L01 Antidepressants

Question 1

Which psychiatric disorder is typically ascribed to being a major cause of work days lost to disability & bejng the major cause of premature death?

Answer 1

Depression

Question 2

What are some symptoms of depression?

Answer 2

Emotional:

• Misery, apathy (esp. remarkable) & pessimism
• Low self-esteem (i.e. feelings of guilt, inadequacy & ugliness)
• Indecisiveness, loss of motivation

Other domains:

• Retardation of thoughts & actions
• Loss of libido
• Sleep disturbances & loss of appetite

DSM-5 for MDD: In SAD CAGES can be helpful.

• Interest
• Sleep, Appetite, Depressed
• Concentration, Activity, Guilt, Energy, Suicidal

Question 3

Describe the major types of depression.

Answer 3

1) Unipolar depression (more common)
- Mood swings are always in the same direction
- Further divided into:
(a) Reactive depression (75%) OR:
- Non-familial; associated w/ life events
- Accompanied by symptoms of anxiety & agitation
(b) Endogenous depression (25%):
- Familial pattern
- NOT directly related to external stress

2) Bipolar depression / Affective disorder
- Alternating between depression & mania
- Mania: Opposite of depression; full of irrational enthusiasm not anchored in reality
- Different etiology from unipolar depression
- Periodicity of oscillations in mood varies; usually over several weeks
- Strongly familial & usually appears in early adulthood

Question 4

Which theory forms the basis of our pathophysiological understanding of depression? Explain why.

Answer 4

Monoamine theory:

• Deficits in monoamine neurotransmitters (NA & 5-HT) cause depression
• Forms the basis of most successful pharmacological strategies for Tx of depression

Question 5

What are some limitations of using monoamine theory to explain the pathophysiology of depression?

Answer 5

1) Hypothesis was originally formulated for NA, but emphasis was subsequently shifted to 5-HT
2) Studies of monoamine markers in depressed pt. yielded inconsistent & equivocal results
- Often obtained from suicide post-mortem pt.
- Tissue damage may affect marker levels
3) Inadequate to explain all pharmacological actions in depression alone
- Most likely monoamine are impt BUT there are complex interactions w/ other neurotransmitter systems!

Question 6

List the five main classes of antidepressants used for the treatment of depression.

Answer 6

1) Monoamine oxidase inhibitors (MAOIs)
2) Tricyclic antidepressants (TCAs)
3) Selective serotonin reuptake inhibitors (SSRIs)
4) Noradrenaline reuptake inhibitors (NARIs)
5) Serotonin & noradrenaline reuptake inhibitors (SNRIs)

Question 7

Name some examples of MAOI.

Answer 7

Phenelzine (irreversible non-selective) & moclobemide (reversible MAO-A selective)

Question 8

Name some examples of TCAs.

Answer 8

In decreasing order of 5-HT selectivity / ascending order of NA selectivity:
Clomipramine > Amitriptyline > Imipramine > Nortriptyline > Desipramine

Question 9

Which type of MAOIs are used in Parkinson’s disease?

Answer 9

MAO-B selective inhibitors (e.g. selegiline)

Question 10

What are the two major forms of monoamine oxidases?

Answer 10

MAO-A & MAO-B:

• 5-HT is broken down mainly by MAO-A
• BUT both MAO-A & MAO-B act on noradrenaline (NA) & dopamine

Question 11

Explain the mechanism of action of MAOIs.

Answer 11

Inhibits monoamine oxidase within presynaptic cleft & thus increases the bioavailability of NA & 5-HT at synapses.

Question 12

What are some side effects of MAOIs? Explain how so.

Answer 12

1) Postural hypotension
- Sympathetic block by an accumulation of dopamine in cervical ganglia
- Dopamine now acts as inhibitory transmitters to cervical ganglia, resulting in dopamine&raquo_space; NA levels, thus sympathetic block

2) Restlessness & insomnia
- Due to increased NA levels

3) Cheese reaction w/ tyramine-containing products
- Less with MAO-A selective and/or reversible inhibitors vs irreversible, non-selective MAOIs
- Results in acute hypertension, severe throbbing HA & occasional intracranial haemorrhage
- As tyramine (i.e. amines) are usually broken down by MAO, tyramine accumulation due to the presence of MAOI results in sympathomimetic effects.
- Tyramine is taken up into adrenergic terminals & competes with NA for the vesicular compartment, which further releases NA into synapse, in addition to blocking NA reuptake in synapses

Question 13

What was the original therapeutic intention behind the development of TCAs?

Answer 13

Initially produced as potential antipsychotics for schizophrenia but found ineffective.

Question 14

What are some DDIs/FDIs to look out for when dispensing MAOIs?

Answer 14

1) Serotonergic drugs (e.g. pethidine, SSRIs, SNRIs & SMS)
- Cause hyperexcitability, increased muscular tone, myoclonus (i.e. jerking, involuntary movements) & loss of consciousness
- i.e. serotonin syndrome

2) Tyramine-containing products
- Cheese & concentrated yeast products (e.g. Marmite)

Question 15

Explain why reversible MAO-A selective inhibitors are less likely to cause the “cheese reaction” when co-administration of tyramine-containing products.

Answer 15

MAO-B is available to break down & alleviate the heightened NA levels when using MAO-A selective inhibitors.
Subsequently, MAO-A will be available to break down after reversible reaction, as compared to non-selective irreversible MAOI.

Question 16

Which TCA is NOT used for the treatment of depression?

Answer 16

Clomipramine: Used as anxiolytic instead.

Question 17

Which TCA has a milder side effect profile as compared to the others?

Answer 17

Nortriptyline > Amitriptyline & Imipramine

- Thus improved adherence

Question 18

Which TCA is selective for norepinephrine transporters?

Answer 18

Desipramine

Question 19

Which TCAs are non-selective for serotonin transporters?

Answer 19

Amitriptyline, imipramine & nortriptyline

Question 20

What are some side effects of TCAs?

Answer 20

FATAL ON OVERDOSE!!

1) Sedation
- Due to H1 histamine receptor antagonism
- Tolerance to sedation develops in 1-2 weeks

2) Postural hypotension
- Due to alpha-adrenoreceptor sympathetic block

3) Anticholinergic side effects
- Dry mouth, blurred vision, constipation
- Due to muscarinic receptor antagonism

Question 21

Explain the mechanism of action of TCAs.

Answer 21

They inhibit the reuptake of serotonin and norepinephrine (i.e. monamines) in presynaptic terminals / autoreceptors, which leads to increased concentration of 5-HT & NA in the synaptic cleft.

Question 22

Describe the PK profile of TCAs.

Answer 22

D: Primarily bound to plasma proteins, resulting in small Vd (i.e. found primarily in blood)
M: Rely on hepatic metabolism for elimination

Question 23

Which class is the first class of drugs developed for the purpose of antidepressant treatment?

Answer 23

Selective serotonin reuptake inhibitors (SSRIs)

Question 24

Name some examples of SSRIs.

Answer 24

Complusory: Fluoxetine, citalopram
Optional: Sertraline, paroxetine, escitalopram

Question 25

Which class of antidepressants are used as first-line in the Tx of depression?

Answer 25

SSRIs (CA1 specific) | SSRIs, SNRIs, Mirtazapine (NaSSA) & Bupropion (NDRI) (Based on MOH CPG)

Question 26

What are some advantages of using SSRIs over TCAs? Explain why.

Answer 26

1) Greater 5-HT reuptake selectivity (50- to 1000- fold) than TCAs - Fluoxetine has approx. 50-fold increase in selectivity for 5-HT uptake. - Citalopram has approx. 1000-fold increase in selectivity for 5-HT uptake. 2) Fewer adverse effects than TCAs, thus better compliance / adherence / tolerance - Lower affinity for alpha-adrenoreceptors, thus less CVS effects expected & safe to give at higher doses - Lack affinity at histamine receptors, resulting in less sedation - Low affinity for muscarinic receptors, thus minimal anticholinergic side effects (e.g. dry mouth, blurred vision & constipation

Question 27

Which SSRI is currently the most widely used prescribed antidepressant?

Answer 27

Fluoxetine

Question 28

Which SSRI still has some H1 histamine receptor antagonism activity that may lead to sedation as a side effect?

Answer 28

Citalopram

Question 29

What are some side effects of SSRIs?

Answer 29

1) Nausea (due to 5HT-3 agonism) 2) Insomnia - Both nausea & insomnia are possible results from discontinuation / rebound smx of withdrawal between doses (i.e. trough effect) - Usually occur in the 1st few weeks of initial administration; non-issue in subsequent weeks 3) Sexual dysfunction (up to 50%) (due to 5HT-2 agonism) - Delayed ejaculation (men) & delayed blocked orgasm (females) - Due to increased stimulation of 5-HT2 receptors - Rarely (10%) leads to discontinuation 4) Serotonin syndrome (due to increased 5-HT availability) - Tremor, headache & CV collapse (potentially more fatal than MAOIs) - Due to concomitant administration of serotonergic drugs (e.g. MAOIs & SNRIs)

Question 30

Which drug can be given to prevent SSRI-induced sexual dysfunction from occurring in pt. with depression?

Answer 30

Cyproheptadine or other 5-HT2 blockers

Question 31

What are some benefits & limitations of using SSRIs in the treatment of depression?

Answer 31

Benefits: - Greater safety, efficacy & tolerability, leading to increased adherence -> first-line Tx Limitations: - Only 2/3 pt w/ depression get remission; etiology of depression may not be based on lack of monoamine, but on other MOA - Adverse effects are prominent at start of Tx - Discontinuation may be problematic in some pt. due to SSRI-induced sexual dysfunction

Question 32

Which class of antidepressants have significantly fewer side effects as compared to TCAs & SSRIs?

Answer 32

Noradrenaline/Norepinephrine reuptake inhibitors (NARIs) | - Due to greater NA reuptake selectivity (approx. 1000-fold) than TCAs (e.g. reboxetine)

Question 33

Name some examples of NARIs.

Answer 33

Reboxetine & maprotiline

Question 34

Which NARI has greater alpha-adrenoreceptor & histamine receptor antagonisms that occasionally caused seizures in pt. with depression?

Answer 34

Maprotiline | Results in CVS effects (e.g. postural hypotension) & sedation.

Question 35

Describe the mechanism of action of SSRIs.

Answer 35

Inhibit the reuptake of serotonin in presynaptic terminals / autoreceptors, which leads to increased concentration of 5-HT in the synaptic cleft.

Question 36

Describe the mechanism of action of NARIs.

Answer 36

Inhibit the reuptake of noradrenaline / norepinephrine in presynaptic terminals / autoreceptors, which leads to increased concentration of NA in the synaptic cleft.

Question 37

What are some side effects of reboxetine?

Answer 37

1) Anticholinergic side effects: - Dry mouth (11%) - Constipation (9%) 2) Adrenergic side effects (due to increased NA): - Insomnia (~9%) - Tachycardia (~3%)

Question 38

Name some examples of SNRIs.

Answer 38

Venlafaxine, desvenlafaxine, duloxetine

Question 39

Describe the mechanism of action of SNRIs.

Answer 39

Inhibit the reuptake of serotonin and norepinephrine in presynaptic terminals / autoreceptors, which leads to increased concentration of 5-HT & NA in the synaptic cleft. - Similar MOA to non-selective TCAs, but have different chemical structures (resembles tramadol with slight differences)

Question 40

What are some side effects of SNRIs?

Answer 40

Similar to SSRI; fewer & less severe than TCAs 1) Nausea (due to 5HT-3 agonism) 2) Insomnia (due to increased NA availability) - Both nausea & insomnia are possible results from discontinuation / rebound smx of withdrawal between doses (i.e. trough effect) - Usually occur in the 1st few weeks of initial administration; non-issue in subsequent weeks 3) Sexual dysfunction (up to 50%) (due to 5HT-2 agonism) - Delayed ejaculation (men) & delayed blocked orgasm (females) - Due to increased stimulation of 5-HT2 receptors - Rarely (10%) leads to discontinuation 4) Serotonin syndrome (due to increased 5-HT availability) - Tremor, headache & CV collapse (potentially more fatal than MAOIs) - Due to concomitant administration of serotonergic drugs (e.g. MAOIs & SSRIs) 5) Withdrawal effects may be more common & stronger than for SSRIs & TCAs.

Question 41

Aside from first-line antidepressants, name some examples of other antidepressants which may be used instead, depending on indications specified for Tx of depression.

Answer 41

1) Noradrenaline/Norepinephrine & specific serotonin antidepressant (NaSSA) - E.g. Mirtazapine - Antagonist of alpha-2-adrenergic autoreceptors & 5-HT2C receptor among others (including H1) 2) Noradrenaline/Norepinephrine & dopamine reuptake inhibitor (NDRI) - E.g. Bupropion 3) Melatonin MT1 & MT2 receptor agonists - E.g. Agomelatine - Also has antagonism at 5-HT2C receptors - Less TCA / SSRI-associated side effects - Helps in sleep disorders 4) Glutamate NMDA receptor antagonist - E.g. Ketamine - Primarily used as IV general anaesthetic; currently evaluated for rapid-onset antidepressant effect 5) Serotonin modulators & stimulators (SMS) - E.g. Vortioxetine - Multimodal serotonergic antidepressant as 5-HT1A receptor agonist, 5-HT1B receptor partial agonist and 5-HT1D, 5-HT7 & 5-HT3 receptor antagonists - In animal studies: Increases in extracellular levels of 5-HT, dopamine, NA, acetylcholine & histamine in major regions of brain associated with depression

Question 42

Which antidepressant may be efficacious in patients resistant to other antidepressants? What are some side effects associated with the use of this antidepressant?

Answer 42

Vortioxetine - May have pro-cognitive effects - Similar side effect profiles as SSRIs (i.e. nausea, insomnia, sexual dysfunction & serotonin syndrome) - May also raise the risk of suicidal thoughts / actions in children & adolescents; require close monitoring in initial stages.