Antidepressants BMS2047.pdf

ANTIDEPRESSANTS DR SARAH TRINDER Weeping Nude, Edvard Munch [email protected] http://www.tenninetyblog.co.uk/ OUTLINE What is depression? 3 key theories on the mechanism behind the pathology of depression Pre-clinical models of depression Antidepressant drugs and their ‘believed’ mechanism of a...

ANTIDEPRESSANTS DR SARAH TRINDER Weeping Nude, Edvard Munch [email protected] http://www.tenninetyblog.co.uk/ OUTLINE What is depression? 3 key theories on the mechanism behind the pathology of depression Pre-clinical models of depression Antidepressant drugs and their ‘believed’ mechanism of action Monoamine uptake inhibitors Monoamine receptor antagonists Monoamine oxidase inhibitors (MAOI) Bipolar disorder & it’s treatment Mechanism of action of lithium BACKGROUND At somepoint in their lives 20% of people will become depressed. Those with depression have a significantly worse survival rate from cancer and heart disease. Excessive consumption of alcohol, associated with higher levels of depression… as well as suicide and self harm. (Photo : Paul Vice Juhlin | Pinterest) No Health without Public Mental Health: The Case for Action, the Royal College of Psychiatrists’ position statement PS4/2010 DEPRESSION Is an affective disorder. Heterogeneous, patients present with one or more core symptoms Two types of depressive syndrome Unipolar – mood always goes in one direction Non-familial, associated with stressful life events (75%) Familial (endogenous depression), usually unrelated to life events (25%) Bipolar – depression alternates with mania Hereditary tendency – no susceptibility genes identified Affects 1-3% of population http://www.snipview.com/q/Joseph_Hirsch THEORIES – MONOAMINE THEORY SCHILDKRAUT 1965 Depression caused by functional deficit of monoamine transmitters (NA/5-HT) at certain sites of the brain Evidence for – reduced central serotonergic and/or noradrenergic activity reserpine depletes brain of NA/5-HT induces depression most antidepressant drugs ↑[amines] in brain Trp TH 5-HTP 5-HT NA metabolites metabolites MAO NA 5-HT neuron Gi/o Gi/o 5-HT1B/D SERT α2 MAO NA neuron NET THEORIES – MONOAMINE THEORY SCHILDKRAUT 1965 Depression caused by functional deficit of monoamine transmitters (NA/5-HT) at certain sites of the brain Evidence against – antidepressants have a rapid (hours) effect on ↑[amines], but ↑mood takes weeks to develop have not robustly shown ↓[amines] in brain of patients cocaine blocks amine uptake, but no antidepressant effect THEORIES - NEUROENDOCRINE Often depression follows periods of stress ↑[cortisol] plasma of depressed patients Negative feedback by cortisol desensitised Corticotrophin-releasing hormone (CRH) in animals mimics depression SSRIs ↑ glucocorticoid receptors in hippocampus ACTH ACTH = adrenocorticotrophic hormone Belmaker, RH, Agam, G. Mechanisms of Disease: Major Depressive Disorder. N Engl J Med 2008; 358:55 THEORIES – NEUROPLASTICITY/NEUROGENESIS Periods of depression associated with decreased brain activity Depression associated with neuronal loss (hippocampus & PFC) Evidence of ventricular enlargement, shrinkage of hippocampus & PFC THEORIES – NEUROPLASTICITY/NEUROGENESIS BDNF - brain-derived neurotrophic factor BDNF receptor - TrkB NE - noradrenaline Duman RS. Dialogues Clin Neurosci 2004; 6(2): 157-169. THEORIES OF DEPRESSION From Rang and Dale’s Pharmacology ANTIDEPRESSANT DRUGS Three main types of antidepressants – Monoamine uptake inhibitors– tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRI) Monoamine receptor antagonists – α2 antagonists, 5-HT2 antagonists Monoamine oxidase inhibitors (MAOI) TRICYCLIC ANTIDEPRESSANTS (TCA) Non-selective, competitive monoamine reuptake inhibitor Chronic administration = ↓ β1, α2, 5-HT1A, 5-HT1B/D, 5-HT2 Gi/o 5-HT1A Trp TH 5-HTP 5-HT NA metabolites metabolites MAO 5-HT neuron Gi/o 5-HT1B/D NA Gi/o SERT α2 MAO NA neuron NET Postsynaptic receptors MECHANISM OF ACTION - TCA NT-R NT-R NT-R NT-R NT-R NT-R NT NT-R NT NT NT-R Health Depressed TCA Normalise postsynaptic Rs Desensitise/downregulate pre-synaptic Rs TCA Other effects – linked to side effects Anti-histamine (H1) – sedative, weight gain Anti-adrenergic (α1) – postural hypotension, dizziness Drug-drug interactions Anti-muscarinic (M1) – constipation, dry mouth, blurred vision Shares metabolism (P450 subtype) with antipsychotics and steroids Potentiate the effects of alcohol and anaesthetics (respiratory depression) Hazardous in overdose and for patients with heart disease – ventricular dysrhythmia THERAPEUTIC WINDOW [drug] toxic therapeutic time SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRI) Competitive or non-competitive inhibitors of SERT Chronic administration = ↓ 5-HT1A, 5-HT1B/D, 5-HT2 Postsynaptic receptors MECHANISM OF ACTION - SSRI 5-HT1A 5-HT1A 5-HT1A 5-HT1B/D 5-HT1B/D 5-HT 5-HT1B/D 5-HT1B/D 5-HT 5-HT 5-HT1B/D Health Depressed SSRI Normalise postsynaptic Rs Desensitise/downregulate pre-synaptic Rs SSRI Safer and better tolerated than TCAs Generally not as effective as TCAs in severe depression Side effects Insomnia, sexual dysfunction – 5-HT2 Nausea, headache – 5-HT3 Not to be combined with MAOIs (‘serotonin syndrome’) or TCAs (TCA toxicity) MONOAMINE OXIDASE INHIBITORS (MAOI) Inhibit the metabolism of monoamines – MAO-A = 5-HT ˃ NA ˃ DA, MAO-B = DA Non-competitive, non-specific, long-lasting inhibitors (many not all) Chronic administration = ↓ β1, β2, α2, 5-HT1A, 5-HT1B/D, 5-HT2, 5-HT3 Gi/o 5-HT1A Trp TH 5-HTP 5-HT NA metabolites metabolites MAO 5-HT neuron Gi/o 5-HT1B/D NA Gi/o SERT α2 MAO NA neuron NET Postsynaptic receptors MECHANISM OF ACTION - MAOI NT-R NT-R NT-R NT-R NT-R met NT-R NT NT-R NT MAO NT NT-R Health Depressed MAOI Normalise postsynaptic Rs Desensitise/downregulate pre-synaptic Rs MAOI Associated with food and drug interactions ‘Cheese reaction’ – tyramine ‘Serotonin syndrome’ – SSRIs Lack specificity - ↓ metabolism of alcohol & opioid analgesics Irreversible & non-selective MAOI NA accumulation = ↑ BP = acute hypertension and severe headache MAOI Further side effects! Postural hypotension & dizziness Tremors, excitement & insomnia ↑ appetite, excessive weight gain Anti-muscarinic (M1) – constipation, dry mouth, blurred vision Only used in severe depression when other therapies have not worked MONOAMINE RECEPTOR ANTAGONISTS Mirtazapine - α2, 5-HT2C, 5-HT3 antagonist Trazodone - 5-HT2A, 5-HT2C, H1 antagonist & weak 5-HT/NA reuptake inhibitor From Rang and Dale’s Pharmacology MONOAMINE RECEPTOR ANTAGONISTS Lack side effects mediated by 5-HT2A, 5-HT3 Sexual dysfunction, nausea, insomnia Anti-histamine (H1) – sedative, weight gain ELECTROCONVULSIVE THERAPY (ECT) Brain electrically stimulated via electrodes Anaesthesia, neuromuscular blocking agents, artificial ventilation Severe depression – last resort 60-80% response rate Faster onset Confusion/memory loss http://image.slidesharecdn.com/ CLINICAL EFFECTIVENESS OF ANTIDEPRESSANT DRUGS BIPOLAR DISORDER PIP PIP2 P G q L C Mood stabilisers PI Lithium (Li+) Valproate (antiepileptic) Risperidone (antipsychotic) IP3 Inositol IP1 Li+ IP2 IP3R ER - Ca2+ ↑[Ca2+] LITHIUM Inhibits glycogen synthase 3 (GSK3) isoforms Slow accumulation over 2 weeks Side effects Nausea Tremor Renal effects Weight gain Hyperthyroidism LEARNING OUTCOMES To describe and explain the main types of depression Discuss the 3 key theories on the mechanism behind the pathology of depression To describe & explain pre-clinical models of depression Discuss the major antidepressant drug categories and their ‘believed’ mechanism of action Monoamine uptake inhibitors Monoamine receptor antagonists Monoamine oxidase inhibitors (MAOI) To describe & explain bipolar disorder & it’s treatment Mechanism of action of lithium