This document summarizes information about affective disorders including major depressive disorder and bipolar disorder. It discusses the role of serotonin in major depressive disorder and the use of tryptophan supplements to elevate serotonin levels. Symptoms of major depressive disorder are outlined. The heritability and biosynthetic pathway of serotonin are also summarized. Information is provided about various antidepressant medications including their mechanisms of action, efficacy, side effects and prevalence of use. Electroconvulsive therapy and cognitive behavioral therapy are discussed as treatments for depression. Diagnosis and treatment of bipolar disorder including the use of lithium is also summarized briefly.

1. Affective Disorders
Brian J. Piper, Ph.D., M.S.

2. Goals
• Serotonin (5-HT)
• Major Depressive Disorder
• Bipolar Disorder

3. 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

4. Edvard Munch (1863-1944) Vincent van Gogh (1853-1890)
Despair (1894) Sorrowing Old Man (‘At Eternity’s Gate’)
1890

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

6. Heritability
BMJ 1999; 319 : 37

7. Biosynthesis
HO: hydroxyl
COOH: carboxyl

8. Biosynthesis
Tryptophan: yogurt, milk, fish, nuts
Tryptophan hydroxylase: rate limiting
step

10. 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)

11. Hamilton Depression Inventory
http://www.psy-world.com/online_hamd.htm

12. Ham-D
Max Hamilton
1912-1988
http://www.psy-world.com/online_hamd.htm

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

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

15. 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.

16. 5-HT & Aggression
• muricide: mouse killing
• PCPA: aggression
• PCPA + 5-HTP: no
aggression
Paxinos et al. (1977). Pharmacology, Biochemistry, Behavior, 6, 439-447.

17. Serotonergic Projects
• Cell bodies in
Raphe
• Projections
throughout CNS

18. 5-HT Functions
Brain stem Nausea
Spinal Cord Sexual dysfunction
Modified from Stahl (2001) p. 182

19. 5-HT Functions
Limbic Anxiety
Brain stem Insomnia
Modified from Stahl (2001) p. 182

20. 5-HT Functions
Frontal Cortex Mood
Hypothalamus Appetite (Bulimia?)
Modified from Stahl (2001) p. 182

21. 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.

22. 5-HT Receptors
Postsynaptic
1A
1B
2A
2C
4
5
6
7
Presynaptic
1A

23. 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.

24. 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.

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

26. 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”)

27. 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

28. Tricyclic Antidepressants
• Developed from antipsychotic drugs
• Have 3 ringed structure

29. SERT & NET Blockade+

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

31. Comparison
MAO-Is TCA SSRIs
Efficacy Moderate Moderate Low
Side-effects “cheese effect”, orthostatic Sexual,
many drug hypertension, OD Discontinuation
interactions Syndrome
Prevalence very low low high
Mechanism 5-HT, NE, DA 5-HT & NE 5-HT
Therapeutic Lag Yes Yes Yes

32. Other Mechanisms of Antidepressants
• 5-HT2
• Intracellelar (e.g. cAMP)
• Brain Derived Neurotrophic Factor

33. 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.

34. 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.

35. 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.

36. 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

37. Cognitive Behavioral Therapy
• Short, evidence based, therapy
• Developed by Aaron T. Beck
• Instruction in how thoughts & feelings
influence behavior
1921-

38. CBT + Medication
• Patients randomized to receive Nefazodone (5-
HT2A/1 antagonist), CBT, or both for 3 months
Nef CBT Nef +CBT
Completers 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.

39. Diagnosis of Bipolar
• Bipolar I: • Bipolar II:
– manic episode – Hypomanic Episode
– depression not – major depressive episode
required – not due to recreational
– not due to drugs
recreational drugs

40. Example of Mania
• Lifetime prevalence: 1%
• 1st Minute:
http://www.youtube.com/watch?v=rcl09ztmo
Dw

41. 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)
Moreno, C. et al. (2007). Arch Gen Psychiatry, 64, 1032-1039.

42. Bipolar Disorder
Many great writers, poets, and composers
suffered from bipolar disorder. During their
manic phase creativity surged, but not during
their depressed phase.
George C. Beresford/ Hulton Getty Pictures Library
Earl Theissen/ Hulton Getty Pictures Library
The Granger Collection
Bettmann/ Corbis
Whitman Wolfe Clemens Hemingway

43. 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.”

44. 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