Affective disorders: Neurobio and treatment

Question 1

Neurobiology of major depression

Answer 1

Adverse childhood experience
Current Stress (Financial hardship, migration, family, multi genetic factors)
Genetic factors
ALL CONTRIBUTING TO DIRECT decrease in 5HT and NA function and INDIRECTLY same through HPA axis function and cortisol effects leading to depressive syndrome

Question 2

Aetiology of depression

Answer 2

Multifactorial
Incompletely understood
Interactions of genetic factors, childhood adversities, past hx of mood disorders, psychological predisposition (neuroticism)
Often precipitated by stressful life events

Question 3

Monoamine dysfunction in depression

Answer 3

All traditional antidepressants affect 5HT/NA systems

Question 4

History of antidepressants

Answer 4

Until the 1950s the hypothesis of depression stemmed from intrapsychic conflicts (Freud)
In the 1950s
- Monoamine oxidase inhibitors were introduced. Iproniazid (first MAOi) was used for treatment of TB but found to have antidepressant effects.
- Tricyclics –> (Impapramine)antihistaminic was found to have an antidepressant effect

Question 5

All traditional antidepressants affect:

Answer 5

All traditional antidepressants affect 5HT/NA systems

• -> decreased 5HT concentrations (acute tryptophan depletion) studies (tryptophan is an experimental way to investigate serotonin bc it is the precursor. A way to reduce tryptophan in a noninvasive way is to change diet)
• -> Reduced 5 HT transporter in post-mortem studies (post mortem studies showed a reduction in 5 HT transporters which further validates the serotonin hypothesis of depression)

Question 6

PET studies in depression

Answer 6

found a reduction in 5HT transporters

Question 7

What part of the brain is the source of Noradrenaline

Answer 7

Locus Coeruleus

Question 8

What part of the brain is the source of serotonin

Answer 8

Raphe Nuclei

Question 9

Both serotonin and noradrenaline

Answer 9

have ascending tracts to the cerebral cortex and limbic area as well as descending tracts to the spinal cord.
Their cell bodies for these tracts originate in major nuclei of the midbrain.
Each nuclei has ascending tracts which project to brain regions (PFC and limbic system) involved in depressive symptoms as well as ascending and descending tracts involved in pain suppression

Question 10

The monoamine hypothesis of depression

Answer 10

suggests a deficiency in synaptic levels of serotonin and noradrenaline in key CNS pathways underlying depressive illness

Question 11

Monoamines and depressive symptoms

Answer 11

Noradrenaline
- attention
Serotonin
- impulsivity and suicidal ideation
Dopamine 
- psychomotor activation and euphoria
All three
- mood, emotions and cognitive functions
NA and Dopamine
- motivation and enerfgy
Noradrenaline and serotonin
- anxiety and irritability
Serotonin and dopamine
- sleep, appetite, sexual functions and aggressiveness

Question 12

1st generation antidepressants

Answer 12

MAOi eg Phenelzine, Tranylcypromine
- Nonselectively inhibit enzymes involved in the breakdown of monoamines including serotonin, dopamine and norepinephrine

TCA eg amytryptiline and clomipramine
- nonselectively inhibit the reuptake of monoamines, including monoamines, including serotonin, dopamine and norepinephrine

Question 13

2nd generation antidepressants

Answer 13

• SSRI: eg setraline, citalopram, fluoxetine
• SN(noradr)RI: eg venlafaxine, duloxetine
• alpha 2 adrenoreceptor and 5HT2c antagonist (modulate serotonin and NA release) eg Mirtazapine
• dopamine- noradrenaline reuptake inhibitor eg bupropion

Question 14

SSRIs

Answer 14

Efficacy equal to tricyclics in outpatients
Large spectrum of action (OCD, PTSD, Panic, GAD, social anxiety)
Low toxicity and safe in overdose
The initial treatment phase is the most delicate, due to prevalence of side effects over benefits- slow titration
Side effects:
- GI symptoms (nausea, diarrhea)
- Headache, irritability, anxiety
- Reduction of libido and sexual dysfunction

Gradual suspension to avoid withdrawal symptoms (worse with venlafaxine and paroxetine due to short half-life)

Question 15

Side effects of TCAs

Answer 15

Anticholinergic effects eg constipation, dry mouth, drowsiness
cardiac toxicity in overdose
Orthostatic hypotension

Question 16

Side effects of MAOi

Answer 16

Anticholinergic effects eg dry mouth, GI, drowsiness

Insomnia, food interactions ie tyramine leading to hypertension crises

Question 17

Side effects of venlafaxine

Answer 17

nausea, vertigo, headache, insomnia

Question 18

Side effects of mirtazapine

Answer 18

drowsiness, sedation, hypotension, increased appetite and weight gain

Question 19

Gene environment interactions evidence for depression

Answer 19

People were stratified to two parameters

1) life adversity
2) gene for type of 5HT transporter

Question 20

HPA dysfunction in mood disorders

Answer 20

The level of cortisol is higher in people with depressive disorder
If you give the dexamethasone test (night before) then bc of feedback on HPA axis will usually suppress cortisol release the following day

However people with depression do not have the typical suppression after dexamethasone. They continue to have the normal circadian rhythm as if their cortisol was not suppressed. This means there is a reduced sensitivity at GR level and HPA activity

Question 21

Inflammation and depression

Answer 21

Raised plasma cytokine levels (IL-6, TNF-α) and inflammatory markers

High comorbidity between chronic inflammation and depression

Administration of cytokines provokes depressive symptoms

Microglial activation in brain of depressed patients (PET studies)

Question 22

Hippocampal size in depression

Answer 22

Decreases in size
Also happens when exposed to high levels of cortisol
evidence link?

Question 23

Neural systems involved in depression

Answer 23

increased activity (Amy; VST, PFC) to negative emotional stimuli (fearful faces)
decreased activity (VST) to positive emotional stimuli, and during receipt and anticipation of reward 

bias of attention towards negative emotional stimuli, and away from positive emotional and reward- related stimuli

Question 24

Factors that play a role in bipolar disorder

Answer 24

Catcholamines
Oxidative stress
Neurotrophins
Inflammation
Stress hormones, glucocorticoids

Question 25

Short term bipolar treatment

Answer 25

to reduce the severity and shorten the duration of the acute episode and achieve remission of symptoms

Question 26

Long term bipolar treatment

Answer 26

prevention of new episodes and to achieve adequate inter-episode control of residual or chronic mood symptoms

Question 27

Overview of drug categories for bipolar disorder treatment

Answer 27

Antipsychotics
Lithium
Anticonvulsants
Antidepressants

Question 28

Antipsychotics

Answer 28

• D2/D3 antagonist
  1st generation: Haloperidol
• D2/D3 antagonists (also targeting 5-HT)
  (2nd generation: Olanzapine, Risperidone, Quetiapine, Lurasidone, Asenapine, Amisulpride, Clozapine)
• DA partial agonist (Aripiprazole)

Rapid anti-manic effect
Often used long-term to maintain same treatment effective in acute episode
Long-term adverse effects on weight, glucose regulation and lipids [except for Aripiprazole, Amisulpride, and Lurasidone]
Full D2 antagonism (Haloperidol) may cause EPSEs

Question 29

Lithium

Answer 29

Element, present in food and drinking water
Multiple mechanisms of actions
Multiple neurotransmitters (including DA)
Cellular signalling
Neurotrophic factors

Anti-suicidal effects
Possible efficacy on impulsive and violent behaviours
Strongest evidence for prevention of relapses of any polarity
Narrow therapeutic index
blood tests every 3 months for the 1st year
Adverse long-term effects on Kidney function with excessive levels
Risk of Lithium toxicity

Question 30

Anticonvulsants

Answer 30

Anticonvulsants

Valproate (valproic acid and sodium valproate)
Actions via GABA, intracellular signalling, sodium channel blockade, epigenetic modulation, etc.
Anti-manic and effective in prevention of mania
Useful in combination, but potential pharmacokinetic interactions
not be used for women of child bearing potential because of its unacceptable risk to the foetus of teratogenesis and impaired intellectual development

Lamotrigine
actions via GABA, Glutamate and sodium channel blockade
Mostly effective in prevention of depressive relapses
Ineffective as anti-manic agent

Carbamazepine
less effective in maintenance treatment than lithium but may be used as monotherapy if lithium ineffective
especially in patients who do not show the classical pattern of episodic euphoric mania
almost exclusively effective against manic relapse
pharmacokinetic interactions

Question 31

Treatment of depressive episodes

Answer 31

Antipsychotics (Quetiapine, lurasidone)

Fluoxetine/Olanzapine combinations

Antidepressants to be co-prescribed with an anti-manic drug

Consider Lamotrigine (usually with antimanic drug

Question 32

Treatment of acute manic episodes

Answer 32

Dopamine antagonists (haloperidol, olanzapine, risperidone and quetiapine)

Valproate

Discontinue any antidepressant treatment

Question 33

Long term treatment of bipolar: prevention of new episodes

Answer 33

Consider long-term treatment following a single severe manic episode

Lithium as initial monotherapy (target serum level range: 0.6-0.8 mmol/l)

Alternatives (if Lithium ineffective, poorly tolerated or unlikely adherence to treatment):
Valproate
Dopamine antagonists/partial agonists
Carbamazepine

Question 34

Adverse effects of long term pharmacological treatments

Answer 34

Weight gain (most medications, particularly Olanzapine and Quetiapine)
Metabolic syndrome (Olanzapine, Quetiapine, Risperidone)
Hyperprolactinemia (Dopamine antagonists)
Tardive dyskinesia (much reduced risk with newer agents)

Liver damage (e.g. Valproate)

Kidney and Thyroid dysfunction (poorly regulated Lithium)