D.Litt. et Phil. (Psychology) / Despite extensive theorizing and research into the nature and etiology of depression there still remains certain prominent and unresolved gaps in our knowledge. In spite of the broad acceptance of cognitive and cognitive behavioral factors and more specific cognitive styles and schemes in the context of the etiology and the manifestation of depression, it appears that finality has not been reached about the specific nature and content of these cognitive styles or schemes. For the purpose of this study, the construct goal-achievement expectation was formulated as being an intermediate cognitive variable or predisposing scheme which does not only signify an important function for the individual's behavior~ but which can also play an antecedent and determining role in the development of depression. In order to investigate the antecedent role of the goal achievement expectation construct, the goal-achievement expectation construct was assessed by means of a questionnaire on the basis of six operationally determined cognitive needs as conceptualized by Rotter (1954)...

The present study investigated the interpersonal schemata of self-criticism and interpersonal dependency as cognitive vulnerability factors to depression. The study's primary hypothesis was that dependency and self-criticism schemata remain stable at remission and that they are independent of mood. Stability in these two factors was related both to their self-report at remission and to their endurance as components influencing the information processing of patients during remission. Twenty clinically depressed individuals, 20 remitted depressives, and 20 normal controls were compared on memory tasks, a modified Stroop task, the Depressive Experience Questionnaire (DEQ) and the Interpersonal Dependency Inventory (IDI). The above instruments converged to measure dependency and self-criticism. Current and remitted depressives reported significantly higher levels of self-criticism and interpersonal dependency than the normal control group, when measured by the DEQ and the IDI. Performance on the three memory tasks was more ambiguous. For the free recall task, remitted depressives recalled more self-critical traits than other traits; however, the control group also recalled more self-critical traits than dependent ones, and the current depressives did not show the predicted bias. Performance on the recognition and impression formation tasks did not support' the study's main hypothesis. For the Stroop interference scores, currently depressed individuals demonstrated a trend to have more interference on the mood-congruent cards than the normal control group. Overall, the three components of the study -- questionnaires, memory tasks and Stroop task -- elicited three different patterns of results. The DEQ and the IDI indicated the presence of self-criticism and dependency in both current and remitted depressives, and thus supported the schemata's stability and independence from mood. Performance on the memory tasks offered weak support to the proposition that remitted depressives process information according to a self-critical schema, although no evidence was obtained for the dependent schema. Results of performance on the Stroop task suggested the presence of a mood congruent attentional bias in currently depressed individuals; however, no evidence was found for a self-critical or dependent attentional bias in either groups of depressives. Two explanations are offered to interpret the conflicting findings. First, a negative mood induction may be necessary to prime the interpersonal schemata. Second, tasks that are more self-focused, such as the questionnaires, than other-focused, such as the memory and Stroop tasks, may be needed to activate the schemata. / Arts, Faculty of / Psychology, Department of / Graduate

This report describes the use of small molecule probes in the modulation of brain chemistry with the ultimate goal of developing novel therapeutics for the treatment of mood disorders. With an increasing number of people suffering from depression, there is a need to explore more diverse mechanisms of these diseases to better understand their cause and therefore provide insight into their treatment. Chapter 1 serves as an introduction and describes the current understanding of depression mechanisms, as well as a history of antidepressant therapeutics. The chapter then goes on to discuss, in depth, the mechanisms of G Protein-Coupled Receptor (GPCR) function and the implications of biased signaling. There is also an introductory overview of basic pharmacological terms. The chapter finishes with a summary of current technology available to measure GPCR function, including those utilized in the rest of this report. The remainder of the report is broken up into two parts. In the first part, I will describe my work to understand the opioid receptor system in the context of mood disorders. In Chapter 2, the atypical antidepressant tianeptine is discovered to act through the mu-opioid receptor (MOR), and a biochemical exploration is reported including an exploration of its unique properties in the context of G protein-dependent and -independent signaling, as well as preliminary in vivo and structure activity relationship studies into the mechanism of action. In Chapter 3, I will describe the biological characterization of the Mitragyna speciosa alkaloids at the opioid receptors. In particular, the major alkaloids mitragynine and 7-OH mitragynine are found to be partial agonists at the MOR and antagonists at the kappa-opioid receptor (KOR) with apparent G protein bias. In Chapter 4, alkaloids inspired by those found in Tabernanthe iboga, such as ibogaine, are synthesized and characterized at the opioid receptors. Through a novel 12- hydroxy-oxaibogamine scaffold, opioid activity is uncovered that is greatly increased in comparison to the ibogaine metabolite noribogaine. Analogs tested have varying degrees of potency and efficacy at all three opioid receptors, and one analog in particular is found to be a selective G protein biased partial KOR agonist. In Chapter 5, I will conclude the opioid section by taking a critical examination of commonly used assays for measuring arrestin recruitment by dissecting assay components and analyzing what is necessary to determine accurate calculations of bias within a cellular system. The alleged G protein bias of KOR agonist dynorphin is studied at great length, and a discussion on the future of understanding ligand bias is presented. In the second part of this report, I move away from opioids and instead focus on the growth factor signaling system as a second approach to uncovering novel therapeutics for depression. In Chapter 6, I describe a second potential mechanism of action of the natural product ibogaine in the context of glial cell line-derived neurotrophic factor (GDNF) signaling. The deconstructed iboga analog XL-008 is studied that is a superior releaser of GDNF and potentiates the signaling of a second growth factor, fibroblast growth factor 2 (FGF2). In the final Chapter 7, I look to the FGF family, both receptor and growth factor, as a novel target for depression. In order to identify small molecule modulators of the FGF receptor 1 (FGFR1), cell- based assays are developed and validated in a pilot screen. The strength of these assays are assessed, and the initial results from a full high throughput screen are presented.

Type 2 diabetes is a highly prevalent disease, projected to increase in prevalence, while expensive to treat. This study sought to identify significant predictors of each of the two study outcome variables—a higher quality of patient-provider communication, and a higher quality of life. The online sample (N=72) was 78% (n=56) female with a mean age of 55.3 years, while 71% Black/African American with a good overall health status. They rated the overall quality of care received from their provider between good and very good. Using the new Patient-Provider Communication Scale (PP-CS-07, patient-provider communication was closest to very good. Health literacy skills were closest to very good, and health literacy self-efficacy was closest to very good. Level of knowledge for caring for type 2 diabetes was closest to very good knowledge. Participants were in an action stage with 80% confidence (very good self-efficacy) to perform seven diabetes self-management behaviors. Some 43.1% experienced depression, 44.4% experienced anxiety, and 20.8% sought counseling in the past year. The mean quality of life rating was closest to good quality of life. While controlling for social desirability, backward stepwise regression showed better quality patient-provider communication was significantly predicted by: received diabetes education, higher rating of health care quality, higher level of health literacy skills, and, being in a lower stage of change for self-care behaviors—with 79.2% of variance explained by this model. Better quality of life was significantly predicted by: female gender, having received diabetes education, no past year anxiety, higher annual household income, lower weight status, higher health literacy self-efficacy, higher rating of knowledge of diabetes self-management—with 69.4% of the variance explained by this model. Findings make a compelling case for screening patients for depression and anxiety, using the brief tool used in this study; and future research evaluating the impact of health educators and providers being trained in motivational interviewing, while using the Patient-Provider Communication Scale (PP-CS-7) as a new tool to compare ratings by patients of providers trained in motivational interviewing. Healthcare policy should mandate such training in brief motivational interviewing, and evaluate the impact of training in containing costs.

Adolescents spend much of their time using the internet and electronic media. Since its inception, the use of online social networking (OSN) sites by adolescents continues to grow. With the proliferation of OSN, it is critical to examine how this activity affects psychological development, but better measurement tools are needed. As researchers struggle to keep up with this rapidly growing field, many gaps remain in the literature investigating the interrelations between adolescent's OSN use and mental health outcomes. Research examining the relationship between OSN and mental health outcomes, specifically depression and anxiety, has produced mixed results suggesting that other factors influence this association. A large research literature documents associations between attachment and mental health. Given that attachment also affects interpersonal communication, several studies have investigated links between attachment and OSN use in adult and college populations. Results indicated that even though attachment to father was independently related to anxiety and depression symptoms, it was not a significant moderator for mental health and OSN. Attachment to mother was a significant moderator for anxiety and depression and several OSN subscales. Based on this information, a greater focus on youth's interpersonal connection and social skills both online and offline may be beneficial when treating adolescents experiencing anxiety or depression.

Indiana University-Purdue University Indianapolis (IUPUI) / Prospective epidemiologic evidence indicates that both stressful life events (SLEs) and depression are associated with an increased risk of subclinical atherosclerosis and cardiovascular disease (CVD) events. Even though stressful life events (SLEs) and depression co-occur and may act together to influence cardiovascular disease (CVD) risk, these psychosocial factors have been mainly examined in isolation. For instance, depression may moderate the relationship between SLEs and CVD outcomes. I hypothesized that depressive symptoms would potentiate the deleterious effect of SLEs on subclinical atherosclerosis. This hypothesis is plausible, given that depressed adults exhibit exaggerated and prolonged sympathetic nervous system, hypothalamic-pituitary-adrenal (HPA) axis, and inflammatory responses to stress, which in turn could promote atherosclerosis. As compared to their nondepressed counterparts, depressed individuals may also be more likely to engage in maladaptive methods to cope with SLEs (e.g., increased tobacco use, alcohol use, and consumption of low-nutrient, energy dense foods), which could also promote atherosclerosis. I examined cross-sectional data from 274 to 279 (depending on the outcome measure) older, African American adults (mean age = 66 years, 67% female) with no evidence of clinical CVD or dementia who participated in the St. Louis African American Health-Heart study (2009–2011). Number of SLEs was assessed using the Life Events Calendar, a structured interview. From this interview, a continuous SLEs variable was computed (number of adult SLEs: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11+). Severity of depression symptoms was measured using the 17-item Hamilton Rating Scale for Depression (HAM-D). Two measures of subclinical atherosclerosis were obtained: carotid intima-media thickness (CIMT; assessed by ultrasonography) and coronary artery calcification (CAC; assessed by multi-detector computerized tomography). I conducted linear (CIMT) and logistic (CAC) regression models, first adjusted for demographics (age, sex, education) and then fully-adjusted (demographics; mean arterial pressure; low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C); hemoglobin A1c; BMI; tobacco use; diabetes diagnosis; and use of antihypertensitve, lipid lowering, antidiabetic, and antidepressant medications). No main effects of SLEs or HAM-D were found for CIMT or CAC. There were also no SLEs by HAM-D interactions for CIMT or CAC. Because the current results are largely inconsistent with prior literature and there is a paucity of studies utilizing African American samples, future research is needed to examine the independent and interactive associations of SLEs and depressive symptoms with measures of subclinical atherosclerosis. If the present results are replicated, it may suggest that SLEs, depressive symptoms, and their interactive effect are not cardiotoxic among African American adults.

We hypothesized that the formation of malevolent introjects undermines the development of self-compassion, which in turn produces greater feelings of shame. We hypothesized that these feelings of shame account for concurrent depressive symptoms in adulthood. To test these hypotheses, we proposed a multiple mediator mediation model in which our independent variable was childhood maltreatment. We modeled child maltreatment as negatively predicting our first mediator, self-compassion, which in turn positively predicted internalized shame. We modeled internalized shame as positively predicting scores on our dependent variable, adult depressive symptoms. Participants were 158 adults fluent in English who were community members and college students living in a southwestern American metroplex. The model accounted for 61.8% of the variance in depressive symptoms in adulthood. A significant indirect effect from child maltreatment passed through both our mediators and ended in depressive symptoms in adulthood. We discuss limitations and theoretical and clinical implications, and future directions.

Indiana University-Purdue University Indianapolis (IUPUI) / Epidemiologic studies suggest that depression is an independent risk factor for cardiovascular disease (CVD). Although several possible mediators of this association have been proposed, few studies have examined the role of moderators. Accordingly, I examined adverse childhood experiences (ACE) as a potential moderator of the depression-CVD association, given that individuals with a history of ACE show a greater inflammatory response to depression, and inflammation plays a role in the development of CVD. Data from Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) were analyzed. Participants were 29,282 adults (58% female, 42% non–white) aged 18–97 years, free of CVD diagnoses at baseline. Lifetime depressive disorder (LDD) was assessed by the Alcohol Use Disorder and Associated Disabilities Interview Schedule–IV (AUDADIS–IV), and adverse childhood experiences (abuse, neglect, and household dysfunction), and CVD were assessed during separate interviews. The primary outcome was incident CVD (n = 1,255), defined as nonfatal arteriosclerosis, angina pectoris, myocardial infarction, and/or stroke reported during the Wave 2 interviews. All analyses were adjusted for demographic and traditional CVD risk factors. Logistic regression models revealed that both LDD (OR = 1.44, 95% CI: 1.28–1.62, p < .001) and any ACE (OR = 1.25, 95% CI: 1.16–1.35, p < .001) were independent predictors of incident CVD. Interactions between LDD x any ACE (p = .024), LDD x neglect (p = .003), and LDD x household dysfunction (p < .001), but not LDD x abuse (p = 0.16), were detected. Analyses stratified by the ACE variables revealed that LDD was a predictor of incident CVD among adults with a history of (1) any ACE (OR = 1.51, 95% CI: 1.32–1.73, p < .001), but not among those without a history (OR = 1.15, 95% CI: 0.87–1.50, p = .332); (2) neglect (OR = 1.59, 95% CI: 1.36–1.87, p < .001) and among those without a history (OR = 1.25, 95% CI: 1.07–1.62, p = .005); (3) household dysfunction (OR = 1.73, 95% CI: 1.46–2.04, p < .001), but not among those without a history (OR = 1.18, 95% CI: 0.96–1.43, p = .11). Overall, the present findings suggest that depression may be a stronger risk factor for CVD among adults with a history of ACE, especially neglect and household dysfunction, than among adults who did not have these experiences.