Depression and anxiety drugs

• depression is a biochemically mediated state most likely based on abnormalities in metabolism of:

  Serotonin (5-HT) and Norepinephrine (NE)
• What are the clinical manifestations of depression?


  here:

  
• True or false: sleep disturbance is a common complaint of depression. characterized by either hypersomnia or insomnia.

  TRUE
• A depressed patient has what decreased neurotransmitters?

  • dopamine
  • NE
  • Serotonin
  • These are known as the monoamines!
• Amine hypothesis and major depression

  suggests that imbalance in the

  monoamines (serotonin

  and norepinephrine) is

  involved in the

  development of major

  depression
• serotonergic neurons


  release serotonin
• noradrenergic neurons


  release NE
• SERT/NET transporters are:


  responsible for the reuptake of serotonin and NE into the presynaptic neuron
• What are some gaps in the amine hypothesis?

  • Postmortem studies do not reveal decreases in the brain levels of NE or 5-HT

  • Antidepressants cause changes in brain amine activity within hours, clinical

  response requires weeks

  • Most antidepressants ultimately cause a downregulation of amine receptors

  • Bupropion has minimal effects on brain NE or 5-HT

  • BDNF is depressed in the brains of depressed patients

  • Chronic use reduces glutamatergic transmission and ketamine with markedly

  rapid antidepressant action
• 1. Downregulation of amine receptors: Long-term use of most antidepressants leads to a downregulation of NE and 5-HT receptors in the brain. This downregulation occurs despite the initial increase in neurotransmitter activity caused by the medication, raising questions about the role of neurotransmitter deficiency in depression.
• Neurotrophic hypothesis


  Suggests that the low levels of BDNF play a role in the development of depression
• Brain-derived neurotrophic factor (BDNF)


  • Critical for regulation of neural plasticity, resilience & neurogenesis
  • Depression is associated with loss of neurotrophic support
  • Antidepressant drugs increase neurogenesis & synaptic connectivity
  • BDNF infusion showed antidepressant-like effects in animals
  • Chronic antidepressant administration increases BDNF levels in brain
  • Mutations in BDNF gene: altered anxiety & depressive behavior
  • BDNF-knockout animals: not always show depressive or anxious behaviors
• MOA inhibitors are:


  rarely used due to side effects
• Tricyclic antidepressants (TCA) are:

  first generation
• What is the MOA of tricyclic antidepressants?

  they nonselectively inhibit both 5HT and NE reuptake
• What is the MOA of SSRIs?

  selectively inhibit 5HT reuptake
• what is the MOA of MAOI?

  inhibits amine metabolism (or breakdown) within the presynaptic neuron. HOW? by inhibiting the enzyme MOA that breaks down the monoamine neurotransmitters => increases their level in brain.
• MOA of heterocyclic agents?

  nonselectively inhibit both 5HT and NE reuptake
• review:


  .

  
• Which classes of drugs inhibit 5HT reuptake?


  :

  
• Which drug inhibits alpha 2 adrenoreceptor?

  Mirtazapine, and when we inhibit this receptor, NE will no longer be inhibitied and more NE will be released

  
• Which class inhibits MOA?

  :

  
• which class inhibits NE reuptake?

  :

  
• Again MOA:


  :