Citalopram (Celexa)
citalopram hydrobromide
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Major Depressive Disorder (MDD) | Adults | Monotherapy | FDA Approved |
Citalopram is FDA-approved solely for the treatment of major depressive disorder in adults. It is the racemic mixture of R- and S-citalopram; the S-enantiomer (escitalopram) is marketed separately as Lexapro. Despite its single approved indication, citalopram is one of the most commonly prescribed antidepressants globally and is included on the WHO Model List of Essential Medicines. It is not approved for paediatric use.
Panic disorder: Effective in multiple RCTs at 20–40 mg/day. Evidence quality: High.
Obsessive-compulsive disorder (OCD): Used at doses of 20–40 mg/day; limited by QT ceiling. Evidence quality: Moderate (RCTs with racemic citalopram).
Generalized anxiety disorder (GAD): Studied at 10–40 mg/day with positive results. Evidence quality: Moderate.
Alcohol use disorder: Used as adjunct to reduce alcohol consumption. Evidence quality: Moderate (RCTs with mixed results).
Premenstrual dysphoric disorder (PMDD): Evidence quality: Moderate.
Vasomotor symptoms (menopause): Evidence quality: Low–Moderate.
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Major depression — initial treatment | 20 mg once daily | 20–40 mg/day | 40 mg/day | Administer once daily, with or without food. Increase after ≥1 week if needed Doses >40 mg not recommended due to QT prolongation risk |
| Depression with comorbid anxiety | 10–20 mg once daily | 20–40 mg/day | 40 mg/day | Lower starting dose if anxiety or panic features predominate to minimise early jitteriness Screen for bipolar disorder before starting |
| Depression in patient on CYP2C19 inhibitor (e.g., omeprazole, cimetidine) | 20 mg once daily | 20 mg/day | 20 mg/day | Cimetidine increased citalopram AUC by 43% and Cmax by 39% Hard cap at 20 mg due to QT risk from elevated drug levels |
Special Population Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Patients >60 years of age | 20 mg once daily | 20 mg/day | 20 mg/day | AUC increased 23–30%, t½ increased 30–50% vs younger adults Higher QT risk; higher hyponatraemia risk |
| Hepatic impairment | 20 mg once daily | 20 mg/day | 20 mg/day | Oral clearance reduced 37%; t½ doubled Hard cap at 20 mg due to QT risk |
| CYP2C19 poor metabolisers | 20 mg once daily | 20 mg/day | 20 mg/day | Cmax +68%, AUC +107% compared to extensive metabolisers Pharmacogenomic testing can identify these patients |
| Mild–moderate renal impairment | 20 mg once daily | 20–40 mg/day | 40 mg/day | Oral clearance reduced by 17%; no dose adjustment required Limited data in severe renal impairment (CrCl <20 mL/min); use with caution |
Citalopram causes dose-dependent QTc prolongation. In a thorough QT study, the predicted QTcNi increase at 40 mg was 12.6 msec (upper bound 14.3 msec). At 60 mg (supratherapeutic), the increase was 18.5 msec (upper bound 21.0 msec). Cases of torsade de pointes, ventricular tachycardia, and sudden death have been reported in the postmarketing setting. Doses above 40 mg/day are not recommended for any patient. The maximum is further reduced to 20 mg/day in patients >60 years, those with hepatic impairment, CYP2C19 poor metabolisers, and those taking CYP2C19 inhibitors.
Pharmacology
Mechanism of Action
Citalopram is a racemic SSRI that exerts its antidepressant effect by selectively inhibiting neuronal reuptake of serotonin (5-HT) in the central nervous system. It is considered the most selective SSRI, having no clinically meaningful affinity for 5-HT1A, 5-HT2A, dopamine D1/D2, adrenergic (α1, α2, β), histamine H1, GABA, muscarinic cholinergic, or benzodiazepine receptors. The S-enantiomer (escitalopram) is primarily responsible for serotonin reuptake inhibition, while the R-enantiomer is essentially inactive at SERT. Citalopram’s metabolites (demethylcitalopram and didemethylcitalopram) are at least 8 times less potent than the parent compound and do not meaningfully contribute to its clinical effect. Citalopram is a weak inhibitor of CYP2D6 and CYP1A2, with minimal impact on most co-administered drugs metabolised by these pathways.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Bioavailability ~80%; Tmax ~4 h; absorption not affected by food; linear pharmacokinetics across 10–40 mg | Predictable dose-exposure relationship; can be taken with or without food at any time of day |
| Distribution | Vd ~12 L/kg; plasma protein binding ~80% for citalopram and metabolites | Moderate tissue distribution; lower protein binding than paroxetine or sertraline, reducing displacement interaction risk |
| Metabolism | Hepatic via CYP3A4 and CYP2C19 (primary N-demethylation); metabolites DCT (~50% parent levels at steady state), DDCT (~10%); metabolites ≥8× less potent; weak CYP2D6/CYP1A2 inhibitor | CYP2C19 poor metabolisers have >2-fold exposure increase (dose cap 20 mg); CYP2C19 inhibitors (e.g., cimetidine, omeprazole) require dose reduction; CYP2D6 status has no significant impact |
| Elimination | t½ ~35 h; systemic clearance 330 mL/min (~20% renal); ~10% excreted in urine as parent, ~5% as DCT; steady state in ~1 week; accumulation factor ~2.5× | Longer half-life than paroxetine or fluvoxamine — lower discontinuation syndrome risk; once-daily dosing; dose adjustment in hepatic impairment (clearance −37%, t½ doubled) and elderly (AUC +23–30%) |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nausea | 21% vs 14% placebo | Most common GI complaint; usually transient; taking with food may help |
| Dry mouth | 20% vs 14% placebo | Despite low muscarinic affinity; may persist; encourage oral hygiene |
| Somnolence | 18% vs 10% placebo | Dose-dependent; consider evening dosing if prominent |
| Insomnia | 15% vs 14% placebo | Only marginally above placebo; dose-dependent; morning dosing may help |
| Increased sweating | 11% vs 9% placebo | Dose-dependent; may persist with chronic use |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Tremor | 8% vs 6% placebo | Fine postural tremor; usually self-limiting |
| Diarrhoea | 8% vs 5% placebo | Serotonergic GI effect; generally mild and transient |
| Ejaculation disorder (males) | 6.1% vs 1% placebo | Primarily ejaculatory delay; the only AE occurring at ≥5% and ≥2× placebo rate |
| Fatigue | 5% vs 3% placebo | Dose-dependent; usually improves with time |
| Dyspepsia | 5% vs 4% placebo | Generally mild; consider antacid if persistent |
| Upper respiratory tract infection | 5% vs 4% placebo | Likely coincidental; comparable to placebo rate |
| Rhinitis | 5% vs 3% placebo | Generally self-limiting |
| Vomiting | 4% vs 3% placebo | Less common than nausea; usually transient |
| Anxiety | 4% vs 3% placebo | More common early in treatment; may represent initial activation |
| Anorexia | 4% vs 2% placebo | Mean weight loss ~0.5 kg in controlled trials (vs no change for placebo) |
| Decreased libido (males) | 3.8% vs <1% placebo | May be underreported; enquire proactively |
| Agitation | 3% vs 1% placebo | Distinguish from akathisia; consider dose reduction |
| Sinusitis | 3% vs <1% placebo | May be coincidental |
| Abdominal pain | 3% vs 2% placebo | Usually self-limiting |
| Impotence (males) | 2.8% vs <1% placebo | Dose-dependent; discuss management strategies |
| Libido decreased (overall) | 2% vs <1% placebo | Females: decreased libido 1.3%, anorgasmia 1.1% |
| Yawning | 2% vs <1% placebo | Dose-dependent serotonergic effect; benign |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| QT prolongation / Torsade de Pointes | Dose-dependent; 1.9% had QTcF >60 msec change; 0.5% >500 msec | Any time; higher risk at doses >40 mg or in predisposed patients | ECG if symptoms (syncope, palpitations); discontinue if QTc >500 msec; correct electrolytes; avoid QT-prolonging co-medications |
| Suicidal thoughts/behaviours | 14 per 1,000 (<18 y); 5 per 1,000 (18–24 y) | First weeks to months | Close monitoring at initiation and dose changes; weekly visits initially |
| Serotonin syndrome | 0.1% in premarketing trials | Hours to days, especially with co-serotonergic drugs | Discontinue all serotonergic agents immediately; supportive care; hospital admission |
| Hyponatraemia (SIADH) | Uncommon; Na <110 mmol/L reported | Days to weeks; higher risk in elderly, diuretic users | Check sodium; discontinue citalopram; appropriate fluid management |
| Mania/hypomania activation | 0.1% (undiagnosed bipolar patients) | Days to weeks | Discontinue antidepressant; psychiatric reassessment |
| Seizures | 0.3% (vs 0.5% placebo) | Any time | Use caution in seizure disorders; evaluate if new seizure occurs |
| Abnormal bleeding | Uncommon | Any time; risk increased with anticoagulants/NSAIDs | Assess bleeding; monitor INR if on warfarin |
| Angle-closure glaucoma | Rare (postmarketing) | Any time | Emergency ophthalmological referral; discontinue citalopram |
| Stevens-Johnson syndrome / TEN | Very rare (postmarketing) | Days to weeks | Immediate discontinuation; dermatology referral |
| Hepatic necrosis | Very rare (postmarketing) | Variable | LFTs if symptomatic; discontinue if transaminases markedly elevated |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Nausea | 4% vs 0% placebo | Most common reason; typically occurs in first 1–2 weeks |
| Insomnia | 3% vs 1% placebo | Dose-dependent; consider timing adjustment before discontinuing |
| Somnolence | 2% vs 1% placebo | Usually transient |
| Dizziness | 2% vs <1% placebo | Usually transient; rule out orthostatic component |
| Dry mouth | 1% vs <1% placebo | Rarely sole reason for discontinuation |
Citalopram is unique among SSRIs in having a formal FDA dose ceiling (40 mg/day) driven by cardiac safety data. Before prescribing, assess for risk factors: congenital long QT syndrome, bradycardia, hypokalaemia, hypomagnesaemia, recent MI, uncompensated heart failure, or co-administration of other QT-prolonging drugs. Obtain baseline electrolytes in at-risk patients and correct abnormalities before initiation. If symptoms suggestive of arrhythmia develop (syncope, palpitations, dizziness), obtain an ECG promptly. The dose cap effectively limits citalopram’s usefulness in conditions like OCD where higher SSRI doses are typically needed.
Drug Interactions
Citalopram is metabolised primarily by CYP3A4 and CYP2C19, with CYP2C19 being the more clinically relevant pathway due to the QT-related dose ceiling. Unlike paroxetine or fluoxetine, citalopram is only a weak inhibitor of CYP2D6, resulting in fewer pharmacokinetic drug interactions with CYP2D6 substrates. The dominant interaction concern is pharmacodynamic: additive QT prolongation with other QT-prolonging drugs, and serotonin syndrome with other serotonergic agents.
Monitoring
-
Mood & Suicidality
Weekly for 4 weeks, biweekly for 8 weeks, then per clinical judgement
Routine Assess for clinical worsening, suicidal ideation, unusual behavioural changes, especially in patients under 25. Use PHQ-9 or equivalent -
ECG
Baseline and after dose changes in at-risk patients
Trigger-based At-risk: cardiac disease, electrolyte abnormalities, co-prescribed QT-prolonging drugs, >60 years. Discontinue if QTc >500 msec. Obtain ECG promptly if syncope, palpitations, or dizziness -
Electrolytes (K+, Mg2+)
Baseline in at-risk patients; periodic monitoring
Trigger-based Correct hypokalaemia and hypomagnesaemia before initiation and periodically during treatment; these increase arrhythmia risk -
Sodium (Na+)
Baseline in at-risk; recheck 2–4 weeks
Trigger-based At-risk: elderly, diuretic users, volume-depleted. Check if confusion, falls, weakness, or seizures develop -
Sexual Function
Baseline, then each visit
Routine Enquire proactively; citalopram has moderate sexual side effect burden among SSRIs -
Weight
Baseline, then every 3–6 months
Routine Initial weight loss (~0.5 kg) may reverse with chronic use; monitor trends -
Bleeding Signs
Each visit if on anticoagulants/NSAIDs
Trigger-based Ask about bruising, epistaxis, GI bleeding. Monitor INR if on warfarin
Contraindications & Cautions
Absolute Contraindications
- Concurrent MAOI use or use within 14 days of stopping an MAOI (including linezolid and IV methylene blue) — serotonin syndrome risk
- Concurrent pimozide — risk of additive QT prolongation and ventricular arrhythmias
- Known hypersensitivity to citalopram or any excipient (angioedema, anaphylaxis reported)
Relative Contraindications (Specialist Input Recommended)
- Congenital long QT syndrome — avoid unless benefits clearly outweigh risks; ECG monitoring essential
- Recent acute myocardial infarction or uncompensated heart failure — increased arrhythmia susceptibility
- Concurrent use of other QT-prolonging drugs — additive risk; use alternative SSRI if feasible
- Uncorrected hypokalaemia or hypomagnesaemia — correct electrolytes before initiation
- Undiagnosed bipolar disorder — risk of mania/hypomania; screen before starting
Use with Caution
- Patients >60 years — max 20 mg/day; increased AUC, higher QT and hyponatraemia risk
- Hepatic impairment — max 20 mg/day; clearance reduced 37%, t½ doubled
- CYP2C19 poor metabolisers — max 20 mg/day; AUC more than doubled
- Seizure disorders — seizures reported in 0.3% of treated patients; use cautiously
- Anatomically narrow angles (untreated) — risk of angle-closure glaucoma
- Late pregnancy — risk of neonatal poor adaptation syndrome and possible PPHN
- Breastfeeding — present in breast milk (relative infant dose 0.7–9.4%); monitor infant for irritability, somnolence, poor feeding
- Bradycardia — additive risk with QT prolongation; consider alternative SSRI
Antidepressants increased the risk of suicidal thinking and behaviour in paediatric and young adult patients in short-term studies. The risk is highest in those under 18 (14 additional cases per 1,000 treated) and in the 18–24 age group (5 additional per 1,000). Citalopram is not approved for paediatric use. All patients initiated on antidepressant therapy should be closely monitored for clinical worsening and emergence of suicidal thoughts, especially during initial months and at dose changes.
The FDA has issued safety communications regarding dose-dependent QT prolongation with citalopram. Doses above 40 mg/day are not recommended for any patient. The maximum is further reduced to 20 mg/day in patients over 60, those with hepatic impairment, CYP2C19 poor metabolisers, and patients taking concomitant CYP2C19 inhibitors. Torsade de pointes, ventricular tachycardia, and sudden death have been reported in the postmarketing setting.
Patient Counselling
Purpose of Therapy
Citalopram increases serotonin levels in the brain to help relieve symptoms of depression. Improvement may begin within 1 to 4 weeks, but full benefit can take longer. It is important to continue taking citalopram as prescribed even after feeling better, unless advised otherwise.
How to Take
Take citalopram once daily, with or without food. Swallow the tablet whole. Do not stop abruptly — discuss any dose changes with your prescriber.
Sources
- CELEXA (citalopram) tablets. Full Prescribing Information. AbbVie Inc. Revised October 2023. FDA Label Primary regulatory source for all dosing, adverse reaction incidence rates, contraindications, QT data, and pharmacokinetics used in this monograph.
- Citalopram capsules. Full Prescribing Information. Revised 2023. FDA Label (Capsules) Capsule formulation PI; confirms dosing and safety data consistent with tablet formulation.
- FDA Drug Safety Communication: Revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses. August 2012. FDA Safety Communication Key FDA communication establishing the 40 mg dose ceiling and 20 mg limits for specific populations based on QT prolongation data.
- Stahl SM. Placebo-controlled comparison of the selective serotonin reuptake inhibitors citalopram and sertraline. Biol Psychiatry. 2000;48(9):894–901. DOI Comparative efficacy trial supporting citalopram’s antidepressant effect in moderate-to-severe depression.
- Montgomery SA, Rasmussen JG, Tanghoj P. A 24-week study of 20 mg citalopram, 40 mg citalopram, and placebo in the prevention of relapse of major depression. Int Clin Psychopharmacol. 1993;8(3):181–188. DOI Long-term relapse prevention study showing continued citalopram treatment reduced relapse vs placebo; both 20 mg and 40 mg effective.
- Witchel HJ, Hancox JC, Nutt DJ. Psychotropic drugs, cardiac arrhythmia, and sudden death. J Clin Psychopharmacol. 2003;23(1):58–77. DOI Review of QT prolongation mechanisms with psychotropics; contextualises citalopram’s cardiac safety profile among SSRIs.
- American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. Washington, DC: APA; 2010. APA APA guideline positioning SSRIs including citalopram as first-line treatment for MDD.
- National Institute for Health and Care Excellence (NICE). Depression in adults: treatment and management. NICE guideline NG222. 2022. NICE UK guideline on SSRI selection, monitoring, and discontinuation; considers citalopram a first-line option.
- Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391(10128):1357–1366. DOI Landmark network meta-analysis comparing antidepressant efficacy and acceptability; citalopram used as the reference comparator.
- Hyttel J. Citalopram — pharmacological profile of a specific serotonin uptake inhibitor with antidepressant activity. Prog Neuropsychopharmacol Biol Psychiatry. 1982;6(3):277–295. DOI Foundational pharmacological characterisation establishing citalopram’s selectivity for SERT over other monoamine transporters and receptors.
- Owens MJ, Knight DL, Nemeroff CB. Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry. 2001;50(5):345–350. DOI Demonstrates that the S-enantiomer (escitalopram) is primarily responsible for serotonin transporter binding in racemic citalopram.
- Gutierrez MM, Abramowitz W. Steady-state pharmacokinetics of citalopram in young and elderly subjects. Pharmacotherapy. 2000;20(12):1441–1447. DOI Pharmacokinetic study in elderly demonstrating increased AUC and half-life, supporting the 20 mg dose cap in patients >60 years.
- Herrlin K, Yasui-Furukori N, Tybring G, et al. Metabolism of citalopram enantiomers in CYP2C19/CYP2D6 phenotyped panels of healthy Swedes. Br J Clin Pharmacol. 2003;56(4):415–421. DOI Demonstrates the role of CYP2C19 in citalopram metabolism and the pharmacogenomic basis for dose adjustment in poor metabolisers.
- Zivin K, Pfeiffer PN, Bohnert ASB, et al. Evaluation of the FDA warning against prescribing citalopram at doses exceeding 40 mg. Am J Psychiatry. 2013;170(6):642–650. DOI Population-level analysis assessing clinical impact of the FDA dose ceiling on citalopram prescribing and patient outcomes.