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
what are SNRIs?
inhibit NA reuptake transporters so that more NA remains in the cleft
- high selectivity
what is the noradrenergic pathway in the CNS? how does it contribute to depression?
- main cell bodies found in locus coeruleus
- functions: arousal, mood, blood pressure regulation, pain
- NA role in regulating sensory processing relates to its withdrawal: increased sleep, anorexia
- deficiency in central NA transmission contributes to depression
how do antidepressants target the noradrenergic pathway in the CNS?
SNRIs (NA reuptake inhibitors) target the frontal cortex to improve mood
TCAs and MAOIs affect NA transmission in the brain
- excessive central stimulation leads to tremors, excitement, insomnia and in overdose, convulsions
- causes increased appetite -> weight gain
what is the serotonergic pathway in the CNS? how does it contribute to depression?
Where is it produced
What are its functions
What process does it regulate
- 5-HT produced in raphe nuclei
- functions: hallucinations, sleep/wake, mood/emotion, feeding, nociception and sensation, body temp
- serotonin regulates the limbic processes and relates to anhedonia
- anhedonia is the inability to gain pleasure from normally pleasureable experiences
what is the precursor of serotonin?
- tryptophan is the precursor to serotonin and is an essential amino acid found in protein rich food
- trp can induce calm and acts as a sleep aid
what are SSRIs used for and why may they be preferable to MAOIs and TCAs? what are their side effects?
- SSRIs: treat depression, anxiety, migrains
- less sedating and less antimuscarinic effects than TCAs as there is no receptor blocking
side effects: nausea, insomnia, sexual dysfunction
what are the serotonin receptor families?
7 subfamilies of serotonin receptors:
- 5-HT3 is the only ionotropic receptor, the rest are GPCRs
- 5-HT1 and 5-HT5 are Gi: 5-HT1 is involved in depression so is often a drug target
- 5-HT2 is Gq
- 5-HT4, 5-HT6, 5-HT7 are Gs
they influence biological and neurological processes such as aggression, anxiety, appetite, cognition, learning, memory, mood, sleep
what is LSD?
a psychedelic
- agonist for 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6 receptors
what is the mechanism of action of SSRIs?
- 5-HT1A receptors inhibit serotonin release and inhibit AP firing at synapses
- at first SSRIs decrease the serotonin levels even further, so patient depression gets worse (at first)
- 5-HT1A receptors then become DESENSITISED, so neuron removes these autoinhibitory receptors
- this leads to increased neuronal activity and more serotonin release
what is citalopram?
SSRI which binds to the P-glycoprotein molecule in the BBB which transports drugs back into bloodstream
human polymorphisms in genes encoding the p-glycoprotein cause altered efficacy of antidepressants
how does BDNF neurotrophin relate to treatment of depression?
increased activity-dependent release of BDNF in mesolimbic areas contributes to slow effects of antidepressants:
- leads to increased activation of CREB to produce more BDNF which stabilise synapses of overactive neurons
- in depressed patients, there is a loss of BDNF, so synapses are not stabilised
- antidepressants boost serotonin to boost BDNF levels to stabilise synapses
what is BDNF? how does it relate to depression?
a neurotrophin which stabilises syapses
- BDNF expression is abundant in adult limbic structures
- if there is reduced BDNF, synapses are less stable, causing depressive symtoms
- chronic stress is caused by a decrease in BDNF in the hippocampus
- treatment with antidepressants increases BDNF signalling
what other approaches are available for treating depression?
- antiepileptic drugs and atypical antipsychotics can be mood stabilisers
- electroconvulsive shock therapy (ECT), electromagnetic therapy (EMT), deep brain stimulation and vagus stimulation
how can bipolar disorders be treated?
lithium narrow therapeutic window:
- plasma levels must be monitored
- permeates voltage-gated Na+ channels, inhibits inositol monophosphatase, AKT signalling and glycogen synthase
- kinase 3 (GSK3 involved in apoptosis) signalling
