Pharmacological treatment and determinants of psychosis in patients with bipolar disorder

Abstract

The underlying pathophysiology of bipolar disorder and the mechanism through which existing pharmacological treatment is effective remains largely unknown. In the first part of this thesis demographical, clinical and neurocognitive characteristics of psychosis in bipolar disorder are investigated to identify a potential subtype within the disorder reflecting increasing level of severity. A large comprehensively characterized sample of 1,342 bipolar disorder type I patients was investigated and showed a high frequency of lifetime psychotic symptoms (73.8%) including delusions (68.9%), hallucinations (42.7%), mood incongruent symptoms (30.1%), Schneiderian symptoms (21.2%) and formal thought disorder (59.7%). The results underscore the high frequency of psychotic symptoms in bipolar disorder type I, which are associated with a more severe disease course consisting of an earlier onset of disease and more frequent hospitalizations for a manic episode. Cognitive functioning did not differ between patients with or without a history of psychotic symptoms. In addition, the results emphasize the strength of the relationship between childhood maltreatment and hallucinations. This relationship is of interest to study the etiology of hallucinations independent from diagnosis. Overall, the results did not distinguish a clear categorical psychotic subtype, but do support a differentiation in severity within BDI based on psychosis vulnerability. The second part of this thesis focused on three pharmacological topics in the treatment of bipolar disorder with the aim to enlarge the knowledge of current psychopharmacological treatment. The first of these three studies investigated the effectiveness of lithium, a widely used mood stabilizer for long-term treatment in particular after a period of discontinuation. The conducted meta-analysis of the current literature showed no evidence for a decrease of effectiveness after a period of discontinuation. The second study described a literature review on cognitive effects of mood stabilizers and antipsychotics in addition to development of new cognitive enhancing agents. In bipolar disorder, findings on cognitive effects of medication must be interpreted with caution, due to relatively small sample sizes and mainly cross-sectional and natural designs. Nevertheless results point to a negative cognitive effect of lithium, anticonvulsants and antipsychotics. Prospective randomized studies are needed to increase the understanding of the effects of different types of medication on cognitive function in bipolar disorder. The third study investigated epigenetic effects, a potential biological mechanism of action of currently available mood stabilizers, antipsychotic and antidepressants in 172 bipolar patients. The results show that use of psychotropic medication affects global blood DNA methylation patters in bipolar disorder patients. Across all six examined medication types (lithium, carbamazepine, lamotrigine, olanzapine, valproic acid and quetiapine) valproic acid and quetiapine were consistently associated with global changes in DNA methylation. These DNA methylation alterations were not only related to quetiapine and valproic acid use, but were also associated with an immune related methylation network, indicating inflammation reducing effects. This study underscores the importance to include the use of medication as a confounder in future epigenetic research. In addition, it can also increase the understanding of the underlying biological mechanisms of current medication. Overall the three studies contribute to the understanding of bipolar disorder and its complex heterogeneous phenotype and attempt to open new avenues for studying the role of psychosis across diagnostic boundaries.