Pharmacology of SSRIs

Introduction to Selective serotonin reuptake inhibitors (SSRIs):

Selective serotonin reuptake inhibitors (SSRIs) are a class of antidepressant drugs that specifically target the serotonin neurotransmitter system in the brain. They are commonly used to treat depression, anxiety disorders, and other mood disorders.

Classification of SSRIs:

Some examples of SSRIs include:

  • Fluoxetine (Prozac)
  • Sertraline (Zoloft)
  • Paroxetine (Paxil, Seroxat)
  • Citalopram (Celexa)
  • Escitalopram (Lexapro)
  • Fluvoxamine (Luvox)

Mechanism of Action:

SSRIs selectively inhibit the reuptake of serotonin (5-HT) at the presynaptic neuronal membrane, increasing serotonin concentration in the synaptic cleft. This enhanced presence of serotonin enhances neurotransmission and is responsible for the antidepressant effect.

Illustration: Imagine two adjacent neurons with a gap (synaptic cleft) between them. When serotonin is released from the first neuron (presynaptic) into the cleft, it usually gets taken back into the same neuron (reuptake). SSRIs block this reuptake, increasing serotonin in the cleft, which can then act on the second neuron (postsynaptic).

antidepressant drugs mechanism of Selective Serotonin Reuptake Inhibitors (SSRIs)



  • Most SSRIs are well-absorbed from the gastrointestinal tract.
  • Food might delay absorption but doesn’t significantly affect the extent of absorption.


  • SSRIs are widely distributed and bind extensively to plasma proteins.

Metabolism and Excretion:

  • Fluoxetine: Metabolized in the liver to its active metabolite, norfluoxetine. The half-life is 1-3 days for fluoxetine and 7-15 days for norfluoxetine. It’s primarily excreted in urine.
  • Sertraline: Metabolized in the liver with a half-life of about 26 hours. It’s excreted in both faeces and urine.
  • Paroxetine: Also metabolized in the liver with a half-life of about 21 hours. Most of it is excreted in the urine.
  • Citalopram: Hepatic metabolism involving CYP3A4 and CYP2C19, with a half-life of about 35 hours. It’s primarily excreted in the urine.
  • Escitalopram: Metabolized in the liver with a half-life of about 27-32 hours. It’s mainly excreted in the urine.
  • Fluvoxamine: Primarily metabolized by CYP1A2 with a half-life of 15-17 hours. Excreted largely in urine.

Pharmacological Actions on Organ Systems:

  • Central Nervous System (CNS): Elevation of mood, decreased anxiety, and improvement in sleep patterns.
  • Gastrointestinal System (GI): Can lead to nausea, diarrhea, or constipation due to increased serotonin in the gut.
  • Cardiovascular System: Fewer effects, but there can be a minor increase in heart rate and potential QT interval prolongation.

Therapeutic Uses:

  • Fluoxetine: Major depressive disorder, OCD, panic disorder, bulimia nervosa, PMDD.
  • Sertraline: Major depression, OCD, panic disorder, social anxiety disorder, PMDD.
  • Paroxetine: Depression, OCD, panic disorder, social anxiety disorder, generalized anxiety disorder, PTSD.
  • Citalopram: Major depressive disorder.
  • Escitalopram: Major depressive disorder, generalized anxiety disorder.
  • Fluvoxamine: OCD, social anxiety disorder.

Onset of Action:

  • Initial Effects: Some people might notice initial effects, often subtle, within the first week or two of treatment. These could be side effects or small changes in mood or energy.
  • Therapeutic Effects: Most people start noticing therapeutic benefits within 2-4 weeks. However, for some, especially those with severe symptoms, it might take longer.
  • Full Effects: The full therapeutic effects of SSRIs, in terms of maximum symptom relief, might not be evident until 6-8 weeks or even longer for some individuals.

The delayed onset of action for SSRIs is a characteristic that has puzzled researchers and clinicians for years. While the exact mechanism is not entirely understood, several theories have been proposed:

  1. Desensitization of Autoreceptors:
    When SSRIs are initiated, they immediately increase serotonin levels in the synaptic cleft. However, increased serotonin can stimulate presynaptic autoreceptors (specifically, 5-HT1A autoreceptors). When stimulated, these autoreceptors actually reduce the release of serotonin, acting as a negative feedback mechanism. Over time, with continued SSRI exposure, these autoreceptors become desensitized and less active, leading to an increased release of serotonin and the eventual therapeutic effects.
  2. Neuroplasticity and Neural Circuitry Changes:
    Chronic administration of SSRIs has been shown to promote neuroplasticity, including increased neurogenesis (the formation of new neurons) in certain parts of the brain, such as the hippocampus. This process takes time, and it’s theorized that these structural changes in the brain could contribute to the therapeutic effects of SSRIs. The remodeling of neural circuits might also play a role in the delayed therapeutic effects.
  3. Downregulation and Desensitization of Post-synaptic Receptors:
    Initially, the increase in serotonin might cause an overstimulation of post-synaptic serotonin receptors. Over time, however, some of these receptors might undergo downregulation (their numbers decrease) or desensitization (they become less responsive). This can lead to a more normalized and therapeutic response to serotonin.
  4. Influence on Other Neurotransmitter Systems:
    SSRIs primarily act on the serotonin system, but serotonin interacts with other neurotransmitter systems, including dopamine and norepinephrine. The modulation of these systems and their receptors might take time and could be a contributing factor to the delayed onset of therapeutic effects.

Side Effects:

  • Fluoxetine: Nausea, insomnia, anxiety, anorexia, sexual dysfunction.
  • Sertraline: Nausea, diarrhea, insomnia, sexual dysfunction.
  • Paroxetine: Drowsiness, dizziness, dry mouth, weight gain, sexual dysfunction.
  • Citalopram: Nausea, dry mouth, drowsiness, sweating, sexual dysfunction.
  • Escitalopram: Nausea, insomnia, fatigue, sexual dysfunction.
  • Fluvoxamine: Nausea, vomiting, upset stomach, diarrhea, dry mouth, drowsiness, dizziness.


  • General for all SSRIs: Concomitant use with MAO inhibitors due to risk of serotonin syndrome.Specific drugs:
  • Fluoxetine: Concomitant use with pimozide and thioridazine.
  • Paroxetine: Pregnancy (due to potential fetal heart defects).

Drug Interactions:

  • General for all SSRIs: Risk of serotonin syndrome with other serotonergic agents, increased bleeding risk with NSAIDs, warfarin, and other anticoagulants.Specific drugs:
  • Fluoxetine: Due to CYP2D6 inhibition – interactions with many drugs like some antipsychotics and beta-blockers.
  • Paroxetine: Strong CYP2D6 inhibitor – potential for many drug interactions.
  • Fluvoxamine: Interacts with drugs metabolized by CYP1A2 and CYP2C19, like theophylline, clozapine, and olanzapine.

Please note that this is a general overview of SSRIs and should not be used as a substitute for professional medical advice. Always consult a qualified healthcare provider for personalized information and guidance regarding medications.

Disclaimer: This article is for informational purposes only and should not be taken as medical advice. Always consult with a healthcare professional before making any decisions related to medication or treatment.

Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always seek the advice of a healthcare provider with any questions regarding a medical condition.

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