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Pharmacology of antidepressants and mood stabilisers

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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

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