Pharmacology of antidepressants Pharmacology of antidepressants and mood stabilisersand mood stabilisers

Dr Caroline Stewartc.a.stewart@dundee.ac.uk

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

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

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

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)

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

H —

N

HOCH2 – CH2 – NH2

CH – CH2 – NH2HO

HO

OH

Noradrenaline pathways in human brain

A

Lateraltegmentalarea

LocuscoeruleusAmygdala

Hippocampus

FrontalCortex

Thalamus

Cingulate Gyrus

• Locus coeruleus– LC → forebrain, brain stem,

spinal cord– control of arousal, sleep-

wake cycle, anxiety

• Brain stem– anterior → limbic structures; posterior → brain stem, spinal cord– role unclear

The noradrenergic synapse

tyr

noradrenaline

AC

(+)

cAMP

Gs2 Gi

(-)

MAOA

COMT

2

NET

ion channels

cellular responses

PLC

Gq

IP3, DAG, Ca2+

1

Tyrosine hydroxylase

L-AA decarboxylase

DA ß-hydroxylase

DOPA

dopamine

VMATX

Reserpine

metabolites

Serotonin pathways in human brain

CaudalRaphe

Amygdala

Hippocampus

FrontalCortex Thalamus

Rostral

Cingulate Gyrus• arousal

• sleep

• stress

• attention

• sexual behaviour

• mood regulation (e.g. aggression)

• processing of sensory information in cerebral cortex

The serotonergic synapse

tryp

5-OHTryp

serotonin

AC

(+)

GsGi

(-)

MAO

MAOB

cAMPion channels

cellular responses

PLC

Gq5HT2C/D 5HT4,5,6

5HT1A

IP3, DAG, Ca2+

5HT1D

5HT3

tryptophan hydroxylase

SERT

L-AA decarboxylaseVMAT

Reserpine

X metabolites

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

Monoamine oxidase inhibitors: site of action

precursor

neurotransmitter

AC

(+)

cAMP

GsGi

(-)

MAO

ion channels

cellular responses

PLC

Gq

IP3, DAG, Ca2+

metabolites

MAO inhibitorX

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

imipramine

Tricyclic & related antidepressants

amitriptyline

nortriptyline

LIVER

LIVER

desmethylimipramine

clomipramine

mianserintrazodone

Tricyclic & related drugs: site of action

precursor

neurotransmitter

AC

(+)

cAMP

GsGi

(-)

MAO

ion channels

cellular responses

PLC

Gq

IP3, DAG, Ca2+

metabolites

X Reuptake inhibitors

Tricyclic antidepressants: adverse effects

• Improvement over MAOIs:– No dietary control required– Less severe drug interactions

• Adverse effects:– muscarinic blockade– sedation– cardiac arrhythmias – postural hypotension

Selective serotonin reuptake inhibitors

citalopram

escitalopram

fluoxetine

fluvoxamine maleate

paroxetine

sertraline

SSRIs: site of action

tryp

5-HTryp

serotonin

AC

(+)

GsGi

(-)cAMPion channels

cellular responses

PLC

Gq5HT2C/D 5HT4,5,6

5HT1A

IP3, DAG, Ca2+

5HT1D

5HT3

SSRIsSE

RT

MAO

metabolites

X

SSRIs: adverse effects

• Improvements over MAOIs & tricyclics– Non sedative– Less cardiac effects

• Adverse effects:– Nausea/diarrhoea– Insomnia– sexual dysfunction– suicidal behaviour

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

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:10.1136/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

Selectivity of uptake inhibitors

Atypical antidepressant drugs

• Agomelatine: a melatonin receptor agonist and a selective serotonin-receptor antagonist

• Mirtazapine: mixed receptor effects (blocks 2, 5-HT2)

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?

Antidepressant drugs: clinical uses

• Moderate to severe depression• Dysthymia• Generalised anxiety disorder• Panic disorder, OCD, PTSD• Premenstrual dysphoric disorder• Bulimia nervosa• Neuropathic pain

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

Lithium therapy

• Discovered accidentally: Normally given as lithium carbonate

• Mode of action:– block of phosphatidylinositol pathway (second

messenger system)?– inhibition of glycogen synthase kinase-?

Inositol depletion hypothesis

AC

(+)

cAMP

GsGi

(-)ion channels

cellular responses

PLC

Gq

IP3, DAG, Ca2+

PIP2

DAG

IP3

IPGlucose

I

PLC

Gq

IMPaseLi+

Side effects of lithium therapy

• nausea, vomiting, anorexia, diarrhoea, tremor, polydipsia, polyuria

• lithium toxicity (drowsiness, ataxia and confusion)

• Blood levels must be monitored

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)

The End