Дисертації з теми "Neurobiology of mood disorders"

Background: Electroconvulsive therapy (ECT) is one of the most effective and fast acting therapeutic options for treatment-resistant psychiatric diseases, in particular mood disorders. Mood disorders are highly heterogeneous, disabling and severe mental illness, at still unknown etiology, which have been associated with a multifaceted pathogenesis, encompassing genetic, epigenetic and metabolic vulnerabilities together psychosocial/lifestyle factors. Among the various biological patterns thought to be involved in the physiopathology of dysthymia, major depression, cyclothymia, bipolar I, II, mixed states and related disorders, alterations in the neuroendocrine and immune systems have been also evidenced. Additionally, an increasing number of studies have highlighted the relevance of impaired mechanisms of defense against reactive oxygen species (ROS) in the progression and severity of BD. Oxidative stress and redox states are indeed part of the metabolic and chemical networks of the immune/inflammation response. Despite such evidences, few studies have examined, by now, the impact of ECT on specific neuroendocrine, immune and oxidative stress paths in patients undergoing this therapy. It has been reported that ECT-induced epileptic seizures stimulate the intra-cerebral release of cytokines, including the cytokine network associated with the pathophysiology of affective disorders. It is therefore challenging to consider that the therapeutic efficacy of ECT may reside on the degree of activation of the immune/inflammatory system and that patients, under depressive, hypomanic, manic or mixed states, may change their specific profile of biochemical/immunological markers by ECT. ECT would thus act on complex biochemical cascades, formed by several neurotransmitters, neuro-hormones, neurotrophic factors and metabolic substrates, playing a significant therapeutic role. Hypothesis: Beside possible neurotransmitter and neurotrophin variations, mood disorder patients would also present significant changes of peripheral cytokine and oxidative stress profiles, before and after ECT; it might be thus possible to identify specific redox chemical and immune features related to the response/Non-response to this treatment. Such a result could also considerably help to detect peripheral molecular correlates of immunochemical dysregulation, refractory symptoms and ECT therapeutic benefits or adverse effects in mood disorders. Aims: The foremost aims of this study were: 1) to explore the degree of expression/activity of peripheral immune and oxidative stress markers during the course of ECT in bipolar patients; 2) to possibly evidence differences of these biochemical parameters among Remitter and Non-Remitter patients, assessed by means of suitable examinations and psychometric questionnaires, administered to recruited patients before, during and after ECT. Methods: From 2016 to 2018, we recruited and investigated 17 consecutive patients with a BD diagnosis accordingly to DSM-V diagnostic criteria, all treated by ECT at the Psychiatry section of the Department of Clinical and Experimental Medicine of the University of Pisa. All patients were examined during three main phases of ECT course, following this schedule: 1) at T0, by both psychometric and biochemical evaluations, before the first application; 2) at T1, by biochemical evaluations carried out 3 hours after the first application; 3) at T2, at the end of the treatment, by both psychometric and biochemical examinations. A forth biochemical assessment was carried out also at T3, 3 hours after the last application, in order to possible appraise a different reactivity of immune/oxidative stress patterns at the end of ECT applications. To constantly monitor patients, psychiatric and physical examinations were always performed for the duration of the study. Psychometric questionnaires carried out prior to (T0) and after (T3) the ECT course, consisted into: the Hamilton Depression Rating Scale-17 (HAM-D), Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale (BPRS) and Clinical Global Improvement Impression (CGI) scale. The CGI subscale “global improvement”, final HAM-D and YMRS total scores were used to identify Remitter and Non-Remitter groups . Biochemical investigations, performed after blood samplings carried out at the 4 scheduled times, T0, T1, T2 and T3, were: 1)-the plasma levels of the immune/inflammatory cytokines IL-6, IL-8 and TNFα; 2)-the plasma levels/ activity of the antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD), total thiols (R-SH), the ferric reducing ability of plasma (FRAP), uric acid as well as an index of oxidative damage, the advanced oxidation plasma protein products (AOPP). Results: At the end of therapy, about the 53% of ECT-treated BD patients was found to remit. Concerning biochemical investigation, we observed that, globally, in 17 subjects, 3 hours after ECT (T1), the activity of SOD in plasma increased nearly attaining the statistical significance, while FRAP was found significantly decreased; when analyzing Remitters and Non-Remitters separately, the nearly significant increased SOD reported in all patients at T1, after the first ECT application, was due to a greater enzyme activity in Remitters, while the global T1 FRAP reduction was due to the significant decrease of plasma ferric reducing power in Non-Remitters only. We also reported that Non-Remitters had a significantly reduced CAT activity both at T1 and in the long term, at the end of ECT course (T2), and a higher percent of responce in uric acid and IL 8 after the last ECT (T3 vs. T2). Also, Non-Remitters tended to concomitantly have, at T2, higher plasma FRAP, SOD,IL6 and lower CAT, Thiols in respect to baseline (T0) values as well as in respect to Remitters. No significant effect on the plasma level of AOPP was observed at any scheduled time in all patients, indicating that no relevant protein damage, due to ROS was reported during ECT sessions. Limitations: The study, at the present stage, had a small sample size; moreover the patient group was heterogeneous, consisting of treatment resistant bipolar patients in different phases of illness and with different pharmacological regimes. Conclusions: According to literature, we showed that ECT is an effective and safe treatment able to heal drug-resistant bipolar patients with very severe clinical presentation and risk of suicide, in all phases of the illness. Preliminary results suggest that ECT can induce changes of the antioxidant system: an increased ROS scavenging activity at T1 seems to be an index of favorable response. The diminuition of antioxidant defense system would be conversely linked to reduced benefits deriving from this therapy. The recruitment of a larger cohort of patients is needed to confirm and pursue this useful investigation of peripheral biomarkers of ECT response. This will permit to perform more robust statistical tests as multivariate regression or principal component analyses and to possibly define peculiar immunochemical changes related to the clinical response.

Background: It has been suggested that two sub types of women with postnatal depression exist. These sub types are distinguishable based on the role that childbirth plays; as either a causative or a non-specific, trigger for the depressive episode. Evidence for these proposed subtypes has been inconsistent to date. Additionally, gaps in research have also been identified relating to the existence of possible subtypes of postnatal anxiety and the differential role of childbirth in triggering anxiety during the postnatal period. Method: 98 postnatal women completed a questionnaire designed to gather information relating to symptoms of depression, general and maternal-specific dysfunctional cognitions and symptoms of state and trait anxiety. A three-step cluster analysis technique was conducted as a method of exploring the existence of subtypes within the sample recruited. Following the identification of subtypes, further statistical analysis explored the stability and validity of the cluster solutions and characteristics of the subtypes. Results: Women with postnatal depression could be categorised into subtypes based on reports of general and maternal-specific dysfunctional cognitions: a) those experiencing a depressive episode specifically related to the experience of childbirth and motherhood, and b) those experiencing a non-specific depressive episode similar to depression experienced at other time of life. Additionally, a subtype of women with postnatal depression was found who did not report any dysfunctional cognitions. Women with postnatal anxiety could be categorised into subtypes based on reports of state and trait anxiety: a) those experiencing anxiety specifically related to the experience of childbirth and motherhood, and b) those experiencing a non-specific anxious episode similar to anxiety experienced at other times of life. Implications: As well as adding to the limited amount of research exploring subtypes of postnatal mood disorders, outcomes include implications for screening and treatment of postnatal depression and anxiety.

Cognitive impairments are present in both schizophrenia and bipolar disorder and are strong predictors of functional outcomes for patients. One barrier in cognitive research of these disorders is the lack of large, well-characterised cross-disorder samples with cognitive data. The aims of this thesis were to examine cognition across the bipolar / schizophrenia diagnostic spectrum and to develop a new online cognitive battery for use in psychiatric research. Cognition was examined in participants with bipolar disorder, schizoaffective disorder and schizophrenia through a meta-analysis of existing studies and analysing data from a large well-characterised sample. The main finding was that there is a gradient of increasing cognitive impairment from bipolar disorder through schizoaffective disorder – bipolar type to schizoaffective disorder – depressive type and schizophrenia. Participants with the subtypes of schizoaffective disorder differed in their cognitive performance. Lifetime history of psychosis was associated with cognitive performance across disorders. An online cognitive battery was developed to assess the domains outlined by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative. The battery was validated against the MATRICS Consensus Cognitive Battery and showed that the tasks provided valid measurements of the majority of the MATRICS domains. A large sample of participants with a range of psychiatric disorders was recruited online. An examination of cognition in participants with major depressive disorder, bipolar disorder and schizophrenia showed that cognitive profiles were similar across disorders but participants with schizophrenia have more severe impairments than participants with bipolar disorder. An important concluding observation was that poorer cognitive performance was associated with poorer functional outcome across disorders. The findings of this thesis add to a growing literature showing the importance of examining cognitive function across psychiatric disorders. To date, it is the first study to develop and utilise an online cognitive assessment for psychiatric research.

Background: Major depressive disorder (MDD) and bipolar disorder (BP) are highly prevalent illnesses that cause substantial burden in the affected individual, their families, and society at large. These consequences underline the importance of etiological research in order to develop superior measures of both prevention and treatment. Although family history is the most consistently replicated risk factor for mood disorders, minimal efforts have been made to outline differences in sociodemographic and clinical characteristics between patients with familial and non-familial forms of these disorders. Moreover, despite the lack of conclusive findings in genome-wide association and linkage studies regarding the particular genes involved in mood disorder etiology, investigators have not yet examined the significance of familial exposure to psychiatrically ill relatives in influencing their onset and course. Methods: Subjects were 378 outpatients with a current DSM-IV diagnosis of MDD (N=139) or BP (N=239). Retrospective chart reviews were conducted in order to examine differences in sociodemographic and clinical characteristics between subjects with and without physician-reported family history. Patient-reported family history was used to compare subjects on a number of self-reported familial exposure variables. Associations between these variables and clinical characteristics were also examined. Results: Mood disorder subjects with physician-reported family history were primarily Canadian born and English speaking, and subjects without such a history were mostly unemployed. In terms of clinical characteristics, BP subjects with physician-reported family history sought psychiatric assistance at a younger age and MDD subjects without such a history were hospitalized more often. Consistent with prior research, BP subjects demonstrated more familial loading of both BP and schizophrenia/psychosis compared to MDD subjects. Furthermore, a family history of schizophrenia/psychosis and drug problems were associated with more frequent hospitalizations. Finally, a family history of drug and alcohol problems as well as living with two or more acutely ill family members, were associated with more lifetime suicide attempts. Conclusions: Family history undeniably plays an instrumental role in both the onset and clinical presentation of mood disorders. Our results particularly emphasize the significance of familial exposures and their ability to operate as risk factors, combined with underlying genetic susceptibility, to produce more severe and impairing cases of these disorders. Clinicians should carefully examine each patient's family history status since it may add value to risk assessments for outcomes like suicide attempts and hospitalizations.
Contexte: Le trouble dépressif majeur (TDM) et le trouble bipolaire (TB) sont des maladies très répandues qui causent le fardeau substantiel dans la personne touchée, leurs familles, et dans la société en général. Ces conséquences soulignent l'importance de la recherche étiologique dans le but d'élaborer des mesures supérieures à la fois de prévention et de traitement. Bien que les antécédents familiaux est le facteur de risque le plus constamment répliqué pour les troubles de l'humeur, des efforts minimes ont été apporté à décrire les différences dans les caractéristiques sociodémographiques et cliniques entre les patients avec des formes familiales et non familiales de ces troubles. Par ailleurs, malgré l'absence de résultats convaincant dans les études d'association pangénomique et les études de liaison concernant les gènes impliqués dans l'étiologie des troubles de l'humeur, les enquêteurs n'ont pas encore examiné l'importance de l'exposition aux membres de la famille souffrant d'une maladie mentale en influençant l'apparition et l'évolution des troubles de l'humeur. Méthodes: Les sujets inclus 378 patients à l'externe avec un diagnostic DSM-IV de la TDM (N=139) ou TB (N=239). Examens rétrospectifs des dossiers ont été menées afin d'examiner les différences dans les caractéristiques sociodémographiques et cliniques entre les sujets avec et sans des antécédents familiaux rapportés par un médecin. Les antécédents familiaux rapportés par le patient ont été utilisés pour comparer des sujets sur plusieurs variables auto-déclarées sur l'exposition aux membres de la famille touchée. Les associations entre ces variables et les caractéristiques cliniques ont également été examinées.Résultats: Les sujets avec un trouble de l'humeur ayant des antécédents familiaux rapportés par un médecin étaient principalement anglais et née au Canada, et les sujets sans une telle histoire étaient pour la plupart au chômage. En termes de caractéristiques cliniques, les sujets avec des antécédents familiaux de TB rapportés par un médecin a demandé l'assistance psychiatrique à un plus jeune âge et les sujets avec un TDM sans une telle histoire ont été hospitalisés plus souvent. En ligne avec la recherche précédente, les sujets avec un TB ont démontré plus de membres de la famille touchée avec soit un TB ou bien de la schizophrénie/psychose par rapport aux sujets de TDM. De plus, des antécédents familiaux de schizophrénie/psychose et de problèmes de drogue ont été associés à des hospitalisations plus fréquentes. Enfin, des antécédents familiaux de problèmes de drogue et d'alcool ainsi que de vivre avec deux ou plusieurs membres de la famille gravement malades, ont été associés à plus de tentatives de suicide à vie. Conclusions: Les antécédents familiaux jouent indéniablement un rôle instrumental dans l'apparition et à la présentation clinique des troubles de l'humeur. Nos résultats met un accent particulier sur l'importance de l'exposition aux antécédents familiaux et leur capacité à fonctionner comme facteurs de risque, en combinaison d'une sous-jacente susceptibilité génétique, pour produire des cas plus graves et débilitantes de ces troubles. Les cliniciens devraient examiner soigneusement les antécédents familiaux de chaque patient, car cela peut ajouter de la valeur aux évaluations de risque pour les tentatives de suicide et les hospitalisations.

Millions of individuals suffer disability or death from immune-based inflammatory diseases. If psychiatric disorders could be empirically linked to the prediction of immune-based inflammatory diseases, there would be a basis for promoting disease prevention measures for individuals diagnosed with one of four psychiatric disorders. Psychoneuroimmunology provided the theoretical base for understanding emotionally induced medical disease development. In this quantitative study, a parallel archival research design was used to investigate the degree to which generalized anxiety disorder, posttraumatic stress disorder, major depression recurrent, and dysthymic disorder predicted the presence of atherosclerosis, cardiovascular heart disease, rheumatoid arthritis, cancer, and type II diabetes. There were 1,209 electronic medical records of adult patients obtained through purposive stratified sampling. A secondary data analysis was employed using descriptive cross tabulation, chi-square test of independence, and multinomial logistic regression. The findings revealed major depression recurrent was a statistically significant predictor for atherosclerosis, rheumatoid arthritis, type II diabetes and cancer. Generalized anxiety disorder was a statistically significant predictor for cancer. The results can promote positive social change by providing information that could be used to develop assessment plans that identity individuals who are at risk of developing the comorbid diseases. The prevention programs could effectively be used to minimize the subsequent development of inflammatory diseases, which in turn could decrease the onset of the medical diseases among individuals with psychiatric disorders.

Both schizophrenia and bipolar disorder are characterised by deficits in cognitive function, particularly in those executive functions subserved by the prefrontal cortex. In order to further our understanding of the neuropathophysiology of cognitive deficits in psychiatric disorders, this thesis examined structural and functional changes in the prefrontal cortex (PFC) in rodent models mimicking some aspects of schizophrenia and bipolar disorder. Chosen models were subchronic phencyclidine (PCP), chronic administration of corticosterone to flatten the glucocorticoid rhythm (CORT) and maternal immune activation (MIA). These models mimic glutamate hypofunction, hypothalamo-pituitary adrenal axis dysfunction and maternal infection, respectively. Behavioural studies established that PCP induced a selective deficit in attentional set shifting whilst CORT and MIA induced reversal learning deficits. In vitro electrophysiological studies established a novel model for measuring synaptic transmission in the infralimbic (IL) region of the medial prefrontal cortex (mPFC). Synaptic transmission was shown to be mediated by glutamate and γ-aminobutyric acid (GABA) and to be subject to inhibitory modulation by serotonin (5-HT) and noradrenaline (NA). Differential changes in both basal synaptic transmission and in the monoaminergic modulation of synaptic transmission were evident in the three animal models. Immunohistochemical studies showed that the three animal models induced differential changes in the numbers of particular subtypes of GABAergic interneurones, suggesting that GABAergic activity in the mPFC was altered. These studies demonstrate that models of select features of psychiatric disorders, glutamate hypofunction, HPA axis dysfunction, and prenatal infection, induce deficits in executive function present in psychiatric disorders. These differential behavioural outcomes might be explained by differential changes in synaptic transmission in the mPFC and in the expression of GABAergic interneurones in the mPFC induced in the three models.

Epigenetics continues to be redefined and new discoveries are likely to revolutionise the field still further. This thesis explores different aspects of how epigenetic regulation of gene expression contributes to human disease. Paper I explores the function of the IKKα kinase in regulating gene expression through the nuclear retinoic acid receptor (RAR). We define a set of genes requiring IKKα for their expression and found recruitment of IKKα to the RAR dependent on structural motifs in its protein sequence. This interplay between the NFκB pathway and nuclear receptor regulated transcription is important to consider when designing therapeutic strategies. Papers II and III focus on the plasma cell malignancy multiple myeloma (MM) and define a gene regulatory circuit defining an underexpressed gene profile in MM dependent on the Polycomb proteins. We provide proof-of-principle that the use of small chemical inhibitors may be operational in reactivating genes silenced by H3K27me3 and that this leads to decreased tumour load and increased survival in the 5T33 in vivo model of MM. We explored the genome-wide distribution of H3K27me3 and H3K4me3, and defined their association with gene expression in freshly-isolated malignant plasma cells from MM patients. Importantly, H3K27me3-marked genes in MM associated with more aggressive stages of the disease and less favourable survival. We present evidence that gene targeting by H3K27me3 is likely to not only involve a small population of tumour cells, but rather represent a common MM profile and further provide a rationale for evaluating epigenetic therapeutics in MM. Paper IV shows that pro-inflammatory gene expression in monocytes of psychiatric patients can be induced in vitro by sodium pump inhibitors, as the steroid hormone ouabain. We suggest that the ouabain-induced gene expression is regulated by an intricate network involving microRNAs, Polycomb and the H3K27me3 demethylase JMJD3. Our data indicates that epigenetic regulators play a role in transmitting cues between intrinsic and/extrinsic stimuli and gene expression in psychiatric illness. This thesis provides novel insights on how seemingly unrelated pathways may converge on transcriptional regulation and evidence that epigenetic modifiers contribute to the pathogenesis of human complex diseases such as multiple myeloma and mood disorders.

The purpose of this study proposal is to examine the potential relationship between linguistic creativity and mood disorders, specifically depression and bipolar disorder. Participants will be approximately 67 adults who have either bipolar disorder, major depressive disorder, or serve as a healthy control group. Participants will complete prompts in order to measure linguistic creativity and then fill out several questionnaires relating to depressed mood, mania, general creativity, and rumination levels. It is predicted that bipolar disorder will have higher levels of certain types of linguistic creativity, such as lexical and semantic creativity, whereas depression will have more syntactic creativity. Furthermore, it is anticipated that higher rumination levels in the depressed group will be associated with higher levels of linguistic creativity, as opposed to participants in the depressed group with lower levels of rumination. Lastly, it is predicted that the type of writing prompt will influence the amount of creativity exhibited by each participant group. The proposed study has implications for therapeutic benefits, the emergence of a new area of research in two separate fields, and a new way of analyzing shifts in speech patterns of those with mood disorders.

We live in an age of 'multimorbidity', yet have a rather poor understanding of the impacts of this phenomenon from cellular to organ and system levels. Bi-directional relationships are observed between cardiometabolic (diabetes mellitus, coronary heart disease) and mood disorders (major depressive disorder), each increasing disease risk and frequently co-existing. This cardiometabolic-mood interaction may reflect an under-appreciated commonality of underlying mechanisms across these pathologies. Importantly, comorbid development of these disorders exacerbates the already profound burdens of these individual chronic disorders. Further, psychosocial stress and ageing – increasingly prevalent features of modern societies - may promote these conditions and worsen outcomes. In assessing the intersections of these inter-related disorders, chronic low-grade inflammation is often highlighted and implicated as a common early substrate in cardiometabolic and mood disorders, linking these dominant diseases. Nonetheless, how immunoinflammatory dysregulation drives multimorbidity, and influences 'multifinality' (diverse disease outcomes from common risks/causes), are unclear. Whether immunoinflammatory changes in metabolic vs mood disorders are unique or involve common motifs, and how these interact in dictating cardiometabolic and mental health, remains to be established. Dysregulation of toll-like receptor (TLR) signalling has been specifically implicated in these diseases, potentially presenting a mechanistic nexus in comorbid development of cardiometabolic and mood disorders. The doctoral work presented in this thesis was designed to address the broad concept of mechanistic intersections contributing to rising multimorbidity. In order to practicably achieve this at a systems level, four major tissues impacted by and contributing to aspects of metabolic and mood disorders were studied: the brain, heart, liver and blood (circulating serum). The brain is an overarching and critical organ, regulating both mood and metabolic homeostasis, and influencing all other organ systems. Cardiac tissue is assessed as it is particularly impacted by type 2 diabetes (T2D); the risk of cardiovascular disease (CVD) is markedly elevated in T2D patients and is the lead cause of death in these patients. Further, CVD is an independent risk factor for both depression and T2D. The liver is fundamental to metabolic homeostasis (the central organ maintaining homeostasis across fed and fasted states via oxidisable substrate storage and release), links the gut to the periphery (gut-liver axis) and contains specialised macrophages which are front-line responders to gut-derived lipopolysaccharides (LPS) (arising with gut permeability changes). Finally, serum was assessed as it is the primary medium for transport of macronutrients, hormones and immunoinflammatory molecules throughout the body. To avoid the pitfalls of reliance upon gene-modified animal models, non-genetic murine models of type 1 and type 2 diabetes development in early adulthood were studied in Chapter 2 to explore potential changes in TLR-related signalling at the gene level. Somewhat unexpectedly, there was little evidence of shifts in TLR signalling in central nervous system (CNS), hepatic or cardiac tissues in these two conditions. Moreover, while modest elevations in circulating interleukin-6 (IL-6) are observed in T2D animals, tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) levels remained unchanged across models. Together with further analysis of gene expression, these data indicate that the T2D model does not develop an overtly pro-inflammatory phenotype, despite clear evidence of metabolic dysregulation. Given that a well-developed diabetic phenotype was observed (increased body weight, moderate hyperglycaemia, insulin resistance), this work called into question the essential role of TLR4 in the pathogenesis of T2D. Data does reveal marked changes in circulating adipokines and catecholamines, suggesting these endocrine systems may be key to disease progression, independent of inflammation. Surprisingly, assessment of circulating LPS revealed serum levels were decreased (although not significantly) in T2D animals, which casts doubt on whether 12 weeks of feeding with a ‘Western diet’ (30% of total calories from fat) is sufficient to disturb gut physiology and trigger the systemic innate immune response. The majority of animal models employ much higher fat percentages (45-60% calories from fat) in their diabetogenic diets, despite such high fat levels vastly exceeding those in a Western diet (~30%) and raising questions of pathophysiological relevance. Given that little evidence of TLR dysregulation was detected at a physiologically relevant fat percentage, a more chronic model (21-week dietary modification) with an intermediate fat content (43% calories from fat) was developed for subsequent experimentation. Studies in Chapter 3 demonstrate that a more profound weight gain is achieved with a higher fat content, which still remains below the extreme 60% levels often studied in animal models: this new feeding regime resulted in significantly greater body weight gain although fasting insulin and glucose levels were not altered when compared with the T2D model assessed in Chapter 2. Nonetheless, despite this more pronounced phenotype, limited TLR4-related gene changes were observed in the model. Selective changes to total cellular nuclear factor-kappa B (NF-κB) protein expression were observed in hepatic tissue, although analysis of the nuclear compartment revealed no changes in response to T2D. Thus, while a greater pool of this critical pro-inflammatory factor was evident, this was not necessarily associated with increased nuclear interaction and thus transcriptional control. These data suggest dysregulation of transcriptional control by NF-κB (particularly TLR4 pathway elements) may not be essential in the evolution of T2D in these animals. Examining a dietary intervention with an omega-3 polyunsaturated fatty acid (n-3 PUFA), α-linolenic acid (ALA), which has been linked to anti-inflammatory outcomes in some chronic disorders, revealed no improvements in the systemic sequalae of T2D. This is consistent with evidence PUFA supplementation may (somewhat paradoxically) have greater influences on metabolic homeostasis in healthy rather than diseased subjects. Unexpected elevations in key inflammatory transcripts were noted with ALA supplementation, potentially reflecting the highly pleiotropic actions of PUFAs. Proteomic profiling of cardiac tissue revealed that a number of inflammatory and related factors beyond TLR-related signalling were impacted by T2D (Serpin-1/PAI-1, leptin, resistin) and/or are sensitive to ALA (IL-10, CD40, VEGF). Data also suggest animal age may be a complicating factor in the protracted disease model, producing apparent independent effects on leptin/insulin expression levels, in turn complicating interpretation of these data. Finally, specific investigation of CNS changes in the model - via analysis of frontal cortex (FC) leptin receptor expression - indicates a sensitivity of central leptin signalling to T2D, which may not only participate in metabolic dysregulation but behavioural outcomes (as suggested in the pathogenesis of depression, for example). This highlights the likely importance of central control and behavioural determinants of disease outcomes. Investigating central control mechanisms and behaviour in more detail, studies presented in Chapter 4 revealed that the T2D phenotype involves induction of anxiety-related behaviours without impacting on hedonic behaviour. Further, despite evidence from other studies of the benefits of PUFA supplementation in mood disorders, ALA supplementation did not reverse anxiety-related behaviours, though increased locomotion in both healthy and T2D animals. Interestingly, analysis suggests ALA supplementation may confer benefits to locomotive activity independently of disease state, although outcomes are better in healthy controls. Examining elements of central reward pathways, neurotransmission, endocrine and inflammatory control in FC and hippocampus revealed select changes with T2D, including elevated Drd2 (dopamine D2 receptor) and reduced Htr1a (serotonin receptor 1A) in the FC, together with shifts in leptin receptor expression. Surprisingly, hippocampal Il1b gene expression remained similar between groups, though this is consistent with no change in hedonic behaviour. Circulating dopamine and leptin were also sensitive to T2D, with hippocampal dopamine levels selectively elevated in T2D animals supplemented with ALA (although the relevance of this finding is not clear). Overall, these data point to dysregulation of central dopamine and leptin signalling, which may contribute to behavioural disruption in T2D, in turn influencing disease development and outcomes. In the final studies, CNS responses were explored in greater detail via RNA-sequencing (Chapter 5), more broadly testing whether metabolic and mood disorders share common nervous system changes. Analyses of transcriptome profiles in the FC of the T2D model assessed in Chapter 5 together with a model of chronic social stress (SS) known to induce anxiety/depressive behaviours again provided limited support for an overarching immunoinflammatory dysregulation as a key driver of behavioural changes. These analyses reveal both distinct and common processes (beyond TLR-signalling) that are dysregulated in disease. Comparison between T2D and SS models reveal commonalities in CNS leptin and insulin receptor changes, congruent with evidence of insulin and leptin resistance in the T2D model and their implication in both human major depressive disorder (MDD) and T2D. A majority of over-represented genes were related to cell/tissue development, cell migration and proliferation, suggesting a dominant role for CNS 'remodelling' with both metabolic and mood disorders. Interestingly, down-regulation of ATP metabolic processes and mitochondrial genes was evident in the SS model but not T2D, supporting a more dominant effect of stress on energy production. Taken together, the findings presented in this doctoral project raise questions regarding the role of dysregulated TLR-signalling in T2D (and stress-related disorders). Despite a clear diabetic phenotype and shifts in behavioural profiles of T2D animals, findings challenge whether TLR-related dysregulation (reported by others) may be a consequence rather than causative factor in disease pathogenesis. Importantly, evidence is presented that insulin, leptin and dopamine signalling (together with other metabolic mediators) may be important linkages between metabolic and mood disorders, and underlie behavioural detriment in T2D. In terms of limiting the development or impacts of disease, n-3 PUFA supplementation resulted in selective benefits in T2D, though these appear unrelated to the metabolic profile of these animals. Finally, shared and unique CNS changes were identified in models of T2D and chronic social stress, supporting structural sensitivity and plasticity with inter-related metabolic and mood disorders.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Griffith Health
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 Background and Objectives: ‘Neurodevelopmental disorders’ is often synonymously used with childhood developmental disorders such as autism spectrum disorder (ASD), however, increasingly new lines of evidence from genetics and epidemiology suggests having schizophrenia and bipolar disorder to be included as well. For example, there is a strong tendency for schizophrenia and bipolar disorder to occur in people with ASD and shared aetiological factors such as prenatal infection and maternal vitamin D deficiency during pregnancy have all been linked with increased risks in all three conditions. To investigate into this, I have turned to brain imaging, a technique which has opened up a new horizon for neurobiologists. Typically, neuroimaging studies focus on one disorder, matching patients with healthy volunteers and compare their brain structures volumetric differences. On the other hand, such studies are limited by various factors including small ample size, low power, no psychiatric control group, and sample or design heterogeneity. Methods: To summarize all the data into a more meaningful biological representation, Anatomical Likelihood Estimation (ALE), a cutting edge meta-analytic approach was applied. The rationale behind ALE is that it identifies brain differences most consistently reported across studies, while filtering away differences that are least documented. In this thesis, a novel application of ALE known as “dual disorder ALE” is introduced, which serves to estimate the extent of brain regional differences implicated in either disorder – in other words, a method to quantify which areas of the brain are more likely to be affected by ASD, schizophrenia or bipolar disorder. Findings: The analysis is separated into two parts. First, dual disorder ALE technique was applied to investigate the relationship between ASD and first-episode schizophrenia. Data from 25 MRI studies was extracted comprising 660 participants (308 ASD, 352 schizophrenia) and 801 healthy controls. In ASD and FE schizophrenia, there were similar brain differences near the limbic-striato-thalamic circuitry, and distinctive brain differences including amygdala, caudate, frontal and medial gyrus for schizophrenia and putamen for ASD. In the second part comparing bipolar disorder and schizophrenia, data from 651 schizophrenic patients, 540 bipolar patients, and 1438 healthy controls was used, and matched one-to-one by pairing up bipolar disorder studies with corresponding schizophrenia studies to minimize confounders. The ALE result indicated that there are substantial overlaps across the two disorders, with schizophrenia having more extensive brain differences than bipolar disorder. Conclusions: Both parts of the analysis suggest that there are similar aetiological pressures affecting neurodevelopmental disorders including ASD, schizophrenia and bipolar disorder.
published_or_final_version
Psychiatry
Master
Master of Philosophy

Transgenic and knockout mouse models of disease and gene function have revolutionised the field of biomedical research and the targeted mutations of genes expressed in the brain are revealing the mechanisms underlying normal behaviour and behavioural abnormalities which has led to the development of behavioural neuroscience. However, it is also clear that the phenomena know as "redundancy" can limit the effectiveness of traditional knockout models by the effects of compensatory mechanisms. This thesis utilises transgenic and knockout mouse models to explore the role of the tachykinins in the pathogenesis of anxiety, depression and epilepsy focusing on the TACl gene products and their functionality via the TACRl (NKl) receptor. The generation of a novel double knockout line via the cross breeding of single knockout models relevant for the tachykinin signalling pathways circumnavigates the problems associated with redundancy and also reveals that this phenomena is contributing to the data generated using the single knockouts. The use of these animals in a variety of experimental models to compare their function with the original "parental" knockouts and their corresponding wildtype controls reveals novel models for the action of the tachykinins in epilepsy and suggests a correlation with serotonin levels with an ultimate effect on the behavioural responses observed.

Background: Metabolic syndrome is a clustering of conditions that increases the risk for cardiovascular disease. These metabolic disturbances are often comorbid with mood disorders, such as depression (MDD) and bipolar disorder (BP), and are associated with poorer psychiatric prognosis and worse functional impairment. Childhood adversity has been hypothesized to be a common risk factor for both metabolic disturbances and mood disorder. However the precise association between childhood adversity, metabolic disturbances, and mood disorders is still unknown. Objectives: (1) To examine the association between childhood adversity and metabolic outcomes. (2) To test whether specific types of childhood adversity (e.g. abuse, neglect, and family/household dysfunction) and type of mood disorder interact to worsen metabolic outcomes.Methods: This was a cross-sectional study of 68 adult outpatients from a university-based, tertiary-care mood disorders clinic with a DSM-IV defined depression (N=28) or bipolar type I or II disorder (N=40). The National Cholesterol Education Program (NCEP) Adult Treatment Panel III clinical criteria for defining metabolic syndrome were measured. Childhood adversity was measured using the Adverse Childhood Experience self-report questionnaire which collects categories of adversity pertaining to abuse, neglect, and family/household dysfunction. Linear and logistic regressions adjusted for age, sex, and education were conducted to examine the association between childhood adversity and metabolic outcomes. Interaction analyses were conducted to test if type of mood disorder modified the effect of childhood adversity on metabolic outcomes.Results: Nearly one-third (32.3%) of the sample met the NCEP criteria for metabolic syndrome. Despite the majority of our sample being overweight (BMI = 25-29.9), all other metabolic outcomes were within a healthy range. Childhood adversity was highly prevalent in this mood sample, with 80.9% of the participants experiencing at least one category of childhood adversity. Childhood adversities included exposure to household mental illness/suicide (45.6%), emotional neglect (33.8%), alcohol/drug abuse (29.4%), emotional abuse (27.9%), physical abuse (25.0%), sexual abuse (25.0%), parental divorce/separation (23.5%), domestic violence towards mother (13.2%), physical neglect (2.9%), and imprisoned household member (1.5%). There were no statistically significant relationships between the total number of childhood adversities and the range of metabolic outcomes. Several associations between type of childhood adversity and metabolic outcomes were found. Firstly, parental divorce/separation was associated with a higher BMI (B = 3.3, p = 0.047), but after controlling for age, sex, and education, parental divorce/separation was no longer significant. Notably in interaction testing, type of mood disorder modified the effect of parental divorce/separation on BMI such that the association between parental divorce/separation and BMI was greater in the presence of BP versus MDD (B = -7.4, p = 0.016). Secondly, emotional neglect was associated with lower diastolic blood pressure (B = -7.0, p = 0.043). Conclusion: This study provides preliminary evidence linking childhood parental divorce/separation and emotional neglect to the specific metabolic risk factors of BMI and diastolic blood pressure. Systematic assessment of childhood experiences, regular monitoring of the metabolic indices, and promotion of healthy lifestyle habits should be emphasized in routine clinical care of individuals with mood disorders.
Contexte: Le syndrome métabolique augmente le risque de maladies cardiovasculaires. Ces perturbations ont souvent une morbidité associée aux troubles de l'humeur, comme la dépression (MDD) et le trouble bipolaire (BP). Elles sont associées à un moins bon pronostic psychiatrique et une dépréciation fonctionnelle plus importante. L'hypothèse a été émise que l'adversité durant l'enfance est un facteur de risque commun pour les troubles métaboliques et les troubles de l'humeur. Cependant l'association précise entre l'adversité durant l'enfance, les troubles métaboliques et les troubles de l'humeur est encore inconnue.Objectifs: (1) Pour examiner l'association entre l'adversité durant l'enfance et les troubles métaboliques de l'hypertension artérielle, l'obésité abdominale, taux élevés de triglycérides, la glycémie à jeun élevée et peu de lipoprotéines de haute densité (HDL). (2) Pour tester si des types spécifiques d'adversité durant la petite enfance (abus, négligence, familles/ménages dysfonctionnels) et le type de trouble de l'humeur interagissent pour aggraver les résultats métaboliques.Méthodes: Ce fut une étude transversale de 68 patients ambulatoires adultes d'une clinique universitaire de soins des troubles de l'humeur avec une dépression telle que définie selon les critères du DSM-IV (N = 28) ou de trouble bipolaire de type I ou II (N = 40). Les critères cliniques définissant le syndrome métabolique du programme national d'éducation du cholestérol (NCEP), Panel de Traitement pour Adultes III, ont été mesurés. L'adversité durant l'enfance a été mesurée à l'aide de l'auto-questionnaire sur l'expérience adverse durant l'enfance qui recueille les catégories d'adversité relatives à l'abus, la négligence et la dysfonction des familles/ménages. Les régressions linéaires et logistiques ajustées pour l'âge, le sexe et le niveau d'éducation ont été effectuées afin d'étudier l'association entre l'adversité durant l'enfance et les résultats métaboliques. Les analyses d'interaction ont été menées afin de tester si le type de trouble de l'humeur (troubles bipolaires versus dépression) a modifié l'effet de l'adversité durant l'enfance sur les résultats métaboliques.Résultats: Près d'un tiers (32,3%) de l'échantillon répondait aux critères pour le syndrome métabolique. En dépit de la majorité de notre échantillon étant en surpoids (IMC = 25-29,9), tous les autres résultats métaboliques étaient se situaient à un niveau normal. L'adversité durant l'enfance était très répandue dans l'échantillon des troubles de l'humeur, avec 80,9 % des participants ayant connu au moins une catégorie de l'adversité durant l'enfance. Les adversités durant l'enfance incluent l'exposition des ménages à la maladie mentale ou au suicide (45,6 %), la négligence affective (33,8 %), l'abus d'alcool et/ou de drogues (29,4 %), la violence psychologique (27,9%), la violence physique (25,0%), les abus sexuels (25,0 %), et la séparation ou le divorce des parents (23,5%). Plusieurs associations entre type d'adversité durant la petite enfance et les résultats métaboliques ont été trouvées. Tout d'abord, le divorce ou la séparation des parents a été associée à un IMC plus élevé (B = 3,3 ; p = 0,047). Cependant, après ajustement pour l'âge, le sexe et le niveau d'éducation, le divorce ou la séparation des parents, cela n'était plus significatif. Deuxièmement, la négligence émotionnelle a été associée à une baisse de la pression diastolique du sang (B = -7,0 ; p = 0,043).Conclusion: Cette étude fournit des preuves préliminaires reliant le divorce ou la séparation des parents durant l'enfance et de la négligence émotionnelle à des facteurs de risque métaboliques tels l'IMC et la pression artérielle diastolique. L'évaluation systématique des expériences durant l'enfance, un suivi régulier des indices métaboliques et la promotion de saines habitudes de vie doivent être soulignés dans les soins cliniques de routine des personnes souffrant de troubles de l'humeur.

The aim of this thesis is to investigate the role of high sugar intake from sweet food/beverages and high fibre intake as predictors of mood disorders, and as moderators of the association between financial insecurity and mood disorders. The study was based on repeat measures of diet and mood disorders in the Whitehall II cohort. Analyses used random effects models with multiple 2, 5 and 10-year follow-up cycles. Diet was measured using food frequency questionnaires and defined as sugar intake from sweet food/beverages and fibre intake. Mood disorders were defined as common mental disorder (CMD, measured with the General Health Questionnaire), depression measured using Center for Epidemiologic Studies Depression scale, and the Revised Clinical Interview Schedule. Sugar intake from sweet food/beverages was associated with increased odds of incident CMD after 5 years in men and with recurrent depression in women. Findings in men were similar when meta-analysing associations with incident antidepressant intake in Whitehall II and the EPIC-Norfolk study. There was no evidence that mood disorders are associated with a change in sugar intake from sweet food/beverages. Fibre intake was associated with reduced odds of incident CMD after 5 and 10 years. There was no strong evidence that mood disorders are associated with a change in fibre intake. Financial insecurity consistently increased odds of mood disorders, but there was no evidence for effect modification by sugar intake from sweet food/beverages or fibre intake. Findings suggest an adverse effect of sugar intake from sweet food/beverages and a protective role of a diet high in fibre in long-term psychological health. There was no evidence that free sugar or fibre intake could moderate associations between financial insecurity and psychological health. Future research needs to clarify whether associations reflect a causal relationship.

INTRODUCTION: Mood disorders are chronic disorders, responsible for disability worldwide. In recent years a growing body of literature has proposed a psycho-neuro-immunological hypothesis, according to which inflammation may play a role in the development and response to treatment of such diseases. Both Major Depressive Disorder and Bipolar Disorder have been associated with peculiar patterns of cytokine alterations and, on the other hand, some psychotropic drugs showed the ability to affect cytokines production, making an immunomodulatory action of these drugs plausible. METHODS: Our research also included a comparison of Neurokinin-1Receptor (NK-1R) expression and Substance P (SP) ability to induce NF-κB activation in monocytes from BD patients and healthy donors (HD). A further study was conducted on human monocytes, which were used as such or differentiated into M1 and M2 macrophages. Cells were treated with vortioxetine before or after differentiation, and their responsiveness, in terms of included oxy-radical and TNFα production, TNFα and PPARγ gene expression, and NF-κB translocation was evaluated. RESULTS: An increase in pro-inflammatory cytokines such as IL-4, TNF-α, soluble interleukin-2receptor (sIL2-R), IL-1β, IL-6, soluble receptor of TNF-alpha type1 (STNFR1) and C-reactive protein (CRP) is reported in BD patients, during all phases of the disease. IL‐1β, IL‐6, and TNF‐α serum levels are elevated and an increased microglial activation can be observed in some brain regions in MDD patients. NK-1R expression showed relevant alterations in BD patients and SP involvement appeared plausible. Vortioxetine showed anti-inflammatory effect. CONCLUSIONS: Neuro-immunomodulation must be taken into consideration when dealing with the pathophysiology of psychiatric disorders and in the choice of antidepressants; the effect of medications affecting the serotoninergic pathway on the innate immune system should be further investigated, also in a disease-specific context.

Abstract Depression is a common consequence of stroke and it is known to be associated with deterioration of quality of life. However, only limited information is available on the relationships between depression and communicative and cognitive disorders. Moreover, the present knowledge of the determinants of the domains of quality of life is limited, and little is known of e.g. the changes in sexual behaviour of stroke patients and their spouses. This prospective study was carried out to evaluate the prevalence of post-stroke depression and aphasia and to study their interrelationships and neuropsychological and functional correlates. The particular aim of the study was to investigate the domain-specific quality of life, and to assess its clinical and sociodemographic correlates, and to study the impact of stroke on the sexual functions of stroke patients and their spouses. The study consisted of 156 first-ever stroke patients. Depression was diagnosed in 53% of the patients at 3 months and in 42% of the patients at 12 months post-stroke according to DSM-III-R-criteria. One third of the patients were aphasic, 70% of them at 3 months and 62% at 12 months after stroke suffering from depression. Among the aphasic patients the prevalence of major depression increased from 11% to 33% during the 12 months follow-up. There was an association between post-stroke depression and cognitive impairment, the domains most likely to be defective being memory, non-verbal problem solving, and attention and psychomotor speed. The non-verbal neuropsychological test performance in the aphasic patients was significantly inferior to that of the patients with dominant hemisphere lesion without aphasia. The quality of life of the patients was low at 3 months after the stroke, and it did not improve during the follow-up of a year. The test domains most often impaired were Physical functioning, Physical role limitations, Vitality and General health. Depression, although mostly minor, and being married emerged as significant independent contributors to low score value of Vitality and Physical role limitations. All the analyzed aspects of sexuality were commonly decreased as a consequence of stroke both in the patients and their spouses. Nocturnal erections were impaired in 21 (55%) of the male patients. The present results demonstrate that more than half of the patients after stroke suffer from depression and the frequency of major depression seems to increase over time, especially among the aphasic patients. Both depression and aphasia increase the liability of cognitive deficits. Stroke affects various dimensions of quality of life extensively, and the most important determinants entailing low quality of life seem to be depression, and, interestingly, being married. As a part of quality of life, sexual function and satisfaction with sexual life are impaired both in stroke patients and spouses. These findings call for multidimensional evaluation of stroke patients and provide new challenges for stroke rehabilitation.

Thesis (Ph. D.)--Ohio State University, 2005.
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Research has found that 90% of those who complete suicide have a history of one or more psychiatric disorders. Mood disorders and substance use disorders (SUDs) are the key disorders related to suicide. This study not only replicates other data from previous research studies but examines other variables such as comorbid mood and SUDs associated with suicide, while also comparing different age ranges. We investigated three main domains. The first parallels work done by numerous groups comparing suicide completers to controls. The second, more novel approach, examined factors that differentiated those with MD/SUDs and those without it. The last approach, also unique to our study, focused on identifying factors associated with the two main age ranges (12-18 years old and 19-25 years old). Becoming aware of the increased risk of suicide completion within these domains can better prepare professionals when addressing treatment options.
Des recherches antérieures ont trouvé que 90% des individus décédés par suicide portent un historique d'un ou plusieurs antécédents psychiatriques. Les troubles de l'humeur ainsi que des troubles de consommation sont ceux qui sont principalement associés au suicide. La présente étude confirme les résultats mentionnés ci-haut et examine de nouvelles variables telles que la comorbidité entre les deux troubles et son association au suicide à travers divers groupes d'âge. Nous avons investigués trois domaines. Le premier présente le travail de plusieurs groupes de recherche ayant comparé le profil d'individus décédés par suicide à un groupe contrôle. Le second, abordé de façon plus novatrice, examine les facteurs qui permettent de différencier les individus souffrant d'un trouble de l'humeur ou d'un trouble de consommation à ceux qui n'en souffrent pas. Le troisième domaine exploré est aussi un qui est unique à notre étude. Par ce dernier, nous visons l'identification de facteurs associés à deux groupes d'âge spécifique, soit les 12 à 18 ans et les 19 à 25 ans. La connaissance de ces facteurs de risque permettrait aux professionnels d'être mieux équipés lorsque vient le temps d'offrir des traitements.

This dissertation work aims to provide new methodological perspectives in the assessment of mood disorders, with the main task of suggesting effective solutions for the evaluation of major depressive episode (MDE), in order to support the differential diagnosis of different forms of depression. Mood disorders are the most prevalent of all mental health diagnoses and their incidence has increased in recent decades, becoming one of the most significant public health problem. Many people fail to go to school or university, lose their jobs, lose their partner and friends, and may commit suicide. The course of these disorders as well as their prognosis are closely related to proper diagnosis and well-timed treatment. Despite this, the risk of misdiagnosis is currently high, with serious consequences both for the current episode and for the course of the illness. In particular, the MDE is often classified without specification, also if there are different possible configurations of symptoms that characterize it. Thus, MDE is almost always treated with antidepressant drugs that in some cases (e.g., agitated depression) may increase the symptoms of agitation and the risk of suicide. The assessment phase plays a crucial role for the proper treatment of the disorder. Physicians after collecting patients information, need to formulate diagnostic hypotheses in a short time to plan effective clinical interventions. The quality of clinical evaluation is crucial for both diagnosis and treatment. Formal Psychological Assessment (FPA; Spoto, 2011; Spoto, Bottesi, Sanavio & Vidotto) is a methodology able to maximize the benefits of both semi-structured interviews and self-reports, trying to overcome their limitations. Indeed, the FPA methodological approach allows the construction of: - Tools that are able to provide qualitative information about patient symptoms that goes beyond the numerical score. - Tools that are able to differentiate patients who obtain the same score, but replied to different items, and therefore have different symptoms configurations. - Adaptive tools (as semi-structured interviews) that allow investigating and deepening the patients symptoms. - Rapid administration as self-report questionnaires. In this three-year project at the University of Padua, the FPA concepts have been applied to achieve different aims. In a first phase, a methodological analysis of the most used self-report questionnaires of depression was carried out to explore their ability to investigate all the symptoms of the MDE. The research is based on the relationship between items and diagnostic criteria for depression, in line with the FPA methodology. In the second phase, a new self-report questionnaire of 41 items was built on the basis of 23 clinical criteria for MDE from DSM-5 and literature. In the third phase, the same questionnaire was validated on non-clinical sample of 265 individuals and clinical sample of 38 patients with MDE diagnosed with major depression or bipolar disorder. The questionnaire provided good results both in terms of validity and reliability. However, the strength of this tool stands in its ability to go beyond the numerical score, allowing to differentiate individuals with the same score but with different symptoms and possibly different severity of the episode. This property is assured by the patients clinical state (the fundamental concept of FPA) as the main output of the test, which is the set of items the individual replied affirmatively with the subset of symptoms investigated by those items. In this way, clinical evaluation will not only be related to the level of depression obtained from the score but also to the specific configuration of symptoms manifested by the individual. In the fourth phase of the research, the computerized algorithm was implemented in the new questionnaire to obtain the adaptive form of the tool. The questionnaire was subdivided into its three sub-scales (affective, somatic and cognitive) corresponding to the three sub factors of the factorial structure. For each sub-scale, through the probability model of the FPA (i.e. the Basic Local Independent Model; BLIM) the false negative, false positives for each item and all the clinical states of the structure were estimated. An interactive procedure was used with maximum likelihood, which provided an estimate of parameters and fit indexes. After being tested on real data, the adaptive form of the tool allows faster and more efficient administration. Indeed, the items to which the individual will respond will depend on previous responses, in a process that mimics the semi-structured interview, avoiding possible logical inferences of the clinician. The new tool called quantitative and qualitative evaluation of Depressive Symptomatology (QuEDS) can be a support for clinicians; in fact, it differentiates the individual's depressive symptoms beyond the score and allows administering only the items related to its symptomatology following the logical flow of question-answer. Thus, two patients who obtain the same score on the test can be treated differently according to their symptoms, since answering the same number of items does not mean responding to the same items. In particular, it is well known that the use of antidepressant drugs is not always recommended in depression. There are mixed depressions, as defined by many authors, because they are characterized by both depressive symptoms and manic symptoms (such as agitation, anguish, irritability, insomnia, mood lability). Two examples of mixed depression are agitated depression and depression with flight of ideas, in which antidepressant drugs not only increase the excitatory component (manic symptoms) worsening the course of the affective episode but, more seriously, increase the risk of suicide. For this reason, understanding all depressive symptoms is crucial in clinical practice. The last part of this project was carried out in England, in collaboration with the University of Cardiff and Worcester, in particular with the Bipolar Disorder Research Network (BDRN). The BDRN data used in this research include 3750 mood disorders patients divided into three subgroups: Major Depressive Disorder (MDD), Bipolar Disorder Type I (BD-I) and Bipolar Disorder Type II (BD-II). The 29.3% of the whole sample had suffered from an episode of agitated depression (AD), particularly AD was more related to bipolar disorder, especially BD-II. Moreover, patients with agitated depression had higher comorbidities with panic disorder and substance abuse, made greater use of psychiatric drugs, and suffer of more mixed states in lifetime. Agitated depression was related to lifetime suicide attempts and suicidal ideation during the affective episode. These results confirm and strengthen the indications of several other studies on smaller clinical samples. The recognition and differential diagnosis of mixed depression is essential to avoid improper treatment with dangerous consequences. The construction of tools to support clinicians task providing the patient symptom configuration with more clinical information can become a strength in clinical practice. The tool presented in this work represents a step in this direction; however, to allow differential diagnosis of each MDE, this step needs to be combined to the experience and awareness of the clinician in the field of mood disorders, and especially to the development of further insights in the methodological context. Indeed, as the data demonstrate, the recognition of mixed depression is a difficult task both from a clinical and from a methodological point of view in relation to the construction of suitable and exhaustive instruments. The fundamental issue that remains unclear concerns the ability to investigate the symptoms of manic component that are underestimated by the patient itself (such as racing crowed thought, mood lability etc.) during depression phase. The first three Chapters form the theoretical framework, and the starting point for the researches. In the first Chapter, mood disorders are described: prevalence, genetic component, diagnostic classification (major depression, dysthymia, bipolar disorder I, bipolar disorder II, cyclotymic disorder, and rapid-cycle disorder); Also depression is described, followed by mixed depression and the differential diagnosis. Finally, the pharmacological treatment and the etiopathogenetic theories of depression are briefly explained. The second Chapter describes the assessment, therefore the tools most used by the clinician with their strengths and weaknesses; The CBA 2.0 (Cognitive Behavioral Assessment) and Adaptive Assessment are also described. The third Chapter is devoted to the explanation of FPA starting from the mathematical theories to the implementation of the method in the clinical context. Chapters 4, 5, 6, 7 describe the four main researches carried out in this PhD project. To conclude, Chapter 8 will present the final discussion.
Il presente lavoro di tesi si propone di offrire nuove prospettive metodologiche nell'assessment dei disturbi dell'umore, con l'obiettivo principale di suggerire alternative efficaci alla valutazione dell'episodio depressivo maggiore, nell'ottica di sostenere la diagnosi differenziale di diverse forme di depressione. I disturbi dell'umore sono il più frequente disturbo mentale e la loro incidenza è aumentata negli ultimi decenni, diventando uno dei più significativi problemi sociosanitari. Perdita del lavoro, divorzio, difficoltà  nel crescere i figli e abuso di sostanze sono solo alcuni dei gravi rischi associati ai disturbi dell'umore. Il suicidio è la più tragica delle conseguenze. Il decorso di questi disturbi così come la loro prognosi sono strettamente legati alla corretta diagnosi e al tempestivo trattamento. Purtroppo, attualmente è molto alto il rischio di diagnosi non corretta, con gravi ripercussioni sul trattamento e quindi sul decorso della malattia. In particolare l'episodio depressivo maggiore viene troppo spesso classificato in un solo modo e senza specificazioni, nonostante le possibili diverse configurazioni di sintomi che lo caratterizzano. Come tale esso viene trattato con farmaci antidepressivi, che in alcuni casi (ad esempio la depressione agitata) possono non solo aumentare i sintomi di agitazione, ma anche aumentare il rischio di suicidio. La fase di assessment riveste un ruolo cruciale in vista di un trattamento adeguato del disturbo. I medici dopo aver raccolto il maggior numero possibile di informazioni sul paziente, devono formulare ipotesi diagnostiche in breve tempo per pianificare interventi clinici efficaci. La qualità  della valutazione clinica è fondamentale sia per la diagnosi che per il trattamento. Il Formal Psychological Assessment (FPA; Spoto, 2011; Spoto, Bottesi, Sanavio & Vidotto, 2013) si configura come una metodologia che unisce i vantaggi delle interviste semi-strutturate e dei self-report, cercando di superare i loro limiti. Infatti l'approccio metodologico dell'FPA permette la costruzione di strumenti: - In grado di restituire delle informazioni qualitative, relative ai sintomi del paziente, che vanno oltre lo score numerico. - In grado di differenziare pazienti che ottengono lo stesso punteggio al test, ma che hanno risposto a item diversi, e che hanno quindi configurazioni diverse di sintomi. - Adattivi (come le interviste semi-strutturate) che permettono di indagare le aree sintomatologiche del paziente e di approfondirle. - Di rapida somministrazione come i questionari self-report. Nel progetto svolto in questi tre anni all'Università di Padova, sono stati utilizzati i concetti dell'FPA in diverse fasi. In una prima fase è stata svolta un'analisi metodologica dei questionari self-report più utilizzati nel campo della depressione per esplorare la loro capacità di indagare tutti i sintomi dell'episodio depressivo maggiore. La ricerca si è basata sulle relazioni tra gli item e i criteri diagnostici per la depressione, in linea con la metodologia dell'FPA. Nella seconda fase, è stato costruito un nuovo questionario di 41 item sulla base di 23 criteri clinici per l'episodio depressivo maggiore, ricavati dal DSM-5, e dalla diffusa letteratura sulla depressione. Nella terza fase il questionario è stato validato su una popolazione non clinica di 265 individui e su una popolazione clinica di 38 pazienti con episodio depressivo maggiore diagnosticati con depressione maggiore o disturbo bipolare. Il questionario ha mostrato buoni risultati sia per i diversi criteri di validità  che per l'affidabilità. Tuttavia, la peculiarità  di questo strumento sta nella sua capacità  di andare oltre lo score numerico, permettendo di differenziare individui con lo stesso punteggio al test ma che presentano diverse sintomatologie. Questa proprietà è garantita dallo stato clinico del paziente (concetto fondamentale dell'FPA), come principale output del test, ossia dall'insieme di item a cui l'individuo ha risposto affermativamente con il sotto-insieme di sintomi indagati da quegli item. In questo modo la valutazione clinica non sarà  solo legata al livello di depressione ottenuto dallo score, ma dalla configurazione specifica di sintomi manifestati da una precisa persona. Nella quarta fase della ricerca, è stato implementato l'algoritmo computerizzato per il nuovo questionario, in modo da ottenere la forma adattiva dello strumento. Per raggiungere quest'ultimo step, il questionario è stato suddiviso nelle sue tre sotto-scale (affettiva, somatica e cognitiva) corrispondenti ai tre sotto-fattori della struttura fattoriale. Per ogni sotto-scala, attraverso il Basic Local Independent Model (BLIM), modello probabilistico dell'FPA, sono stati stimati i parametri relativi alle probabilità di falso positivo, falso negativo per ogni item e di tutti gli stati clinici della struttura. E' stata utilizzata una procedura interattiva per massima verosimiglianza, che ha fornito una stima dei parametri e degli indici di fit. Una volta testato sui dati reali, la forma adattiva dello strumento permette una somministrazione più rapida ed efficiente. Infatti, gli item a cui l'individuo dovrà  rispondere dipenderanno dalle risposte precedentemente date, in un processo che imita l'intervista semi-strutturata, evitando possibili inferenze logiche del clinico. Il nuovo strumento per l'assessment della depressione chiamato QuEDS (Quantitative and Qualitative Evaluation of Depressive Symptomatology) rappresenta quindi un supporto per lo psichiatra o lo psicoterapeuta, in quanto offre la possibilità di distinguere i sintomi depressivi di ogni individuo al di là dello score ottenuto al test, e permette di somministrare solo gli item legati alla sua sintomatologia seguendo il flusso logico di domanda-risposta. Dunque due pazienti che ottengono lo stesso punteggio al test, indice dello stesso potenziale livello di depressione, potranno essere trattati comunque in accordo con i loro sintomi; infatti aver risposto allo stesso numero di item non significa aver risposto agli stessi item. In particolare è noto che l'uso di farmaci antidepressivi non è sempre consigliato nella depressione. Esistono infatti le depressioni miste, così definite da moltissimi autori, perchè caratterizzate sia da sintomi depressivi che da sintomi maniacali (come agitazione, angoscia, irritabilità, insonnia, labilità  emotiva). Due esempi di depressione mista sono la depressione agitata e la depressione con fuga delle idee, in cui i farmaci antidepressivi non solo aumentano la componente eccitatoria (quindi i sintomi maniacali) peggiorando il decorso della malattia ma, problema ancora più grave aumentano il rischio di suicidio. Per questo motivo capire tutta la sintomatologia depressiva risulta fondamentale nella pratica clinica. L'ultima parte del progetto di questi tre anni, è stata svolta in Inghilterra, in collaborazione con le Università di Cardiff e Worcester, in particolare con Il Bipolar Disorder Research Network (BDRN). I dati del BDRN utilizzati in questa ricerca comprendono 3750 pazienti con disturbi dell'umore divisi nei tre sotto-gruppi: Disturbo Depressivo Maggiore (MDD), Disturbo Bipolare di tipo I (BD-I) e Disturbo Bipolare di tipo II (BD-II); nel 29,3% dell'intero campione era presente un episodio di depressione agitata, in particolare la depressione agitata era più presente nel disturbo bipolare, soprattutto BD-II. Inoltre i pazienti con depressione agitata avevano più comorbidità con disturbo di panico e con abuso di sostanze, facevano maggior uso di psicofarmaci, e soffrivano di maggiori episodi misti durante l'arco di vita. La depressione agitata era correlata ai tentati suicidi durante l'arco di vita e all'ideazione suicidaria durante l'episodio affettivo. Questi risultati confermano e rafforzano le indicazioni di diversi altri studi svolti su campioni clinici meno ampi. Il riconoscimento e la diagnosi differenziale della depressione mista è essenziale per evitare una diagnosi scorretta e un successivo trattamento pericoloso. La costruzione di strumenti di supporto al medico, che siano in grado di restituire la configurazione di sintomi del paziente e di garantire maggiori informazioni cliniche può diventare un punto di forza nella pratica clinica. Lo strumento presentato in questo lavoro, rappresenta un passo avanti in questa direzione; tuttavia per permettere una diagnosi differenziale dell'episodio depressivo questo primo step ha bisogno di essere accompagnato dall'esperienza e la consapevolezza del clinico nel campo dei disturbi dell'umore, e soprattutto dallo sviluppo di ulteriori approfondimenti nel contesto metodologico. Infatti come i dati dimostrano, riuscire a catturare i sintomi di una depressione mista risulta un'impresa ardua sia dal punto di vista clinico che dal punto di vista metodologico per quanto concerne la costruzione di strumenti adatti ed esaustivi. La questione fondamentale che resta aperta, riguarda la capacità di riuscire ad indagare quei sintomi di componente maniacale che vengono sottostimati dal paziente stesso (come il flusso rapido dei pensieri, la labilità  emotiva ecc.) in fase depressiva. I primi tre capitoli di questo lavoro formano la cornice teorica, e il punto di partenza per la ricerca. Nel primo capitolo sono infatti descritti nel dettaglio i disturbi dell'umore: la prevalenza, la componente genetica, la classificazione dei vari disturbi (Depressione Maggiore, Distimia, Disturbo Bipolare I, Disturbo Bipolare II, Disturbo Ciclotimico, e disturbo a cicli rapidi); inoltre viene descritta la depressione, e in seguito la depressione mista con particolare attenzione alla diagnosi differenziale. Infine viene brevemente spiegato il trattamento farmacologico e le teorie eziopatogenetiche della depressione. Nel secondo capitolo viene descritto l'assessment, quindi gli strumenti maggiormente utilizzati con i loro punti di forza e di debolezza; vengono inoltre descritti la batteria CBA 2.0 (Cognitive Behavioural Assessment 2.0), e l'assessment adattivo. Il terzo capitolo è dedicato alla spiegazione dell'FPA a partire dalle teorie matematiche sulle quali si fonda fino alla realizzazione del metodo nel contesto clinico. I capitoli 4, 5, 6, 7 descrivono le quattro ricerche principali di questo progetto di dottorato. Infine nel capitolo 8 sarà presentata la discussione finale dell'intero percorso.

Introduction: Cardiovascular disorders contribute significantly to mortality and morbidity amongst patient's psychotic disorders such as schizophrenia and bipolar mood disorders. In addition to conventional risk factors for cardiovascular disorders (smoking, alcohol use, inadequate physical activity, hypertension, diabetes, dyslipidaemia, obesity and metabolic syndrome, and non-modifiable factors such as sex, age and social-economic status) exposure to potentially traumatic events, psychological distress, comorbidity of other medical conditions, and use of antipsychotics may also increase cardiovascular risk in patients with psychosis. There is also evidence to suggest that intervention to mitigate such cardiovascular risk factors are suboptimal, hence contributing to poor outcomes. Despite growing interest in cardiovascular health, there remains a paucity of data on the prevalence of the various cardiovascular risk factors among patients with psychosis in low resource settings such as Sub-Saharan Africa. This is likely to differ from high resource contexts given social-cultural and economic differences as well as differences in the health systems. In order to design contextually relevant cardiovascular risk screening, treatment and prevention guidelines that can be integrated into routine care of the mentally ill patients in low- and middle-income countries (LMICs), further work in this setting is warranted. Objectives: The aim of this thesis was to establish the cardiovascular risk profile among patients treated for psychotic disorders at Moi Teaching and Referral Hospital (MTRH) in Eldoret, Western Kenya. Specific objectives were as follows: 1. To conduct a literature review on the burden and etiological mechanisms of cardiovascular risk in patients with psychosis, with a focus on LMIC. 2. To compare the prevalence, as well as sociodemographic and clinical correlates, of conventional cardiovascular risk factors (smoking, alcohol intake, poor diet, and lack of exercise, diabetes mellitus, hypertension, obesity, dyslipidaemia and metabolic syndrome) in patients with psychosis versus matched controls. 3. To establish the prevalence and correlates of non-conventional risk factors; psychological distress, traumatic events (lifetime and childhood trauma) and comorbid medical disorders in patients with psychosis and controls, and to delineate how these risk factors contribute to the overall cardiovascular risk. 4. To describe current psychopharmacological treatments and explore potential associations with cardiovascular risk among patients with psychosis. 5. To explore the overall 10-year cardiovascular disease risk, as well as the social demographic and clinical correlates among patients and controls. 6 .To determine the proportion of untreated metabolic disorders (hypertension, diabetes mellitus, and dyslipidaemia) in patients with psychotic disorders and matched controls. Methods: This was a cross-sectional descriptive survey comparing 300 patients with psychosis and 300 controls at Moi Teaching and Referral Hospital, Western Kenya. A paper based researcher-administered questionnaire was used to collect data on demographic variables (age, sex, education level, and marital status), and risk factors (smoking, alcohol intake, diet, physical activity). We used the Composite International Diagnostic Interview (CIDI) to assess for presence of other chronic medical disorders. Data on childhood trauma were obtained using the Childhood Trauma Questionnaire (CTQ) while the Life Events Checklist (LEC) was used to obtain data on lifetime exposure to potentially traumatic events. Data on psychological distress among controls were obtained using the Kessler-10 questionnaire. Measurements of weight, height, abdominal circumference and blood pressure were taken from each of the participants. Blood was drawn for measurement of glucose level and lipid profile. Data analysis was undertaken using Stata version 15. T-tests were used to compare continuous variables while Pearson chi-squared tests was used for categorical variables. Regression modelling was undertaken to assess associations between sociodemographic and clinical predictor variables and the cardiovascular risk factors. Results: Data collection took place between July 2018 and March 2019. The mean age of patients was 33 years and of controls was 35 years. Compared to controls, patients were more likely to be unmarried (46% vs 33% p< 0.001), and were reduced among females (OR 0.41 p20). The estimated 10 year cardiovascular risk was significantly associated with female Sex (p=0.007), age (p <0.001), current tobacco smoking (p <0.001) and metabolic syndrome (P<0.001). Among the patients, 280 (94.3%) patients were on antipsychotics with the majority (86.5%) being treated with olanzapine. Of all the participants with diabetes 60% among patients and 22% among controls were not on treatment. Of the total number of participants with hypertension, 65% of patients and 47% controls were not on treatment. Conclusion: In the study setting of Eldoret, Western Kenya, patients with psychosis were found to have high levels of lifestyle cardiovascular risk factors such as smoking, inadequate intake of fruits and vegetables and inadequate physical activity. They were also found to have high rates of metabolic disorders such as hypertension, obesity, metabolic syndrome and dyslipidaemia. There was no evidence of increased cardiovascular risk among participants exposed to traumatic life events, with those experiencing psychological distress or those with other chronic medical disorders. The use of olanzapine was not significantly associated with increased cardiovascular risk in this setting. There was an identifiable gap in the treatment of cardiovascular risk factors in this setting. Given these findings, we recommend efforts to address these risk factors by development of protocols to ensure screening for these risk factors, adequate documentation and appropriate treatment.

Background: Major depressive disorder (MDD) and bipolar disorder (BP) are debilitating mood disorders that are associated with both long-term economic costs and functional impairment. Impulsivity has been implicated in mood disorders, and primarily in BP. Impulsivity is strongly associated with aggression, risk of suicidal behaviour, and overall functional impairment in mood disorders. Studies have found that BP individuals have significantly higher levels of impulsivity than controls, although fewer studies have examined the specific link between impulsivity and BP compared to MDD. Furthermore, there has been very little research pertaining to the differentiation between levels of impulsivity in BP subtypes, including bipolar type I (BPI) and bipolar type II (BPII). As well, impulsivity has been linked with other psychiatric comorbidities, including anxiety disorders as well as substance use disorders (SUDs). However, the role of impulsivity in mood disorders with anxiety disorder or SUD comorbidity has not been established. Objectives: There are two objectives for this study. The first objective is to compare a) MDD and BP subjects and b) MDD, BPI, and BPII subjects on impulsivity, specifically total impulsivity as well as each of the three dimensions of impulsivity: attentional impulsivity, motor impulsivity, and nonplanning impulsivity. The second objective is to examine if comorbid lifetime (a) anxiety disorders or (b) SUDs modify the association between mood disorder (BP and MDD) and impulsivity, specifically total impulsivity as well as each of the three dimensions of impulsivity. Methods: 115 euthymic outpatients with a primary DSM-IV diagnosis of MDD (N=45), BPI (N=53), or BPII (N=17) from the Mood Disorders Program of the McGill University Health Centre were recruited. The Structured Clinical Interview for DSM-IV (SCID) was conducted to diagnose psychiatric disorders. Impulsivity was measured using the self-report questionnaire - Barratt Impulsiveness Scale (BIS-11) - which assesses three dimensions of impulsivity: attentional, motor, and nonplanning impulsivity. A medical chart review was conducted to obtain socio-demographic and psychiatric disorder information. Results: BP subjects had significantly higher total impulsivity as well as motor and nonplanning impulsivity compared to MDD subjects. With regards to specific BP subtypes, BPI subjects had significantly higher total impulsivity and motor impulsivity than MDD subjects, and BPII subjects had significantly higher total impulsivity, as well as attentional, motor, and nonplanning impulsivity than MDD subjects. Finally, BPII subjects had significantly higher attentional impulsivity than BPI subjects. With regards to lifetime psychiatric comorbidity, mood disorder subjects with anxiety disorders had higher levels of attentional impulsivity. For lifetime SUD diagnosis, SUD comorbidity was associated with higher levels of total impulsivity as well as motor and nonplanning impulsivity in mood disorder subjects. There was no interaction between anxiety or SUD comorbidity and mood diagnosis on total or dimensional impulsivity. Conclusions: Impulsivity is an important factor in the clinical presentation of mood disorders. Our results emphasize the importance of impulsivity primarily in BP, as well as impulsivity in BP individuals with a comorbid anxiety disorder or SUD. Further research measuring impulsivity in BP subtypes with different psychiatric comorbidities (e.g., anxiety disorders, SUDs) would help guide health professionals and clinicians in the assessment of impulsivity and the treatment of impulsive aggression, suicidal behaviours, and other clinical correlates of impulsivity in BP subjects.
Contexte: Le trouble dépressif majeur (TDM) et le trouble bipolaire (TB) sont des troubles de l'humeur qui sont associés aux coûts économiques à long terme et la détérioration fonctionnelle. L'impulsivité a été impliquée dans les troubles de l'humeur, principalement dans TB. L'impulsivité est associée à l'agression, le risque de comportement suicidaire, et la détérioration fonctionnelle globale chez les personnes avec un trouble de l'humeur. Des études ont montré que les individus avec le TB ont des niveaux d'impulsivité plus élevés que les témoins, bien que peu d'études aient examiné le lien spécifique entre l'impulsivité et TB contre TDM. En outre, il y a eu peu de recherche relatif à la différenciation entre les niveaux d'impulsivité dans les sous-types TB, y compris le trouble bipolaire de type I (TB-I) et le trouble bipolaire de type II (TB-II). Aussi, l'impulsivité a été liée à d'autres comorbidités psychiatriques, dont les troubles anxieux ainsi que les troubles de toxicomanie. Cependant, le rôle de l'impulsivité chez les personnes avec un trouble de l'humeur et un trouble anxieux ou un trouble de toxicomanie comorbide n'a pas été établi.Objectifs: Il y a deux objectifs pour cette étude. Le premier est de comparer a) TDM et TB sujets et b) TDM, TB-I, et TB-II sur l'impulsivité, spécifiquement l'impulsivité total et les trois dimensions de l'impulsivité: cognitive, motrice, et non-planification. Le deuxième objectif est d'examiner si les troubles anxieux et de toxicomanie, modifient la relation entre les troubles de l`humeur et l`impulsivité. Méthodes: 115 patients en consultation externe avec un diagnostic de TDM (N = 45), TB-I (N = 53), ou TB-II (N = 17) du Programme des troubles de l'humeur du Centre Universitaire de Santé McGill ont été recrutés. L'Entrevues Cliniques Structurées pour le DSM-IV ont été menées pour diagnostiquer les troubles psychiatriques. L'impulsivité a été mesurée à l'aide du questionnaire de l'Échelle d'Impulsivité de Barratt (BIS- 11), qui divise l'impulsivité totale en trois dimensions: cognitive, motrice, et non-planification. Un examen des dossiers médicaux a été réalisée pour obtenir plus d`informations sur les troubles psychiatriques. Résultats: L'impulsivité totale, l'impulsivité motrice, et l'impulsivité non-planification étaient plus élevées chez les sujets avec le TB par rapport aux sujets avec le TDM. Les sujets avec le TB-I avaient l`impulsivité totale et l'impulsivité motrice significativement plus élevées par comparaison avec les sujets avec le TDM, et les sujets avec le TB-II avaient l'impulsivité totale, cognitive, motrice, et non-planification significativement plus élevées par rapport aux sujets avec le TDM. Enfin, l'impulsivité cognitive était significativement plus élevée chez les sujets avec le TB-II par rapport aux sujets avec le TB-I. Les sujets avec le TB et un trouble anxieux avaient des niveaux d'impulsivité cognitive plus élevés par rapport aux sujets avec le TDM et un trouble anxieux. À propos des diagnostics de toxicomanie, avoir une comorbidité de toxicomanie est associée aux niveaux d'impulsivité totale, motrice, et non-planification plus élevées chez les sujets avec le TB par rapport aux sujets avec le TDM. Il n'y avait pas d'interaction entre les comorbidités et le diagnostic de trouble de l'humeur sur l'impulsivité. Conclusions: L'impulsivité est un facteur important dans la présentation clinique des troubles de l'humeur. Nos résultats soulignent l'importance de l'impulsivité chez les individus avec le TB ainsi que chez les individus avec le TB et un diagnostic comorbide. On a besoin de plus de recherche sur l'impulsivité chez les patients avec les sous-types TB avec des comorbidités psychiatriques pour aider les professionnels de la santé à bien évaluer l'impulsivité chez les sujets avec le TB et à bien traiter l'agressivité impulsive, des comportements suicidaires, et d'autres corrélats cliniques de l'impulsivité.

Ein großer Teil der Fragestellungen in den Neurowissenschaften beschäftigt sich mit dem Thema, wie das Säugerhirn Verhalten auslöst und steuert. Die Schreckreaktion ist ein relativ einfaches Verhalten, welches bei Säugetieren ohne großen Aufwand ausgelöst werden kann und variabel auf eine Vielfalt von experimentellen Behandlungen reagiert. Das Ziel der vorliegenden Arbeit war es, Schreckreaktions-Messungen am Max-Planck- Institut für Psychiatrie in München (MPI-P) zu etablieren. Vor dem Hintergrund aktueller Fragestellungen sollten die Experimente zu einsatzbereiten Messmethoden und Verhaltensparadigmen führen. In der vorliegenden Arbeit gelang es nicht, das Paradigma der furchtpotenzierten Schreckreaktion (FPS) zuverlässig in einem häufig am MPI-P eingesetzten Mausstamm anzuwenden. Das FPS maskierende Phänomen, daß die Präsentation eines unkonditionierten Tons bereits zu einer deutlich verstärkten Schreckreaktion in diesen Mäusen führt ("tone enhanced startle", TES) wurde dann charakterisiert und im Folgenden als ergänzendes Paradigma zur Messung und Abschätzung des Hörvermögens, der Stimulus Adaptation und der Aufmerksamkeit in Mäusen vorgeschlagen. Eine Literaturrecherche ergab, daß im Paradigma der Furchtkonditionierung ("fear conditioning", FC) und deren aktives Verlernen ("extinction of FC", ExFC) verwendete Stimulus-Parameter eine hohe Varianz zwischen verschiedenen Laboratorien aufweisen. Der im Verhalten ausgelesene Lernerfolg während einer FC wie auch einem ExFC hingen in den vorliegenden Experimenten wesentlich von der verwendeten Stimulusqualität ab (d.h. sinus-Ton oder weißes Rauschen). Im Umkehrschluß empfiehlt die vorliegende Arbeit einen überlegteren Umgang mit den eingetzten Stimulus-Parametern. Es zeigte sich, daß eine erhöhte Schreckreaktion (Übererregbarkeit) ohne weiteres in einem Tiermodell der Posttraumatischen Belastungsstörung ("posttraumatic stress disorder",PTSD) gemessen werden kann. Im Weiteren konnte gezeigt werden, daß verändertes Hippocampus-Volumen in diesen Tieren, gemessen über ultramikroskopische Aufnahmen und analog zu Hippocampusveränderungen in Patienten, unabhängig von anderen PTSD-ähnlichen Symptomen dieser Mäuse ist. In einem weiteren Abschnitt widmet sich die vorliegende Arbeit der laufenden Charakterisierung der Rolle von Dopaminrezeptoren (DR) in der Präpulsinhibition (PPI) und -Faszilitierung (PPF) der Schreckreaktion. Durch lokale injektion von DR-Antagonisten konnte gezeigt werden, daß die Blockade von DR1 wiederholbar PPI verstärkt, während die Rolle von DR2, getestet mit zwei verschiedenen Antagonisten, als ambivalent gedeutet werden muß. Basierend auf diesen Experimenten wurden optogenetische Methoden in die Schreckreaktionsmessung eingeführt. Transgenen Mäusen, die lichtsensitive Ionenkanäle in ihren neuronalen Zellmembranen bestimmter Zellpopulationen tragen, wurden Lichtblitze ins Gehirn appliziert. Auf diese Weise konnten PPI und PPF unabhängig voneinander manipuliert werden. Daraus folgend, und im Unterschied zur populären Summationshypothese der PPF, schlägt die vorliegende Arbeit einen eigenständigen, von der PPI unabhängigen PPF-Schaltkreis vor, der Pyramidenneuronen der präfrontalen Kortexschicht V beinhaltet. Die vorliegende Arbeit konnte erfolgreich verschiedene Protokolle und Verhaltensparadigmen der Schreckreaktionsmessung am MPI-P etablieren und zur sofortigen Nutzung zur Verfügung stellen. Es wurden nicht nur neue Techniken wie z.B. optogenetische Methoden in die Schreckreaktionsmessung eingeführt, die vorliegenden Experiemente leisten auch ihren Beitrag zur aktiven Forschung, in dem sie z.B. die große Bedeutung der Stimulus-Parameter für den Lernerfolg von Versuchstieren nachweisen.
In neuroscience major efforts are focused on the question of how the mammalian brain generates and controls behaviour. The startle response is a relatively simple behaviour that can be easily elicited in mammals and is sensitive to a variety of experimental treatments. The aim of the present work was to establish startle response measures at the Max-Planck-Institute of Psychiatry (MPI-P), Munich, providing a set of readily applicable methods and paradigms, and contributing to questions in behavioural neuroscience. While the present thesis failed to robustly elicit fear potentiated startle (FPS) in a commonly used mouse strain at the MPI-P, strong unconditioned startle enhancement by acoustic stimulus presentation in that mouse strain was capitalised to propose tone enhanced startle (TES) as an additional paradigm to assess hearing capability, stimulus adaptation and attention in mice. A literature survey revealed considerably varying parameters used in fear conditioning (FC) and extinction of conditioned fear (ExFC). In the present work, FC, ExFC as well as FPS/TES highly depended on the stimulus quality (i.e. sine wave or white noise), demanding a more careful handling of stimulus parameters. Hyper-arousal was readily tested in a mouse model of posttraumatic stress disorder (PTSD). Additionally it was shown that altered hippocampal volume in these animals, assessed by ultramicroscopic measures and mimicking patient data, was independent of other symptoms present in this model. The present thesis contributes to the ongoing characterisation of the role of dopamine receptors (DR) in prepulse inhibition (PPI) and prepulse facilitation (PPF) of startle, manipulating PPI/F by injections of DR-antagonists into the prefrontal cortex of mice. It was found that blockade of DR1 reliably increases PPI, while the effect of DR2 was inconsistent, using to different DR2-antagonists. Based on this work, optogenetic methods were established. Applying intracerebral light flashes to transgenic mice carrying light sensitive ion channels on their neuronal cell membrane, PPI and PPF were manipulated independently, proposing the existence of a discrete PPF mediating pathway including prefrontal layer V pyramidal neurons, contrasting the popular summation hypothesis of PPF. The present work established and developed successfully different startle paradigms that are ready to use for animal characterisation and testing. Apart from combining startle measures with new techniques such as optogenetic methods, the present thesis points out the stimulus parameter dependence of animal learning, suggesting a fundamental discussion about fear conditioning and extinction learning protocols.

There has recently been an intense debate about the increased rate of bipolar disorders (BPD) in children and adolescents observed in clinical settings. Thus, there is great interest in child and adolescent symptoms of hypomania and whether these symptoms subsequently will develop into BPD. More knowledge about early signs could give insight into the development of the disorder. There are also concerns that hypomanic symptoms in adolescence indicate excess risk of other health conditions. It has been reported that patients with mood disorders have a high consumption of prescription drugs in different ATC classes. The primary objective of this thesis was to better understand the mental health outcome of adolescents with hypomania spectrum symptoms and to identify early risk factors for adult bipolar disorder among adolescents with mood disorders. In order to widen the scope and investigate health outcome of mood disorder in general psychopharmacological outcomes were included. A community sample of adolescents (N=2 300) in the town of Uppsala, Sweden, was screened for depressive symptoms. Both participants with positive screening and matched controls (in total 631) were diagnostically interviewed. Ninety participants reported hypomania spectrum episodes, while another 197 fulfilled the criteria for major depressive disorder (MDD) without a history of a hypomania spectrum episode. A follow-up after 15 years included a blinded diagnostic interview, a self-assessment of personality disorders, and national register data on prescription drugs and health services use. Adolescent mood symptoms, non-mood disorders, and family characteristics were assessed. Univariate and multivariate analyses were used. The results indicate that the phenomenology of the hypomania spectrum episodes during childhood and adolescence per se does not predict adult bipolar disorder. However, having both affective symptoms during adolescence and a family history of bipolar disorder increases the risk of developing bipolar disorders in adulthood. Disruptive disorder in childhood or adolescence as well as family histories of BPD emerged as significant risk factors that differentiated between the future development of BPD and MDD. Adolescents with hypomania spectrum episodes and adolescents with MDD do not differ substantially in health outcomes in adulthood. Both groups are at increased risk for subsequent mental health problems, high consumption of prescription drugs, and high health care use, compared with the control group. The high rates of prescription drugs in many ATC classes found among the former depressed females seem to indicate a series of co-morbid somatic illnesses. Thus, it is important to identify and treat children and adolescents with mood disorders, and carefully follow the continuing course. Characteristics such as disruptive disorders and family history warrant particular attention.

Background: Multiple reviews have demonstrated that mood disorders are associated with abnormal pro- and anti-inflammatory immunological markers and recent studies suggest that anti-inflammatory medication may play an important role in the treatment of mood disorders. Aims: 1. To evaluate current evidence on the efficacy and acceptability of anti-inflammatory drugs in patients with major depressive disorder (MDD) and bipolar disorder. 2. To determine whether the anti-inflammatory tetracycline antibiotic minocycline, added to treatment as usual (TAU) for 3 months in patients with treatment-resistant depression leads to an improvement in depressive symptoms and if so, to estimate effect sizes to inform the development of a larger, hypothesis-testing study. Methods: A systematic review and meta-analysis of published trials of anti-inflammatory agents in mood disorders was conducted. The Cochrane Central Register of Controlled Trials, PubMed, EMBASE, PsychINFO and Clinicaltrials.gov were searched from inception until April 15, 2017 for completed and on-going clinical trials of anti-inflammatory agents for MDD and bipolar disorder. Data from randomized controlled trials (RCTs) assessing the antidepressant and antimanic effect of adjunctive mechanistically diverse anti-inflammatory agents were pooled to determine standard mean differences (SMDs) compared with placebo and/or treatment as usual. To address the second aim a multi-site, 12-week, double blind, placebo-controlled, pilot trial was conducted. The trial was of minocycline added to treatment as usual for patients suffering from DSM-5 major depressive disorder whose current episode has failed to respond to at least 2 antidepressants. The primary outcome measure was mean change in Hamilton Depression Rating Scale (HAMD-17) scores from baseline to week 12. Secondary measures were the Clinical Global Impression scale (CGI), Patient Health Questionnaire-9 (PHQ-9), the Generalised Anxiety Disorder scale (GAD-7) and EuroQoL (EQ-5D). Side effects checklists were also used. Minocycline was started at 100 mg once daily (OD) and increased to 200 mg OD after two weeks. Results: The meta-analysis found that patients receiving anti-inflammatory agents showed lower post-treatment depressive symptom scores compared with those receiving placebo with a SMD of -0.71 (6 RCTs, n=214, 95% CI -1.24 to -0.17, p=0.009). Anti-inflammatory treatment was found to reduce post-treatment manic symptom scores with a SMD of -0.72 (3 RCTs, n=96, 95% CI -1.31 to -0.13, p=0.02). Anti-inflammatory treatment was found to yield an improvement in depressive symptom scores from baseline to outcome with a SMD of -0.52 (5 RCTs, n=194, 95% CI -1.01 to 0.05) but this was not statistically significant (p=0.07). In the pilot RCT, a total of 41 participants were randomised, with 21 in the minocycline group and 20 in the placebo group. A large decrease in HAMD scores was observed in the minocycline group compared to the placebo group (Standardized effect size -1.21, p < 0.001). CGI scores in the minocycline group also showed a large improvement compared with placebo (OR: 17.6, p < 0.001). PHQ-9 (ES -0.43), GAD-7 (ES -0.46) and EQ-5D total (ES -0.48) showed more moderate improvements. Conclusions: Anti-inflammatory treatments may confer benefit for both depressive and manic symptoms however current studies are limited by small sample sizes, short durations, differing baseline symptomatology and poorly defined illness durations. The findings of the pilot RCT indicate that adjunctive minocycline leads to improvement in symptoms of treatment-resistant depression. However, the findings require replication in a larger sample. Overall, further high-quality trials are needed before making recommendations for the routine clinical use of anti-inflammatory interventions including minocycline, in the treatment of mood disorders.

Thesis (MA)--University of Stellenbosch, 2002
ENGLISH ABSTRACT: This review examines the medical model's conceptualisation of postnatal depression (pND) from a feminist perspective. The arguments are fourfold: Firstly, it argues that the fundamental problem underlying the concept of PND is its conception as existing on a continuum with psychosis at the most severe end and maternity blues at the least severe end. The link with psychosis implies that it is potentially pathological requiring medical and psychiatric intervention. On the other hand its link with maternity blues gives scientific credence to continued research on emotional sequelae of reproduction that are below the psychiatric threshold of urgency. Secondly, the medical model's construction of PND implies that women are predisposed to mental illness because of their ability to bear children and thus pathologises normal experiences of childbirth. Thirdly, the medical model's preoccupation with classification and categorisation has become little more than an exercise in labeling that has removed women from their own experiences. Focusing on birth as an activity that is separate from the rest of pregnancy objectify women and ignores the socio-political context within which they give birth and care for their infants. Fourthly, it is argued that a different way of researching postpartum mood disorders is necessary to overcome a reductionistic and pathological model of childbirth. This is important if healthcare delivery hopes to provide adequate treatment for all women in the postnatal period. Especially in South Africa, where the dominant culture has for many years defined the experiences of the 'other', it is important to generate research that should include the 'voices' of the 'other' to prevent hegemonic practice from assuming an expert understanding of PND. This review does not deny the contributions from the medical establishment, but argues that a critique of its underlying assumptions is important to prevent women from being further marginalised by ignoring the socio-political context in which their lives are embedded. The implications for research within South Africa are also addressed.
AFRIKAANSE OPSOMMING: Hierdie oorsig ondersoek die mediese model se konseptualisering van postnatale depressie vanuit 'n feministiese perspektief. Die argument is vierledig: Eerstens blyk die konseptualisering van postnatale depressie, naamlik dat dit op 'n kontinuum bestaan, met psigose aan die mees disfunksionele kant en 'maternity blues' aan die minder ernstige kant, 'n fundamentele, onderliggende probleem te wees. Die verband met psigose impliseer dat postnatale depressie potensieel patologies is en mediese en psigiatriese insette benodig. Die verband met 'maternity blues' aan die ander kant, bied wetenskaplike begronding vir volgehoue navorsing op die gebied van emosionele aspekte van kindergeboorte wat nie van psigiatriese belang is nie. Tweedens impliseer die mediese model se konstruksie van postnatale depressie dat vroue 'n predisposisie tot geestessiektes het bloot deur die feit dat hulle die vermoë het om kinders voort te bring. Sodoende word patologiese kenmerke gekoppel aan normale ervarings van kindergeboorte. Derdens het die mediese model se beheptheid met klassifikasie en kategorisering verval in etikettering wat vroue van hul eie ervarings vervreem. Deur te fokus op geboorte as 'n aktiwiteit wat verwyder is van die res van swangerskap maak van vroue objekte wat verwyderd is van die sosio-politieke konteks waarbinne hulle geboorte skenk en sorg vir hul babas. Vierdens word dit beredeneer dat 'n nuwe benadering tot navorsing oor postpartum gemoedsteurings daar gestel behoort te word om 'n reduksionistiese en patologiese model van kindergeboorte te voorkom. Dit is belangrik as gesondheidsorgdienste hoop om toereikende behandeling te bied vir alle vroue in die postnatale periode. Veral in Suid-Afrika, waar 'n dominante kultuurgroep vir so lank die ervarings van ander omskryf het, is dit belangrik om navorsing voort te bring wat die 'stemme' van die 'ander' insluit om sodoende te verhoed dat die heersende praktykvoeringe van die dag 'n eensydige deskundige-verstaan van postnatale depressie voorveronderstel. Hierdie oorsig ontken nie die bydraes van die mediese model nie, maar beredeneer die feit dat 'n kritiese beskouing van die onderliggende aannames belangrik is om sodoende te verhoed dat vroue verder gemarginaliseer word deurdat die sosio-politieke konteks waarin hul lewens gegrond is, buite rekening gelaat word. Die implikasies vir navorsing binne 'n Suid-Afrikaanse konteks word dus ook ondersoek.

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Objetivo Geral • Comparar o desempenho cognitivo e o funcionamento global entre adultos jovens com e sem o diagnóstico de Transtorno Bipolar, bem como correlacionar estas medidas nos sujeitos com Transtorno Bipolar. 2.2 Objetivos Específicos • Comparar o funcionamento global de adultos jovens com e sem diagnóstico de TB; • Comparar o desempenho cognitivo de adultos jovens com e sem diagnóstico de TB; • Correlacionar o desempenho cognitivo e o funcionamento em uma amostra populacional de adultos jovens; • Correlacionar o desempenho cognitivo e o funcionamento nos adultos jovens com Transtorno Bipolar; • Correlacionar a severidade dos sintomas maníacos e depressivos com o desempenho cognitivo e o funcionamento dos jovens com TB.

Background: The uncinate fasciculus (UF) is the largest white matter association tract connecting the prefrontal cortex and the medial temporal lobe, and is the final major association tract to mature with myelination extending into the third decade of life. The UF is typically described as having a temporal stem, a body, and two prefrontal stems extending to the lateral and fronto-polar prefrontal cortex respectively. However, there is increasing evidence of fibers extending from the subgenual cingulate gyrus (Brodmann Area 25: BA25) to the amygdala, along the expected course of the UF. If these fibers are continuous with the UF, they may represent a separate medial subgenual stem. BA25 is implicated in mood disorder pathophysiology, whilst the lateral prefrontal cortex is implicated in the negative symptoms of psychosis. Hypotheses: Given that the UF as a whole has reduced integrity in both mood and psychotic disorders, it is feasible that the lateral stem of the UF is more markedly affected in psychosis and the potential subgenual stem more markedly affected in depression. In addition, since the UF matures during the typical clinical onset age of these disorders, we hypothesize that such changes are present from first onset. Methods: In a series of four manuscripts utilizing diffusion tensor imaging (DTI), the anatomy, anatomical variability, and stem-by-stem microstructural changes in depression and first-onset psychosis patients were investigated within the UF. The use of a stem-by-stem analysis within the UF was a common link across the four articles. Results: A subgenual stem of the UF was consistently demonstrated. Significantly reduced integrity was shown in the subgenual and polar stems of the UF in depressed patients (in both the first-onset and chronic depression cohorts), and in the lateral and polar stems in first-onset psychosis patients. Conclusion: We have demonstrated anatomically distinct patterns of white matter changes within the uncinate fasciculus in mood vs. psychotic disorders, present from the time of first clinical onset.

Mood disorders are ranked as the most burdensome disorders for youth worldwide. The consequences for this age group are serious, including exacerbated symptoms, persistent syndromes, and suicide. A treatment target of interest is sleep-wake and circadian rhythm disturbances, as disruptions in these phenomena trigger and prolong mood symptoms. However, efficacious sleep-wake and circadian rhythm interventions for youth with mood disorders are limited, potentially owing to a lack of youth-specific programs and inadequate assessment of sleep-wake and circadian rhythms as outcome measures. A second treatment target of interest is maladaptive rumination. Maladaptive rumination has been shown to predict depression onset, maintenance, and relapse in youth with mood disorders. Importantly, rumination shares bidirectional links with sleep-wake disturbance in youth. However, the commonalities between these phenomena remain unclear, where shared dimensions may represent valuable intervention targets that could optimise future sleep-wake and circadian rhythm interventions for youth. This thesis aimed to address these potentially significant gaps through a series of empirical and review studies examining sleep-wake and circadian rhythm disturbance, rumination, and the treatment of youth with mood disorders. Within this thesis, five empirical and review studies were conducted: 1) a review of non-pharmacological and psychological interventions targeting sleep-wake and circadian rhythm disturbance in youth with mood disorders; 2) a cross-sectional analysis of circadian rhythm disturbances in youth with mood disorders; 3) a pilot of a novel youth-specific sleep-wake and circadian rhythm intervention for youth with mood disorders; 4) a review of rumination as a key biomarker for mental disorders in youth and as a modifiable treatment target; and 5) a longitudinal examination of common dimensions between sleep-wake disturbance and rumination as trans-diagnostic predictors of illness trajectories in at-risk youth. These findings provide the foundation for an optimised sleep-wake and circadian intervention for youth with mood disorders, and bring to light the necessary dual inclusion of rumination and sleep-wake and circadian rhythms as intervention targets for this patient population.

L’obiettivo principale di questa tesi di dottorato è rappresentato dalla ricerca di nuove evidenze in grado di supportare la conoscenza di un possibile coinvolgimento del Neuropeptide Y (NPY) e dei suoi principali recettori Y1, Y2 e Y5 nei meccanismi che regolano i disturbi dell’umore, quali depressione, ansia ed i disturbi legati all’esposizione allo stress. Questo studio, proposto dal dipartimento di Biologia del Centro Ricerche GlaxoSmithKline di Verona, è stato condotto nell’ambito di varie collaborazioni con centri universitari, quali il Karolinska Institutet di Stoccolma (Svezia), l’Ecòle Polytechnique Fédérale de Lausanne (Svizzera) ed il German Primate Center di Göttingen (Germania). Il possibile ruolo di NPY e dei suoi recettori nella regolazione dei meccanismi implicati nella fisiopatologia dei disturbi dell’umore è stato analizzato utilizzando tecniche sperimentali sia in vitro che in vivo applicate a diversi modelli animali di depressione, ad un modello di topi transgenici ed a tessuti cerebrali umani post-mortem ottenuti da pazienti affetti da disturbi psichiatrici. In particolare si è focalizzata l’attenzione sull’analisi dell’espressione dei trascritti di NPY e dei suoi tre recettori mediante la tecnica dell’ibridazione in situ applicata a tre modelli animali di depressione: i ratti Flinders Sensitive Line, un modello genetico particolarmente interessante data l’influenza della componente genetica in questo tipo di disturbi, il “chronic mild stress” ed il “chronic social defeat”, due modelli di stress; quest’ultimo ritenuto una tra le maggiori cause dei disturbi di depressione ed ansia. Il chronic social defeat è stato studiato su due diverse specie animali: un roditore - il ratto - ed un non roditore - la tupaia o tree shrew (Tupaia belangeri) - considerata la sua elevata omologia genetica con l’uomo. I modelli utilizzati sono serviti ad approfondire lo studio del coinvolgimento del sistema di NPY nei disturbi dell’umore cercando di chiarire i meccanismi attraverso cui questo sistema neuropeptidergico agisce e provando a dimostrare quale dei principali sottotipi recettoriali abbia un ruolo di rilievo nella fisiopatologia di questi disturbi e nei meccanismi di regolazione delle risposte agli stress. Lo studio effettuato evidenzia che i tre sottotipi recettoriali sono differentemente espressi nei vari modelli animali e subiscono variazioni dell’espressione dei loro trascritti di tipo speciespecifico. Si è dimostrato che i tre recettori sono diversamente influenzati dall’esposizione ai vari tipi di stress, tuttavia, sebbene il sottotipo Y5 sembri essere particolarmente affetto da variazioni trascrizionali nei modelli animali considerati, non è stato ancora completamente chiarito quale sia il sottotipo recettoriale maggiormente coinvolto nella regolazione dei disturbi dell’umore. Il coinvolgimento del recettore Y2 in tali disturbi non sembra essere sostenuto da questa ricerca, sebbene numerosi studi preclinici e analisi di tessuti umani postmortem avessero dimostrato un ruolo di questo recettore nell’ansia e nella depressione. In generale, in questo studio le variazioni più consistenti e frequenti di espressione del trascritto di NPY e dei suoi recettori sono state osservate a livello dell’ippocampo, dell’ipotalamo e dell’amigdala, fornendo ulteriore supporto all’importanza cruciale di tali regioni cerebrali nella fisiopatologia dei disturbi affettivi. Al fine di confermare alcuni precedenti studi comportamentali che avevano dimostrato che la delezione del recettore Y2 era in grado di indurre una riduzione dello stato d’ansia ed un aumento della capacità di risposta agli stress, è stato condotto uno studio in vivo sottoponendo alcuni topi transgenici, ai quali era stata effettuata una delezione completa di tale recettore, a test di depressione ed ansia comunemente utilizzati. In contrasto con i risultati precedenti, lo stato d’ansia e lo stato depressivo di tali topi non hanno subito variazioni significative rispetto ai loro controlli sebbene i topi utilizzati in entrambi gli studi fossero stati completamente privati dello stesso recettore: sembra quindi non essere possibile supportare un ruolo diretto del recettore Y2 nei meccanismi che regolano disturbi quali depressione ed ansia. Una possible causa del diverso comportamento legato agli stati d’ansia e di depressione è da ricercarsi nei diversi ceppi a cui i topi analizzati nei due studi appartenevano. L’analisi ha dimostrato l’importanza della scelta del ceppo degli animali: una diversa componente genetica tra i vari ceppi può avere un impatto maggiore sul fenotipo dell’animale rispetto alla delezione di un intero gene e questo fenomeno suggerisce quindi una certa cautela nella scelta degli animali e nell’interpretazione dei dati forniti da animali transgenici. Infine, l’espressione del trascritto del recettore Y2 è stata analizzata attraverso la tecnica dell’ibridazione in situ a livello dell’amigdala e della regione corticale ad essa adiacente in tessuti umani post-mortem ottenuti da pazienti affetti da diversi disturbi psichiatrici e paragonata all’espressione in soggetti di controllo, in cui tali disturbi non sono stati diagnosticati. Anche in questo caso non si è confermato il ruolo di Y2 nei meccanismi che regolano la fisiopatologia dei disturbi affettivi, dato che non è stata dimostrata alcuna differenza tra i diversi gruppi patologici nell’espressione di tale recettore a livello dell’amigdala. Inoltre, l’espressione del recettore Y2 è stata studiata in relazione al consumo di sostanze d’abuso. Differentemente dagli utilizzatori di marijuana, una variazione del trascritto di tale recettore è stata osservata nei soggetti consumatori di cocaina e nicotina, ipotizzando un coinvolgimento di Y2 nei meccanismi che regolano l’assunzione di queste sostanze. Riguardo all’etanolo, questo studio non ha dimostrato alcuna variazione trascrizionale del recettore Y2 in soggetti che ne facevano uso, non potendo confermare alcuni studi che sostengono l’importanza del ruolo del sistema di NPY nella dipendenza da etanolo. La presente tesi ha fornito nuovi interessanti dati riguardanti il coinvolgimento del sistema del Neuropeptide Y nei disturbi affettivi, tuttavia per completare lo studio sarebbero necessari ulteriori approfondimenti in particolare sui tessuti umani. Disturbi quali la depressione rappresentano infatti una condizione tipicamente umana, non esattamente riproducibile nei modelli animali, che possono solamente fornire una semplificazione dello stato depressivo. L’utilizzo di composti antagonisti recettoriali selettivi applicato a studi su modelli animali sarebbe in grado di fornire risultati più dettagliati e specifici che potrebbero meglio indicare il sottotipo recettoriale maggiormente coinvolto in questi disturbi, fornendo così un nuovo bersaglio per il possibile sviluppo di nuovi farmaci ansiolitici ed antidepressivi. Ad oggi questa indagine sembra essere piuttosto difficoltosa da effettuare data la mancanza di composti selettivi verso un sottotipo recettoriale e con caratteristiche tali da essere capaci di agire a livello del sistema nervoso centrale. La sintesi di questo genere di composti permetterebbe di comprendere maggiormente la base dei meccanismi che regolano il funzionamento del sistema di NPY nei disturbi dell’umore e di fornire un trattamento efficace contro l’ansia e la depressione.
Depression has been described by mankind for several millennia. The term melancholia, which means “black bile” in Greek, was first used by Hippocrates around 400 b.C. (Akiskal et al., 2000). The major symptoms of depression and the comorbidity of depression with anxiety and excessive alcohol consumption were recognized in ancient times, indeed similarities between ancient descriptions of depression and those of the modern era are striking. From the middle part of the 19th century the brain became the focus of the efforts to understand the pathophysiology of depression. Today, depressive disorders represent a common psychiatric disorder experienced by more than 10% of the population at least once during the lifetime (Blazer et al., 1994). Women are more prone to the disease than men, with almost a two-fold lifetime prevalence rate: around 21% of women and 13% of men of the Unites States population. The mortality is high: 70% of all suicides can be attributed to depressive disorders and they represent a major cause of morbidity worldwide: studies in the United States suggest that 2–3% of the population is hospitalized or seriously impaired by affective illnesses (Blazer, 2000). The World Health Organization has declared depression as the single largest cause of morbidity for women and the leading cause of disability worldwide. Despite the devastating impact of depressive disorders, little is known about their etiology and pathophysiology.

This article reports the results of a cross-national investigation of patterns of comorbidity between substance use and psychiatric disorders in six studies participating in the International Consortium in Psychiatric Epidemiology. In general, there was a strong association between mood and anxiety disorders as well as conduct and antisocial personality disorder with substance disorders at all sites. The results also suggest that there is a continuum in the magnitude of comorbidity as a function of the spectrum of substance use category (use, problems, dependence), as well as a direct relationship between the number of comorbid disorders and increasing levels of severity of substance use disorders (which was particularly pronounced for drugs). Finally, whereas there was no specific temporal pattern of onset for mood disorders in relation to substance disorders, the onset of anxiety disorders was more likely to precede that of substance disorders in all countries. These results illustrate the contribution of cross-national data to understanding the patterns and risk factors for psychopathology and substance use disorders.

This article reports the results of a cross-national investigation of patterns of comorbidity between substance use and psychiatric disorders in six studies participating in the International Consortium in Psychiatric Epidemiology. In general, there was a strong association between mood and anxiety disorders as well as conduct and antisocial personality disorder with substance disorders at all sites. The results also suggest that there is a continuum in the magnitude of comorbidity as a function of the spectrum of substance use category (use, problems, dependence), as well as a direct relationship between the number of comorbid disorders and increasing levels of severity of substance use disorders (which was particularly pronounced for drugs). Finally, whereas there was no specific temporal pattern of onset for mood disorders in relation to substance disorders, the onset of anxiety disorders was more likely to precede that of substance disorders in all countries. These results illustrate the contribution of cross-national data to understanding the patterns and risk factors for psychopathology and substance use disorders.

Depression is associated with reduced declarative memory performance and decreased hippocampal volume. Depression has also been associated with decreased levels of adult neurogenesis in the dentate gyrus. Computational models propose that neurogenesis is critical for the computational process of pattern separation, whereby distinct memory representations are created for very similar stimuli and events. It has been proposed that depression negatively impacts pattern separation abilities; however, a link between depression and performance in pattern separation memory tasks has yet to be investigated. Accordingly, we designed a study to investigate the relationship between pattern separation performance and the severity of depression symptoms. Participants completed a recognition memory test with high pattern separation demands as well as a set of questionnaires to gauge their level of depression. We found a negative relationship between depression scores and pattern separation scores in support of the theory that depression is negatively related to pattern separation performance.

Objective: To explore the relationship between cerebellar pathology and changes in neuronal activity in mouse models of autism-like phenotypes. Methods: We used the rotarod test as a measure of sensorimotor function in our mice and as a means to trigger neuronal activation. Following behavioural testing we obtained brain tissue from our ASD-like mouse models and used histology and microscopy to examine the expression of cFos (a reporter of neuronal activity) and several other structural and functional markers to evaluate cerebellar pathology. Finally, we looked at differences in the morphology, distribution and number of cerebellar glia in our ASD-like mouse models to determine if reactive gliosis contributes to further cerebellar pathology in adult mice. Results: Compared to wildtype littermates, Lc/+ mutant mice performed significantly worse on the rotarod assay of sensorimotor function (p<0.0001). In addition, Lc/+ mutants have significantly increased neuronal activity in the cerebellum and cortex at rest and following cerebellar rotarod activation as compared to wildtype littermates (p<0.05 for each group). Lurcher chimeras with the severest cerebellar pathology have increased neuronal activity in the GCL and CN neurons, but decreased neural activity in inhibitory PCs and they have increased numbers of activated microglia and Bergmann glia in the cerebellar cortex. Fmr1 KO mice have a slight decrease in PC numbers as compared to Fmr1 wildtypes (p=0.0862 n.s) with alterations in neuronal activity at rest in the cerebellar GCL and cortex. Conclusion: Variable cerebellar pathology seen in human cases of autism and in ASD-like mouse models in the form of neuron loss, microgliosis and astrogliosis leads to changes in excitatory and inhibitory activity in surviving cerebellar neurons. Structural and functional changes documented in Lc/+ mutants, chimeras and Fmr1 KO mice revealed neuroanatomical abnormalities and functional changes in cerebellar neural circuits which may lead to a better understanding of the neurobiological changes occurring in the cerebellum that contribute to ASD-like phenotypes. By identifying cerebellar neurons and glia that are involved in pathological processes in mouse models of neurodevelopmental disorders, it is hoped that these results will provide fresh insights into neurobiological changes underlying ASD-like phenotypes.
Medicine, Faculty of
Graduate