L01 Antidepressants Flashcards
Which psychiatric disorder is typically ascribed to being a major cause of work days lost to disability & bejng the major cause of premature death?
Depression
What are some symptoms of depression?
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
Describe the major types of depression.
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
Which theory forms the basis of our pathophysiological understanding of depression? Explain why.
Monoamine theory:
- Deficits in monoamine neurotransmitters (NA & 5-HT) cause depression
- Forms the basis of most successful pharmacological strategies for Tx of depression
What are some limitations of using monoamine theory to explain the pathophysiology of depression?
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!
List the five main classes of antidepressants used for the treatment of depression.
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)
Name some examples of MAOI.
Phenelzine (irreversible non-selective) & moclobemide (reversible MAO-A selective)
Name some examples of TCAs.
In decreasing order of 5-HT selectivity / ascending order of NA selectivity:
Clomipramine > Amitriptyline > Imipramine > Nortriptyline > Desipramine
Which type of MAOIs are used in Parkinson’s disease?
MAO-B selective inhibitors (e.g. selegiline)
What are the two major forms of monoamine oxidases?
MAO-A & MAO-B:
- 5-HT is broken down mainly by MAO-A
- BUT both MAO-A & MAO-B act on noradrenaline (NA) & dopamine
Explain the mechanism of action of MAOIs.
Inhibits monoamine oxidase within presynaptic cleft & thus increases the bioavailability of NA & 5-HT at synapses.
What are some side effects of MAOIs? Explain how so.
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»_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
What was the original therapeutic intention behind the development of TCAs?
Initially produced as potential antipsychotics for schizophrenia but found ineffective.
What are some DDIs/FDIs to look out for when dispensing MAOIs?
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)
Explain why reversible MAO-A selective inhibitors are less likely to cause the “cheese reaction” when co-administration of tyramine-containing products.
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.
Which TCA is NOT used for the treatment of depression?
Clomipramine: Used as anxiolytic instead.
Which TCA has a milder side effect profile as compared to the others?
Nortriptyline > Amitriptyline & Imipramine
- Thus improved adherence
Which TCA is selective for norepinephrine transporters?
Desipramine
Which TCAs are non-selective for serotonin transporters?
Amitriptyline, imipramine & nortriptyline
What are some side effects of TCAs?
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
Explain the mechanism of action of TCAs.
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.
Describe the PK profile of TCAs.
D: Primarily bound to plasma proteins, resulting in small Vd (i.e. found primarily in blood)
M: Rely on hepatic metabolism for elimination
Which class is the first class of drugs developed for the purpose of antidepressant treatment?
Selective serotonin reuptake inhibitors (SSRIs)
Name some examples of SSRIs.
Complusory: Fluoxetine, citalopram
Optional: Sertraline, paroxetine, escitalopram
Which class of antidepressants are used as first-line in the Tx of depression?
SSRIs (CA1 specific)
SSRIs, SNRIs, Mirtazapine (NaSSA) & Bupropion (NDRI) (Based on MOH CPG)
What are some advantages of using SSRIs over TCAs? Explain why.
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
Which SSRI is currently the most widely used prescribed antidepressant?
Fluoxetine
Which SSRI still has some H1 histamine receptor antagonism activity that may lead to sedation as a side effect?
Citalopram
What are some side effects of SSRIs?
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)
Which drug can be given to prevent SSRI-induced sexual dysfunction from occurring in pt. with depression?
Cyproheptadine or other 5-HT2 blockers
What are some benefits & limitations of using SSRIs in the treatment of depression?
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
Which class of antidepressants have significantly fewer side effects as compared to TCAs & SSRIs?
Noradrenaline/Norepinephrine reuptake inhibitors (NARIs)
- Due to greater NA reuptake selectivity (approx. 1000-fold) than TCAs (e.g. reboxetine)
Name some examples of NARIs.
Reboxetine & maprotiline
Which NARI has greater alpha-adrenoreceptor & histamine receptor antagonisms that occasionally caused seizures in pt. with depression?
Maprotiline
Results in CVS effects (e.g. postural hypotension) & sedation.
Describe the mechanism of action of SSRIs.
Inhibit the reuptake of serotonin in presynaptic terminals / autoreceptors, which leads to increased concentration of 5-HT in the synaptic cleft.
Describe the mechanism of action of NARIs.
Inhibit the reuptake of noradrenaline / norepinephrine in presynaptic terminals / autoreceptors, which leads to increased concentration of NA in the synaptic cleft.
What are some side effects of reboxetine?
1) Anticholinergic side effects:
- Dry mouth (11%)
- Constipation (9%)
2) Adrenergic side effects (due to increased NA):
- Insomnia (~9%)
- Tachycardia (~3%)
Name some examples of SNRIs.
Venlafaxine, desvenlafaxine, duloxetine
Describe the mechanism of action of SNRIs.
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)
What are some side effects of SNRIs?
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.
Aside from first-line antidepressants, name some examples of other antidepressants which may be used instead, depending on indications specified for Tx of depression.
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
Which antidepressant may be efficacious in patients resistant to other antidepressants?
What are some side effects associated with the use of this antidepressant?
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.
