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京都大学 / 新制・課程博士 / 博士(医学) / 甲第23756号 / 医博第4802号 / 新制||医||1056(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 中山 健夫, 教授 村井 俊哉, 教授 小杉 眞司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Made available in DSpace on 2016-04-04T18:29:26Z (GMT). No. of bitstreams: 1 Rosemarie Elizabeth.pdf: 975117 bytes, checksum: b92177ce882a77c11884e90b9344d9f0 (MD5) Previous issue date: 2006-03-03 / The present study analyzed several causes of psychosocial and environment issues (DSM IV revised axis) affecting the incidence of the major depression (axis I) in young women between 16 and 25 years old assisted at the psychiatric ambulatory unit of the State University of Londrina, UEL. At the first phase of this research, it was studied medical records in a descriptive manner. In the second phase, 32 depressive patients of this ambulatory, who were previously submitted to a structured clinical interview (clinical version Scid-I) and DSM-IV axis (psychosocial and environment issues), were selected for inclusion in the study. In the final phase, it was done a therapeutic group attendance composed only by four patients. The results emphasized the significance of the union in a collaborative research, as much as the presence of a holding environment, through the transitional space, which offered perspectives of continuity of the group therapy, with their expectative the cure of depression / O presente estudo investigou a determina??o de v?rios problemas pssicossociais e ambientais (eixo DSM-IV revisado) na incid?ncia da depress?o maior (eixo I), em mulheres jovens com idades entre 16 e 25 anos, atendidas no ambulat?rio de psiquiatria da Universidade Estadual de Londrina, UEL. Na primeira etapa desta pesquisa, foram analisados prontu?rios m?dicos de modo descritivo. Na segunda etapa, foram selecionadas 32 pacientes com depress?o maior, e que foram previamente submetidas ? entrevista cl?nica estruturada (Scid-I vers?o cl?nica) e eixo IV do DSM-IV (problemas pssicossociais e ambientais), para inclus?o no estudo. Na etapa final, foi realizada a consulta terap?utica em grupo, realizada somente em 04 pacientes. Os resultados enfatizaram a import?ncia da integra??o em uma pesquisa colaborativa, bem como a exist?ncia de um ambiente de holding , atrav?s do espa?o transicional oferecido com perspectivas de continuidade deste atendimento em grupo, tendo como expectativa a cura da depress?o

Le cortex est une structure qui supporte de nombreux processus tels que perception sensorielle, processus cognitifs et mémorisation. Il fonctionne grâce à une association de neurones excitateurs (E) et inhibiteurs (I) interconnectés de façon récurrente par des synapses dynamiques qui ciblent les neurones pyramidaux de couche 5 (NPy5) élaborant les signaux de sortie du cortex. Cette organisation neuronale est régulée par un équilibre entre E et I. La dérégulation des réseaux neuronaux peut conduire à des pathologies telles que la dépression ou la schizophrénie. Le fonctionnement du cortex est modulé entre autres par la sérotonine, la dopamine, la D-sérine et la glycine. Ce travail de thèse porte sur l’effet des interactions entre neuromodulateurs via les récepteurs 5-HT1A, D1, D2, NMDA et GlyR sur la balance et la plasticité synaptique de E et I dans le cortex. Mes données électrophysiologiques montrent que l’interaction entre les récepteurs 5-HT1A et D1 limite l’induction de la LTD, tandis que l’interaction entre les récepteurs 5-HT1A et D2, grâce à un carrefour commun de signalisation GSK3β, favorise l’induction de la LTD. Je montre dans le cortex visuel de rat que la D-sérine est nécessaire à l’induction de la LTP et que les GlyR ont un rôle de « shunt » le long de la dendrite des NPy5, ce qui entraîne un basculement d’une LTP en « LTD-like » apparente. / The cortex is crucial for processes such as sensory perception, cognition and memory. Cortical organization is based on neuronal networks composed of excitatory (E) and inhibitory (I) neurons which target layer 5 pyramidal neurons. Dysfunctions of such networks result in psychiatric pathologies including major depression and schizophrenia. Regulations of cortical activity also involve neuromodulators such as serotonin, dopamine, D-serine and glycine. The current body of work decipher the interactions of the effects of 5-HT1A-, D1-, D2-, NMDA- and Glycine-receptors activation on the E-I balance and synaptic plasticity. The electrophysiological data that I have generated in the prefrontal cortex show that concomitant activation of 5-HT1A- and D1-receptors downregulates the induction of LTD whilst 5-HT1A coupled to D2-receptors activation promotes LTD induction, via a common modulation of GSK3β. I also collected data from the visual cortex, showing that D-serine is the co-agonist NMDA-receptor in this brain region and is, as such, required for LTP-induction. Glycine was instead found to act on dendritic Glycine-receptors, resulting in a shunt, which altered dendritic integration and thus turned LTP to a LTD-like effect at the somatic level.

Background. DNA methylation (DNAm) is a removable chemical modification to the DNA sequence intimately associated with genomic stability, cellular identity, and gene expression. DNAm patterning reflects joint contributions from genetic, environmental, and behavioral factors. As such, differences in DNAm patterns may explain interindividual variability in risk liability for complex traits like major depression (MD). Hundreds of significant DNAm loci have been identified using cross-sectional association studies. This dissertation builds on that foundational work to explore novel statistical approaches for longitudinal DNAm analyses. Methods. Repeated measures of genome-wide DNAm and social and environmental determinants of health were collected up to six times across pregnancy and the first year postpartum as part of the Pregnancy, Race, Environment, Genes (PREG) Study. Statistical analyses were completed using a combination of the R statistical environment, Bioconductor packages, MplusAutomate, and Mplus software. Prenatal maternal DNAm was measured using the Infinium HumanMethylation450 Beadchip. Latent growth curve models were used to analyze repeated measures of maternal DNAm and to quantify site-level DNAm latent trajectories over the course of pregnancy. The purpose was to characterize the location and nature of prenatal DNAm changes and to test the influence of clinical and demographic factors on prenatal DNAm remodeling. Results. Over 1300 sites had DNAm trajectories significantly associated with either maternal age or lifetime MD. Many of the genomic regions overlapping significant results replicated previous age and MD-related genetic and DNAm findings. Discussion. Future work should capitalize on the progress made here integrating structural equation modeling (SEM) with longitudinal omics-level measures.

Stress has emerged as one of the most important factors to consider in psychiatric diagnoses and has become a common reason for long-term sick leave (LTSL). Roughly 50% of LTSL due to psychiatric diseases are thought to be associated with work-related stress. The demarcation towards major depression is disputed, and no international consensus exists for how to diagnose and rehabilitate these individuals. The Swedish National Board of Health has suggested the term “exhaustion syndrome” to integrate these individuals into stress-related disorders. Prominent features of this syndrome are fatigue, sleeping disorders, and cognitive dysfunction. The cognitive dysfunction may be due to an interaction between personality features, environmental factors, the biological effects of stress hormones, and dysfunction in key brain areas, notably the hippocampus and prefrontal cortex. A consistent feature of chronic stress is activation of the cortisol, or hypothalamic-pituitary-adrenal, axis, which may be linked to cognitive dysfunction. Increased glucocorticoid levels, mainly cortisol in humans, are known to impair memory performance. The aim of this thesis was to investigate whether patients with exhaustion syndrome exhibit specific alterations in an extensive set of biological, psychological and immunological variables. Patients in Study 1 had significant cognitive impairment for specific tasks assumed to tap frontal lobe functioning. In Study 2 anxiety prone, worrying, pessimistic individuals with low executive drive and a persistent personality type were more likely to develop exhaustion syndrome. Decreased reactivity was found on the pituitary level after corticotropin releasing hormone (CRH) in exhaustion syndrome patients. The cortisol/adrenocorticotropic hormone response to CRH was slightly higher in patients compared to controls, indicating increased sensitivity at the adrenal cortex level. No differences were found in hippocampal volume. In Study 3, functional imaging revealed a different pattern of brain activation in working memory tests in patients with exhaustion syndrome compared to healthy individuals and patients with depression. In summary, our data suggests an intimate link between personality and wellbeing, cognitive performance and neuroendocrine dysfunction, in exhaustion syndrome. We thus find similarities with major depression but also distinct differences between the exhaustion syndrome and major depression.

Psykisk hälsa/ohälsa är ett svårdefinierat begrepp som sätter fingret på ett av de största folkhälsoproblemen i vårt land, där depression är en av de vanligaste diagnoserna. Manualerna DSM-IV TR och ICD-10 används inom stora delar av sjukvården, världen över, i syfte att ge kunskap om lämpligast behandling till patienter med psykiska besvär. Denna studie syftar till att, genom en kvalitativ analys, undersöka vilka grunder som finns bakom de vanligast använda diagnosmanualerna och vilka kriterier som krävs för att uppfylla två vanligt förekommande diagnoser, PTSD och svår depression. Vidare syftar studier till att belysa eventuella likheter och olikheter mellan dessa diagnoser och vad det kan föra med sig. Såväl psykologisk forskning som klinisk praktik utgår idag mestadels från psykiatriska diagnoser, vilket kan ha såväl fördelar som nackdelar, men samtidigt diskuteras huruvida man istället ska lägga fokus på en annan mer underliggande nivå, nämligen processerna som sträcker sig över diagnosernas gränser. Fördelarna med ett transdiagnostiskt perspektiv är att det delvis kan ge en förklaring till den höga komorbiditet som finns i kliniska grupper och som skulle kunna iakttas även i de sjukdomsbilder som denna studie fokuserar på. Unified Protocol är en annan behandlingsmodell som tas upp i studien, vilken baseras på en betydande fenotypisk över-lappning mellan olika ångeststörningar hos patienter, där personer med subkliniska nivåer av symtom ändå kan ha en nedsatt funktionsnivå och ett subjektivt lidande, fastän de inte uppfyller alla de diagnostiska kriterierna för en specifik störning. Resultatet visar på möjligheten att se över diagnosgränser, för att öka chanserna för ett tillfrisknande hos patienten. Människans upplevelser av olika situationer den befinner sig i formas av personens egen uppfattning om sin förmåga, eller oförmåga, att påverka resultatet. Att uppleva sig ha mist kontroll över sitt eget liv kan i sig leda till såväl depression som suicidala tankar/-handlingar. Om symtomen för depression jämförs med kriterierna som står att finna under diagnosbilden “Posttraumatiskt stressyndrom” under kapitlet “ångestsyndrom”, kan många likheter konstateras. Slutsatsen blir att likheterna i symtombild skulle ge patienter med PTSD en behandlingsrekommendation som inte alls överensstämmer med de rekommenderade riktlinjer som är utformade för PTSD. Trots diagnosernas likheter rekommenderas olikartad behandling, och även olika förutsättningar för att fungera i kombination med förvärvsarbete påvisas. Vid så lika symtombilder, men ändå så skilda rekommenderade behandlingsplaner utifrån de olika diagnoserna, torde risken för en felaktig rehabiliteringsplan vara över-hängande. / Mental health/illness is complex to define and this highlight of the biggest public health problems in our country, in which depression is one of the most common diagnoses. The manuals DSM-IV TR and ICD-10 is used in much of health care, worldwide, in order to provide knowledge of appropriate treatment for patients with mental disorders. This study aims to, through a qualitative analysis, examine the grounds behind the most commonly used diagnostic manuals and the criteria required to meet two common diagnoses, PTSD and severe depression. Further studies aimed to highlight any similarities and differences between these diagnoses and what it can bring. Both psychological research and clinical practice today is based mostly from psychiatric diagnoses, which can have both advantages and disadvantages, but also discussed whether they should instead focus on another more underlying level, namely the processes that extend across the diagnostic boundaries. The advantages of a trans-diagnostic perspective are that it may partly explain the high co-morbidity found in clinical groups and that could be observed even in those syndromes which this study focuses on. Unified Protocol is a different treatment model that is entered in the study, which is based on a significant phenotypic overlap between anxiety disorders in patients, where individuals with subclinical levels of symptoms still can have a reduced level of functionality and a subjective suffering, although they do not meet all the diagnostic criteria for a specific disorder. The result shows at the opportunity to review the diagnostic boundaries, to increase the chances for a recovery of the patient. The human experiences of different situations it is in the form of personal self-perception of their ability, or inability, to influence the outcome. To experience they have lost control over his own life in itself can lead to both depression that suicidal thoughts / actions. If the symptoms of depression compared with criteria that are to be found during diagnostic image "Post-traumatic stress disorder" in the chapter "disorder" can be found many similarities. The discourse comes to that the similarities in symptoms would provide patients with PTSD, a treatment recommendation, which did not conform to the recommended guidelines that are designed for PTSD. Despite the diagnosis, the similarities are recommended disparate treatment, and also different conditions to work in conjunction with work shown. At this same symptom pictures, yet so different recommended treatment plans based on the different diagnoses, would risk a false rehabilitation plan to be imminent

Background Lack of coordination between screening studies for common mental disorders in primary care and community epidemiological samples impedes progress in clinical epidemiology. Short screening scales based on the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI), the diagnostic interview used in community epidemiological surveys throughout the world, were developed to address this problem. Method Expert reviews and cognitive interviews generated CIDI screening scale (CIDI-SC) item pools for 30-day DSM-IV-TR major depressive episode (MDE), generalized anxiety disorder (GAD), panic disorder (PD) and bipolar disorder (BPD). These items were administered to 3058 unselected patients in 29 US primary care offices. Blinded SCID clinical reinterviews were administered to 206 of these patients, oversampling screened positives. Results Stepwise regression selected optimal screening items to predict clinical diagnoses. Excellent concordance [area under the receiver operating characteristic curve (AUC)] was found between continuous CIDI-SC and DSM-IV/SCID diagnoses of 30-day MDE (0.93), GAD (0.88), PD (0.90) and BPD (0.97), with only 9–38 questions needed to administer all scales. CIDI-SC versus SCID prevalence differences are insignificant at the optimal CIDI-SC diagnostic thresholds (χ2 1 = 0.0–2.9, p = 0.09–0.94). Individual-level diagnostic concordance at these thresholds is substantial (AUC 0.81–0.86, sensitivity 68.0–80.2%, specificity 90.1–98.8%). Likelihood ratio positive (LR+) exceeds 10 and LR− is 0.1 or less at informative thresholds for all diagnoses. Conclusions CIDI-SC operating characteristics are equivalent (MDE, GAD) or superior (PD, BPD) to those of the best alternative screening scales. CIDI-SC results can be compared directly to general population CIDI survey results or used to target and streamline second-stage CIDIs.

Background: Lithium augmentation is a first-line strategy for depressed patients resistant to antidepressive therapy, but little is known about patients’ subsequent long-term course or outcome predictors. We investigated long-term outcomes of unipolar depressed patients who had participated in a study on the effects of lithium augmentation on the hypothalamic-pituitary-adrenocortical system using the combined dexamethasone/corticotrophin-releasing hormone (DEX/CRH) test. Methods: Twelve to 28 months (mean 18.6 ± 4.6 months) after lithium augmentation, 23 patients were assessed with a standardized interview, of which 18 patients had complete DEX/CRH test results. Relapse was diagnosed by DSM-IV criteria (Structured Clinical Interview for DSM-IV; SCID I). Results: Only 11 patients (48%) had a favorable follow-up, defined as absence of major depressive episodes during the observation period. Patients with a favorable and an unfavorable course did not differ in clinical or sociodemographic parameters, endocrinological results or continuation of lithium. However, fewer previous depressive episodes tended to correlate (p = 0.09) with a favorable course. Conclusion: Results from studies using the DEX/CRH test to predict relapse in depressed patients treated with antidepressants were not replicated for lithium augmentation. Our finding could reflect the elevation of DEX/CRH results by lithium, independent of clinical course. Limitations of the study are its small sample size, the heterogeneous clinical baseline conditions and the lack of lithium serum levels. The fact that lithium continuation did not predict the course might be related to the difference between the efficacy of lithium in controlled studies and its effectiveness in naturalistic settings. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Major depression is a highly prevalent mood disorder with chronic debilitating effects. Additional to a rising rate in incidence, depression is highly co–morbid with other psychiatric disorders, but also chronic cardiometabolic illnesses that present with an inflammatory component. The exact aetiology of depression is still unknown, being multifactorial in its possible aetiology. Various hypotheses have attempted to shed light on both endogenous and exogenous risk factors as well as the underlying pathology that may lead to the development of the disease. This has led to a wide range of mediators being implicated, including biogenic amines, the HPA–axis, neurotrophic factors, inflammatory agents, the cholinergic system and circadian rhythm, to name a few. The mechanisms of action of current treatment strategies, except for a few atypical and novel treatment approaches, are limited to interactions with monoamines and are at best only 65% effective. Many of these are also plagued by troubling side–effects, relapse and recurrence. It has therefore become imperative to explore novel targets for the treatment of depression that may produce more rapid, robust and lasting antidepressant effects with a less daunting side–effect profile. The strong co–morbidity between depression and various cardiometabolic disorders, including cardiovascular disease, atherosclerosis, type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) has led to the proposal that a metabolic disturbance may be a vital component that drives inflammatory and immunological dysfunction in depression. Supporting of this is evidence for a role of inflammatory cytokines and neurotrophic factors in the pathogenesis of depression. It has also been demonstrated that a link exists between insulin– and nitric oxide (NO)– mediated pathways in the brain, which further highlights the role of oxidative stress and cell damage. Furthermore, evidence supports a role for oxidative stress and NO in T2DM and/or insulin resistance. Insulin has also been implicated in various physiological processes in the central nervous system (CNS) and may also influence the release and reuptake of neurotransmitters. Preclinical and clinical evidence has provided support for the antidepressant–like effects of insulin–sensitizing peroxisome proliferator activated receptor (PPAR)– agonists, such as rosiglitazone and pioglitazone. In preclinical studies, however, these effects are limited to acute treatment with pioglitazone or sub–chronic (5 days) treatment with rosiglitazone. It is well–recognized that such findings need to be confirmed by chronic treatment paradigms. The aim of the current study was therefore to further investigate the proposed antidepressant–like effects of pioglitazone in a genetic animal model of depression, the Flinders sensitive line (FSL) rat, using a chronic treatment protocol. The FSL rat model was reaffirmed as presenting with inherent depressive–like behaviour compared to its more resilient counterpart, the Flinders resistant line (FRL) rat. Moreover, imipramine demonstrated a robust and reliable antidepressant–like effect in these animals using the forced swim test (FST), thus confirming the face and predictive validity of the FSL rat model for depression. In contrast to previous preclinical studies, acute dose–ranging studies with pioglitazone in Sprague Dawley rats delivered no significant anti–immobility effects in the FST, whereas results similar to that seen in the dose–ranging studies were observed following chronic treatment using FSL rats. Since altered pharmacokinetics could possibly influence the drug’s performance, another route of administration, viz. the subcutaneous route, was utilized as an additional measure to exclude this possibility. The results of the subcutaneous study, however, were congruent with that observed after oral treatment. In order to confirm an association between altered insulin sensitivity and antidepressant action and demonstration by recent studies that thiazolidinediones may augment the efficacy of existing antidepressants, we therefore investigated whether concomitant treatment with gliclazide (an insulin releaser and insulin desensitizer) or pioglitazone (an insulin sensitizer) may alter the antidepressant–like effects evoked by chronic treatment with imipramine. Pioglitazone did not positively or negatively affect the antidepressant effect of imipramine, although gliclazide tended to decrease the anti–immobility effects induced by this antidepressant. Taken together and considering the current available literature, this finding supports evidence linking the insulin–PPAR pathway to depression. However, further explorative studies are required to delineate the role of insulin sensitivity and glucose homeostasis in depression and antidepressant response. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2012.