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Citalopram
Systematic (IUPAC) name
(RS)-1-[3-(dimethylamino)propyl]-1-
(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile
Identifiers
CAS number 59729-33-8
ATC code N06AB04 N06AB10
PubChem 2771
DrugBank APRD00147
ChemSpider 2669
Chemical data
Formula C20H21FN2O 
Mol. mass 324.392 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 80%
Metabolism hepatic (CYP3A4 & CYP2C19)
Half life 35 hours
Excretion Mostly as unmetabolized citalopram, partly DCT and traces of DDCT in urine
Therapeutic considerations
Pregnancy cat. C(US)
Legal status Prescription only
Routes Oral
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Citalopram is an antidepressant drug used to treat major depression associated with mood disorders. It is also used on occasion in the treatment of body dysmorphic disorder and anxiety.

Citalopram belongs to a class of drugs known as selective serotonin reuptake inhibitors (SSRIs). It is sold under the brand-names Celexa and Cipramil.

Contents

History

Citalopram (pronounced /saɪˈtælɵpræm/)[1] was originally created in 1989[2] 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 (also known as Cipralex or Lexapro), 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.

Indications

Approved

Citalopram HBr tablets in 20 mg (coral, marked 508) and 40 mg (white, marked 509), and a US Penny.

Citalopram is used to treat the symptoms of major depression, social anxiety disorder, panic disorder and OCD.

Citalopram is a Pgp substrate and is actively transported by that protein from the brain. The efficacy of citalopram in people possessing a certain version of Pgp (genetic TT-allele) is likely to be diminished. This suggests that in non-responders to citalopram a switch to an antidepressant which is not a Pgp substrate, such as fluoxetine (Prozac, Fontex) or mirtazapine (Remeron)—but not to venlafaxine (Effexor), amitriptyline (Elavil) or paroxetine (Paxil), which are Pgp substrates—may be beneficial.[3]

Unapproved, off-label and investigational

Citalopram has been found to greatly reduce the symptoms of diabetic neuropathy[4] and premature ejaculation.[5] There is also evidence that citalopram may be effective in the treatment of post-stroke pathological crying.[6]

While on its own citalopram is less effective than amitriptyline in the prevention of migraines, in refractory cases combination therapy may be more effective.[7]

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.[8]

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. [9]

Availability

Citalopram is sold under the brand-names Celexa (U.S. and Canada, Forest Laboratories, Inc.), Cipramil (Australia, Brazil, Finland, Germany, Ireland, Norway, Sweden, United Kingdom, New Zealand), Citol, 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 (South America, Roemmers), Ciprapine (Ireland), Cilift (South Africa), Citox (Mexico), Temperax (Chile, Peru, Argentina), Citopam, Akarin (Denmark, Nycomed), Cipram (Turkey, Denmark, H. Lundbeck A/S), Dalsan (Eastern Europe), Pramcit (Pakistan), and Celius (Greece), Humorup (Argentina), Oropram (Iceland, Actavis).

Side effects and drug interactions

Citalopram is generally considered safe and well-tolerated in the therapeutic dose range of 10 to 80 mg/day (a dose of 60 mg/day is reserved for patients who do not respond to lower doses). A doctor must always monitor a patient taking an SSRI such as citalopram. 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.[10]

Citalopram should not be taken with St John's wort, as the resulting drug interaction could lead to serotonin syndrome.[11] This may be caused by compounds in the plant extract reducing the efficacy of the hepatic cytochrome P450 enzymes that process citalopram.[12] 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.[13] One study found that Hypericum extracts had similar effects in treating moderate depression as citalopram, with fewer side effects.[14]

Citalopram can have a number of adverse effects. In clinical trials, over 10% of patients reported one or more of the following side effects: fatigue, drowsiness, dry mouth, increased sweating (hyperhidrosis), trembling, headache, dizziness, excessive yawning, sleep disturbances, insomnia, cardiac arrhythmia, jaw clenching, hallucinations, blood pressure changes, nausea and/or vomiting, diarrhea, heightened anorgasmia in females, impotence and ejaculatory problems in males. In rare cases (around over 1% of cases), some allergic reactions, convulsions, mood swings, anxiety and confusion have been reported. Also sedation may be present during treatment of citalopram. If this occurs it is advisable to take the dose at bedtime instead of in the morning. Petechia can occur if blood thinners are taken along with Citalopram.[citation needed]

A rare side effect of antidepressant medications is bruxism (teeth grinding).[15]

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 due to this effect.

Citalopram and other SSRIs have been shown to cause some degree of sexual dysfunction in a majority of patients.[16]

Citalopram is contraindicated in individuals taking MAOIs. The drug is considered relatively safe in overdose, although fatal cases of dosages 840 mg to 1960 mg have been reported.[17]

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 Celexa as Prozac has a much longer half-life (i.e. stays in the body longer compared to Celexa). This may avoid many of the severe withdrawal symptoms associated with Celexa discontinuation. This can be done either by administering a single 20mg 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 Celexa may visit a compounding pharmacy where his or her prescription may be re-arranged into progressively smaller dosages. The lowest dose of celexa that can normally be prescribed is 20mg capsules; a compounding pharmacist may divide this into doses of 20, 15, 10, 5 and 2.5mg so that a proper tapered reduction may take place.

Stereochemistry

Citalopram has one stereocenter, to which a 4-fluorophenyl group and an N,N-dimethyl-3-aminopropyl group bind. Due to 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. 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).[18] In both cases, the salt forms of the amine makes these otherwise lipophilic compounds water-soluble.

Metabolites

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

References

  1. ^ "citalopram". Merriam-Webster, Incorporated. http://medical.merriam-webster.com/medical/citalopram. Retrieved 2008-10-13. 
  2. ^ 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. 
  3. ^ Uhr M, Tontsch A, Namendorf C, Ripke S, Lucae S, Ising M, Dose T, Ebinger M, Rosenhagen M, Kohli M, Kloiber S, Salyakina D, Bettecken T, Specht M, Pütz B, Binder EB, Müller-Myhsok B, Holsboer F (2008). "Polymorphisms in the Drug Transporter Gene ABCB1 Predict Antidepressant Treatment Response in Depression". Neuron 57 (2): 203–9. doi:10.1016/j.neuron.2007.11.017. PMID 18215618. 
  4. ^ Sindrup SH, Bjerre U, Dejgaard A, Brøsen K, Aaes-Jørgensen T, Gram LF (1992). "The selective serotonin reuptake inhibitor citalopram relieves the symptoms of diabetic neuropathy". Clin. Pharmacol. Ther. 52 (5): 547–52. PMID 1424428. 
  5. ^ Atmaca M, Kuloglu M, Tezcan E, Semercioz A (2002). "The efficacy of citalopram in the treatment of premature ejaculation (prem-e): a placebo-controlled study". Int. J. Impot. Res. 14 (6): 502–5. doi:10.1038/sj.ijir.3900918. PMID 12494286. 
  6. ^ Andersen G, Vestergaard K, Riis JO (1993). "Citalopram for post-stroke pathological crying". Lancet 342 (8875): 837–9. doi:10.1016/0140-6736(93)92696-Q. PMID 8104273. 
  7. ^ Rampello L, Alvano A, Chiechio S, et al. (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. 
  8. ^ King BH, Hollander E, Sikich L et al. (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). 
  9. ^ Effects of chronic treatment with citalopram on cannabinoid and opioid receptor-mediated G-protein coupling in discrete rat brain regions. Shirley A. Hesketh, Adrian K. Brennan, David S. Jessop and David P. Finn. Springer Berlin / Heidelberg. Volume 198, Number 1 / May, 2008. ISSN: 0033-3158 (Print) 1432-2072 (Online) http://www.springerlink.com/content/2127100x043n3674/
  10. ^ Keller MB (2000). "Citalopram therapy for depression: a review of 10 years of European experience and data from U.S. clinical trials". The Journal of clinical psychiatry 61 (12): 896–908. PMID 11206593. http://www.biopsychiatry.com/citalopram.html. 
  11. ^ Karch, Amy (2006). 2006 Lippincott's Nursing Drug Guide. Philadephia, Baltimore, New York, London, Buenos Aires, Hong Kong, Sydney, Tokyo: Lippincott Williams & Wilkins. ISBN 1-58255-436-6. 
  12. ^ http://www.medsafe.govt.nz/Profs/PUarticles/sjw.htm accessed Feb 27 2009
  13. ^ http://www.umm.edu/altmed/articles/st-johns-000276.htm accessed Feb 27 2009
  14. ^ M. Gastpar, et al. (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. http://www.thieme-connect.com/ejournals/abstract/pharmaco/doi/10.1055/s-2006-931544. Retrieved Feb 27 2009. 
  15. ^ Wise, M.E.J. (2001). "Citalopram-induced bruxism". British Journal of Psychiatry 178: 182. doi:10.1192/bjp.178.2.182. http://bjp.rcpsych.org/cgi/content/full/178/2/182. 
  16. ^ Clayton A, Keller A, McGarvey EL (2006). "Burden of phase-specific sexual dysfunction with SSRIs". Journal of affective disorders 91 (1): 27–32. doi:10.1016/j.jad.2005.12.007. PMID 16430968. 
  17. ^ "Citalopram Hydrobromide Brand name: Celexa Drug monograph; Symptoms and Treatment of Overdosage". Internet Mental Health. August 1999. http://www.mentalhealth.com/drug/p30-c04.html#Head_12. Retrieved 2007-07-25. ]
  18. ^ Celexa.com

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