VC - Depression III

Question 1

What is the therapeutic use of antidepressants? (2)

Answer 1

• Primarily prescribed for treating affective disorders
• Show good efficacy: 40-50% achieve full recovery, 80% experience some benefit

Question 2

What factors influence antidepressant effectiveness? (3)

Answer 2

• Drug interactions (e.g., bipolar disorder requiring both antidepressants and mood stabilizers)
• Co-existing conditions (e.g., heart disease and depression)
• Individual variations, including genetic background

Question 3

Name 3 MOA inhibitors

Answer 3

Ipronazid
phenelzine
Moclobemide

Question 4

What is the mechanism of action and side effects of Iproniazid?

Answer 4

Mechanism: Irreversible inhibition (blocks MAO-A and B)

Side Effects: Long duration of action; many side effects

Question 5

What is the mechanism of action and side effects of Phenelzine?

Answer 5

Mechanism: Non-selective but irreversible

Side Effects: Risk of “cheese reaction” with tyramine-containing foods, insomnia, weight gain, liver damage

Question 6

What is the mechanism of action and side effects of Moclobemide?

Answer 6

Mechanism: MAO-A selective and short-acting

Side Effects: Safer than other MAO inhibitors but still has drug interactions with opioids and sympathomimetic drugs

Question 7

Name 2 tricyclic antidepressants (TCA)

Answer 7

Imipramine
Clomipramine

Question 8

What is the mechanism of action and side effects of TCA

Answer 8

Mechanism: Blocks reuptake of monoamines relatively non-specifically; considered first-generation reuptake inhibitors

Side Effects: Anticholinergic effects (e.g., dry mouth, dizziness), hypertension, seizure, impotence, interactions with CNS depressants and alcohol, risk of overdose due to dysrhythmias of the heart

Question 9

Name 2 SSRIs

Answer 9

Fluoxetine
Fluvoxamine

Question 10

What is the mechanism of action and side effects of Fluoxetine?

Answer 10

Mechanism: Relatively selective for serotonin uptake; second-generation reuptake inhibitor

Side Effects: Nausea, diarrhea, insomnia; inhibits other drug metabolism by P450 (risk of interactions)

Question 11

What is the mechanism of action and side effects of Fluvoxamine?

Answer 11

Mechanism: Similar to Fluoxetine but with improved tolerance regarding side effects (e.g., heart) compared to MAOIs and TCAs

Side Effects: Reduced nausea compared to other SSRIs

Question 12

Name a Noradrenergic and Specific Serotonergic Antidepressant (NaSSA)

Answer 12

Mirtasepine

Question 13

What is the mechanism of action and side effects of Mirtasepine?

Answer 13

Mechanism: Blocks alpha-2, H1, 5HT2, and muscarinic receptors; elevates monoamines by preventing inhibition of release

Side Effects: Dry mouth and sedation; faster-acting than other antidepressants

Question 14

What is the antidepressant paradox? (2)

Answer 14

• Drug administration quickly affects monoamine levels, yet clinical effects take 2-6 weeks
• Implies that long-term changes in brain structure and function are involved

Question 15

What are the short-term effects of antidepressant administration? (3)

Answer 15

• Inhibits monoamine uptake, increasing serotonin signaling
• Raises serotonin in areas like the Raphe nucleus, locus coeruleus, and cortex
• Activation of negative autoreceptors reduces neuronal firing

Question 16

Describe the medium-term effects of antidepressants. (3)

Answer 16

• Prolonged treatment downregulates autoreceptors, reducing feedback inhibition
• Increases neuronal firing and chemical transmission
• Adaptation includes downregulation of postsynaptic β2, α2 autoreceptors, and 5HT2 receptors

Question 17

What are the long-term effects of antidepressants? (3)

Answer 17

• Enhanced serotonin signaling and changes in brain function
• Growth factors (e.g., BDNF) promote synaptic plasticity, neurogenesis, and synaptogenesis
• Supports mood regulation and stability

Question 18

What was observed in the Forced Swim Test in relation to brain connectivity? (2)

Answer 18

• Prefrontal cortex (PFC) connects with structures like the dorsal raphe (DR), locus coeruleus (LC), and VTA
• Reciprocal communication between executive and lower brain centers

Question 19

What are novel approaches to depression treatment?

Answer 19

Murrough et al., 2013: Ketamine clinical trial for treatment-resistant depression
Showed ketamine’s efficacy compared to midazolam

Question 20

Describe ketamine’s rapid action in depression treatment. (2)

Answer 20

• Acts as a channel blocker, blocking NMDA receptors (glutamate receptors)
• Not monoamine-dependent, provides fast-acting relief

Question 21

What is the dose-dependent effect of ketamine? (3)

Answer 21

• 3 mg/kg: anesthesia, thalamic inhibition
• 1 mg/kg: dissociative symptoms, limits subcortical inhibition
• 0.5 mg/kg: used as an antidepressant

Question 22

How does ketamine affect neurotrophic factors? (2)

Answer 22

• Requires acute induction of BDNF protein via translational control
• In BDNF knockout animals, ketamine does not show antidepressant activity

Question 23

How does ketamine work at a circuit level to exert its antidepressant effects? (4)

Answer 23

1. Ketamine blocks NMDA receptors on inhibitory interneurons
2. Blocking NMDA receptors reduces calcium influx and kinase activity
3. Leads to disinhibition, allowing excitatory neurons to become more active
4. Disinhibition increases protein translation, promoting brain plasticity and supporting antidepressant effects