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Anti-Depressant Medications

Anti-Depressant Medications. Brian Ladds, M.D. Outline. Earliest meds: MAOI TCA Neurotransmitter emphasized: NOR More recent meds: SSRI Neurotransmitter emphasized: SE. Discovery of Anti-Depressants. Historical Serendipity: An early anti-TB medication was noted incidentally to have:

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Anti-Depressant Medications

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  1. Anti-Depressant Medications Brian Ladds, M.D.

  2. Outline • Earliest meds: • MAOI • TCA • Neurotransmitter emphasized: NOR • More recent meds: • SSRI • Neurotransmitter emphasized: SE

  3. Discovery of Anti-Depressants • Historical Serendipity: • An early anti-TB medication was noted incidentally to have: • anti-depressant effects • and was found to inhibit MAO enzyme as one of its properties • Since making more monoamines available alleviated depression, perhaps the basis of depression is a deficiency of one or another monoamine in the brain

  4. Monoamines and Depression • For many decades the principal monoamine thought to be most relevant in depression was norepinephrine. • In the last decade, the role of another monoamine, serotonin, has also been emphasized.

  5. Neurotransmitters • 3 principal types of neurotransmitters • monoamine neurotransmitters (MA) • amino acid neurotransmitters • neuropeptide neurotransmitters

  6. Monoamine Neurotransmitters • Catecholamines • dopamine • norepinephrine • tyrosine hydroxylase enzyme • synthesizes l-dopa from tyrosine • rate-limiting step (usually saturated ) • Serotonin • Acetylcholine • (Histamine)

  7. Monoamine Neurotransmitters • Monoamine neurotransmitters comprise only a small percentage of neurons (vs. amino acid neurotransmitters), but: • Monoamines may regulate the balance of: • the excitatory actions of glutamate and the inhibitory actions of GABA • The receptor sites for the monoamine neurotransmitters are involved in many psychiatric disorders

  8. Monoamine Neurotransmitters • The neurons that produce monoamines originate in nuclei of the brainstem (or basal forebrain) and project widely to the cortex, where they release the neurotransmitters.

  9. Norepinephrine Pathways • Locus coeruleus in pons • -> inervation to the forebrain

  10. Life Cycle of the Monoamine Neurotransmitters • Synthesis: • from simple precursors (tyrosine, tryptophan, choline) • Storage: • stored in terminal pre-synaptic vesicles • Release: • into synaptic cleft • Site of Action: • act on post-synaptic receptors and elsewhere • Inactivation

  11. Monoamine Neurotransmitters: Inactivation • Inactivation: • primarily via re-uptake back into the pre-synaptic nerve terminal and then recycled • distinct “re-uptake transporters” (trans-membrane proteins) for: • dopamine vs. norepinephrine vs. serotonin • and also by degradation by intra-cellular (and extra-cellular) enzymes

  12. Monoamine Oxidase Enzyme • Monoamine oxidase (MAO) enzyme • on external membrane of mitochondria • catabolizes (or degrades) monoamines in the nerve terminal cytosol (unprotected by vesicles) • MAOA breaks down serotonin and norepi • MAOB breaks down dopamine

  13. MAO Inhibitors (MAOI) • Examples: phenelzine (Nardil) or tranylcypromine (Parnate) • Irreversibly inhibit MAO enzyme • Therefore takes 2 weeks after stopping the MAOI to replenish new MAO enzyme • Increase the availability of monoamines • such as norepinephrine and serotonin, which are thought to be decreased in depression

  14. MAOI: Side Effects • Tyramine Hypertensive Crises • tyramine: contained in aged cheese, smoked meats, certain wines • is sympathomimetic and causes release of norepi from sympathetic terminals, which in the presence of MAOI can cause acute hypertensive crises and stroke

  15. MAOI: Side Effects • Medication Interactions • hypertensive crises with sympathomimetic medications (as with tyramine) • hyperthermia, e.g. with meperidine (Demerol) (as in the case of Libby Zion) • Other side effects • as with TCA’s

  16. Tri-cyclic Anti-depressants • Tri-cyclic anti-depressants (TCA): • Block re-uptake of monoamines, especially NE (and some block to a lesser extent SE) • the therapeutic mechanism of action

  17. Anti-Depressants: Efficacy • 2/3 respond • Not a euphoriant or stimulant among people who are not depressed

  18. Anti-Depressants: Time Course • Time course: 2-4 weeks delay of therapeutic effect. • Possibly due in part to: • gene expression and the synthesis of new structures & synapses • down-regulation

  19. A Theory of Down-Regulation MAOI and TCA are thought to bring about an anti-depressant effect by: • making more norepinephrine available in the synaptic cleft, • thereby leading to the down-regulation of the post-synaptic adrenergic receptors • restoring them to their normal number and function.

  20. Tri-cyclic Anti-depressants: Side Effects TCA also block post-synaptic: • Histamine receptors • causing sedation, weight gain • Adrenergic receptors • causing hypotension, dizziness • Ach receptors • causing anti-cholinergic side effects

  21. Anti-cholinergic Side Effects • Blurred vision • Urinary retention • Constipation • Dry mouth • (Confusion)

  22. TCA and Risk of Overdose • Can be fatal in overdose

  23. Tri-cyclic Anti-depressants • Some TCA’s and their side effect profile: • Imipramine: one of the earliest, highly effective but many side effects • Desipramine: a metabolite of IMI, only blocks re-uptake of NE (not SE); it is the least anti-cholinergic TCA • Nortriptyline: least likely TCA to cause blood pressure changes • Others: amitriptyline, doxepin, amoxapine

  24. Serotonin

  25. Serotonin • 5-HT (Hydroxy-tryptamine) = Serotonin • synthesized from essential amino acid tryptophan • the rate-limiting enzyme not usually saturated • therefore increased levels of precursors cause increased synthesis of serotonin • (but dietary supplements of tryptophan not very effective AD and have had contaminants)

  26. Serotonin Pathways • Serotonin • several nuclei in the dorsal raphe in the mid-brain • projects to striatum, hypothalamus, and neo-cortex

  27. Inactivation of Serotonin • Inactivation via pre-synaptic re-uptake • This re-uptake transport process is inhibited by some anti-depressants • TCA: imipramine (non-selective) • SSRI: fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), citalopram (Celexa)

  28. SSRI • “Selective Serotonin Re-uptake Inhibitors” • probably as effective as TCA in most sub-types of depression • most are structurally unrelated to TCA’s • minimal anti-cholinergic or cardio-vascular side effects • safe in overdose

  29. Serotonin Receptors • Serotonin receptors (~ 13) • 5HT-1 • 5HT-2 • 5HT-3

  30. SSRI: Side Effects • GI upset • weight loss • insomnia, jitteriness • sexual dysfunction (less libido, ED)

  31. Other Anti-Depressants • There are many other anti-depressants, some with different mechanism of actions, or combinations of receptor effects and side effect profiles • mirtazapine (Remeron) • alpha-2 antagonist; also with 5HT-2, 5HT-3 and histamine antagonist properties • buproprion (Wellbutrin) • NE and DA reuptake inhibitor

  32. Uses of Anti-Depressants • Depression • Dysthymia ? • Anxiety Disorders • Panic Disorder • OCD • Eating disorders • Pain • PTSD

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