Mood Disorders (part 1, 2 and 3) Flashcards
Describe the current diagnosis of a depressive illness
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)
Describe the clinical course of depression
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
How is the severity of depression quantified?
Rating scales;
Beck Depression Inventory
17-item Hamilton
MADRS
Is CBT effective in depression?
Yes; but only mild illness
Not mod/severe as seen in secondary care
In terms of depression; what is a failed adequate trial?
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
How is treatment resistance depression quantified?
Number of failed adequate trials of antidepressants
Rating scales used: MGH-S, ATHF
In terms of evolutionary concepts; what are the links with depressive illness?
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
Describe the 5 main domains of established brain systems?
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
Describe the neural circuits involved with the positive valence system (appetitive system)
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)
Describe the neural circuits involved with the negative valence system (aversive system)
Endogenous opioid (kappa) Ascending 5-HT NA/ CRF/ peptide transmitters Central nucleus of amygdala Hippocampus VA and medial hypothalamus PAG
Describe a depressive illness in terms of a disordered appetitive functioning
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
Describe a manic episode in terms of a disordered appetitive functioning
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
Is there a link between anxiety and mood?
Yes; study has shown with an increased severity of mood disorder (MADRS) in MDD, OCD, BAD there is positive correlation with anxiety severity rating
Is there a link between cognitive impairment and MDD?
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
Is the hippocampus implicated in MDD?
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
Are the hippocampal neurons affected in MDD
Yes; stress and corticosteroids induce dendritic shrinkage
Repeated stress results in atrophy of the dendrites in the CA3 region of the hippocampus
Describe the role of the amygdala in MDD
fMRI and PET imaging studies have demonstrated an abnormally increased amygdala activity in depressive illness
Describe the role of ventral striatum/ N. Acc in MDD
Blunted striatal reward link activation = anhedonia
Abnormally increased hippocampal activity in MDD with aversive stimuli = negative valence system
Describe the role of the anterior cingulate and OFC in MDD
Brain regions assoc with emotional health are abnormally functional in MDD
Is it possible to diagnose depression with a brain scan?
Study using T1 weighted brain scans had a 90% accuracy in diagnosis of depression
Can MDD severity be predicted using a brain scan?
Yes;
Study determining if this was possible;
Increased BDI with predicted BDI using T1 weighted images was very accurate in determination of severity
What areas of the brain were utilised in the studies to determine severity and diagnosis of MDD using T1 weighted MRI images?
Hippocampus
Medial brain structures
Superior temporal gyrus
Describe the beliefs held about 5-HT and DA in the early 70s
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
Describe Daeken and Graeff’s theory of 5-HT function and its link with depression
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)
In line with Deaken’s theory; what is the role of serotonin in anxiety?
Different behavioural requirements for responding to proximal vs distal threats
What is the brain system involved with aversive threats?
Amygdala (medial) to hypothalamus to PAG
Does the amygdala respond to proximal or distal threats?
DISTAL threats; electrical stimulus of amygdala in rates evokes responses like distal threats
Amygdala receives cortical afferents with complex stimuli information
Does the PAG respond to proximal or distal threats?
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`
Why is 5-HT activated in punishment yet it results in inhibition of PAG fight/ flight mechanism?
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
Describe the link between depressive illness and the DRN anxiety/ negative incentive/ escape inhibition system
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
Describe the role of MRN resilience system and MDD
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
In summary; describe D+Gs predictions from animal models about human behaviour
OVERACTIVE; DRN with projections to amygdala, (anxiety) PAG (helplessness) and striatum (anhedonia)
UNDERACTIVE; MRN with underactive projections to the hippocampus (ruminations)
Has there been any studies to back up the theories provided by D+G?
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
Describe Koobs allostasis theory of addiction
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
Describe the predictions of animal based models of allostasis theory of alcohol addiction
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
Clinically, how is the allostatic theory modelled?
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)
What negative valance system abnormalities were seen in binge drinkers?
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
What positive valence system abnormalities were seen in binge drinkers?
Blunted reward -gain system
