Depression + Bipolar Disorder Extra Reading Flashcards
outline depression morphology?
atrophy of hippocampus, enlargement of amygdala
reduced signalling via monoamine transmitters, 5-HT and norepinephrine.
what causes the morphological changes in depression?
increased GLUTAMATE release from hippocampus onto limbic system neurones, which causes long term structural changes in dendrites and synapses e.g reduced hippocampal neurogenesis
what do current depression treatments do in neurones?
inhibit monoamine degradation/reuptake
what was the first ever antidepressant?
lithium
1949 - John Cade
treated psychotic episodes in 70% of patients
remains effective in treating ‘mania’.
what antimicrobial agent made to treat tuberculosis was a breakthrough within antidepressants?
Iproniazid
unexpected psychoactive effects
slowed breakdown of norepinephrine, serotonin and dopamine by inhibiting monoamine oxidase enzyme
founded family of MAO inhibitors still currently used
what do tricylic antidepressants do an what is an example?
Imipramine induced euphoria - it is still used today
inhibits removal of norepinephrine and serotonin from synaptic terminals
what is transient provoked depression?
e.g by grief
different to major depressive illnesses which persist without known provocation
what are the 4 main depressive illnesses?
grief reaction
secondary depression (as result of neurological disease)
clinical (unipolar) depression
bipolar disorder
outline what is meant by secondary depression?
associated with illnesses causing severe pain e.g cancer, stroke, Parkinsons
has potential to resolve spontaneously especially when the cause resolves
how recurrent is depression for women
follows seasonal patterns (seasonal affective disorder) associated with fatigue, carbohydrate craving, weight gain and insomnia
what is the concordance rate of bipolar in identical twins?
80%
what are some cognitive symptoms of bipolar disorder?
impariments in episodic memory
reduced mental flexibility/attention
psychomotor slowing
what is a major risk factor for depression?
endocrine changes resulting in increased cortisol e.g Cushing syndrome
what can insufficient thyroid present with?
depressive symptoms
potentially caused by drugs e.g accutane or cannabis use
what is the lifetime prevalence of depression?
20%
what is the biggest concern associated with depression?
suicide
how did we come to understand the neurobiology of depression?
inferring effects of antidepressants, human imaging and animal models
what is the neurobiology of depression very generally?
region specific neuronal cell loss, with retraction of dendrites which causes persistent changes in synaptic activity
this leads to imbalances in pathways that regulate reward, affect and emotion
which brain areas contain the neural circuits affected?
prefrontal cortex, hippocampus and limbic system (structures that control emotion, reward seeking, motivation and executive function)
what are the important limbic structures in depression
ventral tegmental area (VTA)
nulcues accumbels
locus coreleus
thalamus
hippocampus
amygdala
why is the amygdala associated with depression?
attaches emotional valence to experience, strong amygdala activation associated with sadness in both depressed and not depressed people .
what do imaging studies of depressed poeople show in the amygdala?
those with chronic depression had sustained enhancement of amygdala activity
disrupting this with DBS reduced depression
what are neuromodulators?
all monoamine transmitters providing emotional salience to processed information
what is the monoamine hypothesis
drugs that enhance serotonin and noradrenaline concentrations by inhibiting removal = antidepressant effects
BUT drugs that reduce monoamine production INDUCE depression
why is it too simplistic to call depression an imbalance of monoamines?
antidepressants change concentration of monoamine very quickly (mins) but the effects are slow (weeks) - drug persistently alerts connectivity in neural circuits that drive emotional valence and alter complex signalling cascades involved in structural and functional changes in the networks regulating emotions
outline the cascade from that happens from blocking 5-HT re-uptake by SSRI’s
activation of G protein coupled receptor, leading to enhanced cAMP signalling, leads to transcriptional changes via cAMP-protein kinase A (PKA-cAMP) response element binding (CREB) pathway
what does chronic use of SSRIs alter?
alters expression of transcription factor CREB and Ca2+ binding protein p11.
genes are transcribed including neurotropic factors like BDNF (neuronal survival/growth and plasticity)
what are the structural changes associated with depression?
overall decrease of grey matter volume in PFC and hippocampus
postmortem shows size of pyramidal neurons is reduced and loss of GABAergic ingterneurons
loss of astrocytes and oligodendrocytes
unlike the PFC, what structural changes does the amygdala show in depression (postmortem)?
increase in size of neuronal cell bodies with more complex dendritic branching
- this explains increased amygdala activity measured in fMRI.
what is hippocampal theory in depression?
hippocampal atrophy in depression is not due to degeneration of existing neurons but loss of hippocampal neurogenesis and synaptogenesis
may explain cognitive impairment
stress hormones reduce neurotrophins and enhance hippocampal excitotoxicity
what does current understanding of functional changes underlying depression come from?
investigating the mechanism of action of drugs for stabilising mood
what can ketamine treat supposedly
treatment-resistant unipolar depression
what is ketamine
an NMDA receptor antagonist
drug inducing a dissociative state - often abused
hallucogenic and anaesthetic effects - 60 min
what is suggested about ketamine fro depression - how it works
ketamine enhances activity in prefrontal cortex and limbic structures (basal ganglia and thalamus)
hyperexcitable neurons in the lateral habenula - may be specific target of ketamine
how does ketamine work at the cellular level?
binds to PCP site on NMDA receptor - increases GLUTAMATE levels in brain
parodoxical action - assuming low doses of ketamine preferentially blocks NMDAr on GABAergic interneurones
REDUCES their inhibitory control over PFC - INCREASES glutamate and activates NMDAr and AMPAr in PFC - causes long lasting structural changes in synapse
what are macroscopic changes in depression
reduction in volume of PFC and hippocampus suggestive of neuronal atorphy
at neuronal level number of dendritic spines is reduced
