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Affective DisordersBrian 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  cond...
Edvard Munch (1863-1944)   Vincent van Gogh (1853-1890)Despair (1894)             Sorrowing Old Man (‘At Eternity’s Gate’)...
MDD• Episode = 6 months• Female: Males (2:1)• Age of Onset (younger)
HeritabilityBMJ 1999; 319 : 37
Biosynthesis HO: hydroxyl COOH: carboxyl
BiosynthesisTryptophan: yogurt, milk, fish, nutsTryptophan 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 di...
Hamilton Depression Inventory          http://www.psy-world.com/online_hamd.htm
Ham-D                                           Max Hamilton                                             1912-1988http://w...
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 ...
5-HT & Aggression • muricide: mouse killing • PCPA: aggression • PCPA + 5-HTP: no   aggressionPaxinos et al. (1977). Pharm...
Serotonergic Projects• Cell bodies in  Raphe• Projections  throughout CNS
5-HT Functions   Brain stem   NauseaSpinal Cord     Sexual dysfunction                    Modified from Stahl (2001) p. 182
5-HT Functions  Limbic                AnxietyBrain stem           Insomnia                         Modified from Stahl (20...
5-HT FunctionsFrontal Cortex        MoodHypothalamus        Appetite (Bulimia?)                                          M...
Fenfluramine• Fenfluramine is a 5-HT releaser that was used  with phentermine for weight control• Animal studies indicate ...
5-HT Receptors                 Postsynaptic                 1A                 1B                 2A                 2C   ...
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)tet...
5-HT2A Agonist:             DOI • Example #2: Rats received   MDMA from age 35 to 60 • A DOI (di-methoxy-4-iodophenyl)-   ...
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:  – T...
MAO-Is• Monoamine Oxidase (MAO) is an enzyme that  breaks down 5-HT, NE, & DA• Food Interactions: tyramine foods (aged che...
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 Sel...
Comparison                  MAO-Is             TCA                SSRIsEfficacy          Moderate           Moderate      ...
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 ...
Structural Changes following Elevated                  Cortisol?• Rat research indicate that persistent increases in corti...
Antidepressants &                Neurogenesis    • New neurons are produced in the      hippocampus in adultsECS: electroc...
Electroconvulsive Therapy• The most effective treatment for MDD (especially high  suicide risk)• Controversial!• Potential...
Cognitive Behavioral Therapy• Short, evidence based, therapy• Developed by Aaron T. Beck• Instruction in how thoughts & fe...
CBT + Medication• Patients randomized to receive Nefazodone (5-  HT2A/1 antagonist), CBT, or both for 3 months            ...
Diagnosis of Bipolar• Bipolar I:              • Bipolar II:   – manic episode           – Hypomanic Episode   – depression...
Example of Mania• Lifetime prevalence: 1%• 1st Minute:  http://www.youtube.com/watch?v=rcl09ztmo  Dw
National trends in visits with a diagnosis of bipolar disorder as a percentage of total office-based                  visi...
Bipolar Disorder Many great writers, poets, and composerssuffered from bipolar disorder. During theirmanic phase creativit...
Treatment• Lithium carbonate (Li2CO3)• John Cade, Australian psychiatrist, on giving  lithium to guinea pigs:  – “After a ...
Depression & Pregnancy    • Drug treatment &      pregnancy is a tough      decision.    • Depression may also      occur ...
Neuropharmacology: Affective Disorders
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Neuropharmacology: Affective Disorders

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Lecture 20 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University. Focus is on the pharmacological treatment of depression.

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Transcript of "Neuropharmacology: Affective Disorders"

  1. 1. Affective DisordersBrian J. Piper, Ph.D., M.S.
  2. 2. Goals• Serotonin (5-HT)• Major Depressive Disorder• Bipolar Disorder
  3. 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/planAnna M. Kring, Ph.D. Lecture 14, 19:38-23:08
  4. 4. Edvard Munch (1863-1944) Vincent van Gogh (1853-1890)Despair (1894) Sorrowing Old Man (‘At Eternity’s Gate’) 1890
  5. 5. MDD• Episode = 6 months• Female: Males (2:1)• Age of Onset (younger)
  6. 6. HeritabilityBMJ 1999; 319 : 37
  7. 7. Biosynthesis HO: hydroxyl COOH: carboxyl
  8. 8. BiosynthesisTryptophan: yogurt, milk, fish, nutsTryptophan hydroxylase: rate limitingstep
  9. 9. 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)
  10. 10. Hamilton Depression Inventory http://www.psy-world.com/online_hamd.htm
  11. 11. Ham-D Max Hamilton 1912-1988http://www.psy-world.com/online_hamd.htm
  12. 12. Smith et al. (1997). Lancet, 349, 915-919.
  13. 13. Smith et al. (1997). Lancet, 349, 915-919.
  14. 14. 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 4Paxinos et al. (1977). Pharmacology, Biochemistry, Behavior, 6, 439-447.
  15. 15. 5-HT & Aggression • muricide: mouse killing • PCPA: aggression • PCPA + 5-HTP: no aggressionPaxinos et al. (1977). Pharmacology, Biochemistry, Behavior, 6, 439-447.
  16. 16. Serotonergic Projects• Cell bodies in Raphe• Projections throughout CNS
  17. 17. 5-HT Functions Brain stem NauseaSpinal Cord Sexual dysfunction Modified from Stahl (2001) p. 182
  18. 18. 5-HT Functions Limbic AnxietyBrain stem Insomnia Modified from Stahl (2001) p. 182
  19. 19. 5-HT FunctionsFrontal Cortex MoodHypothalamus Appetite (Bulimia?) Modified from Stahl (2001) p. 182
  20. 20. 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.
  21. 21. 5-HT Receptors Postsynaptic 1A 1B 2A 2C 4 5 6 7 Presynaptic 1A
  22. 22. 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 67Piper et al. (2006) JPET, 317, 838-849.
  23. 23. 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 67Biezonski et al. (2009) Brain Research, 1252, 87-93.
  24. 24. MAO-Is• Monoamine Oxidase (MAO) is an enzyme that breaks down 5-HT, NE, & DA
  25. 25. 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”)
  26. 26. 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
  27. 27. Tricyclic Antidepressants• Developed from antipsychotic drugs• Have 3 ringed structure
  28. 28. SERT & NET Blockade+
  29. 29. Serotonin Reuptake Inhibitors• Prozac (fluoxetine) was the original SRI• Greater affinity for SERT than NET• Not Selective (sigma receptors, CYP2D6)• Anorgasmia
  30. 30. Comparison MAO-Is TCA SSRIsEfficacy Moderate Moderate LowSide-effects “cheese effect”, orthostatic Sexual, many drug hypertension, OD Discontinuation interactions SyndromePrevalence very low low highMechanism 5-HT, NE, DA 5-HT & NE 5-HTTherapeutic Lag Yes Yes Yes
  31. 31. Other Mechanisms of Antidepressants• 5-HT2• Intracellelar (e.g. cAMP)• Brain Derived Neurotrophic Factor
  32. 32. 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.
  33. 33. 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.
  34. 34. Antidepressants & Neurogenesis • New neurons are produced in the hippocampus in adultsECS: electroconvulsive therapy; TCP: trancyclpromine (MAO-I), or Reboxetine (SNRI)Mahlberg (2000). J Neurosciece, 20, 9104-9110.
  35. 35. 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
  36. 36. Cognitive Behavioral Therapy• Short, evidence based, therapy• Developed by Aaron T. Beck• Instruction in how thoughts & feelings influence behavior 1921-
  37. 37. 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.
  38. 38. 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
  39. 39. Example of Mania• Lifetime prevalence: 1%• 1st Minute: http://www.youtube.com/watch?v=rcl09ztmo Dw
  40. 40. 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.
  41. 41. Bipolar Disorder Many great writers, poets, and composerssuffered from bipolar disorder. During theirmanic 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/ CorbisWhitman Wolfe Clemens Hemingway
  42. 42. 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.”
  43. 43. Depression & Pregnancy • Drug treatment & pregnancy is a tough decision. • Depression may also occur Post-partum.Payne, Jenifer L. (2011). Clinical care of Major Depression duringpregnancy. Starts at 31:20: http://videocast.nih.gov/Summary.asp?File=16674
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