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Medsci305 > Lecture 14: affective disorders > Flashcards

Lecture 14: affective disorders Flashcards

1
Q

Why will antipsychotic drugs bind to their receptors immediately while the clinical effects still take a while to occur?

A
  • There is something occuring long term either due to protein formation or changes to the secondary messenger pathways, or even repair of the brain which causes the clinical effect.
  • antipsychotics have been shown to stimulate proliferation and generate new brain cells in the brain repairing process
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2
Q

What are affective disorders?

A

depression or mania

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3
Q

What is the most common manisfestation of affective disorders?

A

major depression.

  • considered a very serious disease
  • listed as one of the top 2 most serious in the world with high effects on morbidity and mortality
  • reduces working time for patients suffering wth this disorder
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4
Q

What are the different types of depression

A
  • major depression (most common)

- post natal depression

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5
Q

What is the prevalence of major depression?

A

affects about 5% of the population per year

this equates to 1 in 4 women and 1 in 5 men

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6
Q

How is major depression diagnosed

A

one of the following symptoms recurring for at least two weeks:

  • general feelings of misery
  • apathy
  • pessimism
  • low self esteem
  • indecisivness/loss of motivation
  • retardation of thought/action (can’t stimulate actually doing anything
  • sleep disturbance (too much or too little sleep)
  • loss of appetite
  • recurrent thoughts of self harm/death
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7
Q

What is bipolar?

A

the opposite in spectrum to major depression
-it is also a recurrent affective disorder which can either be:

  1. repeated episodes of depression or mania or
  2. mixed episodes of a period of mania with no depression or mania with less depression
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8
Q

What are the biochemical theories of depression?

A
  • these state that depression is due to a reduction in monoamines (NA and 5-HT) in the synaptic left, and the impairment in the function of these neurotransmitters
  • the monoamine theory of mania is the opposite
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9
Q

What is the monoamine theory of depression based on?

A
  • Reserpine which reduces the levels of NA and 5-HT can cause depression as a side effect
  • Methyl dopa reduces the release of NA and can also cause depression
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10
Q

What are the limitations to these biochemical theories of depression?

A
  • a lot of biochemical studies in depressive patients do not show this reduction in NA and 5-HT so there is no real evidence to prove this theory
  • drugs which increase NA in synaptic clef like amphetamine do not affect depression
  • like antipsychotics, antidepressant agents also take a week or 4 weeks to achieve their clinical relief which indicates that other factors aside from monoamines are at play
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11
Q

What is the stress and depression theory?

A
  • this is where it is believed that chronic stress is the cause of depression
  • it has been quite clearly shown that prolonged, repeated stress events particularly in early childhood can predispose someone to a depressive effect (child abuse, loss of spouse etc.)
  • with chronic stress, the stress response continues and the HPA becomes dysfunctional and does not switch off
  • (no glucocorticoid release to switch it off)
  • There is continual glucocorticoid release which triggers inflammatory response
  • macrophages come and recruit cytokines which further exacerbate inflammatory response
  • growth factors shut down which causes brain cells to shut down -> loss of function
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12
Q

What is the basis of action of the anti-depressant agents?

A
  • action potential comes down to open the V-gated Ca channels
  • neurotransmitters stored in the vesicles are stimulated to be released into the synaptic cleft
  • these bind to post synaptic neurons to carry on the message
  • we have transporters which recycle 5-HT and NA
  • we also have monoamine oxidases found in the synaptic cleft and presynaptic terminal which degrade monoamines
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13
Q

What are the first line of antidepressants developed?

A

-monoamine oxidase inhibitors e.g. phenelzine and moclobemide

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14
Q

How do phenelzine and moclobemide work?

A
  • These inhibit the monoamine oxidase which degrades the NA and 5-HT
  • NA and 5-HT are in the synaptic cleft for longer and can bind to receptors for longer
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15
Q

What is the difference between phenelzine and moclobemide?

A

-although both are monoamine oxidase inhibitors,

phenelzine is an irreversible inhibitor and inhibits both MAOa and MAOb
it has a long duration of action

Moclobemide is reversible and only inhibits MAOb. It has a shorter duration of action

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16
Q

Why are monoamine oxidases not used regularly anymore?

A

They can hav serious side effects like CHEESE effects

  • there is a build up of tyromine
  • this can interact with common cold and flu OTC products
17
Q

What is the cheese effect?

A

where there is a build up of tyramine which is normally metabolised by MAO as a result of ingesting foods high in tyramine (e.g. cheese) This results in a hypertensive crisis as tyramine can displace dopamine, NA and adrenaline from pre-synaptic vesicles.

The main side effect is severe headaches

18
Q

What are tricyclic antidepressants?

A

e. g. amitriptyline, imipramine
- these block the transporters for either NA or 5-HT on the nerve terminal so that NA/5-HT cannot be uptaken
- Also block a number of neurotransmitter receptors like the muscarinic ACh receptors, 5-HT2 receptors and adrenoreceptors

19
Q

What is the implication of TCAs blocking the muscarinic ACh receptors?

A

-This has no clinical effect but result in the clinical side effects of TCAs

20
Q

What is the implication of TCAs blocking alpha2 adrenoreceptors in the presynaptic terminal?

A

-we are interested in this because this stops the inhibition of further release of NA

21
Q

What are selective serotonin reuptake inhibitors?

A
  • e.g. fluoxetine, paroxetine, sertaline, bupropion

- these are now most commonly prescribed for depression and are mostly effective

22
Q

What is Reboxetine?

A

a selective NA reuptake inhibitor. It has no effect on serotonin

23
Q

What is the hypothesis with prescribing SSRIs?

A

about 20% of depressed patients have reduction in NA and 20% have a reduction in 5-HT
some are mixed, so GP usually puts SSRI first, and if this doesnt work they change to a selective NA inhibitor.
If this fails, then they can go on combined medicines

24
Q

What are the non-selective reuptake inhibitors?

A
  • these are structurally different to TCAs
  • e.g. milnacilran, venlafaxine, duloxetine
  • they inhibit the reuptake of NA, 5-HT and DA
25
Q

What are atypical antidepressants?

A

e. g. Nomifensine, miaserin

- these have less side effects than MAOI and TCAs and possibly better efficacy

26
Q

How does Nomifensine work?

A

nomifensine is very similar to TCAs and NA reuptake inhibitors.
It causes dopamine reuptake as well but has no effect on serotonin

27
Q

How does Miamserin work?

A
  • inhibits NA reuptake

- antagonises 5-HT 2 receptor and alpha 2 adrenoreceptors to extend 5-HT period in the synaptic cleft

28
Q

What is lithium used for?

A

mainly for the treatment of bipolar disorder
-huge number of effects on 2ndary messenger pathways but is very good at treating mania with a mod effectiveness at treating depression

29
Q

What are the two mechanisms of action of lithium?

A
  1. blocks phosphityl inosityl pathway and inhibits any agonist that binds to a receptor that is coupled to pi to stimulate the IP3 formation
  2. inhibits activity of AC o that any receptor activating this is inhibited.

therapeutic effects require long term use
there is an immediate biochemical effect, however clinical symptoms require longer use.

30
Q

Why do anti-depressive drugs (like lithium) require 4-6 weeks for effects to be seen?

A

-may be due to receptor down regulation that occurs after chronic use of drugs
-this occurs with 5-HT2, and alpha 2 adrenoreceptors
-downregulation further results in the inhibitory effect
-5-HT 2 receptor is involved in neuronal excitation via activation of the IP3 pathway.
^ this has a similar mechanism of action to lithium and its effects on IP3

31
Q

What is the strategy for new treatment?

A
  • substance P receptor antagonist.
  • substance P is involved in brain stem and associaed with negative emotions
  • reduces glucocorticoid levels to prevent recurrence of depression
32
Q

What is the relationship between glucocorticoids and depression?

A

-higher GC levels indicates more likelihood of major depression

Medsci305 (17 decks)

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