Adobe Systems Antidepressants [USEMAP] Adobe Systems Depression •the most common affective disorder •pesimistic mood with feelings of dejection, low self-worth or guilt for at least two weeks •different grades of severity •world-wide one of the most common causes of premature death •emotional and biological symptoms •loss of interest, happiness and motivation •loss of self-confidence, remorses, feeling of guilt •suicidal tendencies (in 2/3 patients) •loss of energy and tiredness •attention deficit, indecision •agitation (if anxiety is present) •sleep disorder (characteristic is early wake-up) •change in apettite •decrease of libido Adobe Systems Monoamine theory of depression •depression = monoamine deficit in particular parts of the brain •mania = hyperactivity of monoamines in the CNS •clinical evidence – substances decreasing monoamine activity = mood aggravation •the specific roles of 5-HT and NA are not clear •antidepressants directly or indirectly increase the monoamine activity Adobe Systems Mechanismus účinku antidepresiv http://institute.progress.im/sites/default/files/styles/content_full/public/lundbeck_lic_illustrati oner_02_09_depression_-_normal_-5-ht_transission.png?itok=gkNnBbhO 5-HT1A 5-HT2A 5-HT2C Serotonin SERT 5HT - AUTORECEPTOR MAO MAO MAO MAO NET α2- AUTORECEPTOR α1 β3 iMAO SSRI SNRI TCA NARI Noradrenaline SARI NASSA SMS [USEMAP] Adobe Systems Mode of action of antidepressants ̶most AD increase 5-HT, NA or D activity General modes of action of antidepressants: • MAO inhibition (selective MAO A/ nonselective) • reuptake inhibition (SERT, NAT) • desensitisation/antagonism of presynpatic autoreceptors (5-HT1D, α2) • agonism of postsynaptic receptors 5-HT1A • antagonism of postsynaptic receptors 5-HT2A • increase of 5-HT and/or NA increased BDNF activity [USEMAP] Adobe Systems History of antidepressants ̶ MILLAN, Mark J., et al. Learning from the past and looking to the future: Emerging perspectives for improving the treatment of psychiatric disorders.European Neuropsychopharmacology, 2015, 25.5: 599-656. [USEMAP] Adobe Systems Efficacy of antidepressants • in general partial response or remission in 60-70% of patients • „only 30 %“ in the first line of antidepressant treatment • significant interindividual differences in treatment response • the efficacy of distinct groups of AD is equipotential = criteria of AD selection 1. depression side symptoms (agitation, anxiety, insomnia) 2. decrease of adverse reactions risk Adobe Systems • inhibit also NAT, but more selective for SERT • PK and PD differences between single agents = one SSRI can be replaced by other in case of therapy failure • drugs of choice in most patients • great safety profile – but not tolerability •↑ risk of suicide in tennagers •risk of drug-drug interactions (iCYP 2D6 and 3A4 inhibitors) I: depression, anxiety, OCD, PTSD, migraine, pain SSRI – selective serotonin reuptake inhibitors [USEMAP] Adobe Systems AE • GIT irritation •↑ bleeding, sex. dysfunction, anhedonia Serotonin syndrome -induced by hyperactivity of serotonine in the CNS - high risk in combinations of serotonergic drugs (AD, triptans, analgesics) Antidepressant discontinuation syndrome - FINISH SSRI [USEMAP] Adobe Systems fluoxetine -5-HT2Aantagonist, CYP2D6 strong inhibitor sertraline - the strongest SERT inhibitor - weak DAT inhibitor, anxiolytic activity paroxetine - weak antimuscarinic effect = sedative; CYP2D6 strong inhibitor citalopram - the lowest risk of drug-drug interactions SSRI [USEMAP] Adobe Systems MofA: SERT selective inhibition Indications: depression, anxiety Administration: per os PK: good absorption from GIT, low protein binding, complete biotransformation in liver (CYP2C19), active metabolites, dominantly excreted into urine AE: prolongation of QT, serotonine syndrome DDI: iMAO ↑risk of serotonine syndrome, CYP inhibitors KI: till 18 years, gravidity, lactation SSRI - escitalopram Adobe Systems MofA – nonselective blockade of 5-HT and NA reuptake • „activating“ drugs AE • stimulation of adrenergic receptors = insomnia, sex. impairment, ↓ apetite, hypertension • increased risk of suicide, discontinuation sydrome • venlafaxine + desvenlafaxine • duloxetine – also for neuropathic pain, hepatotoxic SNRI – serotonin and noradrenaline reuptake inhibitors [USEMAP] Adobe Systems bupropion •little effect on 5-HT • in comparison to other DAT and NAT inhibitors does not cause euphoria • in the treatment of smoking cessation AE • risk of seizures • aggravation/development of psychotic signs NDRI – noradrenaline and dopamine reuptake inhibitors [USEMAP] Adobe Systems reboxetine MofA – blockade of NAT: SERT = 20:1 •M, H1 and α1 antagonist AE • stimulation of adrenergic receptros = insomnia, restlessness, anxiety • constipation, sex. dysfunction • atomoxetine –ADHD therapy NARI – noradrenaline reuptake inhibitor [USEMAP] Adobe Systems trazodone MofA •SERT inhibition •5-HT1A agonism •5-HT2A and 2C antagonis •H1 and α1antagonismus AE: hypotension, sleepiness •CYP2D6 substrate, 3A4 inhibitor SARI – serotonine antagonist and reuptake inhibitor [USEMAP] Adobe Systems MofA: block of presynaptic α2 + postsynaptic 5-HT2A, 5-HT2C and 5-HT3 stimulation of 5-HT1 block of H1 and weak antagonism of α1 Administration: per os PK: F from GIT app. 50%, protein binding, substrate of CYP3A4, CYP2D6 and CYP1A2, complete metabolization, some metabolites are active AE: serotonine syndrome, sedation, ↑ weight Interactions: serotonergic drugs, including St. John‘s wort, CYP inducers/inhibitors KI: till 18 years, combination with iMAO ̶drug discontinuation– slow dose decrease ̶suitable in depression with insomnia, low risk of sex. disorders mirtazapine NASSA – noradrenergic and specific serotonergic antidepressants [USEMAP] Adobe Systems vortioxetine MofA: inhibice SERT 5-HT1Aagonism 5-HT1D, 5-HT3 antagonism AE: pruritus, nausea, live dreams • risk of serotonin syndrome •CYP2D6 substrate SMS – serotonin modulator and stimulator [USEMAP] Adobe Systems MofA: MT1 and MT2 agonist 5- HT2C antagonist •increased melatonin release and resynchronizes circadian rhythm •CYP1A2 substrate •risk of hepatotoxicity = monitoring of transaminases •in single dose when going to bed MASSA-melatonine agonist and serotonin selective antagonist [USEMAP] Adobe Systems MofA: 5-HT, NA and D reuptake inhibition + 5-HT2A antagonism and 5-HT1A agonism + antagonism of H1, M, α1 and 5-HT2C => AE serotonergic adrenergic clomipramine imipramine, desipramine amitriptyline, nortriptyline TCA [USEMAP] Adobe Systems AE: antiM – confusion, cognitive deficit, peripheral effects antiH1 – sedation, weight gain antiα1 – ortostatic hypotension anti 5HT2C - weight gain proarrhythmogenic •significant acute toxicity •initial dose usualy titrated TCA [USEMAP] Adobe Systems TCA • liver metabolism - CYP2D6 and 3A4 • plasma protein binding • long t1/2 = risk of drug accummulation • •„older“ drugs, still in use I: resistant depression co-analgesics [USEMAP] Adobe Systems iMAO • ireversible inhibitors today obsolete • reversible selective iMAO A – moclobemide • the strongest effect on 5-HT > NA > D • „cheese reaction“ •positive effect on cognition •inhibitor of CYP2D6, 2C19 and 1A2 AE: hypotension, CNS stimulation, weight gain [USEMAP] Adobe Systems Side effects of antidepressant therapy Nonselective serotonergic activity (SSRI, iMAO, TCA, SNRI) + anxiolytic and antidepressant activity - sex. impairment, emotional flatness, serotonin syndrome Nonselective noradrenergic activity (TCA, NARI) + „activation“ of patient, antidepressant activity - tremor, tachycardia, hypertension Adobe Systems Antihistaminergic activity = sedation, weight gain α1lytic activity= ortostatic hypotension and risk of falls Antimuscarinic activity = cognitive deficit and peripheral effects QT interval prolongation • SSRI, TCA Side effects of antidepressant therapy Adobe Systems activating x sedative AD fluoxetine nortriptyline venlafaxine paroxetine, fluvoxamine, citalopram dosulepin, maprotiline trazodone mirtazapine agomelatine [USEMAP] Adobe Systems Augmentation of antidepressant terapy Antipsychotics •separately or in combination with antidepressants •in depression with psychotic symptoms, and in prophylaxis •atypical antipsychotics • Anxiolytics •in the begining of therapy of depression with significant anxiety component to decrease the risk of suicide Phytopharmacology • • • [USEMAP]