Translational studies on bipolar disorder and anorexia nervosa

Translational medicine aims at closing the gap between basic and clinical sciences in an integrative way. Psychiatry is one of the few medical specialties in which diagnosis is primarily based on clinical observation and all mental disorders are defined by abnormal behaviors and cognitions. The lack of biomarkers supporting diagnostic and therapeutic procedures has been a challenge in psychiatry. A better biological understanding is needed to move the field forward, it will enhance diagnostics and treatment, while reducing the stigma that surrounds mental disorders that are so poorly understood. Over the last years, advances in fundamental sciences like genetics and neuroscience have made it clear that there is shared biology between many psychiatric disorders and that integration of methods might lead to new understandings. The studies presented in this thesis focus on bipolar disorder (BD) and anorexia nervosa (AN), both severe mental disorders with high suicide rates, high heritability, and both lacking in biological understanding. BD, formerly known as manic-depressive disorder, is a mood disorder, characterized by manic or hypomanic episodes, often in combination with depressive episodes. AN is an eating disorder characterized by severe weight loss together with pathological behaviors.

This thesis includes five main studies on the biology underlying these disorders, based on large, well characterized cohorts, covering several methods, including genetic, imaging and protein markers, as well as preliminary data on the establishment of in vitro models. Specifically, in study I, we attempted to replicate previously published findings on the association between subphenotypes of bipolar disorder and genetic variations in the AKT1 gene. Using frequentist and Bayesian approaches, as well as publicly available results from genome-wide association studies (GWAS), we were able to reject previously proposed associations. In study II, we explored the effects of genetic variations in genes involved in glutamate regulation on glutamate levels in two brain regions and their associations with other phenotypes. We found that the minor allele of rs3812778/rs3829280 in the 5’-untranslated region of SLC1A2, coding for a glutamate transporter, is associated (1) with increased glutamate levels in the anterior cingulate cortex, (2) with increased expression levels, in several brain regions, of the transmembrane receptor gene CD44, which is implicated in inflammation and brain development, as well as (3) with an increased risk for rapid-cycling in bipolar disorder, potentially linking CD44/SLC1A2 to a more severe phenotype of BD.

In study III, we investigated the effects of clinical and genetic parameters on lithium pharmacokinetics in order to better understand lithium biology and improve lithium dose prediction models for bipolar patients, using the ratio between serum lithium and daily lithium intake, as outcome. We were able to confirm the association of several clinical predictors. Although no genome-wide significant locus was found, we report that genetic variation is important and might influence the outcome. Finally, based on the results obtained in the study, we developed a prediction algorithm that can be tested in the clinic. In study IV, we investigated the involvement of neuronal degeneration in AN by studying neurofilament light chain (NfL), a known marker of neurodegeneration, in a case-control setting and found increased levels of NfL in patients with active AN in two different cohorts. In study V, we studied the involvement of inflammation in AN, using a panel of 92 inflammatory markers in a case-control setting and report an aberrant inflammatory profile in patients with active AN, but not in patients that have recovered from AN. These studies exemplify possible approaches that can be taken in translational psychiatry. The integration of clinical, technical and analytical approaches illustrates important learning outcomes for an aspiring clinical scientist in psychiatry.

List of scientific papers

I. Millischer V, Matheson GJ, Martinsson L, Römer Ek I, Schalling M, Lavebratt C, Backlund L. (2019). AKT1 and genetic vulnerability to Bipolar Disordery. Psychiatry Research. [Accepted]
https://doi.org/10.1016/j.psychres.2019.112677

II. Veldic M*, Millischer V*, Port JD, Ho AMC, Jia YF, Geske JR, Biernacka JM, Backlund L, McElroy SL, Bond DJ, Villaescusa JC, Skime M, Choi DS, Lavebratt C, Schalling M, Frye MA. (2019). Genetic variant in SLC1A2 is associated with elevated anterior cingulate cortex glutamate and lifetime history of rapid cycling. Translational Psychiatry. 9, 149. *Equal contribution.
https://doi.org/10.1038/s41398-019-0483-9

III. Millischer V, Matheson GJ†, Bergen S†, Ponzer P, Jagiello K, Stenvinkel P, Lindholm B, Martinsson L, Landén M, Backlund L, Lavebratt C, Schalling M. Identification of clinical and genomic factors in lithium pharmacokinetics. †Equal contribution. [Manuscript]

VI. Nilsson IAK, Millischer V*, Karrenbauer VD*, Juréus A, Salehi AM, Norring C, von Hausswolff-Juhlin Y, Schalling S, Blennow K, Bulik CM, Zetterberg H, Landén M. (2019). Plasma neurofilament light chain concentration is increased in anorexia nervosa. Translational Psychiatry. 9, 180. *Equal contribution.
https://doi.org/10.1038/s41398-019-0518-2

V. Millischer V*, Nilsson IAK*, Götesson A, Bulik CB, Schalling M, Landén M. Anorexia nervosa is associated with an aberrant inflammatory profile. *Equal contribution. [Manuscript]