Antidepressants

Antidepressants Competency List:

• What are the symptoms of major depression?
• What is the monoamine hypothesis?
• What are the modes of action of the different antidepressants?
• Can you name examples of antidepressants from different drug
classes?
Clinical Indications

• Mood disorders
• Anxiety disorders
• Eating disorders
• Chronic pain
• Incontinence
Major and sub-classes

• Based on 3 physiological actions:

• 1. Reuptake inhibition
• 2. Enzyme inhibition
• 3. Receptor blockade
(Nash & Nutt, 2007).
Reuptake inhibitors

• Selective Serotonin Reuptake Inhibitors( SSRI)

• Tricyclic Antidepressants (TCAs)
• Selective Serotonin and Nor-Adrenaline Reuptake Inhibitors
(SNRI)
• Nor-adrenaline Reuptake Inhibitor (NARI)
Enzyme inhibitors

• The following antidepressant subclasses work by inhibiting the

action of enzymes:
• Reversible Inhibitors of Mono-Amine Oxidase type A (RIMA)
• Mono-Amine Oxidase Inhibitors (MAOI)
Receptor blockers

• Nor-adrenergic and Specific Serotonin Antidepressants (NaSSA)

work by blocking receptors.
Therapeutic effect
• Time lag of 2-4 weeks before antidepressant effect occurs.
• Side effects & improved sleep occur earlier (Suicide risk).
• 1st episode: Up to 1 year following recovery.
• Repeat episodes: Up to 3 years (Royal Australian and New Zealand College of
Psychiatrists Clinical Practice Guidelines Team for Depression, 2004).
 Stopping anti-d too early can lead to
Normal relapse

Mood

Depression requiring
treatment 2-4 weeks relief depression

1-3 weeks sex drive, self care, activity,

memory

1st week anxiety

sleep

Begin anti-
depressant
SSRIs available

• Citalopram
• Escitalopram
• Fluoxetine
• Fluvoxamine
• Paroxetine
• Sertraline
Indications SSRIs

• Mood disorders
• Anxiety disorders
Off label:
• Premature ejaculation
• Migraine headache,
• Diabetic neuropathy
• Fibromyalgia
SSRI’s Action

1.Normally serotonin,
a brain chemical is
released from a
nerve cell.
2.Serotonin is then
received by the next
nerve cell.
3.Some serotonin is
then reabsorbed into
the 1st nerve cell.
4.Not having enough serotonin may be
associated with depression & anxiety
disorders. SSRI’s block the re-absorption
of serotonin into the 1st nerve cell.
5.This blocking action results in an increased
amount of serotonin being available at the
next nerve cell.
SSRI’s block reuptake of serotonin into
presynaptic neurone
Neurotransmitter

Re-uptake pump Receptor

MAO
Dendrite
Axon

Synapse

Presynaptic storage vesicles

Common Side Effects: SSRI

Drug Daily Inso Sex Agit G.I.T Wt

range mg mnia Dysf. ation gain
SSRI's
Citalopram 20 - 40 ++ +++ + ++ 0
Fluoxetine 20 - 40 ++ +++ ++ ++ 0
Fluvoxamine 100 - 200 ++ +++ ++ ++ 0
Paroxetine 20 - 40 ++ +++ = ++ +
Sertraline 50 - 100 ++ +++ ++ ++ 0
Less common side effects

• Apathy
• Extrapyramidal side effects (EPSEs)
• Increased prolactin levels
• Serotonin syndrome
• Hyponatraemia
• Bruising and bleeding Increased risk of gastrointestinal
bleeding (Loke, Trivedi, & Singh, 2008).
Antidepressant discontinuation symptoms
• F = flu like symptoms
• I = insomnia
• N = nausea
• I = imbalance
• S = sensory disturbances
• H = hyperarousal (anxiety) (Gelenberg, 1998 cited in Carson, 2000, p. 432)
Advantages of SSRI’s

• Minimal cardiac toxicity

• Safe in overdose
• Mild side effects
• Non sedating
• SSRI’s reduce overall suicide rates in depressed patients
significantly more than tricyclic antidepressants. True or
False?
Tricyclic antidepressants:TCA’s

Axon
Dendrite

Dendrite

! Tricyclics block reuptake of noradrenaline & serotonin into

presynaptic neurone.
Indications

• Mood disorders
• OCD
• Panic disorder
• Neuralgia (nerve pain) - best available evidence is for
amitriptyline (Saarto & Wiffen, 2007)
• Nocturnal enuresis
TCA Action: 4 actions

1. Block presynaptic noradrenaline reuptake pump

(black lines).
2. Block the presynaptic serotonin reuptake pump (red
lines).
3. Block histamine receptors (yellow square) = Sedative
side effects.
4. Block post synaptic acetylcholine receptors (grey
square) = Dry mouth, confusion, memory
impairments, blurred vision.
! This blocking action results in an increased amount of
nor-epinephrine & serotonin being available to the
post synaptic neuron.
Side Effects: TCA’s Common

• Sedation (give dose at

night)
• Dry mouth
• Blurred vision
• Weight gain
• Constipation
• Sweating.
TCA S/E. 

Less common but important
• postural hypotension
• urinary retention
• sexual dysfunction
• raised intra-ocular
pressure.
 Side Effects: TCA’s
• Cardio-vascular effects in people with cardiac
disease.
• Impaired Cognitive function in dementia.
• Precipitate a manic swing in bipolar.
• May be fatal in O/D. Admit ICU, cardiac monitor
Tetracyclics: Mianserin SE

• Common: as for TCA’s, plus vivid dreams.

• Less common: anti-cholinergic effects, plus jaundice,
neutropenia, agranulocytosis, effect glucose tolerance &
insulin levels
Tetracyclics: Mianserin SE

• Report sore throat & flu like

symptoms.
• Regular blood glucose tests.
• May be fatal in O/D
Selective Serotonin and Nor-
Adrenaline Reuptake Inhibitors (SNRI)
Venlafaxine
!Low doses inhibits serotonin
!Medium dose inhibits nor-adrenaline
!High dose inhibits dopamine
!Nor-adrenergic drugs tend to have alerting
and energising effects
!Wide therapeutic index – tolerability similar
to SSRIs
!Monitor for elevated blood pressure on high
doses
Nor-adrenaline Reuptake Inhibitor
(NARI)
• NARI available in Australia
• Reboxetine
• Reasonable tolerability – similar to TCAs
Enzyme inhibitors

!Mono-Amine Oxidase Inhibitors (MAOI) – The

first antidepressants discovered
!Alternative mechanism for increasing synaptic
availability of monoamines.
!MAOI & RIMA prevent intracellular destruction
of monamines by MAO
!MAOI’s are available
!Phenelzine
!Tranylcypromine
MAOI & RIMA prevent intracellular destruction
of monamines by MAO
Neurotransmitter

Re-uptake pump Receptor

MAO
Dendrite
Axon

Synapse

Presynaptic storage vesicles

Side Effects: MAOI’s

• Common: as for TCA’s, plus agitation/excess stimulation (do not

give dose after 3 p.m.)
• Rare but serious: Hypertensive crisis caused by ingesting
tryramine containing foods or a drug interaction (cough & cold
remedies, nasal drops & sprays, diet pills, pethidine).
Side Effects: MAOI’s

• Prevention: Follow MAOI diet. Check with Dr before using OTC

medication, notify Dr or dentist prior to anaesthetic.
• Potential for abuse (amphetamine like properties)
• Not well tolerated in > 65y
 MAOI: Diet
• Avoid tyramine containing foods (often in
foods requiring aging): banana peel
(banana flavouring), broad bean pods,
sauerkraut, matured cheeses, aged
meats, smoked or pickled fish, vegemite,
brewers yeast.
 MAOI: Diet

• Limited quantity: raspberries,

avocado, soy sauce,
commercial soups, coffee
substitutes, wine, port, beer,
chocolate.
Reversible Inhibitors of Mono-
Amine Oxidase type A (RIMA)
!RIMAs more selective than older MAOIs
!Do not cause serious dietary and drug
interactions (except at high doses).
!Have greater safety & tolerability compared
to MAOIs but are not as effective in treatment
resistant depression.
RIMA available in Australia
!Moclobemide - Not effective for OCD
Receptor blockers: Antagonists

!Noradrenergic and Specific Serotonergic

Antidepressant (NaSSA)
!Work by completely blocking (antagonist) the
serotonin and nor-adrenaline receptors,
preventing them from latching on to serotonin
and nor-adrenaline (thereby allowing the
neurotransmitters to build up).

!Example:
!Mirtazapine