antidepressants part ii

27
Antidepressants II Brian J. Piper, Ph.D., M.S. January 28, 2013

Upload: brian-piper

Post on 18-Nov-2014

1.936 views

Category:

Health & Medicine


9 download

DESCRIPTION

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

TRANSCRIPT

Page 1: Antidepressants Part II

Antidepressants II

Brian J. Piper, Ph.D., M.S.

January 28, 2013

Page 2: Antidepressants Part II

Goals

• Light therapy for Seasonal Affective Disorder• Tricyclics & Tetracyclics• Monoamine Oxidase Inhibitors• Serotonin Norepinephrine Reuptake Inhibitors

(SNRI)• Saint John’s wort• STAR*D

Page 3: Antidepressants Part II

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.

Page 4: Antidepressants Part II

Light-Therapy Meta-Analysis• Effect Size = (meanExperimental – meanControl)/ Standard Deviation)

– 0.20: small– 0.50: medium– 0.80: large

Golden et al. (1995). American Journal of Psychiatry, 162(4), 656-662.

<- 0.84

Page 5: Antidepressants Part II

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

Page 6: Antidepressants Part II

Affinity (dirty drugs)

->

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

--------------------------------------------------------------------------- ----------------

Page 7: Antidepressants Part II

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, CD006528http://www.howjsay.com/index.php?word=mirtazapine&submit=Submit

Page 8: Antidepressants Part II

Serotonin & Norepinephrine Reuptake Inhibitors

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

Page 9: Antidepressants Part II

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=x0HUtRCEMykLong but sensitive (10 min): http://www.youtube.com/watch?v=2Bt2ftSgDDQNielson et al. (2011). Addiction, 107, 900-908.

Page 10: Antidepressants Part II

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.

Page 11: Antidepressants Part II

Monoamine Oxidase Inhibitors

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

Page 12: Antidepressants Part II

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.

Page 13: Antidepressants Part II

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.

Page 14: Antidepressants Part II

Serotonin Syndrome• Cluster of autonomic, motor & mental status

changes resulting from excess 5-HT (5-HT2A)

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

AgentsMAO-IsTCASSRIsopiate analgesicscough medicines (OTC)antibioticstriptansanti-nauseaherbal productsabused drugs

Page 15: Antidepressants Part II

Case of Libby Zion

• ER visit for fever, agitation, shaking movements

• Interns administered meperidine, later restraints

• Hyperthermia & cardiac arrest• Intern hours/week = 70

1965 - 1984

Page 16: Antidepressants Part II

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.

Page 17: Antidepressants Part II

Prior AntidepressantTrials

Sequenced Treatments Alternatives to Relieve Depression (STAR*D)

Multi-site Yes Yes

Blinded Yes- Randomized Controlled Trial

No-Open

Comorbid Condition Patients

excluded included

Duration 6-12 weeks years

Page 18: Antidepressants Part II

STAR*D Design & Results

Remission: Level 1: 32.9%; Level 2: 30.6%, Level 3: 13.6%Level 2: Switch = 27.0%; Augment = 35%

25.5% 26.6% 25.5% 39.0% 32.9% 29.4% 41.9%

Page 19: Antidepressants Part II

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?

Page 20: Antidepressants Part II

MDD: Endocrine Component?

Stahl (2008). Essential Psychopharmacology, p. 616-616.

Page 21: Antidepressants Part II

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

Page 22: Antidepressants Part II

Summary

• Best ----------------------------------Worst

Tolerability SRI > SNRI > TCA > MAO-IEfficacy TCA > MAO-I > SNRI > SRI

Page 23: Antidepressants Part II

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

-----------

-----------------

Page 24: Antidepressants Part II

Saint John’s wort (Hypericum perforatum)

• MOA: ?, SERT• Adverse Effects: photosensitivity• Concern: quality control• Efficacy: mild to moderate depression

Page 25: Antidepressants Part II

MDD Trial

Davidson et al. (2002). Journal of the American Medical Association, 287, 1807-1814.

-----------------------------------------------------------------------------

Quit27%-29%

Page 26: Antidepressants Part II

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

Page 27: Antidepressants Part II

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