Craviso: Neurobiology of Depression

Question 1

Areas of the brain involved in regulation of mood, emotional expression, reward processing, attention, motivation, stress responses, etc

Answer 1

hypothalamus
hippocampus
cingulate gyrus
amygdala
prefrontal cortex
ventral striatum

Question 2

What are TWO ways to look at structural and functional abnormalities in depression?

Answer 2

1. PET scan - visualize activity-dependent changes in blood flow, tissue metabolism, or biochemical activity
2. MRI

Question 3

In a depressed patient, what happens to these areas of the brain?

hippocampus
cingulate gyrus
amygdala
prefrontal cortex
ventral striatum

Answer 3

decrease in gray matter volume, cell counts, and cell markers

Question 4

What happens to the following in depressed patients?

number of synapses?
number of glial cells?
neuronal size?

Answer 4

all decreased :(

Question 5

PET images show increased blood flow in depressed patients. What areas of the brain receive increased blood flow?

Answer 5

orbital and medial prefrontal cortex
amygdala
mediodorsal nucleus of the thalamus

Question 6

one of the regions where increased metabolism correlates positively with depression severity

Answer 6

anterior cingulate cortex

Question 7

This area of the brain is more active in major depression; activity returns to normal when treated with antidepressants

Answer 7

anterior cingulate cortex

Question 8

In the 1950’s, how did reserpine and iproniazid lead to the view of depression as a deficit of biogenic monoamines (NE and 5HT)?

Answer 8

reserpine was used for HTN and induced depression in a number of patients - it inhibited the vesicular storage of biogenic amines so that they were more prone to degradation by MAO

iproniazid was used to treat TB and had a significant mood-elevating effect - it inhibited MAO leading to higher levels of biogenic amines

Question 9

What is the monoamine hypothesis of depression?

Answer 9

lower levels of monoamines, or dysfunction in the monoamine NT system in general leads to depression

Question 10

What percentage of pts respond in short-term to antidepressants?

Answer 10

60-70%

Question 11

Why is the monoamine hypothesis of depression overly simplistic?

Answer 11

depression involves a lot of changes - it is unrealistic to assume that a single drug restores balance to all the interacting neuronal networks involved

some patients don’t respond to antidepressants

while most antidepressants rapidly increase NT levels, the therapeutic effects are delayed by several weeks

Question 12

Most clinically used antidepressant drugs rapidly increase biogenic amine levels whereas therapeutic effects are delayed by several weeks. What does this suggest?

Answer 12

This suggests that antidepressant effects are more likely due to adaptive changes in the CNS that take time to develop

Question 13

What is one adaptive change that occurs over time with use of antidepressants?

Answer 13

long-term enhancement of monoamine neurotransmitters;
desensitization of autoreceptors on monoamine nerve terminals leads to increased release of the monoamine;
increased activity of certain post-synaptic monoamine receptors

Question 14

Proposes that depression is associated with the loss of neurotrophic support;
effective antidepressant therapies increase neurogenesis and synaptic connectivity in cortical areas such as the hippocampus (neural plasticity/changes in neural network connectivity)

Answer 14

neurotrophic hypothesis

Question 15

Antidepressant drugs cause a slow increase in (blank), which is critical in regulation of neural plasticity, resilience, and neurogenesis. This suggests that long-term adaptive changes involve (blank)

Answer 15

nerve growth factor (brain derived neurotrophic factor); synaptogenesis

Question 16

So, explain how antidepressants are thought to work.

Answer 16

In addition to increasing the amount of NT present, they also increase neurotrophic changes in the brain, allowing for new synapses to form and for old synaptic connections to remodel and become stronger

Question 17

What does chronic stress do to neurons in the hippocampus? What does chronic stress do to brain derived neurotrophic factor?

Answer 17

chronic stress causes atrophy of neurons due to persistently high cortisol; neurons die and this damages the hippocampus; chronic stress also decreases BDNF

Question 18

So, in chronic stress, glucocorticoids like cortisol cause decreased (blank) as well as changes in dendrite structure

Answer 18

brain derived neurotrophic factor (BDNF)

Question 19

Can depression be alleviated faster if drugs can be found that promote “rapid” synaptogenesis (quickly alter neural networks)?

Answer 19

Yes!

Question 20

What drug, when given via IV infusion, can alleviate depressive symptoms and suicidal ideation within hours?

Answer 20

ketamine

**ketamine is also effective for bipolar disorder

Question 21

How does ketamine work?

Answer 21

it is an NMDA receptor antagonist which binds inside the ion channel to block activation of NMDA receptors

Question 22

What is ketamine thought to promote?? (this is a controversial topic, you don’t need to know the mechanism)

Answer 22

synaptogenesis

**hard to understand that a drug that blocks NMDA receptors can cause increased synapses

Question 23

T/F: Ketamine is a promising antidepressant which can be used in the future.

Answer 23

True

**the extent to which repeated infusions will be effective is not yet known
the safety of repeated use has yet to be determined
repeated use has the potential for abuse

Question 24

Mental disorders should be treated more like circuit disorders. What does this mean?

Answer 24

less focus on specific neurotransmitters, more focus on promoting synaptogenesis and neuroplasticity

Question 25

This is a non-pharmacological treatment which can be used for relief of unremitting depression

Answer 25

deep brain stimulation

Question 26

Electric stimulation “quiets” the overactive region – alters excitability by affecting neural networks (synaptogenesis/neural plasticity)

Answer 26

deep brain stimulation

Question 27

DBS is approved by the FDA to treat severe (blank)

Answer 27

OCD