Common side effects include nausea, trouble sleeping, sexual problems, shakiness, feeling tired, and sweating.[7] Serious side effects include an increased risk ofsuicide in those under the age of 25,serotonin syndrome,glaucoma, andQT prolongation.[7] It should not be used in persons who take or have recently taken anMAO inhibitor.[7] There are concerns that use duringpregnancy may harm the fetus.[3]
It appears to be as effective as fluvoxamine and paroxetine in obsessive–compulsive disorder.[24] Some data suggest the effectiveness of intravenous infusion of citalopram in resistant OCD.[5] Citalopram is well tolerated and as effective asmoclobemide in social anxiety disorder.[25] There are studies suggesting that citalopram can be useful in reducing aggressive and impulsive behavior.[26][27] It appears to be superior to placebo for behavioural disturbances associated with dementia.[28] It has also been used successfully for hypersexuality in early Alzheimer's disease.[29]
A meta-analysis, including studies with fluoxetine, paroxetine, sertraline, escitalopram, and citalopram versus placebo, showed SSRIs to be effective in reducing symptoms of premenstrual syndrome, whether taken continuously or just in the luteal phase.[30] For alcoholism, citalopram has produced a modest reductionalcohol intake and increase in drink-free days in studies of alcoholics, possibly by decreasing desire or reducing the reward.[31]
Citalopram and other SSRIs can be used to treathot flashes.[33]: 107
A 2009 multisite randomized controlled study found no benefit and some adverse effects in autistic children from citalopram, raising doubts about whether SSRIs are effective for treating repetitive behavior in children with autism.[34]
Some research suggests 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 effects.[35]
Citalopram is typically taken in one dose, either in the morning or evening. It can be taken with or without food. Its absorption does not increase when taken with food,[36][9] but doing so can help prevent nausea. Nausea is often caused when the5-HT3 receptors actively absorb free serotonin, as this receptor is present within the digestive tract.[37]
Citalopram theoretically causes side effects by increasing the concentration ofserotonin 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 indopamine release associated with increased serotonin. Citalopram is also a mildantihistamine, which may be responsible for some of its sedating properties.[33]: 104
Citalopram and other SSRIs can induce amixed state, especially in those with undiagnosedbipolar disorder.[33]: 105 According to an article published in 2020, one of the other rare side effects of Citalopram could be triggeringvisual snow syndrome; which does not resolve after the discontinuation of the medicine.[41]
Sexual dysfunction is often a side effect of SSRIs.[42] Some people experience persistent sexual side effects when taking SSRIs or after discontinuing them.[43] Symptoms of medication-induced sexual dysfunction from antidepressants include difficulty with orgasm, erection, or ejaculation.[43] Other symptoms may be genital anesthesia,anhedonia, decreased libido, vaginal lubrication issues, and nipple insensitivity in women. Rates are unknown, and there is no established treatment.[44]
In August 2011, the FDA announced, "Citalopram causes dose-dependentQT interval prolongation. Citalopram should no longer be prescribed at doses greater than 40 mg per day".[45] A further clarification, issued in March 2012, restricted the maximum dose to 20 mg for subgroups of patients, including those older than 60 years and those taking an inhibitor of cytochrome P450 2C19.7.[46]
As with other SSRIs, citalopram can cause an increase in serumprolactin level.[47]Citalopram has no significant effect on insulin sensitivity in women of reproductive age[48] and no changes in glycaemic control were seen in another trial.[49]
Antidepressant exposure (including citalopram) during pregnancy is associated with shorter duration ofgestation (by three days), increased risk of preterm delivery (by 55%), lower birth weight (by 75 g), and lowerApgar scores (by <0.4 points). Antidepressant exposure is not associated with an increased risk of spontaneous abortion.[50] It is uncertain whether there is an increased prevalence of septal heart defects among children whose mothers were prescribed an SSRI in early pregnancy.[51][52]
Overdosage may result in vomiting, sedation, disturbances in heart rhythm, dizziness, sweating, nausea, tremors, and rarely amnesia, confusion, coma, or convulsions.[33]: 105 Overdose deaths have occurred, sometimes involving other drugs, but also with citalopram as the sole agent. Citalopram and N-desmethylcitalopram may be quantified 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.[45][53][54] It is the most dangerous of SSRIs in overdose.[55]
SSRI discontinuation syndrome has been reported when treatment is stopped. It includes sensory, and gastrointestinal symptoms, dizziness, lethargy, and sleep disturbances, as well as psychological symptoms such as anxiety/agitation, irritability, and poor concentration.[56] Electric shock-like sensations are typical for SSRI discontinuation.[57] Withdrawal symptoms can occur when this medicine is suddenly stopped, such asparaesthesiae, sleeping problems (difficulty sleeping and intense dreams), feeling dizzy, agitated or anxious, nausea, vomiting, tremors, confusion, sweating, headache, diarrhea, palpitations, changes in emotions, irritability, and eye or eyesight problems. Treatment with citalopram should be reduced gradually when treatment is finished.[58]
Citalopram should not be taken withSt John's wort,tryptophan or5-HTP as the resulting drug interaction could lead toserotonin syndrome.[59] With St John's wort, this may be caused by compounds in the plant extract reducing the efficacy of thehepaticcytochrome P450 enzymes that process citalopram.[60] Tryptophan and 5-HTP are precursors to serotonin.[61] When taken with an SSRI, such as citalopram, this can lead to levels of serotonin that can be lethal. This may also be the case when SSRIs are taken with SRAs (serotonin releasing agents) such as in the case ofMDMA. It is possible that SSRIs could reduce the effects associated with an SRA since SSRIs stop the reuptake of Serotonin by blockingSERT. This would allow less serotonin in and out of the transporters, thus decreasing the likelihood ofneurotoxic effects. However, these concerns are still disputed as the exact pharmacodynamic effects of citalopram and MDMA have yet to be fully identified.[citation needed] Citalopram iscontraindicated in individuals takingMAOIs, owing to a potential forserotonin syndrome.
SSRIs, including citalopram, can increase the risk of bleeding, especially when coupled withaspirin,NSAIDs,warfarin, or otheranticoagulants.[36] Taking citalopram withomeprazole may cause higher blood levels of citalopram. This is a potentially dangerous interaction, so dosage adjustments may be needed or alternatives may be prescribed.[62][63][9]
Citalopram contains two pharmacodynamically distinct enantiomers: (S)-citalopram (escitalopram) and (R)-citalopram. (S)-citalopram is a highly selective serotonin reuptake inhibitor and is thought to be responsible for most of the SRI activity of citalopram.[64][65] (R)-citalopram, by comparison, is a 20-fold less potent SERT inhibitor and antagonizes the actions of (S)-citalopram at this site.[66][67] The mechanism of antagonism is uncertain, but may involve kinetic interactions between the two; it has been proposed that the long-lasting inhibited state of SERT induced by (S)-citalopram may be attenuated by (R)-citalopram binding.[66]
Citalopram has a ~6-fold higher affinity forH1 histamine receptors than (S)-citalopram (Ki = 257nM vs 1500nM), though the clinical significance of this difference is unknown.[68] Both citalopram and escitalopram have similar affinities for theσ1 receptor (Ki = 50nM).[68]
Citalopram is considered safe and well tolerated in thetherapeutic dose range. Distinct from some other agents in its class, it exhibits linearpharmacokinetics and minimaldrug interaction potential, making it a better choice for the elderly orcomorbid patients.[69]
Citalopram has onestereocenter, to which a4-fluorophenyl group and anN, N-dimethyl-3-aminopropyl group bind. As a result of thischirality, the molecule exists in (two)enantiomeric forms (mirror images). They are termedS-(+)-citalopram andR-(–)-citalopram.
(S)-(+)-citalopram
(R)-(–)-citalopram
Citalopram is sold as aracemic mixture, consisting of 50% (R)-(−)-citalopram and 50% (S)-(+)-citalopram. Only the (S)-(+) enantiomer has the desired antidepressant effect.[70]Lundbeck now markets the (S)-(+) enantiomer, the generic name of which isescitalopram. Whereas citalopram is supplied as thehydrobromide, escitalopram is sold as theoxalate salt (hydrooxalate).[36] In both cases, thesalt forms of the amine make these otherwiselipophilic compounds water-soluble.
Citalopram is metabolized in the liver mostly byCYP2C19, but also byCYP3A4 andCYP2D6. Metabolites desmethylcitalopram and didesmethylcitalopram are significantly less energetic and their contribution to the overall action of citalopram is negligible. The half-life of citalopram is about 35 hours. Approximately 80% is cleared by the liver and 20% by the kidneys.[71] The elimination process is slower in the elderly and in patients with liver orkidney failure. With once-daily dosing, steady plasma concentrations are achieved in about a week. Potent inhibitors of CYP2C19 and 3A4 might decrease citalopram clearance.[9]Tobacco smoke exposure was found to inhibit the biotransformation of citalopram in animals, suggesting that the elimination rate of citalopram is decreased after tobacco smoke exposure. After intragastric administration, the half-life of theracemic mixture of citalopram was increased by about 287%.[72]
Citalopram was first synthesized in 1972 by chemist Klaus Bøgesø[77] and his research group at the pharmaceutical companyLundbeck and was first marketed in 1989 in Denmark. It was first marketed in the US in 1998.[78] The originalpatent expired in 2003, allowing other companies to legally produce and marketgeneric versions.
On 19 June 2013, theEuropean Commission imposed a fine of €93.8 million on the Danish pharmaceutical companyLundbeck, plus a total of €52.2 million on several generic pharmaceutical-producing companies. This was in response to Lundbeck entering an agreement with the companies to delay their sales of generic citalopram after Lundbeck'spatent on the drug had expired, thus reducing competition in breach of Europeanantitrust law.[83]
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