Antidepressants Part II
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The document discusses various antidepressants, including their mechanisms of action, efficacy, side effects, and treatment protocols for conditions like seasonal affective disorder and major depressive disorder. It highlights various classes such as tricyclics, tetracyclics, SNRIs, and monoamine oxidase inhibitors, as well as notable factors like drug interactions and patient management strategies. Additionally, it references clinical trials and further explains the implications of these treatments on both mental and physical health.
Antidepressants Part II
- 1. Antidepressants II Brian J. Piper, Ph.D., M.S. January 28, 2013
- 2. Goals • Light therapy for Seasonal Affective Disorder • Tricyclics & Tetracyclics • Monoamine Oxidase Inhibitors • Serotonin Norepinephrine Reuptake Inhibitors (SNRI) • Saint John’s wort • STAR*D
- 3. Seasonal Affective Disorder • Depressive symptoms in fall-winter • Light-Therapy (10k lux, 30 min/day) – retina -> hypothalamus (2) -> pineal (3) – morning/ evening – rapid therapeutic onset (days) – good safety profile 2 3 Pail et al. (2011). Neuropsychobiology, 54, 162-164.
- 4. Light-Therapy Meta-Analysis • Effect Size = (mean Experimental – meanControl)/ Standard Deviation) – 0.20: small – 0.50: medium – 0.80: large <- 0.84 Golden et al. (1995). American Journal of Psychiatry, 162(4), 656-662.
- 5. Tricyclic Antidepressants (TCA) • Developed from antipsychotic drugs (1960s) • MOA: NET/SERT inhibition; anticholinergic • Gold standard for efficacy • Side effects: sedation • Concern with overdose
- 6. Affinity (dirty drugs) --------------------------------------------------------------------------- ---------------- -> Eur J Pharmacol. 340 (2–3): 249–258; Psychopharmacology, 114 (4): 559–565.
- 7. Tetracyclic Antidepressant (TeCA) • Example: mirtazapine (Remeron) • MOA: α2 & 5-HT2 antagonist • Efficacy: equivalent to TCA • Adverse Effects: weight gain, somnolence • Other: onset faster than SSRIs Watanabe et al. (2011). Cochrane Review, Issue 11, CD006528 http://www.howjsay.com/index.php?word=mirtazapine&submit=Submit
- 8. Serotonin & Norepinephrine Reuptake Inhibitors • Example: venlafaxine (Efexor) • MOA: SERT/NET • Efficacy: good ( > SSRIs) • Adverse Effects: nausea, somnolence, sexual • Half-life: 5 hours
- 9. SSRI Discontinuation Syndrome • Occurs for ≈2 weeks following withdrawal of antidepressants that block SERT • Symptoms – Flu-like: nausea, dizziness, diarrhea – “brain zaps” – emotional volatility • Solution: prolonged tapering Example Patient (0:52 – 1:13, 4:45 – 6:30): http://www.youtube.com/watch?v=x0HUtRCEMyk Long but sensitive (10 min): http://www.youtube.com/watch?v=2Bt2ftSgDDQ Nielson et al. (2011). Addiction, 107, 900-908.
- 10. Monoamine Oxidase • MAOA : 5-HT, NE, DA, tyramine • MAOB : phenyltheylamine, DA, tyramine • Inhibition: – Old (1950s): irreversible/non-selective – New (1990s): reversible/selective (MAOA) Stahl, S. (1998). Essential Psychopharmacology, p. 580.
- 11. Monoamine Oxidase Inhibitors • History: tuberculosis (serendipity) • Example: phenelzine (Nardil) • MOA: blocks breakdown of NE, 5-HT > DA • Efficacy: excellent • Adverse Effects: postural hypotension
- 12. MAO-I & “cheese” effect • Old view: avoid cheeses, alcohol, etc. • New View: avoid aged cheese, spoiled meats, – Typical American diet does not contain clinically meaningful levels of tyramine (10 mg) Stahl, S. (2008). Essential Psychopharmacology, p. 587-589.
- 13. MAO-I & “cheese” effect • New View: avoid aged cheese (Cheshire, Danish bleu) McCabe-Sellers et al. (2006). J of Food Composition & Analysis, 19, S58-S65.
- 14. Serotonin Syndrome • Cluster of autonomic, motor & mental status changes resulting from excess 5-HT (5-HT2A) Agents MAO-Is TCA SSRIs opiate analgesics cough medicines (OTC) antibiotics triptans anti-nausea herbal products abused drugs Boyer & Shannon (2005). New England Journal of Medicine, 352, 1112-1120.
- 15. Case of Libby Zion • ER visit for fever, agitation, shaking movements 1965 - 1984 • Interns administered meperidine, later restraints • Hyperthermia & cardiac arrest • Intern hours/week = 70
- 16. Bupropion • MOA: ?, NET & DAT inhibitor • Adverse Effects: dry mouth, high dose seizures • Efficacy: – monotherapy ≈ SRI – augmentation: better than monotherapy • Other: APA recommends as a first-line therapy for moderate depression Moreira, R. (2011). Clinical Drug Investigation, 31(S1), 5-17.
- 17. Prior Sequenced Treatments Antidepressant Alternatives to Relieve Depression (STAR*D) Trials Multi-site Yes Yes Blinded Yes- Randomized No-Open Controlled Trial Comorbid excluded included Condition Patients Duration 6-12 weeks years
- 18. STAR*D Design & Results 25.5% 26.6% 25.5% 39.0% 32.9% 29.4% 41.9% Remission: Level 1: 32.9%; Level 2: 30.6%, Level 3: 13.6% Level 2: Switch = 27.0%; Augment = 35%
- 19. Questions • If you had a family member with MDD, based on the STAR*D results, consider: – How good (efficacious) is the gold standard? – Is there an advantage of augmentation versus switching? – Were any other findings unexpected?
- 20. MDD: Endocrine Component? Stahl (2008). Essential Psychopharmacology, p. 616-616.
- 21. SRIs & Pregnancy • Pregnancy is a high-risk period for depression • SRIs may carry slight risks for the fetus – persistent pulmonary hypertension – low birth weight • Untreated MDD does cause fetal risk
- 22. Summary • Best ----------------------------------Worst Tolerability SRI > SNRI > TCA > MAO-I Efficacy TCA > MAO-I > SNRI > SRI
- 23. ----------- Stahl (2008). Essential Psychopharmaology, p. 519. -----------------
- 24. Saint John’s wort (Hypericum perforatum) • MOA: ?, SERT • Adverse Effects: photosensitivity • Concern: quality control • Efficacy: mild to moderate depression
- 25. MDD Trial ----------------------------------------------------------------------------- Quit 27%-29% Davidson et al. (2002). Journal of the American Medical Association, 287, 1807-1814.
- 26. Saint John’s wort • MOA: ?, SERT • Adverse Effects: photosensitivity • Other: ↑CYP3A4 • Efficacy: “The available evidence suggests that the hypericum extracts tested in the included trials: a) are superior to placebo in patients with major depression; b) are similarly effective as standard antidepressants; c) and have fewer side effects than standard antidepressants.” Linde et al. (2009). Cochrane Reviews, DOI: 10.1002/14651858.CD000448.pub3
- 27. Self-Test • The only antidepressant whose mechanism of action includes inhibiting NET & DAT is: – A) hypericum perforatum – B) fluvoxamine – C) mirtazapine – D) bupropion – E) clomipramine
Editor's Notes
- #2: Libby Zion
- #4: SAD is not a distinct disorder but is listed as a specifier of MDD or bipolar. DSM IV Criteria: A Regular temporal relationship between the onset of majordepressive episodes and a particular time of the year (unrelated to obvious season-related psychological stressors)B Full remission (or change from depression to mania or hypomania) also occurs at a characteristic time of the year.
- #5: #’s in ( ) are the reference #.
- #6: Cardiac effects: hypertension (early and transient), tachycardia, orthostasis and hypotension, and arrhythmias.ECG changes:prolonged QRS, QT, and PR intervals.
- #8: Mirtazapine was more likely to cause weight gain or increased appetite and somnolence than SSRIs but less likely to cause nausea or vomiting and sexual dysfunction. This agent has no appreciable effects on SERT & NET. Better response compared to SRI SNRI were noted at 2 weeks.This drug is also known as Noradrenergic & Serotonin Specific Antidepressant (NaSSA). Mechanism includes blocking all of the receptors shown.
- #9: Adverse reactions: Asthenia, sweating, N/V, headache, diarrhea, constipation, anorexia, insomnia, somnolence, dry mouth, dizziness, nervousness, anxiety, abnormal ejaculation/orgasm, impotence in men. Listing of side effects from Wyeth is available here: http://en.wikipedia.org/wiki/VenlafaxineHalf-life of some bioactive metabolites is 10 hours.
- #10: Symptoms described as "brain zaps", "brain shocks", "brain shivers", "brain pulse-waves", "head shocks", or "cranial zings“. Very gradual discontinuation of dosing may be beneficial.
- #11: Newer agents include moclobemide (not yet approved in US).
- #12: Isoniazid (I so niazid): http://www.howjsay.com/index.php?word=isoniazid&submit=Submit
- #13: 400 mg of tyramine may be needed to increase blood pressure in normal individuals but may be as low as 10 mg in individuals taking an irreversible/nonselective MAO-I (phenelzine).
- #14: Some international foods may be problematic (Marmite yeast extract, shrimp)
- #15: 5-HT2A antagonists can prevent the effects of serotonin toxicity.
- #16: The intern was responsible for 40 patients at the same time! Meperidine has weak SRI effects.
- #17: Bupropion is a weak inhibitor of NET & DAT but metabolites are biologically active (weakly too). This may be good as too much DAT binding could lead to abuse. Dry mouth noted in 15% versus 7% receiving placebo. Half-life is 10 hours but longer for active metabolites.
- #18: Many depressed patients have other psychiatric and medical conditions.
- #19: Venlafaxine: Serotonin/Norepinephrine Reuptake Inhibitor; Sertraline/Citalopram: Serotonin Reuptake Inhibitors; Buspirone: 5-HT1A agonist.
- #22: 14% of pregnant women experience depression.
- #23: ECT would rank above TCA for efficacy.
- #26: Sertraline dose started at 50 mg/day and could be increased, as needed to 150 mg/day. The highest dose used clinically is 300.
- #27: The association of country of origin and precision with effects sizes complicates the interpretation.