DEPRESSION 2 - Substrates
OUR SOURCE: The discussion in Carlson. But it’s all over the map – and
changes significantly in the 11 edition. This is a fairly confusing field.
An ongoing problem with the field, partly because there isn’t a good animal model.
o What’s Known?
o A Model Based on Physiology
o What’s Known
o The Classic Del Gado Experiment
More Pieces to the Puzzle
Are Depression and Anxiety One Disease?
ANATOMY: Not Clear
THIS HAS LONG BEEN ONE OF THE PROBLEMS IN THE FIELD: IF YOU
DON’T KNOW WHERE TO LOOK, IT’S HARD TO FIND THE
1) Gross structural findings: cell loss cause or effect? Most likely effect. This
is different from schizophrenia where cell loss is the cause.
Effects of bipolar episodes: ventricles enlarge (not cause!)
Effects of depression: HPC smaller (a reliable finding)
o possible explanation: stress inhibits neurogenesis
What is neurogenesis?
It is the formation of new neurons. This particularly occurs in the HPC in the fascia
dentate in the sub-granular zone (area of hilus [stratrum polymorph] that
immediately borders stratum granulare). Stress inhibits neurogenesis. HPA axis
very active. Recall: HPA axis is very active in anxious patients as well. 2) Specific structural findings? Not very specific: cell loss all over the place
Abnormalities reported in PFC, BG, HPC, thalamus, cerebellum,
temporal lobes (all grey matter/cell bodies) - also less white matter
The parts that are affected are also so variable that none of them can
accurately identify a depressogenic zone
3) Other structural causes? Depression and the elderly
In the elderly, silent cerebral infarctions (small/silent strokes) are a
major cause of late onset depression – over 50%
Note: Carlson doesn’t mention brain damage or birth trauma – he doesn’t stress
structure in the Eleventh edition
4) 5 HTT (5-HT reuptake transporter) story (combines structure and function)
Individuals with either one or both of their 5 HTT alleles being short
(malfunctional) as opposed to long leads to a greater predisposition for
developing either depression or anxiety
o This doesn’t mean you have abnormal levels of 5-HT as an adult. Although
we would be thinking loss of 5HTT would mean decreased transporter activity
and increased levels of 5HT as an adult. But Carlson says this is not what
happens. He says you have odd levels of 5HT early in brain development and
the brain then becomes somewhat malformed as a result of the abnormal genes
As a result of this 5HTT mutation (short allele), your amygdala and
subgenual ACC (anterior cingulate cortex) are smaller than normal (see
o Not sure if they’re hyper- or hypoactive. Probably
HYPERFUNCTIONAL (just because smaller doesn’t mean they’re
Summary: Anatomical structures probably involved: amygdala, and ACC
Remember, the amygdala and ACC have also been implicated in (slow-
burning) pain and anxiety PHYSIOLOGY
Drevets (2001): amygdala and PFC (Dr. Burnham believes this is specifically the
anterior cingulate cortex – ACC) are overactive in people with depression
(PF = ACC? – Carlson involves a whole host of structures without specificity)
Amygdala: over-active in depressed patients (also in anxiety)
Remember connection to anxiety: co-morbidity is 70%
o There is also co-morbidity with slow pain
Subgenual ACC: underactive (?)
BUT MAYBERG: subgenual ACC overactive (she calls the area CG 25)
Perhaps they mean different parts of the ACC!
Note: Carlson calls the anterior association area the dorsal lateral prefrontal
In Carlson’s model, amygdala excites subgenual ACC, which in turn excites
the dorsal ACC. Excitation of the dorsal ACC inhibits the amygdala. This
enables an inhibitory feedback. Allows not to get too upset in normal people. ************************************
5) Carlson Model in Edition 10:
Built on the 5HTT story
He rejects the 5HTT story in Edition 11, but let’s take a look at the
model, which is actually not dependent on the 5HTT story
Dorsal and subgenual ACC are different parts of the ACC
You inherit one or two short alleles of 5HTT
Don’t get too much 5HT as an adult but do get abnormal pre-natal development
o This leads to a smaller amygdala (but probably hyperactive) and
What does this mean? Hyperactive?
Normally, subgenual ACC correlates with amygdala activation
Dorsal ACC negatively correlates (inhibitory feedback)
o Both of these correlations are less in people with short alleles. The
whole loop is hypoactive. Presumably, the amygdala is still activating
most of its sites, but not activating inhibitory feedback loop
Theory: a negative feedback loop: amygdaloid activity turns on subgenual ACC,
which turns on the dorsal ACC, which inhibits the amygdala
Remember Melazack (pain), Snead (absence patients)
People with short alleles have decreased functional connections across these
systems, resulting in imbalanced feedback, and therefore over-react to
o I.e., Amygdala can become overactivated but feedback inhibition
through the dorsal ACC might not bring activity back down to normal
o Relates to their under-developed amygdala and subgenual ACC?)
Note: Presumably, these folks would still have too few 5HTTs as adults – Carlson
doesn’t comment on that.
Compensation to normalize the system is also possible though. They
would’ve recovered as they had grown older and attained normal 5HT
levels, but their development would’ve been altered due to the initial excess
5-HT as a result of the 5HTT short alleles. What does this mean to the sufferer?
You over-respond to bad events, your amygdala over-reacts to sad photos, you’re
more likely to become depressed (also anxious), you’re less likely to respond to
treatment with antidepressants, you’re more likely to respond to tryptophan
depletion (tie-in to the Delgado story).
Query: Shouldn’t you also be more anxious?
Yes and anxiety is co-morbid with depression
NEUROCHEMISTRY OF DEPRESSION
1) Biogenic amine (monamine) theory (or theories) that often reflect drug
effects/results. Treat a patient with said drug, patient gets better and you then
deduce what the problem was in reference to what the drug does.
Reasoning back from drug actions is never very safe. Many of the