Drugs for Depression

Question 1

What is the lifetime incidence of major clinical depression?

Answer 1

1 in 6 (17%)

Question 2

What are the emotional symptoms of depression?

Answer 2

• misery, apathy, pessimism
• low self-esteem
• indecisiveness, loss of motivation

Question 3

What are non-emotional symptoms of depression?

Answer 3

• retardation of thought and action
• loss of libido
• sleep disturbance and loss of appetite

Question 4

What are the 2 major types of depression?

Answer 4

unipolar and bipolar

Question 5

What are the 2 types of unipolar depression?

Answer 5

• reactive (75%) - non-familial, associated with life events and accompanied by symptoms of anxiety and agitation
• endogenous (25%) - familial and not directly related to external stress

Question 6

Describe bipolar depression

Answer 6

strongly familial with some genetic similarities to susceptibility to schizophrenia

Question 7

What is the main cause of depression?

Answer 7

deficits in monoamine neurotransmitters serotonin (5-HT) and noradrenaline

Question 8

Where is monoamine oxidase found?

Answer 8

intracellularly on the mitochondrial surface of nearly all tissues

Question 9

What are the 2 forms of monoamine oxidase?

Answer 9

MAO-A and B

Question 10

What does MAO-A do?

Answer 10

regulate both the free and intraneuronal concentration and the releasable stores of 5-HT and noradrenaline

Question 11

What does MAO-B do?

Answer 11

regulate both the free intraneuronal concentration and the releasable stores of dopamine

Question 12

How do MAOIs work?

Answer 12

by increasing the biological availability of monoamines

Question 13

What is the mechanism of action of inhibition of MAO-A?

Answer 13

1. initial inhibition reduces breakdown of monoamines then enhances the release of neurotransmitters into the synapse
2. elevated levels of noradrenaline and 5-HT bind to their receptors and intensify their neural activity

Question 14

What is the mechanism of action of inhibition of MAO-B?

Answer 14

1. inhibition decreases breakdown of dopamine and increases its release into the synapse
2. increased levels of dopamine bind to receptors and intensify the effect

Question 15

What are adverse effects of MOAIs?

Answer 15

the cheese reaction

Question 16

What is the cheese reaction?

Answer 16

an interaction of the MAOI with tyramine that can lead to accumulation and a sympathomimetic effect

Question 17

What are symptoms of the cheese reaction?

Answer 17

• severe headache
• nausea and vomiting
• sweating
• rapid heartbeat (tachycardia)
• acute hypertension

Question 18

How can the cheese reaction cause acute hypertension?

Answer 18

tyramine is taken up into adrenergic terminals and initiates release of noradrenaline and subsequent stimulation of cardiovascular sympathetic NS activity

Question 19

What are the 3 key MAOIs?

Answer 19

• irreversible non-selective MAOI e.g. phenelzine
• reversible MAO-A selective MAOI e.g. moclobemide
• irreversible MAO-B selective MAOI e.g. selegiline

Question 20

How do TCAs work?

Answer 20

by blocking the uptake of 5-HT and noradrenaline which increases their concentration in the synapse and intensifies their neuronal effects

Question 21

What is the source of TCA adverse effects?

Answer 21

binding to histamine and muscarinic ACh receptors

Question 22

What are adverse effects of TCAs?

Answer 22

• sedation due to H1 histamine receptor antagonism
• postural hypotension due to α-adrenoreceptor sympathetic block
• dry mouth, blurred vision, constipation due to muscarinic receptor antagonism
• risk of drug induced cardiac dysrhythmias due to block of hERG potassium channel

Question 23

What are the 2 key TCAs?

Answer 23

• non-selective e.g. amitriptyline
• selective for noradrenaline e.g. desipramine TCAs

Question 24

What are SSRIs?

Answer 24

selective serotonin reuptake inhibitors

Question 25

What is the most widely prescribed antidepressant?

Answer 25

fluoxetine

Question 26

What are the 2 main SSRIs?

Answer 26

- fluoxetine (~50-fold selectivity for 5-HT) - citalopram (~1000-fold selectivity for 5-HT)

Question 27

How do SSRIs work?

Answer 27

by restoring the levels of 5-HT in the synaptic cleft by binding at the 5-HT reuptake transporter

Question 28

How do SSRIs have less adverse effects than TCAs?

Answer 28

- low affinity for α-adrenoreceptors → lack of cardiovascular effects so safer in overdose - lack of effect at histamine receptors → reduced sedation - low affinity for muscarinic cholinergic receptors → minimal anticholinergic side effects e.g. dry mouth and constipation

Question 29

What are adverse effects of SSRIs?

Answer 29

- 2/3 of patients get remission - nausea - sexual dysfunction (delayed ejaculation in men and delayed or blocked orgasm in women) - serotonin syndrome

Question 30

What is serotonin syndrome?

Answer 30

severe reaction resulting from drug-drug interactions with other drugs that increase serotoninergic activity e.g. MAOIs (symptoms include tremor, hyperthermia and cardiovascular collapse)

Question 31

What are NARIs?

Answer 31

antidepressants that have have a greater noradrenaline reuptake than TCAs; they have ~1000x higher selectivity for noradrenaline than 5-HT

Question 32

How do NARIs work?

Answer 32

by restoring the levels of noradrenaline in the synaptic cleft by binding at the reuptake transporter

Question 33

What are adverse effects of NARIs?

Answer 33

- dry mouth and constipation due to anticholinergic effects - insomnia due to increased noradrenergic activity in the CNS - tachycardia due to increased availability of noradrenaline at sympathetic synapses

Question 34

What are SNRIs similar to?

Answer 34

non-selective TCAs since they have similar dual 5-HT and noradrenaline reuptake inhibition profiles

Question 35

What is the only clinical SNRI?

Answer 35

venlafaxine

Question 36

What are advantages of SNRIs?

Answer 36

- different structure to and fewer adverse effects than TCA - claimed to work slightly faster than other antidepressants - claimed to work better in treatment-resistant patients

Question 37

How do SNRIs work?

Answer 37

by restoring the levels of 5-HT and noradrenaline in the synaptic cleft by binding at their reuptake transporters

Question 38

What are adverse effects of SNRIs?

Answer 38

- nausea - insomnia - sexual dysfunction - serotonin syndrome - withdrawal effects that are more common and stronger than for SSRIs and TCAs