Pharmacology of antidepressants and mood stabilisers

1. Pharmacology of antidepressants and mood stabilisers Dr Caroline Stewart c.a.stewart@dundee.ac.uk

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. 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

7. 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

8. 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

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 AC PLC 5HT1A Gi Gs 5HT2C/D Gq 5HT4,5,6 (-) (+) 5HT3 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 precursor MAO X neurotransmitter PLC AC Gq Gs Gi (-) (+) ion channels cAMP IP3, DAG, Ca2+ 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 clomipramine mianserin trazodone

15. 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

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 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

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-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. 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

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 Gs Gi (-) (+) ion channels cAMP IP3, DAG, Ca2+ cellular responses DAG PLC Gq IP3 PIP2 I IP Glucose 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