HUF 2-70 Depression and antidepressant drugs

Question 1

Depression

Answer 1

• Major depression: genetically predisposed
• Reactive/adjustment disorder (life events)
• Postpartum depression
• Seasonal affective disorder
• Comorbidity with anxiety

Question 2

Different types of affective / mood disorders

Answer 2

• Major depressive disorder: recurrent depressive episodes
• Bipolar affective disorder: mania/hypomania and depression
• Anxiety disorder

Question 3

Brain systems implicated in mood disorders

Answer 3

• Changes in connectivity between limbic system and prefrontal cortex
  1. 5-HT system: raphe nu.
  2. NA: locus coeruleus

Question 4

Monoamine theory of depression

Answer 4

Depression is caused by functional deficit of monoamine transmitters (NA, 5-HT) at certain sites of brain

Supportive evidence:

• Antidepressant treatments
• Depletion of monoamines by reserpine causes depression

Question 5

5-HT and NA neurons

Answer 5

NA neurons:
- α2 autoreceptor at dendrites and axon terminals
=> ↓ NA from presynaptic neuron when activated

5-HT neurons:

• α1 receptor at dendrites
• α2 heteroreceptor at axon terminals

Question 6

Treatment principle based on monoamine theory of depression

Answer 6

SERT (serotonin transporter)
NET (norepinephrine transporter)
- Functioning: ↓ local conc. of released NT
- Blocked: transmission enhanced

α2 adrenoceptor
5HT-1A/B receptor
- Autoreceptors at presynaptic sides
- Activated: amount of NT ↓ per episode

Question 7

Types of antidepressants

Answer 7

1. MAOI (monoamine oxidase inhibitor)
2. MARI (monoamine reuptake inhibitors)
   - Classical tricyclic antidepressants (TCA)
   - Selective serotonin reuptake inhibitors (SSRI)
   - Selective noradrenaline reuptake inhibitors (NRI)
   - Serotonin-NA reuptake inhibitors (SNRI)
3. Atypical antidepressants (monoamine receptor antagonists)

Question 8

MAOI

Answer 8

MAO-A: metabolise NA, AD 5-HT, DA, tyramine
MaO-B: DA, tyramine

Moclobemide

• Selective reversible inhibitor for MAO-A
• Less likely to produce “cheese rxn”
• Side effects: nausea, insomnia, agitation

Question 9

Tricyclic antidepressants

Answer 9

Each drug shows diff. degree of inhibition on 5-HT/NA reuptake
e.g. Amitriptyline (prodrug) -> Nortriptyline
Imipramine (prodrug) -> Desipramine

Undesirable effects:

• inhibit α1, M, H1
• Sedation, postural hypotension, seizures, sexual dysfunction, cardiac arrhythmia (fatal if overdose)

Question 10

SSRI, NRI, SNRI

Answer 10

Fluoxetine (Prozac), Citalopram, Paroxetine, Sertraline

• Similar efficacy as TCA; fewer side effects, relative safer when overdosed
• Side effect: agitation, insomnia, sexual dysfunction
• DDI with non-selective MAOI and SSRI overdose
  => Serotonin symdrome

NRI: Bupropion => inhibit NA reuptake

SNRI: Venlafaxine => inhibit 5-HT and NA reuptake
- Less unlikely to cause undesirable effects than SSRIs during drug withdrawal

Question 11

Time lag in clinical effectiveness of antidepressants

Answer 11

↑ NT
=> ↑ stimulation of inhibitory autoreceptors (soma, dendrites in raphe nu.)
=> ↑ inhibition of NT synthesis (undesirable effects)
∴ Cancels out beneficial effect of inhibiting reuptake
=> Desensitisation of presynaptic autoreceptors
=> ↓ inhibition of NT synthesis
=> ↑ postsynaptic receptor activity (therapeutic response)

• Gradually increase dose of SSRI

Question 12

DDI of SSRI and TCA

Answer 12

• SSRI: CYP2D6 inhibitors
• TCA: metabolised by CYP2D6
  ∴ When used together
  => DDI: ↑↑↑ 5-HT
  => Serotonin syndrome: agitation, hyperthermia

Question 13

Atypical antidepressants: monoamine receptor antagonist

Answer 13

• Non-selective; inhibit α, 5HT-2 receptors
• Weak effects on monoamine uptake

1. NA control of 5HT release
   - 5HT release under regulation of excitatory action of NA on α1R
   - Inhibitory action on α2R
   - Mirtazapine, Mianserin
   => Antagonise α2 autoreceptor
   => ↑ 5HT release
   - Side effects: seizure, type 1 hypersensitivity
2. 5HT-2AR
   - Higher expression of 5HT-2AR in postmortem brains of teenage suicide victims
   - Trazodone
   => Antagonise postsynaptic 5HT-2AR
   => ↑ DA and NA activity in frontal cortex]
   - Side effects: sedation, cardiac arrhythmia (also blocks M, H1 and α1)

Question 14

Neurogenesis and depression

Answer 14

Adult hippocampal neurogenesis
- Neural stem cells
=> Transiently-amplifying progenitors
=> Immature neurons
=> Fully mature dentate gyrus GC neurons (4-6 weeks)

Reduced neurogenesis in depression
- Antidepressant require adult neurogenesis to improve mood

Question 15

Neurotrophic hypothesis of depression

Answer 15

• ↓ expression of brain-derived neurotrophic factor (BDNF) has adverse effects on neuronal plasticity
  => ↓ neuronal networks
  ↓ neuronal circuitry
  Hippocampal atrophy

Successful long-term antidepressant treatment associated with:

• ↑ BDNF expression
• Restoration of hippocampal function

Question 16

Drug treatments for bipolar disorder

Answer 16

1. Anti-epileptic drugs
   - Valproate, Carbamazepine
   - Mania exhibits episodic patterns involving neural over-activity
   - Calm down CNS neurons
2. Lithium
3. Atypical antipsychotics
   - Olanzapine, Aripiprazole

Question 17

Use of lithium in bipolar disorder

Answer 17

• Acute mania
• Prophylaxis of recurrent manic and depressive episodes (mood stabilisation)

Possible mechanisms of action:
1. Regulate genes that control GLU / 5HT production
2. Substitute for Na+ / Block K+ channels
=> Electrochemical gradients
3. Inhibit glycogen synthase kinase (GSK-3β)
∵ Increased GSK-3β activity associated with apoptosis and ↓ neurogenesis in CNS
=> Regulation transcription and expression of factors
- Neuroprotective, neurotrophic
- Anti-inflammatory, neurogenic, angiogenic
- Mood-stabilising, antidepressant-like anxiolytic
=> Neuroprotective effect

Question 18

Undesirable effects and DDI of lithium

Answer 18

Undesirable effects:

• Acute lithium toxicity: confusion, convulsions, death (narrow therapeutic window)
• Renal: nephrogenic DI
• Hypothyroidism
• Weight gain

DDI:

• Renal toxicity when taken with loop diuretics or NSAIDs
• Neurotoxicity when taken with Haloperidol, Phenothiazines (typical antipsychotics), Carbamazepine (anticonvulsant)