Mood Disorders (part 1, 2 and 3)

Question 1

Describe the current diagnosis of a depressive illness

Answer 1

At least 2 of:
Depressed mood, anhedonia, anergia, fatigue, diminished activity

At least 3 of:
Reduced concentration, low self esteem and confidence, guilt and unworthiness, pessimism, ideas or acts of self harm, reduced sleep, anorexia

FOR 2 WEEKS (minimum)

Question 2

Describe the clinical course of depression

Answer 2

Uncomplicated moderate episode; 4-6 months
54% recovered at 26 weeks
>85% have further episodes
4-10% die from suicide
Around 5-10% will eventually have a manic episode = bipolar

Question 3

How is the severity of depression quantified?

Answer 3

Rating scales;
Beck Depression Inventory
17-item Hamilton
MADRS

Question 4

Is CBT effective in depression?

Answer 4

Yes; but only mild illness

Not mod/severe as seen in secondary care

Question 5

In terms of depression; what is a failed adequate trial?

Answer 5

Adequate trial of antidepressant:
Prescription of a specific antidepressant above a specific minimum dose for a minimum of 6 weeks with reasonable certainty of compliance

Question 6

How is treatment resistance depression quantified?

Answer 6

Number of failed adequate trials of antidepressants

Rating scales used: MGH-S, ATHF

Question 7

In terms of evolutionary concepts; what are the links with depressive illness?

Answer 7

To identify stimuli predicting appetitive or aversive consequences

Generate behavioural and physiological (autonomic and endocrine) responses, and social communications (emotions, cognition) in response to a stimuli

Coordinate and optimise responses and communications to maximise chances of survival

Question 8

Describe the 5 main domains of established brain systems?

Answer 8

Negative valence; fear, anxiety, loss, non-reward

Positive valence; reward learning, valuation, habits

Cognitive; attention, memory, cognitive control

Social system; attachment, communication, perception self/ others

Arousal/ modulatory; circadian rhythm, sleep/wake cycle

Question 9

Describe the neural circuits involved with the positive valence system (appetitive system)

Answer 9

Ascending dopaminergic; mesolimbic/cortical
Endogenous opioid system (mu)
Ventral striatum/ N. Acc
Dorsal striatum (movement)
Amygdala (conditioning/ learning)
Anterior cingulate (attention/ conflict/ response selection)
OFC (relative reward preference/ rule learning)

Question 10

Describe the neural circuits involved with the negative valence system (aversive system)

Answer 10

Endogenous opioid (kappa) 
Ascending 5-HT 
NA/ CRF/ peptide transmitters 
Central nucleus of amygdala
Hippocampus 
VA and medial hypothalamus
PAG

Question 11

Describe a depressive illness in terms of a disordered appetitive functioning

Answer 11

Difficulty identifiying rewarding stimuli
Reduced contact with previously rewarding stimuli
Increased contact with aversive stimuli
Overall reduction in behaviour
Move less, eat less, lose weight, decreased libido

Low mood

Question 12

Describe a manic episode in terms of a disordered appetitive functioning

Answer 12

Previously neutral stimuli become rewarding
Increased exploration/ overall activity
Increased appetite for food, activity, sex etc
Intolerant of aversion/ boredom
Intolerant of frustration

Elated mood

Question 13

Is there a link between anxiety and mood?

Answer 13

Yes; study has shown with an increased severity of mood disorder (MADRS) in MDD, OCD, BAD there is positive correlation with anxiety severity rating

Question 14

Is there a link between cognitive impairment and MDD?

Answer 14

Yes
Unmedicated patients with depression; impaired in cognitive function (attention, executive function, visuospatial learning and memory)
Severity of depression correlated with impairment of learning and memory

Question 15

Is the hippocampus implicated in MDD?

Answer 15

Yes
Study (sheline et al) showed a significant volume reduction in hippocampi between depressed subjects and matched controls (degree of reduction correlated with total duration of MDD)

ENIGMA data; robust reduction in hippocampal volume in MDD patients

Reduction in glial cells predominantly

Question 16

Are the hippocampal neurons affected in MDD

Answer 16

Yes; stress and corticosteroids induce dendritic shrinkage

Repeated stress results in atrophy of the dendrites in the CA3 region of the hippocampus

Question 17

Describe the role of the amygdala in MDD

Answer 17

fMRI and PET imaging studies have demonstrated an abnormally increased amygdala activity in depressive illness

Question 18

Describe the role of ventral striatum/ N. Acc in MDD

Answer 18

Blunted striatal reward link activation = anhedonia

Abnormally increased hippocampal activity in MDD with aversive stimuli = negative valence system

Question 19

Describe the role of the anterior cingulate and OFC in MDD

Answer 19

Brain regions assoc with emotional health are abnormally functional in MDD

Question 20

Is it possible to diagnose depression with a brain scan?

Answer 20

Study using T1 weighted brain scans had a 90% accuracy in diagnosis of depression

Question 21

Can MDD severity be predicted using a brain scan?

Answer 21

Yes;
Study determining if this was possible;
Increased BDI with predicted BDI using T1 weighted images was very accurate in determination of severity

Question 22

What areas of the brain were utilised in the studies to determine severity and diagnosis of MDD using T1 weighted MRI images?

Answer 22

Hippocampus
Medial brain structures
Superior temporal gyrus

Question 23

Describe the beliefs held about 5-HT and DA in the early 70s

Answer 23

Used using animal models
Dopamine at a tonic background level results in vigour with the phasic levels homing animals into the cues predictive of reward

5-HT has an inhibitory effect on behaviour and may have anxiolytic properties
5-HT neurons mediate the effects of punishment on behaviour

Question 24

Describe Daeken and Graeff’s theory of 5-HT function and its link with depression

Answer 24

Dorsal Raphe Nucleus (DRN) neurones functioned in an opposite way to DA projections, being engaged by distal cues predictive of aversive reinforcers, functioning as a “stop” or negative reinforcement signal, guiding the animal away from threats (passive avoidance) and towards DA safety cues (active avoidance)
Linked with 5-HT2c function

Medial Raphe Nucleus (MRN) neurones mediate a disconnecting “unlearning” function during extinction or punishment of instrumental learning.
Linked to 5-HT1a agonists effects on impairment of learning and projections to the hippocampus.
MRN projections act to prevent consolidation of aversive memories allowing tolerance to chronic adversity (resiliance)

Question 25

In line with Deaken’s theory; what is the role of serotonin in anxiety?

Answer 25

Different behavioural requirements for responding to proximal vs distal threats

Question 26

What is the brain system involved with aversive threats?

Answer 26

Amygdala (medial) to hypothalamus to PAG

Question 27

Does the amygdala respond to proximal or distal threats?

Answer 27

DISTAL threats; electrical stimulus of amygdala in rates evokes responses like distal threats
Amygdala receives cortical afferents with complex stimuli information

Question 28

Does the PAG respond to proximal or distal threats?

Answer 28

Proximal = immediate threat
Fight/ flight behaviour
Hard-wired unconditioned reflexive response to proximal threat or imminent death
Detected by touch/ pain/ suffocation (hypoxia and hypercapnia)
PAG activation during panic attacks can be triggered by CO2`

Question 29

Why is 5-HT activated in punishment yet it results in inhibition of PAG fight/ flight mechanism?

Answer 29

They proposed that when threats are perceived at a distance by the amygdala, PAG outputs for autonomic and resp function are activated but the fight/ flight component is inhibited from premature activation by 5-HT release from DRN neurons

This enables learned avoidance strategies to guide organism inconspicuously away from threat; PAG fight/ flight only released when threats imminent

Implies that anticipatory anxiety inhibits panic attacks; clinical evidence supports this e.g. panic attacks are made worse by relaxation therapy

Question 30

Describe the link between depressive illness and the DRN anxiety/ negative incentive/ escape inhibition system

Answer 30

Learned helplessness (animal model of human depressive illness); rats subjected to inescapable shock had increased anxiety and impaired escape behaviour even when escape available

• Mediated by the profound activation of DRN (testable with fMRI)
• Medial frontal cortex detects when punishment controllable and inhibits DRN

Deaken and Graeff proposed that the effects of the DRN on amygdala (fear) and in DA structures (negative incentive, reward opponency) is mediated by high conc of 5-HT2c receptors

Question 31

Describe the role of MRN resilience system and MDD

Answer 31

MRN projections to the hippocampus mediate behavioural adaptation to chronic or repeated aversive experiences (should DRN mechanisms fail to prevent exposure)

Systemic or intrahippocampal administration of 5-HT1a or antidepressants prevented anxiety like behaviour 24 hrs later

Basis of concept of MRN-hippocampal 5-HT1a receptor mediated system for behavioural resilience in the face of chronic adversity;
SSRIs may correct an impairment of 5-HT1a nT

Predicts that recovery from depression is assoc with increased MRN activity and decreased hippocampal activity

Question 32

In summary; describe D+Gs predictions from animal models about human behaviour

Answer 32

OVERACTIVE; DRN with projections to amygdala, (anxiety) PAG (helplessness) and striatum (anhedonia)

UNDERACTIVE; MRN with underactive projections to the hippocampus (ruminations)

Question 33

Has there been any studies to back up the theories provided by D+G?

Answer 33

Yes; human fMRI studies

DRN overactivity confirmed
MRN underactive projections to hippocampus resulting in overactive hippocampal activity during loss events
Abnormally increased accumbens deactivation during loss events in depression

Positive valence system; blunted striatal reward

Abnormal hippocampal correlated with severity of cognitive features of depression

Question 34

Describe Koobs allostasis theory of addiction

Answer 34

Model proposes for brain changes that occur in the development of addiction that explain the persistent vulnerability to relapse long after drug taking ceased

Cycle of spiralling dysregulation of brain reward systems that progressively increases resulting in compulsive use and loss of control over drug taking

Counter adaptive processes, such as opponent-process that are part of the normal homeostatic limitation of reward fail to return within the normal homeostatic range and are hypothesised to form an allostatic state

Allostatic state represents a chronic deviation of the reward set point driven by dysregulated reward circuits and activation of the brain and endocrine stress responses

Question 35

Describe the predictions of animal based models of allostasis theory of alcohol addiction

Answer 35

Repeated stimulus of the reward system by drug use with transient mood elevation
Brain’s natural response (opponent process) is to lower the baseline mood
Repeated drug use over time causes increased sensitivity and blunted reward sensitivity (partly permanent)
Similar to MDD

Question 36

Clinically, how is the allostatic theory modelled?

Answer 36

Binge drinking assoc with transient low mood
Alcohol dependency very strongly assoc with mod/severe MDD
Detox results in euthymia in about 80% of pts

Increased activation of negative valence system (anterior mid-cingulate cortex, bilateral anterior insula, medial hypothalamus, PAG, amygdala-hippocampal complex) to aversive events
Blunted reward-gain activity and decreased positive valence system linked brain regions (striatum, anterior cingulate, amygdala hippocampal complex)

Question 37

What negative valance system abnormalities were seen in binge drinkers?

Answer 37

Overactivity with loss events in hippocampus
Overactivity in dorsal cingulate gyrus correlating with years of alcohol use
PAG overactivity correlating with alcohol units and GABA

Question 38

What positive valence system abnormalities were seen in binge drinkers?

Answer 38

Blunted reward -gain system