Antidepressants I

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

January 25, 2013

Goals

• Major Depressive Disorder• “Selective” Serotonin Reuptake Inhibitors (SRIs)

– pharmacodynamics– adverse effects

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

Anna M. Kring, Ph.D. Lecture 14, 19:38-23:08

No bereavement exclusion

Hamilton Depression Inventory

http://www.psy-world.com/online_hamd.htm

Ham-D

Hamilton, M. (1967). Brit J Soc Clin Psychol, 6, 278-296.

Max Hamilton

1912-1988

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.

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

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.

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.

First Line Therapy• Cognitive behavioral or interpersonal

psychotherapy are 1st for mild or moderate depression

Teter et al. (2011). In DiPiro Pharmacotherapy: A Pathophysiological Approach, p. 1177.

Severe-------------------

Moderate----------

Mild------------

Monoamine (5-HT, NE, DA) Effects of Antidepressants

Stahl, S. (2008). Essential Psychopharmaology, p. 520.

Presynaptic Post- synaptic

Sequential Approach

Stahl, S. (2008). Essential Psychopharmacology, p. 517.

Simultaneous Approach

TCA: tricyclic; SNRIs: selective norepinephrine reuptake inhibitors; NaSSA: noadrenergic & serotonin specific antidepressants

The (not so) Selective Serotonin Reuptake Inhibitors

SRI: serotonin reuptake inhibitorNRI: norepinephrine reuptake inhibitorDRI: dopamine reuptake inhibitor5-HT2C: serotonin 2C antagonistm-ACh: muscarinic Acetylcholineσ: sigma peptideNOS: nitric oxide synthetase

Stahl, S. (2008). Essential Psychopharmaology, p. 531.

sexual side effects

SRIs:fluoxetine (Prozac)sertraline (Zoloft)paroxetine (Paxil)fluvoxamine (Luvox)citalopram (Celexa)escitalopram (Lexapro)

SSRIs & the dynamic 5-HT System• A) block SERT

Stahl, S. (2008). Essential Psychopharmacology, p. 526.

5-HT1-7

SSRIs & the dynamic 5-HT System• A) block SERT• B) down-regulate auto-receptor (5-HT1A)

Stahl, S. (2008). Essential Psychopharmacology, p. 527.

→

SSRIs & the dynamic 5-HT System• A) block SERT• B) down-regulate auto-receptor (5-HT1A)• C) increased 5-HT release

Stahl, S. (2008). Essential Psychopharmacology, p. 528.

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 receptors

Stahl, S. (2008). Essential Psychopharmacology, p. 528.

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 weeks

Stahl, S. (2008). Essential Psychopharmaology, p. 531.

Consequences of 2D6 Inhibition

Wilens et al. (2002). Journal of Clinical Psychopharmacology, 22(2), 169-173.

Other SRIs

sertraline• 2nd best selling

antidepressant

escitalopram• most selective of SRIs

x

Stahl, S. (2008). Essential Psychopharmacology, p. 490.

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. ”

Adults too!

Suicides: Drug = 5.2 /10,000; Placebo = 2.0/10,000; 2.6 foldAttempted Suicide: 3.7 / 1,000; Placebo = 1.6/1,000; 2.3 fold

Healey, D. (2009). Canadian Journal of Psychiatry, 54(2),69-71.