Determinants of long term course in Bipolar disorder

Sammanfattning: Introduction: Bipolar disorder (BP) is a common and severe psychiatric illness with a high variability. An early treatment is often crucial for a good prognosis, but it is difficult for clinicians to define high risk patients in order to predict a more severe course. Our aim was to investigate factors predicting the long-term course of BP. Methods: We have retrospectively investigated the course of illness in 100 BP patients, using a life-charting program. Predictors and their impact on the outcome of lithium treatment were analyzed (Paper I). We then used the Swedish in-patient registry to study the annual incidence rate of BP patients hospitalized for the first time during 1997-2005. We also monitored the readmission rates during five years of patients who had their first admission for bipolar episodes during year 2000 (Paper II). Two groups of BP patients were recruited from a number of psychiatric outpatient clinics for molecular genetic studies. Manic symptoms were assessed and phenotype variations such as mixed episodes (ME), rapid cycling (RC), and the age at onset were defined. Using association analysis, patients with specific symptoms/phenotypes were compared to the other bipolar patients for genetic markers in one small sample. Positive associations identified were then searched for in a larger second sample (Papers III and IV). Results: The number of episodes decreased after the introduction of lithium. An early onset was associated with a longer time until treatment (18.1 vs.10.7 years). The most important predictors for a poor outcome during treatment were RC (OR=10.7), comorbidity (OR=3.8), and ME (OR=2.8) (Paper I). The average length of stay during the first hospitalization was 42 days for ME compared to 30 days for other episodes. Of the 874 participants who had had their first admission for a bipolar episode in 2000, 44% had at least one readmission during the 5-year follow-up. A small group (15%) accounted for more than one half of the readmissions during the same period (Paper II). Utilizing molecular genetics, cognitive symptoms in mania were found to be associated with the SNP rs1718119 (p<0.0006; Paper III), and RC with the SNP rs2230912 (p<0.004; paper IV), both SNPs being located in the P2RX7 gene. Combining the SNP rs2230912 in the P2RX7 gene and the previously associated rs10838524 in the CRY2 gene in an epistasis analysis yielded evidence of a strong association with RC (p=0.000005; OR=7.4). Conclusions: The life-charting methodology can be useful in studying the long-term course of BP. A limitation is that the multitude of data on each studied patient limits the possibility of dealing with large samples. Our findings support the results of previous studies suggesting that RC, ME and comorbidity for other Axis I disorders are important predictors for a more severe course of illness. Most of the first admitted BP patients were not readmitted in the subsequent 5-year period. The genetic findings suggest that different symptoms in BP are associated with specific genes, making the biological pathways behind BP more transparent. The finding that BP patients with a specific combination of variations in the P2RX7 and CRY 2 genes run a 7-fold greater risk of developing RC that those patients not having this combination, is a new contribution to the research field, which increase the possibility of identifying patients who risk developing a more severe course of BP.