Presentation on theme: "Pharmacology of antidepressants and mood stabilisers"— Presentation transcript:
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 levelsDescribe the principal adverse effects of each drug classDefine the term “mood stabiliser” and give examples
3 Core Clinical Problems Altered MoodAnxietyArrested Intellectual DevelopmentBehavioural Problems in AdultsDeliberate Self HarmEating DisordersMedically Unexplained SymptomsMemory ProblemsMisusing Drugs or AlcoholPsychological Responses to TraumaPsychosis
4 CNS pharmacology Synaptic transmission (chemical) Formation, storage, release, action, inactivation of neurotransmittersVariety and distribution of neurotransmitters and receptor subtypesAccess of drugs to the brain (BBB)see “Neuropharmacology introduction” on Blackboard
5 Antidepressant drugs Monoamine oxidase inhibitors Monoamine reuptake inhibitorsTricyclics & relatedselective serotonin reuptake inhibitorsother non-selective reuptake inhibitorsAtypical 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 moodCSF from depressed patients have reduced levels of monoamines or metabolitesMost drugs that treat depression act to increase monoaminergic transmissionCH – CH2 – NH2HOOHH — NHOCH2 – CH2 – NH2Monoamine transmitters contain a single amine (green) group.
9 Serotonin pathways in human brain arousalsleepstressattentionsexual behaviourmood regulation (e.g. aggression)processing of sensory information in cerebral cortexCingulate GyrusFrontalCortexThalamusHippocampusRostralAmygdalaCaudalRaphe
11 Monoamine oxidase inhibitors MAOA (expressed in NA neurones) – selective for NA, 5-HTMAOB (expressed in 5-HT neurones) – selective for -phenylethylamine, benzylamineBoth – DA, tyramine, tryptamineMAOA inhibition – clorgyline, tranylcypromine, phenelzine, isocarboxazidMAOB inhibition – selegiline , tranylcypromine, phenelzine, isocarboxazidMeclobemide is reversible MAOA inhibitor
12 Monoamine oxidase inhibitors: site of action metabolitesMAO inhibitorXprecursorMAOneurotransmitterPLCACGqGiGs(-)(+)ion channelsIP3, DAG, Ca2+cAMPcellular 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 restrictionDrug preparations also containing amines should be avoided (e.g. pseudoephedrine)Potentiates the effects of tricyclic antidepressants e.g. on hypertensionPotentiates effects of depressant drugs (e.g. barbiturates, morphine, ethanol) by decreasing their metabolism
14 Tricyclic & related antidepressants LIVERimipraminedesmethylimipramineLIVERamitriptylinenortriptylinemianserintrazodoneclomipramine
15 Tricyclic & related drugs: site of action metabolitesprecursorMAOneurotransmitterXReuptake inhibitorsPLCACGqGiGs(-)(+)ion channelsIP3, DAG, Ca2+cAMPcellular responses
16 Tricyclic antidepressants: adverse effects Improvement over MAOIs:No dietary control requiredLess severe drug interactionsAdverse effects:muscarinic blockadesedationcardiac arrhythmiaspostural hypotension
20 Other monoamine reuptake inhibitors Dual reuptake inhibitors e.g venlafaxineMode 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 DATReboxetine selective inhibitor of NET which was approved for major depression in 1997Systematic review and meta-analysis (BMJ 341: c4737–c4737. doi: /bmj.c4737) has now determinedno overall significant difference compared to controlinferior response compared to SSRIsgreater harm than placebo or SSRIs for adverse events
23 Atypical antidepressant drugs Agomelatine: a melatonin receptor agonist and a selective serotonin-receptor antagonistMirtazapine: 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 differMost 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 depressionDysthymiaGeneralised anxiety disorderPanic disorder, OCD, PTSDPremenstrual dysphoric disorderBulimia nervosaNeuropathic pain
26 Bipolar affective disorder treatment Acute treatment of symptoms:antipsychotics for episodes of maniaantidepressants for episodes of depressionStabilise mood and prevent recurrence (prophylaxis):lithium saltsanticonvulsants
27 Lithium therapyDiscovered accidentally: Normally given as lithium carbonateMode of action:block of phosphatidylinositol pathway (second messenger system)?inhibition of glycogen synthase kinase-?
29 Side effects of lithium therapy nausea, vomiting, anorexia, diarrhoea, tremor, polydipsia, polyurialithium 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 disorderMode of action: very unclear, perhaps block overactive pathways (kindling model of bipolar disorder)Side effects:carbamazepine: drowsiness, ataxia, cardiovascular effects, induces liver enzymesvalproate: liver failure, teratogenicity (neural tube defects)