength of supporting evidence for recommendations was rated. The guidelines cover the diagnosis of anxiety disorders and key steps in clinical management, including acute treatment, relapse prevention and approaches for patients who do not respond to first-line treatments.

Introduction Alcoholism represents a chronic recurring disorder that affects 15 million people nationwide, 4% of which fall within the adolescent age range (12-17). Clinical data indicate that adolescents who binge drink greatly increase their chances of suffering from several dangerous health outcomes (i.e., suicide, risky sexual behavior, car wreck, etc.) as well as the likelihood they will develop an alcohol-use disorder later in life. Moreover, research indicates that cues (i.e. flavors) paired with alcohol drinking produce significant cue-induced alcohol craving, contributing to relapse in adolescence and adult populations. Therefore, the current study sought to model the effect of adolescent exposure to flavor cues, paired with alcohol, on subsequent cue-induced alcohol-seeking in adulthood. Methods Alcohol naïve alcohol-preferring (P) rats were randomly assigned to a paired or unpaired group. During the adolescent period, all animals had 24-hour access to 3 bottles; (paired group: 0.1% blueberry flavor extract (BB) + 15% v/v alcohol, and two water; unpaired group: 0.1% BB, 15% v/v alcohol, and water). The animal’s body and bottle weights were recorded daily. In the first two weeks of adulthood, all rats experienced daily 60-minute self-administration sessions to measure fluid intake. Paired animals could consume 0.1% BB + 15% alcohol or water and unpaired animals could consume 0.1% BB or 15% alcohol. The following two weeks all rats were kept in their home cage with access to only water. Following this 2 week period of imposed abstinence, rats were returned to the chambers and consumption of 0.1% BB or water was measured to examine cue-induced alcohol-seeking. Results Data indicate adolescent exposure to BB + alcohol did not promote faster acquisition of self-administration. Additionally, during adolescence and adulthood, both groups consumed similar levels of alcohol. When tested for cue-induced alcohol-seeking, paired rats exhibited significant resistance to extinction of sipping on the BB sipper (no alcohol). Conclusions Overall, data suggest that cues paired with alcohol during adolescence and early adulthood may contribute to prolonged alcohol-seeking behavior thus increasing risk of relapse following subsequent cue exposure.

L’innovation thérapeutique est limitée en psychiatrie. De nombreux médicaments sélectionnés sur la base de résultats encourageants dans les essais chez l’animal se révèlent décevants lors des essais cliniques. La validité limitée des modèles animaux, et leur utilisation pour tenter de mimer des pathologies définies de façon catégorielle sur la base de regroupement de symptômes de surface sans lien clair avec les processus cérébraux, les mécanismes biologiques ou la génétique, participent à ces difficultés. Une branche des neurosciences cognitives, l’étude de l’apprentissage par renforcement, associée à l’utilisation d’interventions pharmacologiques ciblées chez le sujet malade ou le sujet sain, représente une opportunité de mieux caractériser les processus cérébraux sous-tendant certaines dimensions cardinales des pathologies psychiatriques. Nous illustrons l’utilisation de l’étude de l’apprentissage par renforcement avec intervention pharmacologique dans deux études expérimentales. La première cherche à caractériser l’effet de l’aripiprazole, un antipsychotique atypique, chez des patients atteints du syndrome Gilles de la Tourette, en utilisant une tâche d’apprentissage contrefactuel, évaluant la capacité à apprendre non seulement des conséquences de ses actions, mais également des conséquences hypothétiques d’actions alternatives possibles. La seconde étude, randomisée contrôlée et en double aveugle, étudie l’effet de deux classes différentes d’antidépresseurs, l’escitalopram et l’agomélatine, chez le sujet sain. L’effet de leur administration est évalué à court terme (3 jours) et à long terme (8 semaines) dans deux tâches probabilistes de sélection de stimulus, l’une simple, l’autre avec renversements occasionnels. L’utilisation de cette approche pourrait participer à la définition d’endophénotypes et, en collaboration avec la recherche préclinique, aider à la création de nouveaux modèles animaux pour en améliorer la valeur prédictive
Successful new drug development has declined in psychiatry in the last decades. This is in part the resut of a high failure rate in translating positive preclinical efficacy results to positive clinical trials. Limitations in the validity of animal models and shortcomings in the usefullnes of the current categorical diagnostic system. Cognitive neurosciences and particularly reinforcement learning and its computational analysis might provide biomarkers required to develop new ways of classifying mental disorders on the basis of both observable behaviour and neurobiological measues. Used in conjunction with pharmacological challenges, it may bring new insights into the physiopahtology and brain mechanisms underlying psychiatric disorders. It may also help design new animal models with imporved predictive validity for the develoment of medications relying on innovative mechanisms of action. We illustrate the use of reinforcement learning and pharmacological challenge in two experimental studies. In the first experiment, we administered a reinforcement learning task that involves both direct learning from obtained outcomes and indirect learning from forgone outcomes to two groups of Gilles de la Tourette patients, one receiving aripiprazole, one unmedicated and to a group of healty subjects. In the second experiment, we administered two probabilistic stimulus selection learning tasks (one simple, one with occasional reversals) to healthy subjects randomly and blindly allocated to either escitalopram, a typical serotonin reuptake inhibitor, agomelatine, an antidepressant with a different mechanism of action, or placebo. The experiment compard the effect of these two classes of antidepressants to placebo after both short term (3 days) and long term (8 weeks) treatment. These experiments bring insights into the understanding of the clinical condition studied, and the effects of the drugs tested. Implications of this approach for the translational approach to drug development is discussed

Psychostimulant dependence is a major public health issue in many parts of the world associated with a wide range of psychological, medical and social problems. Psychosocial interventions are the mainstay of treatment for psychostimulant problems, although their effectiveness is compromised by poor uptake and compliance. Despite increasing knowledge of the neurobiological consequences of psychostimulant use, no medications to date have been any more successful than placebo in reducing psychostimulant use in dependent patients. Modafinil is a non-amphetamine type psychostimulant that may have potential as an agonist pharmacotherapy for psychostimulant dependence. The aim of this thesis was to examine the safety, efficacy and cost-effectiveness of modafinil 200 mg/day over ten weeks plus a four session brief CBT intervention for methamphetamine and cocaine dependence through two concurrent randomised placebo controlled trials. There were no statistically significant differences between modafinil and placebo in treatment retention, medication adherence, psychostimulant abstinence, psychostimulant craving or severity of psychostimulant dependence. Methamphetamine-dependent subjects tended to provide more illicit psychostimulant negative urine samples while in treatment than those who received placebo. There appeared to be a reduction in self-reported days of psychostimulant use among methamphetamine-dependent subjects who received modafinil compared to placebo, but the effect size was too small to be statistically significant in this sample. The reduction in self-reported psychostimulant use did reach statistical significance in methamphetamine-dependent subjects with no other substance dependence. Uptake of counselling was the most significant predictor of reduced psychostimulant use post treatment, and the addition of counselling improved the cost-effectiveness of modafinil relative to placebo. Modafinil appeared to be safe, well-tolerated, and non-reinforcing in this treatment population. Compared to placebo, there was a significant increase in weight in subjects who completed the 10-week course of treatment, and a significant decrease in systolic blood pressure in methamphetamine-dependent subjects who received modafinil. The results support further trials of modafinil in methamphetamine-dependent patients, although future trials in cocaine-dependent patients from this treatment population were not likely to be viable. Modafinil appeared to be modestly effective in reducing, but not stopping, methamphetamine use in selected patients. Multi-centre trials with larger sample sizes, and measures sensitive enough to detect quantitative changes in psychostimulant use would be needed to confirm the findings. Blood pressure and weight may be important indicators of clinical outcome, and warrant particular attention in future trials, particularly given the cardio-toxicity of both methamphetamine and cocaine. Strategies to enhance medication adherence including a higher dose and counselling adherence are recommended to improve outcomes. Given the predominance of behavioural and psychosocial factors in psychostimulant dependence, it is likely that the role of medications such as modafinil will be as an adjunct to psychosocial therapy.

Serotonin (5-HT) has long been implicated in the pathophysiology of depression and anxiety, and the therapeutic effect of treatments. Several drugs useful in treatment produce either acute or neuroadaptive changes in 5-HT_2C receptor activity, and there has been growing interest in how alterations in the 5-HT_2C receptor might be important in mediating antidepressant and anxiolytic activity. The neuropsychological hypothesis of drug action implies that the clinical effects of medications active in anxiety and depression are best understood through the effects of these agents on the processing of emotional information. Thus far, however, there has been no systematic attempt to identify the role of the 5-HT_2C receptor in drug-induced changes in emotional processing in humans. The current research therefore investigated the effects of drug treatments with 5-HT_2C blocking properties on neural and behavioural responses to emotional information in healthy volunteers. An fMRI study demonstrated that a single dose of mirtazapine, an antidepressant with action at the 5-HT_2C receptor, reduces activation in regions important in emotional processing, such as the amygdala and the fusiform gyrus, to threat-relevant stimuli. A series of behavioural studies utilized drugs acting, at least in part, as 5-HT_2C antagonists and agonists to show that these drugs are able to alter emotional processing, particularly emotional memory. A seven-day administration of mirtazapine was shown to increase the recall of positive versus negative personality characteristics. A single dose of agomelatine, also an antidepressant with putative action at the 5-HT_2C receptor, did not increase slow wave sleep, suggesting, the drug had no effect of 5-HT_2C blockade in the brain. In Chapter 4, agomelatine and mCPP, a 5-HT_2C agonist, also shown to had no significant effect on emotional processing measures, but there was a statistical trend for agomelatine to increase memory for positive stimuli, and for mCPP to increase memory for negative stimuli. These findings suggest that antidepressants may work by altering the bias in emotional processing. Overall, the results of this exploration of the role of the 5-HT_2C receptor in emotional processing have contributed to the understanding of antidepressant treatment, and raise new possibilities for the continuation of study in this field.

O uso de drogas de abuso pode levar a alterações neuroplásticas duradouras no encéfalo, entre elas a sensibilização comportamental (SC), um fenômeno relacionado à dependência. O enriquecimento ambiental (EA) permite estudar a influência do ambiente na resposta a diversas manipulações, entre elas o tratamento com drogas de abuso. O objetivo deste trabalho foi avaliar o efeito do EA sobre a SC ao etanol, e sobre a expressão de proteínas envolvidas nas respostas às drogas de abuso: BDNF, TrkB e Egr-1. Para tanto, camundongos foram expostos ao EA, e então tratados repetidamente com uma dose baixa (1,8 g/kg) de etanol. Outros grupos foram submetidos ao protocolo de SC e posteriormente expostos ao EA. O EA protegeu os animais de desenvolverem a SC ao etanol, bem como promoveu sua reversão. O EA diminuiu os níveis de BDNF no córtex pré-frontal e de TrkB no hipocampo, e aumentou a expressão de Egr-1 no córtex insular. O EA pode ser considerado uma estratégia útil para a reversão dos efeitos da SC, que está associada à fissura e a episódios de recaídas na dependência.
The use of addiction drugs can lead to long-term neuroplastic changes on the brain, such as behavioral sensitization (BS), a phenomenon related to addiction. Environmental enrichment (EE) is a strategy used to study the environmental influence on the response to several manipulations, including the treatment with addiction drugs. The aim of this work was to evaluate the effects of EE on the BS to ethanol and on the expression of proteins related to the response to drugs of abuse, as BDNF, TrkB and Egr-1. Thus, mice were exposed to EE and then repeatedly treated with a low dose (1.8 g/kg) of ethanol. Other group of mice was first submitted to the BS protocol and then exposed to EE. EE protected the mice from developing the BS to ethanol, and promoted its reversion. EE decreased BDNF levels in the prefrontal cortex and TrkB in the hippocampus, and increased Egr-1 expression in the insular cortex. EE can be considered and useful strategy to block BS effects, a phenomenon related to craving and relapse.