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Antidepressants IIBrian J. Piper, Ph.D., M.S. January 28, 2013

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Goals• Light therapy for Seasonal Affective Disorder• Tricyclics & Tetracyclics• Monoamine Oxidase Inhibitors• Serotonin Norepinephrine Reuptake Inhibitors (SNRI)• Saint John’s wort• STAR*D

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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 3Pail et al. (2011). Neuropsychobiology, 54, 162-164.

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Light-Therapy Meta-Analysis • Effect Size = (mean Experimental – meanControl)/ Standard Deviation) – 0.20: small – 0.50: medium – 0.80: large <- 0.84Golden et al. (1995). American Journal of Psychiatry, 162(4), 656-662.

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Tricyclic Antidepressants (TCA)• Developed from antipsychotic drugs (1960s)• MOA: NET/SERT inhibition; anticholinergic• Gold standard for efficacy• Side effects: sedation• Concern with overdose

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Affinity (dirty drugs) --------------------------------------------------------------------------- ---------------- ->Eur J Pharmacol. 340 (2–3): 249–258; Psychopharmacology, 114 (4): 559–565.

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Tetracyclic Antidepressant (TeCA) • Example: mirtazapine (Remeron) • MOA: α2 & 5-HT2 antagonist • Efficacy: equivalent to TCA • Adverse Effects: weight gain, somnolence • Other: onset faster than SSRIsWatanabe et al. (2011). Cochrane Review, Issue 11, CD006528http://www.howjsay.com/index.php?word=mirtazapine&submit=Submit

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Serotonin & Norepinephrine Reuptake Inhibitors• Example: venlafaxine (Efexor)• MOA: SERT/NET• Efficacy: good ( > SSRIs)• Adverse Effects: nausea, somnolence, sexual• Half-life: 5 hours

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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 taperingExample Patient (0:52 – 1:13, 4:45 – 6:30): http://www.youtube.com/watch?v=x0HUtRCEMykLong but sensitive (10 min): http://www.youtube.com/watch?v=2Bt2ftSgDDQNielson et al. (2011). Addiction, 107, 900-908.

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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.

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Monoamine Oxidase Inhibitors• History: tuberculosis (serendipity)• Example: phenelzine (Nardil)• MOA: blocks breakdown of NE, 5-HT > DA• Efficacy: excellent• Adverse Effects: postural hypotension

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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.

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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.

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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 drugsBoyer & Shannon (2005). New England Journal of Medicine, 352, 1112-1120.

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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

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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 depressionMoreira, R. (2011). Clinical Drug Investigation, 31(S1), 5-17.

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Prior Sequenced Treatments Antidepressant Alternatives to Relieve Depression (STAR*D) TrialsMulti-site Yes YesBlinded Yes- Randomized No-Open Controlled TrialComorbid excluded includedConditionPatientsDuration 6-12 weeks years

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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%

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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?

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MDD: Endocrine Component?Stahl (2008). Essential Psychopharmacology, p. 616-616.

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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

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Summary • Best ----------------------------------WorstTolerability SRI > SNRI > TCA > MAO-IEfficacy TCA > MAO-I > SNRI > SRI

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-----------Stahl (2008). Essential Psychopharmaology, p. 519. -----------------

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Saint John’s wort (Hypericum perforatum)• MOA: ?, SERT• Adverse Effects: photosensitivity• Concern: quality control• Efficacy: mild to moderate depression

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MDD Trial ----------------------------------------------------------------------------- Quit 27%-29%Davidson et al. (2002). Journal of the American Medical Association, 287, 1807-1814.

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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

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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