Paroxetine

Pharmacogenomic (PGx) testing can help predict how a patient is likely to respond to paroxetine, a widely used SSRI for depression and anxiety. Genetic variations in drug metabolism—especially involving the CYP2D6 enzyme—can significantly impact both efficacy and tolerability.

In particular, patients who are ultra-rapid metabolisers may clear the drug too quickly, leading to treatment failure (24). Identifying this in advance can support more personalised and effective prescribing.

Interactions with Other Medicines and Supplements

Paroxetine is the strongest serotonin reuptake inhibitor in its class, meaning it significantly increases serotonin levels (16). When combined with other substances that raise serotonin—such as St. John’s wort or tryptophan—the risk of serotonin syndrome increases (3).

In fact, paroxetine may carry a higher theoretical risk of triggering serotonin syndrome during such interactions compared to other SSRIs. Patients should always inform their GP or pharmacist if they are taking herbal remedies or supplements alongside antidepressants.

Paroxetine also acts as a very strong inhibitor of the CYP2D6 enzyme, which affects the breakdown of many other medicines. This can lead to unexpected drug interactions, including with beta-blockers, tamoxifen, and certain opioids. It is vital to inform your GP or specialist about all current medications before starting paroxetine.

Increased Suicidal Thoughts in Early Treatment

As with other SSRIs, paroxetine may increase suicidal thoughts during the first four weeks of treatment (2, 10, 11). This risk is particularly relevant in children, adolescents, and young adults, and both patients and carers should be made aware. In most cases, these symptoms are temporary and reduce as the medication begins to take effect. Regular monitoring and open communication are essential during this early phase.

Paroxetine Side Effects

SSRIs like paroxetine are generally considered safe, but genetic differences can make some people more vulnerable to certain side effects. Pharmacogenomic (PGx) testing can help identify patients at higher risk for serious reactions, such as serotonin syndrome, prolonged QT interval, or hyponatraemia. These complications—while rare—are more commonly associated with SSRIs than with older antidepressants and should be recognised early.

Antimuscarinic Effects: Similar to Tricyclics

Paroxetine is unique among SSRIs in that it has strong antimuscarinic activity, similar to older tricyclic antidepressants (TCAs) (16). This is due to its high binding affinity for muscarinic receptors, which can lead to symptoms such as:

• Weight gain
• Constipation
• Dry mouth (14, 16)

These side effects can be particularly problematic in older adults or those with pre-existing gastrointestinal or metabolic concerns.

Discontinuation Symptoms and Movement Issues

Because of its short half-life, paroxetine is cleared from the body relatively quickly. This increases the risk of withdrawal effects, especially if the medication is stopped suddenly. Patients may experience:

• Dystonia – involuntary muscle contractions
• Akathisia – restlessness and an inability to stay still (14)

Gradual dose reduction is strongly recommended to minimise these symptoms.

Serotonin Syndrome

Serotonin syndrome (5) is a potentially serious condition caused by excessive serotonin in the nervous system, often triggered by medication interactions or dose increases. Symptoms may include:

• 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

Symptoms can develop within 1 hour of starting a new medicine or within 6 hours in most cases. While some cases are mild, serotonin syndrome can be life-threatening and requires immediate medical attention.

Prolonged QT Interval

Although citalopram is most often associated with QT prolongation, paroxetine can also increase this risk—particularly in susceptible individuals. Symptoms may include:

• Palpitations
• Dizziness or fainting
• Light-headedness
• Seizures (in rare cases)

Risk factors for QT prolongation (7) include:

• Female sex
• Older age
• Multiple QT-prolonging medications
• Electrolyte imbalance (e.g. low potassium, magnesium, or calcium)
• Diuretic use
• Liver or kidney impairment
• Bradycardia
• Genetic predispositions (e.g. long QT syndrome)
• Heart disease or digitalis therapy

If any of these symptoms develop, patients should seek urgent medical care.

Hyponatraemia

Hyponatraemia (8) is a potentially dangerous drop in sodium levels that can occur with SSRIs, including paroxetine. It can cause a wide range of neurological and psychiatric symptoms, depending on its severity and speed of onset.

• Severe cases: May cause brain swelling, vomiting, confusion, coma, or even death
• Mild to moderate cases: May result in mood changes, disorientation, or behaviour changes

Even mild hyponatraemia requires timely medical attention to avoid complications.

Paroxetine’s metabolism is highly dependent on the CYP2D6 enzyme, meaning genetic variation in this pathway can strongly influence treatment outcomes.

• Poor metabolisers of CYP2D6 may accumulate paroxetine more rapidly, increasing the risk of side effects, including sedation, weight gain, and withdrawal symptoms.
• Ultrarapid metabolisers, on the other hand, may clear the drug too quickly—leading to subtherapeutic levels and ineffective treatment.

Pharmacogenomic (PGx) testing allows clinicians to identify these metaboliser types in advance, offering an opportunity to:

• Choose an alternative SSRI with more predictable metabolism
• Adjust the dose with greater precision
• Reduce the time spent trialling ineffective or poorly tolerated medications

This approach is particularly valuable in treatment-resistant depression, polypharmacy, and female patients, where paroxetine’s interaction with tamoxifen may affect cancer outcomes.

Related Medications:

Pharmacogenetic considerations and metabolic pathways also apply to other antidepressants, particularly those influenced by CYP2D6 or CYP2C19. These include:

• Escitalopram – influenced by CYP2C19
• Sertraline – affected by both CYP2C19 and CYP2D6 to a lesser extent
• Amitriptyline – a tricyclic antidepressant metabolised via both CYP2C19 and CYP2D6
• Citalopram – primarily influenced by CYP2C19

Pharmacogenomic testing helps determine which option may be most appropriate based on a patient’s metabolic profile—enabling safer, faster, and more effective treatment selection.