Depression Flashcards
(119 cards)
1
Q
What is depression generally described as
A
Depression is a heterogenous and episodic neuropsychiatric syndrome associated with various synaptic changes.
2
Q
What are the two fundamental diagnostic symptoms of depression
A
The fundamental symptoms for diagnosing depression are depressed mood and anhedonia.
3
Q
What types of associated symptoms are linked with depression besides fundamental ones
A
Depression is associated with emotional, neurovegetative, and neurocognitive symptoms.
4
Q
What determines the severity of depression
A
The severity of depression depends on the number of symptoms, their severity, and the degree of distress and interference with daily activities.
5
Q
What did the monoamine theory of depression suggest
A
The monoamine theory of depression suggested low levels of SE and NA were responsive for depressive symptoms.
6
Q
What is considered a first-line treatment for depression
A
SSRIs and TCAs are first line treatments for depression.
7
Q
How do SSRIs and TCAs increase monoaminergic function
A
SSRIs and TCAs increase monoaminergic function by preventing the reuptake of monoamines.
8
Q
What effect does blocking monoamine reuptake have on NT concentration
A
Blocking reuptake increases the concentration of NT in the synaptic cleft potentiating post-synaptic effects of monoamines.
9
Q
Give examples of SSRIs mentioned
A
Examples of SSRIs mentioned are Prozac and citalopram.
10
Q
Give an example of a TCA mentioned
A
An example of a tricyclic antidepressant mentioned is amitriptyline.
11
Q
What does the slow time course of SSRI effects suggest
A
The slow time course of action ~6 weeks suggests modulation of plasticity in neural circuits is taking place aimed at reversing the impact of stress.
12
Q
Is the pharmacological effect of SSRIs on reuptake immediate
A
Drugs like SSRIs have an immediate pharmacological effect on blocking reuptake or increasing synaptic NT concentration.
13
Q
Do SSRIs always lead to a rapid reduction in depressive symptoms
A
No the effect of SSRIs on depressive symptoms takes several weeks unlike drugs like ketamine or psilocybin.
14
Q
Are SSRIs effective for everyone with depression
A
No many people do not respond to SSRIs only partially respond or relapse during maintenance therapy.
15
Q
What interconnected brain sites are implicated in stress-mediated depression where plasticity should be explored
A
Interconnected sites implicated in stress-mediated depression include the medial Prefrontal Cortex (mPFC), the hippocampus, and the lateral habenula (LHb).
16
Q
What type of changes occur at the level of the synapse in mPFC in depression
A
In the mPFC there is a loss of synapses, decreased synaptic spines or growth, which may mediate symptoms.
17
Q
What type of change occurs in the LHb in depression instead of synaptic loss
A
In the LHb there is not a loss of synapses instead there is a burst firing of neurons.
18
Q
How do rapidly acting antidepressant drugs like ketamine and psilocybin relate to plasticity changes
A
Rapidly acting antidepressant drugs like ketamine and psilocybin potentiate the plasticity changes and act through different mechanisms.
19
Q
What is a key characteristic of all animal models of depression
A
All animal models of depression mentioned are stress-mediated depression models, involving long or short-term stress.
20
Q
What are the key characteristics of a good animal model for depression research
A
A good animal model must have Construct validity, Face validity, and Predictive or pharmacological validity.
21
Q
How is construct validity achieved in animal models of depression
A
Construct validity may be achieved through exposure of an animal to a well-validated environmental risk factor such as early life maternal separation, chronic corticosterone, Chronic uncontrolled stress (CUS), or social stress.
22
Q
What does face validity indicate in an animal model
A
Face validity indicates that a model recapitulates important anatomical, biochemical, neuropathological, or behavioural features of a human disease like neurogenesis, anhedonia, or poor grooming.
23
Q
Give an example of how anhedonia is measured in mouse models of depression
A
Anhedonia can be represented by a mouse choosing water over sucrose-water indicating a loss of sucrose preference.
24
Q
What does predictive or pharmacological validity signify
A
Predictive or pharmacological validity signifies that a model responds to treatments in a way that predicts the effects of those treatments in humans, such as symptoms being reversed by antidepressants.
25
Name some tests used to determine the efficacy of antidepressant drugs in animal models
Tests include the **Forced swim test** measuring swimming effort, **Novelty suppressed feeding** measuring latency to feed, and **Chronic mild stress** measuring grooming and sucrose preference.
26
What combination of factors might constitute a good animal model for depression
A good model might involve exposure to **long term CUS**, a decline in well-being indicated by **poor grooming and anhedonia**, and **reversal by antidepressant drugs**.
27
What symptoms are typically measured in rodents in depression models
Usually a subset of symptoms like **anhedonia, fatigue, motivation, and psychomotor behaviour** are measured in rodents.
28
Does neurogenesis continue in the adult brain
Yes **neurogenesis continues throughout life in the hippocampus** specifically within the dentate gyrus where new neurons are born throughout adulthood.
29
What is adult hippocampal neurogenesis
Adult Hippocampal Neurogenesis (AHN) is the **birth and incorporation of new neurons** into existing neural circuits in the hippocampus during adulthood.
30
What factors increase AHN
AHN increases after **Electroconvulsive shock, Exercise, Antidepressant treatment like SSRIs, and Environmental enrichment**.
31
What factors decrease AHN
AHN decreases after **Chronic stress in adult Ageing and Maternal separation**.
32
What conditions are associated with decreased hippocampal size
Hippocampal size decreases in **geriatric depression, major depressive disorder (MDD) and PTSD**.
33
How can AHN be ablated in mice
Ablation of AHN in adult mice can be achieved by **molecular means or by using X-radiation**.
34
What happens to the response to antidepressant treatment when AHN is knocked out in mice
Knocking out AHN in mice **abolishes response to antidepressant treatment** like SSRIs Imipramine and fluoxetine as measured by tests like latency to feed and coat score.
35
What does the abolition of antidepressant response after AHN knockout suggest
This suggests that the **efficacy of antidepressant treatment requires functional neurogenesis**.
36
How has the hypothesis about MDD shifted from monoamine deficiency
There is a shift towards a **neuroplasticity hypothesis of depression** where downstream effects of antidepressants such as increased adult hippocampal neurogenesis contribute to improvements in cognition and mood.
37
What might explain the delayed onset of antidepressant effects according to the neuroplasticity hypothesis
The delayed onset of antidepressant effects might possibly be explained by **downstream effects like increased adult hippocampal neurogenesis** contributing to mood improvements.
38
What structural change is observed in the Prefrontal Cortex of depressed patients
The **volume of the PFC is reduced** in depressed patients and this volume loss is correlated with the length of illness.
39
What imaging evidence suggests synaptic loss in depressed patients' PFC
PET scanning reports **decreased levels of ligand binding to synaptic vesicle glycoprotein 2A SV2A** in depressed patients indicating synaptic loss.
40
Is synaptic loss in the PFC supported by post-mortem analysis
Yes **synaptic loss is also seen in post-mortem analysis** of depressed patients.
41
What changes are observed in mPFC neurons in animal models of depression
In animal models of depression there is a **decrease in spine density and dendrite complexity** of medial PFC neurons.
42
What do these findings about the mPFC suggest about depression
These findings provide **good evidence that synaptic changes are occurring in the mPFC** of depressed patients.
43
What type of receptor antagonist is ketamine
Ketamine is a **non-competitive NMDAR antagonist**.
44
What are some dose-dependent effects of ketamine
Ketamine can act as a **general anaesthetic, hallucinogen, analgesic or antidepressant** depending on the dose.
45
How rapid is the antidepressant response to a single low dose of ketamine
A single low dose of ketamine produces a **rapid antidepressant response within hours** that lasts for up to 7 days.
46
What are the acute effects of subanaesthetic ketamine administration in humans
Acutely within about 1 hour subjects may experience **psychomimetic symptoms, perceptual aberrations, and cognitive impairments** although this is dose dependent.
47
What are the sustained effects of subanaesthetic ketamine administration in humans with depression
On a longer timescale about 2-4 hours subjects with major depressive episodes report **robust antidepressant effects** that remain for about 1 week.
48
What pathway does ketamine rapidly activate in the mPFC
Ketamine rapidly activates the **mTOR (mammalian target of rapamycin) pathway** in the mPFC.
49
What does the mTOR pathway control
The mTOR pathway is a **major controller of protein translation and growth**.
50
What does ketamine activation of the mTOR pathway lead to in rat mPFC
Activation leads to **increased production of synaptic signalling proteins** and **increased number and function of new spine synapses** in mPFC of rats.
51
Where do these structural changes from ketamine primarily occur
The changes are occurring at the level of the **dendritic spine** which is the site of excitatory transmission.
52
How does stress affect dendritic spines and excitability
Stress **reduces spine number and size** which reduces excitability.
53
How does ketamine affect dendritic spines and excitability via mTOR
Ketamine activates the mTOR pathway which rapidly **increases spine number and spine growth** and therefore **increases excitability**.
54
What substance can reverse the action of ketamine by blocking the mTOR pathway
The action of ketamine can be reversed with **rapamycin** which blocks the mTOR pathway.
55
How does blocking mTOR signalling with rapamycin affect ketamine induced behavioural recovery in depression models
Blockage of mTOR signalling with rapamycin **inhibits ketamine induced recovery of behavioural responses** in models of depression.
56
What in vitro evidence supports ketamine's effect through upregulating the mTOR pathway
In vitro experiments demonstrate that the ability of ketamine to induce dendritic spine growth **can be reversed with rapamycin** proving ketamine effects occur through upregulating the mTOR pathway.
57
What did Moda-Sava et al 2019 demonstrate about spine reformation after stress and ketamine
Moda-Sava et al 2019 demonstrated that spines eliminated by depression induced through corticosteroid intake **can be reformed following ketamine injection**.
58
How was spine growth tracked in the Moda-Sava et al 2019 study
Changes in spine growth could be specifically tracked using a **photoactivatable probe Rac1 and photon imaging** allowing observation from baseline through stress induced reduction to reformation after ketamine treatment.
59
What experimental evidence suggests that the formation of new spines by ketamine is responsible for antidepressant behaviour
Injecting a virus with a photoactivatable probe was able to **specifically target and ablate the dendritic spines formed by ketamine treatment** which resulted in a return of depressive symptoms.
60
What is the key signalling pathway for the growth of spines according to the ketamine evidence summary
The **mTOR pathway** is the key signalling pathway for the growth of spines.
61
What critical role does prefrontal spinogenesis play in antidepressant effects
Prefrontal spinogenesis plays a **critical role in sustaining specific antidepressant behavioural effects** and maintaining long-term behavioural remission.
62
Is prefrontal spinogenesis required for the initial induction of antidepressant effects
No prefrontal spinogenesis was required for the **long-term maintenance** of antidepressive effects on motivated escape behaviour **but not for their initial induction**.
63
How is depression like behaviour associated with postsynaptic dendritic spines on prefrontal projection neurons
Depression like behaviour was associated with **targeted branch-specific elimination of postsynaptic dendritic spines** on prefrontal projection neurons.
64
How does antidepressant dose ketamine affect the eliminated spines on prefrontal neurons
Antidepressant dose ketamine reversed these effects by **selectively rescuing eliminated spines**.
65
What is a potential problem with the hypothesis that ketamine directly affects excitatory neurons via NMDAR antagonism
Dendritic spines are growing even though ketamine an NMDAR antagonist **should make pyramidal output neurons less excitable**.
66
What alternative hypothesis is suggested for ketamine's action despite being an NMDAR antagonist
It is suggested that the target for ketamine is the **inhibitory interneuron** inactivating interneurons would release the pyramidal neuron from inhibition increase excitability and potentiate growth by activating mTOR.
67
Are there other possible mechanisms for ketamine's antidepressive effects besides NMDAR actions
Yes it has also been hypothesised that ketamine could mediate its antidepressive effects by **additional non-NMDAR targets**.
68
When does the Lateral Habenula LHb appear to be most active
The LHb appears to be most active when life **fails to meet our expectations**.
69
How is the LHb activity related to depression
The LHb region is often **hyperactive in people with depression**.
70
What does the LHb encode and inhibit
The LHb encodes for **negative RPEs (disappointment)** and inhibits the **dopaminergic neurons in the ventral tegmental pathway (anti-reward)** and the SE pathways.
71
How might the LHb pathologically mediate depression
The LHb may pathologically mediate depression by **turning off the mesodopamine pathway**.
72
What brain region projects to the LHb
The **mPFC projects to the LHb**.
73
How does activating the mPFC projection to the LHb affect motivated escape behaviour in mice
Activation of the mPFC projection to the LHb **reduces motivation to escape** in depressed mice.
74
What plastic changes occur in the LHb in depressive states
Depressive states are associated with **burst firing of LHb neurons** meaning the LHb becomes hyperactive.
75
How does ketamine reverse depressive states related to LHb activity
Ketamine reverses depressed states by **blocking NMDA receptors in LHb neurons** and reducing burst firing which **silences anti-reward signalling**.
76
What drives burst firing in the LHb
Burst firing in the LHb is driven by **NMDA receptors** and by an **upregulation of the astrocytic K+ channel Kir4.1**.
77
How does upregulated astrocytic Kir4.1 maintain burst firing
Over time astrocytic Kir4.1 channels are upregulated and **maintain burst firing by sucking up extracellular K+** leaving the neuronal membrane hyperpolarised.
78
What other brain region's deficits does ketamine reverse after stressful experience
Ketamine also **reverses deficits seen in mPFC** after stressful experience.
79
What is the LHb sometimes called
The LHb is sometimes called the **Disappointment Center**.
80
What might the burst firing in the LHb be a neural mechanism for
Burst firing in the LHb could be the neural mechanism underlying the **depressive-like state associated with social status loss**.
81
What experimental evidence supports the link between social status loss and LHb activity
Experimental evidence demonstrates the mouse brain responds to an unexpected loss of social status which is a major risk factor for depression in humans especially men.
82
How does forced loss of social status affect the LHb circuit in mice
Forced loss of status generates **negative RPE in LHb** activates the LHb circuit and induces **LHb burst firing**.
83
How does LHb burst firing affect the mPFC and subordination
LHb burst firing inhibits the mPFC and reinforces subordination probably through an action on VTA that relays to mPFC.
84
How did a dose of ketamine affect rodents who experienced social status loss
After a dose of ketamine the rodents mood improved and they **regained their previous social status** within their colony.
85
Is the action of ketamine generalized or localized in the brain
The action of ketamine is **localised to specific areas of the brain**.
86
What kind of channel blocker is ketamine and what does its action depend on
Ketamine is a **use-dependent channel blocker** meaning its action depends on the neuronal firing pattern and the number of NMDA receptors available.
87
Where does ketamine preferentially act due to its use-dependent property
Ketamine **preferentially acts in regions of high activity** for example specifically blocking NMDARs in LHb neurons which demonstrate burst firing.
88
Does ketamine inhibit hippocampal CA1 neurons in depressed mice
No ketamine **does not inhibit hippocampal CA1 neurons** in depressed mice.
89
Does the antidepressant effect of ketamine require the NR1 subunit
Yes the antidepressant effect of ketamine **requires the NR1 subunit in LHb**.
90
What neurotrophic factor does ketamine increase in the hippocampus
Chen et al found that ketamine increases levels of **brain-derived neurotrophic factor (BDNF)** in the hippocampus.
91
What is required for the ketamine induced increase in hippocampal BDNF
The ketamine induced increase in hippocampal BDNF requires **NMDAR function in LHb** and is regulated by serotonin.
92
How might psychedelics work
Psychedelics likely work by **dysregulating activity in systems and circuits that encode habits** of thought and behaviour allowing them to recalibrate.
93
What do neuroimaging measures like MEG and electrophotography reveal about brain activity under psychedelics
They reveal a **major loss of typical rhythmical activity** resulting in a state of extreme **desynchronisation or enhanced entropy**.
94
What happens to brain connectivity under psychedelics
Under psychedelics the brain escapes from its usual working leading to a **global increase in connectivity**.
95
What conditions might benefit therapeutically from psychedelic induced brain changes
These changes may lead to therapeutic changes in conditions such as **depression, addiction, and OCD** which are driven by dysfunctional brain processing.
96
What neurobiological pathways do serotonergic psychedelics modulate related to mood disorders
Serotonergic psychedelics modulate a range of **neurobiological pathways associated with mood disorders** and thus facilitate psychotherapeutic processes.
97
What evidence exists for the efficacy of serotonergic psychedelics in depression
**Randomized placebo-controlled trials** have shown serotonergic psychedelics to be effective at reducing **treatment-resistant depression**.
98
Where do serotonergic psychedelics mostly act
Serotonergic psychedelics mostly act at the **5-HT2a-Rs** and increase mood scores.
99
Name some psychedelic drugs mentioned
Psychedelics mentioned include **psilocybin (magic mushrooms) DMT (ayahuasca), and LSD**.
100
What type of drug is psilocybin
Psilocybin is a **serotonergic psychedelic**.
101
How is psilocybin typically administered in therapy
Psilocybin is typically given **1-3 times with psychotherapy**.
102
What is the relapse rate for some patients after psilocybin therapy
Some patients have long term benefit but **half relapse in 6 months**.
103
What receptor does psilocybin primarily act as an agonist on
Psilocybin is an **agonist at the 5-HT2a receptor** which is highly expressed in cortical layer 5 pyramidal neurons.
104
What kind of neuroplasticity do psychedelics promote
Psychedelics promote **structural and functional neuroplasticity** including neurogenesis, spinogenesis, and synaptogenesis.
105
What structural change in the frontal cortex does psilocybin induce in mice studies
Psilocybin induces **rapid and persistent growth of dendritic spines** in the frontal cortex.
106
How does psilocybin affect spine density and size in frontal cortical pyramidal cells
Psilocybin **increases spine density and spine size** in frontal cortical pyramidal cells.
107
Does psilocybin affect stress-related behaviour deficits in mice
Yes psilocybin **ameliorates stress-related behaviour deficit** in mice.
108
How persistent is the structural remodelling evoked by psilocybin in mice
The structural remodelling evoked by psilocybin is **persistent for at least 1 month**.
109
What accompanies the dendritic rewiring caused by psychedelics
The dendritic rewiring is accompanied by **elevated excitatory neurotransmission** and leads to **long lasting modifications to the neural architecture** in mice.
110
What pathways are known to underlie psychedelic induced plasticity
**mTOR and 5-HT2A signalling** are known to underlie psychedelic-induced plasticity.
111
What other factors are suggested to have a role in psychedelic plasticity effects
It is now suggested that **BDNF and TrKB**- the BDNF receptor- have a role in its plasticity effects.
112
What did Casarotoo et al 2021 suggest about the mechanism of action for all antidepressants
Casarotoo et al 2021 suggested that all antidepressants **act by directly binding to the TrKB neurotrophin receptor**.
113
What types of antidepressants were found to bind directly to TrKB
Several antidepressants including **psychedelics, SSRIs, and ketamine** directly bind to TrKB.
114
How does antidepressant binding to TrKB affect BDNF signalling
Antidepressants bind to TrKB and **allosterically increase BDNF signalling** thereby directly linking their effects to neuronal plasticity.
115
How do psychedelics specifically act at TrKB
Psychedelics act **allosterically by facilitating the effects of endogenous BDNF release** in active synapses.
116
What is a suggestion about how different antidepressants achieve robust effects
It is suggested that these antidepressants **work in different ways in different parts of the brain** and their collective effects underlie their robust antidepressant effects.
117
What plastic change occurs in the Hippocampus related to antidepressant effects
In the hippocampus there is **neurogenesis induced by an increase in BDNF**.
118
What plastic change occurs in the mPFC related to ketamine and psilocybin
In the mPFC there is **ketamine or psilocybin induced spine growth** which increases excitability.
119
What effect does ketamine have on the LHb
Ketamine **inhibits burst firing** in the LHb.
