Neuropharmacology: Affective Disorders

Affective Disorders

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

Goals

• Serotonin (5-HT)• Major Depressive Disorder• Bipolar Disorder

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

Edvard Munch (1863-1944)

Despair (1894)

Vincent van Gogh (1853-1890)

Sorrowing Old Man (‘At Eternity’s Gate’)1890

MDD

• Episode = 6 months• Female: Males (2:1)• Age of Onset (younger)

Heritability

BMJ 1999; 319 : 37

Biosynthesis

HO: hydroxylCOOH: carboxyl

Biosynthesis

Tryptophan: yogurt, milk, fish, nuts

Tryptophan hydroxylase: rate limitingstep

Role of 5-HT in MDD

• Methods: 15 un-medicated women with a history of 2+ episodes of depression were on a low protein diet for 1 week, then randomly assigned to receive:– Tryptophan + : L-tryptophan (1.9 g), L-alanine (4.6

g) L-arginine (4.1 g)

– Tryptophan - : L-alanine (4.6 g) L-arginine (4.1 g)

Hamilton Depression Inventory

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

Ham-D

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

Max Hamilton

1912-1988

Smith et al. (1997). Lancet, 349, 915-919.

Smith et al. (1997). Lancet, 349, 915-919.

5-HT & Aggression

• Para-chlorophenylalanine (PCPA): irreversible tryptophan hydroxylase inhibitor

• PCPA treated rats were tested for muricide

Killers Non-killers

Control 0 13

PCPA 14 4

Paxinos et al. (1977). Pharmacology, Biochemistry, Behavior, 6, 439-447.

5-HT & Aggression• muricide: mouse killing• PCPA: aggression• PCPA + 5-HTP: no

aggression

Paxinos et al. (1977). Pharmacology, Biochemistry, Behavior, 6, 439-447.

Serotonergic Projects

• Cell bodies in Raphe

• Projections throughout CNS

5-HT Functions

Spinal Cord Sexual dysfunction

Brain stem Nausea

Modified from Stahl (2001) p. 182

5-HT Functions

Limbic Anxiety

Brain stem Insomnia

Modified from Stahl (2001) p. 182

5-HT Functions

Frontal Cortex Mood

Hypothalamus Appetite (Bulimia?)

Modified from Stahl (2001) p. 182

Fenfluramine• Fenfluramine is a 5-HT releaser that was used

with phentermine for weight control• Animal studies indicate fenfluramine causes 5-HT

axotomy• Methods: Former fenfluramine users (N=15) and

controls (N=17) completed PET imaging

McCann et al. (2007). Molecular Imaging & Biology, 9, 151-157.

5-HT Receptors

Postsynaptic1A1B2A2C4567

Presynaptic1A

5-HT1A Agonist: 8-OH-DPAT

• Example#1: Rats received MDMA from age 35 to 60• A 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin)

challenge was administered at age 67

Piper et al. (2006) JPET, 317, 838-849.

5-HT2A Agonist: DOI

• Example #2: Rats received MDMA from age 35 to 60

• A DOI (di-methoxy-4-iodophenyl)-2-aminopropane) challenge was administered at age 67

Biezonski et al. (2009) Brain Research, 1252, 87-93.

MAO-Is

• Monoamine Oxidase (MAO) is an enzyme that breaks down 5-HT, NE, & DA

MAO-Is

• Monoamine Oxidase (MAO) is an enzyme that breaks down 5-HT, NE, & DA; peak use in 1970s

• Food Interactions: – Tyramine: amino acid breakdown product of

tyrosine, doesn’t cross BBB but causes norepinephrine release

– Tyramine rich foods (aged cheese, beer, wine) + MAO-I results in increased blood pressure & headaches (“cheese effect”)

MAO-Is

• Monoamine Oxidase (MAO) is an enzyme that breaks down 5-HT, NE, & DA

• Food Interactions: tyramine foods (aged cheese, beer, wine) results in increased norepinephrine (blood pressure)

• Drug Interactions: increased activity of drugs that elevated 5-HT, NE, DA (cocaine, hypericum, ritalin)

• 1st generation were irreversible inhibitors (1960s), 2nd generation are reversible inhibitors

Tricyclic Antidepressants

• Developed from antipsychotic drugs• Have 3 ringed structure

SERT & NET Blockade+

Serotonin Reuptake Inhibitors

• Prozac (fluoxetine) was the original SRI• Greater affinity for SERT than NET• Not Selective (sigma receptors, CYP2D6)• Anorgasmia

ComparisonMAO-Is TCA SSRIs

Efficacy Moderate Moderate Low

Side-effects “cheese effect”, many drug interactions

orthostatic hypertension, OD

Sexual, DiscontinuationSyndrome

Prevalence very low low high

Mechanism 5-HT, NE, DA 5-HT & NE 5-HT

Therapeutic Lag Yes Yes Yes

Other Mechanisms of Antidepressants

• 5-HT2

• Intracellelar (e.g. cAMP)• Brain Derived Neurotrophic Factor

Cortisol

• The Hypothalamus-Pituitary-Adrenal (HPA) axis control 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.

Structural Changes following Elevated Cortisol?

• Rat research indicate that persistent increases in cortisol are toxic to hippocampal neurons.

• Studies examining the volume of the hippocampus in MDD were inconsistent.• A meta-analysis showed that the left (-4.5%) and right hippocampus (-4.0%)

showed reductions.

Cole et al. (2011). J of Affective Dis 134, 483-487.

Antidepressants & Neurogenesis

• New neurons are produced in the hippocampus in adults

ECS: electroconvulsive therapy; TCP: trancyclpromine (MAO-I), or Reboxetine (SNRI)

Mahlberg (2000). J Neurosciece, 20, 9104-9110.

Electroconvulsive Therapy

• The most effective treatment for MDD (especially high suicide risk)

• Controversial!• Potential memory loss• George, David T. (2011). Electroconvulsive therapy. Starts at

54:50: http://videocast.nih.gov/Summary.asp?File=16674

Cognitive Behavioral Therapy

• Short, evidence based, therapy• Developed by Aaron T. Beck• Instruction in how thoughts & feelings

influence behavior

1921-

CBT + Medication• Patients randomized to receive Nefazodone (5-

HT2A/1 antagonist), CBT, or both for 3 months

Nef CBT Nef +CBTCompleters 69.5% 72.2% 76.5%

No Response 44% 48% 15%Remission 22% 24% 42%

Keller et al (2000). New England J of Medicine, 342, 1462-1470.

Diagnosis of Bipolar

• Bipolar I: – manic episode– depression not

required– not due to

recreational drugs

• Bipolar II:– Hypomanic Episode– major depressive episode– not due to recreational

drugs

Example of Mania

• Lifetime prevalence: 1% • 1st Minute:

http://www.youtube.com/watch?v=rcl09ztmoDw

Moreno, C. et al. (2007). Arch Gen Psychiatry, 64, 1032-1039.

National trends in visits with a diagnosis of bipolar disorder as a percentage of total office-based visits by youth (aged 0-19 years) and adults (aged >= 20 years)

Bipolar Disorder

Many great writers, poets, and composers suffered from bipolar disorder.

During their manic phase creativity surged, but not during their depressed

phase.

Whitman Wolfe Clemens Hemingway

Bettm

ann/ Corbis

George C

. Beresford/ H

ulton Getty P

ictures Library

The G

ranger Collection

Earl T

heissen/ Hulton G

etty Pictures L

ibrary

Treatment

• Lithium carbonate (Li2CO3)• John Cade, Australian psychiatrist, on giving

lithium to guinea pigs:– “After a latent period of about two-hours, the animals, although fully conscious

became extremely lethargic and unresponsive to stimuli for one to two hours before once again becoming timid and active. Those who have experimented with guinea pigs know to what extent a ready startle reaction is part of their makeup. It was even more startling to find that after the injection of a solution of lithium carbonate they could be turned on their backs and that, instead of the usual frantic righting behavior, they merely lay there and gazed placidly back at him.”

Depression & Pregnancy

• Drug treatment & pregnancy is a tough decision.

• Depression may also occur Post-partum.

Payne, Jenifer L. (2011). Clinical care of Major Depression during pregnancy. Starts at 31:20: http://videocast.nih.gov/Summary.asp?File=16674