Females are disproportionately affected by stress- related mood disorders. Child abuse is the single greatest environmental risk factor for mood disorders. An animal model of child abuse, juvenile social subjugation (JSS), was used to determine whether males and females differentially process stress, specifically in the bed nucleus of the stria terminalis (BST). Rats (n=36) were randomly assigned to one of three conditions: JSS, Benign Control (BC) or Handled Control (HC). Following this procedure, brains were processed for Fos, which indicates neural activity. It was hypothesized that the JSS condition would evoke more neural activation than other conditions and would do so more in females. Across both sexes, we hypothesized there would be significantly more activation in the posterior BST than in the anterior BST. Based on earlier research, we hypothesized there would be and a sex difference in total neuron number, favoring males, in the posterior BST.

The World Health Organisation predicts that by 2020 depression will be the second highest cause of death and disability in the world (World Health Organisation, 2010). Selective serotonin reuptake inhibitors (SSRIs) have been found to be the most suitable antidepressant for first-line treatment of a mood disorder (National Institute for Health and Clinical Excellence, 2004), but less than half of all individuals achieve complete remission after therapy with a single antidepressant. Others display partial or intolerant responses to treatment (Nemeroff & Owens, 2002). This emphasises a need to develop alternative treatment options. There is evidence that micronutrients have fewer side effects than antidepressants (Dalmiya, Darnton-Hill, Schyltink & Shrimpton, 2009). Kaplan, Crawford, Field and Simpson (2007) suggest that errors in metabolism may result in unstable mood, leading to possible mood disorders. Mutation of metabolism is correctable by giving the malnourished individual additional vitamins thereby correcting metabolism and creating a more stable mood. An online survey completed by 661 participants (141 males, 520 females) assessed acceptance levels towards the use of micronutrients as an alternative treatment for mood disorders. As predicted, healthcare and medical professionals scored lower in acceptance (t(659)=3.12, p=0.002) and people who lead healthy lifestyles scored higher in acceptance (r=0.105, n=658, p <0.05). There were no significant effects of gender (t(659) =1.74, p=0.082), experience with mood disorders (F(3, 657)=0.86, p=0.46) or low household incomes (r=-0.066, n=661, p<0.05). Treatment users and providers alike seek more knowledge about the effectiveness of micronutrients and acceptance of micronutrients is largely granted on the basis of a combination treatment with conventional methods. The study is limited by an overrepresentation of females in the sample.

Females are disproportionately affected by stress- related mood disorders. Child abuse is the single greatest environmental risk factor for mood disorders. An animal model of child abuse, juvenile social subjugation (JSS), was used to determine whether males and females differentially process stress, specifically in the bed nucleus of the stria terminalis (BST). Rats (n=36) were randomly assigned to one of three conditions: JSS, Benign Control (BC) or Handled Control (HC). Following this procedure, brains were processed for Fos, which indicates neural activity. It was hypothesized that the JSS condition would evoke more neural activation than other conditions and would do so more in females. Across both sexes, we hypothesized there would be significantly more activation in the posterior BST than in the anterior BST. Based on earlier research, we hypothesized there would be and a sex difference in total neuron number, favoring males, in the posterior BST.

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.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. Inst., 2002. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 6 uppsatser.

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.

Mood disorders (MD) are among the most common mental disorders worldwide. Low treatment adherence and treatment resistance are two of the most substantial challenges facing clinicians who treat persons with MD. This thesis examined: (1) a pilot study investigating whether a one-on-one personalized medication training program, called PIMM/SAM, improves medication adherence in persons with MD; and (2) a systematic review and meta-analysis on the effects of electroconvulsive therapy (ECT) on cognitive functioning in persons with depression. To evaluate the impact of PIMM/SAM on medication adherence, a randomized controlled trial was launched in a mood disorders inpatient unit to compare PIMM/SAM (partnership in medication management/self-administered medication) program to standard prescribing practice (SPP). Over follow-up in the feasibility portion of the trial, participants in the PIMM/SAM group (n = 7) held fewer negative beliefs about medications and had lower depersonalization scores compared to participants in the SPP group (n = 5). Between-group differences on the Medication Adherence Rating Scale favoured the PIMM/SAM group, but were not statistically significant. To examine the effects of bilateral versus unilateral ECT on cognitive performance in persons with TRD, 18 studies across 10 different cognitive domains were meta-analyzed. In the 8- to 30-day timeframe post-ECT, persons who received bilateral versus unilateral ECT had over double the odds of worse cognitive performance in global cognition, non-verbal memory delayed recall, verbal memory immediate and delayed recall, subjective memory, and verbal memory immediate recall. A personalized medication training program in a mood disorders clinic may have positive implications for medication adherence. The trial to evaluate PIMM/SAM versus SPP is ongoing and further evidence about the training program is expected within the next 12 months. The systematic review and meta-analysis showed that cognitive performance was worse in persons who received bilateral versus unilateral ECT in some cognitive domains at 8 to 30 days post-treatment. / Thesis / Doctor of Philosophy (PhD) / Mood disorders (MD), including major depressive disorder (MDD) and bipolar disorder, are among the most common mental disorders worldwide. Treating MD is a challenge because of long treatments, the presence of other illnesses, treatment side effects, problems with memory, attention, and decision-making, a lack of understanding about medications, or incorrect beliefs about medication (BAM). Persons with MD who do not respond to drug treatment are often given electroconvulsive therapy (ECT). This thesis explored the challenges of treating persons with MD through: (1) a pilot study examining whether a one-on-one personalized medication training program, called PIMM/SAM, would help persons with MD take their medications as prescribed; and (2) a study of the effects of ECT on cognitive functioning in depression. Results: (1) participants randomized to PIMM/SAM group held fewer negative BAM than participants receiving standard care; (2) evidence showed worse cognitive functioning in persons who received more intense forms of ECT.

Introduction: Through large neuroimaging consortia, researchers have identified a series of neuroanatomical alterations in mood and psychotics disorders, such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ). However, the mechanism behind these alterations is not well understood. One of the existing hypotheses suggests that the observed brain changes are related to a process of accelerated brain ageing. Studies investigating this hypothesis use a measure called the brain age gap (i.e., the difference between machine learning model predictions of brain age and chronological age). Thus far, there is limited understanding on how mood and psychotic disorders affect model predictions, how can predictions be clinically useful, and what is the biological meaning behind the brain age gap. In this thesis, we investigated accelerated brain ageing in mood and psychotic disorders. We sought to estimate the effect of the brain age gap and propose new ways of modeling brain age. We also explored the clinical utility and meaning of the brain age gap. Results: We confirmed the presence of a brain age gap in MDD, BD, and SCZ through a systematic review and meta-analysis. SCZ presented the highest levels of brain age gap, followed by BD and MDD. We analyzed the clinical utility of brain age for antidepressant treatment response and concluded that the brain age gap is not a predictor of antidepressant treatment response in weeks 8 and 16. We proposed a new method for brain age prediction that is more interpretable than previous approaches while preserving good predictive performance. We have also used model explanation strategies and identified that the brain age gap is largely associated with total gray matter volume reduction and ventricle enlargement in SCZ. Conclusion: The results of this thesis suggest that the brain age gap is present across mood and psychotic disorders. The results have also helped to clarify the meaning behind the brain age gap, a largely used but still poorly understood measure in neuroimaging research. So far, there is no indication that the brain age gap can be a useful tool for treatment response prediction in MDD. / Thesis / Doctor of Philosophy (PhD)