Bipolar spectrum disorders (BSDs) and substance use disorders (SUDs) are highly co-occurring and both are associated with dysfunction in neural networks that mediate reward processing and motivated behavior. Furthermore, despite their high comorbidity rate, limited research into their shared neural mechanisms or potential prospective risk factors exists. This study attempted to elucidate common neural pathways for these disorders, and adds to the small but growing literature on possible prospective predictors of these disorders. We employed a task-based functional magnetic resonance imaging (fMRI) study to examine regions-of-interest (ventral striatum [VS], orbitofrontal cortex [OFC], ventromedial prefrontal cortex [vmPFC], dorsolateral prefrontal cortex [dlPFC]) and connectivity (VS-OFC, VS-vmPFC, vmPFC-dlPFC) analyses to examine neural reward processing as potential predictors of future substance and mood symptoms, and to explore differences among groups of participants with and without BSDs and SUDs. Results from this study provided evidence that blunted activation in the VS and dlPFC and greater negative connectivity between the vmPFC and dlPFC, key reward and control circuits, is implicated in prospective substance use. However, we did not find evidence to support our hypothesis that reward-related neural responses predict BSD symptoms or could differentiate individuals with co-occurring BSDs and SUDs from healthy volunteers. The study highlights the importance of larger, longitudinal studies to more fully probe neurodevelopmental trajectories in mood, substance, and related disorders. We also conducted an extensive review of the neural reward literature in BSDs and SUDs to understand possible pre-existent mechanisms. Results of the review provided support for an equifinality/multifinality perspective in that similar neural reward processing dysfunctions can lead to both BSDs and SUDs and different neural reward processing abnormalities can lead to a single outcome (e.g., SUDs). Taken together, results from the dissertation address an important gap in the literature on BSD-SUD comorbidity, suggest possible shared mechanisms that predispose to both disorders, and provide a backdrop for future work in this area to inform more theoretically-targeted interventions and prevention. / Psychology

Clinicians and researchers have identified a pattern of "mixed" symptoms that are sometimes exhibited by individuals with bipolar spectrum disorders (BSDs). However, the criteria for these mixed states as outlined by the American Psychological Association have been criticized for being too stringent for most individuals that experience impairing episodes of mixed symptomatology (e.g., Akiskal, 1996). Mixed states are associated with a more impairing course of illness and suicidality. More research is needed on mixed states, and there is particularly little evidence for risk factors in recent-onset samples. The aims of this study were to 1) examine the prevalence of mixed states in a sample of individuals with recent-onset bipolar spectrum disorders, 2) examine the symptom structure of hypomanic and depressive episodes, and 3) examine some of the risk factors associated with mixed states. Participants in sample 1 were adolescents, initially aged 14-19, selected for exhibiting either moderate or high Behavioral Approach System (BAS) risk for first onset of BSDs. Participants in sample 2 were 18-24 year old undergraduates from Temple University recruited for having a bipolar spectrum diagnosis. Mixed states captured 37.10% of all episodes examined in sample 1, yet only 13 (10.48%) of these episodes met available research criteria for mixed mood episodes. Factor analysis yielded two adequate models that fit the data; one model had two factors that aligned with traditional depressive and hypomanic symptomatology, and another model had three factors that aligned with hypothesized overactivity, inhibited depression, and irritable risk taking components of bipolar disorder. Latent class analysis allowed for examining observed patterns of responses within individuals, and then grouping heterogeneous groups of individuals into classes based on similarities on dimensions of interest, performance within dimensions, or both (Nylund, Bellmore, Nishina, & Graham, 2007). The latent class analysis showed that three classes best defined bipolar spectrum individuals in sample 1: low impulsivity, aggressive, and substance problems classes were obtained. The `aggressive' class was significantly more likely than the `low impulsivity' class to experience any mixed symptomatology, although a continuous measure of mixed symptoms did not yield significant differences between classes. Overall, the results from the current study support findings suggesting that mixed mood states are more commonly experienced than originally believed. These results extend previous studies to include individuals with bipolar spectrum disorders, not solely bipolar I and II disorders. These findings also suggest that non-treatment-seeking samples may have different types of mixed mood states than those seeking treatment. These findings add support to the literature that individuals with BSDs and comorbid substance use diagnoses are at increased risk for chronic illness, and show that these individuals are also more likely to experience mixed mood states than those without comorbid substance use diagnosis. Treatment providers should be aware of the complications that are inherent in bipolar individuals with comorbid substance diagnoses, as they are more likely to experience more episodes as well as mixed symptoms. / Psychology

The morbidity and societal burden of youth bipolar spectrum disorders (BSD) are high. These disorders are multisystemic in that adult populations there are clear interactions with inflammatory processes and steroidal physiological systems. There are much less data concerning these areas of study in youth populations with BSD. This is surprising given the association of youth-onset BSD with puberty and its associated physiological changes. In this mini-review, we overview the theoretical role of inflammatory processes and steroidal physiological systems in youth BSD, describe the greater literature in adult populations, detail the literature in youth populations when available, and overview current proposed molecular mechanistic pathways and interaction effects based on the available data. We also attend to the interplay of this complex system with body composition and weight gain, an especially important consideration in relation to the role of second generation antipsychotics as the first line treatment for youth with BSD in major clinical guidelines. A developmental model of early onset BSD for boys is hypothesized with pubertal hormonal changes increasing risk for first (hypo-)manic/depressive episode. The dramatic androgen rise during puberty might be relevant for first onset of BSD in boys. A shift from general hypercortisolism driven by glucocorticoid resistance to hypocortisolism with further disease progression is assumed, while increased levels of inflammation are functionally associated with endocrine dysregulation. The interacting role of overweight body habitus and obesity in youth with BSD further indicates leptin resistance to be a central moderator of the dynamic neurobiology of BSD in youth. The intent of this mini-review is to advance our knowledge of youth BSD as multisystemic disorders with important contributions from endocrinology and immunology based on a developmental perspective. This knowledge can influence current clinical care and more importantly inform future research.

The morbidity and societal burden of youth bipolar spectrum disorders (BSD) are high. These disorders are multisystemic in that adult populations there are clear interactions with inflammatory processes and steroidal physiological systems. There are much less data concerning these areas of study in youth populations with BSD. This is surprising given the association of youth-onset BSD with puberty and its associated physiological changes. In this mini-review, we overview the theoretical role of inflammatory processes and steroidal physiological systems in youth BSD, describe the greater literature in adult populations, detail the literature in youth populations when available, and overview current proposed molecular mechanistic pathways and interaction effects based on the available data. We also attend to the interplay of this complex system with body composition and weight gain, an especially important consideration in relation to the role of second generation antipsychotics as the first line treatment for youth with BSD in major clinical guidelines. A developmental model of early onset BSD for boys is hypothesized with pubertal hormonal changes increasing risk for first (hypo-)manic/depressive episode. The dramatic androgen rise during puberty might be relevant for first onset of BSD in boys. A shift from general hypercortisolism driven by glucocorticoid resistance to hypocortisolism with further disease progression is assumed, while increased levels of inflammation are functionally associated with endocrine dysregulation. The interacting role of overweight body habitus and obesity in youth with BSD further indicates leptin resistance to be a central moderator of the dynamic neurobiology of BSD in youth. The intent of this mini-review is to advance our knowledge of youth BSD as multisystemic disorders with important contributions from endocrinology and immunology based on a developmental perspective. This knowledge can influence current clinical care and more importantly inform future research.