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Pharmacology of antidepressants and mood stabilisers Dr Caroline Stewart

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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)

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 H — N HO CH 2 – CH 2 – NH 2 CH – CH 2 – NH 2 HO OH

7 Noradrenaline pathways in human brain A Lateral tegmental area Locus coeruleus Amygdala Hippocampus Frontal Cortex 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

8 The noradrenergic synapse tyr noradrenaline AC (+)(+) cAMP GsGs 22 GiGi (-) MAO A COMT  22 NET ion channels cellular responses PLC GqGq IP 3, DAG, Ca 2+ 11 Tyrosine hydroxylase L-AA decarboxylase DA ß-hydroxylase DOPA dopamine VMAT X Reserpine metabolites

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

10 The serotonergic synapse tryp 5-OHTryp serotonin AC (+)(+) GsGs GiGi (-) MAO MAO B cAMP ion channels cellular responses PLC GqGq 5HT 2C/D 5HT 4,5,6 5HT 1A IP 3, DAG, Ca 2+ 5HT 1D 5HT 3 tryptophan hydroxylase SERT L-AA decarboxylase VMAT Reserpine X metabolites

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

12 Monoamine oxidase inhibitors: site of action precursor neurotransmitter AC (+)(+) cAMP GsGs GiGi (-) MAO ion channels cellular responses PLC GqGq IP 3, DAG, Ca 2+ metabolites MAO inhibitor X

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

15 Tricyclic & related drugs: site of action precursor neurotransmitter AC (+)(+) cAMP GsGs GiGi (-) MAO ion channels cellular responses PLC GqGq IP 3, DAG, Ca 2+ metabolites X Reuptake inhibitors

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 SSRIs: site of action tryp 5-HTryp serotonin AC (+)(+) GsGs GiGi (-) cAMP ion channels cellular responses PLC GqGq 5HT 2C/D 5HT 4,5,6 5HT 1A IP 3, DAG, Ca 2+ 5HT 1D 5HT 3 SSRIs SERT MAO metabolites X

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: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

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-HT 2 )

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 AC (+)(+) cAMP GsGs GiGi (-) ion channels cellular responses PLC GqGq IP 3, DAG, Ca 2+ PIP 2 DAG IP 3 IP Glucose I PLC GqGq 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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