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PHAR0003 > Depression > Flashcards

Depression Flashcards

1
Q

Why are depression & anxiety thought to be highly linked?

A

Both involve -ve emotional states
Have largely overlapping circuits
Share genetic & environmental risk factors
60% comorbidity
Anxiety commonly precedes depression onset

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2
Q

What is the physiological evidence for stress as a factor of depression?

A

Stress hormones elevated in depression: Cortisol, corticotrophin-releasing hormone (CRH), adreno-corticotrophic hormone (ACTH)

Cortisol inhibits CRH & ACTH secretion (natural feedback mechanism) - this system is impaired in ~50% depression patients

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3
Q

What are the brain regions involved in depression?

A

Anterior cingulate cortex
Hippocampus & amygdala
Nucleus accumbens
Hypothalamic-pituitary-adrenal (HPA) axis

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4
Q

How is the anterior cingulate cortex involved in depression?

A

ROSTRAL anterior cingulate cortex most linked with depression - role in emotion & large connectivity with hippocampus, amygdala & PFC

Increased activity of the SUBGENUAL REGION correlates with depression, decreased activity correlates with treatment success

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5
Q

How are the hippocampus & amygdala involved in depression?

A

Patients with depression often have simultaneously:
- Increased amygdala volume & activity - involved in fear learning & Pavlovian conditioning
- Decreased hippocampal volume & activity - centre for learning & memory

Suggesting that there is an imbalance between the functioning of the amygdala & hippocampus

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6
Q

Dysfunction of the nucleus accumbens in depression is thought to contribute to which symptom?

A

State of anhedonia

(NAc = ‘reward centre’ of the brain)

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7
Q

How is the hypothalamic-pituitary-adrenal (HPA) axis involved in depression?

A

Regions that control CRH & ACTH feedback - involved in both acute & chronic stress response
Feedback loop impaired & inc CRH & ACTH in depression

Amygdala & hippocampus have opposite effects on this circuit

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8
Q

What are the 3 different types of antidepressants?

A

Monoamine oxidase inhibitors
Tricyclic antidepressants
Selective serotonin reuptake inhibitors (SSRIs)

*None of these treatments are very effective & are very vague & non selective

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9
Q

What are the 3 hypotheses of depression?

A

Monoamine hypothesis
Neurotrophin hypothesis
Excitatory synapse hypothesis

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10
Q

What is the monoamine hypothesis? (Aka. Serotonin hypothesis)

A

Prediction: increase serotonin (monoamine) in brain should relieve depression - led to development of SSRIs

Serotonin is released from neurones originating in the dorsal raphe nucleus which project to many brain regions involved in depression: hippocampus, amygdala, anterior cingulate cortex, nucleus accumbens

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11
Q

What is the problem with the monoamine hypothesis?

A

Fails to offer mechanistic explanation

Only vague evidence that serotonin levels (or its metabolites) correlate with depression - i.e., comparing blood from someone with and someone without depression - no difference in 5-HT levels

Takes weeks to exert effect - appears not to be direct

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12
Q

What is the evidence for the excitatory synapse hypothesis?

A

Chronic stress inhibits excitatory synapse transmission and plasticity in the cortex, NAc & hippocampus

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13
Q

What is the relationship between the excitatory synapse hypothesis and the other 2 hypotheses?

A

5-HT & neurotrophin both generally increase excitatory transmission and plasticity in cortex, NAc & hippocampus - could they be working indirectly by modifying excitatory synaptic connectivity?

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14
Q

What are the (3) formal statements for the excitatory synapse hypothesis?

A
  1. Depression is caused by a weakening of specific subsets of excitatory synapses in multiple brain regions associated with affect & reward
  2. Restoration of excitatory synapse strength should help depressive behaviour and is the crucial action of ADs, inc. classical treatments such as SSRIs & ECT
  3. Targeted changes in excitatory transmission should be quicker & more effective than current treatments
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15
Q

What are neurotrophins?

A

They are types of growths factors (proteins) which induce survival, development & function of neurones. They can signal particular cells to survive, differentiate & grow.

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16
Q

Reduced neurotrophin signalling can result in…

A

Impaired neurogenesis
Dendritic atrophy
Impaired plasticity

17
Q

Which neurotrophin has lots of evidence to support its role in depression?

A

BDNF

18
Q

What is the evidence to support the role of BDNF (neurotrophin) in depression?

A

Reduced BDNF in blood of depressed patients (compared to no difference in 5-HT levels). This is normalised after AD treatment.

Polymorphism in BDNF gene (Val66Met) associated with depression, dec hippocampal volume & suicide.

BDNF & TrkB mRNA reduced in post-mortem brains of suicide victims.

19
Q

How does the neurotrophin hypothesis provide a mechanism which accounts for the decreased hippocampal volume in depressed patients?

A

Reduced neurotrophin signalling can result in:
Impaired neurogenesis
Dendritic atrophy
Impaired plasticity

Observed mostly in hippocampus

20
Q

What is the experimental evidence for the neurotrophin hypothesis?

A

Experiment:

Hypothesis
- Impairing BDNF signalling should produce depression phenotype

Results
- BDNF knockout mice have smaller hippocampus + depression phenotype.
- BDNF knockout mice show impaired responses to ADs

21
Q

What are the problems with the neurotrophin hypothesis?

A

BDNF is crucial for circuit development

BDNF has different effects depending on circuit acting on - i.e., in PFC & hippocampus - promotes stress resilience, but in NAc - promotes susceptibility

Hypothesis INCOMPLETE - there is no mechanism linking ADs to changes in levels of BDNF / TrkB so there is no explanation to how SSRIs activate this pathway

22
Q

How is depression distinguished from normal sadness / grief?

A

Severity, pervasiveness, duration of symptoms

Psychological / behavioural symptoms:
Insomnia / sleep disturbance, loss of appetite / weight loss, decreased energy.

Cognitive symptoms:
Hopelessness, suicidal thoughts, lack of concentration, poor memory.

23
Q

What is the influence of genetic factors on depression?

A

Runs in families, similar to SCZ - spread inconsistent with simple Mendelian genetics (i.e., not a single gene)
Quantified by the recurrent risk ratio - inc risk with sibling / twin with depression - but lower genetic risk than SCZ

Promising genetic factor: mutation in the BDNF gene Val66Met

24
Q

[Mouse Experiment]
Are specific subsets of excitatory synapses in multiple brain regions weakened in models of depression?

A

Subjecting mice to chronic restraint stress / chronic unpredictable mild stress / social isolation leads to anhedonia - shown by loss of sucrose preference + other indicative behaviours

Chronic restraint stress - dec NAc excitatory connectivity - shown by change in AMPA:NMDA ratio (lower) - fewer AMPA receptors & ‘weaker synapses’

Overall - stress seems to weaken specific important excitatory connections

25
Q

[Mouse experiment]
Does blocking AMPA receptor removal rescue depressive behaviour?

A

Blocking via synthetic G2CT peptide - blocks binding site on receptor for trafficking molecule

Expressive G2CT in NAc blocks stress behaviour - suggesting that weakening of synapses is needed for stress-induced depressive behaviour

Shown experimentally by loss of anhedonia symptoms in mice

26
Q

Do classical ADs (i.e., SSRIs) have their effects via excitatory synapses?

A

SSRIs potentiate excitatory hippocampal synapses

SSRI induced potentiation can be blocked by mutation in GluA1 AMPA receptor - suggesting AD effects of SSRIs is due to interaction with excitatory synapses

27
Q

Are targeted changes in excitatory transmission quicker & more effective than current treatments?

A

NMDA receptor antagonists - e.g., Ketamine
Shown to have rapid, robust & sustained AD effects in both rodents & humans

28
Q

What are the 2 phases of action of microdosing ketamine for depression?

A
  1. Induction (1-2hr) - ketamine present @ sufficient levels to block NMDA receptors
  2. Expression (1-2 weeks) - no drug present - suggesting it is causing a change which gives a longer-term solution:
    - large increases in excitation cause plasticity
29
Q

What are the 2 hypotheses of action of ketamine on depression?

A

Preferential action on interneurones = results in NMDAR block of only inhibitory neurones - overall excitation

Relief of ongoing, spontaneous NMDAR activation - which normally suppresses plasticity mechanisms - disinhibition of this via ket inc excitation

No NMDAR dependent activation & potentiation of AMPARs through ketamine metabolites

30
Q

What are potential therapies in line with the excitatory synapse hypothesis?

A

Direct +ve allosteric modulators of AMPARs
- LY292098 has AD effects in mice, undergoing human trials

Deep brain stimulation (DBS)
- already some success with NAc stimulation in depressed humans

ECT
- 100Hz for 20s
- ECT in rats shown to cause marked LTP

(But relatively new idea - need more experiments, relies on correlation rather than causation)

PHAR0003 (14 decks)

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