Selective serotonin reuptake inhibitors

Definition and Overview
Selective serotonin reuptake inhibitors (SSRIs) are a class of antidepressants that act by inhibiting the reabsorption (reuptake) of serotonin (5-hydroxytryptamine or 5-HT) in the central nervous system (CNS), thereby increasing serotonin availability in the synaptic cleft. SSRIs exert their antidepressant, anxiolytic, and anti-obsessional effects by enhancing serotonergic neurotransmission at postsynaptic 5-HT receptors.

SSRIs are the first-line pharmacologic treatment for a range of psychiatric disorders due to their efficacy, relatively favorable side effect profile, and low toxicity in overdose compared to older antidepressants like tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs).

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Mechanism of Action

SSRIs selectively block the serotonin transporter (SERT) on presynaptic neurons, which is responsible for serotonin reuptake. This inhibition:

• Increases serotonin levels in the synaptic cleft

• Enhances 5-HT receptor activity

• Normalizes mood, anxiety, and obsessive-compulsive symptoms

Unlike tricyclics, SSRIs do not significantly inhibit norepinephrine or dopamine reuptake and do not block histaminergic, muscarinic, or adrenergic receptors, resulting in fewer anticholinergic and cardiovascular side effects.

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Common SSRIs and Brand Names

Generic Name	Brand Name(s)	Primary Indications
Fluoxetine	Prozac	MDD, OCD, bulimia, panic disorder
Sertraline	Zoloft	MDD, OCD, panic disorder, PTSD, SAD
Paroxetine	Paxil	MDD, GAD, PTSD, OCD, SAD, panic disorder
Citalopram	Celexa	MDD, anxiety
Escitalopram	Lexapro	MDD, GAD
Fluvoxamine	Luvox	OCD, SAD

Clinical Indications

Disorder	Preferred SSRI(s)
Major Depressive Disorder (MDD)	All SSRIs
Generalized Anxiety Disorder (GAD)	Escitalopram, Paroxetine
Obsessive-Compulsive Disorder (OCD)	Fluvoxamine, Fluoxetine, Sertraline
Panic Disorder	Sertraline, Paroxetine, Fluoxetine
Post-Traumatic Stress Disorder (PTSD)	Sertraline, Paroxetine
Social Anxiety Disorder (SAD)	Sertraline, Paroxetine, Fluvoxamine
Premenstrual Dysphoric Disorder (PMDD)	Fluoxetine, Sertraline
Bulimia Nervosa	Fluoxetine

Pharmacokinetics and Metabolism

Drug	Half-Life	Active Metabolite	Metabolism Pathway
Fluoxetine	~1–4 days; 7–15 days (metabolite)	Norfluoxetine	CYP2D6, CYP2C9
Sertraline	~26 hours	Yes	CYP2B6, CYP2C19, CYP3A4
Paroxetine	~21 hours	No	CYP2D6
Citalopram	~35 hours	Yes	CYP2C19, CYP3A4
Escitalopram	~27–32 hours	No	CYP2C19, CYP3A4
Fluvoxamine	~15–22 hours	No	CYP1A2, CYP2D6

Dosing Guidelines

Drug	Starting Dose	Target Dose Range
Fluoxetine	10–20 mg/day	20–60 mg/day
Sertraline	25–50 mg/day	50–200 mg/day
Paroxetine	10–20 mg/day	20–60 mg/day
Citalopram	10–20 mg/day	20–40 mg/day (max 20 mg if >60 yrs)
Escitalopram	5–10 mg/day	10–20 mg/day
Fluvoxamine	25–50 mg/day	100–300 mg/day

Adverse Effects

Systemic Effect	Common Reactions	Severe Reactions
Gastrointestinal	Nausea, diarrhea	GI bleeding (esp. with NSAIDs)
Neurological/Psychiatric	Headache, insomnia, agitation	Suicidal thoughts (esp. adolescents)
Sexual Dysfunction	↓ libido, delayed orgasm, anorgasmia	Persistent Sexual Arousal Syndrome (rare)
Weight	Variable (weight gain with paroxetine)
Cardiovascular	QT prolongation (especially citalopram)	Hyponatremia, orthostatic hypotension
Others	Sweating, tremor	Serotonin syndrome, SIADH

Drug Interactions

Interacting Agent	Effect and Mechanism	Affected SSRIs
MAOIs	Risk of serotonin syndrome	All (contraindicated within 14 days)
Triptans	↑ Serotonin syndrome risk	All
NSAIDs, Aspirin	↑ Bleeding risk	All
Warfarin	↑ INR and bleeding risk	All
CYP2D6 substrates	Paroxetine, fluoxetine inhibit metabolism	TCAs, antipsychotics, tamoxifen
Linezolid, methylene blue	↑ Serotonin syndrome risk	All
Alcohol	↑ CNS depression (especially fluoxetine)	All

Contraindications and Cautions

• Concomitant use of MAOIs or pimozide

• History of seizures

• Bipolar disorder – risk of manic switching

• QT prolongation – especially citalopram

• Elderly – risk of hyponatremia/SIADH

• Pregnancy Category C or D – paroxetine is associated with fetal cardiac risks

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Discontinuation Syndrome

Abrupt cessation of SSRIs may lead to:

• Dizziness

• Electric shock sensations

• Fatigue

• Flu-like symptoms

• Irritability

• Insomnia

Paroxetine and fluvoxamine are associated with the highest risk due to short half-life. Fluoxetine has the lowest risk due to its long half-life.

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Monitoring Parameters

• Suicidal ideation (especially in children and adolescents)

• Serum sodium levels in elderly

• ECG for QT interval (citalopram, escitalopram)

• Weight and appetite changes

• Liver function if clinical suspicion

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Comparison with Other Antidepressants

Class	Reuptake Targets	Sedation	Weight Gain	Sexual Dysfunction	Overdose Risk
SSRIs	Serotonin	Low–Mod	Low–Mod	Common	Low
SNRIs	Serotonin + NE	Low	Mod	Common	Low–Mod
TCAs	Serotonin + NE + H1	High	High	Common	High
MAOIs	All monoamines	Mod	Variable	Common	High
Atypicals	Variable	Low–High	Variable	Lower (e.g., bupropion)	Low

Special Populations

Group	Recommendations
Pediatrics	Use fluoxetine (only FDA-approved in children ≥8)
Geriatrics	Start low (e.g., citalopram max 20 mg)
Pregnancy	Avoid paroxetine; fluoxetine and sertraline safer options
Hepatic impairment	Dose reduction required
Renal impairment	Use cautiously with monitoring

Black Box Warning (All SSRIs)

Increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults (age <25) during the initial treatment period and dose changes.

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Clinical Pearls

• Fluoxetine has the longest half-life and is self-tapering.

• Sertraline is well tolerated and widely used across anxiety disorders.

• Paroxetine is more sedating and anticholinergic; often avoided in the elderly.

• Citalopram carries a QTc warning, especially at doses >40 mg/day.

• Escitalopram is the S-enantiomer of citalopram, with cleaner profile.