6 - depression: pathophysiology and clinical management Flashcards
what is depression?
a state of low mood and aversion to activity that can have a -ve effect on a person’s thoughts, behaviour, feelings, world view, and physical well-being
there is an increased risk of depression in what medical conditions?
hypothyroidism, Addison’s disease, MS, influenza, post-stroke, menopause, alcohol/drug abuse
depression is a side effect of what drugs?
corticosteroids, beta blockers, statins, oral contraceptives (particularly progestogens) etc…..
in psychiatry, what 2 ways is the word ‘depression’ normally used in?
- as a SYMPTOM — ie. feeling down, depressed or hopeless
- as shorthand for a sustained period of mental illness which is more correctly called a major depressive episodes (MDE) or a depressive episode
what is major depressive disorder (MDD)?
a mental disorder characterised by recurrent major depressive episodes or a single chronic episode
what is anhedonia?
having little interest or pleasure in doing things
what is psychomotor retardation?
moving or speaking so slowly that other people could have noticed
what is psychomotor agitation?
being so figety or restless that you have been moving around a lot more than usual
what is the depression test questionnaire?
PHQ-9
how is a major depressive episode diagnosed?
5+ symptoms present during same 2 week period and represent a change from normal
- either anhedonia or depressed mood must be present
- cause significant distress or impairment of functioning
- not part of bipolar disorder
- not due to the direct psychological effects of a substance (alcohol, drug, medication)
- not better accounted for by bereavement
5 or more in green
is the burden of depression 50% higher for females or males?
females
what are the 2 types of monoamines?
catecholamines and indoleamines
name 2 catecholamines
dopamine and noradrenaline
name an indoleamine
serotonin (5-HT)
describe catecholamine structure
catechol moiety + amine side chain
= benzene ring with 2 OH side groups and amine side chain
describe indoleamine structure
- indole moiety + amine side chain
= bicyclic benzene ring fused to form pyrrole ring and amine side chain
what are catecholamines derived from?
tyrosine amino acid
what is serotonin derived from?
tryptophan
both dopamine and 5-HT are synthesised in a 2 stage enzymatic process involving what 2 steps?
- hydroxylation
- decarboxylation
what enzyme is used for the decarboxylation step in both dopamine and 5-HT synthesis?
L-Aromatic amino acid decarboxylase (L-AADC)
describe dopamine synthesis
tyrosine — (tyrosine hydroxylase TH) —> L-DOPA —(L-AADC) —> dopamine
describe noradrenaline and adrenaline synthesis
dopamine —(dopamine B-hydroxylase DBH)—>noradrenaline —(phenylethanolamine N-methyltransferase)—> adrenaline
describe serotonin synthesis
tryptophan —(tryptophan hydroxylase)—> 5-hydroxytryptophan —(L-AADC)—> 5-hydroxytryptamine = serotonin
monoamines function as what?
both neurotransmitters and hormones, depending on where they’re produced
catecholamines act as hormones when produced by what?
adrenal glands (majority of adrenaline made here)
where is 90% of serotonin found?
in enterochromaffin cells in the GI tract — regulate intestinal movements
describe the noradrenaline system
- active transport of tyrosine across BBB
- converted into NA in neuronal cell bodies in pons, particularly locus ceruleus
- NA packaged into vesicles in cell body and transported along axon to terminals for release
NA system extends extensively to entire brain and upper spinal cord
what is tyrosine
a non-essential large neutral amino acids derived from phenylalanine and the diet
where is locus ceruleus?
in dorsal pons
cell bodies of noradrenergic neurons form nuclei where?
only in pons
what is tryptophan?
- a dietary, essential, large neutral amino acid (LNAA)
- absorbed from GI tract into bloodstream
describe the 5-HT system
- active transport of tryptophan across BBB
- converted into 5-HT in neuronal cell bodies in chain of brainstem nuclei (raphe nuclei), particularly the dorsal and medial raphe
- 5-HT packed into vesicles and transported along axon to terminals for release
5-HT system extends extensively to entire brain
where is raphe nuclei?
runs entire length of brainstem from medulla to midbrain
signal by 5-HT and NA after being released into synaptic cleft is terminated by what 2 methods?
reuptake and enzymatic degradation
what are the methods of termination for 5-HT and noradrenaline?
serotonin
- SERT = serotonin reuptake transporter
- MAO-A = monoamine oxidase
NA
- NAT = noradrenaline reuptake transporter
- MAO-A
- COMT = catechol-O-methyl transferase
where is the conc of the reuptake enzymes highest and what is the effect of this?
the conc of these reuptake enzymes is higher in the terminal than in the synapse, so that when the neurotransmitters are taken back up into the terminal the majority undergoes enzymatic degradation there too, by MAO-A for serotonin, and by both MAO-A and COMT in the case of noradrenaline
what happens to the small proportion of neurotransmitters that evade enzymatic degradation after reuptake?
recycled directly into vesicles for further release
what does MAO-A (monoamine oxidase) do?
break down 5-HT and NA into metabolites
what are the main metabolites for 5-HT and NA enzymatic degradation?
5-HT —> 5-HIAA = 5-hydrpoxyindole acetic acid
NA —> VMA (vanillyandelic acid) + MHPG
NA that survives reuptake of enzymatic degradation is free to do what?
act at a range of noradrenergic receptors