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INFOMATION:
Citalopram (/sɪˈtælɵpræm/ or /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,[1] which it received in 1998[2] and is prescribed off-label for other conditions. In Australia, the UK, Germany, Portugal, Poland, and most European countries it is licenced for depressive episodes and panic disorder with or without agoraphobia. In Spain it is also used for obsessive-compulsive disorder.
Medical uses
Citalopram HBr tablets in 20 mg (coral, marked 508) and 40 mg (white, marked 509), and a United States one-cent coin (size 19.05mm/0.75").Depression
Evidence does not show a benefit from citalopram in children with depression.
Anxiety disorders
There is controversy over selective publishing of SSRI clinical trials by pharmaceutical companies. A meta-analysis analyzing published as well as unpublished trials found the benefits of SSRIs over placebos to be insignificant in all but the severe cases of depression (benefits over placebo were substantial in severe cases).
According to other authors citalopram is an established first-line antidepressant, of comparable efficacy to other antidepressants. In NICE (National Institute for Health and Clinical Excellence) ranking of the 10 antidepressants for efficacy and cost-effectiveness citalopram is fifth in effectiveness (after mirtazapine, escitalopram, venlafaxine and sertraline) and fourth in cost effectiveness. The ranking results were based on the metaanalysis by Andrea Cipriani In another analysis by Cipriani citalopram turned out to be more efficacious than paroxetine and reboxetine and more acceptable than tricyclics, reboxetine and venlafaxine, however it seemed to be less efficacious than escitalopram.
Panic disorder
Citalopram is licensed in the UK and other European countries for panic disorder, with or without agoraphobia. The dose is 10 mg/d for a week, increasing to 20–30 mg/d, with a maximum of 60 mg/d. It appears equally effective as escitalopram.
SSRIs develop their action over two weeks, but most studies were not powered to detect earlier onset. Some authors suggest that onset of action may be quicker than two weeks, although there are contrary opinions.
Off-label
Citalopram is frequently used off-label to treat anxiety, panic disorder, dysthymia premenstrual dysphoric disorder, body dysmorphic disorder and obsessive–compulsive disorder.
It has been shown to be effective in 85% patients with GAD (generalized anxiety disorder), including some who had failed with other SSRIs It also appears to be as effective as fluvoxamine and paroxetine in obsessive-compulsive disorder. Some data suggests the effectiveness of intravenous infusion of citalopram in resistant OCD. Citalopram 40 mg/d is well tolerated and as effective as moclobemide in social anxiety disorder. There are studies suggesting that citalopram can be useful in reducing aggressive and impulsive behavior. It appears to be superior to placebo for behavioural disturbances associated with dementia. It has also been used successfully for hypersexuality in early Alzheimer’s disease.
A meta analysis, including studies with fluoxetine, paroxetine, sertraline, escitalopram and citalopram versus placebo, showed that SSRIs are effective in reducing symptoms of premenstrual syndrome (PMS), whether taken continuously or just in the luteal phase. Citalopram has produced a modest reduction in alcoholic drink intake and increase in drink-free days in studies of alcoholics, possibly by decreasing desire or reducing the reward
Citalopram has been found to reduce the symptoms of diabetic neuropathy.
While on its own citalopram is less effective than amitriptyline in the prevention of migraines, in refractory cases combination therapy may be more effective.
Citalopram and other SSRIs can be used to treat hot flashes.: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.
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.
Administration
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, 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. 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.
Adverse effects
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, 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. This is known as post-SSRI sexual dysfunction. One study showed however that when remission of major depressive disorder is achieved, quality of life is reported to be higher in spite of sexual side effects.
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.:104
Common side effects of citalopram include drowsiness, insomnia, nausea, weight changes, vivid dreaming, frequent urination, decreased sex drive, anorgasmia, dry mouth, 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, severe allergic reactions and photosensitivity. If sedation occurs, the dose may be taken at bedtime rather than in the morning. There is data suggesting that citalopram may cause nightmares.
Withdrawal symptoms can occur when this medicine is suddenly stopped. These include paraesthesiae, sleeping problems such as difficulty sleeping and intense dreams, feeling dizzy, agitated or anxious, nausea, vomiting, tremors, confusion, sweating, headache, diarrhoea, palpitations, changes in emotions, irritability, and eye or eyesight problems. Treatment with citalopram should be reduced gradually when treatment is finished.
Abnormal heart rhythm QTc prolongation
In August 2011, the US Food and Drug Administration (FDA) announced that “Citalopram causes dose-dependent QT interval prolongation. Citalopram should no longer be prescribed at doses greater than 40 mg per day”. 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 2 C19.7 This change, affecting the most widely prescribed antidepressant in the US, left clinicians unclear about appropriate next-step strategies because of the lack of data comparing citalopram with other antidepressants. In a cross-sectional study using electronic health records with almost 40 000 participants modest dose dependent QTc prolongation was confirmed . It was also true for escitalopram and amitriptyline although the effect sizes were small and there is no epidemiological evidence for higher risk of cardiac arythmia. It is clear that randomised investigation is still required in this field. Another large study found no elevated risks of ventricular arrhythmia or all-cause, cardiac, or noncardiac mortality associated with citalopram dosages >40 mg/day. Higher dosages were associated with fewer adverse outcomes, and similar findings were observed for a comparison medication, sertraline, not subject to the FDA warning. Based on these results the authors suggest that continued merit of the FDA warning should be considered.
Citalopram appears safe after the MI (myocardial infarction) and response to citalopram and mirtazapine may improve mortality after the MI Although QTc prolongation warning must be taken into account especially in case of acute myocardial infarction, heart failure decompensation, in patients with bradycardia, low potassium and magnesium levels and in case of dose higher than 40 mg
Bone cell function
Some data suggests that SSRIs increase bone fragility and fracture risk through inhibition of bone cell function via apoptosis. Citalopram seems to have the weakest effect of the SSRIs tested, as order of potency is: sertraline>fluoxetine>paroxetine>fluvoxamine>citalopram
Endocrine effects
As with other SSRI’s, citalopram can cause an increase in serum prolactine level. Citalopram has no significant effect on insulin sensitivity in women of reproductive age and no changes in glycaemic control were seen in another trial.
Exposure in pregnancy
Antidepressant exposure (including citalopram) during pregnancy is associated with shorter duration of gestation (by three days), increased risk of preterm delivery (by 55%), lower birth weight (by 75 g), and lower Apgar scores (by <0.4 points). Antidepressant exposure is not associated with an increased risk of spontaneous abortion.
Citalopram and other SSRIs can induce a mixed state, especially in those with undiagnosed bipolar disorder.:105
Interactions
Citalopram should not be taken with St John's wort, tryptophan or 5-HTP as the resulting drug interaction could lead to serotonin syndrome. 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. 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. One study found that Hypericum extracts had similar effects in treating moderate depression as citalopram, with fewer side effects. 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. This may also be the case when SSRI's are taken with SRA's (Sertonin Releasing Agents) such as in the case of MDMA. It's possible that SSRI's could reduce the effects associated due an SRA, due to the fact that SSRI's stop the reuptake of Serotonin by blocking SERT. This would allow less Serotonin in and out of the transporters, thus decreasing the likelihood of neurotoxic effects. However, these concerns are still disputed as the exact pharmacodynamic effects of Citalopram and MDMA have yet to be fully identified.
SSRIs, including citalopram, can increase the risk of bleeding, especially when coupled with aspirin, NSAIDs, warfarin, or other anticoagulants. Citalopram is contraindicated in individuals taking MAOIs, owing to a potential for serotonin syndrome.
Taking citalopram with Omeprazole may cause higher blood levels of citalopram. This is a potentially dangerous interaction, so dosage adjustments may be needed or alternatives may be prescribed .
SSRI discontinuation syndrome has been reported when treatment is stopped. It includes sensory, gastrointestinal symptoms, dizziness, lethargy, and sleep disturbances, as well as psychological symptoms such as anxiety/agitation, irritability, and poor concentration. Electric shock-like sensations are typical for SSRI discontinuation. 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 Fluoxetine 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 Fluoxetine or by beginning on a low dosage of Fluoxetine 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.
Overdosage
Overdosage may result in vomiting, sedation, disturbances in heart rhythm, dizziness, sweating, nausea, tremor, and rarely amnesia, confusion, coma, or convulsions.: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. It is the most dangerous of SSRIs in overdose.
Suicidality
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.
Stereochemistry
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)-(–)-citalopramCitalopram 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). In both cases, the salt forms of the amine make these otherwise lipophilic compounds water-soluble.
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