• Depression is a chronic and
recurrent illness that can affect at
least 20% of the population at
some period in their lifetime.
• Associated with depletion of brain
• 5-HT and
• 1950: Reserpine Induce depression
• Study: Reserpine depletes storage of amine
neurotransmitters such as serotonin and norepinephrine
• Break-through: MAOI and TCA
• Then: Depression Amine-dependent synaptic
(Antidepressants Amine by means of reuptake and
• Conclusion: Major model for the subsequent
antidepressants, except Buproprion.
Biogenic Theory of Depression
• The precise cause of affective disorders
• Evidence implicates alterations in the firing
patterns of a subset of biogenic amines in
• Norepinephrine (NE) and
• Serotonin (5-HT).
Activity of NE and 5 -HT systems?.
Sensory input Motor output
serotonin dopamine histamine
Sensory input Motor output
Almost all NE pathways in the brain originate from the cell
bodies of neuronal cells in the locus coereleus in the
midbrain, which send their axons diffusely to the cortex,
cerebellum and limbic areas (hippocampus, amygdala,
• Mood: -- higher functions performed by the
• Cognitive function: -- function of cortex.
• Drive and motivation: -- function of brainstem
• Memory and emotion: -- function of the
hippocampus and amygdala.
• Endocrine response: -- function of hypothalamus.
Reuptake of NE
Monoamine oxidase, located on outer membrane
of mitochondria; deaminates catecholamines free in
nerve terminal that are not protected by vesicles
reboxetine Cocaine blocks the NE
Symptoms of Depression
• Highly recognizable, both to those affected and to those closest
to them, once they are told what to look for.
• Here is a checklist of symptoms of Depressive illness:
– Loss of energy and interest.
– Diminished ability to enjoy oneself.
– Decreased -- or increased -- sleeping or appetite.
– Difficulty in concentrating; indecisiveness; slowed or fuzzy
– Exaggerated feelings of sadness, hopelessness, or anxiety.
– Feelings of worthlessness.
– Recurring thoughts about death and suicide.
– If most of these symptoms last for two weeks or more, one
probably has Depressive Illness. Sometimes depression alternates
with "mania" and is called Manic-Depressive Illness (Bipolar).
Biochemical Theory of Affective Disorders
Affective Disorders Serotonin
Rx Drugs that decrease NE Drugs that increase NE
What is the evidence to support this theory ?
Amphetamine and mania while Clonidine and methyldopa produce
Classification of Antidepressants Based on
Site of Action
A ) Drugs that Block the RE-uptake of NE and 5-
HT ( e.g.:Most tricyclics)
B) Drugs that Selectively Block Re-Uptake of 5-
HT (SSRIs) (Fluoxetine; Paroxetine;
C) Drugs that Block Presynaptic α2- adrenoceptors
(e.g.: Mirtazapine, Mianserin).
D) Drugs that Inhibit Mono Amino Oxidase
(MAOIs, Phenelzine, Tranylcypraine,
Mechanism of Action of Antidepressants
1) Inhibition of reuptake of NE and or 5-HT ?? or
increases the release of NE or 5-HT. ???
2) Desensitization (down-regulation) of β-
adrenoceptors (decrease c-AMP). (very important
and related to clinical response).
How do SSRIs desensitize β-adrenoceptors?
Hint: Remember Raphe nuclei!!
• Very effective but potentially
unacceptable side effect
profile i.e. antihistaminic,
• Lethal in overdose (even a one
week supply can be lethal!)
• Can cause QT lengthening
even at a therapeutic serum
• Potent sedative
• Weight gain ++
• Anticholinergic ++
• Most researched
• 150mg / day
(Therapeutic in 95%
• Similar side effects
• Said to be best for
• 150mg / day
Monoamine Oxidase Inhibitors (MAOIs)
• Bind irreversibly to monoamine oxidase thereby
preventing inactivation of biogenic amines such as
norepinephrine, dopamine and serotonin leading to
increased synaptic levels.
• Are very effective for depression
• Side effects include orthostatic hypotension, weight
gain, dry mouth, sedation, sexual dysfunction and
• Hypertensive crisis can develop when MAOI’s are
taken with tyramine-rich foods or
• First choice in
• First choice if heart
• First choice if
• More expensive.
• Like TCA reduce
• Gut problems
• Flat dose response
curve – so no need
to titrate dose
Selective Serotonin Reuptake Inhibitors
• Block the presynaptic serotonin reuptake
• Treat both anxiety and depressive sx
• Most common side effects include GI upset, sexual
dysfunction (30%+!), anxiety, restlessness,
nervousness, insomnia, fatigue or sedation, dizziness
• Very little risk of cardiotoxicity in overdose
• Can develop a discontinuation syndrome with
agitation, nausea, disequilibrium and dysphoria
– Long half-life so decreased incidence of discontinuation syndromes.
Good for pts with medication noncompliance issues
– Initially activating so may provide increased energy
– Secondary to long half life, can give one 20mg tab to taper someone
off SSRI when trying to prevent SSRI Discontinuation Syndrome
– Long half life and active metabolite may build up (e.g. not a good
choice in patients with hepatic illness)
– Significant P450 interactions so this may not be a good choice in pts
already on a number of meds
– Initial activation may increase anxiety and insomnia
– More likely to induce mania than some of the other SSRIs