Neurobiology of Depression - Craviso

Question 1

What areas of the brain are involved in depression?

Answer 1

Those that are important in the regulation of mood, emotional expression, reward processing, attention, motivation, stress responses and neuro-vegetative function.

Question 2

List specific areas of the brain involved in depression.

Answer 2

1. hypothalamus
2. hippocampus
3. cingulate gyrus
4. amygdala
5. prefrontal cortex
6. ventral striatum
   Hypothalamus, cingulate gyrus, amygdala together make up the limbic system

Question 3

What types of technology have been used in research to identify areas of the brain that are abnormal with depression?

Answer 3

1. Positron emission tomography or PET scan - used to visualize activity-dependent changes in blood flow, tissue metabolism or biochemical activity
2. Magnetic resonance imaging or MRI - detailed spatial images of the brain at any location and orientation
3. post mortem analysis

Question 4

In research, what types of structural abnormalities of the brain have been found in those with depression?

Answer 4

1. reduced number of synapses and glial cells
2. reduced neuronal size
3. reduced gray matter volume in hippocampus, cingulate gyrus, prefrontal cortex and ventral striatum. may be reduced or increased in amygdala
4. reduced cell count and cell markers in the hippocampus, cingulate gyrus, prefrontal cortex, amygdala and ventral striatum

Question 5

What kinds of functional abnormalities in the brain have been found in those with depression?

Answer 5

1. PET images show increased blood flow to the amygdala and prefrontal cortex
2. increased metabolic activity in the anterior cingulate cortex and the rostral anterior cingulate cortex

Question 6

Increased metabolic activity in the rostral anterior cingulate cortex in depressed individuals can be used as a marker for what?

Answer 6

Can be used as a marker of prediction of how well an individual will respond to pharmacologic treatment.

Question 7

Initially, it was found that Reserpine and Iproniazid were drugs that affected depression. What were these drugs used for and how are they similar?

Answer 7

Reserpine was used to control hypertension and Iproniazid was used to treat tuberculosis. Reserpine induced depression and Iproniazid elevated mood. The basis for the effect on depression had to do with their MOA.

Question 8

Describe Reserpine.

Answer 8

1. an alkaloid derived from rauwolfia plant
2. inhibits vesicualr storage of biogenic amines (NE,D,5HT) resulting in their intraneuronal metabolism by monoamine oxidase
3. causes depletion of neuronal stores of biogenic amines which led to depression in some patients using it

Question 9

Describe Iproniazid.

Answer 9

1. inhibits intraneuronal monoamine oxidase

2. causes higher levels of biogenic amines causing some patients using it to have elevated moods

Question 10

What theory about depression came out of the studies of Reserpine and Iproniazid?

Answer 10

The monoamine hypothesis of depression - dysfunction of monoamine neurotransmitter systems that cause a deficit of biogenic amines (particularly NE and 5HT) causes depression.

Question 11

The monoamine hypothesis of depression is consistent with what?

Answer 11

The biogenic amines found to be correlated with depression are part of the neurotransmitter systems in key areas of the brain that regulate mood.

Question 12

What are some weaknesses of the monoamine hypothesis of depression?

Answer 12

1. depression includes a constellation of changes in addition to mood - such as sleep patterns, appetite and cognitive function. it is unrealistic to assume a single drug can restore balance among all the interacting neuronal networks involved
2. about 60-70% of patients resound in the short term to antidepressants and total remission of symptoms occurs in about 50% - but not all depressed patients
3. most clinically used antidepressants rapidly increase biogenic amine levels whereas the therapeutic effects are delayed by several weeks - antidepressant effects more likely due to adaptive changes in CNS that take time to develop

Question 13

What types of adaptive changes occur with treatment via antidepressants?

Answer 13

1. long term enhancement of monoamine neurotransmission including desensitization of auto receptors (increases release of the monoamine) and increased activity of certain post synaptic monoamine receptors
2. these changes are thought to contribute to the antidepressant effects

Question 14

What is another theory of the cause of depression?

Answer 14

The neurotrophic hypothesis - depression is associated with loss of neurotrophic support. Use of antidepressants actually increases neurogenesis and synaptic connectivity in cortical areas such as the hippocampus (site of neural plasticity).

Question 15

What findings support the neurotrophic hypothesis?

Answer 15

1. currently available antidepressants cause a slow increase in nerve growth factor expression (BDNF) that is critical in the regulation of neural plasticity, resilience and neurogenesis
2. evidence suggests that antidepressants are involved in long term adaptive changes that involve synaptogenesis
   * BDNF stands for brain derived neurotrophic factor *

Question 16

What other findings lend support to the neurotrophic hypothesis?

Answer 16

In the hippocampus:

1. there is atrophy of neurons in response to persistently elevated levels of cortisol
2. there is death of neurons with severe and prolonged stress leading to damage of the hippocampus
3. chronic stress decreases BDNF
4. it was found that glucocorticoids cause inhibition of BDNF in a depressed state that can be reversed in a treated state

Question 17

Based on the association between synaptogenesis and the neurotrophic hypothesis it is thought that a drug that could cause long term potentiation (increases synaptogenesis) can alleviate the symptoms of depression more quickly. What findings support this?

Answer 17

1. A single dose of an NMDA glutamate receptor antagonist called ketamine delivered via intravenous infusion alleviated depressive symptoms within hours
2. it also reduced suicidal ideation
3. ketamine was found to be effective for patients who failed to respond to two or more conventional antidepressants
4. found to be effective for treating bipolar disorder
5. effects of ketamine lasted for several days to a week

Question 18

What is a side effects of ketamine?

Answer 18

Causes dissociation.

Question 19

If ketamine is an NMDA receptor antagonist then how does it cause synaptogenesis?

Answer 19

The mechanism is not known but it is thought that it may rapidly and transiently increase glutamate neurotransmission possibly by inhibition of tonically active GABAergic interneurons leading to increased levels of BDNF and AMPA receptors causing LTP type effects.

Question 20

What are some drawbacks of ketamine?

Answer 20

1. has poor biovailability when taken orally
2. extent to which repeated infusion will be effective is not yet known
3. safety of repeated use is not yet determined
4. repeated use has the potential for abuse

Question 21

What is the new, prevailing theory about depression?

Answer 21

The new hypothesis is that depression is not caused by specific neurotransmitters. Mental disorders are thought to be circuit disorders and so it is now thought that synaptogeneis and neuroplasticity play a big role.

Question 22

What is a new type of therapy that may be available for treating refractory depression, OCD and Parkinson’s disease?

Answer 22

Deep brain stimulation - electric stimulation that quiets the overactive regions of the brain - alters excitability by affecting neural networks. Current therapies are invasive but new non-invasive therapies are being developed