Affective disorders: Neurobio and treatment Flashcards
(34 cards)
Neurobiology of major depression
Adverse childhood experience
Current Stress (Financial hardship, migration, family, multi genetic factors)
Genetic factors
ALL CONTRIBUTING TO DIRECT decrease in 5HT and NA function and INDIRECTLY same through HPA axis function and cortisol effects leading to depressive syndrome
Aetiology of depression
Multifactorial
Incompletely understood
Interactions of genetic factors, childhood adversities, past hx of mood disorders, psychological predisposition (neuroticism)
Often precipitated by stressful life events
Monoamine dysfunction in depression
All traditional antidepressants affect 5HT/NA systems
History of antidepressants
Until the 1950s the hypothesis of depression stemmed from intrapsychic conflicts (Freud)
In the 1950s
- Monoamine oxidase inhibitors were introduced. Iproniazid (first MAOi) was used for treatment of TB but found to have antidepressant effects.
- Tricyclics –> (Impapramine)antihistaminic was found to have an antidepressant effect
All traditional antidepressants affect:
All traditional antidepressants affect 5HT/NA systems
- -> decreased 5HT concentrations (acute tryptophan depletion) studies (tryptophan is an experimental way to investigate serotonin bc it is the precursor. A way to reduce tryptophan in a noninvasive way is to change diet)
- -> Reduced 5 HT transporter in post-mortem studies (post mortem studies showed a reduction in 5 HT transporters which further validates the serotonin hypothesis of depression)
PET studies in depression
found a reduction in 5HT transporters
What part of the brain is the source of Noradrenaline
Locus Coeruleus
What part of the brain is the source of serotonin
Raphe Nuclei
Both serotonin and noradrenaline
have ascending tracts to the cerebral cortex and limbic area as well as descending tracts to the spinal cord.
Their cell bodies for these tracts originate in major nuclei of the midbrain.
Each nuclei has ascending tracts which project to brain regions (PFC and limbic system) involved in depressive symptoms as well as ascending and descending tracts involved in pain suppression
The monoamine hypothesis of depression
suggests a deficiency in synaptic levels of serotonin and noradrenaline in key CNS pathways underlying depressive illness
Monoamines and depressive symptoms
Noradrenaline - attention Serotonin - impulsivity and suicidal ideation Dopamine - psychomotor activation and euphoria All three - mood, emotions and cognitive functions NA and Dopamine - motivation and enerfgy Noradrenaline and serotonin - anxiety and irritability Serotonin and dopamine - sleep, appetite, sexual functions and aggressiveness
1st generation antidepressants
MAOi eg Phenelzine, Tranylcypromine
- Nonselectively inhibit enzymes involved in the breakdown of monoamines including serotonin, dopamine and norepinephrine
TCA eg amytryptiline and clomipramine
- nonselectively inhibit the reuptake of monoamines, including monoamines, including serotonin, dopamine and norepinephrine
2nd generation antidepressants
- SSRI: eg setraline, citalopram, fluoxetine
- SN(noradr)RI: eg venlafaxine, duloxetine
- alpha 2 adrenoreceptor and 5HT2c antagonist (modulate serotonin and NA release) eg Mirtazapine
- dopamine- noradrenaline reuptake inhibitor eg bupropion
SSRIs
Efficacy equal to tricyclics in outpatients
Large spectrum of action (OCD, PTSD, Panic, GAD, social anxiety)
Low toxicity and safe in overdose
The initial treatment phase is the most delicate, due to prevalence of side effects over benefits- slow titration
Side effects:
- GI symptoms (nausea, diarrhea)
- Headache, irritability, anxiety
- Reduction of libido and sexual dysfunction
Gradual suspension to avoid withdrawal symptoms (worse with venlafaxine and paroxetine due to short half-life)
Side effects of TCAs
Anticholinergic effects eg constipation, dry mouth, drowsiness
cardiac toxicity in overdose
Orthostatic hypotension
Side effects of MAOi
Anticholinergic effects eg dry mouth, GI, drowsiness
Insomnia, food interactions ie tyramine leading to hypertension crises
Side effects of venlafaxine
nausea, vertigo, headache, insomnia
Side effects of mirtazapine
drowsiness, sedation, hypotension, increased appetite and weight gain
Gene environment interactions evidence for depression
People were stratified to two parameters
1) life adversity
2) gene for type of 5HT transporter
HPA dysfunction in mood disorders
The level of cortisol is higher in people with depressive disorder
If you give the dexamethasone test (night before) then bc of feedback on HPA axis will usually suppress cortisol release the following day
However people with depression do not have the typical suppression after dexamethasone. They continue to have the normal circadian rhythm as if their cortisol was not suppressed. This means there is a reduced sensitivity at GR level and HPA activity
Inflammation and depression
Raised plasma cytokine levels (IL-6, TNF-α) and inflammatory markers
High comorbidity between chronic inflammation and depression
Administration of cytokines provokes depressive symptoms
Microglial activation in brain of depressed patients (PET studies)
Hippocampal size in depression
Decreases in size
Also happens when exposed to high levels of cortisol
evidence link?
Neural systems involved in depression
increased activity (Amy; VST, PFC) to negative emotional stimuli (fearful faces) decreased activity (VST) to positive emotional stimuli, and during receipt and anticipation of reward
bias of attention towards negative emotional stimuli, and away from positive emotional and reward- related stimuli
Factors that play a role in bipolar disorder
Catcholamines Oxidative stress Neurotrophins Inflammation Stress hormones, glucocorticoids
