Depression Flashcards
What are mood disorders caused by?
Anxiety?
How does depression & anxiety overlap?
What is their comorbidity?
What does anxiety phenotype do?
Why do good animal models exist for these disorders?
Why is mood hard to experimentally measure?
How can you measure mood in rodents?
Why is depression different to feeling poorly?
Depression & elated/manic episodes
Abnormal regulation of fear
Symptoms of restlessness, excessive worrying & agitation - but also overlapping circuits of the brain & genetic/environmental risk factor
60% that when you have 1 you have the other
Often precedes onset of depression
Study in lab as emotions are transient responses to stimuli which can be reproduced
Subjective measures & mice can’t speak how feeling
By producing chronic stress in them
Change in body’s physiology
How is depression defined?
What are the features of depressive episodes? 4
What distinguishes this to normal anguish/grief? 3
What are the physiological symptoms of depression? 3
Cognitive symptoms? 4
Why is depression hard to diagnose?
Why is researching the cause important?
Untreated depressive episodes that last 4-12 months (DSM)
- Unpleasant/dysphoric mood
- Mental anguish
- Inability to experience pleasure - anhedonia
- Generalised loss of interest in the world
Severity, pervasiveness (spread) & duration
Insomnia, loss appetite, decreased energy
Hopelessness, suicidal thoughts, lack concentration, poor memory
Relies heavily on symptoms which is seen in normal people but dependent on severity, pervasiveness & duration
Produce drugs to prevent depression not relieve symptoms
How is depression genetically linked?
What is the reoccurrence risk ratio?
What is the problem with this?
How does the reoccurrence risk ratio in siblings/twins with major depression differ with schizophrenia & bipolar disorder?
Runs in families - due to several gene loci but not consistent with Mendelian genetics (dominant/recessive etc)
Quantifying genetic contribution of complicated genetic disorder - likelihood/increased risk of developing that genetic disorder through relation to an affected individual - rough measure of aggregate influence of genes
Doesn’t consider how many genes are involved
Much smaller (2x more likely if sibling has compared to 9x with SCZ) showing that has less of a genetic contribution
What is a strong environmental risk factor for depressive symptoms?
What does this correlate with?
What about physiological correlation?
What does transient/acute stress result in - elevating stress hormones for fight/flight? 4
Therefore what is correlated with depression? Examples 3
Why is this more problematic in earlier life?
What is one example of chronic stress that can physiologically affect someone?
What areas of the brain are susceptible to stress?
Stress in early life/adolescence
Stressful episodes prior to onset
Stress hormones elevated in depression - cortisol, corticotrophin-releasing hormone (CRH) and adreno-corticotropic hormone (ACTH)
- Suppress immune system to save energy
- Induce catabolic state to provide energy
- Sharpens cognition
- Increases confidence
Long term/chronic stress: emotional trauma, social isolation & traumatic head injury (prolonged physiological stress)
Brain is more plastic - can result in permanent physiological changes in regulation of the stress response & hormone release
Cortisol function is impaired - normally inhibits ACTH & CRH release
Involved with value, motivation & planning
What part of the brain is involved in depression and where is it located?
What are the 2 subdivisions of this area & what are they involved in?
What is most specifically linked to depression?
What happens when you decrease activity of this area?
Anterior cingulate cortex - rostral/front of brain
- Rostral part - emotional response & connected to hippocampus, amygdala & prefrontal cortex
- Caudal part - cognitive processes - planning
Subgenual region of rostral part - increased activity of this part correlates with depressive symptoms
Correlates with successful treatment
Why is the amygdala involved in depression?
Why is the hippocampus involved in depression?
How are these parts of the brain altered in patients with depression?
Associated with fear learning & pavlovian conditioning - dysfunction to make dissociations between stimuli & negative ideas
Learning & memory
Increased amygdala volume & activity - overuse
Decreased hippocampal volume & neurones - underuse
What is the nucleus accumbens/ventral striatum involved with?
What does dysfunction of this show?
What is seen in patients with depression?
Reward
Anhedonia - inability to feel pleasure
Reduced activity in the NAc after a reward
What region controls CRH and ACTH feedback?
What effect on this does the hippocampus & amygdala have?
Therefore how does chronic stress relate to depression?
What are the 3 types of antidepressants and what do they do?
What are some drug names for each?
What else can be used to treat depression?
What is the problem with the drugs?
Hypothalamic-pituitary-adrenal axis
Amygdala promotes release & hippocampus inhibits release
Chronic stress means higher activity of amygdala & lower activity of hippocampus - leading to change in volume (seen in depressed patients)
- Monoamine oxidase inhibitors - block breakdown of dopamine, noradrenaline and serotonin/5-HT
- Tricyclic antidepressants - binds to presynaptic transporter proteins to prevent 5-HT and noradrenaline reuptake
- Selective serotonin reuptake inhibitors (SSRIs) - prevent serotonin/5-HT re-uptake following release
MAOI = tranylcypromine (parnate), phenelzine (nardil)
TCA = imipramine (tofranil), clomipramine
SSRIs = sertraline, fluoxetine (prozac)
Psychotherapy, cognitive behaviour therapy, electroconvolusive therapy
Non-selective & vague - only prevents re-uptake of 5-HT but not actual solving the problem of why there is less 5-HT
What is the monoamine/serotonin hypothesis?
In what neurones is serotonin released & why are they significant?
Therefore why are SSRIs used?
What do SSRIs do?
What are the problems with the serotonin hypothesis? 6
What can you conclude about the hypothesis?
Mood-altering compounds act on the monoaminergic system of the nervous system involved in serotonin, noradrenaline & dopamine release where more monoamines = happier and less monoamines = sadder
Dorsal raphe nucleus in back of brain - project to hippocampus, amygdala, anterior cingulate cortex & nucleus accumbens - all involved with depression
Increasing serotonin should relieve depression - SSRIs have fewer side effects compared to TCAs & MAOIs
Just prolong amount / indirectly increase serotonin at synapse at anyone time - but doesn’t directly involve serotonin binding to 5-HT receptors
- Too simple that complex phenotype results simply from change in neurotransmitter system
- All statements of serotonin hypothesis fail to show mechanistic explanations
- Vague evidence suggesting serotonin levels/its metabolites correlate with depression
- Directly manipulating serotonin levels is inconclusive - indirectly manipulating through re-uptake inhibitors have an effect but directly increasing serotonin levels does not - showing it’s to do with the mechanism of increasing serotonin levels not increasing the serotonin conc itself
- Results of successful treatments seen through SSRI manipulating serotonin levels
- Effect of SSRIs take weeks to exert effects - not a direct effect - has an effect via a mechanism not directly the serotonin itself
Theory works but it is incomplete - no mechanistic sense
What is the neurotrophin hypothesis?
What are neurotrophins?
What does reduced neurotrophin signalling result in? 3
Where are these observations found?
Which neurotrophin & its receptor is involved in depression & what happens after the treatment with anti-depressants?
What other observation is seen with this neurotrophin in suicide victims?
What mutation in this neurotrophin is related to depression & what other symptoms?
How did they alter mice to have a depressive phenotype & what was observed?
What were the problems with this experiment?
Environment, stress, genetic risk factors for depression coverage impair on the neurotrophin signalling pathway
Proteins that induce survival, development & function of neurones - secreted (class of growth factors) capable of signalling for cell survival, differentiation & growth
- Impaired neurogenesis - inability to produce new neurones
- Dendritic atrophy - dendrites retracted/smaller
- Impaired plasticity - strength synapses unable to change
Hippocampus - decreased volume & neurones in depressed patients
BDNF and its receptor trkB - which BDNF has low blood concentration with depression & on treatment the blood concentration normalises (and higher than controls)
Reduced BDNF & trkB mRNA in postmortem brains
BDNF gene Val66Met - hippocampal volume, suicide
Mutated the BDNF gene - had smaller hippocampus & slow, impaired responses to antidepressants
- BDNF required for circuit development - knockout mice not good system
- BDNF has different effects on different circuits - prefrontal cortex & hippocampus increasing BDNF promotes stress resilience, whereas nucleus accumbens promotes stress susceptibility
- No mechanism linking antidepressants & change in BDNF level
- No explanation as to whether SSRIs activate this pathway
How does esketamine treat depression?
What does MDMA do?
Binds tightly to NMDA-R receptors & hence inhibits the receptors & binding of glutamate more than ketamine - but need lower dose
Binds to 5-HT receptors inducing Ca2+ influx & increased release activity of serotonin (also dopamine & noradrenaline) and blocks their re-uptake
What is the excitatory hypothesis?
How has this been shown?
How can excitatory synaptic transmission/plasticity be increased?
What are the 4 statements of this hypothesis?
Changes of excitatory connectivity in depression
Chronic stress exerts inhibition of excitatory synaptic transmission & plasticity - in cortex, NAc & hippocampus
Serotonin & neurotrophin - increase this in same regions as inhibition in chronic stress - be used to modify excitatory synaptic connectivity
- Depression is caused by weakening of excitatory synapses in parts of brain associated with affect & reward (NAc)
- Restoring excitatory synapse strength should rescue depressive behaviour
- Restoring excitatory synapse strength should be the action of antidepressants - SSRIs
- Targeted changes in excitation transmission should be quicker & more effective than current treatments
Studying depression in mice
What is the chronic restraint test?
What is the chronic unpredictable mild stress test?
What is the sucrose preference test?
How does the chronic restraint stress change NAc excitatory synapses?
How was this measured?
What did the chronic unpredictable mild stress test show?
What do these experiments conclude?
Putting a mouse in a tube (stressed) and a control mouse not in a tube for 7 days - mouse in tube is more stress & loses weight whereas control gains weight
Producing unpredictable stress conditions (e.g changing time of lights, playing sounds) everyday for an hour over the course of several weeks
Putting control & test mouse (with stressful conditions) with choice of both sucrose feed and water feed - over time sucrose preference decreases & less sucrose taken up due to anhedonia (either chosen to equal extent)
Decreases their connectivity
Ratio of AMPA:NMDA receptors - smaller AMPA:NMDA ratio (fewer AMPA) in stressed mice compared to control - weaker synapses
Decreased hippocampal excitatory connectivity - also measured with AMPA:NMDA which was smaller than in control & hence weaker synapses
Specific subset of excitatory synapses in the NAc & hippocampus are weakened in stress conditions/depression
How is weakening of synapses caused?
How can you block the weakening of synapses? How does this work?
What was observed in controlled peptide & synthetic peptide mice undergoing stress conditions in the chronic restraint test and sucrose test? 2 things
What can you conclude?
Fewer AMPA receptors
Synthetic peptide G2CT - blocks removal of AMPA receptors by blocking binding site for its trafficking molecule
- G2CT stressed mice gained weight like wt, whereas controlled stress lost weight
- Control peptide (& control) stressed mice developed anhedonia/loss of preference whereas G2CT-P mice had preference for sucrose like control (unstressed) mice
Blocking changes in NAc synapses blocks stress behaviour
How was SSRIs tested to determine whether they work through AMPARs?
What does this show?
How was SSRI determined to be acting via strengthening excitatory synapses?
How does this determine how SSRIs act?
Used SSRI & SSRI blocker on CA1 synapses & measured EPSP - with SSRI synapse was stimulated/excitatory and with blocker it was not
SSRIs potentiate excitatory hippocampal synapses = opposite of stress-induced depression (weakening)
Used peptide (or GluA1 AMPAR mutation) to stop synapses being strengthened in wild type and SSRI mice - shows that SSRI + blocker no change in excitatory synaptic strength - vs SSRI mice which did show increase in excitatory synaptic strength
Mutation inhibits SSRI from strengthening the excitatory synapse strength
