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:

• 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.

Norepinephrine Pathways

• Locus coeruleus in pons

• -> inervation to the forebrain

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)

TCA and Risk of Overdose

• Can be fatal in overdose

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

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

Serotonin Receptors

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

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

Uses of Anti-Depressants

• Depression– Dysthymia ?

• Anxiety Disorders– Panic Disorder– OCD

• Eating disorders• Pain• PTSD