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Depression Depression •Known as a Mood/Affective Disorder Affect = emotions Major Types •Bipolar •Unipolar •Seasonal Affective Disorder Depression Unipolar (major depression) •Most common affective disorder •19 million Americans/year (17%) •11 million clinical & major depression •15% parasuicide •Most effectively treated Depression Unipolar (major depression) Problems with diagnosis… Both a mental disorder & normal mood state Depression Reactive-Exogenous triggered by an obvious event Endogenous No trigger No obvious event Duration & Intensity •Anhedonia (experience pleasure) •Weight gain or loss •Hypersomnia, insomnia • Fatigue, loss of energy • feelings of worthlessness guilty • difficulty concentrating Clinical Depression (5 symptoms) (2 symptoms) Genetic Risk Concordance rate of 68% in monozygotic Concordance rate of 15% dizygotic Family member = 10 tx more likely Theories of Depression Most Dominant Theory of Depression Monoamine Hypothesis of Depression Depression is associated with an under activity at serotonergic and noradrenergic synapses (Indolamines & catecholamines) 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 Evidence in Support - Tryptophan depletion in depressed pt (Delgado, 1990) Put on Low Trypto. Diet (salad, corn, gelatin) Then, amino ccid cocktail (no trypto.)…so hi other amino acids Trypto. Dropped! = relapse -Healthy…no effect of diet or cocktail …PET shows prefrontal cortex trypto less 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 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 Treatment – Biochemical Therapies Antidepressants •Monoamine Oxidase Inhibitors (MAOIs) •Tricyclics •Selective Monoamine Reuptake Inhibitors (SSRIs) Monoamines? Monoamines Catecholamines: Norepinephrine Indolamines: Serotonin •Monoamine Oxidase Inhibitors (MAOIs) - MAOIs block the enzyme monoamine oxidase… - MAO breaks down monoamines into inactive metabolites MAOIs: •Iproniazid (eye-pron-eye-a-zid) •First antidepressant (1957) - originally marketed as rocket fuel - TX for TB A flop!…serendipity intervened •Isocarboxazid •Phenelzine •Tranylcypromine MAOIs: •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) 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 Tricyclics Called tricyclics because chemical structure Includes 3-ring structure – 2 benzene rings & 1 central seven membered ring Tricyclics works by preventing presynaptic reuptake Tricyclics 1st 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 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 Second Generation: Selective Serotonin Reuptake Inhibitors (SSRIs) “Atypical” Antidepressants SSRIs: Block Reuptake SSRIs -Just Like the tricyclics but selective to block serotonin uptake Fluoxotine (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 selfesteem, fear of failure, OCD, Binge eating & purging (Bulimia) 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)