BS42017 L6,7,8 Flashcards
what is the criteria for a depressive episode in ICD-10 criteria?
At least two of the following: - Depressed mood - Loss of interest and enjoyment - Reduced energy - Fatigue - Diminished activity Plus at least three of: - Reduced concentration and attention - Low self-esteem and confidence - Ideas of guilt and unworthiness - Pessimism - Ideas or acts of self harm - Disturbed sleep - Reduced appetite For at least 2 weeks!
what can you say about the diagnostic bar for depression?
it is set too low
how long does an uncomplicated moderate episode of depression last?
4-6 months
what can be used to quantify illness severity? (3)
long established rating scales eg. Beck Depression Inventory, 17-item Hamilton, MADRS.
what could be used to treat “mild” illness?
cognitive behavioural therapy (CBT)
what could be used to treat moderate-severe illness?
antidepressants and ECT?
what does an “adequate trial” of antidepressants include?
prescriptions of specific antidepressant above a specific minimum dose for a minimum of 6 weeks with reasonable certainty the patient took the medication as prescribed
what determines treatment-resistance?
number of failed adequate trials
what are the five research domain criteria (RDoC)?
- Negative valence system- e.g. fear, anxiety, loss, non-reward
- Positive valence system- e.g. reward learning and valuation, habits
- Cognitive system- e.g. attention, memory, cognitive control
- Social system- e.g. attachment, communication, perception of self/others
- Arousal/modulatory system- e.g. circadian rhythm, sleep/wake cycle.
what does positive valence do and what systems contribute to it? (7)
Positive valence system- function to mediate seeking and approach behaviours (incl. pleasure)
- Ascending dopamine systems; mesolimbic/cortical projection
- Endogenous opiate system (mu opioid receptors)
- Ventral striatum/accumbens
- Dorsal striatum (movement)
- Amygdala (conditioning/learning)
- Anterior cingulate (attention/conflict response selection)
- Orbitofrontal cortex (relative reward preference/rule learning)
what does negative valence do and what systems contribute to it? (7)
Negative valence system- functions to promote survival in the event of threat (fear/pain)
- Endogenous opioid systems (kappa receptors)
- Ascending serotonin systems
- Noradrenaline/CRF/ peptide transmitters.
- Central nucleus of amygdala
- Hippocampus
- Ventral anterior and medial hypothalamus
- Periaqueductal grey matter
how do you describe depression? (6)
- Difficulty identifying “rewarding” stimuli
- Reduced contact with previously rewarding stimuli
- Increased contact with aversive stimuli
- Overall reduction of behaviour
- Move less, eat less, lose weight, less interest in sex etc.
- Low mood
how do you describe mania? (7)
- Previously neutral stimuli become “rewarding”
- Increased exploration/overall activity
- Increased “appetite” for food, activity, sex, etc
- Intolerant of “aversion”/boredom
- Intolerant of frustration
- Elevated/elated mood
- Could be irritable
Is it possible to diagnose depression by only using a brain scan?
Many neuroimaging studies of mood disorder reporting abnormal brain structure and function show statistical differences based on standard statistical tests e.g. t-test. there is a highly significant group level difference between patients and controls (e.g. reduced hippocampal volume in MDD cf controls).
what is the problem with classical univariate statistics?
Group level (t-test) difference that is highly significant (p«0.05) may have lots of overlap on single measure e.g. hippocampal volume for individual patients. This means a single measure on its own is clinically useless.
Classical significance level (p<0.05) approach is not useful in psychiatry and there has bee no progress for over half a century as evidence of this. what is the solution to this?
a multivariate approach so instead of one measure, use lots of variables and statistical frameworks (machine learning)
Multi-centre study (Edinburgh and Aberdeen) using structural brain scans (T1 weighted) showed machine learning to be what?
machine learning based approach has 90% accuracy in diagnosis of depression.
where does the evidence of D&G’s theory come from?
- mainly animal model evidence
- a few psychopharmacology tests on humans
There is considerable evidence by the early 70s for dopamine being involved in reward. It is thought that serotonin might have what effect?
a “complementary” role (or “mirror opposite”).
what did D&G propose dorsal raphe nucleus neurons do?
functioned in opposition to dopaminergic 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 dopaminergic safety cues (active avoidance).
what did D&G propose median nucleus neurons do?
mediate a disconnecting “unlearning” function during extinction or punishment of instrumental learning.
later suggested that MRN projections prevent consolidation of aversive memories allowing tolerance to chronic adversity (resilience).
what are the two roles of 5-HT in anxiety?
different behavioural requirements for responding to proximal vs distal threats.
what does the brain system responsible for responding to aversive threats include? (3)
amygdala –> (medial) hypothalamus –> periaqueductal grey matter (PAG).
what structure responds to distal threats?
amygdala
what does the PAG respond to?
proximal threats
when is there abnormal activation of PAG? (clinical)
panic attacks- triggered by CO2
Why might 5-HT be activated in punishment yet inhibit PAG fight/flight mechanism?
When threats are perceived at a distance by the amygdala, PAG outputs for autonomic and respiratory function are activated, but fight/flight component is inhibited from premature activation by 5-HT release from DRN neurons.
This enables learned avoidance strategies to guide the organism inconspicuously away from the threat. PAG fight/flight is only released when threats are imminent.
This implies that anticipatory anxiety inhibits panic attacks.
what are panic attacks made worse by?
relaxation therapy
what animal model recapitulates some (but not all) aspects of depressive illness?
learned helplessness model
what is learned helplessness mediated by?
profound activation of DRN (testable with fMRI)
what detects when punishment is controllable?
Medial frontal cortex detects when punishment controllable and inhibits DRN.
Deaken and Graeff proposed that effects of DRN on the amygdala (fear processing) and in dopaminergic structures (negative incentive, reward opponency) is mediated by what?
by high concentration of 5-HT2c receptors
Deaken and Graeff proposed that MRN projections to hippocampus mediated what?
behavioural adaptation to chronic or repeated aversive experiences (should DRN mechanisms fail to prevent exposure).
Systematic or intrahippocampal administration of what to MRNs prevented anxiety-like behaviour 24 hours later.
5-HT1a agonists or antidepressants
what does D&G’s theory predict that recovery from depression is associated with?
with increased MRN activity with reduced hippocampal activity- testable with fMRI and PET.
overall, what were D&G’s predictions from animal models about human depressive illness?
Overactive dorsal raphe nucleus (DRN) with overactive projections to the amygdala (anxiety), periaqueductal grey (PAG; helplessness), caudate/striatum (anhedonia).
Underactive median raphe nucleus (MRN) with underactive projections to hippocampus (ruminations).
How many of D&G’s predictions did Douglas Steele’s research team confirm (2015)? (RDoC negative valence system)
1) Dorsal Raphe nucleus overactivity
2) MRN underactive projection to hippocampus resulting in overactive hippocampus during loss events (abnormal hippocampal activity in D&G’s predictions)
what did Steele 2015 additionally find to D&G’s predictions of negative valance system?
abnormally increased accumbens deactivation during loss events in depression
Were D&G’s predictions confirmed by Douglas Steele’s research team (2015)? (RDoC positive valence system)
yes- blunted striatal reward activity
There is a high co-morbidity of depression and anxiety. This may be valuable for antidepressants to have what properties?
anxiolytic properties
what is meant by an animal model of human disease?
An attempt to mimic the physiology and symptoms of a human disease in an animal, including animals that do not normally suffer from that disease
how can you intervene to create an animal model of human disease?
- Pharmacological treatment
- Genetic alteration or selective breeding
- Experience
- Surgery
what validity do animal models ideally have?
- face validity; does the model capture some or all of the symptoms of the human disease?
- construct validity; do the pathophysiology and aetiology mirror the human disease?
- predictive validity; does the model predict which treatments will be effective in human patients?
what is the difference between animal models and behavioural tests?
Animal models- the attempt to reproduce a disease state in an animal. It involves changes in physiology and behaviour observed. It may only attempt to model one aspect of the pathology associated with a disease.
Behavioural tests/pharmaceutical screens- attempt to assess the impact of a treatment on disease symptoms.
give examples of animal models of depression (6)
- Learned helplessness (chronic despair)
- Unpredictable chronic mild stress
- Maternal separation/early life stress
- Social defeat
- Olfactory bulbectomy
- Genetic models (e.g. GR+/- mice)
how can you test for depression-like behaviour? (3 + examples)
- Resignation/despair; forced swimming test, tail suspension
- Anhedonia (inability to experience pleasure): sucrose preference test, reduced intra-crania self-stimulation
- Lack of motivation: decreased grooming, decreased nest building
pros and cons of: forced swimming test
Pros;
- Easy and cheap, high throughput
- Good predictive validity for monoaminergic drugs
Cons;
- Measures the response to an acute stressor, but not necessarily “depression-like” symptoms
- Sensitive to acute treatment with monoaminergic drugs (cf. SSRIs)
- Predictive validity for non-monoaminergic drugs uncertain
pros and cons of: tail suspension
Pros;
- Easy and cheap, high throughput
- Good predictive validity?
Cons;
- Measures the response to an acute stressor, but not necessarily “depression-like” symptoms.
- Sensitive to acute treatment with monoaminergic drugs (cf. SSRIs)
- Predictive validity for non-monoaminergic drugs is uncertain
- Suitable for only mice as rats are too heavy.
pros and cons of: sucrose preference
Pros;
- Simple
- Not time consuming
- possible modifications in motility, anxiety, and learning induced by the exposure to one of the stress models do not significantly affect the response in the test
cons;
- variability in the results obtained in different laboratories.
- The low reproducibility in the same laboratory, often related to low adherence to good laboratory practices (size of the bottles, accuracy in removing and placing again the bottles in the cage, frequency of switching position of the bottles, etc.)
- a recent study demonstrated that the standard practice of handling mice by their tails, as opposed to tunnel handling, decreases responses to reward in terms of sucrose consumption and licking bouts.
pros and cons of: intracranial self stimulation
Pros;
- compared with food self-administration it is not influenced by satiation or stress-induced anxiety
- allows longitudinal study of the development of anhedonia
- performance in ICSS is considered a measure of motivation but also of the rewarding value of a stimulus (predictive validity).
Cons;
- Technical
- Time-demanding
- Invasive
