Antidepressants

Question 1

Describe the monoamine theory and its limitations.

Answer 1

Deficits in monoamine neurotransmitters (NA and 5-HT) cause depression.

Limitations:

• hypothesis originally formulated for NA, but emphasis later shifted to 5-HT
• studies of monoamine markers in depressed pts yielded inconsistent results
• MA hypothesis alone is inadequate to explain all the pharmacological actions in depression

Question 2

Describe unipolar depression.

Answer 2

Mood swings always in same direction.

• Reactive depression (75%): non-familial, associated with life events
• Endogenous depression (25%): familial, not directly related to external stress

Question 3

Describe bipolar depression.

Answer 3

Depression alternates with mania.

• periodicity of oscillations in mood usually occur over several weeks
• strongly familial
• usually appears in early adulthood

Question 4

What are the symptoms of depression?

Answer 4

Emotional Smx:

• Misery, apathy and pessimism
• Low self-esteem
• Indecisiveness, loss of motivation

Others:

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

Question 5

Which form of MAO breaks down 5-HT, NA and dopamine?

Answer 5

5-HT mainly by MAO-A, but also MAO-B.

NA and dopamine by both forms.

Question 6

How do MAOIs work?

Answer 6

Inhibit breakdown of MA to increase MA availability in the synapse

Question 7

List examples of MAOIs.

Answer 7

Phenelzine: non-selective, irreversible
Moclobemide: MAO-A selective, reversible

Question 8

Major adverse effects of MAOIs?

Answer 8

1. Postural hypotension - accumulation of dopamine in cervical ganglia, where it inhibits NA production
2. Restlessness and insomnia - CNS stimulation
3. (When combined with other drugs enhancing serotonergic function) Hyperexcitability, increased muscular tone, myoclonus (jerking, involuntary movements), loss of consciousness

Question 9

Describe the “Cheese Reaction” (drug-food interaction between MAOIs and cheese/concentrated yeast products)

Answer 9

Acute hypertension, giving severe throbbing headache and occasionally, intracranial haemorrhage.

MAOIs inhibit breakdown of tyramine, tyramine accumulates and causes sympathomimetic effect. Tyramine competes with NA for reuptake + storage in vesicles ➝ more NA released into synapses.

Question 10

List some common TCAs.

Answer 10

Non-selective for SERT/NET: imipramine, amitriptyline, nortriptyline
Selective for NET: desipramine

Question 11

Why is nortriptyline preferred to imipramine or amitriptyline?

Answer 11

Second gen TCA, milder side effects and improved compliance

Question 12

Major adverse effects of TCAs

Answer 12

1. Postural hypotension - blocks alpha adrenergic receptors
2. Sedation - due to H1 histamine receptor antagonism. Tolerance to sedation can develop in 1-2 weeks
3. Dry mouth, blurred vision, constipation - muscarinic receptor antagonism
4. DDIs - plasma protein bound; hepatically metabolised

Question 13

What are the advantages of SSRIs over TCAs?

Answer 13

Overall, safer in overdose + better compliance.

1. Lack of effect at histamine receptors - reduced sedation. (*citalopram can still cause some sedation)
2. Low affinity for alpha-adrenoceptors - lack of cardiovascular effects, safer in overdose
3. Low affinity for muscarinic receptors - minimal anticholinergic side effects e.g. dry mouth, constipation

Question 14

Adverse effects of SSRIs

Answer 14

• Nausea and insomnia (between doses)
• Sexual dysfunction due to increased stimulation of 5HT2 receptors (can prevent with cyproheptadine or other 5HT2 blockers)

Question 15

What are the effects of serotonin syndrome?

Answer 15

• Tremor
• Hyperthermia
• Cardiovascular collapse

Question 16

Name the classes of antidepressants.

Answer 16

1. MAOIs
2. TCA
3. SSRI
4. NARI
5. SNRIs
6. NaSSa

Question 17

Which NARI has similar adverse effects to TCAs?

Answer 17

Maprotiline. Due to alpha adrenoceptor and histamine receptor effects. (Also occasionally caused seizures)

Question 18

Adverse effects of Reboxetine

Answer 18

New drug, so adverse effects not well described.

• Anticholinergic effects: dry mouth mouth, constipation
• Effects of increased NA: Tachycardia, insomnia

Question 19

SNRIs have similar profile to which class? Similar side effects as which class?

Answer 19

Similar profile to non-selective TCAs (dual 5-HT and NA reuptake inhibition). But fewer adverse effects than TCAs.

Similar side effects as SSRIs (nausea, insomnia, sexual dysfunction). Serotonin syndrome when combined with other serotonergic drugs and MAOIs. Withdrawal effects may be more common and stronger than for SSRIs and TCAs.

Question 20

Examples of SNRIs

Answer 20

Venlafaxine, desvenlafaxine, duloxetine

Question 21

What is mirtazapine?

Answer 21

NaSSA. Alpha2 autoreceptor antagonist and 5HT2C receptor antagonist

Question 22

What is bupropion?

Answer 22

NDRI noradrenaline dopamine reuptake inhibitor

Question 23

What is agomelatine?

Answer 23

Agonist of melatonin MT1 and MT2 receptors.

Question 24

Advantages and disadvantages of vortioxetine?

Answer 24

Novel drug, multimodal serotonergic antidepressant.

May be efficacious in in patients resistant to other antidepressants. Seems to work well in children.

May ↑ risk of suicidal thoughts or actions in children and teens. Close monitoring required in the initial stages.

Question 25

What is ketamine?

Answer 25

Glutamate NMDA receptor antagonist used as an anaesthetic, currently evaluated for rapid-onset antidepressant effect.