Joseph Schildkraut: "The Catecholamine Hypothesis of Affective Disorders“, 1965

1969 by Carlsson et al. =>first SSRI: zimelidine (1971) … fluoxetine marketed in 1988

The molecular mechanism of long-term antidepressant treatments Duman: July 1997 Arch Gen Psychiatry

Stress Decreases and Antidepressant Treatments Increase the Expression of Brain-derived Neurotrophic Factor in the Hippocampus Duman et al.,1997 Stress : restrain stress (90 mins) Fluoxetine : administration 21 days BDNF mRNA were determined by in situ hybridization

H= haloperidol D= desipramine I= imipramine F= fluoxetine novelty-suppressed feeding test (NSF) Science 2003;301:805-9

Chronic fluoxetine treatment increases BrdU uptake and neurogenesis in the dentate gyrus of mice NeuN : neuron-specific nuclear protein GFAP : glial fibrillary acidic protein Confocal micrograph of cell double- labeled for BrdU and NeuN or GFAP Science 2003;301:805-9 BrdU is incorporated into DNA in place of thymidine then injected into the brain (CSF). BrdU-positive indicates synthesis of DNA and a generation of new cells.

SGZ= subgranular zone SVZ= subventricular zone S= sham X= X-ray V= vehicle F= fluoxetine I= imipramine

Inescapable stress => Antidepressant (IP) or BDNF infusion

Results DG J Neuroscience 2002;22:3251–61

Inhibition of tyrosine kinase (by K252a) or MEK (by U0126) blocks the antidepressant effect of BDNF J Neuroscience 2002

TKI-induced Depression Profound depression emerged from seven patients treated with tyrosine kinase inhibitors (TKI), five treated with imatinib and two with dasatinib. All were coping well with their disease psychologically before imatinib/dasatinib therapy. They experienced complete remission or improvement of symptoms after dose reduction or drug discontinuation. Two patients had relapse of depression after TKI rechallenge. J Clin Oncology 2009

Egan: Cell 2003

Scince 2006; 314: Contexual freezing

Anxiety-related behavior in BDNF Met/Met mice Chen: Science 2006

16 Acquisition & extinction of fear (BDNF imitators) 7,8-Dihydroxyflavone (7,8-DHF) p≤ 0.05, N=10 Am J Psychiatry 2011

Conditioned fear After extinction training Am J Psychiatry 2011

Neuron,2008

No training Learned safety Learned safety No training Neuron,2008