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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, monoamineagonists
-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 – BiochemicalTherapies
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 interactiondrug 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 MAOIheadaches 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 structureIncludes 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 hypertensionDo not worry about food interaction
However side effect: nervousness 25% nausea-10% nausea (Prozac & Zoloft) Priapism (trazadone) - protracted & painful penile erectionSocial anxiety disorder, PTSD, Panic disorder, OCD)ALSO: Selective Norepi Reuptake Inhibitors (Reboxetine)