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

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