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 1997Arch 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 daysBDNF mRNA were determined by in situ hybridization

H= haloperidolD= desipramineI= imipramineF= 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 proteinGFAP : 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 zoneSVZ= subventricular zoneS= shamX= X-rayV= vehicleF= fluoxetineI= 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; 314:140-143

Contexual freezing

Anxiety-related behavior in BDNF Met/Met mice

Chen: Science 2006

16

Acquisition & extinction of fear

187 (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

Neuron,2008