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  • What is the Monoamine Theory of Depression?
  • What is this theory based on?

  • Monoamine theory depression results from functionally deficient monoamine (NE and/or 5-HT) transmission in the CNS
  • Based on pharmacological evidence of the ability of known antidepressant drugs (TCAs and MAO inhibitors) to facilitate monaminergic transmission of drugs, such as reserpine, that depletes amines to cause depression


Describe neurotransmitter localization in the brain:

  1. Locus coeruleus: 
  2. Raphe nuclei:  
  3. Substantia nigra & Ventral tegmental area of the midbrain: 
  4. Basal Forebrain Complex:

  • Locus coeruleus: 
    • Neurons contain: norepinephrine 
    • Innervate nearly every part of the CNS
  • Raphe nuclei: 
    • Neurons contain: serotonin
    • Projection: most of the brain
  • Substantia nigra & Ventral tegmental area of the midbrain: 
    • Neurons contain: dopamine
    • Projection:
      • striatum ⇒ substantia nigra
      • Ventral tegmental area of the midbrain ⇒ prefrontal cortex and parts of the limbic system
  • Basal Forebrain Complex: 
    • Septal nuclei and nucleus basalis 
    • Neurons contain: ACh
    • Projection: hippocampus, neocortex


What is the mechanism of action of TCAs?

Increases NE and 5-HT in the synapse (block reuptake)


What is the mechanism of action for SSRIs?

Inhibits serotonin-specific reuptake


What is the mechanism of action for drugs like phenelzine?

Nonselectively inhibits MAO, which increases levels of amine neurotransmitters



  • Drugs
  • Clinical Use
  • Side Effects
  • Toxicity

  • Drugs
    • Fluoxetine, paroxetine, sertraline, citalopram
  • Clinical Use
    • Depression, generalized anxiety disorder, panic disorder, OCD, bulimia, social phobias, PTSD
  • Side Effects
    • nausea, insomnia, sexual dysfunction
  • Toxicity
    • Serotonin Syndrome, no food reactions

*FDA warning: Neuroleptic malignant syndrome


When do symptoms of SSRI withdrawal manifest?

Symtoms begin 1 - 7 days following SSRI stoppage


List the symptoms of SSRI withdrawal (15):

  1. dizziness,
  2. light-headedness
  3. vertigo or feeling faint
  4. shock-like sensations
  5. paresthesia
  6. anxiety
  7. diarrhea
  8. fatigue
  9. gait instability
  10. headache
  11. insomnia
  12. irritability
  13. nausea or vomiting
  14. tremor
  15. visual disturbances


SSRI approved uses:

  • Major Depression
  • Obsessive-Compulsive disorder
  • Panic disorder
  • Social Anxiety Disorder
  • PTSD
  • Generalized Anxiety disorder
  • PMS –Now PDD (Premenstrual Dysphoric Disorder)
  • Hot flashes associated with menopause


What are the commonly prescribed SSRIs and their clinical use?

  1. Fluoxetine (Prozac®) 
    • Effects on drug metabolism
    • Long half-life active metabolite - 7 days or more
    • Sustained release product - PMS
  2. Sertraline (Zoloft®) 
    • Similar in action to fluoxetine with less effects on drug metabolism
    • Shorter half-life
    • OCD, PTSD, Panic attacks
  3. Paroxetine (Paxil®)  
    • also approved for hot flashes associated with menopause
  4. Fluvoxamine (Luvox®)
    • approved for OCD
  5. Citalopram (Celexa®) and Escitalopram (Lexapro®)


  • What is the mechanism of action of SNRIs?
  • How does the side effect profile compare to SSRIs?

  • Drugs block both 5-HT and NE reuptake
  • Side effect profile is more SSRI-like than TCA-Like


What are the commonly prescribed SNRIs and their clincial use?

  • Duloxetine (Cymbalta®)
    • Major Depressive Disorder and anxiety
    • Also approved for neuropathic pain syndromes, fibromyalgia, back pain and osteoarthritis pain
    • Use with caution in patients with liver disease
  • Venlafaxine (Effexor®)
    • Major Depressive Disorder and anxiety
  • Milnacipran (Savella®)
    • approved for fibromyalgia
    • also levomilnacipran (Fetzima®) which is approved for major depressive disorder


What is the definition of an atypical antidepressant?

  • Drugs without typical tricyclic structure or SSRI or SNRI action
  • May or may not block catecholamine uptake


List the Atypical Antidepressants (5):

  1. Bupropion (Wellbutrin® and Zyban®)
  2. Mirtazapine (Remeron®)
  3. Trazodone (Oleptro®)
  4. Vilazodone (Viibryd®)
  5. Vortioxetine (Brintellix®)


What are the differences between the atypical antidepressants?

  • Bupropion (Wellbutrin® and Zyban®)
    • Weakly blocks NE and dopamine uptake
    • also approved for nicotine withdrawal and seasonal affective disorder
    • No weight gain or sexual dysfunction
  • Mirtazapine (Remeron®)
    • Blocks presynaptic α2 receptors in brain
    • Increases appetite
    • Used for AIDS patients
  • Trazodone (Oleptro®)
    • Weak SSRI-like effect
    • Sedating (used for insomnia)
    • Low incidence of cardiovascular side effects
    • Can cause priapism
  • Vilazodone (Viibryd®)
    • serotonin uptake inhibitor and also a partial agonist of the 5-HT1A receptor
    • recently approved antidepressant
  • Vortioxetine (Brintellix®)
    • newest drug approved to treat MDD
    • Has a SSRI-like action in addition to 5-HT1A agonist and 5-HT3 antagonist activity



Pharmacologic Properties and Side Effects


Describe the cardiovascular side effects caused by TCAs:

  • Due to anticholinergic effects and increased NE concentrations
  • Palpitations, tachycardia and arrhythmias
  • EKG changes such as lengthened QRS intervals and flattened or inverted T-waves reflect a slowed conduction time and significant alterations in the electrophysiology of the heart


  • What are the symptoms of TCA overdose?
  • How is treated?

  • Symptoms include:
    • hyperpyrexia
    • changes in blood pressure
    • seizures
    • coma
    • cardiac conduction defects
  • Treatment is symptomatic
    • Observe for at least 3 days because of long half-lives


How do TCAs potentially affect other drugs?

  • Guanethidine - blocks guanethidine uptake
  • Sympathomimetic drugs - particularly indirect acting agents
  • Effects absorption and metabolism of other drugs


What are the therapeutic uses of TCAs?

  • Major depressive disorder
  • Enuresis in childhood - imipramine
  • Chronic pain - amitriptyline
  • OCD – clomipramine and SSRIs



Pharmacological Effects and Toxicity

  • Antidepressant action takes about 2 weeks
  • Actions in depressed patients:
    • Produces mood elevation  
      • May progress to hypomania particularly in bipolar disease
    • Corrects sleep disorders 
      • May produce stimulation in normals
  • Lowers blood pressure
    • often produces orthostatic hypotension.
  • Acute toxicity
    • agitation, hallucinations, hyperpyrexia, convulsions and changes in blood pressure


How do MAOIs affect the metabolism of tyramine?

  • Due to MAO inhibtion in the liver, tyramine metabolism is also inhibited  
  • Leads to increased levels of tyramine


What foods are high in tyramine and may be contraindicated with MAOI use?

wine and cheese


What are the theapeutic uses of MAOIs?

  • Major depression -- not drug of first choice
  • Narcolepsy


What else can be used if antidepressants drugs are ineffective alone?

  • Augmentation with antipsychotic agents
  • Approved drugs for treatment resistant major depressive disorder include:
    • Olanzapine (Zyprexa®)
    • Aripiprazole (Abilify®)
    • Quetiapine (Seroquel®)
  • Ketamine –experimental treatment
  • Physiological treatments
    • ECT (Electroconvulsive therapy)
    • TMS (Transcranial Magnetic Stimulation)
    • (Experimental) Deep Brain Stimulation


St. John's Wort

  • What does it contain? 
  • What is its mechanism of action? 
  • ??? What is its best efficacy? 
  • What are the drug interactions? 

  • Hypericum perforatum
    • Contains hypericin
  • MAOI activity
  • Evidence of efficacy??? Better evidence for ffects on mild depression than more serious forms
  • Drug interactions - Increases 3A4 expression
    • Lowers effectiveness of:
      • Birth control pills
      • Protease inhibitors used in AIDs
      • Cyclosporine