Mental Health Pharmacology Depression, Anxiety and Bipolar

Question 1

Name clinically recognised states of anxiety:

Answer 1

GAD
Social anxiety disorder
Phobias
Panic disorder
PTSD
OCD

Question 2

Describe the pathophysiology of anxiety:

Answer 2

Anxiety arises from an abnormal regulation of fear response
Genetic component- runs in families
Amygdala is activated by induction of fear-neuroimaging suggests patients have heightened activity in amygdala circuits

Question 3

Name the main drugs used for anxiety:

Answer 3

1. Antidepressants (SNRIs and SSRIs)
2. Benzodiazepines
3. Buspirone (5HT1a receptor agonist) (for GAD)
4. Gabapentin, pregabalin, valproate
5. Atypical antipsychotics
6. Propranolol
7. Non-pharmacological

Question 4

Describe antidepressants used in anxiety:

Answer 4

Increase 5HT and NA levels- need 2 weeks to see improvement
e.g escitalopram and paroxetine, venlafaxine, duloxetine

Question 5

Describe benzodiazepines used in anxiety:

Answer 5

Enhance action of GABA on GABAa receptor containing a2 subunit (G2 and a2 subunits needed)
e.g lorazepam, diazepam, flurazepam- more acute treatment
SEs are sedation, confusion, tolerance and dependence

Question 6

Describe buspirone used in anxiety:

Answer 6

5HT1A receptor agonist
5HT1Ar can act as inhibitory auto receptors on serotonergic neurones, post synaptic 5HT1Ar are involved in emotional behaviour
Can take few weeks for clinical effect due to desensitisation of 5HT1Ar

Question 7

Describe how gabapentin, pregabalin and valproate are used in anxiety:

Answer 7

Valproate- Effect NaV channels
Gaba and pregab- effect CaV channels
Anxiolytic properties

Question 8

Describe how atypical antipsychotics are used in anxiety:

Answer 8

Olanzapine, quetiapine
Effective in GAD and PTSD

Question 9

Describe how propranolol can be used in anxiety:

Answer 9

BB which can be used for relief of situational anxiety, GAD

Question 10

Describe the non-pharmacological anxiety treatments:

Answer 10

Counselling
Cognitive therapy
Dietary and lifestyle advice

Question 11

Describe the pathophysiology of bipolar:

Answer 11

Dendritic spine loss, altered cellular connectivity and neural plasticity

Question 12

Describe the MoA of lithium in BPD:

Answer 12

Monovalent cation
Mimic role of sodium (move through NaV)-but not pumped out by Na/K ATPase
Thought to accumulate inside cells, cause inhibition of inositol phosphate pathway and inhibition of GSK3 affecting cellular responses
Inhibit GSK3- the phosphorylate important downstream proteins

Question 13

Name anti epileptics which are used for BPD:

Answer 13

Carbamazepine, valproate, lamotrigine

Question 14

Describe the use of anti epileptics in BPD:

Answer 14

Affect NaV channels
Blocking action of NaV (inactivated) channels prevents A/P generated
These show use dependance therefore more activity is seen with higher firing rates (e.g in epilepsy)

Question 15

Describe the MoA of anti epileptics in BPD:

Answer 15

Lamotrigine had a broader MoA, also affects NT release and may have activity on CaV
Due to decrease in neuronal excitation leads to stabilisation in mood
Better SE profile than lithium

Question 16

Name atypical antipsychotics used in BPD:

Answer 16

Olanzepine
Quetiapine
Risperidone
Aripriprazole

Question 17

Describe the MoA of atypical antipsychotics in BPD:

Answer 17

Act as antagonists at D2 (GPCR) and 5HT2Ar
Also may have activity at several other GPCRs including a1, H1, 5HT1A and mAChr
Effective against mania

Question 18

Describe the monoamine theory of depression:

Answer 18

Functional deficit of MAO NTs (5HT and NA) in areas of brain
Arose due to clinical effects on drugs that alleviated symptoms or caused depressive symptoms

Question 19

Describe the pharmacological evidence for MAO theory which increase mood:

Answer 19

TCA- block MAO uptake
MAOi- prevent degradation of MAO
Tryptophan- increases 5HT synthesis

Question 20

Describe the pharmacological evidence for MAO theory which decreased mood:

Answer 20

Reserpine- inhibits MAO storage
a-methyltyrosine and methyldopa- inhibits NA synthesis

Question 21

Describe the findings of the MAO theory:

Answer 21

Inhibition of NA and 5HT NT reuptake equally effective
Direct neurochemical actions are rapid but clinical antidepressants effect takes weeks to develop
2º adaptive changes are thought to be responsible (trophic)
Drugs may have acute effects on cognition- a +ve effect on emotions

Question 22

Name drug targets for depressive disorders:

Answer 22

SLC6 transporters:
SERT (SLC6A4)
NET (SLC6A2)

Question 23

Describe the SLC6 transporters:

Answer 23

Symporters, use co-transporter Na+ as driving force
Dependent on extracellular Cl-
Some SLC transporters also move K+

Question 24

Describe the SERT transporter:

Answer 24

12 TMD
Intracellular N and C terminal
Large glycosylated extracellular loop between TM3 and 4

Question 25

Describe the alternative access model for the SCL6 transporters:

Answer 25

Substrate binding site is accessible to either the external or internal medium Onward facing (open)-> inward facing (open)

Question 26

What are reuptake inhibitors?

Answer 26

Found on SERT and NET neurons Prevent the reuptake of serotonin or NA into the neurons Enhances the synaptic levels of serotonin and/ or NA

Question 27

Name SSRIs:

Answer 27

5HT selective Fluoxetine Paroxetine Sertraline Citalopram Escitalopram Fluvoxamine

Question 28

Name SNRIs:

Answer 28

NA selective Bupropion Reboxetine Atomoxetine

Question 29

Name mixed (non-selective) reuptake inhibitors:

Answer 29

Venlafaxine Duloxetine

Question 30

Name TCAs:

Answer 30

Imipramine Desipramine (NA selective) Amitriptyline Clomipramine

Question 31

What are the consequences of increasing 5HT and NA?

Answer 31

Increases signalling through 5HT and NA r -pre and post synaptic Gene expression changes, neurogenesis and chronic adaptive changes

Question 32

Describe 5HT reuptake in the absence of a reuptake inhibitor:

Answer 32

Serotonergic neuron- serotonin0 actis on post synaptic 5HT Serotonin then reuptake in pre-synaptic by SERT

Question 33

Describe the acute action of serotonin reuptake inhibitors on the conc of 5HT:

Answer 33

Increase synaptic 5HT by decreased reuptake But 5HT acts on 5HT1A on some dendrites to inhibit 5HT release This cancels out some effects of SSRIs

Question 34

Describe the chronic action of serotonin reuptake inhibitors on the conc of 5HT:

Answer 34

Elevated 5HT level will induce desensitisation of 5HT1Ar This in turn will decrease the inhibitory effect of 5HT This need for desensitisation could explain the slow onset of action

Question 35

Describe how NA can control 5HT levels:

Answer 35

NA can control 5HT release NA can act on excitatory a1r to enhance 5HT release a2r are down regard by antidepressants- removing -ve regulation of serotonin release a2r antagonists could further enhance 5HT release e.g mirtazapine, mianserin

Question 36

Describe MAO:

Answer 36

MAO controls the degradation of MAO NTs There are 2 forms MAO-A and B MAO-A has a substrate preference for 5HT and NA, MAO-B prefers dopamine Inhibitors of this enzyme will cause an increase in tissue MAO

Question 37

Describe the effect of MAOi:

Answer 37

Increase in cytoplasmic stores of NA and 5HT in nerve terminals

Question 38

Name and describe irreversible non-competitive MAOi:

Answer 38

Phenelzine, iproniazid Most are non-selective for different forms of MAO

Question 39

Name and describe reversible MAOi:

Answer 39

A selective inhibitor- moclobemide Can decrease SEs Can be increased in spontaneous release of NT and increase in release by sympathomimetic amines (e.g tyramine)

Question 40

Name and describe side effects of MAOi:

Answer 40

Hypotension- common Central stim- tremors, excitement, insomnia Increased appetite causing weight gain

Question 41

Name the drug/ food interaction with MAOi:

Answer 41

The cheese reaction Ingestion of tyramine in foods such as ripe cheese and marmite Tyramine typically degrades in gut by MAO With MAOi- tyramine not metabolised into gut and instead absorbed into circulation and has sympathomimetic effect Acute HTN and severe headaches

Question 42

Name other hypotheses for depression:

Answer 42

1. Neuroendocrine mechanism-HPA axis 2. Inflammatory mechanisms- sickness behaviour 3. Structural changes in the brain 4. Neuroplasticity and neurogenesis

Question 43

Describe the HPA axis:

Answer 43

Hypothalamus, Pituitary, Adrenal axis Normal: Hypothalamus, CRF (corticotrophin releasing hormone), Pituitary, ACTH (Adrenocorticotropic hormone), Adrenal cortex, corticoids which reg brain

Question 44

Describe the neuroendocrine mechanism for depression:

Answer 44

Increased plasma cortisol levels in severe depression Impaired glucocorticoid induced feedback control

Question 45

Describe evidence of the neuroendocrine mechanism for depression:

Answer 45

Injection of CRH (CRF) into brain can mimic aspects of depression Cushing's syndrome (increased cortisol) often causes depression No current clinical intervention

Question 46

Describe the inflammatory mechanism for depression:

Answer 46

Behavioural changes experienced with infections can mimic depressive like behaviour Cytokines cause these changes act directly on neurons, astrocytes microglia

Question 47

Describe evidence of the inflammatory mechanism for depression:

Answer 47

Infusion of particular cytokines induces depression in humans and rodents IL2 and IFN-Y People with AID more likely to have depression Post mortem evidence of microglial activation in pts with depression

Question 48

Describe the structural changes in the brain for depression:

Answer 48

Regional specific neuronal cell loss, changes in synaptic activity causing imbalances in NT

Question 49

Describe evidence of the structural changes in the brain for depression:

Answer 49

Function imagine studies show a decrease in grey matter volume in pre-frontal cortex and hippocampus Smaller volume of important brain structures Post mortem studies confirm a loss in GABAergic neurons, astrocytes and oligodendrocytes in the pre frontal cortex

Question 50

What does neurogenesis mean?

Answer 50

Formation of new neurons from pluripotent stem cells- hippocampus

Question 51

What does neuroplasticity mean?

Answer 51

Growth and adaptability of neurons

Question 52

How is neurogenesis controlled?

Answer 52

Is controlled by trophic factors e.g BDNF (brain derived neurotrophic factors)

Question 53

Describe neuroplasticity and neurogenesis in depression:

Answer 53

Humans- decreased BDNF in CSF of patients Antidepressants can raise BDNF levels In animal models, decreased neurogenesis can prevent the action of ADs Injection of BDNF has an AD effect

Question 54

Describe esketamine as a treatment for resistant depression:

Answer 54

Nasal spray No delay in the AD effect NMDAr non-competitive channel blocker MoA blocking NMDAr on GABA interneurons prevent tonic activity Causes a glutamate surge which sig increases BDNF