Presentation on theme: "Pharmacology of antidepressants and mood stabilisers"— Presentation transcript:
1Pharmacology of antidepressants and mood stabilisers Dr Caroline Stewart
2Learning 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
3Core Clinical Problems Altered MoodAnxietyArrested Intellectual DevelopmentBehavioural Problems in AdultsDeliberate Self HarmEating DisordersMedically Unexplained SymptomsMemory ProblemsMisusing Drugs or AlcoholPsychological Responses to TraumaPsychosis
4CNS 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
5Antidepressant 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.
6The 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.
7Noradrenaline pathways in human brain Cingulate GyrusFrontalCortexThalamusLocus coeruleusLC → forebrain, brain stem, spinal cordcontrol of arousal, sleep-wake cycle, anxietyHippocampusALocuscoeruleusAmygdalaLateraltegmentalareaBrain stemanterior → limbic structures; posterior → brain stem, spinal cordrole unclear
9Serotonin pathways in human brain arousalsleepstressattentionsexual behaviourmood regulation (e.g. aggression)processing of sensory information in cerebral cortexCingulate GyrusFrontalCortexThalamusHippocampusRostralAmygdalaCaudalRaphe
11Monoamine 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
12Monoamine oxidase inhibitors: site of action metabolitesMAO inhibitorXprecursorMAOneurotransmitterPLCACGqGiGs(-)(+)ion channelsIP3, DAG, Ca2+cAMPcellular responses
13Monoamine 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
14Tricyclic & related antidepressants LIVERimipraminedesmethylimipramineLIVERamitriptylinenortriptylinemianserintrazodoneclomipramine
15Tricyclic & related drugs: site of action metabolitesprecursorMAOneurotransmitterXReuptake inhibitorsPLCACGqGiGs(-)(+)ion channelsIP3, DAG, Ca2+cAMPcellular responses
16Tricyclic antidepressants: adverse effects Improvement over MAOIs:No dietary control requiredLess severe drug interactionsAdverse effects:muscarinic blockadesedationcardiac arrhythmiaspostural hypotension
20Other 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
21Selective 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
23Atypical antidepressant drugs Agomelatine: a melatonin receptor agonist and a selective serotonin-receptor antagonistMirtazapine: mixed receptor effects (blocks 2, 5-HT2)
24Efficacy 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?
25Antidepressant drugs: clinical uses Moderate to severe depressionDysthymiaGeneralised anxiety disorderPanic disorder, OCD, PTSDPremenstrual dysphoric disorderBulimia nervosaNeuropathic pain
26Bipolar affective disorder treatment Acute treatment of symptoms:antipsychotics for episodes of maniaantidepressants for episodes of depressionStabilise mood and prevent recurrence (prophylaxis):lithium saltsanticonvulsants
27Lithium therapyDiscovered accidentally: Normally given as lithium carbonateMode of action:block of phosphatidylinositol pathway (second messenger system)?inhibition of glycogen synthase kinase-?
29Side effects of lithium therapy nausea, vomiting, anorexia, diarrhoea, tremor, polydipsia, polyurialithium toxicity (drowsiness, ataxia and confusion)Blood levels must be monitored
30Anticonvulsants 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)