Drug products: Cipramil, Cipramil®, Citalopram 2care4, Citalopram Actavis, Citalopram Alternova, Citalopram Arrow, Citalopram Bluefish, Citalopram BMM Pharma, Citalopram Ebb, Citalopram Jubilant, Citalopram Lundbeck, Citalopram Mylan, Citalopram Oral Solution, USP, Citalopram Orifarm, Citalopram Orion, Citalopram ratiopharm, Citalopram Sandoz, Citalopram STADA®, Citalopram Teva, Citalopram Vitabalans, Citalopram® CNSpharma
ATC code: N06AB04
Substances: citalopram, citalopram hydrobromide, citalopram hydrochloride
Results from studies in patients with depression are inconclusive regarding treatment differences between men and women.
Older patients should not be treated with citalopram doses over 20 mg daily due to the risk of QT-prolongation and arrhythmias. QT-prolongation and ventricular tachycardia such as Torsade de Pointes have been reported more frequently in women with low potassium and heart disease. When using higher doses of citalopram, the risk of ventricular tachycardia caused by QT-prolongation should be considered in elderly patients, particularly in elderly women.
Depression is almost twice as common in women as in men . Women have an earlier age of onset and increased duration of depressive episodes. Differences in neurobiology [2, 3], hormones, inflammatory markers, diagnostic tools, or health seeking behavior [4, 5] may be of importance. Although depression is more prevalent in women, most preclinical studies on depression have used male animals .
Women are two to three times more likely to suffer from an anxiety disorder . Sex differences in symptomatology and comorbidity may be due to genetic, hormonal, neurodevelopmental, environmental, and neurobiological factors .
Pharmacokinetics and dosing
There are contradictory results from pharmacokinetic studies of citalopram (CIT) and escitalopram (S-CIT). No sex differences in the pharmacokinetics of the metabolites desmethylcitalopram (DCIT) and didemethylcitalopram (DDCIT) have been shown.
For citalopram, AUC was 1.5–2 times higher in women than in men in three pharmacokinetic studies (in total 32 patients) conducted by the original manufacturer. However, in five other pharmacokinetic studies (in total 114 patients) no sex differences were seen. Clinical studies (237 men, 338 women) showed no differences in citalopram concentration between men and women [7, 8]. Also in healthy volunteers, no differences in pharmacokinetics between men and women after a single dose of 20 mg citalopram were found .However, in a sample of patients taking citalopram (216 men, 300 women), the dose corrected citalopram concentration was found to be higher in men than women in the higher dose range, 70-200 mg citalopram daily. No difference in citalopram concentration was observed for the lower dose, 10-60 mg daily  .In a TDM study (247 men, 502 women), women had higher dose corrected concentrations for citalopram and DCIT and also lower citalopram clearance than men (21.7 vs. 25.5 L/h). No differences were observed in DCIT to citalopram ratio . Similar to this, another TDM study observed 25% higher citalopram and 9% higher escitalopram concentrations in women than men after receiving 20 mg citalopram daily or 10 mg escitalopram daily (1344 men, 2456 women) . Contrary to these findings, another TDM study in psychiatric patients (57 men, 112 women) found no significant sex differences in pharmacokinetics for citalopram and the metabolite DCIT after a mean daily dose of 40 mg  .
For escitalopram, the concentrations of escitalopram and the metabolites DCIT and DDCIT were analyzed in patients (50 men, 105 women) with a median daily dose of 20 mg daily. No differences in dose-normalized concentrations were found. However, the DCIT/escitalopram ratio was higher in women (0.64 vs. 0.50) as well as the concentration-over-dose for DCIT variance (45% vs. 35%) .
Despite these findings, the clinical studies have shown effect with similar doses in men and women and no dose adjustment based on patient’s sex has been suggested [7, 8].
The original manufacturers of citalopram and escitalopram report no relationship between treatment outcome and patient’s sex . However, results vary between clinical studies. The large STAR*D study of major depression (1043 men, 1833 women, age 18-75 years), showed that women had better self-rated response and remission than men after treatment with citalopram for 12–14 weeks. Similar proportions of men and women completed treatment for 8 weeks or more . However, another study in patients with major depression (96 men, 196 women) showed no sex differences in response or dropout rates after 5 weeks of treatment with citalopram dose of 40 mg daily  .
Menopausal women had a worse SSRI treatment response compared to non-menopausal women in a clinical study of different SSRIs including citalopram (59 men, 95 menopausal women, 147 non-menopausal women). In contrast, no differences were shown between men and women .
For use of citalopram in alcohol dependence, a placebo-controlled study showed men to have a better outcome. After 12 weeks of treatment of citalopram 40 mg daily in patients with alcohol dependence (16 men, 15 women), the men reduced their average drinks per day by 44% compared to 27% for women . However, citalopram and escitalopram are not approved on this indication in Sweden.
A general alert has been issued about older patients, especially older women, and the risk of QT-prolongation when treated with citalopram doses above 20 mg daily [19, 20]. It is well described in cardiology reports that treatment with citalopram and escitalopram induces QT-prolongation and increases the risk of lethal ventricular tachycardia type Torsade de Pointes to a greater extent in women, especially with hypokalemia and/or heart diseases. Also, elderly women are at higher risk of citalopram-induced hyponatremia [21, 22].
The STAR*D study reported no sex differences in overall serious adverse effects or psychiatric serious adverse effects .
Reproductive health issues
Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Drug utilization of ten commonly prescribed antidepressants during the period 2009-2014 in Sweden, Denmark, Germany, and Spain were analyzed in a large register study (in total 4,833,774 initiators included). Women comprised the majority of initiators for all antidepressants studied. In Sweden, 65.3% of the initiators on citalopram and 64.9% on the initiators on escitalopram were women .
Date of litterature search: 2021-03-08
- Nationella riktlinjer för vård vid depression och ångestsyndrom 2021. Socialstyrelsen [www]. Socialstyrelsen. [updated 2021-04-01, cited 2021-05-14]. länk
- LeGates TA, Kvarta MD, Thompson SM. Sex differences in antidepressant efficacy. Neuropsychopharmacology. 2019;44(1):140-154. PubMed
- Sramek JJ, Murphy MF, Cutler NR. Sex differences in the psychopharmacological treatment of depression. Dialogues Clin Neurosci. 2016;18(4):447-457. PubMed
- Kerber CS, Dyck MJ, Culp KR, Buckwalter K. Antidepressant treatment of depression in rural nursing home residents. Issues Ment Health Nurs. 2008;29(9):959-73. PubMed
- Labaka A, Goñi-Balentziaga O, Lebeña A, Pérez-Tejada J. Biological Sex Differences in Depression: A Systematic Review. Biol Res Nurs. 2018;20(4):383-392. PubMed
- Jalnapurkar I, Allen M, Pigott T. Sex Differences in Anxiety Disorders: A Review. J Psychiatr Depress Anxiety. 2018;4(1):2-9.
- CELEXA (citalopram). US National Library of Medicine. DailyMed [www]. [updated 2019-08-13, cited 2021-03-08]. länk
- LEXAPRO (escitalopram). US National Library of Medicine. DailyMed [www]. [updated 2020-09-09, cited 2021-03-08]. länk
- Fudio S, Borobia AM, Piñana E, Ramírez E, Tabarés B, Guerra P et al. Evaluation of the influence of sex and CYP2C19 and CYP2D6 polymorphisms in the disposition of citalopram. Eur J Pharmacol. 2010;626:200-4. PubMed
- Le Bloc'h Y, Woggon B, Weissenrieder H, Brawand-Amey M, Spagnoli J, Eap CB et al. Routine therapeutic drug monitoring in patients treated with 10-360 mg/day citalopram. Ther Drug Monit. 2003;25:600-8. PubMed
- Reis M, Lundmark J, Bengtsson F. Therapeutic drug monitoring of racemic citalopram: a 5-year experience in Sweden, 1992-1997. Ther Drug Monit. 2003;25:183-91. PubMed
- Reis M, Aamo T, Spigset O, Ahlner J. Serum concentrations of antidepressant drugs in a naturalistic setting: compilation based on a large therapeutic drug monitoring database. Ther Drug Monit. 2009;31:42-56. PubMed
- Leinonen E, Lepola U, Koponen H, Kinnunen I. The effect of age and concomitant treatment with other psychoactive drugs on serum concentrations of citalopram measured with a nonenantioselective method. Ther Drug Monit. 1996;18:111-7. PubMed
- Reis M, Chermá MD, Carlsson B, Bengtsson F, Task Force for TDM of Escitalopram in Sweden. Therapeutic drug monitoring of escitalopram in an outpatient setting. Ther Drug Monit. 2007;29:758-66. PubMed
- Young EA, Kornstein SG, Marcus SM, Harvey AT, Warden D, Wisniewski SR et al. Sex differences in response to citalopram: a STAR*D report. J Psychiatr Res. 2009;43:503-11. PubMed
- Hildebrandt MG, Steyerberg EW, Stage KB, Passchier J, Kragh-Soerensen P, Danish University Antidepressant Group. Are gender differences important for the clinical effects of antidepressants?. Am J Psychiatry. 2003;160:1643-50. PubMed
- Pinto-Meza A, Usall J, Serrano-Blanco A, Suárez D, Haro JM. Gender differences in response to antidepressant treatment prescribed in primary care Does menopause make a difference?. J Affect Disord. 2006;93:53-60. PubMed
- Naranjo CA, Knoke DM, Bremner KE. Variations in response to citalopram in men and women with alcohol dependence. J Psychiatry Neurosci. 2000;25:269-75. PubMed
- Läkemedelsverket. Citalopram – sänkt maxdos rekommenderas. Nyhet 2011-10-27.
- Food and Drug Administration (FDA). FDA Drug Safety Communication: Revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses.
- Cipramil (citalopram). Summary of Product Characteristics. Swedish Medical Products Agency. [updated 2020-12-08, cited 2021-03-08]. länk
- Cipralex (escitalopram). Summary of Product Characteristics. Swedish Medical Products Agency . [updated 2021-03-01, cited 2021-03-08]. länk
- Forns J, Pottegård A, Reinders T, Poblador-Plou B, Morros R, Brandt L et al. Antidepressant use in Denmark, Germany, Spain, and Sweden between 2009 and 2014: Incidence and comorbidities of antidepressant initiators. J Affect Disord. 2019;249:242-252. PubMed
- Statistikdatabas för läkemedel. Stockholm: Socialstyrelsen. 2020 [cited 2021-03-10.] länk
Reviewed by: Carl-Olav Stiller, Pauline Raaschou
Approved by: Karin Schenck-Gustafsson