Depression Flashcards
Why are depression & anxiety thought to be highly linked?
Both involve -ve emotional states
Have largely overlapping circuits
Share genetic & environmental risk factors
60% comorbidity
Anxiety commonly precedes depression onset
What is the physiological evidence for stress as a factor of depression?
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
What are the brain regions involved in depression?
Anterior cingulate cortex
Hippocampus & amygdala
Nucleus accumbens
Hypothalamic-pituitary-adrenal (HPA) axis
How is the anterior cingulate cortex involved in depression?
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
How are the hippocampus & amygdala involved in depression?
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
Dysfunction of the nucleus accumbens in depression is thought to contribute to which symptom?
State of anhedonia
(NAc = ‘reward centre’ of the brain)
How is the hypothalamic-pituitary-adrenal (HPA) axis involved in depression?
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
What are the 3 different types of antidepressants?
Monoamine oxidase inhibitors
Tricyclic antidepressants
Selective serotonin reuptake inhibitors (SSRIs)
*None of these treatments are very effective & are very vague & non selective
What are the 3 hypotheses of depression?
Monoamine hypothesis
Neurotrophin hypothesis
Excitatory synapse hypothesis
What is the monoamine hypothesis? (Aka. Serotonin hypothesis)
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
What is the problem with the monoamine hypothesis?
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
What is the evidence for the excitatory synapse hypothesis?
Chronic stress inhibits excitatory synapse transmission and plasticity in the cortex, NAc & hippocampus
What is the relationship between the excitatory synapse hypothesis and the other 2 hypotheses?
5-HT & neurotrophin both generally increase excitatory transmission and plasticity in cortex, NAc & hippocampus - could they be working indirectly by modifying excitatory synaptic connectivity?
What are the (3) formal statements for the excitatory synapse hypothesis?
- Depression is caused by a weakening of specific subsets of excitatory synapses in multiple brain regions associated with affect & reward
- Restoration of excitatory synapse strength should help depressive behaviour and is the crucial action of ADs, inc. classical treatments such as SSRIs & ECT
- Targeted changes in excitatory transmission should be quicker & more effective than current treatments
What are neurotrophins?
They are types of growths factors (proteins) which induce survival, development & function of neurones. They can signal particular cells to survive, differentiate & grow.
Reduced neurotrophin signalling can result in…
Impaired neurogenesis
Dendritic atrophy
Impaired plasticity
Which neurotrophin has lots of evidence to support its role in depression?
BDNF
What is the evidence to support the role of BDNF (neurotrophin) in depression?
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.
How does the neurotrophin hypothesis provide a mechanism which accounts for the decreased hippocampal volume in depressed patients?
Reduced neurotrophin signalling can result in:
Impaired neurogenesis
Dendritic atrophy
Impaired plasticity
Observed mostly in hippocampus
What is the experimental evidence for the neurotrophin hypothesis?
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
What are the problems with the neurotrophin hypothesis?
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
How is depression distinguished from normal sadness / grief?
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.
What is the influence of genetic factors on depression?
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
[Mouse Experiment]
Are specific subsets of excitatory synapses in multiple brain regions weakened in models of depression?
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
[Mouse experiment]
Does blocking AMPA receptor removal rescue depressive behaviour?
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
Do classical ADs (i.e., SSRIs) have their effects via excitatory synapses?
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
Are targeted changes in excitatory transmission quicker & more effective than current treatments?
NMDA receptor antagonists - e.g., Ketamine
Shown to have rapid, robust & sustained AD effects in both rodents & humans
What are the 2 phases of action of microdosing ketamine for depression?
- Induction (1-2hr) - ketamine present @ sufficient levels to block NMDA receptors
- 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
What are the 2 hypotheses of action of ketamine on depression?
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
What are potential therapies in line with the excitatory synapse hypothesis?
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)
