Mechanism of Action of SSRIs (Selective Serotonin Reuptake Inhibitors)

Mechanism of Action of SSRIs (Selective Serotonin Reuptake Inhibitors)

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Introduction

Selective Serotonin Reuptake Inhibitors (SSRIs) are first-line antidepressants commonly used in the treatment of major depressive disorder, generalized anxiety disorder, panic disorder, and other psychiatric conditions. They act by increasing the availability of serotonin (5-HT) in the synaptic cleft and are preferred for their favorable side effect profile compared to older antidepressants.

Common SSRIs include:

• Fluoxetine
• Sertraline
• Paroxetine
• Citalopram
• Escitalopram
• Fluvoxamine

SSRIs are heavily tested in exams like USMLE, NCLEX, GPAT, and NEET-PG.

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Stepwise Mechanism of Action of SSRIs

1. Presynaptic inhibition of serotonin reuptake
   SSRIs bind to and inhibit the serotonin transporter (SERT) on the presynaptic neuron.
2. Increased serotonin in synaptic cleft
   This inhibition leads to increased extracellular serotonin levels at serotonergic synapses.
3. Enhanced serotonin signaling
   The elevated 5-HT levels increase serotonergic neurotransmission, particularly in brain regions involved in mood regulation such as the prefrontal cortex and hippocampus.
4. Downregulation of post-synaptic 5-HT receptors
   Chronic SSRI use leads to adaptive receptor changes, including desensitization of certain post-synaptic serotonin receptors, which contributes to the delayed clinical response.
5. Mood stabilization and anxiolytic effect
   These changes collectively improve mood, reduce anxiety, and stabilize emotional response over 2–6 weeks.

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Pharmacokinetic Parameters of SSRIs

Drug	Half-life	Metabolism	CYP Interaction	Excretion
Fluoxetine	1–3 days (norfluoxetine ~7 days)	Hepatic (CYP2D6)	Strong CYP2D6 inhibitor	Renal + fecal
Sertraline	~26 hours	Hepatic (CYP2C19, CYP2B6)	Moderate	Renal + fecal
Paroxetine	~21 hours	Hepatic (CYP2D6)	Strong CYP2D6 inhibitor	Renal
Citalopram	~35 hours	Hepatic (CYP2C19)	Mild	Renal
Escitalopram	~27–32 hours	Hepatic (CYP2C19, CYP3A4)	Mild	Renal
Fluvoxamine	~15–22 hours	Hepatic (CYP1A2)	Strong CYP1A2 inhibitor	Renal

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Clinical Uses of SSRIs

• Major depressive disorder (MDD)
• Generalized anxiety disorder (GAD)
• Panic disorder
• Social anxiety disorder
• Obsessive-compulsive disorder (OCD)
• Premenstrual dysphoric disorder (PMDD)
• Post-traumatic stress disorder (PTSD)
• Bulimia nervosa (fluoxetine)
• Off-label uses: premature ejaculation, fibromyalgia

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Adverse Effects of SSRIs

• Gastrointestinal symptoms – nausea, diarrhea
• Sexual dysfunction – decreased libido, anorgasmia
• Weight changes – gain (paroxetine), loss (fluoxetine)
• Sleep disturbances – insomnia or drowsiness
• Initial anxiety/agitation
• Serotonin syndrome – when combined with other serotonergic agents
• Suicidal ideation – increased risk in adolescents (boxed warning)
• Withdrawal symptoms – especially with paroxetine (short half-life)

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Comparative Analysis: SSRIs vs TCAs

Feature	SSRIs	TCAs
Receptor selectivity	Highly selective for SERT	Non-selective (SERT + NET + others)
Side effect profile	Better tolerated	More anticholinergic effects
Lethal in overdose	Rare	Yes
Onset of action	2–4 weeks	2–4 weeks
Weight gain	Moderate	Common

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Practice MCQs

Q1. What is the primary target of SSRIs?
a. Norepinephrine transporter
b. Monoamine oxidase
c. Serotonin transporter ✅
d. GABA receptor

Q2. SSRIs increase serotonin by:
a. Inhibiting its synthesis
b. Enhancing receptor binding
c. Blocking its reuptake ✅
d. Stimulating its release

Q3. Which SSRI has the longest half-life?
a. Sertraline
b. Paroxetine
c. Fluoxetine ✅
d. Fluvoxamine

Q4. A major sexual side effect of SSRIs is:
a. Premature ejaculation
b. Increased libido
c. Anorgasmia ✅
d. Priapism

Q5. Which condition is fluoxetine specifically approved for besides depression?
a. PTSD
b. Bulimia nervosa ✅
c. ADHD
d. Schizophrenia

Q6. SSRIs are contraindicated with:
a. NSAIDs
b. Antacids
c. MAO inhibitors ✅
d. Beta-blockers

Q7. What causes serotonin syndrome?
a. SSRI overdose
b. SSRIs combined with other serotonergic drugs ✅
c. Abrupt SSRI discontinuation
d. Antipsychotic use

Q8. Which SSRI is most associated with withdrawal symptoms?
a. Escitalopram
b. Sertraline
c. Paroxetine ✅
d. Fluoxetine

Q9. SSRIs take how long to produce clinical benefit?
a. 24–48 hours
b. 1 week
c. 2–6 weeks ✅
d. Immediately

Q10. Which enzyme metabolizes fluoxetine?
a. CYP1A2
b. CYP2D6 ✅
c. CYP3A4
d. CYP2E1

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FAQs

Q1: Can SSRIs be used in children?
Yes, but with caution. Fluoxetine is FDA-approved for pediatric depression and OCD.

Q2: Do SSRIs work immediately?
No. Clinical effects typically appear after 2–4 weeks of regular dosing.

Q3: Can SSRIs cause withdrawal symptoms?
Yes. Abrupt discontinuation can cause dizziness, nausea, irritability, especially with short-acting SSRIs like paroxetine.

Q4: Are SSRIs addictive?
No. They are not habit-forming or addictive in the traditional sense.

Q5: Can SSRIs be combined with other antidepressants?
Generally avoided due to serotonin syndrome risk, especially with MAO inhibitors or other serotonergic agents.

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References

• KD Tripathi – Essentials of Medical Pharmacology
• Goodman & Gilman – The Pharmacological Basis of Therapeutics
• Review of Pharmacology – Sparsh Gupta
• FDA Labeling and Prescribing Info
• NCBI: https://www.ncbi.nlm.nih.gov/books/NBK538495/