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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

Anti-Depressant Medications

Brian Ladds, M.D.


  • Earliest meds:

    • MAOI

    • TCA

  • Neurotransmitter emphasized: NOR

  • More recent meds:

    • SSRI

  • Neurotransmitter emphasized: SE

Discovery of anti depressants
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

Monoamines and depression
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.


  • 3 principal types of neurotransmitters

    • monoamine neurotransmitters (MA)

    • amino acid neurotransmitters

    • neuropeptide neurotransmitters

Monoamine neurotransmitters
Monoamine Neurotransmitters

  • Catecholamines

    • dopamine

    • norepinephrine

      • tyrosine hydroxylase enzyme

        • synthesizes l-dopa from tyrosine

        • rate-limiting step (usually saturated )

  • Serotonin

  • Acetylcholine

  • (Histamine)

Monoamine neurotransmitters1
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

Monoamine neurotransmitters2
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.

Norepinephrine pathways
Norepinephrine Pathways

  • Locus coeruleus in pons

  • -> inervation to the forebrain

Life cycle of the monoamine neurotransmitters
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

Monoamine neurotransmitters inactivation
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

Monoamine oxidase enzyme
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

Mao inhibitors maoi
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

Maoi side effects
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

Maoi side effects1
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

Tri cyclic anti depressants
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

Anti depressants efficacy
Anti-Depressants: Efficacy

  • 2/3 respond

  • Not a euphoriant or stimulant among people who are not depressed

Anti depressants time course
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

A theory of down regulation
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.

Tri cyclic anti depressants side effects
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

Anti cholinergic side effects
Anti-cholinergic Side Effects

  • Blurred vision

  • Urinary retention

  • Constipation

  • Dry mouth

  • (Confusion)

Tca and risk of overdose
TCA and Risk of Overdose

  • Can be fatal in overdose

Tri cyclic anti depressants1
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


  • 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)

Serotonin pathways
Serotonin Pathways

  • Serotonin

    • several nuclei in the dorsal raphe in the mid-brain

    • projects to striatum, hypothalamus, and neo-cortex

Inactivation of serotonin
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)


  • “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

Serotonin receptors
Serotonin Receptors

  • Serotonin receptors (~ 13)

    • 5HT-1

    • 5HT-2

    • 5HT-3

Ssri side effects
SSRI: Side Effects

  • GI upset

  • weight loss

  • insomnia, jitteriness

  • sexual dysfunction (less libido, ED)

Other anti depressants
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

Uses of anti depressants
Uses of Anti-Depressants

  • Depression

    • Dysthymia ?

  • Anxiety Disorders

    • Panic Disorder

    • OCD

  • Eating disorders

  • Pain

  • PTSD