1. Depression

2. Depression Known as a Mood/Affective Disorder Affect = emotions Major Types Bipolar Unipolar Seasonal Affective Disorder

3. Depression Unipolar (major depression) Most common affective disorder 19 million Americans/year (17%) 11 million clinical & major depression 15% parasuicide Good news…Most effectively treated

4. Depression Unipolar (major depression) Problems with diagnosis? Both a mental disorder & normal mood state

5. Depression Reactive-Exogenous triggered by an obvious event Endogenous No trigger No obvious event Duration & Intensity Problems with diagnosis

6. Anhedonia (experience pleasure) Weight gain or loss Hypersomnia, insomnia Fatigue, loss of energy feelings of worthlessness guilty difficulty concentrating

7. Clinical Depression (5 symptoms) (2 symptoms)

8. MOOD

9. Cognition

10. Physical

11. 3

12.  Genetic Risk Concordance rate of 68% (monozygotic) Concordance rate of 15% (dizygotic) Family member = 10 tx more likely

15. Theories of Depression (Biological)

16. Most Dominant Theory of Depression Monoamine Hypothesis of Depression Depression is associated with an under activity at serotonergic and noradrenergic synapses (Indolamines & catecholamines)

17. Evidence in Support CSF of depressed pt suicidal low levels of 5HIAA Post Mortem brains from depressed pt (prefontal) above avg # of 5HT & Norepi receptors  upregulation Post Mortem Suicide low 5HT low Norepi

18. Evidence in Support - Tryptophan depletion in depressed pt (Delgado, 1990) Put on Low Trypto. Diet (salad, corn, gelatin) Then, amino acid cocktail (no trypto.)…so hi other amino acids Trypto. Dropped! = relapse -Healthy…no effect of diet or cocktail …PET shows prefrontal cortex trypto less

19. Evidence in Support -Antidepressants Work!..so, monoamine agonists -Monoamine Antagonist = depression ex: Reserpine (Rauwolfia serpentina) 100’s years ago used to - calm insanity - treat hi BP = 15% got depressed

20. Evidence Refuting the Monoamine Hypothesis -Antidepressants Work…in 80% of the clinical population …what’s up with the other 20%??? -“Lag Time” time it takes a drug to work in the brain vs the time we see a behavioral effect  3 to 4 weeks to see behave effect…although in the brain

21. Evidence Refuting the Monoamine Hypothesis Neurogenesis Theory of Depression Dentate Gyrus: Hippocampus

22. Section of the dentate gyrus of the hippocampus, showing newly formed cells. These are the darker cells in the subgranular zone (SGZ), and they have been labelled with 5-bromo-2-deoxyuridine (BrdU), an analogue of thymidine. The histogram shows that various antidepressant treatments increase the number of new labelled cells. The treatments tested include electroconvulsive shock (ECS), the MAOI tranylcypromine (TCP), the SSRI fluoxetine (FLU), and the selective norepinephrine reuptake inhibitor reboxetine (REB). Santerelli et al, 2003, Science Antidepressant increase neurogenesis in hippocampus

23. Evidence Refuting the Monoamine Hypothesis Neurogenesis Theory of Depression

24. proliferation survival Exercise….

25. Treatment – Biochemical Therapies

26. Antidepressants Monoamine Oxidase Inhibitors (MAOIs) Tricyclics Selective Monoamine Reuptake Inhibitors (SSRIs)

27. Monoamines Catecholamines: Norepinephrine Indolamines: Serotonin

28. Monoamine Oxidase Inhibitors (MAOIs) - MAOIs block the enzyme monoamine oxidase… - MAO breaks down monoamines into inactive metabolites

29. MAOIs: Iproniazid (eye-pron-eye-a-zid) First antidepressant (1957) - originally marketed as rocket fuel - TX for TB A flop!…serendipity intervened

30. MAOIs: Isocarboxazid Phenelzine Tranylcypromine Side effects: hypertension (BP): headaches, sweating, nausea, vomiting Side effects represent drug interaction drug X food Tyramine – cheese, wine, licorice, raisins MAO breaks down tyramine= too much  intracranial hemorrage (stroke)

31. MAOIs: “Cheese Effect” Pharmacist G.E.F. Rowe wife was being treated with MAOI headaches after eating cheese Blackwell et al found that cheese causes a large increase in BP without MAO increase in tyramine indirectly acts on sympathetic release of Norepi

32. Tricyclics Called tricyclics because chemical structure Includes 3-ring structure – 2 benzene rings & 1 central seven membered ring

33. Tricyclics works by preventing presynaptic reuptake

34. Tricyclics 1 st tricyclic: Imipramine (Tofranil) serendipity! - Synthesized in 1948 as an antihistamine - Used in Schizophrenia – no help with psychosis but less depressed Side effects: (safer than MAOI) - block histamine receptors: produces drowsiness - block acetylcholine receptors: dry mouth, difficulty urinating - Na+ Channels: heart irregularities

35. Tricyclics Appear to work better with: - Early morning awakenings - Loss of appetite - Weight loss - Morning depression heightened Contraindicated for Bipolar depression  can trigger the mania

36. Second Generation: Selective Serotonin Reuptake Inhibitors (SSRIs) “Atypical” Antidepressants

37. SSRIs: Block Reuptake

38. SSRIs -Just Like the tricyclics but selective to block serotonin uptake Fluoxetine (Prozac) -first on the market in 1980s -most prescribed -not more effective in tx depression * fewer dangerous side effects * effective in a wide range of affective problems  lack of self-esteem, fear of failure, OCD, Binge eating & purging (Bulimia)

39. SSRIs (Sertraline:Zoloft, Paroxetine:Paxil (Fluvoxamine: Luvox, Citalopram:Celexa) Side Effects: SSRIs do not effect:  MAO – little risk of hypertension  Do not worry about food interaction However side effect: nervousness 25% nausea-10% nausea (Prozac & Zoloft) Priapism (trazadone) - protracted & painful penile erection Social anxiety disorder, PTSD, Panic disorder, OCD) ALSO: Selective Norepi Reuptake Inhibitors (Reboxetine)