MDD Flashcards
• Axelrod (1961):
Cats were given following amphetamine, imipramine and resperine and then H3-NA→found elevated levels of catecholamines in plasma so seems that these drugs reduced uptake
o Only 3 cats, did not look in the brain
• Hyde et al (2016):
75000+ with clinical depression and 200000 with no family of depression and meta-analysis revealed 17 independent SNPs from 15 loci identified to be significantly associated with depression
• Delgado et al (1999):
Patients suffering depression on course of treatment with SSRI Fluoxetine and tryptophan depletion cause relapse. Within hours their mood worsens and recovers the following day, controlled mixture had no effect. Suggest that SSRI are working though increasing 5HT
o Measuring TRP and so assuming it depletes 5HT in the synapses
• Ruhe et al 2007
Meta-analyses looking at depletion studies and found that 5HT or DA/NE depletion does not lower mood in healthy controls but does induce relapse in patients with MDD in remission
• Caspi et al (2003):
Epidemiological study assessing probability of individuals having depression with SLEs. 5HTTLPR was assessed and then assess life history calendar between 3-26 found GxE interaction with patients with s allele had a much greater probability of depression with more SLEs. Also found when assessing childhood maltreatment
o Controversial and lack of replication
• Uher and McGuffin (2010):
Meta-analysis found that the length polymorphism of the serotonin transporter gene moderates the effect of environmental adversity in the development of depression but inconsistent findings in adolescent males suggests there is a developmental and sex-specific protective mechanism
• Culverhouse et al (2017
Meta-analyses, found there was no subgroups or variable definition for which an interaction between stress and 5HTTLPR gene type was significant.
• Parsey et al (2006):
PET of 11C-DASB binding in healthy subjects with administration of sertraline and found displacement of 5HT transporter labelling by acute SSRI indicating that SSRI occupy 5HTT
• Saarelainen et al (2003)
Found that trkB.T1 overexpressing mice (which show reduced trkB activation in the brain, as well as heterozygous BDNF null mice, are resistant to the effects of antidepressants in forced swim test. In western blotting found that acute and chronic antidepressant induced autophosphorylation and activation of trkB in cerebral cortex. Suggests that antidepressants acutely increase the trkB signalling in a BDNF dependant manner in cerebral cortex and that this signalling is required for the behavioural effects typical of anti-depressants
o Only look at one antidepressant
• Santarelli et al (2003)
Looked at mice with fluoxetine treatment, found antidepressant effects on behavioural novelty supressed feeding and that there as about a 60% increase in BrdU+/NeuN+ cells in the DG and the increase takes about 2-3 weeks. This is abolished in 5HT1A KO mice for both the neurogenesis and behavioural tests. Indicate that antidepressant drugs may stimulate adult hippocampal neurogenesis and explains the delayed onset of therapeutic effects.
o Not replicated in other strains of mice such as BALB/cJ (Holick et al 2008)
Chan et al (2015)
): Compared the hippocampal volume using fMRI between never depressed individuals with elevated risk (high neuroticism), recovered depressed match level of neuroticism and those with no history of depression and low neuroticism. Reduced hippocampal volume in the recovered group, but never depressed high risk group had increased volume, Reduced hippocampal volume may be a neural marker for the scar effect of depression or a vulnerability marker for the development and larger hippocampal volume may be associated with resistance
o Small sample size, and unable to look to see if medication was associated
• Covington et al (2010
Looked at the expression of IEGs zif268, c-fos and arc in the PFC of clincially depressed humans (postmortem) and found significant reductions, found that this was similar in the mPFC of mice with chronic social defeat stress and optogenetic activation of mPFC exerted potent antidepressant effects
• Chaudhury et al(2013):
Used optogenetics induction of phasic but not tonic firing in VTA DA neurons of mice undergoing a subthreshold social-defeat paradign rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference in previously resilient mice. Show that VTA-naC neurons but not VTA-mPFC induced susceptibility to social defeat stress. Optogenetic inhibition of VTA-NAc neurons induced resilience but to the mPFC promoted susceptibility suggesting a novel firing pattern and neural circuit specific mechanism for depression. Also suggest that the functional role for VTA-NAc pathway but not VTA-mPFC pathway in encoding reward related information in context of depression
• Autry et al (2011):
examined the acute effect of ketamine in wt mice and detectible notable behavioural responses in antidepressant predictive tasks, including forced swim tests, novelty suppressed feeding and learned helplessness however these fast acting effects were not observed in Bdnf-KO mice and in wt mice western blotting and ELISA showed a marked increase in BDNF at 30 mins after ketamine treatment. Indicated that Ketamine produces rapid acting antidepressant treatment that appears to be via BNDF (found this was due to decreased Eefk2 activity)
• Berman et al (2000):
7 subjects with major depression completed 2 tests days of ketamine hydrochloride or saline and subjects showed significant improvement in depressive symptoms within 72 hours after ket but not placebo infusion
o Very short term and very small sample size
