Sertraline

Pharmacogenomic (PGx) testing can help predict how a patient is likely to respond to sertraline. Genetic variations in drug metabolism may affect both how well the drug works and the likelihood of side effects. Understanding these differences allows for more personalised—and safer—prescribing decisions.

Sertraline May Be Better for Certain Types of Depression

In addition to its genetic considerations, sertraline’s effect on dopamine gives it a unique role in managing depression marked by low energy, low motivation, and reduced activity. It’s often a better choice when patients struggle to engage with daily tasks or feel emotionally flat.

However, sertraline may not be the best option for people experiencing depression with agitation, restlessness, or high levels of anxiety and motor activity (14, 15). In such cases, other SSRIs may be more suitable.

Sertraline, Depression, and Cardiovascular Health

Emerging research (17–21) highlights a strong link between cardiovascular events (such as heart attacks) and the onset of neuropsychiatric symptoms like depression or anxiety. This relationship is thought to be driven by complex mechanisms—anatomical, metabolic, and inflammatory.

SSRIs have been shown to reduce inflammatory markers, and this anti-inflammatory effect may partially explain their benefits in reducing stress-related cardiovascular outcomes (17–22).

Among SSRIs, sertraline plays a special role. It has a lower risk of drug–drug interactions and a favourable cardiovascular profile, making it a sensible choice in patients with heart disease or those taking multiple medications (13).

Increased Suicidal Thoughts in the First Four Weeks

Like all SSRIs, sertraline can temporarily increase suicidal thoughts, especially during the first four weeks of treatment (2, 10, 11). This effect is most commonly seen in children, adolescents, and young adults. Patients and carers should be made aware of this risk and know what to look out for.

These symptoms usually fade as the medication begins to take effect—and sertraline can be very effective once stabilised.

Caution with Supplements and Other Medicines

Although sertraline is less likely to interact with other prescription medications, it can still interact with supplements—particularly those that affect serotonin levels.

If your patient is taking supplements such as tryptophan or St. John’s wort, it’s important they speak with a pharmacist or GP. Combining these with sertraline can lead to serotonin syndrome, a potentially serious condition caused by dangerously high levels of serotonin in the body (3).

Sertraline Side Effects

Due to its unique action on dopamine signalling—alongside its serotonin-enhancing effects—sertraline has a more activating profile compared to other SSRIs. This may lead to side effects such as anxiety, particularly at the beginning of treatment or in sensitive individuals (14, 15).

At doses above 100mg per day, sertraline can block the sigma-1 receptor, which may increase drowsiness or fatigue—especially in people with a specific genetic variant in the hypocretin receptor gene (HCRTR2 G1246A) (15). This interaction illustrates how pharmacogenomic differences can directly influence side effect profiles.

Like all SSRIs, sertraline is generally safe, but genetic variation can increase the risk of rare but serious reactions. Pharmacogenomic (PGx) testing can help identify patients who are more susceptible to complications such as serotonin syndrome, prolonged QT interval, or hyponatremia—making treatment safer and more tailored to individual needs.

Serotonin Syndrome

Serotonin syndrome (5) is a potentially serious reaction that can begin quickly—within 1 hour of taking a new medicine or within 6 hours in most cases. It’s often triggered by medication interactions that raise serotonin levels too high.

Symptoms may affect:

• Brain function: Agitation, confusion, anxiety, hypomania, hypervigilance, seizures, or coma
• Muscle reflexes: Tremors, poor coordination, or rhythmic muscle twitching (myoclonus)
• Autonomic system: Sweating, rapid heartbeat, diarrhoea, fever, or body temperature above 40°C

You don’t need to have all these symptoms for a diagnosis. While some cases are mild, others can be life-threatening and require immediate medical attention.

Prolonged QT Interval

Although citalopram is most commonly associated with QT prolongation, sertraline also carries some risk—particularly in patients with additional risk factors or relevant genetic predispositions (2, 3).

Symptoms may include:

• Palpitations
• Dizziness or light-headedness
• Fainting or near-fainting
• Seizures in rare cases

Risk factors for prolonged QT interval (7) include:

• Female sex
• Older age
• Use of multiple QT-prolonging drugs
• Low electrolyte levels (e.g. potassium, magnesium, calcium)
• Diuretic use
• Liver or kidney dysfunction
• Slow heart rate (bradycardia)
• Undiagnosed genetic conditions (e.g. silent LQTS)
• Underlying heart disease
• Digitalis use

It’s worth stressing that **sertraline is among the SSRIs with the lowest cardiovascular risk, especially when compared to dose-dependent risks seen with citalopram. However, patients should still be aware of this possibility and seek urgent care if symptoms arise.

Hyponatremia

Hyponatremia (8) refers to abnormally low sodium levels in the blood—a recognised risk of SSRI treatment, including sertraline.

• Severe cases can lead to brain swelling, vomiting, coma, or death
• Moderate cases may cause confusion, mood changes, or cognitive problems
• Even mild cases should be treated promptly to avoid worsening symptoms

Older adults and those on diuretics are at higher risk.

Other Common Side Effects

In addition to rare but serious reactions, sertraline can cause common side effects that vary from person to person. These may include:

• Anxiety (particularly early in treatment)
• Diarrhoea
• Changes in appetite
• Joint pain
• Chronic fatigue
• Trouble concentrating
• Dry mouth

Sertraline is more frequently associated with diarrhoea than other SSRIs (16), which is particularly relevant for patients with conditions like irritable bowel syndrome (IBS) or other digestive sensitivities.

Pharmacogenomic testing may help explain why some individuals experience these side effects more acutely than others—and guide adjustments to treatment.

Sertraline is metabolised primarily by CYP2C19 and CYP2D6—two enzymes whose activity is governed by genetic variation (24). These differences can significantly affect how well the medication works and how likely a patient is to experience side effects.

• Poor metabolisers of CYP2C19 may process sertraline more slowly, leading to higher drug levels in the bloodstream. This can increase the risk of side effects such as QT prolongation or sedation.

• Ultra-rapid metabolisers may clear the drug too quickly, reducing its effectiveness before it has time to act.

Knowing a patient’s CYP2C19 status can help clinicians make safer, more effective prescribing decisions—either by adjusting the dose or choosing an alternative treatment.

Related Medications:

Pharmacogenomic factors affecting sertraline may also apply to several other antidepressants, especially those metabolised through CYP2C19 or CYP2D6. These include:

• Escitalopram – closely related to citalopram; also influenced by CYP2C19

• Amitriptyline – a tricyclic antidepressant affected by both CYP2C19 and CYP2D6

• Paroxetine – mainly metabolised by CYP2D6

• Citalopram – shares similar PGx markers with sertraline and is influenced strongly by CYP2C19

Pharmacogenomic testing can help clinicians determine which SSRI is best suited to each patient, rather than relying solely on symptom-based trial and error.