Depression, Anxiety and Schizophrenia

Question 1

Describe the drug evolution of drugs used to treat mental health

Answer 1

The oldest of these drugs originate in the 1950s
before any knowledge of receptors or transporters.
Anti-psychotics
Olanzapine
Clozapine
Quetiapine
Originally pre-med for surgery due to antihistamine action now antipsychotic

chlorpromazine
Evaluated in various psychiatric conditions
introduced as antidepressants in 1960s
(known as tricyclic antidepressants)
amitriptyline
imipramine
Discovered ability to inhibit NA reuptake.
Developed reuptake inhibitors that were
more selective for serotonin
- Fluoxetine (1988, Prozac)

Question 2

What was the monoamine theory for depression?

Answer 2

1950/60 s = accumulating evidence for involvement of noradrenaline and serotonin

Mood improved by:
- Tricyclic antidepressants inhibit NA and 5HT reuptake
- MAO inhibitors increase stores of NA and 5HT

Mood decreased by :
- Reserpine - inhibits noradrenaline and 5HT storage a-methyl tyrosine and methyldopa inhibit noradrenaline synthesis

Question 3

What are some ideas of the causes of depression?

Answer 3

• affect on systems such as GABA systems
• Effect on transmitter levels is fast but development of antidepressant action is slow
• Regulation of neurogenesis may be involved - potentiall role for growth factor receptors
• 2000s theory based on potential for changes in gene transcription

Question 4

What are the classes of antidepressants?

Answer 4

• Uptake inhibitors
• Monamine Oxidase inhibitors
• Monoamine receptor antagonists
• Miscellaneous

Question 5

What are tricyclic antidepressants?

Answer 5

e.g. amitriptyline, imipramine
a.k.a. SNRls : block both NA and 5HT reuptake
Also have antimuscarinic activity and
antihistamine activity
Dangerous in overdose and when taken with
alcohol.
Unwanted effects:
Dry mouth, constipation, blurred vision, urinary
retention, sedation, confusion, postural
hypotension, impotence, seizures.
Can cause prolonged QT sudden cardiac
death (quinidine-like)

Question 6

What are examples of uptake inhibitors - depression?

Answer 6

• Different transporters for 5HT, NA and dopamine can show selectivity or not
• Older drugs (e.g. amitriptyline and imipramine have little selectivty whilst fluoxetine is selective and citalopram is very selective for SERT)
• Loferpramine = selective for NET - A tricyclic antidepressant also known as NRI (noradrenaline reuptake inhibitor)

Question 7

What are some unwanted effects of SSRIs, SNRIs and NRIs uptake inhibitors?

Answer 7

SSRls
e.g. fluoxetine, citalopram,
sertraline
Unwanted effects: nausea,
diarrhoea, insomnia
Low risk of overdose
Do not use in combination
with MAO inhibitors
Can inhibit metabolism of
other drugs.
Not recommended in
children
Can get prolonged QT
sudden cardiac death

SNR’s
e.g. venlafaxine, duloxetine,
Unwanted effects:
sedation, dizziness
Low risk of overdose
Do not use in combination
with MAO inhibitors
Note: St John’s wort
Few reported side effects
Can inhibit metabolism of
other drugs.

NRls
e.g. lofepramine
Unwanted effects:
headache, dry mouth,
insomnia
Used in depression ,associated with anxiety.

Question 8

What are MAO inhibitors ?

Answer 8

Depression — MAO Inhibitors
Non-selective e.g. tranylcypromine,
MAO-A selective e.g. moclobemide
Increase NA, 5HT and dopamine levels within neurons
Have largely been superseded.
Can get “cheese effect” — foods that contain tyramine-> sympathomimetic.
Tyramine displaces NA from vesicles -Y leaks out into synapse sympathomimetic

Question 9

What are some drug types used to treat Depression ?

Answer 9

• Mirtazepine = a2 and 5HT2c and histamine receptor antagonist
• Increase NA and 5HT release

Bupropion = noradrenaline and dopamine uptake inhibition
Melatonin agonist = agomelatine for severe depression
Ketamine = non-competitive NMDA channel blocker ( memantine is not an antidepressant)
in trials