Depression + Bipolar Disorder Extra Reading

Question 1

outline depression morphology?

Answer 1

atrophy of hippocampus, enlargement of amygdala
reduced signalling via monoamine transmitters, 5-HT and norepinephrine.

Question 2

what causes the morphological changes in depression?

Answer 2

increased GLUTAMATE release from hippocampus onto limbic system neurones, which causes long term structural changes in dendrites and synapses e.g reduced hippocampal neurogenesis

Question 3

what do current depression treatments do in neurones?

Answer 3

inhibit monoamine degradation/reuptake

Question 4

what was the first ever antidepressant?

Answer 4

lithium
1949 - John Cade
treated psychotic episodes in 70% of patients
remains effective in treating ‘mania’.

Question 5

what antimicrobial agent made to treat tuberculosis was a breakthrough within antidepressants?

Answer 5

Iproniazid
unexpected psychoactive effects
slowed breakdown of norepinephrine, serotonin and dopamine by inhibiting monoamine oxidase enzyme
founded family of MAO inhibitors still currently used

Question 6

what do tricylic antidepressants do an what is an example?

Answer 6

Imipramine induced euphoria - it is still used today
inhibits removal of norepinephrine and serotonin from synaptic terminals

Question 7

what is transient provoked depression?

Answer 7

e.g by grief
different to major depressive illnesses which persist without known provocation

Question 8

what are the 4 main depressive illnesses?

Answer 8

grief reaction
secondary depression (as result of neurological disease)
clinical (unipolar) depression
bipolar disorder

Question 9

outline what is meant by secondary depression?

Answer 9

associated with illnesses causing severe pain e.g cancer, stroke, Parkinsons
has potential to resolve spontaneously especially when the cause resolves

Question 10

how recurrent is depression for women

Answer 10

follows seasonal patterns (seasonal affective disorder) associated with fatigue, carbohydrate craving, weight gain and insomnia

Question 11

what is the concordance rate of bipolar in identical twins?

Answer 11

80%

Question 12

what are some cognitive symptoms of bipolar disorder?

Answer 12

impariments in episodic memory
reduced mental flexibility/attention
psychomotor slowing

Question 13

what is a major risk factor for depression?

Answer 13

endocrine changes resulting in increased cortisol e.g Cushing syndrome

Question 14

what can insufficient thyroid present with?

Answer 14

depressive symptoms
potentially caused by drugs e.g accutane or cannabis use

Question 15

what is the lifetime prevalence of depression?

Answer 15

20%

Question 16

what is the biggest concern associated with depression?

Answer 16

suicide

Question 17

how did we come to understand the neurobiology of depression?

Answer 17

inferring effects of antidepressants, human imaging and animal models

Question 18

what is the neurobiology of depression very generally?

Answer 18

region specific neuronal cell loss, with retraction of dendrites which causes persistent changes in synaptic activity
this leads to imbalances in pathways that regulate reward, affect and emotion

Question 19

which brain areas contain the neural circuits affected?

Answer 19

prefrontal cortex, hippocampus and limbic system (structures that control emotion, reward seeking, motivation and executive function)

Question 20

what are the important limbic structures in depression

Answer 20

ventral tegmental area (VTA)
nulcues accumbels
locus coreleus
thalamus
hippocampus
amygdala

Question 21

why is the amygdala associated with depression?

Answer 21

attaches emotional valence to experience, strong amygdala activation associated with sadness in both depressed and not depressed people .

Question 22

what do imaging studies of depressed poeople show in the amygdala?

Answer 22

those with chronic depression had sustained enhancement of amygdala activity
disrupting this with DBS reduced depression

Question 23

what are neuromodulators?

Answer 23

all monoamine transmitters providing emotional salience to processed information

Question 24

what is the monoamine hypothesis

Answer 24

drugs that enhance serotonin and noradrenaline concentrations by inhibiting removal = antidepressant effects
BUT drugs that reduce monoamine production INDUCE depression

Question 25

why is it too simplistic to call depression an imbalance of monoamines?

Answer 25

antidepressants change concentration of monoamine very quickly (mins) but the effects are slow (weeks) - drug persistently alerts connectivity in neural circuits that drive emotional valence and alter complex signalling cascades involved in structural and functional changes in the networks regulating emotions

Question 26

outline the cascade from that happens from blocking 5-HT re-uptake by SSRI’s

Answer 26

activation of G protein coupled receptor, leading to enhanced cAMP signalling, leads to transcriptional changes via cAMP-protein kinase A (PKA-cAMP) response element binding (CREB) pathway

Question 27

what does chronic use of SSRIs alter?

Answer 27

alters expression of transcription factor CREB and Ca2+ binding protein p11.
genes are transcribed including neurotropic factors like BDNF (neuronal survival/growth and plasticity)

Question 28

what are the structural changes associated with depression?

Answer 28

overall decrease of grey matter volume in PFC and hippocampus
postmortem shows size of pyramidal neurons is reduced and loss of GABAergic ingterneurons
loss of astrocytes and oligodendrocytes

Question 29

unlike the PFC, what structural changes does the amygdala show in depression (postmortem)?

Answer 29

increase in size of neuronal cell bodies with more complex dendritic branching
- this explains increased amygdala activity measured in fMRI.

Question 30

what is hippocampal theory in depression?

Answer 30

hippocampal atrophy in depression is not due to degeneration of existing neurons but loss of hippocampal neurogenesis and synaptogenesis
may explain cognitive impairment
stress hormones reduce neurotrophins and enhance hippocampal excitotoxicity

Question 31

what does current understanding of functional changes underlying depression come from?

Answer 31

investigating the mechanism of action of drugs for stabilising mood

Question 32

what can ketamine treat supposedly

Answer 32

treatment-resistant unipolar depression

Question 33

what is ketamine

Answer 33

an NMDA receptor antagonist
drug inducing a dissociative state - often abused
hallucogenic and anaesthetic effects - 60 min

Question 34

what is suggested about ketamine fro depression - how it works

Answer 34

ketamine enhances activity in prefrontal cortex and limbic structures (basal ganglia and thalamus)
hyperexcitable neurons in the lateral habenula - may be specific target of ketamine

Question 35

how does ketamine work at the cellular level?

Answer 35

binds to PCP site on NMDA receptor - increases GLUTAMATE levels in brain
parodoxical action - assuming low doses of ketamine preferentially blocks NMDAr on GABAergic interneurones
REDUCES their inhibitory control over PFC - INCREASES glutamate and activates NMDAr and AMPAr in PFC - causes long lasting structural changes in synapse

Question 36

what are macroscopic changes in depression

Answer 36

reduction in volume of PFC and hippocampus suggestive of neuronal atorphy
at neuronal level number of dendritic spines is reduced