anti-depressant medications
DESCRIPTION
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: - PowerPoint PPT PresentationTRANSCRIPT
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:
• 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
• 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.
Neurotransmitters
• 3 principal types of neurotransmitters – monoamine neurotransmitters (MA)– amino acid neurotransmitters– neuropeptide neurotransmitters
Monoamine Neurotransmitters• Catecholamines
– dopamine– norepinephrine
• tyrosine hydroxylase enzyme– synthesizes l-dopa from tyrosine
– rate-limiting step (usually saturated )
• Serotonin• Acetylcholine• (Histamine)
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 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.
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
• 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 (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)
• 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
• 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 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 (TCA):
• Block re-uptake of monoamines, especially NE (and some block to a lesser extent SE)– the therapeutic mechanism of action
Anti-Depressants: Efficacy
• 2/3 respond
• Not a euphoriant or stimulant among people who are not depressed
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
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
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
• Blurred vision
• Urinary retention
• Constipation
• Dry mouth
• (Confusion)
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
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)
Serotonin Pathways
• Serotonin– several nuclei in the dorsal raphe in the mid-
brain – projects to striatum, hypothalamus, and neo-
cortex
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)
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
SSRI: Side Effects
• GI upset
• weight loss
• insomnia, jitteriness
• sexual dysfunction (less libido, ED)
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