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PR3136 PT4 > L01 Antidepressants > Flashcards

L01 Antidepressants Flashcards

1
Q

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

A

Depression

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2
Q

What are some symptoms of depression?

A

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
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3
Q

Describe the major types of depression.

A

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

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4
Q

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

A

Monoamine theory:

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

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

A

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!

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6
Q

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

A

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)

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7
Q

Name some examples of MAOI.

A

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

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8
Q

Name some examples of TCAs.

A

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

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9
Q

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

A

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

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10
Q

What are the two major forms of monoamine oxidases?

A

MAO-A & MAO-B:

  • 5-HT is broken down mainly by MAO-A
  • BUT both MAO-A & MAO-B act on noradrenaline (NA) & dopamine
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11
Q

Explain the mechanism of action of MAOIs.

A

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

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12
Q

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

A

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

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13
Q

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

A

Initially produced as potential antipsychotics for schizophrenia but found ineffective.

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14
Q

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

A

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)

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15
Q

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

A

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.

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16
Q

Which TCA is NOT used for the treatment of depression?

A

Clomipramine: Used as anxiolytic instead.

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17
Q

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

A

Nortriptyline > Amitriptyline & Imipramine

- Thus improved adherence

18
Q

Which TCA is selective for norepinephrine transporters?

A

Desipramine

19
Q

Which TCAs are non-selective for serotonin transporters?

A

Amitriptyline, imipramine & nortriptyline

20
Q

What are some side effects of TCAs?

A

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

21
Q

Explain the mechanism of action of TCAs.

A

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.

22
Q

Describe the PK profile of TCAs.

A

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

23
Q

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

A

Selective serotonin reuptake inhibitors (SSRIs)

24
Q

Name some examples of SSRIs.

A

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

25
Q

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

A

SSRIs (CA1 specific)

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

26
Q

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

A

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

27
Q

Which SSRI is currently the most widely used prescribed antidepressant?

A

Fluoxetine

28
Q

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

A

Citalopram

29
Q

What are some side effects of SSRIs?

A

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)

30
Q

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

A

Cyproheptadine or other 5-HT2 blockers

31
Q

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

A

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
32
Q

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

A

Noradrenaline/Norepinephrine reuptake inhibitors (NARIs)

- Due to greater NA reuptake selectivity (approx. 1000-fold) than TCAs (e.g. reboxetine)

33
Q

Name some examples of NARIs.

A

Reboxetine & maprotiline

34
Q

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

A

Maprotiline

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

35
Q

Describe the mechanism of action of SSRIs.

A

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

36
Q

Describe the mechanism of action of NARIs.

A

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

37
Q

What are some side effects of reboxetine?

A

1) Anticholinergic side effects:
- Dry mouth (11%)
- Constipation (9%)

2) Adrenergic side effects (due to increased NA):
- Insomnia (~9%)
- Tachycardia (~3%)

38
Q

Name some examples of SNRIs.

A

Venlafaxine, desvenlafaxine, duloxetine

39
Q

Describe the mechanism of action of SNRIs.

A

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)

40
Q

What are some side effects of SNRIs?

A

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.

41
Q

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

A

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

42
Q

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

A

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.

PR3136 PT4 (14 decks)

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