Understanding mania in bipolar disorder : perspectives on causation and pathogenesis

The cardinal feature of bipolar disorder type I (BDI) is mania. Episodes of mania may lead to marked impairments in social and occupational functioning and impose a significant financial burden on both patient and health-care system. In order to alleviate this burden a more detailed understanding of the aetiology and pathogenesis of mania is important to direct development of improved treatments. Chapter 1 is an introduction to the psychopathology, course, antecedents, precipitants, treatment response and pathogenesis of mania in bipolar disorder type I. Understanding of the underlying pathophysiology of mania is limited. The thesis identifies a series of studies based on review methodologies that bring together four perspectives on the causes and processes involved in episodes of mania. These perspectives comprise: Comparison of mania with a reference condition, namely partial seizures arising from the temporal lobe (PS) as a strategy for identifying localising pathways in the brain based on precipitating factors in common between the two conditions; Comparison of cognitive deficits between illness episodes in BD and temporal lobe epilepsy (TLE), to cast light on the underlying neuropsychological substrates that may indicate vulnerability and brain pathology; Treatment response of mental disorders to an evidence-based therapy used in epilepsy, the ketogenic diet; and Examination of a subset of substance-induced mania, that was reported in association with the use of herbal medicines. The second part of chapter 1 is an introduction to temporal lobe epilepsy (note: the nomenclature temporal lobe epilepsy (TLE) is synonymous with partial seizures (PS) or focal seizures (FS) arising from the temporal lobe, the term used in this thesis depends on the most common usage in the literature being reviewed). The third part introduces the studies, presented as four papers published in refereed journals, which follow in chapters 2 to 5. Chapter 2 presents a published paper that considers precipitating factors of recurrent episodes of mania. It identifies common precipitating factors for mania and partial seizures in TLE (PS) as stress, sleep deprivation, antidepressant medication and, tentatively, emotion; for mania alone, goal-attainment events, spring and summer season, postpartum, and drugs including steroids and stimulants; for PS alone, winter season, menstruation and specific triggers in complex reflex epilepsies. The overlap of precipitating factors in mania and PS implies that common brain processes may contribute to both, consistent with findings from neuroscience research regarding mechanisms, which are discussed in detail. Chapter 3 presents a published paper comprising a systematic review and comparison of cognitive function in euthymic BD-I and pre-surgical TLE. It is important to consider interepisode BD in order to better understand the neurobiological substrates involved in the propensity to mania. This review concludes that both disorders exhibit deficits in executive function and verbal memory suggestive of both frontal and temporal lobe involvement. Chapter 4 presents a published paper regarding the status of the ketogenic diet as a treatment in mental disorders. There is a well-established overlap in medications for BD and epilepsy, particularly with mood stabilizers such as sodium valproate. An evidence-based treatment for epilepsy, the ketogenic diet (KD) has received limited attention in mental disorders. In BD, the mechanism by which KD may be effective is based on the hypothesis that acidosis achieved through ketosis reduces intra-cellular sodium, calcium, both of which are elevated in the disorder. Mood stabilizers reduce intra-cellular sodium in an activity-dependant manner within the context of KD, through acidification of the blood. The literature regarding KD in mental disorders was reviewed and included studies on anxiety, depression, bipolar disorder, schizophrenia, autism spectrum disorder and attention deficit hyperactivity disorder. This identified the need for carefully controlled research to resolve whether KD has therapeutic potential in mental disorders and the potential utility of direct ketone supplementation (as opposed to a restrictive diet inducing ketosis) as a treatment modality. Chapter 5 presents a published paper examining case reports of substance-induced mania specifically associated with use of herbal medicines (HM). All case reports (n=35) were associated with use rather than withdrawal of HM. Causal attributions are problematic given the paucity of reports, antidepressant co-prescribing in 12 cases, inclusion of 7 cases with a past diagnosis of mania, insufficient data regarding pattern and type of HM use, and lack of a reference frequency of spontaneous mania. Putative pathophysiological mechanisms for each reported HM inducing mania are discussed. These centre on HPA-axis activation and increased monoamine activity. Chapter 6 Discusses the findings of chapters 2 to 5, concluding that the use of multiple perspectives and the reference condition of TLE identifies leads that may enhance understanding of basic mechanisms involved in episodes of mania. Directions for future research arising from the results are outlined.