1. Pharmacology of antidepressants and mood stabilisers
Dr Caroline Stewart

2. Learning Outcomes List the main classes of antidepressant drug
Describe the effects of antidepressant drugs on synaptic monoamine levels
Describe the principal adverse effects of each drug class
Define the term “mood stabiliser” and give examples

3. Core Clinical Problems
Altered Mood
Anxiety
Arrested Intellectual Development
Behavioural Problems in Adults
Deliberate Self Harm
Eating Disorders
Medically Unexplained Symptoms
Memory Problems
Misusing Drugs or Alcohol
Psychological Responses to Trauma
Psychosis

4. CNS pharmacology Synaptic transmission (chemical)
Formation, storage, release, action, inactivation of neurotransmitters
Variety and distribution of neurotransmitters and receptor subtypes
Access of drugs to the brain (BBB)
see “Neuropharmacology introduction” on Blackboard

5. Antidepressant drugs Monoamine oxidase inhibitors
Monoamine reuptake inhibitors
Tricyclics & related
selective serotonin reuptake inhibitors
other non-selective reuptake inhibitors
Atypical drugs (post-synaptic receptor effects)
Most of the drug used have a similar efficacy but different profile of side effects.

6. The monoamine hypothesis
Depression results from a functional deficit of monoamine transmitters (Schildkraut 1965) particularly:
noradrenaline and serotonin (5-HT)
Drugs that deplete stores of monoamines (e.g. reserpine) can induce low mood
CSF from depressed patients have reduced levels of monoamines or metabolites
Most drugs that treat depression act to increase monoaminergic transmission
CH – CH2 – NH2 HO OH
H — N HO
CH2 – CH2 – NH2
Monoamine transmitters contain a single amine (green) group.

7. Noradrenaline pathways in human brain
Cingulate Gyrus
Frontal
Cortex
Thalamus
Locus coeruleus
LC → forebrain, brain stem, spinal cord
control of arousal, sleep-wake cycle, anxiety
Hippocampus A
Locus
coeruleus
Amygdala
Lateral
tegmental
area
Brain stem
anterior → limbic structures; posterior → brain stem, spinal cord
role unclear

8. The noradrenergic synapse
Tyrosine hydroxylase
Reserpine
L-AA decarboxylase X
tyr
VMAT
metabolites
DOPA
MAOA
dopamine 2
DA ß-hydroxylase
noradrenaline
NET
COMT
PLC 1 2 AC Gq Gi Gs 
(-)
(+)
ion channels
IP3, DAG, Ca2+
cAMP
cellular responses

9. Serotonin pathways in human brain
arousal
sleep
stress
attention
sexual behaviour
mood regulation (e.g. aggression)
processing of sensory information in cerebral cortex
Cingulate Gyrus
Frontal
Cortex
Thalamus
Hippocampus
Rostral
Amygdala
Caudal
Raphe

10. The serotonergic synapse
Reserpine
tryptophan hydroxylase X
tryp
metabolites
VMAT
L-AA decarboxylase
MAOB
5-OHTryp
5HT1D
serotonin
SERT
MAO
PLC AC
5HT1A Gi Gs
5HT2C/D Gq
5HT3
(-)
(+)
5HT4,5,6
ion channels
cAMP
IP3, DAG, Ca2+
cellular responses

11. Monoamine oxidase inhibitors
MAOA (expressed in NA neurones) – selective for NA, 5-HT
MAOB (expressed in 5-HT neurones) – selective for -phenylethylamine, benzylamine
Both – DA, tyramine, tryptamine
MAOA inhibition – clorgyline, tranylcypromine, phenelzine, isocarboxazid
MAOB inhibition – selegiline , tranylcypromine, phenelzine, isocarboxazid
Meclobemide is reversible MAOA inhibitor

12. Monoamine oxidase inhibitors: site of action
metabolites
MAO inhibitor X
precursor
MAO
neurotransmitter
PLC AC Gq Gi Gs
(-)
(+)
ion channels
IP3, DAG, Ca2+
cAMP
cellular responses

13. Monoamine oxidase inhibitors: adverse effects
“Cheese reaction” caused by inhibition of MAO-A in gut (& liver). Irreversible inhibitors prevent breakdown of dietary tyramine – requires dietary restriction
Drug preparations also containing amines should be avoided (e.g. pseudoephedrine)
Potentiates the effects of tricyclic antidepressants e.g. on hypertension
Potentiates effects of depressant drugs (e.g. barbiturates, morphine, ethanol) by decreasing their metabolism

14. Tricyclic & related antidepressants
LIVER
imipramine
desmethylimipramine
LIVER
amitriptyline
nortriptyline
mianserin
trazodone
clomipramine

15. Tricyclic & related drugs: site of action
metabolites
precursor
MAO
neurotransmitter X
Reuptake inhibitors
PLC AC Gq Gi Gs
(-)
(+)
ion channels
IP3, DAG, Ca2+
cAMP
cellular responses

16. Tricyclic antidepressants: adverse effects
Improvement over MAOIs:
No dietary control required
Less severe drug interactions
Adverse effects:
muscarinic blockade
sedation
cardiac arrhythmias
postural hypotension

17. Selective serotonin reuptake inhibitors
citalopram
escitalopram
fluoxetine
fluvoxamine maleate
paroxetine
sertraline

18. X SSRIs: site of action SSRIs tryp metabolites 5-HTryp serotonin MAO
5HT1D
serotonin X
SERT
SSRIs
PLC AC
5HT1A Gi Gs
5HT2C/D Gq
5HT3
(-)
(+)
5HT4,5,6
ion channels
cAMP
IP3, DAG, Ca2+
cellular responses

19. SSRIs: adverse effects
Improvements over MAOIs & tricyclics
Non sedative
Less cardiac effects
Adverse effects:
Nausea/diarrhoea
Insomnia
sexual dysfunction
suicidal behaviour

20. Other monoamine reuptake inhibitors
Dual reuptake inhibitors e.g venlafaxine
Mode of action: Block the reuptake of monoamines (noradrenaline and/or 5-HT) into presynaptic terminals.
Side effects: Lack major receptor-blocking actions so fewer side effects

21. Selective NA reuptake inhibitors?
Atomoxetine inhibits NET and also DAT
Reboxetine selective inhibitor of NET which was approved for major depression in 1997
Systematic review and meta-analysis (BMJ 341: c4737–c4737. doi: /bmj.c4737) has now determined
no overall significant difference compared to control
inferior response compared to SSRIs
greater harm than placebo or SSRIs for adverse events

22. Selectivity of uptake inhibitors

23. Atypical antidepressant drugs
Agomelatine: a melatonin receptor agonist and a selective serotonin-receptor antagonist
Mirtazapine: mixed receptor effects (blocks 2, 5-HT2)

24. Efficacy of current antidepressants
Most classes of drug have a similar clinical efficacy (40-70%)
Side effect profiles differ
Most have delayed onset of action (several weeks)
How do they actually work?
Long-term adaptation in receptor density/function?
Alterations in corticosteroid receptors/HPA function?

25. Antidepressant drugs: clinical uses
Moderate to severe depression
Dysthymia
Generalised anxiety disorder
Panic disorder, OCD, PTSD
Premenstrual dysphoric disorder
Bulimia nervosa
Neuropathic pain

26. Bipolar affective disorder treatment
Acute treatment of symptoms:
antipsychotics for episodes of mania
antidepressants for episodes of depression
Stabilise mood and prevent recurrence (prophylaxis):
lithium salts
anticonvulsants

27. Lithium therapy
Discovered accidentally: Normally given as lithium carbonate
Mode of action:
block of phosphatidylinositol pathway (second messenger system)?
inhibition of glycogen synthase kinase-?

28. Inositol depletion hypothesis
PLC AC Gq Gi Gs
(-)
(+)
ion channels
IP3, DAG, Ca2+
cAMP
cellular responses
PIP2
DAG
IP3 IP
Glucose I
PLC Gq
IMPase
Li+

29. Side effects of lithium therapy
nausea, vomiting, anorexia, diarrhoea, tremor, polydipsia, polyuria
lithium toxicity (drowsiness, ataxia and confusion)
Blood levels must be monitored

30. Anticonvulsants as mood stabilisers
Drugs like carbamazepine and valproic acid are now being for prophylaxis in bipolar disorder
Mode of action: very unclear, perhaps block overactive pathways (kindling model of bipolar disorder)
Side effects:
carbamazepine: drowsiness, ataxia, cardiovascular effects, induces liver enzymes
valproate: liver failure, teratogenicity (neural tube defects)

31. The End