Depression

Question 1

What are the three grades of Major Depressive Disorder?

Answer 1

Mild depression
Moderate depression
Severe depression

DSMV requires >5 symptoms, occurring nearly every day for 2 weeks for diagnosis of mild depression, >2 years for chronic depression (ICD-10 >4)

Question 2

What are the symptoms?

Answer 2

Have to consider:
Feeling
Thoughts
Behaviour
Physical symptoms

Key Symptoms:
persistent sadness or low mood; and/or
marked loss of interests or pleasure

If key symptoms present, look for:
disturbed sleep (decreased or increased compared to usual)
decreased or increased appetite and/or weight
fatigue or loss of energy
agitation or slowing of movements
poor concentration or indecisiveness
feelings of worthlessness or excessive or inappropriate guilt
suicidal thoughts or acts

Question 3

Which areas of the brain have increased/decreased activity during depression?

Answer 3

Reward vs stress circuits

Decreased activity:
Prefrontal cortex
Hippocampus (so can cause downgrade in memory)

Increased activity:
Amygdala
Hypothalamus (HPA)

Question 4

What are the different theories for depression?

Answer 4

1) Neurotransmitter
Monoamines:
- Serotonin (5HT)
- Noradrenaline

2) Neurohormonal
- Steroids
- HPA axis (Stress, Anxiety)

3) Immune (auto?)
4) Circadian

Question 5

Describe the actions of 5-HT/Serotonin?

Answer 5

Main sites of production are the raphé nuclei in the brainstem

Acts centrally in multiple areas

Involved in:
Mood, agitation, OCD, anxiety, appetite, insomnia, sexual function, nausea and vomiting, GI function

Question 6

Describe the actions of noradrenaline?

Answer 6

Main sites of production are the Locus Coeruleus and Lateral tegmental area

Acts Centrally and peripherally (particularly involved in ANS transmission)

Multiple Functions: depression, attention, energy homeostasis, agitation, emotions, blood pressure, heart rate, bladder control, motor function

Question 7

Describe 5HT-NA interactions

Answer 7

Large interaction between 5HT and NA neurons centrally

Interactions in the brainstem speed activity

Interactions in the cortex slow activity

Question 8

What is the role of inflammation in depression?

Answer 8

Inflammatory mediators* lead to:
Microglia activation
Cell dysfunction
Cell death

Leads to spectrums of disorders

*NB. This related to inflammation/damage occurring within the central nervous system, peripheral damage will not cross the blood-brain barrier unless there are points of weakness

Question 9

How can the gut-brain axis affect mood?

Answer 9

Significant communication between the enteric nervous system, ANS and CNS.

Basic premise:

• Inflammation in the gut can trigger altered activity in the brain.
• Altered microbiota can lead to breakdown of the protection – ‘leaky gut’ – normally held together by tight junctions, allows small molecules to get transported into CNS
• Probiotics shown to reduce anxiety/improve mood

Question 10

Describe the role of neurogenesis in depression

Answer 10

Depression is associated with decreased dendritic arborisation

Also with decreased number of synapses

And overproduction of receptors (probably why there is a delay in antidepressants (to reset number of receptors))

This deficit can be reversed by neuronal growth factors (e.g. BDNF) and also…by antidepressants

Question 11

What are the different treatments for depression?

Answer 11

Cognitive Behavioural Therapy (CBT) or Interpersonal therapy (IPT)

Pharmacological*
Selective Serotonin Reuptake Inhibitors (SSRIs)
Tricyclic Antidepressants (TCAs)
Monoamine Oxidase Inhibitors (MAOI-A)
Atypical Antidepressants

Transcranial Magnetic Stimulation (TMS)

Transcranial Direct Current Stimulation (tDCS)

Electroconvulsive Therapy (ECT)†

Question 12

How can the placebo effect work?

Answer 12

30% of patients respond to placebo

Can change neuronal activity levels

Different effects to ADs

Works even if told!

Question 13

How does transcranial magnetic stimulation (TMS) work?

Answer 13

Good for severely depressed patients who don’t respond to antidepressants

Significantly less stigma that ECT

Magnetic pulses targeted at:
Prefrontal cortex
Limbic system

Increased activity

Fewer side effects

Question 14

How does electroconvulsive therapy work?

Answer 14

Gold standard for severe depression*

50% show improvement

Side effects:
Memory loss
Short term muscle aches

Question 15

How do SSRIs work?

Answer 15

Increases 5HT levels by inhibiting re-uptake pump

Sertraline
Citalopram – better tolerated in older patient
Paroxetine
Fluoxetine (aka Prozac)

Slow onset and can have an increase in negative symptoms before mood improves.
Common side-effects include: nausea, sleep disorders, sexual dysfunction, increased bleeding
Watch out for interactions – increasing 5HT levels can lead to serotonin syndrome which is hyperactivity in autonomic nervous system

Question 16

How do atypical antidepressants work?

Answer 16

Noepinephrine Re-uptake Inhibitors work in the same way as SSRIs
-Reboxetine

Serotonin Norepinephrine Reuptake Inhibitor (atypical) combined 5HT and NA reuptake inhibitors
-Venlafaxine

Noradrenaline Dopamine Reuptake Inhibitor (atypical) combined DA and NA reuptake inhibitors
-Bupropion

Question 17

How do monoamine oxidase inhibitors work?

Answer 17

Increases NA/5HT levels by inhibiting enzymatic breakdown

Moclobemide (RIMA)
Phenelzine
Isocarboxazide

Side effects:
Similar to TCAs
Many cross drug reactions
(DO NOT USE WITH SSRIs/TCAs)
Postural hypotension
Restlessness
Convulsions
Sleep disorders
‘cheese reaction’ – tyramine (dietary amines increase levels of noradrenaline)

Question 18

How do tricyclic antidepressants work?

Answer 18

Tricyclic Antidepressants have 5 main actions:

1) 5HT reuptake blocker
2) NA reuptake blocker
3) α1 adrenoreceptor antagonist
4) H1 receptor antagonist
5) M1 receptor antagonist

Main action to inhibit NA uptake, 5HT effects often variable

Two most commonly used are amitriptyline and nortriptyline, plus imipramine and clomipramine

Side effects:
Sedation
Postural hypotension
Confusion
Visual problems
Cardiac dysrhythmia
Mania
Many drug interactions, from aspirin to alcohol

Question 19

What are augmenting antidepressants?

Answer 19

Associated with increased side-effects but can use:

• Another antidepressant: e.g. mirtazapine
• Mood stabiliser: Lithium
• Antipsychotics

Question 20

How can α-adrenoceptor modulation affect depression?

Answer 20

Under normal conditions
α-1 receptors increase transmitter release
α-2 receptors slow transmitter release

So α-1 agonists and α-2 antagonists increase transmission

Mirtazapine - α-2 antagonist

Question 21

How does lithium work?

Answer 21

• General mood stabiliser, CNS mechanisms not well understood
• Acts to reduce G-protein function and inhibits IP pathway signalling, inhibits various kinases.
• Suppresses gene function
• Increases neurogenesis
• Salt used
• Slow absorption, modified release form often used
• Side effects various depending on intoxication levels
• Mainly used for bipolar disorders spectrum, as an adjunct to antidepressants or treatment resistance in recurrent unipolar depression

Question 22

When can buspirone be used?

Answer 22

Anxiolytic/Adjunct

• Can be useful in agitated patients but not in common use
• Benzodiazepines and buspirone used short term only
• Buspirone: 5HT partial agonists reduce activity to increase transmitter levels
• Buspirone
• Trazodone
• Tandospirone (Japan)

These have fewer side effects than SSRIs