SSRIs are the first-line treatment for depression. They work by selectively inhibiting the reuptake of serotonin, increasing levels in the brain. Compared to older antidepressants, SSRIs have fewer side effects and are safer due to their selectivity for serotonin over other neurotransmitters. Common side effects include sleep problems, headache, nausea, and sexual dysfunction. Risks include discontinuation syndrome upon abrupt withdrawal and serotonin syndrome if taken with other serotonergic drugs. SSRIs are effective for several other disorders involving serotonin imbalance like anxiety disorders.

2. Selective Serotonin Reuptake Inhibitors
(SSRIs)
Contents:
 Introduction
 List of drugs
 Mechanism of action
 Advantage over TCAs1 and MAOIs2
 Indications
 Pharmacokinetics
 Adverse Drug Reactions (ADRs) / Side-effects
 Discontinuation Syndrome
 Serotonin Syndrome
1TCAs = Tri-cyclic Anti-depressants
2MAOIs = Monoamine Oxidase Inhibitors

3. Introduction
 SSRIs are the „drugs of choice‟ for treating
depression.
 Highly selective for serotonin transporter 
gives them advantage over other drugs of
this class.
 Fluoxetine is the prototype drug.

4. Drugs include:
Can = Citalopram
Effectively = Escitalopram
Form = Fluoxetine
Favorable = Fluvoxamine
Potentials of = Paroxetine
Serotonin = Sertraline

5. Mechanism of Action
 Primary aim in treatment of depression  balance
levels of neurotransmitters to boost mood.
 SSRIs act on serotonin transporter  block
reuptake of serotonin in pre-synaptic neuron 
more serotonin persists in the synaptic cleft 
more post-synaptic neuronal activities.
 Balancing of serotonin seems to help brain cells
send and receive chemical messages, which in
turn boosts mood.
 Very selective for serotonin transporter  300- to
3000-fold more selective for serotonin than for nor-
epinephrine transporter.

6. Advantage over TCAs and MAOIs
 TCAs and MAOIs  affect re-uptake of serotonin
as well as nor-epinephrine.
 Also have blocking activity at muscarinic, α-
adrenergic, histaminic H1 receptors.
 SSRIs  very selective for serotonin  don‟t
exhibit antagonist activity at any other receptors.
 Hence side effects associated with TCAs and
MAOIs like orthostatic hypotension, sedation, dry
mouth, blurred vision not seen with SSRIs
 Fewer side effects, relatively safer in overdose and
equally effective as TCAs
 Acquired status of first line treatment for
depression.

7. Indications
 Primary indication: Depression
 Others:
Panic Disorder
 Generalized Anxiety Disorder
 Post-traumatic Stress Disorder
 Social Anxiety Disorder
 Bulimia Nervosa (only Fluoxetine)
 Obsessive – compulsive disorder
 How?  imbalance in the level of
neurotransmitters activates the „alarm-system‟ of
brain  anxiety, obsessive-compulsive disorder etc
 SSRIs balance the amount of neurotransmitter.

8. Pharmacokinetics
 Well-absorbed after oral administration  Fluoxetine
also available as sustained-release preparation.
 Max. bioavailability in 2-8 hours and average half-lives
of 16-36 hours.
 Fluoxetine  longest half-life  50 hours, it‟s
metabolite (nor-fluoxetine)  10 days half-life.
 Metabolized by cytochrome P450 enzyme system.
 Enzyme-drug interactions: Inhibit various iso-enzymes
of CYP450 system (e.g. CYP2D6)  hence, decreases
metabolism of drugs like TCAs, neuroleptic
drugs, antiarrhythmic, beta-adrenergic antagonist
drugs.
 Excretion: Urine. Sertaline and Paroxetine  Also fecal
excretion.

9. Side-effects
 Sleep disturbances: Paroxetine and Fluvoxamine
 sedating.
Fluoxetine and Sertraline  more activating.
 Suicidal tendencies in children and teenagers.
 Headache, sweating, anxiety, agitation, weakness,
fatigue, changes in weight.
 GIT disturbances: nausea, vomiting, diarrhea
 Overdose: Tendency to cause Seizures
 How? by reducing seizure threshold.

10. Discontinuation Syndrome
 Occurs on abrupt withdrawal of SSRIs.
 Symptoms include: headache, malaise,
agitation, irritability, flu-like symptoms,
nervousness, changes in sleep pattern.
 Agents with short half-lives, inactive
metabolites  abrupt washout  higher
risk.
 So, Fluoxetine  lowest risk for
discontinuation syndrome.

11. Serotonin Syndrome
 “Excess of everything is harmful”
 Administration of an SSRI in presence of
another highly serotonergic drug such as
MAOI  life-threatening „serotonin
syndrome‟
 Excess of serotonin  changes in mental
status and vital signs, hyperthermia, muscle
rigidity, muscle twitching.
 Washout period of 2 weeks before
administration of an MAOI (6 weeks for
Fluoxetine)