Antidepressants Flashcards
what is depression?
- affective mental disorder
- often associated with disorders including anxiety, eating disorders and drug addiction
- multiple brain regions involved: prefrontal cortex, amygdala, hippocampus
what are the 2 types of depression?
bipolar depression = depression alternates with mania
- excessive exuberance, enthusiasm, self confidence combined with irritability, impatience, aggression
- hereditary
- episodes last several weeks
unipolar depression: mood swings always in the same direction
- reactive (75%): associated with stressful life and anxiety
- endogenous (25%): unrelated to external stresses
what are the symptoms of depression?
- low mood (anhedonia), negative thoughts, misery, pessimism,
irritability - apathy: loss of interest in daily activities
- severe loss or gain in weight/appetite
- low self-esteem, feelings of worthlessness or guilt
- Sleep disturbance: insomnia or excessive sleeping
- loss of appetite & libido
- diminished ability to think/concentrate
what is the diagnosis and risk of depression?
- subjective-qualitative: patients exhibit depressed behaviour for >2 weeks and symptoms disrupt normal social and occupational function
- stressful life events: personal loss, financial or professsional crisis
- genetic risk is 40%
- can be a secondary effect of an illness (e.g. Cushing’s) or the side effect of a drug
which brain regions are implicated in depression?
- subgenial cingulate cortex/nucleus accumbens (NAc)
- ventral tegmental area (VTA)
- amygdala
- hypothalamus, hippocampus
how is the nucleus accumbens/cingulate cortex involved in depression?
Deep brain stimulation of NAc/CC has an antidepressant effect on individuals with treatment-resistant depression
- mediated through inhibiting the activity of these regions by depolarisation blockade or stimulation of passing axonal fibres
- depression in this area causes increased secretion of BDNF
- NAc is part of limbic system and uses dopamine as neurotransmitter
how is the ventral tegmental area involved in depression?
- there is an increased activity-dependent release of BDNF in the mesolimbic dopamine circuit of the VTA
- this mediates the susceptibility to social stress
- occurs through activation of transcription factor CREB by phosphorylation
how is the amygdala involved in depression?
- important limbic node for processing emotions e.g. fear
- depression occurs through decreased concentrations of neurotrophins like BDNF and decreased CREB activity
- decreased activity of CREB and therefore less BDNF causes high concs of cortisol which increase anxiety`
how is the hypothalamus and other limbic regions such as the hippocampus involved in depression?
- metabolic hormones such as leptin and ghrelin produce mood-related changes via effects on hypothalamus and limbic regions
- disruption in the signalling of these hormones leads to abnormal feeding behaviour
-affects limbic regions such as dorsal raphe, locus coeruleus and prefrontal cortex - hippocampus is affected by decreased BDNF so less memory formation
what is postnatal depression?
- usually occurs 2-8 weeks after delivery
- can stay over a year after birth
- alters the baby’s brain waves if the mother is stressed due to epigenetic changes
why is treatment for depression so important?
- many depressed people don’t get help
- counselling in combination with antidepressants is recommended
- antidepressants enable changes in brain chemistry that only these drugs can achieve
- even if the reason for the depression is gone, people may remain depressed due to the biochemical changes the depression has caused at synapses
- antidepressants take around 6 weeks to show any effects
how do animal models show the effectiveness of antidepressants?
Learned helplessness experiment:
- animals develop a range of behavioural, neurochemical and biochemical changes that reflect symptoms seen in depression
- changes in transcription factors in several brain regions can be seen e.g. VTA reward pathways can be mimicked in animals
- learned helplessness of animal via random electric shocks
- analgesics do not decrease the animal’s depressed behaviour
- antidepressant drugs help increase the no. of attempts the animal makes to escape
- model mirrors the therapeutic delay of 4-6 weeks when treating humans
which neurotransmitters are involved in depression?
- functional deficit in serotonin and NA
- long term trophic effects on neuronal stability and generation
- act through 5-HT1A receptors and alpha2-adrenoreceptors to promote neurogenesis
- drugs used to correct these monoamine deficits take weeks to have effect - BDNF/TrkB reduced neurogenesis
- BDNF exerts action through TrkB
- in depression, there are reduced levels of BDNF, reduced activation of TrkB and therefore reduced neurogenesis - glutaminergic (NMDA) neurodegeneration is implicated
- overactivation of NMDA leads to neuronal apoptosis in depression
what evidence is there to support the role of monoamines in depression?
- iproniazid, the first antidepressant, is a MAO inhibitor, causing increased levels in NA and serotonin transmission as their breakdown is stopped
- reserpine, which produces depression and parkinsonism, depletes the stores of monoamine transmitters
- tricyclic antidepressants inhibit reuptake transporters of serotonin and/or NA so more remain in the cleft
which monoamines modulate different brain regions from the midbrain and brainstem nuclei?
Where is DOPA form
Where is 5HT from
Where is NA from
- dopamine from VTA
- serotonin from dorsal raphe in periaqueductal grey area
- NA from locus coeruleus
all areas are known to control alertness, awareness and emotion
what are the biochemical and clinical effects of antidepressants?
- they have an immediate biochemical effect, but their clinical effects may take 3-4 weeks to emerge
- time lag suggests that regulatory mechanisms of receptors are involved
- effect of antidepressant treatments involve downregulation of serotonin autoreceptors e.g. somatodendritic 5-HT receptors on raphe neurons, or auto- and heteroreceptors on NA and serotonin terminals
what drugs can be used as antidepressants?
- monoamine oxidase inhibitors (MAOIs): e.g. phenelzine (suicide inhibitor), moclobemide (reversible inhibitor)
- prevent metabolism of monoamines - tricyclic antidepressants (TCAs): ee.g. imipramine
- blocks uptake of monoamines so they remain in cleft for longer - selective serotonin reuptake inhibitors (SSRIs): e.g. fluoxetine
- selectively controls serotonin levels - monoamine receptor agonists
- drugs with selectivity for NA and serotonin uptake inhibitors
what is the mechanism of action of MAOIs?
- they inhibit MAO type A to produce antidepressant effect
- MAO regulates intraneuronal levels of monoamines and is important for inactivation of endogenous and ingested amines e.g. tyramine
- MAOIs, e.g. phenelzine (suicide inhibitor) blocks MAO, resulted in a rapid and sustained increase in serotonin, NA and dopamine
what is the major side effect of MAOIs?
- NA depletion PNS in in sympathetic synaptic terminals causes postural hypotension and headaches
what is the cheese effect of MAOIs?
when combined with dietary sources of tyramine, MAOIs cause the hypertension cheese effect:
- MAO inhibition leads to buildup of endogenous amines and causes increased leakage of amines which indirectly activate sympatomimetic amines such as tyramine
- tyramine enters sympathetic neurons, displaces NA from vesicles and then causes leakage of NA into cleft
- this leads to a hypotensive crisis
which antidepressant avoids the cheese effect?
moclobemide: selective, reversible MAO-A inhibitor
what is the mechanism of action of TCAs?
- TCAs inhibit neuronal reuptake of serotonin and NA (little selectivity)
what are the unwanted effects of TCAs?
Off-target side effects associated with:
- anticholinergic effects: mAChR block, dry mouth, blurred vision, constipation
- adrenergic effects: a2 block, postural hypotension
- histaminergic effects: H1 block, sedation
dangerous in overdose: confusion, mania, cardiac disrhythmias, coma and respiratory depression
- cardiotoxicity due to blocking of HERG channels
what is the mechanism of action of SSRIs?
- inhibit serotonin reuptake transports so that more serotonin remains in the cleft
- less side effects as it is highly selective
e.g. fluoxetine, citalopram
