1. Amine hypothesis of Depression and Mania
    • Mood disorders are related to alterations in levels of SER and NE
    • *Low levels = depression
    • *High levels = mania
  2. Therapeutic overview: Depression
    • TCA: most effective for pt severely dep
    • SSRIs: drug of choice for mod dep pts
    • Atypical antidep
    • MAOI: historically 1st to be used now limited due to side effects
  3. Therapeutic overview: Bipolar disorder
    • Lithium salts (carbonate and citrate)
    • Antidep(fluoxetine w/olanzapine)
    • Antipsychotics (risperidone, olanzapine, quetiapine)
    • Anticonvulsants (valproic acid, carbamazepine, lamotrigine)
  4. TCA: pharmacokinetics
    • orally active
    • readily absorbed, sm int
    • therapeutic effect req >2wks
    • highly lipid soluble- penetrates CNS
    • long 1/2 life - 5-40 hrs
    • high plasma protein binding
    • met by liver
    • elimated by kidneys
  5. TCA: side effects
    • LOTS
    • Major = CV: cardiac over + (tachycardia), slowing of A-V conductance
  6. SSRI
    • Most widely used, fewer side effects
    • *- of uptake achieved rapidly (w/in hrs); however mood improvement occurs after more than 2 wks b/c + neurogenesis
  7. SSRIs: Pharmacokinetics
    • orally active
    • readily absorbed, sm int
    • high 1st pass hepatic met
    • therapeutic effect req >2wks
    • Long 1/2 life (1-3 day)
    • high binding plasma proteins
    • Block several liver enzymes = drug interactions
    • eliminated by kidney
  8. SSRI: Side effects
    • Early: nausea, anxiety, sleep disturbance/insomnia
    • Late: anorexia, sexual dysfunction, induction of mania in pts w/bipolar
  9. SSRI: Drug interaction
    Block several liver P450 enzymes: TCA, neuroleptics (haloperidol), antiarrhythmics, some beta-adrenorec antag
  10. Atypical Drugs
    • Bupropion: - DA reuptake (bipolar)
    • Venlafaxine: - Ser and NE reuptake
    • Nefazodone: - Ser reuptake and 5-HT2 rec
    • Mirtazapine: inc NE and Ser release by blocking alpha-2 rec
  11. Atypical: side effects
    • headache, nausea, tinnitus, insomnia, nervousness
    • fewer than TCA, often combo w/TCA, similar TI as TCAs and SSRIs
  12. MAOIs = 3rd line
    limited due to severe and often unpredictable side effects
  13. MAOI: pharmacokinetics
    • oral
    • transdermal patch: selegiline
    • therapeutic effect req 2-4 wks
    • eliminated via kidney
    • blocks MAO IRREV: activity persists long after drug met and eliminated
  14. MAOI: Side effects
    • Lots, severe, unpredictable
    • *elevated tyramine (met by MAOI) will cause release of lg amts of catecholamines ->HTN, cardia arrhythmias, stroke, headache, nausea
  15. Lithium Salts
    • Drug of choice bipolar
    • onset several wks (3-4(
    • will substitute for Na and produce undesirable effects
    • very toxic - extremely low TI
  16. Lithium: pharmacokinetics
    • oral
    • rapid absorption from GI
    • soluble ion
    • peak plasma 2-4 hrs, 1/2 life 20-24 hrs
    • eliminated by kidney
    • reduced kidney function w/toxicity
  17. Lithium: side effects
    • CNS: tremors, mental confusion, convulsions, coma
    • CV: arrythmias
  18. Stimulants
    • Amphetamine and its derivatives: amphetamine, dextroamphetamine, methylphenidate
    • Tx: ADHD and Narcolepsy
    • MOA: act by inc release of DA and NE in brain
    • Numerouse side effects
    • Other drugs: atomoxetine (ADHD, not +), Modafinil (narcolepsy)
  19. Lithium Summary
    • alone or in combo w/antidep, neuroleptics and antiepileptics
    • EXTREMELY low TI
  20. MAOI Summary
    • THIRD LINE DRUG for dep in pt resistant to other antidep
    • inc presynaptic [MA] by blocking MAO
    • Phenelzine, tranycypromine, selegiline, transdermal
    • when combo w/SSRIs may lead to SER syndrome
    • Restrictions in diet: tyramine-free food (cheese-effect)
  21. Atypical Antidep: summary
    • Heterogenous group of drugs to tx dep
    • inc NE and 5HT synaptic transmission in brain
    • Therapeutic efficacy similar to TCA and SSRIs
    • Less toxic overall compared to TCA
    • Bupropion, mirtazapine, venlafaxin, nefazodone
  22. SSRIs: Summary
    • fewer side effects than TCA
    • Fluoxetine, citalopram, escitalopram, sertaline
  23. TCA: Summary
    • Bloock reuptake of SER and NE
    • Also block muscarinic, adrenergic, and HIS rec
    • Amitriptyline, imipramine, nortriptyline, amoxapine
    • Numerous side effects
  24. Amphetamine: Side effects
    • CNS: Euphoria, anxiety, vertigo, insomnia, confusion
    • *Paranoia, psychoses, suicidal/homicidal impulses
    • CV: Arrhythmias, HTN
    • GI: Nausea, Diarrhea
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