Lecture 13

• SSRI


  Selective serotonin reuptake inhibitor
• TCA


  Tricyclic antidepressant
• MAOI


  Monoamine oxidase inhibitor
• Atypical antidepressants


  Eg mirtazepine, nefazodone, mianserin
• Tricyclic antidepressants (TCAs)


  • Effective but many side effects
  • Eg amitriptyline, imipramine, lofepramine
  • Inhibit NA + 5-HT uptake — therapeutic effect
  • Also inhibit AChM1 — dry mouth, blurred vision, urinary retention
  • Block H1 — sedation, weight gain
  • Blocks α1 — postural hypotension
  • Clinical use: Severe treatment resistant depression, Pain (low dose), Migraine, Not used in elderly, cardiac patients, drivers, suicidal patients — toxic in overdose
• Selective serotonin reuptake inhibitors (SSRIs)


  • Selective for 5-HT transporter
  • Eg paroxetine, fluoxetine, sertraline
  • Fewer side effects
  • Side effects: Sexual dysfunction, GI disturbances, Dry mouth, Do not cause sedation or anticholinergic side effects
  • Clinical uses: Panic disorder, OCD + eating disorders
• SNRI + NARI


  • Serotonin + noradrenaline reuptake inhibitor (SNRI) eg duloxetine + noradrenaline reuptake inhibitor (NARI) eg reboxetine
  • Selective for 5-HT/NA or NA transporters — no affinity for postsynaptic receptors (fewer side effects)
• TCAs vs SSRIs


  • Equivalent efficacy
  • Better side effect profile than TCAs
  • Important bc lag time before onset = ADs given long term
• Monoamine oxidase inhibitors (MAOIs)

  • Monoamine oxidases: A+B isoforms, 70% sequence homology, MAOA higher affinity — 5-HT + NA, MAOB higher affinity — DA
  • Both isoforms usually blocked by MAOIs irreversibly
  • Eg tranylcypromine, phenelzine
  • Stimulant effects, dietary restrictions, dangerous in combination with other ADs
  • New MAOIs selective for MAOA — reversible RIMA = less stimulant + safer
  • MAOI interactions: MAOI + tyramine (food)/medicines containing 1° amine = Cheese reaction ⇒ hypertensive crisis, MAOIs + serotonin = Serotonin syndrome ⇒ hyperthermia, confusion + hypertensive crisis, MAOIs + releasing agents (MDMA) = Serotonin syndrome
• Atypical antidepressants


  • Eg mirtazepine, nefazodone + mianserin
  • Range of affinities for different MA transporters + receptors
• Mechanism of action of delayed AD response

  1. Lag time before therapeutic benefit

  2. Takes time for 5-HT neurotransmission to increase + incr starts another process → autoreceptor activation/desensitisation

  3. Autoreceptor activation/desensitisation: SSRIs/TCAS → block transporter at cell body, Acute activation of 5-HT1A in raphe → 5-HT neuronal activity + release, Synaptic 5-HT levels restrained — similar mechanism for MAOIs

  4. Other causes of 5-HT restrain: Terminal 5-HT1B autoreceptors — restrain release once 1A desensitises, High synaptic levels of 5-HT ⇒ overcome transporter blockade by SSRI, Persistently high 5-HT = transporters downregulate

  5. Neuroplasticity: SSRIs increase brain derived neurotrophic factor (BDNF), Also seen in ECT, lithium, exercise, BDNF → synaptic remodelling req for therapeutic effect

  6. How this fits with 5-HT hypothesis: BDNF + 5-HT co-regulate each other, 5-HT stimulates expression of BDNF, BDNF enhances growth + survival of 5-HT neurones

  7. Spine density: Increased BDNF signalling caused by ADs = increased spine density + synaptic strength, Serum BDNF lower in depressed patients than controls, Chronic CORT = reduced dendritic complexity + no of spines → synaptic pruning
• Accelerating therapeutic response

  1. 5-HT: More rapid desensitisation, Autoreceptor antagonists + SSRI — 1A + 1B, Drive 5-HT neurotransmission other ways eg. SNRI, α1 agonist, α2 antagonist, Adjunct or drug with mixed effects

  2. Newer approaches: Ketamine - Acute antidepressant effect, Increases BDNF, Increases spine maturation, Psychedelics eg psilocybin - Promote plasticity by directly binding to BDNF receptor TrkB
• Autoreceptor desensitisation/activation

  5-HT1A receptor -> desensitised with persistent activation -> reduced 5-HT reuptake

  A) raphe

  B) forebrain

  C) transporter

  D) 5-HT1A autoreceptor

  E) -ve

  F) transporter