Citalopram

Indications

• FDA-approved only for major depressive disorder in adults, given once daily at 20-40 mg/day with or without food.
• Off-label but well supported for generalized anxiety disorder, panic disorder, and social anxiety disorder at the same dose range.
• Off-label for obsessive-compulsive disorder, though the QT ceiling prevents the high doses that OCD typically requires for response.
• Off-label for premenstrual dysphoric disorder, given either continuously or restricted to the luteal phase of each menstrual cycle.
• Off-label at 20-30 mg/day for agitation in Alzheimer disease, where the CitAD trial showed benefit offset by QT and cognitive effects.
• Not approved for any pediatric indication, so all use under age 18 is off-label and requires close suicidality monitoring.

Mechanism of action

• The most selective serotonin transporter inhibitor of the SSRIs, with essentially no affinity for norepinephrine or dopamine transporters.
• Racemic mixture of S-citalopram, which carries all the transporter activity, and R-citalopram, which is inactive and may blunt the S-enantiomer.
• Increased synaptic 5-HT gradually desensitizes 5-HT1A autoreceptors, restoring raphe firing over two to six weeks as symptoms improve.
• Mild histamine H1 antagonism explains the modest sedation seen at higher doses relative to fluoxetine or sertraline.
• Blocks the cardiac hERG potassium channel in a concentration-dependent way, which is the pharmacologic basis of its QT ceiling.

Pharmacokinetics

• Bioavailability is about 80 percent and is unaffected by food, with peak plasma concentrations reached roughly four hours after a dose.
• Half-life is about 35 hours, giving once-daily dosing and steady state at approximately one week after initiation or dose change.
• Metabolized by CYP2C19 and CYP3A4 with a minor CYP2D6 contribution; demethylcitalopram is far less potent and clinically unimportant.
• CYP2C19 poor metabolizers reach roughly double the plasma exposure, which is why their maximum dose is capped at 20 mg/day.
• Only a weak CYP2D6 inhibitor, so citalopram is one of the easiest antidepressants to combine with other psychotropic medication.

Dosing

• Start 20 mg PO once daily and increase to a maximum of 40 mg/day after no less than one week if response is inadequate.
• Doses above 40 mg/day are not recommended at any age because QT prolongation increases with concentration without added efficacy.
• Cap the dose at 20 mg/day in patients over 60 years, in hepatic impairment, in CYP2C19 poor metabolizers, and with any CYP2C19 inhibitor.
• Available as 10, 20, and 40 mg tablets and a 10 mg/5 mL oral solution, which is useful for slow tapers and for pediatric off-label use.
• No adjustment is required in mild to moderate renal impairment; use caution and consider slower titration if creatinine clearance is under 20 mL/min.
• Taper gradually over two to four weeks when stopping, since abrupt withdrawal causes dizziness, paresthesia, insomnia, and irritability.

Adverse effects

• Nausea, dry mouth, somnolence, insomnia, and increased sweating are the most common early effects and usually settle within two weeks.
• Sexual dysfunction affects roughly 30-40 percent of patients and includes reduced libido, delayed ejaculation, and anorgasmia.
• Dose-dependent QTc prolongation is the defining safety issue, with mean increases of about 8 msec at 20 mg/day and 19 msec at 60 mg/day.
• Torsades de pointes has been reported in overdose and with concurrent QT-prolonging drugs, hypokalemia, or hypomagnesemia.
• Hyponatremia from SIADH, increased bleeding on NSAIDs or anticoagulants, and treatment-emergent mania are the other prescribing-relevant risks.
• Weight change is close to neutral over the first year, less than paroxetine but slightly more than fluoxetine in comparative cohorts.

Monitoring

• Obtain a baseline ECG in patients with cardiac disease, bradycardia, electrolyte disturbance, or concurrent QT-prolonging drugs.
• Correct hypokalemia and hypomagnesemia before starting, and recheck electrolytes when adding diuretics or during any illness with vomiting.
• Monitor suicidality, activation, and agitation weekly for four weeks and after each dose change, with special attention under age 25.
• Check serum sodium at baseline and within two to four weeks in older adults, diuretic users, and anyone with new confusion or falls.
• Track response with PHQ-9 or GAD-7 every two to four weeks, recognizing that dose escalation beyond 40 mg/day is not an option.

Interactions

• Contraindicated with MAOIs and within 14 days of stopping one, and with linezolid or intravenous methylene blue.
• Any CYP2C19 inhibitor, including omeprazole, esomeprazole, fluconazole, fluvoxamine, and cimetidine, caps the dose at 20 mg/day.
• Avoid combining with amiodarone, sotalol, methadone, ondansetron, or antipsychotics that prolong QT unless an ECG is followed closely.
• Additive serotonin syndrome risk with triptans, tramadol, fentanyl, lithium, and St. John's wort; watch for clonus and hyperthermia.
• Increases bleeding risk with aspirin, NSAIDs, and anticoagulants through impaired platelet serotonin uptake.

Special populations

• No consistent teratogenic signal in pregnancy, though late-gestation exposure carries small risks of neonatal adaptation and pulmonary hypertension.
• Compatible with breastfeeding at a relative infant dose near 3 to 5 percent, higher than sertraline but generally considered acceptable.
• Not approved in pediatrics; escitalopram carries the pediatric approval and is preferred when a citalopram-family agent is wanted in youth.
• In patients over 60 the maximum dose is 20 mg/day, reflecting both reduced clearance and greater vulnerability to QT prolongation.
• Hepatic impairment also caps the dose at 20 mg/day, while renal impairment requires no change unless clearance falls below 20 mL/min.

Clinical pearls

• Hard ceiling: 40 mg/day, and 20 mg/day if over 60, hepatic impairment, or on a 2C19 inhibitor.
• Cleanest SSRI for interactions, so a good choice on complex medical regimens without QT risk.
• Omeprazole is the interaction people miss; it halves clearance and caps citalopram at 20 mg.