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 Duration & Intensity 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)



Concordance rate of 68% in monozygotic 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

Tryptophan depletion in depressed 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

Antidepressants Work…in 80% of the clinical population 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

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)

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 self- esteem, 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)