Citalopram

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Not to be confused with Escitalopram.
Citalopram
Systematic (IUPAC) name
(RS)-1-[3-(dimethylamino)propyl]-1-
(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile
Clinical data
AHFS/Drugs.com monograph
MedlinePlus a699001
Pregnancy cat. C (US)
Legal status ℞ Prescription only
Routes Oral
Pharmacokinetic data
Bioavailability 80%
peak at 4 hours[1]
Metabolism hepatic (CYP3A4 & CYP2C19)
Half-life 35 hours
Excretion Mostly as unmetabolized citalopram, partly DCT and traces of DDCT in urine
Identifiers
CAS number 59729-33-8 YesY
ATC code N06AB04
PubChem CID 2771
DrugBank DB00215
ChemSpider 2669 YesY
UNII 0DHU5B8D6V YesY
KEGG D07704 YesY
ChEBI CHEBI:3723 YesY
ChEMBL CHEMBL549 YesY
Chemical data
Formula C20H21FN2O 
Mol. mass 324.392 g/mol
 YesY (what is this?)  (verify)

Citalopram (/saɪˈtælɵpræm/; brand names: Celexa, Cipramil) is an antidepressant drug of the selective serotonin reuptake inhibitor (SSRI) class. It has U.S. Food and Drug Administration (FDA) approval to treat major depression, and is prescribed off-label for other conditions.

Contents

Medical uses [edit]

Citalopram HBr tablets in 20 mg (coral, marked 508) and 40 mg (white, marked 509), and a coin(size 19.05mm/0.75").

Citalopram is approved to treat the symptoms of major depression.[1]

Adult dosing: discontinue with gradual dose reduction and monitoring for withdrawal symptoms. Doses above 40 mg/day are not recommended because of the risk for QT prolongation

Depression: initial, 20 mg/day ORALLY as a single dose in the morning or evening; dose increases should usually occur in increments of 20 mg at intervals of no less than one week; MAX, 40 mg/day

A test of the GRIK4 gene can be made in order to know if a depressed patient will respond to the citalopram.[2]

Efficacy [edit]

There is controversy over selective publishing of SSRI clinical trials by pharmaceutical companies.[3] A meta-analysis analyzing published as well as unpublished trials found the benefits of SSRIs over placebos to be insignificant in all but the most severe cases of depression (benefits over placebo were substantial in very severe cases).[4][5]

Off-label [edit]

Citalopram is frequently used off-label to treat anxiety, panic disorder, PMDD, body dysmorphic disorder and OCD.[6]

Citalopram has been found to greatly reduce the symptoms of diabetic neuropathy[7] and premature ejaculation.[8] There is also evidence that citalopram may be effective in the treatment of post-stroke pathological crying.[9]

While on its own citalopram is less effective than amitriptyline in the prevention of migraines, in refractory cases combination therapy may be more effective.[10]

Citalopram and other SSRIs can be used to treat hot flashes.[11]:107

A 2009 multisite randomized controlled study found no benefit and some adverse effects in autistic children from citalopram, raising doubts whether SSRIs are effective for treating repetitive behavior in children with autism.[12]

Some research suggests that citalopram interacts with cannabinoid protein-couplings in the rat brain, and this is put forward as a potential cause of some of the drug's antidepressant effect.[13]

Administration [edit]

Citalopram is typically taken in one dose, either in the morning or evening. Citalopram can be taken with or without food. The absorption of citalopram does not increase when taken with food,[1] but doing so can help prevent nausea. Nausea is often caused when the 5HT3 receptors actively absorbs free serotonin, as this receptor is present within the digestive tract.[14] The 5HT3 receptors stimulate vomiting. This side effect, if present, should subside as the body adjusts to the medication.

Citalopram is considered safe and well tolerated in the therapeutic dose range. Distinct from some other agents in its class, citalopram exhibits linear pharmacokinetics and minimal drug interaction potential, making it a better choice for the elderly or comorbid patients.[15]

Adverse effects [edit]

Sexual dysfunction is often a side effect with SSRIs. Specifically, common side effects include difficulty becoming aroused, lack of interest in sex, and anorgasmia (trouble achieving orgasm). Genital anesthesia,[16][17] loss of or decreased response to sexual stimuli, and ejaculatory anhedonia are also possible. Although usually reversible, in some people these sexual side effects become permanent after the drug has been completely withdrawn.[18] This is known as post-SSRI sexual dysfunction.

Citalopram theoretically causes side effects by increasing the concentration of serotonin in other parts of the body (e.g., the intestines). Other side effects, such as increased apathy and emotional flattening, may be caused by the decrease in dopamine release that is associated with increased serotonin. Citalopram is also a mild antihistamine, which may be responsible for some of its sedating properties.[11]:104

Common side effects of citalopram include drowsiness, insomnia, nausea, weight changes, vivid dreaming, frequent urination, decreased sex drive, anorgasmia, dry mouth,[1] increased sweating, trembling, diarrhea, excessive yawning, and fatigue. Less common side effects include bruxism, vomiting, cardiac arrhythmia, blood pressure changes, dilated pupils, anxiety, mood swings, headache, and dizziness. Rare side effects include convulsions, hallucinations, and severe allergic reactions.[1] If sedation occurs, the dose may be taken at bedtime rather than in the morning.

Citalopram and other SSRIs can induce a mixed state, especially in those with undiagnosed bipolar disorder.[11]:105

Citalopram should not be taken with St John's wort, tryptophan or 5-HTP as the resulting drug interaction could lead to serotonin syndrome.[19] With St John's wort, this may be caused by compounds in the plant extract reducing the efficacy of the hepatic cytochrome P450 enzymes that process citalopram.[20] It has also been suggested that such compounds, including hypericin, hyperforin and flavonoids, could have SSRI-mimetic effects on the nervous system, although this is still subject to debate.[21] One study found that Hypericum extracts had similar effects in treating moderate depression as citalopram, with fewer side effects.[22] Tryptophan and 5-HTP are precursors to serotonin and can cause a rise in serotonin. When taken with an SSRI, such as citalopram, this can lead to levels of serotonin that can be lethal.

In the US, Federal health regulators are warning doctors not to prescribe high doses of Citalopram because of the risk of fatal heart complications. The Food and Drug Administration (FDA) said the drug could interfere with the heart’s electrical activity at doses above 40 milligrams and lead to sudden death. In addition, 20 mg per day is the maximum dose recommended by the FDA for patients with hepatic impairment, who are greater than 60 years of age, who are CYP 2C19 poor metabolizers, or who are taking concomitant cimetidine (brand name: Tagamet), because these factors lead to increased blood levels of citalopram, increasing the risk of QT interval prolongation and Torsade de Pointes.

SSRIs, including citalopram, can increase the risk of bleeding, especially when coupled with aspirin, NSAIDs, warfarin, or other anticoagulants.[1] Citalopram is contraindicated in individuals taking MAOIs, owing to a potential for serotonin syndrome.

When taken with Prilosec, the clearance of citalopram may be reduced, leading to higher blood levels of citalopram. Prilosec inhibits the CYP450 2C19 enzyme, one of the two primary enzymes responsible for the metabolism of citalopram. Dosage adjustments may be needed to counter this effect.[citation needed]

SSRI discontinuation syndrome has been reported when treatment is stopped. Tapering off citalopram therapy, as opposed to abrupt discontinuation, is recommended in order to diminish the occurrence and severity of discontinuation symptoms. Some doctors may choose to switch a patient to Prozac (Fluoxetine) when discontinuing Citalopram as Prozac has a much longer half-life (i.e. stays in the body longer compared to Citalopram). This may avoid many of the severe withdrawal symptoms associated with Citalopram discontinuation. This can be done either by administering a single 20 mg dose of Prozac or by beginning on a low dosage of Prozac and slowly tapering down. Either of these prescriptions may be written in liquid form to allow a very slow and gradual tapering down in dosage. Alternatively, a patient wishing to stop taking Citalopram may visit a compounding pharmacy where his or her prescription may be re-arranged into progressively smaller dosages.

According to the FDA, Celexa "can cause abnormal changes to the electrical activity of the heart." and can lead to fatal changes in the heart's rhythm. The higher the dose, the greater the risk to the heart.[23]

Suicidality [edit]

In the United States, citalopram, like other antidepressants, carries a black box warning stating that it may increase suicidal thinking and behavior in those under age 24.[1]

Abnormal heart rhythm [edit]

The U.S. Food and Drug Administration (FDA) is informing healthcare professionals and patients that the antidepressant Celexa (citalopram hydrobromide; also marketed as generics) should no longer be used at doses greater than 40 mg per day because it can cause abnormal changes in the electrical activity of the heart that are extremely rare but potentially serious. Previously, the citalopram drug label stated that certain patients may require a dose of 60 mg per day. Patients at particular risk for developing prolongation of the QT interval include those with underlying heart conditions and those who are predisposed to low levels of potassium and magnesium in the blood. The FDA advised that if you are currently taking more than 40 mg of Celexa a day, to contact your health care professional.[24]

Overdosage [edit]

Overdosage may result in vomiting, sedation, disturbances in heart rhythm, dizziness, sweating, nausea, tremor, and rarely amnesia, confusion, coma, or convulsions.[11]:105 Overdose deaths have occurred, sometimes involving other drugs but also with citalopram as the sole agent. Citalopram and N-desmethylcitalopram may be quantized in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients or to assist in a medicolegal death investigation. Blood or plasma citalopram concentrations are usually in a range of 50-400 μg/L in persons receiving the drug therapeutically, 1000-3000 μg/L in patients who survive acute overdosage and 3–30 mg/L in those who do not survive.[25][26][24]

Stereochemistry [edit]

Citalopram has one stereocenter, to which a 4-fluorophenyl group and an N,N-dimethyl-3-aminopropyl group bind. As a result of this chirality, the molecule exists in (two) enantiomeric forms (mirror images). They are termed S-(+)-citalopram and R-(–)-citalopram.

S-(+)-citalopram R-(–)-citalopram
S-(+)-citalopram R-(–)-citalopram
(S)-(+)-citalopram (R)-(–)-citalopram

Citalopram is sold as a racemic mixture, consisting of 50% (R)-(−)-citalopram and 50% (S)-(+)-citalopram. Only the (S)-(+) enantiomer has the desired antidepressant effect.[27] Lundbeck now markets the (S)-(+) enantiomer, the generic name of which is escitalopram. Whereas citalopram is supplied as the hydrobromide, escitalopram is sold as the oxalate salt (hydrooxalate).[1] In both cases, the salt forms of the amine make these otherwise lipophilic compounds water-soluble.

Metabolites [edit]

Citalopram metabolites desmethylcitalopram and didesmethylcitalopram are significantly less energetic and their contribution to the overall action of citalopram is negligible.

History [edit]

Citalopram was originally created in 1989[28] by the pharmaceutical company Lundbeck. The patent expired in 2003, allowing other companies to legally produce generic versions. Lundbeck has recently released an updated formulation called escitalopram,[citation needed] which is the S-enantiomer of the racemic citalopram (see b), and acquired a new patent for it. In the United States, Forest Labs manufactures and markets the drug.

Brand names [edit]

Citalopram is sold under the brand-names Celexa (U.S. and Canada, Forest Laboratories, Inc.), Citalopram (USA, United Kingdom, Denmark, Spain, Switzerland), Citta, Denyl (Brazil), Cipramil (Australia, Brazil, Belgium, Finland, Germany, Netherlands, Ireland, Israel, Norway, Sweden, United Kingdom, New Zealand, South Africa, Russia), Elopram (Italy), Clitoram (United Kingdom), Citol (Russia), Vodelax (Turkey), Citrol, Seropram, Talam (Europe and Australia), Citabax, Citaxin (Poland), Citalec (Slovakia, Czech Republic), Recital (Israel, Thrima Inc. for Unipharm Ltd.), Zetalo (India), Celapram, Ciazil (Australia, New Zealand), Zentius, Cimal (South America, by Roemmers and Recalcine), Ciprapine (Ireland), Cilift, Cilate (South Africa), Citox (Mexico), Temperax (Chile, Peru, Argentina), Talohexal (Australia), Citopam (Australia), Akarin (Denmark, Nycomed), Cipram (Turkey, Denmark, H. Lundbeck A/S), Dalsan (Eastern Europe), Pram (Russia), Pramcit (Pakistan), Cipralex (Greece), Humorup (Argentina), Humorap (Peru), Humorap (Bolivia), Oropram (Iceland, Actavis), Opra (Russia), and Zylotex (Portugal),[29] Citalo (Egypt), Citalex (Iran).

References [edit]

  1. ^ a b c d e f g h "Celexa (citalopram hydrobromide) Tablets/Oral Solution" (pdf). Prescribing Information. Forest Laboratories, Inc. 
  2. ^ Paddock S, Laje G, Charney D, Rush AJ, Wilson AF, Sorant AJ, Lipsky R, Wisniewski SR, Manji H, McMahon FJ (August 2007). "Association of GRIK4 with outcome of antidepressant treatment in the STAR*D cohort". Am J Psychiatry 164 (8): 1181–8. doi:10.1176/appi.ajp.2007.06111790. PMID 17671280. 
  3. ^ Ioannidis JP (2008). "Effectiveness of antidepressants: an evidence myth constructed from a thousand randomized trials?". Philos Ethics Humanit Med 3: 14. doi:10.1186/1747-5341-3-14. PMC 2412901. PMID 18505564. 
  4. ^ Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC, Fawcett J (January 2010). "Antidepressant drug effects and depression severity: a patient-level meta-analysis". JAMA 303 (1): 47–53. doi:10.1001/jama.2009.1943. PMID 20051569. 
  5. ^ Kirsch et al. (February 2008). Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. doi:10.1371/journal.pmed.0050045. PMID PMC2253608. Retrieved 04/14/2013. 
  6. ^ Poore J. "Celexa (citalopram hydrobromide)". Crazy Meds. 
  7. ^ Sindrup SH, Bjerre U, Dejgaard A, Brøsen K, Aaes-Jørgensen T, Gram LF (November 1992). "The selective serotonin reuptake inhibitor citalopram relieves the symptoms of diabetic neuropathy". Clin. Pharmacol. Ther. 52 (5): 547–52. doi:10.1038/clpt.1992.183. PMID 1424428. 
  8. ^ Atmaca M, Kuloglu M, Tezcan E, Semercioz A (December 2002). "The efficacy of citalopram in the treatment of premature ejaculation: a placebo-controlled study". Int. J. Impot. Res. 14 (6): 502–5. doi:10.1038/sj.ijir.3900918. PMID 12494286. 
  9. ^ Andersen G, Vestergaard K, Riis JO (October 1993). "Citalopram for post-stroke pathological crying". Lancet 342 (8875): 837–9. doi:10.1016/0140-6736(93)92696-Q. PMID 8104273. 
  10. ^ Rampello L, Alvano A, Chiechio S, Malaguarnera M, Raffaele R, Vecchio I, Nicoletti F (2004). "Evaluation of the prophylactic efficacy of amitriptyline and citalopram, alone or in combination, in patients with comorbidity of depression, migraine, and tension-type headache". Neuropsychobiology 50 (4): 322–8. doi:10.1159/000080960. PMID 15539864. 
  11. ^ a b c d Stahl SM (2011). The Prescriber's Guide (Stahl's Essential Psychopharmacology). Cambridge, UK: Cambridge University Press. ISBN 0-521-17364-7. 
  12. ^ King BH, Hollander E, Sikich L, McCracken JT, Scahill L, Bregman JD, Donnelly CL, Anagnostou E, Dukes K, Sullivan L, Hirtz D, Wagner A, Ritz L (June 2009). "Lack of efficacy of citalopram in children with autism spectrum disorders and high levels of repetitive behavior: citalopram ineffective in children with autism". Arch. Gen. Psychiatry 66 (6): 583–90. doi:10.1001/archgenpsychiatry.2009.30. PMID 19487623. Lay summary – Los Angeles Times (2009-06-02). 
  13. ^ Hesketh SA, Brennan AK, Jessop DS, Finn DP (May 2008). "Effects of chronic treatment with citalopram on cannabinoid and opioid receptor-mediated G-protein coupling in discrete rat brain regions". Psychopharmacology (Berl.) 198 (1): 29–36. doi:10.1007/s00213-007-1033-3. PMID 18084745. 
  14. ^ Rang HP (2003). Pharmacology. Edinburgh: Churchill Livingstone. p. 187. ISBN 0-443-07145-4. 
  15. ^ Keller MB (December 2000). "Citalopram therapy for depression: a review of 10 years of European experience and data from U.S. clinical trials". J Clin Psychiatry 61 (12): 896–908. doi:10.4088/JCP.v61n1202. PMID 11206593. 
  16. ^ Bolton JM, Sareen J, Reiss JP (2006). "Genital anaesthesia persisting six years after sertraline discontinuation". J Sex Marital Ther 32 (4): 327–30. doi:10.1080/00926230600666410. PMID 16709553. 
  17. ^ "Numb Genitals, Anyone?". Retrieved 9 November 2012. 
  18. ^ Csoka AB, Csoka A, Bahrick A, Mehtonen OP (January 2008). "Persistent sexual dysfunction after discontinuation of selective serotonin reuptake inhibitors". J Sex Med 5 (1): 227–33. doi:10.1111/j.1743-6109.2007.00630.x. PMID 18173768. 
  19. ^ Karch AM (2006). Lippincott's Nursing Drug Guide. Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 1-58255-436-6. 
  20. ^ "Interactions with St John's wort preparations". Prescriber Update Articles. New Zealand Medicines and Medical Devices Safety Authority. 2000. 
  21. ^ "St. John's wort". Medical Reference. University of Maryland Medical Center. 2011. 
  22. ^ Gastpar M, Singer A, Zeller K (March 2006). "Comparative efficacy and safety of a once-daily dosage of hypericum extract STW3-VI and citalopram in patients with moderate depression: a double-blind, randomised, multicentre, placebo-controlled study". Pharmacopsychiatry 39 (2): 66–75. doi:10.1055/s-2006-931544. PMID 16555167. 
  23. ^ "FDA Drug Safety Communication: Revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses". Drug Safety and Availability. United States Food and Drug Administration. 2012-05-22. 
  24. ^ a b "Abnormal heart rhythms associated with high doses of Celexa (citalopram hydrobromide)". Safety Communication. United States Food and Drug Administration. 2011-08-24. 
  25. ^ Personne M, Sjöberg G, Persson H (1997). "Citalopram overdose--review of cases treated in Swedish hospitals". J. Toxicol. Clin. Toxicol. 35 (3): 237–40. doi:10.3109/15563659709001206. PMID 9140316. 
  26. ^ Luchini D, Morabito G, Centini F (December 2005). "Case report of a fatal intoxication by citalopram". Am J Forensic Med Pathol 26 (4): 352–4. doi:10.1097/01.paf.0000188276.33030.dd. PMID 16304470. 
  27. ^ Lepola U, Wade A, Andersen HF (May 2004). "Do equivalent doses of escitalopram and citalopram have similar efficacy? A pooled analysis of two positive placebo-controlled studies in major depressive disorder". Int Clin Psychopharmacol 19 (3): 149–55. doi:10.1097/01.yic.0000122862.35081.cd. PMID 15107657. 
  28. ^ Dorell K, Cohen MA, Huprikar SS, Gorman JM, Jones M (2005). "Citalopram-induced diplopia". Psychosomatics 46 (1): 91–3. doi:10.1176/appi.psy.46.1.91. PMID 15765832. 
  29. ^ "Citalopram". International. Drugs.com. 

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