Neuropharmacology

Question 1

How can a receptor antagonist work?

Answer 1

Richelson, 1999:
It may act on the presynaptic autoreceptors and lead to increased release of neurotransmitter – opposite effect to that which is expected (blocks negative feedback) since these receptors usually have negative feedback on neurotransmitter release
- Prevent reuptake of the neurotransmitter
- Chronic drug treatment may lead to desensitisation of the receptor to the neurotransmitter, due to a compensatory receptor change, and this may explain how antidepressants work (reduces negative feedback)
- But receptors can also become supersensitive to the neurotransmitter following chronic drug treatment, which may explain some of the side effects of the drug (e.g. tariff dyskinesia following chronic treatment with neuroleptics that block dopamine-D2 receptors) and some of the withdrawal effects following abrupt cessation of some antidepressants

Question 2

What are allosteric binding sites on receptors?

Answer 2

A second ligand binding site on the extracellular part of the receptor
- Binding of the co-agonist alters the action of the main agonist

Question 3

What is an example of a drug that uses an allosteric binding site?

Answer 3

Benzodiazepines and barbiturates can bind to an allosteric binding site on GABA-A receptor, enhancing the effects of GABA

• Increased binding affinity of the receptor for GABA
• Leads to an increased chloride influx
• They act in different ways

Question 4

What are some antagonist drugs that alter synaptic transmission?

Answer 4

• Botulinum toxin
• Dopamine antagonists for psychosis/schizophrenia treatment
• Tricyclic antidepressants – prevents reuptake of noradrenaline and serotonin
• SSRIs
• Monoamine oxidase inhibitors – prevent the breakdown of amine neurotransmitters
• – Irreversibly binds to MAO which is used to breakdown noradrenaline and serotonin

Question 5

How can antagonist drugs be used as antidepressants?

Answer 5

Can act on noradrenaline or serotonin (involved in sleepiness, impulse control and appetite)

• Tricyclics (inhibits re-uptake of serotonin and noradrenaline but less specifically than SNRIs, can also block muscarinic acetylcholine receptors)
• SNRIs (serotonin and noradrenaline re-uptake inhibitors)
• NARIs (noradrenaline re-uptake inhibitors)
• MAO inhibitors (prevent degradation of noradrenaline and serotonin

Question 6

How effective are antidepressants?

Answer 6

Ramsberg, Asseburg and Henriksson, 2012
- Multiple treatment comparison meta-analysis
- To determine relative efficacy in terms of remission of 10 antidepressants
- Results: most favourable pharmacological treatment in terms of remission was escitalopram (SSRI) - has a high acquisition cost but is cost effective since it has good clinical effectiveness
- Only evaluated over a year
- Included 87 studies
Barbui et al, 2011
- Systematic review and meta-analysis of double blind randomised controlled trials comparing antidepressants or benzodiazepines vs placebo in adults with minor depression
- There is unlikely to be a clinically important advantage for anti-depressants over placebo in individuals with minor depression
— Data from 3 studies showed no statistically significant difference between anti-depressants and placebo
- There is no evidence available for benzodiazepanes so it is not possible to determine their potential therapeutic role in this condition
- Intention-to-treat analysis
- Included only 6 studies
— Overall quality of these studies was graded as low
— But confidence intervals were not very wide
— All studies had short-term follow-up
— Incomplete data reporting was a major issue
Bollini et al., 1999
- Meta-analysis of 33 studies to determine if higher doses of antidepressants are more effective than low effective
- A higher dose than 100-200mg of imipramine equivalents does not increase efficacy, but lower doses have reduced efficacy
- Risk of adverse effects increased with dose

Question 7

How do antidepressants work?

Answer 7

Harmer, Goodwin and Cowen, 2009
- Results suggest that antidepressants modulate emotional processing and increase positive emotional processing much earlier than effects on mood
— These changes in emotional processing are associated with neural modulation in limbic and prefrontal circuitry (carried out by the antagonistic action of some of the drugs)
- There is a few weeks between the detection of a blockade of transporters by an SSRI and a therapeutic effect
— Suggests that the actual antagonistic action is not as important as the consequences of it, such as the down regulation of receptors and desensitisation of receptors
Richelson, 1999
- Blockage of serotonin receptors: alleviation of depression, reduction of anxiety, promotion of deep sleep, alleviation of psychosis