Week 9 Flashcards
Irisin fall, redemption
* Non-canonical** (** not **)
* Possibly a **
* Non-detectable levels of **
* Issues with **
* Not **
* Used ** to detect actual proteins
* Showed ** following ** as expected
* “Cheated” a bit by ** samples and removed ** and **
Irisin fall, redemption
* Non-canonical start codon (ATA not ATG)
* Possibly a pseudo-gene
* Non-detectable levels of protein
* Issues with antibody-based detection
* Not reproducible in everyone’s hands
* Used tandem-mass spectroscopy to detect actual proteins
* Showed elevation following exercise as expected
* “Cheated” a bit by using de-glycosylated samples and removed IgGs and albumins
Hedges’ g – population statistics
* Interesting phenomenon reported for **and **
* Hedges’ g is a statistical measure of **
Hedges’ g – population statistics
* Interesting phenomenon reported for ADMs in depression and usage in bipolar disorder
* Hedges’ g is a statistical measure of effect
size and this graph shows that the value is
decreasing with increased usage
- Why our studies are messed up now
* Best studied effects of placebo effects are on **, **, ** and others
* Kirsch and Saperstein, 1998 report that there is a significant placebo effect when ** (almost
as effective as medication itself)
* Evidence of significant and increasing rates of placebo responses in published trials of new anti-depressant medication
(Hedges’ g) - Factors mediating Placebo
* Principal mechanisms underlying the placebo involve ** (**, ** and **
- Why our studies are messed up now
* Best studied effects of placebo effects are on psychiatric disorders, analgesia, Parkinson’s Disease and others
* Kirsch and Saperstein, 1998 report that there is a significant placebo effect when using anti-depressant medication (almost
as effective as medication itself)
* Evidence of significant and increasing rates of placebo responses in published trials of new anti-depressant medication
(Hedges’ g) - Factors mediating Placebo
* Principal mechanisms underlying the placebo involve expectancy (patient perceives benefit), behavioural conditioning and patient-physician interactions
Brain structures and placebo
* can inhibit pain signals by activating the ** – the **
* Placebo effects driven by this pathway can be blocked by (** or **)
* ** also blocks these effects (so ** levels are important considerations in the placebo effect)
Brain structures and placebo
* Dorsolateral prefrontal cortex (DLPFC) can inhibit pain signals by activating the opioidergic system – the descending pain
pathway
* Placebo effects driven by this pathway can be blocked by giving an opioid receptor antagonist (naloxone or naltrexone)
* CCK also blocks these effects (so D2/D3/CCK levels are important considerations in the placebo effect)
Are some people better responders?
* Is there some biomarker or bio-signature for someone who would be more responsive to placebos? Allow for better controls on clinical trials and for drug responsiveness? **
* Genetic variants of ** have been shown to be better placebo responders
* ** gene promoter region has **
* ** made you a better clinical responder to placebos
* Same for long variant of the ** promoter
Are some people better responders?
* Is there some biomarker or bio-signature for someone who would be more responsive to placebos? Allow for better controls on clinical trials and for drug responsiveness? SNPs
* Genetic variants of serotonin have been shown to be better placebo responders
* Tryptophan-hydoxylase 2 (TPH-2) gene promoter region has polymorphisms G703T variant
* Homozygous for the G703 variant made you a better clinical responder to placebos
* Same for long variant of the 5-HTPLLR promoter
More genetic markers
* Individuals with higher ** (G) had ** placebo responses that were correlated with **
* **() polymorphisms (V158M) that produced ** (** alleles) also
had ** placebo responses (remember COMT breaks down **….)
* How the genetic markers for systems involved in social anxiety and major depressive disorders are involved in placebo
responses remains to be seen
More genetic markers
* Individuals with higher MAO-A activity (G/T polymorphisms) had lower placebo responses that were correlated with GG
polymorphisms
* Catechol-O-methyltransferase (COMT) polymorphisms (V158M) that produced lower COMT activity (M/M alleles) also
had higher placebo responses (remember COMT breaks down dopamine….)
* How the genetic markers for systems involved in social anxiety and major depressive disorders are involved in placebo
responses remains to be seen
- Does Placebo always work – NO
* Regions in the ** are affected in various neurodegenerative conditions including
**
* AD patients that had marked reductions in **Tests also showed a ** effect when the researchers followed up with the AD patients after one year (Benedetti et al., 2006)
* This was the first study to show that ** - Other disruptions
* ** blocks the ** pathway in pain control in the **
* Also can block these pathways in a non-pharmacologic fashion using ** (or **)
* Placebo induced **, ** and **were completely blocked by **
- Does Placebo always work – NO
* Regions in the dorsolateral prefrontal cortex (DLPFC) are affected in various neurodegenerative conditions including
Alzheimer’s Disease (AD)
* AD patients that had marked reductions in Frontal Assessment Battery (FAB) Tests also showed a reduced placebo analgesic effect when the researchers followed up with the AD patients after one year (Benedetti et al., 2006)
* This was the first study to show that lack of prefrontal control affected placebo analgesia - Other disruptions
* Naloxone blocks the opioidergic pathway in pain control in the prefrontal cortex
* Also can block these pathways in a non-pharmacologic fashion using rTMS (or transcranial magnetic stimulation)
* Placebo induced analgesia, pain tolerance and pain thresholds were completely blocked by rTMS
