joseph schildkraut: "the catecholamine hypothesis of affective disorders“, 1965
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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Joseph Schildkraut: "The Catecholamine Hypothesis of Affective Disorders“, 1965
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1969 by Carlsson et al. =>first SSRI: zimelidine (1971) … fluoxetine marketed in 1988
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The molecular mechanism of long-term antidepressant treatments
Duman: July 1997Arch Gen Psychiatry
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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
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H= haloperidolD= desipramineI= imipramineF= fluoxetine
novelty-suppressed feeding test (NSF)
Science 2003;301:805-9
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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.
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SGZ= subgranular zoneSVZ= subventricular zoneS= shamX= X-rayV= vehicleF= fluoxetineI= imipramine
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Inescapable stress => Antidepressant (IP) or BDNF infusion
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Results
DG
J Neuroscience 2002;22:3251–61
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Inhibition of tyrosine kinase (by K252a) or MEK (by U0126) blocks the antidepressant effect of BDNF
J Neuroscience 2002
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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
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Egan: Cell 2003
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Scince 2006; 314:140-143
Contexual freezing
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Anxiety-related behavior in BDNF Met/Met mice
Chen: Science 2006
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16
Acquisition & extinction of fear
187 (BDNF imitators)
7,8-Dihydroxyflavone (7,8-DHF)
p≤ 0.05, N=10
Am J Psychiatry 2011
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Conditioned fear
After extinction training
Am J Psychiatry 2011
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Neuron,2008
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No training Learned safety Learned safety No training
Neuron,2008
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Neuron,2008