Antidepressants
Psychoanaleptics
Mood Elevators
Sanjaya Mani Dixit
Assistant Prof of Pharmacology

Depression
• 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
neurotransmitters:
• 5-HT and
• NA.

Amine Hypothesis
• 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
transmission
(Antidepressants  Amine by means of reuptake and
metabolism)
• Conclusion: Major model for the subsequent
antidepressants, except Buproprion.

Biogenic Theory of Depression
• The precise cause of affective disorders
remains elusive.
• Evidence implicates alterations in the firing
patterns of a subset of biogenic amines in
the CNS,
• Norepinephrine (NE) and
• Serotonin (5-HT).
 Activity of NE and 5 -HT systems?.

MAO
COMT
Amine neurotransmitters are
either degraded (metabolized)
or re-uptaken
Mito

Information integration
cognition, thought,
mood, emotion
Cerebral cortex
Sensory input Motor output
acetylcholine norepinephrine
serotonin dopamine histamine
Information integration
cognition, thought,
mood, emotion
Cerebral cortex
Sensory input Motor output

NE System
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,
hypothalamus, thalamus).
• Mood: -- higher functions performed by the
cortex.
• 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.
 and  receptors.

A synapse that uses norepinephrine (NE)

Reuptake of NE
Monoamine oxidase, located on outer membrane
of mitochondria; deaminates catecholamines free in
nerve terminal that are not protected by vesicles
Selective inhibitor,
reboxetine Cocaine blocks the NE
Antidepressant
MAO Inhibitors
Stimulant

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
thinking.
– 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
NE NE
Mania Depression
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
depression.

Antidepressants
• Drugs which
elevate mood in
depressive illness
• Affect mono-
aminergic
transmission in
the brain in one
way or the other.

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;
Sertraline; Citalopram)
C) Drugs that Block Presynaptic α2- adrenoceptors
(e.g.: Mirtazapine, Mianserin).
D) Drugs that Inhibit Mono Amino Oxidase
(MAOIs, Phenelzine, Tranylcypraine,
Moclobemide)

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!!

TCAs
• Very effective but potentially
unacceptable side effect
profile i.e. antihistaminic,
anticholinergic,
antiadrenergic
• Lethal in overdose (even a one
week supply can be lethal!)
• Can cause QT lengthening
even at a therapeutic serum
level

Tricyclics
Amitryptyline
• Potent sedative
• Weight gain ++
• Anticholinergic ++
• Most researched
• 150mg / day
(Therapeutic in 95%
of adults)
Clomipramine
• Similar side effects
to amitryptyline.
• Said to be best for
obsessional
symptoms.
• 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
sleep disturbance
• Hypertensive crisis can develop when MAOI’s are
taken with tyramine-rich foods or
sympathomimetics.

SSRI
• First choice in
elderly.
• First choice if heart
disease.
• First choice if
suicide risk.
• More expensive.
Side effects
• Like TCA reduce
with time.
• Gut problems
predominate.
• Flat dose response
curve – so no need
to titrate dose
upwards.
?

Selective Serotonin Reuptake Inhibitors
(SSRIs)
• 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

Fluoxetine (Prozac)
• Pros
– 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
• Cons
– 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

Serotonin/Norepinephrine reuptake
inhibitors (SNRIs)
• Inhibit both serotonin and
noradrenergic reuptake
like the TCAS but without
the antihistamine,
antiadrenergic or
anticholinergic side effects
• Used for depression,
anxiety and possibly
neuropathic pain

www.medipuzzle.com
Trusted by
10K + Students

That’s All
ENJOY
24