antidepressants part i

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This PPT is part 1 of 2 lectures given to second year pharmacy students in a pharmacology & toxicology class.


  • 1. Antidepressants IBrian J. Piper, Ph.D., M.S. January 25, 2013

2. Goals Major Depressive Disorder Selective Serotonin Reuptake Inhibitors (SRIs) pharmacodynamics adverse effects 3. Major Depressive Disorder Five + (1 or 2) causing significant social oroccupational impairment not due to medicalcondition 1) Depressed mood most of the day, nearly every day 2) Marked diminished interest or pleasure, in activities 3) Significant weight loss/gain (+5%/month) 4) Insomnia/hypersomnia 5) Fatigue or loss of energy 6) Diminished ability to think or concentrate 7) recurrent thoughts of death, suicidal attempt/plan No bereavement exclusion Anna M. Kring, Ph.D. Lecture 14, 19:38-23:08 4. Hamilton Depression Inventory 5. Ham-DMax Hamilton 1912-1988Hamilton, M. (1967). Brit J Soc Clin Psychol, 6, 278-296. 6. Montgomery-Asberg DepressionInventory 10 items x 6 points each 0-6: normal 7 to 19: mild depression 20 to 34: moderate depression 35 to 60: severe depression Response: total score reduced by >50% Partial Response: total score reduced by 25-49% Non-Response: total score reduced by 0 24%Williams et al. (2008). British Journal of Psychiatry, 192(1), 52-58. 7. MDD Pathophysiology: Imbalance? MDD patients do not show measurable deficits in 5-HT, norepinephrine, dopamine or their metabolites MDD is not a simple chemical imbalance Avoid misinformation (even well intentioned)Serotonin & Depression (9 min): 8. MDD Pathophysiology: Cortisol The Hypothalamus-Pituitary-Adrenal (HPA) axiscontrols release of the stress hormone cortisol. As many as half of depressed patients showelevations in cortisol. Drugs that turn off the HPA axisare ineffective.Belmaker & Agam (2008). New England Journal of Medicine, 358, 55-68. 9. General Adage it is becoming more and more difficult toprove that antidepressants even well-established antidepressants actually workany better than placebo in clinical trials.Stahl, S. (2008). Essential Psychopharmaology, p. 514.Begley, S. (2/8/2010). Newsweek, 2/8/2010, 155(6). Stephen M. Stahl, M.D., Ph.D. 10. First Line Therapy Cognitive behavioral or interpersonalpsychotherapy are 1st for mild or moderatedepression Severe------------------- Moderate---------- Mild------------Teter et al. (2011). In DiPiro Pharmacotherapy: A Pathophysiological Approach, p. 1177. 11. Monoamine (5-HT, NE, DA) Effects of Antidepressants Presynaptic Post- synapticStahl, S. (2008). Essential Psychopharmaology, p. 520. 12. Sequential ApproachStahl, S. (2008). Essential Psychopharmacology, p. 517. 13. Simultaneous ApproachTCA: tricyclic; SNRIs: selective norepinephrine reuptake inhibitors; NaSSA:noadrenergic & serotonin specific antidepressants 14. The (not so) Selective Serotonin Reuptake InhibitorsSRIs:fluoxetine (Prozac)sertraline (Zoloft)paroxetine (Paxil)sexual side effectsfluvoxamine (Luvox)citalopram (Celexa)escitalopram (Lexapro)SRI: serotonin reuptake inhibitorNRI: norepinephrine reuptake inhibitorDRI: dopamine reuptake inhibitor5-HT2C: serotonin 2C antagonistm-ACh: muscarinic Acetylcholine: sigma peptideNOS: nitric oxide synthetaseStahl, S. (2008). Essential Psychopharmaology, p. 531. 15. SSRIs & the dynamic 5-HT System A) block SERT5-HT1-7Stahl, S. (2008). Essential Psychopharmacology, p. 526. 16. SSRIs & the dynamic 5-HT System A) block SERT B) down-regulate auto-receptor (5-HT1A)Stahl, S. (2008). Essential Psychopharmacology, p. 527. 17. SSRIs & the dynamic 5-HT System A) block SERT B) down-regulate auto-receptor (5-HT1A) C) increased 5-HT releaseStahl, S. (2008). Essential Psychopharmacology, p. 528. 18. SSRIs & the dynamic 5-HT System A) block SERT B) down-regulate auto-receptor (5-HT1A) C) increased 5-HT release D) down-regulate post-synapticreceptorsStahl, S. (2008). Essential Psychopharmacology, p. 528. 19. Fluoxetine 5-HT-Catecholamine Crosstalk 5-HT2C Agonist: NE/DA 5-HT2C Antagonist: NE/DA FDA approved for: Major Depression (Adults) Major Depression (Children) Half-life Fluoxetine: 3 days Norfluoxetine: 2 weeksStahl, S. (2008). Essential Psychopharmaology, p. 531. 20. Consequences of 2D6 InhibitionWilens et al. (2002). Journal of Clinical Psychopharmacology, 22(2), 169-173. 21. Other SRIssertralineescitalopram 2nd best selling most selective of SRIs antidepressant 22. xStahl, S. (2008). Essential Psychopharmacology, p. 490. 23. FDA Warning (2004) Antidepressants increased the risk of suicidal thinkingand behavior (suicidality) in short-term studies inchildren and adolescents with MDD and otherpsychiatric disorders. Anyone considering the use of___________ or any other antidepressant in a child oradolescent must balance this risk with the clinicalneed. Patients who are started on therapy should beobserved closely for clinical worsening, suicidality, orunusual changes in behavior. Families and caregiversshould be advised of the need for close observationand communication with the prescriber. 24. Adults too! Suicides: Drug = 5.2 /10,000; Placebo = 2.0/10,000; 2.6 fold Attempted Suicide: 3.7 / 1,000; Placebo = 1.6/1,000; 2.3 foldHealey, D. (2009). Canadian Journal of Psychiatry, 54(2),69-71.