Lecture 14: affective disorders Flashcards
Why will antipsychotic drugs bind to their receptors immediately while the clinical effects still take a while to occur?
- 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
What are affective disorders?
depression or mania
What is the most common manisfestation of affective disorders?
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
What are the different types of depression
- major depression (most common)
- post natal depression
What is the prevalence of major depression?
affects about 5% of the population per year
this equates to 1 in 4 women and 1 in 5 men
How is major depression diagnosed
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
What is bipolar?
the opposite in spectrum to major depression
-it is also a recurrent affective disorder which can either be:
- repeated episodes of depression or mania or
- mixed episodes of a period of mania with no depression or mania with less depression
What are the biochemical theories of depression?
- 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
What is the monoamine theory of depression based on?
- 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
What are the limitations to these biochemical theories of depression?
- 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
What is the stress and depression theory?
- 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
What is the basis of action of the anti-depressant agents?
- 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
What are the first line of antidepressants developed?
-monoamine oxidase inhibitors e.g. phenelzine and moclobemide
How do phenelzine and moclobemide work?
- 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
What is the difference between phenelzine and moclobemide?
-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
Why are monoamine oxidases not used regularly anymore?
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
What is the cheese effect?
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
What are tricyclic antidepressants?
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
What is the implication of TCAs blocking the muscarinic ACh receptors?
-This has no clinical effect but result in the clinical side effects of TCAs
What is the implication of TCAs blocking alpha2 adrenoreceptors in the presynaptic terminal?
-we are interested in this because this stops the inhibition of further release of NA
What are selective serotonin reuptake inhibitors?
- e.g. fluoxetine, paroxetine, sertaline, bupropion
- these are now most commonly prescribed for depression and are mostly effective
What is Reboxetine?
a selective NA reuptake inhibitor. It has no effect on serotonin
What is the hypothesis with prescribing SSRIs?
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
What are the non-selective reuptake inhibitors?
- these are structurally different to TCAs
- e.g. milnacilran, venlafaxine, duloxetine
- they inhibit the reuptake of NA, 5-HT and DA
What are atypical antidepressants?
e. g. Nomifensine, miaserin
- these have less side effects than MAOI and TCAs and possibly better efficacy
How does Nomifensine work?
nomifensine is very similar to TCAs and NA reuptake inhibitors.
It causes dopamine reuptake as well but has no effect on serotonin
How does Miamserin work?
- inhibits NA reuptake
- antagonises 5-HT 2 receptor and alpha 2 adrenoreceptors to extend 5-HT period in the synaptic cleft
What is lithium used for?
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
What are the two mechanisms of action of lithium?
- blocks phosphityl inosityl pathway and inhibits any agonist that binds to a receptor that is coupled to pi to stimulate the IP3 formation
- 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.
Why do anti-depressive drugs (like lithium) require 4-6 weeks for effects to be seen?
-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
What is the strategy for new treatment?
- substance P receptor antagonist.
- substance P is involved in brain stem and associaed with negative emotions
- reduces glucocorticoid levels to prevent recurrence of depression
What is the relationship between glucocorticoids and depression?
-higher GC levels indicates more likelihood of major depression
