Pharmacology of antidepressants and mood stabilisers
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Pharmacology of antidepressants and mood stabilisers. Dr Caroline Stewart [email protected] Learning Outcomes. List the main classes of antidepressant drug Describe the effects of antidepressant drugs on synaptic monoamine levels

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Pharmacology of antidepressants and mood stabilisers

Pharmacology of antidepressants and mood stabilisers

Dr Caroline Stewart

[email protected]


Learning outcomes
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
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
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
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

OH

CH– CH2 –NH2

HO

HO

CH2 – CH2 –NH2

HO

H — N

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


Noradrenaline pathways in human brain
Noradrenaline pathways in human brain

Cingulate Gyrus

Frontal

Cortex

Thalamus

Hippocampus

  • Locus coeruleus

    • LC → forebrain, brain stem, spinal cord

    • control of arousal, sleep-wake cycle, anxiety

Locus

coeruleus

A

Amygdala

Lateral

tegmental

area

  • Brain stem

    • anterior → limbic structures; posterior → brain stem, spinal cord

    • role unclear


The noradrenergic synapse
The noradrenergic synapse

Tyrosine hydroxylase

Reserpine

L-AA decarboxylase

X

tyr

VMAT

metabolites

DOPA

MAOA

dopamine

2

DA ß-hydroxylase

noradrenaline

NET

PLC

1

AC

2

Gq

Gs

Gi

COMT

(-)

(+)

ion channels

cAMP

IP3, DAG, Ca2+

cellular responses


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


The serotonergic synapse
The serotonergic synapse

Reserpine

tryptophan hydroxylase

X

tryp

metabolites

VMAT

L-AA decarboxylase

MAOB

5-OHTryp

5HT1D

serotonin

SERT

MAO

AC

PLC

5HT1A

Gi

Gs

5HT2C/D

Gq

5HT4,5,6

(-)

(+)

5HT3

ion channels

cAMP

IP3, DAG, Ca2+

cellular responses


Monoamine oxidase inhibitors
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
Monoamine oxidase inhibitors: site of action

metabolites

MAO inhibitor

precursor

MAO

X

neurotransmitter

PLC

AC

Gq

Gs

Gi

(-)

(+)

ion channels

cAMP

IP3, DAG, Ca2+

cellular responses


Monoamine oxidase inhibitors adverse effects
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


Tricyclic & related antidepressants

LIVER

imipramine

desmethylimipramine

LIVER

amitriptyline

nortriptyline

clomipramine

mianserin

trazodone


Tricyclic related drugs site of action
Tricyclic & related drugs: site of action

metabolites

precursor

MAO

neurotransmitter

X

Reuptake inhibitors

PLC

AC

Gq

Gs

Gi

(-)

(+)

ion channels

cAMP

IP3, DAG, Ca2+

cellular responses


Tricyclic antidepressants adverse effects
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
SSRIs: site of action

tryp

metabolites

MAO

5-HTryp

5HT1D

serotonin

X

SERT

SSRIs

AC

PLC

5HT1A

Gi

Gs

5HT2C/D

Gq

5HT4,5,6

(-)

(+)

5HT3

ion channels

cAMP

IP3, DAG, Ca2+

cellular responses


Ssris adverse effects
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
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
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



Atypical antidepressant drugs
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
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
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

Bipolar affective disorder treatment

Stabilise mood and prevent recurrence (prophylaxis):

  • lithium salts

  • anticonvulsants


Lithium therapy
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
Inositol depletion hypothesis

PLC

AC

Gq

Gs

Gi

(-)

(+)

ion channels

cAMP

IP3, DAG, Ca2+

cellular responses

DAG

PLC

Gq

IP3

PIP2

I

IP

Glucose

IMPase

Li+


Side effects of lithium therapy
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
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)



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