Anti-Depressant Medications

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Anti-Depressant Medications

• Brian Ladds, M.D.

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Outline

• Earliest meds
• MAOI
• TCA
• Neurotransmitter emphasized NOR
• More recent meds
• SSRI
• Neurotransmitter emphasized SE

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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

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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.

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Neurotransmitters

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

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Monoamine Neurotransmitters

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

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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

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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.

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Norepinephrine Pathways

• Locus coeruleus in pons
• -gt inervation to the forebrain

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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

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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

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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

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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

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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

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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 TCAs

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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

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Anti-Depressants Efficacy

• 2/3 respond
• Not a euphoriant or stimulant among people who
  are not depressed

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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

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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.

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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

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Anti-cholinergic Side Effects

• Blurred vision
• Urinary retention
• Constipation
• Dry mouth
• (Confusion)

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TCA and Risk of Overdose

• Can be fatal in overdose

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Tri-cyclic Anti-depressants

• Some TCAs 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

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Serotonin
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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)

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Serotonin Pathways

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

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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)

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SSRI

• Selective Serotonin Re-uptake Inhibitors
• probably as effective as TCA in most sub-types of
  depression
• most are structurally unrelated to TCAs
• minimal anti-cholinergic or cardio-vascular side
  effects
• safe in overdose

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Serotonin Receptors

• Serotonin receptors ( 13)
• 5HT-1
• 5HT-2
• 5HT-3

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SSRI Side Effects

• GI upset
• weight loss
• insomnia, jitteriness
• sexual dysfunction (less libido, ED)

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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

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Uses of Anti-Depressants

• Depression
• Dysthymia ?
• Anxiety Disorders
• Panic Disorder
• OCD
• Eating disorders
• Pain
• PTSD