Mood Disorders 2 Flashcards
Monoamine oxidase A
present in CNS: role to metabolize 5HT, NA, dopamine
important in periphery- metabolizes Dietary monoamines
Monoamine oxidase B
CNS: primarily metabolism of dopamine;
in periphery metabolize Dietary monoamines (but not as important as A)
found in presynaptic nerve terminal, Located on outer mitochondrial membrane
inhibiting MAO
increases presynaptic MA, boosting MA transmission
weakness of MA hypothesis
effect on monoamines immediate but takes two weeks to see the clinical effect of anti depressants
examples of older MAO inhibitors
phenelzine, tranylcypromine, isocarboxazid
older MAO inhibitors
Non selective (A vs B) irreversible inhibitors
Very effective in MDD, bipolar (+ mood stabilizer), anxiety disorders
Doctors very reluctant to prescribe due to large number of interactions
cheese reaction
cheese reaction
Tyramine normally broken down in liver by MAO
When MAO-A inhibited, tyramine from diet can cause big problems!
-cant cross the BBB, but can cause problems in the periphery
tyramine
Tyramine acts as a false substrate for NET (noradrenaline transporter) so can be taken up into vesicles and displace noradrenaline
That noradrenaline then gets released into the synapse via non-vesicular release
This causes massive activation o the sympathetic nervous system and in turn hypertensive crisis
-this can result in stroke and death
People taking irreversible non-selective inhibitors need to be careful of things in their diet because it could trigger this adverse reaction
what causes serotonin syndrome
SSRI or tricyclic AD with MAOI
what is serotonin syndrome?
Massive increase in synaptic serotonin
confusion, agitation
muscle twitching, sweating
seizures, arrhythmias, coma (death)
what is the warrior gene
a 30 base repeated sequence inn the promoter of monoamine oxidase. Copies vary from 2-5 and affect the expression of MOA-A
alleles that result in low expression (such as the two repeat variant) have been associated with increased risk of violent behaviour
-however this is likely to be dependent on the presence of other risk factors such as childhood trauma
example of newer MAOI
moclobemide
newer MAOI
selective for MAO-A
reversible
-therefore we dont get dietary interactions
-if concentration of tyramine goes up it will be able to compete with the MAO inhibitor for the active site of MAO and we still get the breakdown of MAO
very fewer adverse affects
relatively fast onset
useful in MDD, bipolar (plus mood stabiliser), anxiety disorder
prejudice against MAO inhibitors because of the dangers associate with older drugs
SSRI meaning
selective serotonin reuptake inhibitors
SNRI meaning
serotonin/ noradrenaline (norepinephrine) reuptake inhibitors
NRI meaning
noradrenaline reuptake inhibitors
what are the most widely used anti-depressants (2nd generation AD drugs)
SSRIs
examples of SSRIs
citalopram, paroxetine, sertraline, fluoxetine
first SSRI drug used
fluoxetine
example SNRIs
venlafaxine, duloxetine
examples NRIs
reboxetine, atomoxetine
what are NRIs, SNRIs and SSRIs useful for?
major depressive disorders, anxiety disorders, premature ejaculation
risk of suicide in newer MAOIs compared to other drugs
much lower risk than TCA and older MAOIs
2nd/ 3rd generation reuptake inhibitors
block the transporter (SERT and NET), increasing synaptic concentrations of the neurotransmitter
have side effects that tend to be short lived and manageable
SSRI, SNRI and NRI unwanted effects
nausea, anorexia in many
anorexia in some
discontinuation syndrome in all
anorgasmia
increased aggression, suicide ideation and self harm possible in the early stages of treatment
discontinuation syndrome
flu like symptoms if you stop taking the drug suddenly, insomnia, motor and cognitive problems
normally last like 1 to 4 weeks
some people find it very difficult to deal with so doctors suggest that patients taper off the dose
can occur in up to 50% of people
anorgasmia
lack of sensitivity to sexual stimulation
beneficial effect if you suffer from premature ejaculation (sometimes useful to treat men)
why to NICE only recommend the SSRI fluoxetine
fluoxetine has a good benefit to risk ratio
drugs increase suicide ideation, which can be dangerous as people may still feel depression in the early stages of treatment but have the energy to follow through on ideation
when are 2nd generation MOAIs recommended
only after other treatments, like talking therapies, haven’t worked
affects of tricyclic antidepressants
mAChR: important ANS
H receptors: sedative effects
5HT receptors
alpha1 adrenergic
very dirty drugs
when were tricyclic antidepressants
developed in 1950s
first line treatment for MDD
what have TCA been replaced by
largely by SSRIs and SNRIs
when are TCAs used
sometimes used as a last resort treatment for resistant MDD
used at lower doses to treat difficult difficult to manage pain
downsides of TCA
many side effects
high suicide mortality in overdose
examples of tricyclic antidepressants
amitriptyline, nortriptyline, imipramine
what are the worst anti depressants for discontinuation syndrome
duloxetine and venlafaxine
SSRIs such as citalopram and paroxetine can also produce significant withdrawal symptoms
what can discontinuation syndrome be explained by
the oppositional tolerance model
oppositional tolerance model
when a drug perturbates neurotransmitter systems, the brain will down or up regulate components of the system to try and oppose the actions of the drugs
why has controversy regarding the efficacy of antidepressants risen
partially due to a lack of transparency regarding clinical trials
what is needed to get a drug licenced, what are the problems with this system
a pharmaceutical only needs to submit 2 or 3 successful trials to the regulator
they may have conducted many other clinical trials which have been unsuccessful in the past. Data from these trials have only rarely been published
Makes it difficult to know how much bias has happened due to lack of reporting of unsuccessful trials
what type of drug is NaSSA
Noradrenergic and specific serotonergic antidepressant
example of a NaSSa
mirtazapine
actions of mirtazapine
Antidepressant actions probably due to actions as an Antagonist of 𝛂2 adrenoceptors and 5HT2A, C receptors
Highly sedating (H1 antagonist)
has highest receptor affinity for H1 histamine receptors and this cause major sedating effect and increased appetite
side effects of miratazapine
appetite in crease
sedation
discontinuation syndrome
has fewer side effects than many of the other drugs we’ve met
generally very effective and well tolerated
faster onset of action than other AD drugs
mirtazapine mechanism
Find alpha 2 adrenoreceptors on presynaptic nerve terminals of serotonergic and noradrenergic neurons
-function to inhibit neurotransmitter release via feedback inhibition
-in serotonergic neurons they are responding to noradrenaline that has drifted in from neighbouring noradrenergic terminals
Mirtazapine inhibits these receptors leading to an increased release of monoamines (S or N)
Has an effect on postsynaptic 5HT2a2c receptors
-These receptors seem heavily involved in mood and when they are overactive may contribute to depression and anxiety
Additional effect: can be used to reduce nausea and vomiting
Act as an antagonist of 5HT3 receptor
-ligand gated ion channel, actions here produce antiemetic effects
newer treatments for depression
esketamine and ketamine, psychedelic drugs and agomelatine
esketamine
S-enantiomer of ketamine (which is racaemic)
strong antidepressant effects in clinical trials
occurs quickly (4 hrs after dose)
nasal spray recently been licenced in the uk to treat depression
ketamine
dissociative anaesthetic
strong antidepressant effects in clinical trials
effects occur quickly after administration
administered intravenously
effects of a single doses usually last at least 10 days
-maintenance therapy would presumably involve a dose every two weeks
what does ketamine abuse cause?
bladder dysfunction
neuronal lesions
mechanism of esketamine and ketamine
related to their actions as non competitive antagonists of NMDA?
how this links to depression is unclear
psychedelic drugs as depression treatment
act to resolve depression much quicker than conventional antidepressants
-many see improvements in one week
legal restrictions on lsd, psilocybin and MDMA make it difficult to see how these could be licenced in the UK `
agomelatine as a treatment of depression
moderately potent agonist of 5HT receptors
main mechanism of action as a melatonin receptor agonist
approved in europe for the use of MDD treatment in 2009
may also give some benefits in anxiety disorders
prophylaxis
mood stabilising drugs
prevent swinging between depressed and manic mood
examples of prophylaxis
lithium
anticonvulsant: e.g., lamotrigine and valproate
olanzapine (antipsychotic)
managing mania
if already on mood stabilising drug then increase its dose
antipsychotic. e.g., olanzapine or quetiapine
-on top of mood stabilising drug or stand alone
-may add lithium or valproate
managing depression (bipolar)
add olanzapine and fluoxetine, or olanzapine/ quetiapine to existing drugs
if someone is on an antidepressant and they present with mania there is a good chance it was precipitated by the antidepressant. They should be taken off immediately
lithium possible mood stabilising mechanism
inhibition of teh IP3 pathway
changes neurotropic factors
inhibition of glycogen synthase kinase - 3
modulation of cAMP signalling
problems with lithium
narrow therapeutic window - need to monitor plasma levels
lots of adverse effects
other drugs to treat bipolar
NRIs
ketamine
opioids
drugs acting via GTC mechanisms
talking therapies for depression
group physical activity
cognitive behavioural therapy
CBT for more severe forms of depression
electroconvulsive therapies
done using anaesthetics and muscle relaxants
can be highly effective and produces a rapid resolution of depression in many patients and can also be used for bipolar disorder and schizophrenia (mainly for catatonia)
side effects of ECT
most common: memory loss.
-Usually transient, but for some people it can last a long time or even be permanent.
short term effects
nausea and loss of appetite,
a headache
confusion/drowsiness.
longer term cognitive problems such as difficulty concentrating and assimilating new information
blunting of their emotional responses.
animal model of depression
introducing a young animal into a cage with a dominant older male rat
subjecting the animals to chronic unpredictable mild stress was such as illuminating the cage at night, withholding food and water or tilting the cage.
Measures of depression in these models can be things like loss of interest in pleasurable stimuli such as sweetened water.
placed in a stressful situation from which it cannot escape. For example, being suspended by its tail or placed in a beaker of water from which it cannot escape. These situations can induce a condition called “learnt helplessness” or “behavioural despair”. Essentially, the animal will struggle or swim for a while before it becomes hopeless and passive and accepts the stress.
The time that the animal spends struggling/swimming and the time it spends immobile is a measure of how “depressed” it is.
