Prescribing Sertraline: Why Pharmacogenomics Matters

What Makes Sertraline Different From Other SSRIs?

For general practitioners, psychiatrists, and other prescribers, sertraline remains one of the most frequently chosen SSRIs. Its dual serotonergic and mild dopaminergic action makes it a versatile option across different presentations of depression and anxiety. Yet response to sertraline is highly variable, and side effects can range from mild to clinically significant.

Pharmacogenomics (PGx) offers a way to reduce this uncertainty. By understanding how genetic variants such as CYP2C19 and CYP2B6 influence sertraline metabolism, clinicians can move beyond trial-and-error prescribing and make more confident, evidence-based decisions from the outset.

Why Does Sertraline Make Some People Sleepy While Activating Others?

The variability in response is partly explained by pharmacogenomics. At lower doses, sertraline may feel more activating due to its dopaminergic action. As doses increase, particularly beyond 100 mg, some patients experience sedation or fatigue. Pharmacogenes such as CYP2C19 and CYP2B6 influence the speed of metabolism, helping to explain these different clinical presentations.

How Do CYP2C19 and CYP2B6 Affect Sertraline Metabolism?

The liver uses enzymes—coded by genes—to break down medications. For sertraline, two key players are CYP2C19 and CYP2B6. Variations in these genes change how the body processes the drug:

• CYP2C19 Poor Metabolisers (PMs): Break down sertraline too slowly. This can lead to higher blood concentrations, increasing the risk of side effects like nausea, sedation, or QT prolongation. Dose reductions or switching medicines may be recommended.

• CYP2C19 Ultra-Rapid Metabolisers (UMs): Break down sertraline so quickly that standard doses may not be effective. This can cause treatment failure because therapeutic levels are never reached. In these cases, a higher dose or a different antidepressant may be needed.

• CYP2B6 Variants: Also influence metabolism, though the evidence is less extensive than CYP2C19. They may play a role in side effect sensitivity and drug clearance.
  
  

What Happens if Your Patient Is an Ultra-Rapid Metaboliser of Sertraline?

If you patient carries a genetic variant that makes them an ultra-rapid metaboliser, their body clears sertraline too fast. Even at normal doses, they may never reach therapeutic levels. The practical result is that sertraline may feel like it “doesn’t work.” In this case, you could consider adjusting the dose upwards under careful supervision, or prescribing a different antidepressant that is less dependent on CYP2C19.

What Side Effects Should Clinicians Monitor in Patients Taking Sertraline?

Like all SSRIs, sertraline is associated with common adverse effects such as transient anxiety at initiation, gastrointestinal upset (especially diarrhoea), fatigue, or dry mouth. More clinically significant risks include:

• Serotonin Syndrome: Often due to drug or supplement interactions, presenting with agitation, tremor, fever, and confusion.
• QT Prolongation: A low but notable risk, particularly in poor metabolisers or patients taking other QT-prolonging agents.
• Hyponatraemia: More common in older adults or those on diuretics.

Pharmacogenomic testing can help identify patients more vulnerable to these complications, supporting safer prescribing.

Can Sertraline Interact With Supplements Or Other Medicines?

Although sertraline has fewer drug–drug interactions than some SSRIs, clinically important interactions remain. Supplements such as St John’s Wort and tryptophan increase serotonergic tone and heighten the risk of serotonin syndrome when combined with sertraline. Clinicians should routinely review concurrent supplement and medication use before initiating or adjusting therapy.

What Is Pharmacogenomics And Why Is It Useful For Sertraline?

Pharmacogenomics (PGx) links genetic variation with drug response. For sertraline, CYP2C19 and CYP2B6 genotyping provides valuable information for dose optimisation and treatment selection. Instead of relying on trial-and-error, PGx results guide clinicians toward more precise prescribing, reducing adverse effects and the likelihood of treatment failure.

Which Other Antidepressants Are Affected By Pharmacogenes?

Sertraline is not alone in being influenced by pharmacogenetics. Other SSRIs such as citalopram and escitalopram are also heavily affected by CYP2C19. Tricyclic antidepressants like amitriptyline depend on both CYP2C19 and CYP2D6. By contrast, drugs with different metabolic pathways may be better choices if a patient’s genetic profile predicts poor response to sertraline.

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