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.

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  • DSM5 will by released May 22, 2013.
  • Its estimated that as much as 75% of the response to anti-depressants may be due to the placebo effect!
  • Other side effects are typically short-lived and include g.i. upset, nausea, and diarrhea.
  • There is a unique distribution of 5-HT receptors. The 2A/2C in amygdala may be involved with short-term anxiety that may be produced by these agents; 2A in basal ganglia may be involved in motor movements; 2A in brainstem could be involved with sleep; 2A/2C in spinal cord and delayed ejaculation.
  • Fluoxetine is only FDA approved agent for MDD in children. Fluoxetine is also approved for bulimia and premenstrual dysphoric disorder. NET inhibition may only be relevant at high doses.
  • Children (mean age=10) and adolescents (mean age = 15) received 20 mg/day for many weeks. Although there appear to be age differences, these differences disappear when corrected for weight differences.
  • Sertraline was the second most prescribed antidepressant on the U.S. in 2011 (citalopram was #1). FDA approved for MDD, OCD, panic, and social anxiety disorder. Escitalopram is made by Lundbeck (Dutch company).
  • The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%.
  • Antidepressants Part I

    1. 1. Antidepressants IBrian J. Piper, Ph.D., M.S. January 25, 2013
    2. 2. Goals• Major Depressive Disorder• “Selective” Serotonin Reuptake Inhibitors (SRIs) – pharmacodynamics – adverse effects
    3. 3. Major Depressive Disorder• Five + (1 or 2) causing significant social or occupational impairment not due to medical condition – 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. 4. Hamilton Depression Inventory http://www.psy-world.com/online_hamd.htm
    5. 5. Ham-D Max Hamilton 1912-1988Hamilton, M. (1967). Brit J Soc Clin Psychol, 6, 278-296.
    6. 6. Montgomery-Asberg Depression Inventory • 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. 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): http://www.npr.org/blogs/health/2012/01/23/145525853/when-it-comes-to-depression-serotonin-isnt-the-whole-story
    8. 8. MDD Pathophysiology: Cortisol• The Hypothalamus-Pituitary-Adrenal (HPA) axis controls release of the stress hormone cortisol.• As many as half of depressed patients show elevations in cortisol. Drugs that turn off the HPA axis are ineffective.Belmaker & Agam (2008). New England Journal of Medicine, 358, 55-68.
    9. 9. General Adage • “ … it is becoming more and more difficult to prove that antidepressants – even well- established antidepressants – actually work any 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. 10. First Line Therapy • Cognitive behavioral or interpersonal psychotherapy are 1st for mild or moderate depression Severe------------------- Moderate---------- Mild------------Teter et al. (2011). In DiPiro Pharmacotherapy: A Pathophysiological Approach, p. 1177.
    11. 11. Monoamine (5-HT, NE, DA) Effects of Antidepressants Presynaptic Post- synapticStahl, S. (2008). Essential Psychopharmaology, p. 520.
    12. 12. Sequential ApproachStahl, S. (2008). Essential Psychopharmacology, p. 517.
    13. 13. Simultaneous ApproachTCA: tricyclic; SNRIs: selective norepinephrine reuptake inhibitors; NaSSA:noadrenergic & serotonin specific antidepressants
    14. 14. The (not so) Selective Serotonin Reuptake Inhibitors SRIs: fluoxetine (Prozac) sertraline (Zoloft) paroxetine (Paxil) sexual side effects fluvoxamine (Luvox) citalopram (Celexa) escitalopram (Lexapro) SRI: serotonin reuptake inhibitor NRI: norepinephrine reuptake inhibitor DRI: dopamine reuptake inhibitor 5-HT2C: serotonin 2C antagonist m-ACh: muscarinic Acetylcholine σ: sigma peptide NOS: nitric oxide synthetaseStahl, S. (2008). Essential Psychopharmaology, p. 531.
    15. 15. SSRIs & the dynamic 5-HT System• A) block SERT 5-HT1-7Stahl, S. (2008). Essential Psychopharmacology, p. 526.
    16. 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. 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. 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-synaptic receptorsStahl, S. (2008). Essential Psychopharmacology, p. 528.
    19. 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. 20. Consequences of 2D6 InhibitionWilens et al. (2002). Journal of Clinical Psychopharmacology, 22(2), 169-173.
    21. 21. Other SRIssertraline escitalopram• 2nd best selling • most selective of SRIs antidepressant
    22. 22. xStahl, S. (2008). Essential Psychopharmacology, p. 490.
    23. 23. FDA Warning (2004)• “Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with MDD and other psychiatric disorders. Anyone considering the use of ___________ or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. ”
    24. 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.

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