Lecture 20 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (email@example.com) at Willamette University. Focus is on the pharmacological treatment of depression.
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/planAnna M. Kring, Ph.D. Lecture 14, 19:38-23:08
Edvard Munch (1863-1944) Vincent van Gogh (1853-1890)Despair (1894) Sorrowing Old Man (‘At Eternity’s Gate’) 1890
MDD• Episode = 6 months• Female: Males (2:1)• Age of Onset (younger)
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 Max Hamilton 1912-1988http://www.psy-world.com/online_hamd.htm
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 (2001) p. 182
5-HT FunctionsFrontal Cortex MoodHypothalamus 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-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.
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.
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
Serotonin Reuptake Inhibitors• Prozac (fluoxetine) was the original SRI• Greater affinity for SERT than NET• Not Selective (sigma receptors, CYP2D6)• Anorgasmia
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
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 adultsECS: 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 +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.
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
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 visits by youth (aged 0-19 years) and adults (aged >= 20 years) Moreno, C. et al. (2007). Arch Gen Psychiatry, 64, 1032-1039.
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
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 duringpregnancy. Starts at 31:20: http://videocast.nih.gov/Summary.asp?File=16674