week 7- Mental Health and Affective Disorders Sway

Question 1

what are are risk factors for depressive diorders?

Answer 1

-stress
-chronic stress increases cortisol release from adrenal cortex due to CRH produced in the hypothalamus (HPA axis)
• Genetic factors – high heritability of depressive disorders in twin
studies
• Family history
• Intensive efforts made to find genes linking to depression but GWAS
have given few clues
• Candidate gene studies have identified ~200 genes, SLC6A4 is one
• Substance abuse

Question 2

what is the first theory for the pathophysicology of depression? what it means?

Answer 2

-monamine theory
-If we identify the cause of depression = we can effectively treat it
-there was a functional deficit of monoamine
neurotransmitters (5-HT and noradrenaline) and dopamine in areas of the brain
-

Question 3

what is the effect of Tricyclic antideppressants and how do they work?

Answer 3

Block monoamine reuptake Enhance mood

Question 4

what is the effect of MAO inhibitors and how do they work?

Answer 4

Prevent degradation of
monoamines
Enhance mood

Question 5

what is the effect of tryptophan and how do they work?

Answer 5

Increase 5-HT synthesis

enhance mood

Question 6

what is the effect of reserpine and how do they work?

Answer 6

Inhibit monoamine storage Reduce mood

Question 7

what is the effect of α-Methyltyrosine and how do they work?

Answer 7

Inhibit noradrenaline synthesis

Reduce mood

Question 8

what is the effect of Methyldopa and how do they work?

Answer 8

Inhibit noradrenaline synthesis

Reduce mood

Question 9

what neurotransmitters can cause depression?

Answer 9

NA and 5-HT (SEROTONIN)

Question 10

what are the drug targets for depressive disorders?

Answer 10

• the reuptake transporers for both 5-HT and NA
• they are in the SLC6 family
• known as SERT and NET

Question 11

what does SERT stand for?

Answer 11

seretonin reuptake transporters

-SLC6A4

Question 12

what does NET stand for?

Answer 12

Norarenaline reuptake transporters

-SLC6A2

Question 13

what type of transporter is SERT and NET?

Answer 13

-symporters
-use co-transporter of sodium as a driving force for carrying their substrate (neurotransmitter) across the plasma membrane
-• Dependent on extracellular Cl-
• Some SLC transporters also move K+

Question 14

what is the structure of SERT?

Answer 14

• 12 transmembrane domains• Intracellular N and C-termini• Large glycosylated EC loop
between TM3 and 4
• Alternating access model
• Substrate binding site is
accessible to either the
external or internal medium

Question 15

how is the substrate is moved across the plasma membrane through SERT?

Answer 15

• substrate and Na+ comes in
• it becomes bound and occuluded
• then transporter opens and the substate and counter transporter ion is rleased

Question 16

where are SERT and NET found?

Answer 16

on the pre synatic terminals of the seretinergic and noradrenergic neurones

Question 17

how do reuptake inhibitors work/

Answer 17

-only work once the neurotrasmitters have been released
• Prevent the reuptake of serotonin or NA into the neurons
• Enhances the synaptic levels of serotonin and/or noradrenaline within the synapse and lengthen the amount of time the Neurotrasmitter is avavliable to then bind to the receptor on the post synpatic neuron

Question 18

what are some examples of of anti-depressants?

Answer 18

• SSRIs:
Fluoxetine, paroxetine, sertraline, citalopram, escitalopram, fluvoxamine
• SNRIs:
Buproprion, reboxetine, atomoxetine
• Mixed (non-selective both):
Venlafaxine, duloxetine
• Tricyclic antidepressants (non selective)
Imipramine, desipramine(selective for NA), amitryptyline, clomipramine

Question 19

what does SSRI mean?

Answer 19

selective serotonin reuptake

inhibitors

Question 20

what does SNRI mean?

Answer 20

serotonin & noradrenaline

reuptake inhibitors

Question 21

WHAT ARE THE CONSEQUENCES OF INCREASED 5-HT AND NA?

Answer 21

• Increased signalling through 5-HT receptors and NA receptors
- Pre-synaptic and post-synaptic
• Gene expression changes, neurogenesis – chronic adaptive changes

Question 22

how is controlling serotonin levels with reuptake inhibitors?

Answer 22

• Acute action – increases synaptic 5-HT by reducing reuptake
• But 5-HT acts on 5-HT1A on soma/dendrites to inhibit 5-HT release
• This cancels out some of the effect of SSRIs
• Chronic administration – elevated 5-HT level will induce
desensitisation of 5-HT1A receptors
• This in turn will reduce the inhibitory effect of 5-HT
• This need for desensitisation could explain the slow onset of action

Question 23

how is NA controling 5-HT levels?

Answer 23

• Noradrenaline can control 5-HT release
• NA can act on excitatory α1
receptors to enhance 5-HT release
• α2 receptors are downregulated by antidepressants
• α2 receptor antagonists could
further enhance 5-HT releasee.g. mirtazapine, mianserin

Question 24

what is monoamine oxidase (MAO)

Answer 24

• Monoamine Oxidase (MAO) controls the degradation of monoamine
neurotransmitters
• There are two forms of MAO –A and B(dopamine preference)
• MAO-A has substrate preference for 5-HT and NA
• Inhibitors of this enzyme will cause an increase in tissue monoamines (5-HT, NA, Dopamine)

Question 25

how do MAO inhibitors work?

Answer 25

• Increase cytoplasmic stores of noradrenaline and 5-HT in nerve
terminals
• Irreversible non-competitive inhibitors – e.g. phenelzine, iproniazid
• Most are non-selective for different forms of MAO
• Reversible MAO-A selective inhibitors – moclobemide
• Can be increase in spontaneous release of neurotransmitter and
increase in release by sympathomimetic amines (e.g.tyramine)

Question 26

what are some side effects of MAO Inhibitor?

Answer 26

• Hypotension – common side effect
• Central stimulation – tremors, excitement, insomnia
• Increased appetite causing weight gain
• Drug & food interaction – the cheese reaction
  • Ingestion of tyramine in foods such as ripe cheese and marmite
  • Typically degraded in gut by MAO
  • With MAOI – tyramine absorbed into circulation and has sympathomimetic
  effect
  • Acute hypertension and severe headaches

Question 27

what is the neuroendocrine mechanism?

Answer 27

-stimulation of the hypothalmus causes the release of CRF
-CRF which then acts on on the piturity gland which then releases ACTH which then acts on the adrenal cortex which releases gluccorticosteriod
• Increased plasma cortisol levels in severe depression
• Impaired glucocorticoid induced feedback control
• Injection of CRH (CRF) into brain can mimic aspects of
depression
• Cushing’s syndrome – often causes depression
• No current clinical intervention

Question 28

why are gluccorticosteriod important?

Answer 28

-they regulate the brain

Question 29

what is the inflammatory mechanism in causing depression?

Answer 29

-comes from sickness behaviour
• Behavioural changes experienced with infections can mimic depressive-like behaviour
• Cytokines cause these changes
• Infusion of particular cytokines induces depression in humans and rodents
• IL-2 and IFN-γ
• People with autoimmune disease more likely to have depression
• Post-mortem evidence of microglial activation in patients with depression

Question 30

what is the structural changes in the brain?

Answer 30

• Regional specific neuronal cell loss, changes in synaptic activity
causing the imbalances in neurotransmitters
• Functional imaging studies show a decrease in gray matter volume in
pre-frontal cortex and hippocampus
• Smaller volume of important brain structures
• Post-mortem studies conform a loss in GABAergic neurons, astrocytes and oligodendrocytes in the pre-frontal cortex

Question 31

what is the neuroplasticity and neurogenesis?

Answer 31

• Neurogenesis – formation of new neurons from pluripotent stem cells
• Neuroplasticity – growth and adaptability of neurons
• Neurogenesis is controlled by trophic factors such as BDNF
• Humans – reduced BDNF in CSF of patients
• Antidepressants can raise BDNF levels
• In animal models reducing neurogenesis can prevent the action of
antidepressants
• injection of BDNF has an antidepressant effect

Question 32

what is esketamine?

Answer 32

• Ketamine derivative
• No delay in the anti-depressant effect
of esketamine
• NMDA receptor non-competitive
channel blocker
• Approved by EMA for treatmentresistant depression in 2019
• Proposed mechanism: blocking NMDA
receptors on GABA interneurons
prevents tonic activity – causes a
glutamate surge which increases BDNF signalling

Question 33

what are some problems with antidepressants?

Answer 33

• Do not work in everybody
• Side effects for SSRIs include nausea, insomnia, sexual dysfunction,
paroxetine linked to increased suicidality, risk of drug interactions CYP
• Tricyclics can have a sedating effect, anticholinergic effects, confusion, motor incoordination effect, higher risks with overdose
• SNRIs side effects include sedation, dizziness, nausea and some can
have withdrawal effect
• Monoamine oxidase inhibitors (MAOI) side effects include CNS
stimulation, weight gain, insomnia, postural hypotension
• Major problem with MAOI is the cheese reaction – tyraminecontaining foods – increased tyramine causes sympathomimetic
effect (acute hypertension, headache)

Question 34

what are the two types of bipolar?

Answer 34

• Bipolar I (episodes of mania) and bipolar II (episodes of

hypomania and depression)

Question 35

what is the pathophysiology of bipolar disorder?

Answer 35

• Pathophysiology involves
dendritic spine loss, altered
cellular connectivity and neural
plasticity

Question 36

what is some treatment for bipolar disorder?

Answer 36

• Stabilisation of mood is the overall goal
• Lithium - taken orally as lithium carbonate
• Used in prophylaxis and treatment of mania
• Carbamazepine, valproate and lamotrigine anti-epileptic drugs can be used• Quetiapine, olanzepine and other anti-psychotic drugs can be used
• Benzodiazepines can be used for calming effect
• Use of anti-depressants is not recommended – can lead to switching to
manic phase

Question 37

how does lithium work in bipolar disorder?

Answer 37

• Lithium is a monovalent cation
• Lithium is thought to
accumulate inside cells, cause
inhibition of inositol phosphate
pathway and inhibition of GSK3
affecting cellular responses
-accumulates as it isnt pumped out the cells through sodium potassium symporter

Question 38

what antiepileptic drugs can be used to treat bipolar disorder?

Answer 38

• Carbamazepine, valproate and lamotrigine – affect NaV channels
• Blocking action on NaV channels prevents action potential generation
• These drugs show use dependence therefore more activity is seen with higher firing rates (e.g. in epilepsy)
• Lamotrigine has a broader mechanism of action – also affects neurotransmitter
release and may have activity on CaV channels
• Mechanism of action in bipolar disorder – due to reduction in neuronal excitation• Better side effect profile than lithium

Question 39

what atypical antipsychotics can be used to treat bipolar disorder?

Answer 39

• Olanzepine, quetiapine, risperidone, aripiprazole – act as antagonists at D2 and 5-HT2A receptors
• Also may have activity at several other receptors including α1, H1, 5-HT1Aand mAChR
• Second generation antipsychotics
• Effective against treatment of mania

Question 40

what are anxiety disorders?

Answer 40

• Chronic disorder
• Depression is often co-morbid with anxiety
• Clinical recognised anxiety states include:
- Generalised anxiety disorder (GAD)
- Social anxiety disorder
- Phobias
- Panic disorder
- PTSD
- OCD

Question 41

what are the pathophysiology of anxiety disorders?

Answer 41

• Anxiety arises from an abnormal regulation of fear response
• Fear – subjective response to threatening stimulus
• Anxiety is longer lasting and can persist due to lack of signs of safety
• Disorders are distinguished based on
• symptoms
• precipitating factors
• Genetic component – run in families
• Amygdala is activated by induction of fear – neuroimaging suggests
patients have heightened activity in amygdala circuits

Question 42

what is the treatment for anxiety disorder?

Answer 42

• Psychological approaches are used as well as medication
• Main drugs used:
1. Antidepressants (SSRIs, SNRIs) – increase 5HT and NA levels
• E.g. Escitalopram and paroxetine, venlafaxine, duloxetine
2. Benzodiazepines – enhance action of GABA on GABAA
receptors containing α2 subunit e.g. lorazepam, diazepam, flurazepam
Benzodiazepine side effects are sedation, confusion, tolerance and dependence
3. Buspirone (5HT1A receptor agonist) – can be used to treat generalised anxiety disorder
• 5HT1A receptors can act as inhibitory autoreceptors on serotonergic neurons, postsynaptic 5HT1A receptors are involved in emotional behaviour
4. Gabapentin, pregabalin, valproate – affect NaV and CaV channels – anxiolytic properties
5. Atypical antipsychotics – olanzepine, quetiapine – can be effective in GAD and PTSD
6. Propranolol - a β-blocker which can be used for relief of situational anxiety, GAD
7. Non-pharmacological treatments:
Counselling
Cognitive therapy
Dietary and lifestyle changes