Affective Disorders Flashcards
what is the aetiology of mood disorders?
genetic predisposition - not sure what the genes are,
early aversive life experience contributes to vulnerability
trauma or stressful daily events in adulthood produce biological alterations/pathophysiology causing symptoms
what are the 2 main bodies of evidence for neurobiological changes in mood disorders
- monoamine pathology
- hypothelamic pituitary adrenal axis (HPA) pathology
which neurotransmitters are monoamines?
5-HT
NA (noradrenaline)
DA (dopamine)
outline the distribution and function of monoamines?
widespread distribution in the forebrain
mood anxiety, sleep and congnition
outline the history of monoamine hypothesis of depression
Reserpine (hypertension drug) had high incidence of depression as side effect (worked by depleting monoamines)
Isoniazid (used for TB) improved mood by blocking breakdown of monoamines
what is the monoamine theory of depression?
depression happens due to decrease in function of monoamine neurotransmitters in brain
what was monoamine theory later refined into
5-HT theory
depression due to decrease in function of serotonin in brain
where are the serotonin pathways in the brain mainly?
terminal fields throughout forebrain and cell bodies located in nuclei in midbrain - the largest is the dorsal raphe nuclei
how many serotonin receptors are there
7 different families
most abundant are: 5-HT1 5-HT2
5-HT3
outline the 5-HT1 family of receptors
5-Ht1a-f
G-protein coupled
5-Ht1a,b,d - autoreceptors and postsynaptic receptors
5-Ht1a on 5-Ht cell bodies
5-HT1b,d on 5-Ht terminals (b in rodent, d in humans)
decrease cAMP
generally inhibitory (hyperpolarisation, inhibition of firing and release)
how many populations of 5-Ht1a are there?
2 populations - post synaptically but also in cell body
what is the hypothesis of how 5-HT1a works in the PFC?
it is located on pyramidal neurones (glutaminergic)
5-Ht1a activation -> decreased activity of pyramidal neuron -> decreased activity of GABA inhibitory interneurons -> DA and NA released from GABA inhibition -> increase DA and NA activity
outline the 5-Ht2 family of receptors?
5-Ht2a,b,c
G protein coupled
act as postsynaptic receptors
coupled to Gq/11 activates phospholipase c leading to increase in IP3 and DAG
generally stimulatory
outline the hypothesis of how 5-HT2a acts in PFC
located on pyramidal neurons (glutaminergic)
5-HT2a stimulate -> increase activity of pyramidal neuron -> increase activity of inhibitory GABA interneurons -> DA and NA GABA inhibition -> decrease in DA and NA activity
how would antidepressants (like atypical ones used now) act on 5-HT2a
block the receptor to decrease activity of pyramidal neurons, decrease GABA inhibtiory interneurones which meand DA AND NA in brain stem released from GABA inhibition which increases DA and NA.
outline 5-Ht3 receptors?
pentameric ligand gated cation channel (ionotropic receptor)
excitatory
what are 5-Ht3 antagonists used as?
antiemetics
outline the hypothesis of how 5-HT3 works in the brainstem?
located on GABA inhibitory interneurons
5-Ht3 is stimulated
increases activity of GABA inhibitory interneuons
DA and NA in brain stem GABA inhibition
decrease in DA and NA activity
what evidence exists AGAINST the monoamine theory of depression?
- just increasing monoamines is not effective in treating depression - we know this because antidepressants take weeks to become effective
- there are no studies sowing lowered monoamine metabolites in CSF of depressed patients
- amphetamine which increases monoamine release is NOT an effective antidepressant
what are the 4 main bodies of evidence FOR the monoamine theory of depression?
- tryptophan depletion (causes relapse in depressed symptoms)
- endocrine responses gto 5-HT drugs
- PET binding for SERT and 5-Ht1a (attenuated in depressed patients)
- 5-HT1a hypothermic response - also attenuated
what is tryptophan?
tryptophan hydroxylase is the rate limiting enzyme which to which tryptophan is the precursor to
if enzyme is not saturated (amount decreased using large neutral amino acid load) this DECREASES 5-HT synthesis
this causes a relapse in euthymic patients
outline endocrine responses to 5-Ht drugs for evidence for the monoamine theory of depression
hormones in the blood (ACTH, Prolactin, Cortisol) are sensitive to changes in 5-HT
so these hormones can be used as a marker for monoamine receptor function
what can you stimulate the 5-HT system with - endocrine hormones wise?
Fenfluramine - 5-HT releasing agent
tryptophan = 5-HT precursor, increases 5-HT release
so therefore what are endocrine changes used as?
an indirect measure of whats going on with 5-HT
what is the prolactin response in depression?
studies looked at prolactin levels in families with high susceptibility of depression and found attenuated prolactin can be a PREDICTOR of depression susceptibility
this response happens when administering Fenfluramine
what do PET studies show in support of the monoamine theory of depression?
5-HT1a - both cell body and postsynaptic populations appear to be decreased
imaging is direct evidence
where is 5-Ht1a located
cell body region of dorsal raphe nucleus - where it acts as autoreceptor
and postsynaptic 5-HT neurons in the forebrain
what else have PET studies shown
serotonin transporter SERT is also decreased in depressed patients
what is some more indirect evidence for 5-Ht theory of depression
hypothermic response - if you give person 5-HT1a receptor agonsit, get small drop in core body temperature of 3 degrees but in depressed people this is attenuated (doesnt happen)
what is the most important evidence for the monoamine theory of depression?
antidepressant action
not evidence of pathology but evidence that drugs are working via 5-HT system
what is the HPA axis compromised of?
hypothalamus
anterior pituitary
adrenal cortex
controls the synthesis and release of cortisol from adrenal cortex
outline the HPA axis cascade
CRH released from hypothalamus acts on pituitary which secreted ACTH
ACTH acts on adrenals to cause synthesis and release of cortisol
what is the HPA axis regulated by?
circadian rhythm - levels of cortisol are high in the morning and drop during course of the day
stress regulates it too (mental/physical)
feedback regulation - negative feedback system -cortisol being release from adrenals feeds back onot tissues of axis and turns OFF activity
why do people think the HPA axis is associated with mood disorders?
patients with Cushings syndrome (excess cortisol) have high incidence of mood disorders
cortisol levels in depressed patients appear to be raised
hypercortisolaemia and depression
throughout course of the day our cortisol is naturally higher in the morning
depressed patients is slightly elevated compared to normal
what could cause this raised cortisol in depressed people?
could be the negative feedback loop
what does the dexamethasone suppression test do
direct test of glucocorticoid mediated negative feedback function - to check if the negative feedback loop is impaired in depressed patients
what happens in the dexamethasone suppression test in depressed patinets?
dexamethasone suppression is attenuated in depressed patients compared to controls
so depressed patients have a compromised GR mediated feedback
what is an extension of the dex test
CRH test
stimulates axis to release cortisol
get better idea of effectiveness
this effectively tests the negative feedback system
what does the dex/crh test show in normal patients
when you give CRH, dex resitricts the ability of CRH to stimulate the release of cortisol
what does the dex/crh test show in dperessed patients
in depressed patients this restriction is gone because it seems to be a dysfunctional negative feedback
why are we so concerned about hypercortisolaemia?
cortisol regultes transcription of many proteins and has numerous central effects
there is well-documented interaction between 5-HT and cortisol - it decreases the sensitivity of 5-HT1a receptor function
is cortisol the underlying effect of the 5-HT system?
what can early life adversity cause?
compromise 5-HT function
compromise HPA axis
outline a study of how early life adveristy affects cortisol levels
childhood parental loss and cortisol levels in adult men
cortisol levels elevated in the morning and throughout course of day compared to controls
what is the main goal of antidepressant treatment?
increasing DA and NA
outline how 5-HT is released from presynaptic to postsynaptic neurone
tryptophan is a precursor amino acid to 5-HT, it synthesises 5-HTP by TPH, then 5-HTP synthesised into 5-HT by AADC
5-HT stored in vesicles for release by exocytosis
A.P comes down axon 5-HT is released, acts on 15 different receptor types
presynaptic receptor has 5-Ht1a and 5-Ht1d which are autoreceptors and control activity
5-Ht taken back into neuron via SERT
5-HT either metabolised by monoamine oxidase and excretes as 5HIAA or its recycled
what stage of 5-HT biosynthesis do antidepressants act on
termination stage
how do TCAs and SSRIs act on the termination stage
they decrease 5-HT reuptake to keep it in the synapse
outline tricyclic antidepressants
inhibit 5-HT and NA reuptake so they can stay longer in the synapse
the problem is the therapeutic effect is delayed 4-6 weeks but side effects are immediate
why do tricyclic depressants have so many side effects - what do they block?
block M1 receptors = dry mouth, constipation, blurred vision
block H1 receptors = sedation, weight gain
block alpha 1 receptors = postural hypotension
^ because of the tricylic structure
who cannot use tricyclic antidepressants?
elderly/young
cardiac patients
suicidal patients
drivers
what are SSRI, SNRI and NARI?
SSRI = selective serotonin reuptake inhibitors
SNRI - selective serotonin/noradrenaline reuptake inhibitor
NARI - noradrenaline reuptake inhibitor
2nd generation antidepressants
why do SSRIs not cause as many side effects as TCAs?
they do not have the tricyclic structure so dont have affinity for M1, H1 alpha 1 receptors to cause them
outline the selectivity of reuptake inhibitors
selectivity is always relative and not 100%
Citalopram is most popular
do SSRI and TCA vary in efficacy?
no they are equal
what are some side effects of SSRIs
sexual dysfunction (impotence)
gastrointestinal
can induce anxiety early in treatment
what other disorders are SSRIs used for?
OCD
eating disorder
panic disorder
what is an antidepressant which doesnt inhibit uptake
monoamine oxidase inhibitors MAOIs
what happens by blocking MAO enzyme?
more 5-Ht is shifted into the vesicle
what are the two isoforms of MAO
MAOa = breaks down 5-HT and NA
MAOb = breaks down DA
what did old MAOIs do?
blocked both isoforms irreversably
lead to stimulant effects (because too much DA) and dangerous in overdose
what are new MAOIs like
selective for MAOa
RIMA (reversible inhibitors of monoamine oxidase)
safer and less stimulant
what do MAOIs and cheese interactions cause?
cheese has high levels of amines, there is a lot of MAO in the gut which is important for breaking down dietary amines
MAO blocked = dietary amines are absorbed into bloodstream, noradrenaline released causing hypertension
what is the interaction between MAOI and serotonin
serotonin syndrome
hyperthermia, confusion, hypertensive crisis
what are atypical antidepressants?
they have affinity for a range of monoaime transporters and receptors
e.g Mirtazepine , Nefazodone, Mianserin
outline Mirtazepine
high affinity for H1 receptor, which causes sedation but still effective antidepressant as it is fast acting and something people can get used to
how do atypical antidepressants act on 5-HT
increase 5-Ht synthesis by increasing tryptophan availability
which improves mood
also increase 5-HT release
what drugs are used to treat bipolar disorder
antimanic agents - control of acute mania, sedatives, antipsychotics
mood stabilisers = used to prevent recurrence of manic or depressive episodes e.g lithium salts, anticonvulsants
outline how lithium works in BPD treatment
unknown mechanism of action despite 60 years of use
may inhibit dopamine function
may target glycogen synthase kinase 3 beta which has a role in dopamine transmission
neuronal plasticity frequent because of angiogenesis
outline anticonvulsants within BPD treatment
e.g Valproate, Carbamazepine
mechanism of action unknown
block voltage gated sodium channels which decreases neuronal excitability?
inhibit glutamate function?
enhance GABA inhibitory function?
outline Valproate proposed mechanism of action
increases GABA transmission
GABA released into synapse->broken down by transaminase and recycled
Valproate enhances GABAa as induces GAD (enzyme for GABA synthesis) but at same time inhibits SSDH and GABA transaminase
what would you expect from TCA/SSRI pharmacology
they would be effective immediately, but they have 2-3 week lag time before therapeutic benefit is apparent
what are some possible explanations for the delayed therapeutic effect of antidepressant action
- 5-HT is increased acutely but produces therapeutic effect by trophic action which results in synaptic remodelling
- acute autoreceptor activation restrains the ability of SSRIs to increase synaptic 5-HT and emergence of therapeutic efficacy relates to autoreceptor desensitisation
what is the evidence for the trophism hypothesis?
when rats are given SSRIs it increases BDNF (brain derived neurotrophic factor) expression
its possible BDNF and/or trophic factors cause synaptic remodelling which is required for therapeutic effect
do different types of antidepressants all increase BDNF?
yes
same with electroconvulsive therapy
outline how and why serum BDNF is affected in depressed patients
chronic SSRI use alters the expression of CREB and Ca2+ binding protein pII, leading to transcription of genes like BDNF which controls neuronal plasticity, and is co-regulated with 5-HT
what did one study find about serum BDNF in depressed patients and the effect of antidepressants
significant increase in those treated with antidepressants compared to drug naive people
how does BDNF fit into the HT/HPA hypothesis?
BDNF and 5-HT co-regulate one another
5-HT stimulates expression of BDNF
BDNF enhances the growth and survival of 5-HT neurones
how are autoreceptors activated by SSRI?
SSRI blocks transporter , 5-HT accumulated in synapse,
5-HT is also at cell body region and acts on 5-HT1a autoreceptor, it is activated and negative feedback blocks the A.P, so activity off and release is decreased
normally there is balance between inhibition and increase
why does autoreceptor desensitisation happen?
overtime, continual activation of autoreceptor leads to desensitisation
no more negative feedback
5-HT is released again - need this to happen to see therapeutic effect
in summary what is the autoreceptor desensitisation hypothesis?
acute autoreceptor (5-HT1a) activation inhibits 5-HT neuronal activity
results in decreased 5-HT release at terminal and restrains ability of SSRIs to increase synaptic 5-HT
emergence of therapeutic efficacy relats to autoreceptor desensitisation
