Episode-specific differential gene expression of peripheral blood mononuclear cells in rapid cycling supports novel treatment approaches

• Published in: Molecular medicine (Cambridge, Mass.) Mass.), 2008-09, Vol.14 (9-10), p.546-552
• Main Authors: Begemann, Martin, Sargin, Derya, Rossner, Moritz J, Bartels, Claudia, Theis, Fabian, Wichert, Sven P, Stender, Nike, Fischer, Benjamin, Sperling, Swetlana, Stawicki, Sabina, Wiedl, Anne, Falkai, Peter, Nave, Klaus-Armin, Ehrenreich, Hannelore
• Format: Article
• Language: English
• Subjects: 3-Hydroxysteroid Dehydrogenases - genetics; 3-Hydroxysteroid Dehydrogenases - metabolism; Aldo-Keto Reductase Family 1 Member C3; Bipolar Disorder - diagnosis; Bipolar Disorder - drug therapy; Bipolar Disorder - genetics; Bipolar Disorder - metabolism; Celecoxib; Computational Biology; Cyclooxygenase Inhibitors - administration & dosage; Cyclooxygenase Inhibitors - therapeutic use; Female; Gene Expression Profiling; Gene Expression Regulation; Humans; Hydroxyprostaglandin Dehydrogenases - genetics; Hydroxyprostaglandin Dehydrogenases - metabolism; Intramolecular Oxidoreductases - genetics; Intramolecular Oxidoreductases - metabolism; Leukocytes, Mononuclear - metabolism; Lipocalins - genetics; Lipocalins - metabolism; Middle Aged; Oligonucleotide Array Sequence Analysis; Proteins - genetics; Proteins - metabolism; Pyrazoles - administration & dosage; Pyrazoles - therapeutic use; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sulfonamides - administration & dosage; Sulfonamides - therapeutic use; Treatment Outcome
• ISSN: 1076-1551; 1528-3658
• DOI: 10.2119/2008-00053.Begemann

Molecular mechanisms underlying bipolar affective disorders are unknown. Difficulties arise from genetic and phenotypic heterogeneity of patients and the lack of animal models. Thus, we focused on only one patient (n = 1) with an extreme form of rapid cycling. Ribonucleic acid (RNA) from peripheral blood mononuclear cells (PBMC) was analyzed in a three-tiered approach under widely standardized conditions. Firstly, RNA was extracted from PBMC of eight blood samples, obtained on two consecutive days within one particular episode, including two different consecutive depressive and two different consecutive manic episodes, and submitted to (1) screening by microarray hybridizations, followed by (2) detailed bioinformatic analysis, and (3) confirmation of episode-specific regulation of genes by quantitative real-time polymerase chain reaction (qRT-PCR).Secondly, results were validated in additional blood samples obtained one to two years later. Among gene transcripts elevated in depressed episodes were prostaglandin D synthetase (PTGDS) and prostaglandin D2 11-ketoreductase (AKR1C3), both involved in hibernation. We hypothesized them to account for some of the rapid cycling symptoms. A subsequent treatment approach over 5 months applying the cyclooxygenase inhibitor celecoxib (2 x 200 mg daily) resulted in reduced severity rating of both depressed and manic episodes. This case suggests that rapid cycling is a systemic disease, resembling hibernation, with prostaglandins playing a mediator role.