The aetiology of major depressive disorder (MDD) is poorly understood. Current evidence suggests immune activation and gut microbiota may play a role. Recent studies demonstrated that behavioural traits can be transferred through microbiota transplantation into germ-free (GF) mice. Here we study whether microbiota from patients with MDD can induce depressive-like behaviour. Methods: GF NIH Swiss mice were colonized with stool microbiota from a patient with MDD with elevated faecal β-defensin 2, or a healthy donor (HC). After three weeks, behaviour was assessed using standard tests. Expression of neuroimmune markers was assessed in the gut and brain using gene expression profiling and immunohistochemistry. Microbiota composition was assessed by 16S rRNA sequencing. Results: Microbiota profiles differed between the two groups of mice (p=0.001). Mice colonised with microbiota from a single characterised MDD patient (MDD1), exhibited lower preference for sucrose (p=0.002) and more emotionality (p=0.003) than mice with HC microbiota, however other MDD mice did not display abnormal behaviour. Abnormal MDD1 behaviour was associated with lower BDNF expression in the dentate gyrus of the hippocampus (p=0.02). Mice colonised with another characterised MDD patient (MDD4 mice) did not have differences in BDNF expression in the same region (p=0.20). MDD1 and MDD4 mice had altered hippocampal and gut gene expression for genes associated with the immune and nervous system. In summary, GF mice colonized with MDD1 microbiota exhibit depression-like behaviors. This appears to be accompanied by changes in intestinal permeability and neuroimmune function. These results suggest that gut microbiota has the capacity to influence the expression of MDD in some patients. / Thesis / Master of Science (MSc)

The brain has the capacity to modify itself structurally and functionally, to adapt to novel circumstances. Adaptive changes in neural circuitry that become intransigent, such as continued hypervigilance after resolution of a threat situation, become maladaptive and may facilitate development of psychiatric disorders such as Major Depressive Disorder (MDD). Although MDD pathogenesis is unclear, hypothalamic-pituitary-adrenal axis dysregulation may facilitate the neuroplastic changes observed in MDD. Whether these neuroplastic changes facilitate the development of MDD or develop due to MDD remains unclear. The characterization of neuroplastic changes in MDD has resulted in sometimes contradictory findings. There are gaps in understanding the timing of neuroplastic changes in MDD, and how and when they are affected by antidepressant treatment. Characterization of neuroplasticity in MDD may uncover different phenotypes and aid in the discovery of a predictive biomarker of antidepressant treatment response. This dissertation presents the results of a series of neuroimaging studies. Chapter 1 provides an introduction to neuroplasticity and MDD. In Chapter 2 results of a study examining hippocampal memory function in treatment naïve patients with MDD are presented. Chapter 3 exhibits findings from a study examining effects of an acute tryptophan depletion paradigm in midlife women receiving estrogen-based treatment on an emotional conflict task. Chapter 4 discusses results from an examination of unmedicated patients with MDD and healthy control participants on an emotional conflict task. Chapter 5 presents longitudinal data of the sample from Chapter 4, and the effect of 8 weeks of treatment with antidepressant escitalopram on performance on an emotional conflict task. In Chapter 6 a case study is presented of a patient with long-standing overt ventriculomegaly, whose chief complaint was of mood and cognitive impairments. Chapter 7 summarizes the findings and contributions of this body of research and discusses clinical implications and future directions. / Dissertation / Doctor of Philosophy (PhD) / The characterization of brain changes in Major Depressive Disorder (MDD) has resulted in contradictory findings, and gaps in understanding how the brain changes in response to antidepressant treatment. This dissertation aims to characterize brain changes in MDD through a series of neuroimaging studies. Chapter 1 provides an introduction to MDD and brain changes in MDD. Chapter 2 presents an examination of memory in treatment naïve patients with MDD. Chapter 3 presents a study of acute tryptophan depletion in midlife women receiving estrogen-based treatment on an emotional conflict task. Chapter 4 examines unmedicated patients with MDD and healthy control participants on an emotional conflict task. Chapter 5 examines the effects of antidepressant treatment on performance on an emotional conflict task. Chapter 6 presents a case study of a patient with ventriculomegaly with mood and cognitive impairments. Chapter 7 summarizes the contributions of this research and discusses implications and future directions.

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Bakgrund: Postpartumdepression definieras som en episod av egentlig depression(måttlig till svår) hos en nybliven förälder som har sin debut upp till ett år efter enförlossning. Forskning om nyblivna pappors upplevelser av att insjukna ipostpartumdepression är närapå obefintlig. Förståelse för pappors upplevelser avpostpartumdepression bland sjuksköterskor kan bidra till ett gott bemötande av dennapatientgrupp. Syfte: Syftet var att beskriva nyblivna pappors erfarenheter av att insjukna ipostpartumdepression. Metod: En litteraturstudie av åtta vetenskapliga artiklar genomfördes. Databassökningägde rum i Cinahl, Pubmed, PsychInfo samt PubMed. Analys genomfördes med inspirationav kvalitativ innehållsanalys. Resultat: Analysen resulterade i tre huvudkategorier och sju subkategorier. Huvudkategorierna var ”behöva tolka och hantera ansträngande symtom”, ”behöva stöd” samt ”negativt påverkade familjerelationer”. Konklusion: Litteraturstudiens resultat visade att pappor beskrev upplevelser avbristande stöd från vården i form av kunskapsbrist. En kartläggning av kunskapsläget ompostpartumdepression hos pappor bland sjukvårdspersonal skulle kunna motiverakunskapshöjande interventioner eller införande av rutinmässig screening. I mötet mednyblivna pappor kan sjuksköterskan med kunskap om symtombilden vidpostpartumdepression bistå med att detektera depressionssymtom samt erbjuda stöd för att tillgodose pappors grundläggande behov. / Background: Postpartum depression is defined as an episode of major depressivedisorder within a year postpartum. There is to this point almost no research about fathers’experiences with onset of postpartum depression. Understanding of such experiencesamong nurses could facilitate better treatment of depressed fathers in interactions with thehealthcare system. Aim: The aim was to describe new fathers experiences with onset of postpartumdepression. Methods: A literature study consisting of eight scientific articles was conducted. Database search was conducted in Cinahl, PubMed, PsychInfo and Scopus. To analyze thestudies, qualitative content analysis was used. Results: The analysis resulted in three main categories and seven sub categories. Themain categories consisted in “Interpreting and Handling Exhausting Symptoms”, “Needfor Support”, and “Negatively Influenced Family Relationships”. Conclusion: Fathers describe lack of knowledge among healthcare providers. Futureresearch about healthcare professionals knowledge about postpartum depression could,depending on results, motivate awareness raising interventions or screening routines.With further knowledge about symptoms of postpartum depression in new fathers, nursescan help detecting such symptoms and offer support in accommodate fathers’ basal needs.

Major depressive disorder (MDD) is considered the current leading cause of disability worldwide (Friedrich, 2017), yet the recovery process in MDD, including neurobiological underpinnings, clinical features and optimal approaches to treatment remains ambiguous. Current definitions of recovery are disputed and involve measures considered subjective in nature, such as thresholds for questionnaires and clinical interviews of symptoms and their duration (De Zwart and Jeronimus, 2019; Fava et al., 2007; Keller, 2003, 2004). Symptom-based measures, although informative of clinical presentation, are not informative of neurobiological underpinnings that may persist even when symptoms are reduced. Indeed, even after treatment, persistent residual symptoms, impairments in quality of life, and vulnerabilities for future return to more severe psychopathology persist (Gotlib and Hammen, 2008; IsHak et al., 2011; Judd et al., 1998a; Kennedy et al., 2004; Kennedy and Foy, 2005; Kennedy and Paykel, 2004). Without assessment of neural mechanisms of recovery in MDD, efforts toward developing novel treatment approaches that are able to address neural processes of illness and to provide sustained remission are slowed. The following collection of studies provide neural and clinical insights into MDD recovery and relate findings to potential treatment approaches that are optimized to individual differences in symptoms and neural functioning and able to address neural vulnerabilities to provide sustained remission. In pursuit of individualized treatment selection in MDD, study one involved a meta-analysis of prior prognostic fMRI studies of response to cognitive behavioral therapy (CBT) or a selective serotonin reuptake inhibitor (SSRI) in MDD. Study one also reported on the application of resulting meta-analytic regions (subgenual and perigenual anterior cingulate cortex) in a confirmatory MDD sample. Although regions showed some predictive potential in the confirmatory sample, when predicting SSRI response, effects were inconsistent with prior studies, suggesting methodological confounds may hinder ready translation. In an assessment of the course of MDD, the second study documented depression symptoms and quality of life across 9-14 years after acute treatment (CBT or SSRI) and found that persistent residual depression symptoms and quality of life deficits were common. In light of the normality of chronic symptoms and impairment, the third study evaluated neural features of treatment (CBT) resistance in MDD within the context of neural mechanisms of change. The third study found a vermis-centered cerebellar cluster that was unresponsive to CBT, whereas prefrontal and parietal cortical regions were responsive, providing support of prior theories that CBT directly affects cognitive control and cortical regulatory processes in contrast to salience-driven subcortical functioning (Clark and Beck, 2010; DeRubeis et al., 2008; Frewen et al., 2008; Mayberg, 2003). In consideration of findings, clinical recommendations that pertain to treating residual symptoms and associated neural features toward asymptomatic remission are provided. Future research directions are also provided regarding neuroscience informed precision medicine, current therapy and medication practices, and the larger picture of MDD chronicity broadly. / Doctor of Philosophy / Major depressive disorder (MDD) is considered the leading cause of disability worldwide (Friedrich, 2017), yet there are many aspects of MDD recovery that are unclear such as neural and clinical features and optimal treatment approaches. Current definitions of recovery involve questionnaires and interviews, which may not accurately represent all aspects of recovery (De Zwart and Jeronimus, 2019; Fava et al., 2007; Keller, 2003, 2004). For example, they do not assess neural or biological features of recovery that may continue even if symptoms improve. Indeed, even after treatment, often some minimal depression symptoms, impairments in quality of life, and risks for future more severe symptoms continue (Gotlib and Hammen, 2008; IsHak et al., 2011; Judd et al., 1998a; Kennedy et al., 2004; Kennedy and Foy, 2005; Kennedy and Paykel, 2004). Without assessing neural features of MDD and recovery, developing treatments that can address illness- related neural features and provide sustained recovery are slowed. The following studies report on neural and clinical features of MDD recovery to approach treatment and sustained recovery with consideration of individual differences in symptoms and neural functioning. Pursuing neuroimaging measures of individual differences to inform treatment selection, study one involved a statistical review of prior neuroimaging prediction studies of MDD treatment. Study one also reported on whether the regions suggested by the statistical review to inform treatment selection would be useful when applied to a prior MDD treatment study. Findings suggested functioning of the identified brain regions can help inform treatment selection, but method differences among studies included in the review hinder application of resulting regions. In an assessment of the course of MDD, the second study documented depression symptoms and quality of life across 9-14 years after treatment and found at least minimal depression symptoms as well as impairments in quality life commonly continued after treatment. In light of persistent symptoms and impairment, the third study aimed to identify neural features of MDD that did not respond to treatment, as well as neural features that were responsive to treatment. The third study found that therapy directly affects cognitive control processes, but may not affect brain regions associated more with emotion-driven processes. Clinical recommendations pertain to treating depression symptoms that continue after treatment toward asymptomatic recovery. Future research directions pertain to neuroscience informed treatment selection, current therapy and medication practices, and the larger picture of persistent depression symptoms broadly.

Disrupted emotion processes are central features of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), which are linked to altered neural response patterns. However, inconsistent results have led to questions about the reliability of such findings. Heterogeneous clinical presentations across individuals with PTSD and MDD are likely to be associated with heterogeneous neurobehavioral changes which may differ depending on the emotion process studied. Similarly, neurobehavioral signatures of treatment response prediction may vary based on the task or context probed. In these studies, we examined how neuroimaging of emotion processes may shed light on mechanisms underlying symptom heterogeneity in PTSD (Study 1) and how similar neuroimaging signatures may be useful for predicting response to MDD treatment (Study 2). Results showed re-experiencing and hyperarousal symptoms had opponent effects on neural habituation to negative images, such that while increasing severity of hyperarousal symptoms was related to diminished habituation, increasing severity of re-experiencing symptoms was associated with enhanced habituation. Additionally, across MDD studies, two regions of the brain, the right anterior insula and the subgenual anterior cingulate cortex, exhibited pretreatment responses to negative emotional stimuli that were predictive of clinical response to treatment. Considered together, this work demonstrates the translational utility of neuroimaging of negative emotion processes to enhance our understanding of symptomatology and treatment prediction in PTSD and MDD. / Ph.D. / People who have posttraumatic stress disorder (PTSD) or depression often notice changes in the intensity and range of emotions they experience. These changes are thought to be related to differences in how the brain processes emotional information. Using neuroimaging to visualize changes that occur in the brains of individuals with PTSD or depression when they are experiencing negative emotions, we may gain a better understanding of how their symptoms are impacting them and how they may respond to different types of treatments. In these studies, I used brain imaging to measure responses to emotional images of people with and without PTSD. I found that certain PTSD symptoms affected the way people's brains responded over time to negative and neutral images. More several arousal symptoms were linked to less decreases of brain responses over time or less habituation. More severe symptoms of intrusive memories or distress when exposed to reminders of trauma were associated with greater decreases of brain responses to negative images. In a second study, I found that across studies of people with depression, two regions of the brain that are involved in emotion processing and stress responsivity, show pretreatment responses to negative emotional stimuli that are related to how they are likely to respond to treatment for depression. Overall, my research demonstrates how brain responses to negative emotions may be useful for understanding symptoms of mental health disorders and may help with predicting how individuals will respond to treatment.

Background and Aims: Executive dysfunction is pervasive in substance-dependent individuals (Verdejo-García, Bechara, Recknor, & Perez-Garcia, 2006). As many as four-fifths of individuals in treatment for substance use disorders (SUDs) have co-existing lifetime psychopathology. Executive function deficits are tied to markers of decreased quality of life including increases in negative life events (Green, Kern, Braff, & Mintz, 2000), maladaptive social functioning (Kurtz, Moberg, Ragland, Gur, & Gur, 2005) and worsened treatment outcomes (Czuchry & Dansereau, 2003). Despite evidence of executive dysfunction across several mental disorders, few studies investigate how the co-occurrence of psychopathologies in SUDs impacts executive functioning. Methods: Here, we compare measures of executive function (i.e., the Iowa Gambling Test, Letter Number Sequencing Test, Stroop Test, Wisconsin Card Sorting Test, Continuous Performance Test, Towers Test, and Delay Discounting Test) in individuals with a) substance use disorder, b) substance use disorder and co-occurring major depressive disorder, c) substance use disorder and co-occurring antisocial personality disorder, d) substance use disorder and co-occurring major depressive disorder and antisocial personality disorder and e) no substance use disorder or co-occurring psychopathology. Results: Regression models of respective executive function measure outcomes as a function of education, income, age, and group membership indicated that the Delay Discounting Test and Continuous Performance Test were the only significant overall models (F(4, 313) = 12.699, p < 0.001 and F(4, 307) = 2.659, p = 0.033, respectively). Conclusions: Overall the Delay Discounting Test and Continuous Performance Test were the most sensitive to differences between substance use and psychopathology profiles assessed. / Master of Science

Diss. (sammanfattning) Umeå : Umeå universitet, 2010.

O estudo teve como objetivos avaliar a melhora precoce em uma e duas semanas no tratamento com quatro diferentes antidepressivos e placebo, assim como avaliar as medidas de acurácia da melhora precoce como preditor de resposta e remissão em oito semanas de tratamento em pacientes com TDM. Poucos estudos fizeram essa comparação. Para a análise foram utilizadas amostras de bancos de dados de quatro ensaios clínicos com dados de resposta ao tratamento com sertralina (n=50), venlafaxina (n=67), mirtazapina (n=28), fluoxetina (n=17), placebo (n=42). Todos pacientes foram avaliados pela escala de avaliação de Hamilton de 17 itens ao início do tratamento e após uma, duas e oito semanas. A ocorrência da melhora precoce foi avaliada de seis formas, utilizando-se os pontos de corte sugeridos pelo relatório da força tarefa da ISBD para avaliação de curso e desfecho. As variáveis relativas à melhora precoce estão relacionadas a seguir: (a) melhora precoce em uma semana >= 25%; (b) melhora precoce em uma semana >= 25% e < 50%; (c) melhora precoce em uma semana >= 50%; (d) melhora precoce em duas semanas >= 25%; (d) melhora precoce em duas semanas >= 25% e < 50%; (f) melhora precoce em duas semanas >= 50%. As variáveis de desfecho testadas quanto a associação com melhora precoce foram duas: (a) resposta em oito semanas (melhora >= 50%); (b) remissão em oito semanas (HAM-D-17 <= 7). Para cada par de variáveis foram calculados o valor preditivo positivo, valor preditivo negativo, sensibilidade, especificidade e acurácia. A associação foi testada pelo teste qui-quadrado de Pearson ou pelo teste exato de Fisher. Em todos os grupos houve porcentagem considerável de pacientes que apresentaram melhora precoce em uma ou duas semanas, com destaque para mirtazapina, em que 53,57% dos pacientes apresentaram algum tipo de melhora precoce em uma semana e 71,43% dos pacientes apresentaram melhora precoce em duas semanas. Ao final de duas semanas o grupo que apresentou maior taxa de melhora precoce foi o grupo tratado com venlafaxina (73,13%). Foi encontrada associação da melhora precoce em uma semana com resposta em oito semanas ao nível de significância de 5% no grupo tratado com mirtazapina e no grupo que reúne todos antidepressivos. No grupo tratado com mirtazapina a melhora precoce maior ou igual a 25% tem alto valor preditivo positivo (0,94), porém baixo valor preditivo negativo (0,58). A melhora precoce em uma semana está associada à remissão em oito semanas nos tratamentos com venlafaxina e mirtazapina. Os resultados mais consistentes ocorreram no teste da associação entre melhora precoce em duas semanas e resposta em oito semanas, na qual foi encontrada associação entre as variáveis em todos os antidepressivos (exceção à fluoxetina). A melhora precoce com Mirtazapina foi a que apresentou o maior valor preditivo positivo e a melhor medida de acurácia, de 0,86, resultado mais consistente em toda a amostra analisada. Com placebo foi encontrada associação entre melhora precoce maior que 50% e resposta em oito semanas. O baixo valor preditivo positivo indica que essa melhora sustenta-se em oito semanas menos do que nos grupos tratados com antidepressivo. O valor preditivo negativo foi de 0,81, o maior entre todos os grupos, significando que quando há melhora com placebo, em geral ela ocorre em até duas semanas. Nos testes da melhora precoce em duas semanas como preditor de remissão foram encontrados resultados mais significativos na melhora precoce maior que 50% com diferentes acurácias em cada grupo. O antidepressivo com resultados mais robustos foi a mirtazapina, com uma acurácia de 0,86. Tanto no grupo tratado com mirtazapina quanto no grupo tratado sertralina tivemos altos valores preditivos negativos, respectivamente 0,89 e 0,83, indicando que ausência de melhora rápida maior que 50% diminui muito as chances de remissão / This study aimed to evaluate the early improvement in one and two weeks\' treatment with four different antidepressants and placebo, as well as evaluate the measures of accuracy of early improvement as a predictor response and remission in eight weeks of treatment with TDM patients. Few studies have done this comparison. For this analysis, data samples from four clinical trials with treatment response with sertraline (n = 50), venlafaxine (n = 67), mirtazapine (n = 28), fluoxetine (n = 17), placebo (n = 42). All patients were evaluated at baseline on the 17 item Hamilton Rating Scale of Depression (HAM-D 17) in the begging of the treatment and after one, two and eight weeks. The occurrence of early improvement was evaluated in six ways, using the cut-off points suggested by the ISBD task force report for course and outcome evaluation. The variables related to early improvement are listed below: (a) early improvement in one week >= 25%; (b) early improvement in one week >= 25% and < 50%; (c) early improvement in one week >= 50%; (d) early improvement in two weeks >= 25%; (d) early improvement in two weeks >= 25% and < 50%; (f) early improvement in two weeks >= 50%. The outcome variables tested in association with early improvement were two: (a) response at eight weeks (improvement >= 50%); (B) remission in eight weeks (HAM-D-17 <= 7). For each pair of variables were calculated the positive predictive value, negative predictive value, sensitivity, specificity and accuracy. The association was tested by Pearson\'s chi-square test or by Fisher\'s exact test. In all groups, there was considerable percentage of patients that achieved early improvement in one or two weeks, especially mirtazapine, in which 53.57% of the patients achieved early improvement in one week and 71.43% of the patients achieved early improvement in two weeks. At the end of two weeks the group that presented the highest rate of early improvement was the group treated with venlafaxine (73.13%). We found an association of early improvement in one week with an 8-week response at a significance level of 5% in the mirtazapine group. In the group treated with mirtazapine, early improvement greater than or equal 25% had high PPV (0.94), but low NPV (0.58). The early improvement in 1 week was associated to the 8 weeks remission on treatments with venlafaxine and mirtazapine. The most consistent results occurred on the association test between early improvement in two weeks and response in eight weeks, where an association between variables in all antidepressants (except fluoxetine) was found. Mirtazapine was the antidepressant that presented the highest VPP and the best measures of accuracy, of 0,86, the most consistent of all sample analyzed. With placebo, an association was found between early improvement higher than 50% and response in eight weeks. The low VPP indicates that this improvement sustains itself in eight weeks less than groups treated with antidepressant. VPP was 0,81, the highest among all groups, meaning that when there is improvement with placebo, in general it occurs in up to two weeks. Less robust results were found for the early improvement in two weeks as a remission predictor. In the tests of early improvement in two weeks as a predictor of remission, more significant results were found in early improvement higher than 50% with different accuracies in each group. The antidepressant with the most robust results was mirtazapine, with an accuracy of 0,86. Both in the group treated with mirtazapine and the one treated with sertraline, we had high VPN, 0,89 and 0,83 respectively, indicating that the lack of quick improvement higher than 50% diminishes the chances of remission significantly