Table of Contents. Preface Abstract Acknowledgements... 9

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2 Table of Contents Preface... 5 Abstract... 7 Acknowledgements Introduction Bipolar Affective Disorder History and Symptomatology of Bipolar Disorder Pharmacotherapy Mood Stabilization Lithium Antiepileptics Atypical Antipsychotics Antidepressant Therapy Selective Serotonin Reuptake Inhibitors (SSRI) NASSA (Noradrenaline and Serotonin Specific Antidepressant) SNRI (Serotonin and Noradrenaline Reuptake Inhibitor) NARI (Noradrenaline Reuptake Inhibitor) SRE (Serotonin Reuptake Enhancer) NDRI (Noradrenaline and Dopamine Reuptake Inhibitor) Tricyclic Antidepressants Tetracyclic Antidepressants MAO Inhibitors DSA (Dual Serotonergic Antidepressant) Bright Light Therapy Epidemiology of Bipolar Disorder Basic Principles of Genetics Structure of DNA

3 1.2.2 Gene Expression- from DNA to Proteins Transcription Initiation of Transcription Elongation of Transcription Termination of Transcription Proteinbiosynthesis (Translation): Initiation of Protein Biosynthesis in Eukaryotes Elongation Termination Replication Initiation of Replication Epigenetics Mutations Gene mutations Point mutations Insertions, Deletions, Duplications and Repeat Polymorphisms Chromosomal mutations Structural Chromosomal Mutations Chromosome Number Aberrations Methods of Molecular Bipolar Disorder Research Association Studies Genome Wide Association Studies (GWAS) Linkage studies Methods Genetics of Bipolar Disorder Heritability of Bipolar Disorder Candidate Genes at One View Genes of the Serotonergic System Serotonin Receptor Genes HT1 Receptor Genes HTR1A HTR1B and HTR1D HT2 Receptor Genes HTR2A HTR2C Gene HT3 Receptor Genes HT4 Receptor Genes

4 5-HT5 Receptor Genes HT6 Receptor Genes HT7 Receptor Genes Serotonin Transporter Gene (= SLC6A4, SERT, 5HTT) Polymorphism of the 5-HTTLPR and the Untranslated Region The Variable-Number-Tandem-Repeat (VNTR) within Intron Insertion/deletion in the Promoter Region of the Serotonin Transporter Genes Involved in Biogenic Amine Modulation MAOA Animal Studies Antidepressants Association Studies CA-Repeat Microsatellite in Intron Fnu4H1 RFLP (Fnu4H1 Restriction Fragment Length Polymorphism) EcoRV Polymorphism (T-to-C Substitution at Position 1460) T-to-A Substitution at Position 1077 (Promoter VNTR) Variable Number of Tandem Repeats (VNTR) Polymorphism in Intron Linkage studies MAOB COMT TPH TH Clock Genes The Circadian Oscillator in the Suprachiasmatic Nucleus Role of clock genes in bipolar disorder ARNTL (BMAL1 or MOP3) NPAS NR1D Period Genes (PER1, PER2, PER3) CRY CLOCK DBP CSNKD

5 14 CSNKE TIMELESS PPARGC1B Summary of clock genes Growth Hormones BDNF Functions of BDNF BDNF Signal Transduction BDNF Polymorphisms Dinucleotide repeat (GT)n (BDNF-LCPR) Val66Met Polymorphism Association of BDNF Variants with Bipolar Disorder Antidepressants, Mood Stabilizers and Animal Studies Serum Levels of BDNF Linkage studies for chromosome GWAS- Genome wide association studies Genetic association studies and family based genetic studies Reasons for controversies BDNF and subtypes of bipolar disorder or related disease Summary of Association Studies for BDNF and Bipolar Disorder (BD) NRG NCAM RELN Genes of the Lithium signal transduction pathways DGKH Ion channels and associated proteins ANK CACNA1C NTNG1 and NTNG KCNC P2RX7/ ATP2A SLC24A SLC39A HPA axis, cortisol and stress Genes of the dopaminergic system DAT

6 DRD DRD DRD DRD DRD Genes of the noradrenergic system NET (SLC6A2) Genes of the GABAergic system GABRBI GABRB GABRB GABRA Genes of the Glutamatergic system GRIN genes GRIA GRM GRM GRM GRIK genes Copy number variations (CNVs) Others GCHI CHMP Genetic overlaps between psychiatric diseases Overlaps between mood disorders and schizophrenia Schizophrenia Overlaps between mood disorders and schizophrenia Symptomatic overlaps between psychiatric diseases Genetic overlaps between mood disorders and schizophrenia. 117 COMT Serotonin transporter polymorphisms SERT (=5HTT = serotonin transporter gene) VNTR in intron 2 of the serotonin transporter gene Deletion/insertion in the promoter region of SERT G72/G30 gene (DAOA) DAO CACNA1C DTNBP Neuregulin

7 DISC BDNF MAOA Dopamine receptor genes DRD DRD DRD DRD DRD Summary of the overlaps between mental diseases Gene-environment-interactions and prevention Epigenetics Sleep deprivation Nutrition and famines Infections and risk of bipolar disorder Season of birth Urban/rural residency and genotype Antidepressant induced mania and genotypes Stress, gene expression and bipolar disorder Mood changes after delivery Maltreatment and negative life events MAOA polymorphism Hypothalamic-pituitary-adrenal axis FKBP Serotonin transporter 5-HTTLPR polymorphism BDNF COMT Implications for clinical practice Treatment and genotype Antidepressant treatment and genotype Antimanic treatment and genotype Psychotherapy Lifestyle changes Conclusion References