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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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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

slide9

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
slide14

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
slide17

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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