depression. depression known as a mood/affective disorder affect = emotions major types bipolar...
TRANSCRIPT
DepressionDepression•Known as a Mood/Affective Disorder
Affect = emotions
Major Types
•Bipolar
•Unipolar
•Seasonal Affective Disorder
DepressionUnipolar (major depression)
•Most common affective disorder
•19 million Americans/year (17%)•11 million clinical & major depression•15% parasuicide•Good news…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
Problems with diagnosis
•Anhedonia (experience pleasure)•Weight gain or loss•Hypersomnia, insomnia• Fatigue, loss of energy• feelings of worthlessness guilty• difficulty concentrating
Genetic Risk Concordance rate of 68% (monozygotic) Concordance rate of 15% (dizygotic) Family member = 10 tx more likely
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 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
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
Evidence Refuting the Monoamine Hypothesis
Neurogenesis Theory of Depression
Dentate Gyrus: Hippocampus
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
Antidepressants
•Monoamine Oxidase Inhibitors (MAOIs)
•Tricyclics
•Selective Monoamine Reuptake Inhibitors (SSRIs)
•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
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
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)
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 erection
Social anxiety disorder, PTSD, Panic disorder, OCD)ALSO: Selective Norepi Reuptake Inhibitors (Reboxetine)