1 / 77

Sean Lynch

Antidepressants - the nuts and bolts. Sean Lynch Consultant Psychiatrist and Honorary Associate Professor, University of Exeter Medical School. Summary of Main Objectives for Session. Aims Today Awareness of antidepressant types, efficacy, activity and adverse effects

tait
Download Presentation

Sean Lynch

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Antidepressants - the nuts and bolts Sean Lynch Consultant Psychiatrist and Honorary Associate Professor, University of Exeter Medical School

  2. Summary of Main Objectives for Session Aims Today • Awareness of antidepressant types, efficacy, activity and adverse effects • Basic awareness of transmitters implicated in depression. • Novel antidepressants • Examples of possible MCQ AND CASC type questions

  3. How psychopharmacology comes into MRCPsych exams • Basic sciences • EBM analysis of papers related to drug treatments • CASC questions on treatment / treatment resistance

  4. Suggested Background Reading and Resources • Stahl – Pharmacology of Antidepressants • Maudsley Prescribing Guidelines • NICE guidelines for anxiety and depression • Gaskell series (College) • Recent BMJ and BJPsych/APT review articles • BAP website • RCPsych website (look for Psychopharmacology links) • ABPI

  5. Reactions to stressful experiences • Acute reactions - immediate and brief responses to sudden intense stressors in a person who does not have other psychiatric disorder at time • Post-traumatic stress disorder - prolonged and abnormal response to exceptionally intense stressful circumstances • Adjustment disorder - more gradual and prolonged response to stressful changes in a person’s life • Depression?

  6. Reactions to stressful experiences • There are implications for mechanism of action of antidepressants and effectiveness • Will antidepressants alter an intact but activated stress-response system? • Will continued stress overcome the effectiveness of antidepressants?

  7. Disability adjusted life years All causes Unipolar major depression Iron deficiency anaemia Falls Alcohol use COPD Bipolar disorder Congenital anomalies Osteoarthritis Schizophrenia Obsessive compulsive disorders The ten leading causes of disabilityworldwide (1990) Total (millions)* % of total 472.7 50.8 10.7 22.0 4.7 22.0 4.6 15.8 3.3 14.7 3.1 14.1 3.0 13.5 2.9 13.3 2.8 12.1 2.6 10.2 2.2 Murray & Lopez eds. The Global Burden of Disease. Harvard University Press, 1996

  8. Depression • Depressive disorders are common, prevalence 2-5% (5-10% primary care settings). It affects around 121 million people worldwide (WHO) • Associated with significant morbidity and mortality. Recently the WHO have announced it is likely to be the single cause for burden of any disease by 2030 due to years lost of life or through severe disability. • More prevalent in developing countries

  9. Depression • Pathophysiology • Structural, neurochemical changes in hippocampus, frontal cortex • once thought to be a result of neurotransmitter deficiencies (e.g., NA, 5-HT) • More recent evidence suggests reductions in neurotrophic hormones and reduced neuronal plasticity

  10. Depression • Multisystem disorder (e.g. endocrine, immune changes, increased risk of some physical illnesses)? • Dysregulation of stress-response system • Alteration in environmental adaptation and learning • Role of 5HT1a and 5HT2 • Role of NA, Dopamine • More recent interest in NMDA and glutamate

  11. Possible changes in depression 5HT1a upregulation 5HT2 antagonism ß adrenoceptor downregulation Possible effects on dopamine Possible effects on neuropeptides Altered HPA / corticotrophin function Effects on plasticity and neural growth Other systems may have changes (glutamate, cholinergic)

  12. Receptor types • 1.lonotropic receptors • Ion channels - permeable to Ca2+ , Na+ K+Cl- Strong electrical response e.g. GABA, Nicotinic Ach • 2. Metabotropic receptors • Receptor signal via metabolism. Most are G-protein coupled receptors where NT binds leading to activation of second messenger e.g. • CAMP - adenylyl cyclase • CGMP - guanylylcyclase

  13. Basics of Receptor mechanisms D- D7 Blockade in Psychosis, augmentation in mood, reward/addiction 5HT1a,b,c Agonism in anxiety, depression, antagonism in migraine 5HT2 a,b,c Antagonism in depression, psychosis? 5HT3 Antagonism in anxiety, psychosis? NA ß Blockade ?depression α Not fully understood ? partial agents

  14. Inactivation of Neurotransmitters • Diffusion • Enzymatic degradation • Re-uptake

  15. Antidepressant Mechanisms • Reuptake inhibition • MAO inhibition • Receptor Antagonism • Receptor Antagonism • Novel

  16. The problem of which theoretical model of brain function to use

  17. Neurotransmitters implicated in depression Dopamine? Glutamate Acetylcholine Serotonin Noradrenaline -Aminobutyric acid (GABA) Neuropeptides Corticotrophins

  18. Antidepressant Classes and Interactions • Tricyclics • SSRI • SNRI • MAOI • Novel – NASSA, Melatonin Modulation • Experimental

  19. Effectiveness in depression • All antidepressants appear to be as effective in moderate severity illness (outpatient level), we are not sure about in different severities or subtypes of depression, however. • Previous response to one class does not necessarily predict future response • In some patients response can occur in subsequent episodes with different antidepressant classes • Antidepressants might differ in effectiveness in long-term maintenance and relapse prevention

  20. Effectiveness in depression • Highest in moderate severity - 60-80% in trials but high placebo response (40-60%) • Lower in mild severity and also high placebo response • Lower in severe (?50+% but few good trials), however lower placebo response • Issues about what constitutes a response versus remission • Issues about placebo design and “unblinding” in RCTs

  21. Antidepressants Selective serotonin reuptake inhibitors: SSRIs • 1st line: citalopram, sertraline, fluoxetine, paroxetine ad fluvoxamine • Max effect 4-6 weeks • Side effects: commonest GI side effects, headaches, insomnia • Few anticholinergic side effects • Low cardiotoxicity so safer in overdose. • Withdrawal effects; worse if stopped suddenly: nausea, dizziness, agitation, insomnia

  22. SSRIs • Side Effects and Other Concerns • Serotonin Syndrome • Serotonin Withdrawal Syndrome • SSRI-Induced Sexual Dysfunction • Gastrointestinal Bleeding • Effects in Pregnancy/Breast-Feeding • Recent increases in reports of fetal malformations • Suicidality and aggression

  23. Serotonin Syndrome • Due to excess serotonin • Can be due to SSRIs and other antidepressants • Causes: overdose, drug combinations/interactions, sometimes at normal doses • Can be fatal • Symptoms: Neurological (confusion, agitation, coma), Neuromuscular (rigidity, tremors, myoclonus, hyperreflexia), Autonomic (hyperthermia, tachycardia, hyper/hypotension, GI upset)

  24. TCAs • Adrenergic - postural hypotension • Anticholinergic - dry mouth, blurred vision, constipation • Antihistaminic - sedation • Other Cardiovascular - tachycardia, blockade, arhythmias Epileptic threshold Weight gain Sexual dysfunction Tremor Parkinsonian effects

  25. TCAs • Pharmacokinetics well absorbed orally long half-lives, metabolised in liver can have active metabolites e.g. imipramine and lofepramine • Pharmacodynamic Active metabolites Calcium channel blockers? Antihypertensives?

  26. Dual Action Antidepressants • Nefazodone • 5-HT2 receptor antagonist and 5-HT/NA reuptake blocker; chronic use down regulates NA/5-HT receptors., α1 and α2 activity, • Similar properties in trazadone • Mirtazepine • 5-HT2/5-HT3 receptor antagonist; potent antihistamine, α2 antagonist • Venlafaxine 5HT > NA reuptake • Duloxetine 5-HT/NA reuptake blocker, mild DA activity

  27. NARIs • Reboxetine • first NARI specifically developed for depression. • improved attention and speed of cognitive functioning

  28. MAOIs • Pharmacology • Inhibition of monoamine oxidase • MAO-A (depression) MAO-B (Parkinsons) • Side Effects • potentially serious interactions with adrenergic drugs some anaesthetics and opiates. • Recent advances • Transdermal delivery of selegiline

  29. MAOIs • Monoamine oxidase inhibitors • Isocarboxazid, Phenelzine • “Cheese reaction”: tyramine rich food can cause a hypertensive crisis: need to avoid foods rich in tyramine e.g. cheese, red wine, liver, yeast products. • RIMA: moclobemide

  30. Have we made any progress with antidepressants?

  31. Future Antidepressants? • Buspirone group • Tianeptine • Omega-3 Fatty Acids • NK1 antagonists • DHEA (glucocorticoid hormone) or modulators • Glutamate modulators? (Recent trial of IV ketamine, rapid and sustained effects in TRD)

  32. Antidepressant Effectiveness • Efficacy • Clinical Effectiveness • Safety and Adverse Outcomes

  33. Clinical Effectiveness Drug Efficacydepends upon: • pharmacology, • pharmacodynamics, • pharmacogenetics Clinical Effectivenessdepends upon: • efficacy, • tolerability, • adherence

  34. Antidepressant activity - evidence based? 1.Success rate of treatment for episode • Severity of episode • Dosage • Compliance • Duration 2. Effectsonillnessduration,riskofrelapse and risk of recurrence • Symptomatic • Shorten episode • Some prophylactic effects • Hard to know who should take these and for how long i.e markers, how big the effect • Little scientific evidence regarding predictors of relapse or recurrence

  35. Antidepressant activity - evidence based? 3.Basicpropertiesofantidepressants • All equally effective in moderate illness • Similar lag phase before therapeutic activity • Differential responses occur • May not all be as effective in different types of depression, OCD, anxiety disorders • Antidepressantwithdrawalsyndromes • Documented for all antidepressants • Usually just physiological adaptation • Some have psychological dependence (MAOI’s) • Some produce EPS

  36. Antidepressants - safe? Discontinuation symptoms / syndrome Suicidality Aggression - “the Prozac Defence” Treatmentresistance “Switching”

  37. Antidepressant activity - evidence based? Antidepressantaugmentation • Evidence for Li, L-tryptophan • Less evidence for T3, anticonvulsants Treatmentresistance The basic principles are similar to those for any treatment resistance. • Is diagnosis correct? • Is drug treatment dose optimum? Compliance, pharmacokinetics, pharmacodynamics • Has drug been given for right period? • High dosage regimens can be used with TDM and regular safety monitoring • Rate response on recognised scale • Change to a different antidepressant class (some debate about this and some suggest second drug within same class e.g. if SSRI and then change) • Some patients respond with any switch (?placebo response) • Augmentation therapy:- Lithium, L-tryptophan • Cocktail approach - little firm evidence they are helpful.

  38. Drug-related poisoning deaths, England & Wales, 1993 to 2000 21,631 drug-related poisoning deaths 50% of these suicides 3,959 - deaths which mention antidepressants 79% of thesesuicides

  39. Trends in antidepressant-related deaths, England & Wales, 1993 to 2000

More Related