ANTIDEPRESSANTS

BY DR MARY ONYANGO
Symptoms of Depression
• The symptoms of Depressive Illness are 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, you
probably have Depressive Illness. Sometimes depression
alternates with "mania" and is called Manic-
Depressive Illness (Bipolar).
 INTRODUCTION
• They are useful in the treatment of major
depressive disorders
• Other uses include
– Panic disorders
– Anxiety disorders
– Obsessive compulsive disorders
– Neuropathic pain
– Premenstrual dysphoric disorders
– Stress urinary incontinence
 Pathophysiology of depression
hypotheses
• Momoamine hypothesis
– Depression is related to deficiency in the amount or
function of cortical and limbic serotonin (5-HT),
nerepinephrine and dopamine
• Neurotrophic hypothesis
– Depression is associated with loss of neurotrophic
support ( deficiency of brain derived neurotrophic
factors)
• Depression is also associated with a number of
neuroendocrine abnormalities
 Cont.
• All these hypothesis are interrelated in various
important pathways
• All pay a role in the pathophysiology of
depression
 BIOLOGY OF DEPRESSION
• the “amine hypothesis” based on pharmacological studies
stated depression resulted from a lack of biogenic amines
(eg.; reserpine; antidepressants themselves).

• current theory favors the notion of a dysregulation of both NE

and 5-HT leading to alterations in NE and 5-HT receptors.

• antidepressants re-regulate receptor sensitivity.

• drug-induced re-regulation of the receptors takes weeks

(downregulation of some).
 SEROTONIN-A KEY PLAYER
 Serotonin has widespread distribution and density of innervation in CNS
(mood, memory, pleasure, aggression, hypothalamic control)

 Alterations of serotonin in depressed drug-free patients: The reduction point

of view

 decreased 5-HT levels in CSF

 increased amounts of 5-HT2 receptors in brain and platelets
 reduced levels of plasma tryptophan
 blunted neuroendocrine responses to the serotonin releasing drug
fenfluramine
 efficacy of SSRI’s in treating depression
 loss of SSRI efficacy with tryptophan depletion
 Increased presynaptic alpha-2 noradrenergic receptor sensitivity=greater
reduction in 5-HT release
 SEROTONIN--A KEY PLAYER
 The overactive point of view

 In some depressives CSF 5-HT is elevated

 Approx. 30% of depressed patients do not respond to SSRIs
 Depletion of 5-HT by inhibition of tryptophan hydroxylase (TH)
alleviates depressive symptoms in some patients
 Tianeptine, a 5-HT reuptake enhancer that works opposite to
SSRIs, is a marketed antidepressant
 A selective TH inhibitor shows activity in an animal model of
depression
 The activation of TH by stress can be blocked by Prozac
 Classes of antidepressant agents
1. Selective serotonin reuptake inhibitors
2. Serotonin and norepinephrine reuptake
inhibitors
1. SNRI
2. Tricyclic antidepressants (TCA)
3. 5-HT2 antagonists
3. Tetracyclic and unicyclic antidepressants
4. Monoamine oxidase inhibitors
 Selective serotonin reuptake inhibitors
(SSRIs)
• Examples
– Fluoxetine (prototype)
– Sertraline
– Citalopram
– Escitalopram (s – isomer of citalopram)
– Paroxetine
– fluvoxamine
 SSRIs
mechanism of action
• They inhibit the serotonin transporter on the
presynaptic membrane
• It binds to the site different from the site
where 5-HT binds to inhibit it
• 5-HT transport back to the presynaptic neuron
is inhibited
• Leads to increased serotonergic activity
 SSRIs
adverse effects
• Due to increased serotonergic effects
– Nausea
– GI upset
– Diarrhoea
– Reduced sexual function
– Headache, insomnia or hypersomnia
– Weight gain
– Sudden discontinuation syndrome
 Serotonin norepinephrine reuptake
inhibitors
1) SNRI (newer agents)
– Venlafaxine
– Desvenlafaxine (active metabilite)
– Duloxetine
– Milnacipram
• They are chemically unrelated
• Unlike TCA they do not have affinity for other
receptors e.g. muscarinic, adrenergic and
histamine
• Better tolerated than TCA
 SNRIs cont
mechanism of action
• Inhibit both SERT and the NET
• The binding to the transporters varry
• They increase both serotonergic and noradrenergic activities
• Adverse effects are due to excess serotonergic activity and
NE activity
– Raised BP
– Increased HR
– Insomnia
– Anxiety
– Agitation
– Hepatotoxicity with duloxetine
 2) TCA
• Imipramine
• Desipramine
• Amitriptylline
• Doxepin
• Clomipramine
• Trimipramine
• protriptylline
 TCA cont
• Inhibit both SERT and NET
• Has effects on other receptors e.g. muscarinic,
histamine and alpha adrenergic receptors
• Poorly tolerated
• Side effects due to
– Serotonergic effects
– NE effects
– Anticholinergic effects
• Dry mouth, constipation, urinary retention,
– Arrhythmias
– Sedation
– Weight gain
 TCA TOXICITIES
• a commonly used drug for suicide (less common with
increased use of SSRIs)

• lowers threshold for convulsions

• cardiac arrhythmias

• cardiac conduction defects

 3) 5-HT2 antagonists
• Include
– Trazodone
– Nafazodone
• Block the 5-HT 2A receptor in addition to inhibiting SERT and
NET
• Have antianxiety, antipsychotic and antidepressant effects
• Adverse effecte
– Sedation – trazodone
– GI effects
– Priapism- trazodone
– Ortostatic hypotension
– Hepatotoxicity - nafazodone
 Tetracyclic and unicyclic agents
• Bupropion- unicyclic
• Amoxapine
• Maproline
• Mirtazapine
– Heterogeneous group
– Act via different mechanisms
 Cont.
• Bupropion – mechanism is poorly understood
– Has an active metabolite
– Effect due to presynaptic release of catecholamines
– No effect on serotonin
– Modest inhibitor of NE and dopamine reuptake
• Mirtazapine- complex action
– Antagonise presynaptic alpha 2 autoreceptors
– Enhance release of both NE and 5-HT
– Potent H1 antagonist - sedation
 Cont..
• Amoxapine and maproline
– Potent NET inhibitor less SERT inhibition
– Anticholinergic effect
– Amoxapine has moderate inhibitory activity on the
D2 receptors
• This contributes to antipsychotic effect
 Monoamine oxidase inhibitors
– Phenelzine
– Isocarboxazid
– Tranylcypromine
– Moclobemide
– Selegiline
• Well absorbed orally
• Undergo extensive first pass metabolism
 MAO inhibitors cont.
• Increase the monamine contents
• The inhibit degradation
• Adverse effects
– Orthostatic hypotenson
– Weight gain
– Sexual dysfunction
– Insomnia and restlessness
– Sedation – phenelzine
– Confusion with high doses
– Sudden discontinuation syndrome
 Interractions
• MAOI’s enhance any indirectly acting
sympathomimetic.

• tyramine in certain foods is not metabolized in

presence of MAOI and potentiates catecholamine
release.

• ingredients in OTC cold preps can also lead to

markedly enhanced sympathomimetic effects.
 SEROTONIN SYNDROME
• A potentially fatal interaction when SSRI’s and
MAOI’s are combined
• Symptoms:
• autonomic instability (labile HR/BP)
• hyperthermia
• rigidity and myoclonus
• confusion,delirium
• seizures
• coma
Thank You