Side Effects of Citalopram (Celexa)

Celexa (citalopram) is a selective serotonin reuptake inhibitor (SSRI) antidepressant used to treat depression. It is also used off-label to treat alcoholism, binge-eating disorder, generalized anxiety disorder, panic disorder, hot flashes, and obsessive-compulsive disorder (OCD). 

SSRIs affect neurotransmitters, the chemicals that nerves within the brain use to communicate with each other. Neurotransmitters are manufactured and released by nerves and then travel and attach to nearby nerves. 

Many experts believe an imbalance among neurotransmitters is the cause of depression. Celexa works by preventing the uptake of the neurotransmitter serotonin by nerve cells after it has been released. 

Since uptake is an important mechanism for removing released neurotransmitters and terminating their actions on adjacent nerves, the reduced uptake caused by Celexa results in more free serotonin in the brain to stimulate nerve cells. 

Drug interactions of Celexa include monoamine oxidase inhibitors (MAOs), because such combinations may lead to confusion, high blood pressure, tremor, and hyperactivity. If treatment is to be changed from Celexa to an MAOI or vice-versa, there should be a 14-day period without either drug before the alternative drug is started.

Tryptophan, a common dietary supplement, can cause headaches, nausea, sweating, and dizziness when taken with any SSRI. Linezolid and intravenous methylene blue are also MAO inhibitors and should not be combined with Celexa. Use of an SSRI with aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), or other drugs that affect bleeding may increase the likelihood of upper gastrointestinal bleeding. 

Exposure of neonates to Celexa in the third trimester of pregnancy may cause complications. 

Celexa is excreted in breast milk. Breastfeeding by a Celexa treated woman may cause adverse effects in the infant.

What are the common side effects of Celexa?

The most common side effects associated with citalopram are

• nausea,
• dry mouth,
• vomiting,
• excessive sweating,
• headache,
• tremor,
• drowsiness, and
• inability to sleep.

What are the serious side effects of Celexa?

Serious side effects of Celexa include

• increased risk of suicidal thinking and behavior (suicidality) in children and adolescents with depression and other psychiatric disorders.

Overall, between 1 in 6 and 1 in 5 persons experience a side effect. Citalopram is also associated with sexual dysfunction.

Suicidal Behavior

Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with depression and other psychiatric disorders. Anyone considering the use of citalopram or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be closely observed for clinical worsening, suicidality, or unusual changes in behavior.

Drug Abuse And Dependence

Some patients may experience withdrawal reactions upon stopping citalopram. Symptoms of withdrawal include:

• dizziness,
• tingling sensations,
• tiredness,
• vivid dreams, and
• irritability or poor mood.

Controlled Substance Class

• Celexa (citalopram HBr) is not a controlled substance.

Physical And Psychological Dependence

• Animal studies suggest that the abuse liability of Celexa is low.
• Celexa has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence.
• The premarketing clinical experience with Celexa did not reveal any drug-seeking behavior.
• However, these observations were not systematic and it is not possible to predict, on the basis of this limited experience, the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed.
• Consequently, physicians should carefully evaluate Celexa patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).

Serotonergic Drugs

• See prescribing information.

Triptans

• There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan.
• If concomitant treatment of Celexa with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

CNS Drugs

• Given the primary CNS effects of citalopram, caution should be used when it is taken in combination with other centrally acting drugs.

Alcohol

• Although citalopram did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by depressed patients taking Celexa is not recommended.

Monoamine Oxidase Inhibitors (MAOIs)

See prescribing information.

Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.)

• Serotonin release by platelets plays an important role in hemostasis.
• Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate the risk of bleeding.
• Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin.
• Patients receiving warfarin therapy should be carefully monitored when Celexa is initiated or discontinued.

Cimetidine

• In subjects who had received 21 days of 40 mg/day Celexa, combined administration of 400 mg twice a day cimetidine for 8 days resulted in an increase in citalopram AUC and Cmax of 43% and 39%, respectively.
• Celexa 20 mg/day is the maximum recommended dose for patients taking concomitant cimetidine because of the risk of QT prolongation.

Digoxin

• In subjects who had received 21 days of 40 mg/day Celexa, combined administration of Celexa and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin.

Lithium

• Coadministration of Celexa (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium.
• Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of citalopram, caution should be exercised when Celexa and lithium are coadministered.

Pimozide

• In a controlled study, a single dose of pimozide 2 mg co-administered with citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone.
• Citalopram did not alter the mean AUC or Cmax of pimozide. The mechanism of this pharmacodynamic interaction is not known.

Theophylline

• Combined administration of Celexa (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline.
• The effect of theophylline on the pharmacokinetics of citalopram was not evaluated.

Sumatriptan

• There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a SSRI and sumatriptan.
• If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram) is clinically warranted, appropriate observation of the patient is advised.

Warfarin

• Administration of 40 mg/day Celexa for 21 days did not affect the pharmacokinetics of warfarin, a CYP3A4 substrate.
• Prothrombin time was increased by 5%, the clinical significance of which is unknown.

Carbamazepine

• Combined administration of Celexa (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate.
• Although trough citalopram plasma levels were unaffected, given the enzymeinducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of citalopram should be considered if the two drugs are coadministered.

Triazolam

• Combined administration of Celexa (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either citalopram or triazolam.

Ketoconazole

• Combined administration of Celexa (40 mg) and ketoconazole (200 mg) decreased the Cmax and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram.

CYP2C19 Inhibitors

• Celexa 20 mg/day is the maximum recommended dose for patients taking concomitant CYP2C19 inhibitors because of the risk of QT prolongation.

Metoprolol

• Administration of 40 mg/day Celexa for 22 days resulted in a two-fold increase in the plasma levels of the beta-adrenergic blocker metoprolol.
• Increased metoprolol plasma levels have been associated with decreased cardioselectivity.
• Coadministration of Celexa and metoprolol had no clinically significant effects on blood pressure or heart rate.

Imipramine And Other Tricyclic Antidepressants (TCAs)

• In vitro studies suggest that citalopram is a relatively weak inhibitor of CYP2D6.
• Coadministration of Celexa (40 mg/day for 10 days) with the TCA imipramine (single dose of 100 mg), a substrate for CYP2D6, did not significantly affect the plasma concentrations of imipramine or citalopram. However, the concentration of the imipramine metabolite desipramine was increased by approximately 50%.
• The clinical significance of the desipramine change is unknown. Nevertheless, caution is indicated in the coadministration of TCAs with Celexa.

Electroconvulsive Therapy (ECT)

• There are no clinical studies of the combined use of electroconvulsive therapy (ECT) and Celexa.

• The premarketing development program for Celexa included citalopram exposures in patients and/or normal subjects from 3 different groups of studies:
  • 429 normal subjects in clinical pharmacology/pharmacokinetic studies;
  • 4422 exposures from patients in controlled and uncontrolled clinical trials, corresponding to approximately 1370 patient-exposure years.
• There were, in addition, over 19,000 exposures from mostly open-label, European postmarketing studies.
• The conditions and duration of treatment with Celexa varied greatly and included (in overlapping categories) open-label and double-blind studies, inpatient and outpatient studies, fixed-dose and dose-titration studies, and shortterm and long-term exposure.
• Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic examinations.
• Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing.
• Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories.
• In the tables and tabulations that follow, standard World Health Organization (WHO) terminology has been used to classify reported adverse events.
• The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Adverse Findings Observed In Short-Term, Placebo-Controlled Trials

Adverse Events Associated With Discontinuation Of Treatment

Among 1063 depressed patients who received Celexa at doses ranging from 10 to 80 mg/day in placebo-controlled trials of up to 6 weeks in duration, 16% discontinued treatment due to an adverse event, as compared to 8% of 446 patients receiving placebo.

The adverse events associated with discontinuation and considered drug-related (i.e., associated with discontinuation in at least 1% of Celexa-treated patients at a rate at least twice that of placebo) are shown in TABLE 2. It should be noted that one patient can report more than one reason for discontinuation and be counted more than once in this table.

TABLE 2 : Adverse Events Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled, Depression Trials

Adverse Events Occurring at an Incidence of 2% or More Among Celexa -Treated Patients

Table 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred among 1063 depressed patients who received Celexa at doses ranging from 10 to 80 mg/day in placebo-controlled trials of up to 6 weeks in duration. Events included are those occurring in 2% or more of patients treated with Celexa and for which the incidence in patients treated with Celexa was greater than the incidence in placebo-treated patients.

The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators.

The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied.

The only commonly observed adverse event that occurred in Celexa patients with an incidence of 5% or greater and at least twice the incidence in placebo patients was ejaculation disorder (primarily ejaculatory delay) in male patients (see TABLE 3).

TABLE 3 : Treatment-Emergent Adverse Events : Incidence in Placebo-Controlled Clinical Trials *

Dose Dependency Of Adverse Events

The potential relationship between the dose of Celexa administered and the incidence of adverse events was examined in a fixed-dose study in depressed patients receiving placebo or Celexa 10, 20, 40, and 60 mg. Jonckheere's trend test revealed a positive dose response (p<0.05) for the following adverse events: fatigue, impotence, insomnia, sweating increased, somnolence, and yawning.

Male And Female Sexual Dysfunction With SSRIs

Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences.

The table below displays the incidence of sexual side effects reported by at least 2% of patients taking Celexa in a pool of placebo-controlled clinical trials in patients with depression.

• In female depressed patients receiving Celexa, the reported incidence of decreased libido and anorgasmia was 1.3% (n=638 females) and 1.1% (n=252 females), respectively.
• There are no adequately designed studies examining sexual dysfunction with citalopram treatment.
• Priapism has been reported with all SSRIs.
• While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.

Vital Sign Changes

• Celexa and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, and diastolic blood pressure) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables.
• These analyses did not reveal any clinically important changes in vital signs associated with Celexa treatment.
• In addition, a comparison of supine and standing vital sign measures for Celexa and placebo treatments indicated that Celexa treatment is not associated with orthostatic changes.

Weight Changes

• Patients treated with Celexa in controlled trials experienced a weight loss of about 0.5 kg compared to no change for placebo patients.

Laboratory Changes

• Celexa and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables, and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables.
• These analyses revealed no clinically important changes in laboratory test parameters associated with Celexa treatment.

ECG Changes

• In a thorough QT study, Celexa was found to be associated with a dose-dependent increase in the QTc interval.
• Electrocardiograms from Celexa (N=802) and placebo (N=241) groups were compared with respect to outliers defined as subjects with QTc changes over 60 msec from baseline or absolute values over 500 msec post-dose, and subjects with heart rate increases to over 100 bpm or decreases to less than 50 bpm with a 25% change from baseline (tachycardic or bradycardic outliers, respectively).
• In the Celexa group 1.9% of the patients had a change from baseline in QTcF >60 msec compared to 1.2% of the patients in the placebo group.
• None of the patients in the placebo group had a post-dose QTcF >500 msec compared to 0.5% of the patients in the Celexa group.
• The incidence of tachycardic outliers was 0.5% in the Celexa group and 0.4% in the placebo group.
• The incidence of bradycardic outliers was 0.9% in the Celexa group and 0.4% in the placebo group.

Other Events Observed During The Premarketing Evaluation Of Celexa (citalopram HBr)

Following is a list of WHO terms that reflect treatment-emergent adverse events, as defined in the introduction to the Adverse Reactions section, reported by patients treated with Celexa at multiple doses in a range of 10 to 80 mg/day during any phase of a trial within the premarketing database of 4422 patients.

All reported events are included except those already listed in Table 3 or elsewhere in labeling, those events for which a drug cause was remote, those event terms which were so general as to be uninformative, and those occurring in only one patient.

It is important to emphasize that, although the events reported occurred during treatment with Celexa, they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions:

• frequent adverse events are those occurring on one or more occasions in at least 1/100 patients;
• infrequent adverse events are those occurring in less than 1/100 patients but at least 1/1000 patients;
• rare events are those occurring in fewer than 1/1000 patients.

Cardiovascular

• Frequent: tachycardia, postural hypotension, hypotension.
• Infrequent: hypertension, bradycardia, edema (extremities), angina pectoris, extrasystoles, cardiac failure, flushing, myocardial infarction, cerebrovascular accident, myocardial ischemia.
• Rare: transient ischemic attack, phlebitis, atrial fibrillation, cardiac arrest, bundle branch block.

Central And Peripheral Nervous System Disorders

• Frequent: paresthesia, migraine.
• Infrequent: hyperkinesia, vertigo, hypertonia, extrapyramidal disorder, leg cramps, involuntary muscle contractions, hypokinesia, neuralgia, dystonia, abnormal gait, hypesthesia, ataxia.
• Rare: abnormal coordination, hyperesthesia, ptosis, stupor.

Endocrine Disorders  

• Rare: hypothyroidism, goiter, gynecomastia.

Gastrointestinal Disorders

• Frequent: saliva increased, flatulence.
• Infrequent: gastritis, gastroenteritis, stomatitis, eructation, hemorrhoids, dysphagia, teeth grinding, gingivitis, esophagitis.
• Rare: colitis, gastric ulcer, cholecystitis, cholelithiasis, duodenal ulcer, gastroesophageal reflux, glossitis, jaundice, diverticulitis, rectal hemorrhage, hiccups.

General

• Infrequent: hot flushes, rigors, alcohol intolerance, syncope, influenza-like symptoms.
• Rare: hayfever.

Hemic and Lymphatic Disorders

• Infrequent: purpura, anemia, epistaxis, leukocytosis, leucopenia, lymphadenopathy.
• Rare: pulmonary embolism, granulocytopenia, lymphocytosis, lymphopenia, hypochromic anemia, coagulation disorder, gingival bleeding.

Metabolic and Nutritional Disorders

• Frequent: decreased weight, increased weight.
• Infrequent: increased hepatic enzymes, thirst, dry eyes, increased alkaline phosphatase, abnormal glucose tolerance.
• Rare: bilirubinemia, hypokalemia, obesity, hypoglycemia, hepatitis, dehydration.

Musculoskeletal System Disorders

• Infrequent: arthritis, muscle weakness, skeletal pain.
• Rare: bursitis, osteoporosis.

Psychiatric Disorders

• Frequent: impaired concentration, amnesia, apathy, depression, increased appetite, aggravated depression, suicide attempt, confusion.
• Infrequent: increased libido, aggressive reaction, paroniria, drug dependence, depersonalization, hallucination, euphoria, psychotic depression, delusion, paranoid reaction, emotional lability, panic reaction, psychosis.
• Rare: catatonic reaction, melancholia.

Reproductive Disorders /Female*

• Frequent: amenorrhea.
• Infrequent: galactorrhea, breast pain, breast enlargement, vaginal hemorrhage.

Respiratory System Disorders

• Frequent: coughing.
• Infrequent: bronchitis, dyspnea, pneumonia.
• Rare: asthma, laryngitis, bronchospasm, pneumonitis, sputum increased.

Skin and Appendages Disorders

• Frequent: rash, pruritus.
• Infrequent: photosensitivity reaction, urticaria, acne, skin discoloration, eczema, alopecia, dermatitis, skin dry, psoriasis.
• Rare: hypertrichosis, decreased sweating, melanosis, keratitis, cellulitis, pruritus ani.

Special Senses

• Frequent: accommodation abnormal, taste perversion.
• Infrequent: tinnitus, conjunctivitis, eye pain.
• Rare: mydriasis, photophobia, diplopia, abnormal lacrimation, cataract, taste loss.

Urinary System Disorders

• Frequent: polyuria.
• Infrequent: micturition frequency, urinary incontinence, urinary retention, dysuria.
• Rare: facial edema, hematuria, oliguria, pyelonephritis, renal calculus, renal pain.

Other Events Observed During The Postmarketing Evaluation Of Celexa (citalopram HBr)

It is estimated that over 30 million patients have been treated with Celexa since market introduction. Although no causal relationship to Celexa treatment has been found, the following adverse events have been reported to be temporally associated with Celexa treatment, and have not been described elsewhere in labeling:

• acute renal failure,
• akathisia,
• allergic reaction,
• anaphylaxis,
• angioedema,
• choreoathetosis,
• chest pain,
• delirium,
• dyskinesia,
• ecchymosis,
• epidermal necrolysis,
• erythema multiforme,
• gastrointestinal hemorrhage,
• angle closure glaucoma,
• grand mal convulsions,
• hemolytic anemia,
• hepatic necrosis,
• myoclonus,
• nystagmus,
• pancreatitis,
• priapism,
• prolactinemia,
• prothrombin decreased,
• QT prolonged,
• rhabdomyolysis,
• spontaneous abortion,
•  thrombocytopenia,
• thrombosis,
• ventricular arrhythmia,
• torsade de pointes, and
• withdrawal syndrome.