Fluoxetine

Pharmacogenomic (PGx) testing can help predict how a patient is likely to respond to many antidepressants. However, fluoxetine is unique among SSRIs in that there are currently no formal pharmacogenetic prescribing guidelines for it (24). Its metabolism is distinct, and response is less tightly linked to known PGx variants.

Managing Drug and Supplement Interactions with Fluoxetine

Drug interactions remain a key concern—and fluoxetine is especially noteworthy here due to its very long half-life. In fact, its metabolite (norfluoxetine) is even more pharmacologically active than the original compound and can remain in the body for weeks after stopping treatment (29, 3). This makes fluoxetine particularly prone to delayed interactions, even after discontinuation.

Patients should inform their GP or pharmacist about any supplements or medications they’re taking—especially those that increase serotonin levels, such as:

• Tryptophan

• St. John’s Wort

Combining these with fluoxetine increases the risk of serotonin syndrome, a potentially life-threatening condition caused by excessive serotonin activity.

As with other SSRIs, fluoxetine may increase suicidal thoughts during the first four weeks of treatment (2, 10, 11), particularly in children, adolescents, and young adults. Patients and carers should be aware of this risk. These effects are typically temporary and diminish as treatment becomes established.

Fluoxetine Side Effects

SSRIs like fluoxetine are generally considered safe, but individual responses vary—sometimes significantly—due to genetic differences. Pharmacogenomic (PGx) testing can help identify people who are more likely to experience serious side effects such as serotonin syndrome, QT interval prolongation, or hyponatraemia.

While fluoxetine is often described as having a relatively favourable side effect profile, the evidence is mixed. Some sources suggest it has a more activating effect, leading to anxiety, restlessness, or increased motor activity—while others report the opposite (3, 14, 28). This inconsistency reflects both individual variability and the context-dependent nature of SSRI treatment.

Compared to other SSRIs, fluoxetine is more commonly associated with:

• Gastrointestinal side effects – such as nausea, vomiting, and diarrhoea

• Weight loss – which may be helpful or problematic, depending on the patient (3, 28)

Serotonin Syndrome

Serotonin syndrome (5) is a potentially life-threatening condition that results from excess serotonin activity, often due to drug interactions or combining serotonergic agents.

Symptoms can develop rapidly:

• In 30% of cases, symptoms start within 1 hour

• In 60%, onset occurs within 6 hours

Fluoxetine is particularly risky in this regard due to its long half-life and its active metabolite, norfluoxetine, which remains in the body even longer. As a result, interactions can occur days or even weeks after discontinuation—and in some cases, have led to severe or even fatal serotonin syndrome (29).

Symptoms include:

• Mental state: Agitation, confusion, anxiety, hypomania, hypervigilance, seizures, coma

• Neuromuscular effects: Tremors, poor coordination, myoclonus (rhythmic muscle twitches)

• Autonomic signs: Sweating, tachycardia, diarrhoea, fever, hyperthermia (>40°C)

You do not need all symptoms to be diagnosed. While it can be mild, serotonin syndrome should always be treated as a medical emergency.

Prolonged QT Interval

Fluoxetine is associated with QT interval prolongation (2, 3), which can increase the risk of cardiac arrhythmias. Symptoms may include:

• Palpitations

• Light-headedness

• Fainting or near-fainting

• Seizures (in some cases)

Risk factors for QT prolongation include (7):

• Female sex

• Older age

• Use of multiple QT-prolonging drugs

• Electrolyte imbalances (low potassium, magnesium, calcium)

• Diuretic use

• Liver or kidney dysfunction

• Bradycardia

• Genetic predispositions (e.g. long QT syndrome)

• Existing heart disease (e.g. heart failure, LV hypertrophy, MI)

• Digitalis therapy

If any symptoms of QT prolongation occur, patients should seek immediate medical attention.

Hyponatraemia

Hyponatraemia (8) is a potentially dangerous drop in blood sodium levels that can occur with SSRI use, including fluoxetine. Its severity and rate of onset determine the type and intensity of symptoms.

• Severe cases: Brain swelling, vomiting, altered consciousness, coma

• Moderate cases: Mood changes, disorientation, fatigue

• Mild cases: May still require urgent treatment to prevent deterioration

This condition is especially relevant in older adults and those on diuretics.

While fluoxetine’s complex metabolism means there are no formal PGx-based dosing guidelines, CYP2D6 genotype may still influence clinical response. According to current guidance (24):

“For CYP2D6 ultrarapid and poor metabolisers, it may be reasonable to monitor these patients more closely if they are prescribed fluoxetine, or to select an alternative SSRI not extensively metabolised by CYP2D6, due to conflicting/inconclusive data describing how CYP2D6 status influences fluoxetine therapy.”

This doesn’t mean PGx testing can’t help—it simply means that for fluoxetine, testing is better used to inform clinical judgment rather than to dictate a specific dose. In some cases, an alternative SSRI with more predictable pharmacogenetic behaviour may be a better fit.

Related Medications:

Pharmacogenetic considerations and metabolic pathways may also apply to other antidepressants, especially those affected by CYP2D6 and CYP2C19, including:

• Escitalopram – influenced by CYP2C19

• Sertraline – affected by both CYP2C19 and CYP2D6

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

• Paroxetine – primarily influenced by CYP2D6