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
•Good news…Most effectively treated
Depression
Unipolar (major depression)
Problems with diagnosis?
Both a mental disorder & normal mood
state
Depression
Problems with diagnosis
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)
3
 Genetic Risk
Concordance rate of 68% (monozygotic)
Concordance rate of 15% (dizygotic)
Family member = 10 tx more likely
Theories of Depression
(Biological)
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, 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
Evidence Refuting the Monoamine Hypothesis
Neurogenesis Theory of Depression
Dentate Gyrus: Hippocampus
Antidepressant increase neurogenesis in 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
Evidence Refuting the Monoamine Hypothesis
Neurogenesis Theory of Depression
proliferation
survival
Exercise….
Treatment – Biochemical
Therapies
Antidepressants
•Monoamine Oxidase Inhibitors (MAOIs)
•Tricyclics
•Selective Monoamine Reuptake
Inhibitors (SSRIs)
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
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 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)