drugs for mood disorders Flashcards
depression
most common type of the affective disorder - mood and actions are innappropriate to circumstances
unipolar depression
major depression - the mood changes in the same direction
bipolar disorder
(manic depression) - oscillates between depression and mania (excessive enthusiasm and self-confidence, impatience and aggression)
monoamine theory of depression
hypothesized based on clinical effects of drugs that cause or alleviate symptoms of depression and their known neurochemical effects of monoaminergic transmission
a functional deficit of noradrenaline and serotonin in certain brain regions
problem with the monoamine theory
- doesnt differentiate between noradrenaline and serotonin as to which neurotransmitter plays a dominant role
drugs affecting either are equally effective - antidepressatn drugs have immidate neurochemical effect, yet symptom relief is not seen for two weeks, belived that serotonin and noradrenlaine are mediating long term antidepressant effects
imipramine
block noradrenaline and serotonin uptake
depressed schitzophrenics show mood improvement
ipromiazid
monoamine oxidase inhibitor (MAOI)
improved mood of depressed people
reserpine
inhibit noradrenaline and serotonin storage
patients developed depression
time scale of neurotransmission
immediate effects due to release of transmitters and fast synaptic transmission
long term effects due to structural remodelling and degeneration/regeneration
brain-derived neurotrophic factor BDNF
a member of the neurotrophic factor family
CNS development and neuronal plasticity
binds to TrkB (tropomyosin receptor kinase B), which activates three signalling pathways
all three pathways converge on the transcription factor CREB (cAMP response element binding protein) to up-regulate gene expression
how is BDNF produced in the body
prepro-BDNF (a precursor protein) - cleaved into pro-BDNF - further cleaved into mature BDNF
CREB
(cAMP response element binding protein)
up-regulates gene expression
what does BDNF bind
binds to TrkB (tropomyosin receptor kinase B), which activates three signalling pathways
all three pathways converge on the transcription factor CREB
chronic elevated levels of cortisol inhibits the transcriptional activity of of
CREB
chornic elevated levels of corticol is caused by
stress
reduced transcriptional activity of CREB causes
reduced BDNF expression > apoptosis of prefrontal cortex and hippocampus
increased transcriptional activity of CREB promotes
BDNF expression (BDNF binds to TrkB) > neurogenesis of prefrontal cortex and hippocampus
neuroplasticity theory of depression
depression is as a result of extended decreased BDNF levels in the hippocampus/prefrontal cortex
2 theories of cause of depressioon
- monoamine theory
- neuroplasticity theory
evidence for neuroplasticity theory
in animal studies, chronic stress decreased BDNF expression in hippocampus
antidepressant treatment increased BDNF levels in hippocampus
BDNF infusion into hippocapmus produced antidepressant like effects
post mortem analysis in humans shows decreased hippocampal BDNF levels in suicide victims and depressed individuals
selective serotonin reuptake inhibitors
bind to 5-HT transporter - block reuptake of 5-HT - elevate synaptic [5-HT], but
decrease release of 5-HT (due to negative feedback)
desensitisation of somatodendritic 5-HT1a receptor (weeks to develop) and increase in synaptic [5-HT]
4 examples of SSRIs
- fluoxetine (prozac)
- paroxetine
- sertraline
- citalopram
adverse effects associated with SSRIs
better side effect profile - due to no affinity for mAch receptors and histamine H1-receptors
safer than TCAs and MAOIs in overdose
5-HT2 receptor - agitation and insomnia
5-HT3 receptor - nausea
sexual dysfunction
‘serotonin syndrome’ if combined with MAOIs
CYP2D6-mediated drug-drug interactions - co-administration of fluoxetine with drugs that are metabolised by CYP2D6
serotonin syndrome
can occur if SSRIs are combined with MAOIs
mirtazapine
antagonist at A2 adrenoceptors, 5-HT 2A/C, 5-HT3, and H1 receptors
mirtazapine side effect profile
does not cause agitation and nsomnia at the 5-HT2 receptor (antagonist for 5HT2a/c)
does not cause nausea at the 5-HT3 receptor (antagonist)
lower tendency of sexual dysfunctions
also causes weight gain
no significant drug-drug interactions
how does mirtazapine work
released noradrenaline activates a2-adrenoceptor - inhibits noradrenaline release (negative feedback)
mirtazapine is a a2- adrenoceptor antagonist
mirtazapine is helpful when
alternative to SSRIs if SSRI- related side effects are problematic
tricyclic antidepressants
competitive binding at 5-HT and noradrenaline transporters - inhibit reuptake of 5-HT and noradrenaline - enhance synaptic [5-HT] and [noradrenaline]
adverse effects of TCAs
long acting - long half life
repeated dosing increases risk of adverse effects
antagonist at mAChR - dry mouth, blurred vision (atropine-like effects)
antagonist at H1-receptor - sedation
CYP2D6-mediated drug-drug interactions
should not be combined with MAOIs
what should TCAs not be combined with
MAOIs
MAOIs stand for
monoamine oxdase inhibitors
MAOIs act by
inhibit MAO-a and/or MAO-b
increases cytoplasmic concentrations of monoamines
increase in spontaneous leakage of monoamines
irreversible MAOIs
phenelzine
non selective - acts on MAO (a and b)
long acting
reversible MAOI
moclobemide
short acting
reversible
adverse effects of MAOIs
atropine like effects - dry mouth, nausea, insomnia
drug-drug interaction - other drugs that increase serotonin levels
cheese reaction
MAOI interact with tyramine rich food eg. cheese, tofu
causes hypertensive crisis - increase in sympathetic cardiovascular activity
minimal for moclobemide
why does tyramine react with MAOI
normally tyramine is metabolised by MAO in the small intestine and liver, preventing it from reaching the circulation
in the presence of MAOI this is reduced, meaning tyramine reaches the circulation where it is transported into the synaptic nerve terminal by the same transporter responsible for noradrenaline reuptake
it replaces noradrenaline stored in vessicles causing noradrenaline to be released into the cytoplasm and released into the synaptic cleft, increasing [noradrenaline] in the synapse, stimulating adrenergic receptors
ketamine
a non-competative NMDA receptor antagonist
rapid antidepressant actions (hours), including in treatment resistant depression
how is ketamine different
works to release BDNF that has already been synthesised
how is ketamine used
as a nasal spray - must be used in conjuction with an oral antidepressant
lithium
lithium carbonate - tablet
plasma concentration monitoring is crucial
lithium plasma level
clinically effective 0.5-1 mmol
toxicity >1/5 mmol
lethal 3-5 mmol
lithium clearance
renally cleared
monitoring - patients with renal impariment
use of drugs that effect renal functions - diuretics, NSAIDs
adverse effects of lithium
nausea, vomiting, diarrhoea, weight gain
prolonged treatment can cause renal tubular damage
prolonged treatment with lithium can cause
renal tubular damage
