Depression. Depression Known as a Mood/Affective Disorder Affect = emotions Major Types Bipolar Unipolar Seasonal Affective Disorder.

DepressionDepression

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

Clinical Depression

(5 symptoms)

(2 symptoms)

MOOD

Cognitio

n

Physical

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, 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

Evidence Refuting the Monoamine Hypothesis

Neurogenesis Theory of Depression

proliferation

survival

Exercise….

Treatment – BiochemicalTherapies

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

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

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)