Major Depressive Disorder

Question 0

Based on DSM 4 what symptoms needed for diagnosis of MDD

Answer 0

5 or mor symptoms present in last 2 columns (more than half the days) during the same 2 week period.
Little interest doing things, feeling down, trouble falling asleep, feeling tired, poor appetite, feeling bad about self, trouble concentrating, moving or speaking slowly.
Also add if thoughts of death are on several days

Question 1

Whatis depression

Answer 1

State of low mood and aversion to activity that can have negative affect on persons behaviour, thoughts, feelings, world view and physical well being

Question 2

Epidemiology of MDD

Answer 2

At least 350 million people have it
Burden for depression is 50% higher in women
Leading cause of disability worldwide

Question 3

Monoamines types

Answer 3

Cathecolamines: dopamine, noradrenaline

Indoleamines: serotonin

Question 4

Formation of dopamine

Answer 4

Starts with tyrosine
This is hydroxylated to form L DOPA
L DOPA undergoes decarboxylation to form dopamine

Question 5

Formation of adrenaline

Answer 5

Starts with the dopamine
This is hydroxylated to form noradrenaline
Noradrenaline is metabolised to form adrenaline

Question 6

Formation of serotonin

Answer 6

Starts with tryptopham
Undergoes hydroxylation to form 5-hydroxytryptopham
This then undergoes decarboxylation to form serotonin (5-Hydroxytryptamine)

Question 7

Noradrenaline system

Answer 7

Tyrosine is dietary essential amino acid
Actively transported across BB barrier
Converted into NA in neuronal cellbodies in locus ceruleus in pons
NA packaged into vesicles and transported along axon to terminals to be released into synaptic cleft
Extends to entire brain

Question 8

Serotonin system

Answer 8

Tryptopham is also a dietary amino acid
Active transport across BBB
Converted into 5-HT in neuronal cell bodies in the raphe nuclei in brainstem
Then packages into vesicles and travels in axons to be released at clefts

Question 9

How is the serotonin and NA signal terminated

Answer 9

By reuptake into nerve terminal

And enzymatic degradation

Question 10

What breaks down serotonin

Answer 10

MAO-A

Question 11

What breaks down NA

Answer 11

MAO-A

COMT

Question 12

What does breakdown of serotonin form

Answer 12

5-HIAA

Question 13

What does breakdown of NA form

Answer 13

VMA

or MHPG

Question 14

Noradrenergic receptors

Answer 14

a1 and b1-3 are all excitatory

a2 in inhibitory

Question 15

Serotonin receptors

Answer 15

16 receptor subtypes
All Gprotein coupled receptors (adenylate cyclase)
EXCEPT 5-HT3 which is ion coupled

Question 16

Serotonin and NA interactions

Answer 16

Both act on muscles with their specific receptor
But NA cell also projects to the 5-HT cell (which has NA a1 and a2 receptors)
NA cell has NA a2 receptor on it

Question 17

What effect does released NA have on each of these neurones

Answer 17

NA release via a1 receptor on serotonin cell causes the increased release of serotonin (cell firing)
NA release via a2 receptor on NA and serotonin neurone causes decreased cell firing

Question 18

Monoamine hypothesis of MDD

Answer 18

Decreased monoamine caused depression (reserpine drug)

WE WANT TO INCREASE SYNAPSE LEVELS OF 5-HT AND NA

Question 19

Other chemical causes of depression

Answer 19

Upregulation of 5-HT 2a receptors causes chronically reduced synaptic serotonin levels leading to depression

Rapid tryptopham depletion also caused depression

Question 20

Reserpine

Answer 20

Antipsychotic
Vesicular MonoAmine Transporter blocker
This transporter transported NA and serotonin into vesicles for release
Reserpine irreversibly blocks VMAT
The cytoplasmic MAO and COMT broke down the serotonin and NA

Question 21

MAOI antidepressants

Answer 21

Iproniazid developed for TB found to decrease depression, but toxic

Safer ones have been developed
MAO-A are antidepressants
MAO-B used to treat parkinsons (^dopamine)

Question 22

MAO-A inhibitors names

Answer 22

Irreversible: phenelzine, tranylcypromine

Reversible: moclobomide

Cant metabolise other monoamines (cheese, red wine, marmite)

Question 23

Tricyclic and SSRI antidepressant action

Answer 23

Reversibly block the SERT and NET reuptake transporters

Caused increase synaptic serotonin and NA

Question 24

Tricyclic AD names

Answer 24

Desipramine Amitrypamine Clomipramine

Question 25

SSRI names

Answer 25

``` Fluoxetine Paroxetine Fluvoxamine Sertraline Citalopram Escitalopram ```

Question 26

Mirtazapine

Answer 26

Newer antidepressant Adrenergic a2 receptor blocker Blocks negative feedback causing reduced NA release Therefore increases NA and serotonin release

Question 27

5-HT 2a receptors in MDD

Answer 27

Postsynaptic on glutamate pyramidal neurones and GABA interneurones Upregukated after chronic 5-HT depletion MDD causes reduction in 5-HT and postmortem shows us that there sre increased 5-HT 2a receptors in MDD

Question 28

5-HT 2a blockage to treat MDD

Answer 28

Most atypical antipsychotics strongly block 5-HT 2a receptors (clozapine, risperidone) Adding this to an AD augments antidepressant potency Mirtazapine already blocks these receptors

Question 29

Recurrence of MDD

Answer 29

Up to 90% relapse in 3 years Risk twice as high in first year Kindling: more episodes you have, the more easily it will be to trigger. Lowers the threshold

Question 30

Ventral neural system

Answer 30

Identification of emotional significance of stimuli and production of affective states

Question 31

Dorsal neural system

Answer 31

Integration of emotional inputs and performance of executive functions

Question 32

Ventral neural system abnormality in MDD

Answer 32

Overactive VO cortex3: Enhanced sens to pain, anxiety, depressive ruminations and tension Vetral ACC: depressed mood Amygdala: process negative stimuli more

Question 33

Dorsal neural system abnormality in MDD

Answer 33

Underactive DLPRFC and dorsal ACC: psychomotor retardation, apathy, deficits in attention and working memory Hippocampus: memory consolidation

Question 34

Amygdala in MDD

Answer 34

Enlargement Modulates processing of faces. Will be overactive when shown sad face Can be treated with CBT

Question 35

Hippocampus in MDD

Answer 35

Reduced volume with longer durations of untreated depression

Question 36

Stress hormones in MDD | Glucocorticoids

Answer 36

- Chronic stress releases excessive glucocorticoids and CRH | - ^glucocorticoids dysregulate amygdala

Question 37

Stress hormones in MDD | Cytokines

Answer 37

- adrenaline oroduced by stress which ^symp tone causing release of inflammatory cytokines (TNF, IL-1, IL-6) - cytokines and gcorticoids cause ^MAO, decreasing levels of 5-HT, NA, DA - cytokines and gc also decrease BDNF(brain derived neurotrophic factor) which decreases hippocampal volume - cytokines (inflammatory) also increase physical illness symptoms like CVD

Question 38

Genetics and MDD

Answer 38

Genetic variability in the 5-HTT gene | Short and long alleles (s/s has greatest development of MDD)

Question 39

Treatment of mild depression

Answer 39

Dont use AD routinely But consider if history of recurrent severe or moderate depression or if persisted for more than 2 months Offer low intensity pyschosocial treatment (computerised CBT, self help based on CBT principles, structured group physical activity)

Question 40

Treatment of moderate or sever depression

Answer 40

Combination of AD and high intensity psychological treatment like CBT

Question 41

Steps for ADs in severe or moderate depression

Answer 41

8-10 week trials 1. SSRI 2. Venlafaxine, mirtazapine 3. Add atypical antipsychotic then lithium 4. TCA 5. MAOI (reversible then irreversible)