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Pharmacology > Antidepressants > Flashcards

Antidepressants Flashcards

1
Q

what is depression?

A
  • affective mental disorder
  • often associated with disorders including anxiety, eating disorders and drug addiction
  • multiple brain regions involved: prefrontal cortex, amygdala, hippocampus
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2
Q

what are the 2 types of depression?

A

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

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3
Q

what are the symptoms of depression?

A
  • 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
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4
Q

what is the diagnosis and risk of depression?

A
  • 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
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5
Q

which brain regions are implicated in depression?

A
  • subgenial cingulate cortex/nucleus accumbens (NAc)
  • ventral tegmental area (VTA)
  • amygdala
  • hypothalamus, hippocampus
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6
Q

how is the nucleus accumbens/cingulate cortex involved in depression?

A

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

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7
Q

how is the ventral tegmental area involved in depression?

A
  • 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
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8
Q

how is the amygdala involved in depression?

A
  • 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`
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9
Q

how is the hypothalamus and other limbic regions such as the hippocampus involved in depression?

A
  • 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
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10
Q

what is postnatal depression?

A
  • 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
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11
Q

why is treatment for depression so important?

A
  • 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
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12
Q

how do animal models show the effectiveness of antidepressants?

A

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

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13
Q

which neurotransmitters are involved in depression?

A
  1. 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
  2. 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
  3. glutaminergic (NMDA) neurodegeneration is implicated
    - overactivation of NMDA leads to neuronal apoptosis in depression
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14
Q

what evidence is there to support the role of monoamines in depression?

A
  • 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
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15
Q

which monoamines modulate different brain regions from the midbrain and brainstem nuclei?
Where is DOPA form
Where is 5HT from
Where is NA from

A
  1. dopamine from VTA
  2. serotonin from dorsal raphe in periaqueductal grey area
  3. NA from locus coeruleus

all areas are known to control alertness, awareness and emotion

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16
Q

what are the biochemical and clinical effects of antidepressants?

A
  • 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
17
Q

what drugs can be used as antidepressants?

A
  1. monoamine oxidase inhibitors (MAOIs): e.g. phenelzine (suicide inhibitor), moclobemide (reversible inhibitor)
    - prevent metabolism of monoamines
  2. tricyclic antidepressants (TCAs): ee.g. imipramine
    - blocks uptake of monoamines so they remain in cleft for longer
  3. selective serotonin reuptake inhibitors (SSRIs): e.g. fluoxetine
    - selectively controls serotonin levels
  4. monoamine receptor agonists
  5. drugs with selectivity for NA and serotonin uptake inhibitors
18
Q

what is the mechanism of action of MAOIs?

A
  • 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
19
Q

what is the major side effect of MAOIs?

A
  • NA depletion PNS in in sympathetic synaptic terminals causes postural hypotension and headaches
20
Q

what is the cheese effect of MAOIs?

A

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

21
Q

which antidepressant avoids the cheese effect?

A

moclobemide: selective, reversible MAO-A inhibitor

22
Q

what is the mechanism of action of TCAs?

A
  • TCAs inhibit neuronal reuptake of serotonin and NA (little selectivity)
23
Q

what are the unwanted effects of TCAs?

A

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

24
Q

what is the mechanism of action of SSRIs?

A
  • inhibit serotonin reuptake transports so that more serotonin remains in the cleft
  • less side effects as it is highly selective

e.g. fluoxetine, citalopram

25
Q

what are SNRIs?

A

inhibit NA reuptake transporters so that more NA remains in the cleft
- high selectivity

26
Q

what is the noradrenergic pathway in the CNS? how does it contribute to depression?

A
  • 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
27
Q

how do antidepressants target the noradrenergic pathway in the CNS?

A

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

28
Q

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

A
  • 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
29
Q

what is the precursor of serotonin?

A
  • 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
30
Q

what are SSRIs used for and why may they be preferable to MAOIs and TCAs? what are their side effects?

A
  • 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

31
Q

what are the serotonin receptor families?

A

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

32
Q

what is LSD?

A

a psychedelic
- agonist for 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6 receptors

33
Q

what is the mechanism of action of SSRIs?

A
  • 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
34
Q

what is citalopram?

A

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

35
Q

how does BDNF neurotrophin relate to treatment of depression?

A

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

36
Q

what is BDNF? how does it relate to depression?

A

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

37
Q

what other approaches are available for treating depression?

A
  • antiepileptic drugs and atypical antipsychotics can be mood stabilisers
  • electroconvulsive shock therapy (ECT), electromagnetic therapy (EMT), deep brain stimulation and vagus stimulation
38
Q

how can bipolar disorders be treated?

A

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

Pharmacology (10 decks)

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