Transcript Side effects

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)