Citalopram

Article Author:
Nazila Sharbaf Shoar
Article Author:
Kamron Fariba
Article Editor:
Ranjit Padhy
Updated:
4/13/2020 12:14:32 AM
PubMed Link:
Citalopram

Indications

Citalopram hydrobromide is a selective serotonin reuptake inhibitor.[1] The only FDA-approved clinical use for citalopram hydrobromide is for the treatment of depression in adults (18 years or older)[2]:

  • Recommendation: Adult, class IIa
  • Strength of Evidence: Adult, category B

Common off-label use: 

  • Obsessive-compulsive disorder (OCD)
  • Panic disorder
  • Generalized anxiety disorder (GAD)
  • Social anxiety disorder (SAD)
  • Separation anxiety disorder 
  • Premenstrual dysphoric disorder (PMDD)

The advantages and disadvantages of using this drug in the non-FDA approved conditions have their basis on the patient's condition and the clinician's judgment.

Mechanism of Action

Citalopram hydrobromide acts as an antidepressant by potentiating serotonergic activity in the central nervous system (CNS). Multiple studies confirmed that citalopram hydrobromide is a selective serotonin reuptake inhibitor (SSRI) and that it has minimal effects on norepinephrine (NE) and dopamine (DA) neuronal reuptake.[3] It has a low affinity for muscarinic acetylcholine receptors, mild antagonist actions at histamine (H1), but no significant effect on alpha- or beta-adrenergic receptors or dopamine-1, dopamine-2, gamma-aminobutyric acid, opioid, or benzodiazepine receptors.[4][5][4]

  • The onset of action for depression is about 1 to 4 weeks. However, the full response may take 8 to 12 weeks after initiation of treatment.
  • Bioavailability is 80%: Tablets and oral solution are bioequivalent
  • Half-life is 24 to 48 hours (average: 35 hours); however, half-life significantly increases in patients with hepatic impairment, mild-to-moderate renal impairment, in elderly patients (60 years or older), and poor CYP2C19 metabolizers
  • metabolized by CYP450 3A4 and 2C19; a weak inhibitor of CYP450 2D6

Administration

The oral route for adults younger than 60 years:

  • An initial dose of 20 mg once daily (morning or evening, with or without food)
  • Increase the dose to 40 mg after one week (maximum dose of 40 mg daily)
  • The maximum dose is 20 mg daily for patients older than 60 years old or poor metabolizers of CYP2C19 20

Currently, anecdotal reports suggest that higher doses may benefit those afflicted with OCD; however, doses of more than 40 mg daily are not recommended due to the risk of QT prolongation.[6][7][8]

Adverse Effects

Reports suggest that adverse reactions occur up to 10% of patients[9][10][11]:

More common side effects include[12]:

  • CNS: Drowsiness, insomnia, dizziness, headache (dose dependant)
  • Dermatologic: Diaphoresis
  • Gastrointestinal (GI): Nausea, vomiting, xerostomia, constipation, diarrhea
  • Sexual: Ejaculation disorder (dose dependant)

Less common serious adverse effects:

  • Cardiovascular: Myocardial infarction, prolonged QT interval, Torsades de pointes
  • Hematologic: Hemorrhage, abnormal
  • Neurologic: Cerebrovascular accident
  • Psychiatric: Suicidal ideation, suicide, induction of mania
  • Other: Serotonin syndrome 

A rare adverse effect is hyponatremia resulting from SIADH (syndrome of inappropriate antidiuretic hormone secretion). Citalopram has shown to induce hyponatremia in case reports involving elderly patients. In addition to advanced age, other factors such as female gender, concurrent diuretic use, low body weight, and recent pneumonia may increase the likelihood of hyponatremia.

There are suggestions that there is a direct correlation between dose and symptom severity for the following adverse effects: impotence, fatigue, somnolence, insomnia, sweating, and yawning.

Abrupt discontinuation of antidepressant (also known as discontinuation syndrome):

Discontinuation syndrome is common in patients who suddenly stop antidepressant therapy. The most common symptoms include nausea, vomiting, diarrhea, headaches, light-headedness, dizziness, diminished appetite, sweating, chills, tremors, fatigue, somnolence, and sleep disturbances.  Less common symptoms include electric shock-like sensations, cardiac arrhythmias, myalgia, arthralgia, and balance difficulties. Due to these side effects, gradual tapering of the antidepressant over several weeks to several months (based on the treatment duration) is a strong recommendation. The half-life of drugs and duration of the therapy should factor in these decisions as antidepressants with a shorter half-life may need to be tapered more conservatively.

Black Box Warning

Citalopram hydrobromide has correlated with suicidality and worsening depression, especially in children, adolescents, and young adults (younger than 24 years old). Antidepressants increased the risk of suicidal thinking compared to placebo in children, adolescents, and young adults. The advantages and disadvantages of using citalopram hydrobromide or any other antidepressant in these populations depend on the patient's condition and the clinician's judgment.[13]

Patients of any age who start antidepressant therapy should be monitored and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Citalopram hydrobromide does not have approval for use in pediatric patients.

Increased risk of suicidal ideation and treatment-emergent suicidal ideation (TESI) is a concern in younger patients at the onset of therapy. However, an analysis of 17 controlled clinical trials involving 5000 patients treated with either citalopram, a tricyclic antidepressant, another SSRI, or a placebo indicated that the group receiving citalopram had the lowest incidence of suicide.

Family and twin studies provide some evidence of a genetic influence on suicidal behavior, and some postulate that genetic influences may play a role in TESI.

Contraindications

Citalopram is contraindicated with concomitant use of monoamine oxidase inhibitors (MAOIs). Evidence suggests that concurrent use of citalopram alongside an MAOI can result in serotonin syndrome (serotonergic hyperactivity). Symptoms of serotonin syndrome include rigidity, hyperthermia, autonomic instability, mental status changes, and coma. Similar adverse reactions are possible in patients who had abruptly switched from an SSRI to an MAOI; therefore, recommendations are to wait 14 days after discontinuing citalopram to initiate an MAOI.[14]

Citalopram is also contraindicated in patients with a history of hypersensitivity to the drug.

Secondary to its inhibitory effects on 2D6, it could hypothetically increase concentrations of thioridazine, inducing dangerous arrhythmias.

Not an absolute contraindication in pregnancy but is not generally recommended, especially during the first trimester. 

Canadian labeling includes additional contraindications not included in United States labeling: known QT interval prolongation or congenital long QT syndrome.

Monitoring

Before initiation of the treatment:

Monitor and evaluate the electrolytes, especially potassium and sodium, prior to initiating therapy. Reevaluating electrolyte in patients at risk for electrolyte disturbances during the treatment is recommended.  

Monitor patients for QT-prolongation.  ECG is necessary for patients with congenital long QT syndrome, bradycardia, hypokalemia or hypomagnesemia, recent acute myocardial infarction, uncompensated heart failure, or concomitant use of other QT-prolonging drugs.[15]

During the treatment:

Patients need to be assessed and monitored for worsening of depression, suicidality, or unusual changes in behavior during the initial few months of therapy or when the dose increases or decreases. Weekly face-to-face contact with patients during the initial first month of treatment, followed by visits every other week for the next month, and ultimately at three-month intervals, is recommended.

Weight and growth should be monitored regularly by a physician during treatment in children and adolescents.

Toxicity

Studies reveal that even at doses up to 100 mg, toxicity is not common. However, there is a chance of developing serotonin hyperactivity at therapeutic doses, primarily if using another serotonergic medication concomitantly.

In the event of an intentional overdose, the ingestion of more than 600 mg citalopram requires 8 hours of cardiac monitoring. At the end of the observation period, if the patient is asymptomatic and QTc is less than 450 milliseconds, the patient can be discharged. However, in patients with QTc of greater than 450 milliseconds at the end of the observation period, inpatient continued cardiac monitoring is necessary.[16]

Enhancing Healthcare Team Outcomes

Citalopram hydrobromide is a widely prescribed antidepressant by the nurse practitioner, primary care provider, psychiatrist, internist, and the neurologist. While the drug is effective for depression, its use requires monitoring. The drug has correlations with suicidality and worsening depression, especially in children, adolescents, and young adults (younger than 24 years old).  Also, one should monitor electrolytes and obtain an ECG before starting treatment because of the risk of prolonged QT syndrome. Patients should be educated not to combine the drug with alcohol, sedatives, and other antidepressants. 


References

[1] Lochmann D,Richardson T, Selective Serotonin Reuptake Inhibitors. Handbook of experimental pharmacology. 2019 Mar 6;     [PubMed PMID: 30838457]
[2] Cipriani A,Purgato M,Furukawa TA,Trespidi C,Imperadore G,Signoretti A,Churchill R,Watanabe N,Barbui C, Citalopram versus other anti-depressive agents for depression. The Cochrane database of systematic reviews. 2012 Jul 11     [PubMed PMID: 22786497]
[3] Luo Y,Chaimani A,Kataoka Y,Ostinelli EG,Ogawa Y,Cipriani A,Salanti G,Furukawa TA, Evidence synthesis, practice guidelines and real-world prescriptions of new generation antidepressants in the treatment of depression: a protocol for cumulative network meta-analyses and meta-epidemiological study. BMJ open. 2018 Dec 9;     [PubMed PMID: 30530583]
[4] Hyttel J, Citalopram--pharmacological profile of a specific serotonin uptake inhibitor with antidepressant activity. Progress in neuro-psychopharmacology & biological psychiatry. 1982     [PubMed PMID: 6128769]
[5] Baumann P, Pharmacokinetic-pharmacodynamic relationship of the selective serotonin reuptake inhibitors. Clinical pharmacokinetics. 1996 Dec     [PubMed PMID: 8968657]
[6] Wagner E,Löhrs L,Siskind D,Honer WG,Falkai P,Hasan A, Clozapine augmentation strategies - a systematic meta-review of available evidence. Treatment options for clozapine resistance. Journal of psychopharmacology (Oxford, England). 2019 Jan 30;     [PubMed PMID: 30696332]
[7] Escitalopram 2006;     [PubMed PMID: 30000334]
[8] Alušík Š,Paluch Z, [Citalopram and QT prolongation]. Vnitrni lekarstvi. Winter 2018;     [PubMed PMID: 29334745]
[9] Hekmatjah J,Tareen K,Tareen RS, Citalopram-Associated Alopecia: A Case Report and Brief Literature Review. Current drug safety. 2019 Feb 14;     [PubMed PMID: 30767750]
[10] Aboukarr A,Giudice M, Interaction between Monoamine Oxidase B Inhibitors and Selective Serotonin Reuptake Inhibitors. The Canadian journal of hospital pharmacy. 2018 May-Jun;     [PubMed PMID: 29955193]
[11]     [PubMed PMID: 10863884]
[12]     [PubMed PMID: 1711447]
[13] Rahikainen AL,Vauhkonen P,Pett H,Palo JU,Haukka J,Ojanperä I,Niemi M,Sajantila A, Completed suicides of citalopram users-the role of CYP genotypes and adverse drug interactions. International journal of legal medicine. 2019 Mar;     [PubMed PMID: 30173302]
[14]     [PubMed PMID: 15014625]
[15]     [PubMed PMID: 1431024]
[16] Macaluso M,Preskorn SH, Knowledge of the Pharmacology of Antidepressants and Antipsychotics Yields Results Comparable With Pharmacogenetic Testing. Journal of psychiatric practice. 2018 Nov;     [PubMed PMID: 30395549]