VA Class:CN609

AHFS Class:

• Selective Serotonin-reuptake Inhibitors 28:16.04.20

Generic Name(s):

• Citalopram Hydrobromide

Chemical Name:

• 1-[3-(Dimethylamino)-propyl]-1-( p -fluorophenyl)-5-phthalancarbonitrile

Molecular Formula:

• C₂₀H₂₁FN₂O

Citalopram hydrobromide, a selective serotonin-reuptake inhibitor (SSRI), is an antidepressant.1,18,26,52

Citalopram hydrobromide is used in the treatment of major depressive disorder.1,62,69,78,89,99,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,140,141,142,163,187,341,361 In addition, citalopram has been used for the treatment of obsessive-compulsive disorder†,172,173,174,175,176,183,184,186 panic disorder†,28,29,174,189,288,289 social phobia† (social anxiety disorder),350,351,352,353,354,355 alcohol dependence†,40,42,43,44,45,46,47 premenstrual dysphoric disorder†,181,182 premature ejaculation†,273 eating disorders†,15,16 diabetic neuropathy†,279,280 and posttraumatic stress disorder†.281,282

Major Depressive Disorder

Citalopram hydrobromide is used in the treatment of major depressive disorder.1,62,69,78,89,99,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,140,141,142,163,187,341,361,394 A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks).1,102 According to DSM-IV criteria, a major depressive episode includes at least 5 of the following 9 symptoms (with at least one of the symptoms being either depressed mood or loss of interest or pleasure): depressed mood most of the day as indicated by subjective report (e.g., feels sad or empty) or observation made by others; markedly diminished interest or pleasure in all, or almost all, activities most of the day; significant weight loss (when not dieting) or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite; insomnia or hypersomnia; psychomotor agitation or retardation (observable by others, not merely subjective feelings of restlessness or being slowed down); fatigue or loss of energy; feelings of worthlessness or excessive or inappropriate guilt (not merely self-reproach or guilt about being sick); diminished ability to think or concentrate or indecisiveness (either by subjective account or as observed by others); and recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or specific plan for committing suicide.1,13,102,103,104

Treatment of major depressive disorder generally consists of an acute phase (to induce remission), a continuation phase (to preserve remission), and a maintenance phase (to prevent recurrence).13,103,104,187 Various interventions (e.g., psychotherapy, antidepressant drug therapy, electroconvulsive therapy [ECT]) are used alone or in combination to treat major depressive episodes.13,103,104 Treatment should be individualized, and the most appropriate strategy for a particular patient is determined by clinical factors such as severity of depression (e.g., mild, moderate, severe), presence or absence of certain psychiatric features (e.g., suicide risk, catatonia, psychotic or atypical features, alcohol or substance abuse or dependence, panic or other anxiety disorder, cognitive dysfunction, dysthymia, personality disorder, seasonal affective disorder), and concurrent illness (e.g., asthma, cardiac disease, dementia, seizure disorder, glaucoma, hypertension).13 Demographic and psychosocial factors as well as patient preference also are used to determine the most effective treatment strategy.13

While use of psychotherapy alone may be considered as an initial treatment strategy for patients with mild to moderate major depressive disorder (based on patient preference and presence of clinical features such as psychosocial stressors), combined use of antidepressant drug therapy and psychotherapy may be useful for initial treatment of patients with moderate to severe major depressive disorder with psychosocial issues, interpersonal problems, or a comorbid axis II disorder.13 In addition, combined use of antidepressant drug therapy and psychotherapy may be beneficial in patients who have a history of poor compliance or only partial response to adequate trials of either antidepressant drug therapy or psychotherapy alone.13

Antidepressant drug therapy can be used alone for initial treatment of patients with mild major depressive disorder (if preferred by the patient) and usually is indicated alone or in combination with psychotherapy for initial treatment of patients with moderate to severe major depressive disorder (unless ECT is planned).13 ECT is not generally used for initial treatment of uncomplicated major depression, but is recommended as first-line treatment for severe major depressive disorder when it is coupled with psychotic features, catatonic stupor, severe suicidality, food refusal leading to nutritional compromise, or other situations when a rapid antidepressant response is required.13 ECT also is recommended for patients who have previously shown a positive response to or a preference for this treatment modality and can be considered for patients with moderate or severe depression who have not responded to or cannot receive antidepressant drug therapy.13 In certain situations involving depressed patients unresponsive to adequate trials of several individual antidepressant agents, adjunctive therapy with another agent (e.g., buspirone, lithium) or concomitant use of a second antidepressant agent (e.g., bupropion) has been used; however, such combination therapy is associated with an increased risk of adverse reactions, may require dosage adjustments, and (if not contraindicated) should be undertaken only after careful consideration of the relative risks and benefits.13,105,106,165,167,168,337,394,399 (See Drug Interactions: Serotonergic Drugs, Tricyclic and Other Antidepressants under Drug Interactions: Drugs Undergoing Hepatic Metabolism or Affecting Hepatic Microsomal Enzymes, and Drug Interactions: Lithium.)

The efficacy of citalopram for the management of major depression has been established in short-term (4-6 weeks' duration), placebo-controlled studies in outpatients 18-66 years of age who met DSM-III or -III-R criteria for major depressive disorder.1,62,127,142,163 In a 6-week study in which patients received fixed citalopram dosages of 10, 20, 40, or 60 mg daily, the drug was effective at dosages of 40 and 60 mg daily as measured by the Hamilton Depression Rating Scale (HAM-D) Total Score, the HAM-D Depressed Mood Item (Item 1), the Montgomery Asberg Depression Rating Scale, and the Clinical Global Impression (CGI) Severity Scale.1,163 This study showed no clear antidepressant effect of the 10 or 20 mg daily dosages, and the 60 mg daily dosage was not more effective than the 40 mg daily dosage.1,163

In a 4-week, placebo-controlled study in depressed adult patients, of whom 85% met criteria for melancholia, those who were treated with citalopram (at an initial dosage of 20 mg daily, titrated to the maximum tolerated dosage or to a maximum daily dosage of 80 mg) showed greater improvement than patients receiving placebo on the HAM-D Total Score, HAM-D Item 1, and the CGI Severity score.1,127,142 In 3 additional placebo-controlled depression trials, the difference in response to treatment between patients receiving citalopram and patients receiving placebo was not statistically significant, possibly due at least in part to a high spontaneous response rate, a high placebo response rate, small sample size, or, in the case of one study, too low a dosage.1,349

In 2 placebo-controlled studies, depressed adult patients who had responded to an initial 6- to 8-week course of citalopram (fixed dosage of 20 or 40 mg daily in one study and flexible dosages ranging from 20-60 mg daily in the second study) were randomized to continue receiving citalopram or placebo for up to 6 months.1 In both of these studies, patients receiving citalopram experienced substantially lower relapse rates over the subsequent 6 months compared with those receiving placebo.1 In the fixed-dose study, the decreased rate of depression relapse was similar in patients receiving 20 or 40 mg daily of citalopram.1 An analysis of these data for possible age-, gender-, and race-related effects on treatment outcome did not suggest any difference in antidepressant efficacy based on the age, gender, and race of the patient.1 In a placebo-controlled trial, citalopram also was shown to help prevent recurrences of depression in patients with recurrent major depression receiving the drug for up to 6-18 months.187

While the optimum duration of citalopram therapy has not been established, many experts state that acute depressive episodes require several months or longer of sustained antidepressant therapy.1,13,107,108,109,110,111,112,113,187 In addition, some clinicians recommend that long-term antidepressant therapy be considered in certain patients at risk for recurrence of depressive episodes (such as those with highly recurrent unipolar depression).13,108,109,110,111,112,113,114,115,187 In placebo-controlled studies, citalopram has been shown to be effective for the long-term (e.g., up to 18 months) management of depression.1,62,187,340 In addition, the drug has been used in some patients for longer periods (e.g., up to 28 months) without apparent loss of clinical effect or increased toxicity.69,116,117,118,119,187,340 However, when citalopram is used for extended periods, the need for continued therapy should be reassessed periodically.1 (See Dosage and Administration: Dosage.)

The manufacturer states that efficacy of citalopram as an antidepressant in hospital settings has not been studied adequately to date;1 however, the drug has been shown to be effective in hospitalized patients with depression, including severe depression,124,162 in several studies.62,69,99,120,121,122,123,124,125,126,162

As with other antidepressants, the possibility that citalopram may precipitate hypomanic or manic attacks in patients with bipolar or other major affective disorder should be considered.1 Citalopram is not approved for use in treating bipolar depression.1

Considerations in Choosing an Antidepressant

A variety of antidepressant drugs are available for the treatment of major depressive disorder, including selective serotonin-reuptake inhibitors (SSRIs; e.g., citalopram, fluoxetine, paroxetine, sertraline), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs; e.g., desvenlafaxine, duloxetine, venlafaxine), tricyclic antidepressants (e.g., amitriptyline, amoxapine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine), monoamine oxidase (MAO) inhibitors (e.g., phenelzine, tranylcypromine), and other antidepressants (e.g., bupropion, maprotiline, nefazodone, trazodone, vilazodone).13,397,406,425 Most clinical studies have shown that the antidepressant effect of usual dosages of citalopram in patients with depression is greater than that of placebo1,62,118,127,142 and comparable to that of usual dosages of tricyclic antidepressants (e.g., amitriptyline,128,129,130 imipramine,131,133 clomipramine),131,132 other SSRIs (e.g., fluoxetine,134,135 fluvoxamine,135,136 paroxetine,135 sertraline),135,137,138 and other antidepressants (e.g., mirtazapine,140 venlafaxine).135 Escitalopram, the active S -enantiomer of citalopram, also is commercially available for the treatment of depression.217,340,345 Although there is some evidence that escitalopram may offer some clinical advantages compared with citalopram or other SSRIs (e.g., increased efficacy, more rapid onset of therapeutic effect, fewer adverse effects), additional studies are needed to confirm these initial findings.217,348,349 The onset of antidepressant action of citalopram appears to be comparable to that of tricyclic antidepressants and other SSRIs,118,133,137,341 although there is some evidence that the onset of action may occur slightly earlier with citalopram than with some other antidepressants, including sertraline.137,141,142 However, additional study is needed to confirm these findings.141

In general, response rates in patients with major depression are similar for currently available antidepressants, and the choice of antidepressant agent for a given patient depends principally on other factors such as potential adverse effects, safety or tolerability of these adverse effects in the individual patient, psychiatric and medical history, patient or family history of response to specific therapies, patient preference, quantity and quality of available clinical data, cost, and relative acute overdose safety.13,139,167,395 No single antidepressant can be recommended as optimal for all patients because of substantial heterogeneity in individual responses and in the nature, likelihood, and severity of adverse effects.13,139,167,395 In addition, patients vary in the degree to which certain adverse effects and other inconveniences of drug therapy (e.g., cost, dietary restrictions) affect their preferences.13

In the large-scale Sequenced Treatment Alternatives to Relieve Depression (STAR*D) effectiveness trial, patients with major depressive disorder who did not respond to or could not tolerate citalopram therapy were randomized to switch to extended-release (“sustained-release”) bupropion, sertraline, or extended-release venlafaxine as a second step of treatment (level 2).395 Remission rates as assessed by the 17-item Hamilton Rating Scale for Depression (HRSD-17) and the Quick Inventory of Depressive Symptomatology—Self Report (QIDS-SR-16) were approximately 21 and 26% for extended-release bupropion, 18 and 27% for sertraline, and 25 and 25% for extended-release venlafaxine therapy, respectively; response rates as assessed by the QIDS-SR-16 were 26, 27, and 28% for extended-release bupropion, sertraline, and extended-release venlafaxine therapy, respectively.395 These results suggest that after unsuccessful initial treatment of depressed patients with an SSRI, approximately 25% of patients will achieve remission after therapy is switched to another antidepressant, and either another SSRI (e.g., sertraline) or an agent from another class (e.g., bupropion, venlafaxine) may be reasonable alternative antidepressants in patients not responding to initial SSRI therapy.395

Patient Tolerance Considerations

Because of differences in the adverse effect profile between selective serotonin-reuptake inhibitors and tricyclic antidepressants, particularly less frequent anticholinergic effects, cardiovascular effects, and/or weight gain with selective serotonin-reuptake inhibitors, these drugs may be preferred in patients in whom such effects are not tolerated or are of potential concern.13,139 The decreased incidence of anticholinergic effects associated with citalopram and other selective serotonin-reuptake inhibitors compared with tricyclic antidepressants is a potential advantage, since such effects may result in discontinuance of the drug early during therapy in unusually sensitive patients.13,128,129,130,131,133,139,143 In addition, some anticholinergic effects may become troublesome during long-term tricyclic antidepressant therapy (e.g., persistent dry mouth may result in tooth decay).13,109 Although selective serotonin-reuptake inhibitors share the same overall tolerability profile, certain patients may tolerate one drug in this class better than another.144,145,361 Antidepressants other than selective serotonin-reuptake inhibitors may be preferred in patients in whom certain adverse GI effects (e.g., nausea, anorexia), nervous system effects (e.g., anxiety, nervousness, insomnia), and/or weight loss are not tolerated or are of concern, since such effects appear to occur more frequently with citalopram and other drugs in this class.13,143

Pediatric Considerations

The clinical presentation of depression in children and adolescents† can differ from that in adults and generally varies with the age and developmental stages of the child.13,146 Younger children may exhibit behavioral problems such as social withdrawal, aggressive behavior, apathy, sleep disruption, and weight loss; adolescents may present with somatic complaints, self-esteem problems, rebelliousness, poor performance in school, or a pattern of engaging in risky or aggressive behavior.13

Only limited data are available to date from controlled clinical studies evaluating various antidepressant agents in children and adolescents, and many of these studies have methodologic limitations (e.g., nonrandomized or uncontrolled, small sample size, short duration, nonspecific inclusion criteria).146,147,148 However, there is some evidence that the response to antidepressants in pediatric patients may differ from that seen in adults, and caution should be used in extrapolating data from adult studies when making treatment decisions for pediatric patients.147,148,149

Results of several studies evaluating tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine, nortriptyline) in preadolescent and adolescent patients with major depression indicate a lack of overall efficacy in this age group.147,148 Based on the lack of efficacy data regarding use of tricyclic antidepressants and MAO inhibitors in pediatric patients and because of the potential for life-threatening adverse effects associated with the use of these drugs, many experts consider selective serotonin-reuptake inhibitors, including citalopram, the drugs of choice when antidepressant therapy is indicated for the treatment of major depressive disorder in children and adolescents.146,147,148 However, the US Food and Drug Administration (FDA) states that, while efficacy of fluoxetine has been established in pediatric patients, efficacy of other newer antidepressants (i.e., citalopram, desvenlafaxine, duloxetine, escitalopram, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, venlafaxine) was not conclusively established in clinical trials in pediatric patients with major depressive disorder.1,340,370,397,406 In addition, FDA now warns that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders.1,370,371,376 (See Cautions: Pediatric Precautions.) FDA currently states that anyone considering using an antidepressant in a child or adolescent for any clinical use must balance the potential risk of therapy with the clinical need.1,370,376 (See Cautions: Precautions and Contraindications.)

Geriatric Considerations

The response to antidepressants in depressed geriatric patients without dementia is similar to that reported in younger adults, but depression in geriatric patients often is not recognized and is not treated.103,104,407 In geriatric patients with major depressive disorder, SSRIs appear to be as effective as tricyclic antidepressants but may cause fewer overall adverse effects than these other agents.78,103,130 Geriatric patients appear to be especially sensitive to anticholinergic (e.g., dry mouth, constipation, vision disturbance), cardiovascular, orthostatic hypotensive, and sedative effects of tricyclic antidepressants.78,104,130,407 The low incidence of anticholinergic effects associated with citalopram and other SSRIs compared with tricyclic antidepressants is a potential advantage in geriatric patients, since such effects (e.g., constipation, dry mouth, confusion, memory impairment) may be particularly troublesome in these patients.1,13,20,52,103,130 However, SSRI therapy may be associated with other troublesome adverse effects (e.g., nausea and vomiting, agitation and akathisia, parkinsonian adverse effects, sexual dysfunction, weight loss, and hyponatremia).407 Some clinicians state that SSRIs including citalopram may be preferred for treating depression in geriatric patients in whom the orthostatic hypotension associated with many antidepressants (e.g., tricyclics) potentially may result ininjuries (such as severe falls).13,68,139,151 However, despite the fewer cardiovascular and anticholinergic effects associated with SSRIs, these drugs did not show any advantage over tricyclic antidepressants with regard to hip fracture in a case-control study.73 In addition, there was little difference in the rates of falls between nursing home residents receiving SSRIs and those receiving tricyclic antidepressants in a retrospective study.74 Therefore, all geriatric patients receiving either type of antidepressant should be considered at increased risk of falls and appropriate measures should be taken.73,74 In addition, clinicians prescribing SSRIs in geriatric patients should be aware of the many possible drug interactions associated with these drugs, including those involving metabolism of the drugs through the cytochrome P-450 system.407 (See Drug Interactions.)

Patients with dementia of the Alzheimer's type (Alzheimer's disease, presenile or senile dementia) often present with depressive symptoms, such as depressed mood, appetite loss, insomnia, fatigue, irritability, and agitation.152,153,407 Most experts recommend that patients with dementia of the Alzheimer's type who present with clinically significant and persistent depressive symptoms be considered as candidates for pharmacotherapy even if they fail to meet the criteria for a major depressive syndrome.152,153,407 The goals of such therapy are to improve mood, functional status (e.g., cognition), and quality of life.152,153,407 Treatment of depression also may reduce other neuropsychiatric symptoms associated with depression in patients with dementia, including aggression, anxiety, apathy, and psychosis.407 Although patients may present with depressed mood alone, the possibility of more extensive depressive symptomatology should be considered.152,153,407 Therefore, patients should be evaluated and monitored carefully for indices of major depression, suicidal ideation, and neurovegetative signs since safety measures (e.g., hospitalization for suicidal ideations) and more vigorous and aggressive therapy (e.g., relatively high dosages, multiple drug trials) may be needed in some patients.152,153,407

Although placebo-controlled trials of antidepressants in depressed patients with concurrent dementia have shown mixed results,152,153,407 the available evidence and experience with the use of antidepressants in patients with dementia of the Alzheimer's type and associated depressive manifestations indicate that depressive symptoms (including depressed mood alone and with neurovegetative changes) in such patients are responsive to antidepressant therapy.152,154,155,156,157 In some patients, cognitive deficits may partially or fully resolve during antidepressant therapy, but the extent of response will be limited to the degree of cognitive impairment that is directly related to depression.152,407 SSRIs such as citalopram, escitalopram, fluoxetine, paroxetine, or sertraline generally are considered first-line agents in the treatment of depressed patients with dementia since they usually are better tolerated than some other antidepressants (e.g., tricyclic antidepressants, monoamine oxidase inhibitors).152,153,154,155,340,407 Some possible alternative agents to SSRIs include bupropion, mirtazapine, and venlafaxine.407 Some geriatric patients with dementia and depression may be unable to tolerate the antidepressant dosages needed to achieve full remission.407 When a rapid antidepressant response is not critical, some experts therefore recommend a very gradual dosage titration to increase the likelihood that a therapeutic dosage of the SSRI or other antidepressant will be reached and tolerated.407 In a controlled study comparing citalopram and placebo in elderly patients with dementia, citalopram was found to improve depression as well as cognitive and emotional functioning more than placebo.157 In an open study in a limited number of patients with dementia and behavioral disturbances, citalopram was found to improve the behavioral complications associated with dementia†.156

Cardiovascular Considerations

Clinical studies of citalopram for the management of depression generally did not include individuals with cardiovascular disease (e.g., those with a recent history of myocardial infarction or unstable cardiovascular disease).399

Citalopram causes dose-dependent QT_c-interval prolongation, and torsades de pointes, ventricular tachycardia, and sudden death have been reported in postmarketing experience in patients receiving the drug.399,416,417,418,419,420,421,424 Patients with congenital long QT syndrome, uncompensated heart failure, bradyarrhythmias, recent acute myocardial infarction, or hypokalemia or hypomagnesemia or who are receiving other drugs that prolong the QT interval are at higher risk of developing torsades de pointes.416,417,424 (See Cautions: Cardiovascular Effects, Cautions: Precautions and Contraindications, and Drug Interactions: Drugs that Prolong the QT Interval.)

Sedative Considerations

Because citalopram and other selective serotonin-reuptake inhibitors generally are less sedating than some other antidepressants (e.g., tricyclics), some clinicians state that these drugs may be preferable in patients who do not require the sedative effects associated with many antidepressant agents or in patients who are prone to accidents; however, an antidepressant with more prominent sedative effects (e.g., trazodone) may be preferable in certain patients (e.g., those with insomnia).13,139,407

Suicidal Risk Considerations

Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.1,370,371,376 However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidal thinking and behavior (suicidality) in certain patients during the early phases of treatment.1,370 FDA states that antidepressants increased the risk of suicidality in short-term studies in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders.1,370,371 (See Cautions: Pediatric Precautions.) An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age and a reduced risk was observed in adults 65 years of age or older.1,370,371 It currently is unknown whether the suicidality risk extends to longer-term antidepressant use (i.e., beyond several months); however, there is substantial evidence from placebo-controlled maintenance trials in adults with major depressive disorder that antidepressants can delay the recurrence of depression.1,370,371 Because the risk of suicidality in depressed patients may persist until substantial remission of depression occurs, appropriate monitoring and close observation of patients of all ages who are receiving antidepressant therapy are recommended.1,370 (See Cautions: Precautions and Contraindications.)

Other Considerations

Citalopram has been effective in patients with moderate to severe depression,124,129,162,163,164 endogenous depression,69,122,123,124,125 post-stroke depression and pathologic crying,160,161,179 and depression associated with chronic hepatitis C virus infection.159

In an open study in a limited number of patients with bipolar depression† (mainly bipolar I disorder), citalopram was effective and well tolerated when added to monotherapy or combined therapy with lithium, divalproex sodium, and/or carbamazepine.342,343 Controlled studies are needed to confirm these preliminary findings.342,343 The manufacturer states that citalopram is not approved for use in treating bipolar depression, and that the possibility that the drug may precipitate hypomanic or manic attacks in patients with bipolar or other major affective disorder should be considered.1 For detailed information on bipolar disorder, including its management, see Uses: Bipolar Disorder, in Lithium Salts 28:28.

In patients with refractory depression, citalopram was more effective when given in combination with buspirone in one placebo-controlled study.165 However, combined citalopram and buspirone therapy was not found to be more effective than citalopram monotherapy in another placebo-controlled study.166 In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) level 2 trial, patients with major depressive disorder who did not respond to or could not tolerate citalopram therapy were randomized to receive either extended-release (“sustained-release”) bupropion or buspirone therapy in addition to citalopram.394 Although both extended-release bupropion and buspirone were found to produce similar remission rates, extended-release bupropion produced a greater reduction in the number and severity of symptoms and a lower rate of drug discontinuance than buspirone in this large-scale effectiveness trial.394 These results suggest that augmentation of SSRI therapy with extended-release bupropion may be useful in some patients with refractory depression.394 The addition of lithium to citalopram in depressed patients not responding to citalopram alone also has been found to be effective and well tolerated in a double-blind, placebo-controlled trial.168 (See Drug Interactions: Lithium.)

In a limited number of depressed patients not responding to citalopram alone, the addition of carbamazepine was effective and well tolerated in an open study.337 However, the possibility of serotonin syndrome and drug interactions should be considered pending further clinical experience with this combination.1,336,337 (See Drug Interactions: Serotonergic Drugs and Carbamazepine under Drug Interactions: Drugs Undergoing Hepatic Metabolism or Affecting Hepatic Microsomal Enzymes.)

Citalopram was found to improve personality disturbances† (decrease in anxiety and aggression-related symptoms and increase in social desirability and socialization) in depressed patients in one study.180

Obsessive-Compulsive Disorder

Citalopram has been used in the treatment of obsessive-compulsive disorder†.172,173,174,175,176,183,184,186 In a large, double-blind, placebo-controlled trial evaluating citalopram (20, 40, or 60 mg daily for 12 weeks) in adults with obsessive-compulsive disorder, the drug was more effective than placebo as measured by Yale-Brown Obsessive-Compulsive Scale score changes at all 3 dosages.172 The highest response rate (65%) was observed in those who received 60 mg daily; this compared with 52 or 57% in those receiving 40 or 20 mg daily, respectively.172 An analysis of predictors of response to citalopram therapy from this trial suggested that patients with a longer duration of obsessive-compulsive disorder, more severe symptoms, or a history of previous selective serotonin-reuptake inhibitor therapy were less likely to respond to therapy with citalopram.184 In an open trial, 76% of patients with obsessive-compulsive disorder receiving citalopram therapy (usually 40 or 60 mg daily) for 24 weeks demonstrated improved symptoms associated with this condition.173 In another open study, citalopram (40 mg daily) was effective in a limited number of patients with refractory obsessive-compulsive disorder who had failed to respond to therapy with other selective serotonin-reuptake inhibitors.183 Clinical experience to date indicates that citalopram is well tolerated in patients with obsessive-compulsive disorder.172,173,183 Additional study is needed to determine the long-term efficacy of citalopram in the treatment of this condition.348,349

For additional information on the use of selective serotonin-reuptake inhibitors in the treatment of obsessive-compulsive disorder, see Uses: Obsessive-Compulsive Disorder, in Sertraline Hydrochloride 28:16.04.20.

Panic Disorder

Citalopram has been used in the treatment of panic disorder with or without agoraphobia†.28,29,174,189,288,289 In a randomized, single-blind study comparing citalopram and paroxetine in adults with panic disorder, both drugs were found to be effective and well tolerated, with 86% of the citalopram-treated patients and 84% of the paroxetine-treated patients responding well to 2 months of therapy.288 In a limited number of adults with panic disorder, citalopram therapy (20-60 mg daily) produced a full remission in 66% of the patients and improved symptomatology.189

In a large, double-blind, placebo-controlled trial evaluating the efficacy and tolerability of long-term therapy (up to 1 year) with citalopram at 3 dosages (10-15 mg daily, 20-30 mg daily, 40-60 mg daily) or clomipramine in adult outpatients with panic disorder with or without agoraphobia, both drugs were more effective than placebo.289 Citalopram was more effective than placebo at all dosages studied, with a dosage of 20-30 mg daily being the most effective maintenance dosage in most patients.289

For additional information on the use of selective serotonin-reuptake inhibitors in the treatment of panic disorder, see Uses: Panic Disorder, in Sertraline Hydrochloride 28:16.04.20.

Social Phobia

Like some other selective serotonin-reuptake inhibitors, citalopram has been used in the treatment of social phobia† (social anxiety disorder).350,351,352,353,354,355 However, additional evidence from well-designed studies is needed to more fully elucidate the role of the drug in this disorder.350,351,354

In an open study in a limited number of patients with social phobia, 86% of patients responded to citalopram 40 mg daily after 12 weeks as rated by the Clinical Global Impressions (CGI) score and the Liebowitz Social Anxiety Scale (LSAS).354

In an open, flexible-dose study in patients with social anxiety disorder with comorbid major depression, response rates after 12 weeks of citalopram therapy (mean dosage: 38 mg daily) were approximately 67 and 76% for social anxiety disorder and depression, respectively.351 However, the depression symptoms responded more rapidly and completely than the social anxiety symptoms after 12 weeks of citalopram therapy, suggesting that a longer duration of therapy may be necessary to fully assess the clinical efficacy of the drug in such patients.351

In a randomized, open trial comparing citalopram and moclobemide (not commercially available in the US) in patients with social phobia, similar improvements in the CGI-improvement score and LSAS were noted with these drugs.352 Clinical experience to date suggests that citalopram generally is well tolerated in patients with social phobia.353 However, well controlled studies are needed to confirm the efficacy and safety and to determine the optimal dosage of citalopram in patients with this condition.350,351,354

Alcohol Dependence

Like some other selective serotonin-reuptake inhibitors (fluoxetine, zimelidine [not commercially available in the US]), citalopram has been used in the management of alcohol dependence†.40,42,43,44,45,46,47 In clinical studies, citalopram has been shown to reduce alcohol consumption in alcohol-dependent, nondepressed drinkers receiving short-term therapy with 40 mg of the drug daily.40,43,45,46,47 In clinical studies conducted to date with selective serotonin-reuptake inhibitors in alcoholic patients, considerable interindividual variability in response has been observed, with reduction in alcohol consumption ranging from 10 to more than 70%.40,43,45,46,47 Several factors, including gender, alcoholic subtype, presence or absence of depression, and extent of drinking, appear to affect the clinical efficacy of selective serotonin-reuptake inhibitors in the management of alcohol dependence.40,44,46,47 Additional study is required to fully determine the safety and efficacy of citalopram in the management of alcohol dependence.40,42,46 (See Pharmacology: Effects on Alcohol Intake and also see Drug Interactions: Alcohol.)

Premenstrual Dysphoric Disorder

Like some other selective serotonin-reuptake inhibitors (e.g., fluoxetine, paroxetine, sertraline), citalopram has been used in a limited number of women with premenstrual dysphoric disorder† (previously late luteal phase dysphoric disorder).181,182 Clinical experience to date suggests that the onset of action of serotonin-reuptake inhibitors in women with premenstrual dysphoric disorder is more rapid than when used for other psychiatric conditions; therefore, administration only during the luteal phase of the menstrual cycle may potentially be effective in this condition.181,182

In a placebo-controlled trial, intermittent administration of citalopram (10-30 mg daily during the luteal phase) for 3 menstrual cycles appeared to be more effective than continuous (10-30 mg daily throughout the menstrual cycle) or semi-intermittent administration (5 mg daily during the follicular phase and 10-30 mg daily during the luteal phase) of the drug and substantially more effective than placebo.181 Citalopram was well tolerated in all 3 regimens, and adverse effects generally were mild and transient.181 Additional controlled studies are needed to determine whether the efficacy of the drug is sustained during longer-term, maintenance therapy in women with this condition.348,349

Premature Ejaculation

Like some other selective serotonin-reuptake inhibitors, citalopram has been used for the treatment of premature ejaculation†.273 However, studies with citalopram to date have only involved a limited number of patients and there is some evidence that the drug may be less effective than certain other selective serotonin-reuptake inhibitors (e.g., paroxetine).273 In a double-blind study in men with premature ejaculation, citalopram 20 mg daily delayed ejaculation to a slight degree (1. 8-fold increase in intravaginal ejaculation latency time) compared with a marked increase (8. 9-fold increase) with paroxetine 20 mg daily following 6 weeks of therapy.273 These preliminary findings suggest that paroxetine may be more effective than citalopram in the treatment of premature ejaculation.273

Eating Disorders

Citalopram has been used in a limited number of patients for the treatment of bulimia nervosa† or anorexia nervosa†.15,16 Although citalopram reportedly has been effective in some patients with these eating disorders,16 underweight patients with anorexia nervosa who received citalopram in conjunction with psychotherapy did worse (i.e., experienced greater weight loss) than those receiving psychotherapy alone in one open-label study.15 Because of limited evidence and experience to date, the role if any of citalopram in the management of eating disorders remains to be elucidated. For information on the use of selective serotonin-reuptake inhibitors in the treatment of eating disorders, see Uses: Eating Disorders, in Fluoxetine Hydrochloride 28:16.04.20.

Diabetic Neuropathy

Tricyclic antidepressants generally have been considered a mainstay of therapy for the treatment of diabetic neuropathy. However, because of potentially improved patient tolerability, therapy with selective serotonin-reuptake inhibitors or selective serotonin- and norepinephrine-reuptake inhibitors (e.g., duloxetine, venlafaxine) has been attempted as an alternative.279,280,410 In a double-blind, placebo-controlled trial, citalopram (40 mg daily) substantially reduced the symptoms associated with diabetic neuropathy† (pain, paresthesia, and dysesthesia) in a limited number of patients and generally was well tolerated.279,280 When compared with earlier results obtained with imipramine in the management of this condition, selective serotonin-reuptake inhibitors such as citalopram, fluoxetine, paroxetine, and sertraline appear to be less effective but better tolerated overall.279,280 Additional study and experience are needed to elucidate the relative roles of selective serotonin-reuptake inhibitors versus tricyclic antidepressants, selective serotonin- and norepinephrine-reuptake inhibitors, anticonvulsants (e.g., pregabalin, gabapentin), and other forms of treatment in the management of this condition.279,280,410

Posttraumatic Stress Disorder

Citalopram has been used in a limited number of adults with civilian- or combat-related posttraumatic stress disorder† (PTSD).281,282 In an open study, patients treated with citalopram for 8 weeks showed marked improvement in PTSD manifestations (reexperiencing, hyperarousal, and avoidance) as well as in depression and anxiety.281 Well-designed,281,282 controlled studies are needed to confirm these preliminary findings.281,282

For additional information on the use of selective serotonin-reuptake inhibitors in the treatment of PTSD, see Uses: Posttraumatic Stress Disorder, in Prazosin Hydrochloride 24:20, Paroxetine 28:16.04.20, and Sertraline Hydrochloride 28:16.04.20.

Administration

Citalopram hydrobromide is administered orally.1 Citalopram also has been administered by IV infusion†, but a parenteral dosage form is not commercially available in the US.1,162

Citalopram usually is administered once daily in the morning or evening.1 Since food does not substantially affect the absorption of citalopram, the drug may be administered without regard to meals.1

Hypokalemia and hypomagnesemia, if present, should be corrected prior to initiation of citalopram therapy and electrolytes should be monitored periodically during therapy as needed.399,416 (See Cautions: Cardiovascular Effects and also see Cautions: Precautions and Contraindications.)

Dispensing and Administration Precautions

Because of similarity in spelling of Celexa^® (citalopram hydrobromide), Celebrex^® (celecoxib), and Cerebyx^® (fosphenytoin sodium), extra care should be exercised in ensuring the accuracy of prescriptions for these drugs.346

Dosage

Dosage of citalopram hydrobromide is expressed in terms of citalopram.1

Patients receiving citalopram should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustment.1,370,371,376 (See Cautions: Precautions and Contraindications.)

The manufacturers state that at least 2 weeks must elapse between discontinuance of a monoamine oxidase (MAO) inhibitor intended to treat psychiatric disorders and initiation of citalopram therapy and that at least 2 weeks must elapse between discontinuance of citalopram and initiation of MAO inhibitor therapy intended to treat psychiatric disorders.399,615 For additional information on potentially serious drug interactions that may occur between citalopram and MAO inhibitors or other serotonergic agents, see Cautions: Precautions and Contraindications and also see Drug Interactions: Serotonergic Drugs.

Because withdrawal effects may occur with discontinuance of citalopram, other selective serotonin-reuptake inhibitors (SSRIs), and selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), abrupt discontinuance of these drugs should be avoided whenever possible.399 When citalopram therapy is discontinued, the dosage should be reduced gradually (e.g., over a period of several weeks) and the patient monitored for possible withdrawal symptoms.13,14,17,399,407 If intolerable symptoms occur following a dosage reduction or upon discontinuance of therapy, the drug may be reinstituted at the previously prescribed dosage.399 Subsequently, the clinician may continue decreasing the dosage, but at a more gradual rate.399 (See Cautions: Nervous System Effects and see Chronic Toxicity.)

Major Depressive Disorder

For the management of major depressive disorder in adults, the recommended initial dosage of citalopram is 20 mg once daily, with an increase to a maximum dosage of 40 mg once daily at an interval of not less than 1 week.399,424 Previously, the prescribing information for citalopram stated that certain patients may require a dosage of 60 mg daily.399,416,417 However, citalopram dosages above 40 mg once daily no longer are recommended because of the risk of QT-interval prolongation (see Cautions: Cardiovascular Effects and see also Cautions: Precautions and Contraindications) and because they provide no additional therapeutic benefit.399,416,424 A dose-response study did not show the 60-mg daily dosage to be more effective than the 40-mg daily dosage overall.399 Although antidepressant effects may be evident within 1 week in some patients, the full antidepressant effect of citalopram may not be observed for several weeks.18,118,141,174,348,349

While the optimum duration of citalopram therapy has not been established, many experts state that acute depressive episodes require several months or longer of sustained antidepressant therapy.1,13,107,108,109,110,111,112,113,187 In addition, some clinicians recommend that long-term antidepressant therapy be considered in certain patients at risk for recurrence of depressive episodes (such as those with highly recurrent unipolar depression).13,108,109,110,111,112,113,114,115,187 Whether the dosage of citalopram required to induce remission is identical to the dosage needed to maintain and/or sustain euthymia is unknown.1 In placebo-controlled studies, the antidepressant efficacy of citalopram was maintained for up to 8 months in patients receiving 20-60 mg daily.1 In addition, the drug has been used in some patients for longer periods (e.g., up to 28 months) without apparent loss of clinical effect or increased toxicity.69,116,117,118,119,187

If troublesome adverse effects occur during maintenance therapy, the manufacturer states that a decrease in dosage to 20 mg daily can be considered.1 If citalopram is used for extended periods, the need for continued therapy should be reassessed periodically.1

Obsessive-Compulsive Disorder

For the management of obsessive-compulsive disorder† in adults, citalopram usually has been given orally in an initial dosage of 20 mg daily and the dosage was then gradually increased according to clinical response.172,173,174,183 The usual maintenance dosage in adults has been 40 or 60 mg daily;21,172,173,174,183 however, citalopram dosages exceeding 40 mg daily no longer are recommended due to the risk of QT prolongation.399,416,424

Panic Disorder

For the management of panic disorder† in adults, the usual initial dosage of citalopram is 10 mg daily.174 After an interval of at least 1 week, the dosage may be gradually increased in increments of 10-20 mg up to a dosage of 20-40 mg daily, depending on individual patient response and tolerability.28,29,174,288,289 The usual maintenance dosage in adults has been 20-30 mg daily.28,29,289 Citalopram dosages exceeding 40 mg daily no longer are recommended due to the risk of QT prolongation.399,416,424

Dosage in Geriatric Patients

Major Depressive Disorder

For the management of depression in geriatric patients over 60 years of age, the maximum recommended citalopram dosage is 20 mg once daily due to the risk of QT-interval prolongation.399,424 (See Cautions: Cardiovascular Effects.)

For the management of depressive symptoms associated with dementia of the Alzheimer's type in geriatric patients, some experts recommend a lower initial citalopram dosage of 5-10 mg once daily.407 The dosage may then be gradually increased at intervals of at least several weeks up to the maximum recommended dosage of 20 mg once daily.399,407,424

Dosage in Hepatic and Renal Impairment

In depressed patients with hepatic impairment, the maximum recommended citalopram dosage is 20 mg once daily due to the risk of QT-interval prolongation.399,416,424 (See Cautions: Cardiovascular Effects and also see Pharmacokinetics: Elimination.)

Dosage adjustment is not necessary in depressed patients with mild to moderate renal impairment.4,88,399,416 Severe renal failure did not substantially affect the pharmacokinetics of citalopram in one study, suggesting that dosage adjustment also may be unnecessary in patients with severe renal impairment.88 However, the manufacturer recommends that the drug be used with caution in patients with severe renal impairment.399 (See Pharmacokinetics: Elimination.)

Dosage in Poor CYP2C19 Metabolizers or Patients Receiving CYP2C19 Inhibitors

For the management of major depressive disorder in patients who are poor metabolizers of the cytochrome P-450 (CYP) isoenzyme 2C19 and in patients receiving cimetidine or another CYP2C19 inhibitor, the maximum recommended dosage of citalopram is 20 mg once daily due to the risk of QT-interval prolongation.399,416,424 (See CYP2C19 Inhibitors under Drug Interactions: Drugs Undergoing Hepatic Metabolism or Affecting Hepatic Microsomal Enzymes and see also Pharmacokinetics: Elimination.)

Treatment of Pregnant Women during the Third Trimester

Some neonates exposed to citalopram and other SSRIs or SNRIs late in the third trimester of pregnancy have developed severe complications.212,213,380,381,382,383,399 When treating pregnant women with citalopram during the third trimester, the clinician should carefully consider the potential risks and benefits of therapy.383,399 (See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.)

The adverse effect profile of citalopram is similar to that of other selective serotonin-reuptake inhibitors (SSRIs) (e.g., escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline).62,65,118,341 Because citalopram is a highly selective serotonin-reuptake inhibitor with little or no effect on other neurotransmitters, the incidence of some adverse effects commonly associated with tricyclic antidepressants, such as anticholinergic effects (e.g., dry mouth, constipation), certain cardiovascular effects (e.g., orthostatic hypotension), drowsiness, and weight gain, is lower in patients receiving citalopram.1,65,407 However, certain adverse GI (e.g., nausea, anorexia), nervous system (e.g., somnolence, anxiety, nervousness, insomnia), and sexual function effects appear to occur more frequently with citalopram and other SSRIs than with tricyclic antidepressants.1,65,274,407

In controlled studies, the most common adverse effects occurring more frequently in patients receiving citalopram than in those receiving placebo included nervous system effects such as somnolence, insomnia, anxiety, agitation, fatigue, tremor, and yawning; GI effects such as nausea, dry mouth, diarrhea, dyspepsia, anorexia, vomiting, and abdominal pain; sweating; ejaculation dysfunction (principally ejaculation delay) and impotence in male patients, decreased libido, and dysmenorrhea; fever, arthralgia, and myalgia; and upper respiratory tract infection, rhinitis, and sinusitis.1,65,274

The results of a fixed-dose clinical study in depressed patients suggest that somnolence, insomnia, increased sweating, fatigue, impotence, and yawning are dose-related adverse effects of citalopram.1

In short-term, placebo-controlled trials (6 weeks or less), discontinuance of citalopram therapy was required in approximately 16% of depressed patients, principally because of adverse psychiatric (e.g., insomnia, somnolence, agitation), other nervous system (e.g., dizziness, asthenia), or GI (e.g., nausea, vomiting, dry mouth) effects.1

Nervous System Effects

Somnolence1,65 and insomnia1 , which appear to be dose related, are the most common adverse nervous system effects of citalopram, occurring in approximately 18 and 15% of depressed patients, respectively, receiving the drug and in approximately 10 and 14% of those receiving placebo, respectively, in short-term controlled clinical trials.1 Insomnia or somnolence required discontinuance of therapy in about 3 or 2% of patients, respectively.1 However, because insomnia is a symptom also associated with depression, relief of insomnia and improvement in sleep patterns may occur when clinical improvement in depression becomes apparent during antidepressant therapy.244 Sleep disorders1 have been reported in at least 2% of citalopram-treated patients in clinical trials, although a causal relationship to the drug has not been established.1

Fatigue,1 which appeared to be dose related, occurred in approximately 5% of patients receiving citalopram in short-term clinical studies.1 Asthenia1 has been reported in at least 2% of citalopram-treated patients in clinical trials and required discontinuance of therapy in about 1% of patients.1

Tremor1 occurred in about 8%, anxiety1 in about 4%, and agitation1 in about 3% of patients receiving citalopram in short-term clinical studies;1 agitation resulted in discontinuance of therapy in about 1% of patients receiving the drug.1 Nervousness,1 headache,1 yawning,1 and dizziness have been reported in at least 2% of citalopram-treated patients in clinical trials.1 Yawning appeared to be dose related.1 Dizziness1 required discontinuance of therapy in 2% of patients.1

Impaired concentration,1 amnesia,1 apathy,1 depression1 and aggravated depression,1 confusion,1 paresthesia,1 and migraine1 each have been reported in at least 1% of patients receiving citalopram; however, these adverse effects have not been definitely attributed to the drug.1

Adverse nervous system effects reported in at least 0.1% of patients receiving citalopram include aggressive reaction,1 paroniria (disagreeable or terrifying dreams),1 depersonalization,1 hallucinations,1 euphoria,1 psychotic depression,1 delusion,1 paranoid reaction,1 emotional lability,1 panic reaction,1 psychosis,1 vertigo,1 neuralgia,1 abnormal gait,1 hyperkinesia,1 hypertonia,1 hypoesthesia,1 and ataxia;1 a causal relationship to the drug has not been clearly established.1

Seizures occurred in 0.3% of patients receiving citalopram and in 0.5% of patients receiving placebo in clinical studies.1 A causal relationship to citalopram remains to be established in these cases.1,62,65 (See Cautions: Precautions and Contraindications.) Nonconvulsive status epilepticus also has been reported in a geriatric patient receiving citalopram for poststroke depression.364 In addition, involuntary muscle contractions1 have been reported in less than 1% of patients receiving the drug.1

Activation of mania and hypomania have occurred in 0.2% of depressed patients receiving citalopram in placebo-controlled trials; some of these trials included patients with bipolar disorder.1,236,237,327 In an analysis of postmarketing clinical trials, manic episodes were reported in 0.62% of unipolar depressed patients.236 (See Cautions: Precautions and Contraindications.) Such reactions have been reported in patients receiving other antidepressant agents1,238,239,240,241,242 and may be caused by antidepressant-induced functional increases in catecholamine activity within the CNS, resulting in a “switch” from depressive to manic behavior.238,241 There is some evidence that patients with bipolar disorder may be more likely to experience antidepressant-induced hypomanic or manic reactions than patients without evidence of this disorder.238,240,241,243 In addition, limited evidence suggests that such reactions may occur more frequently in bipolar depressed patients receiving tricyclics and tetracyclics (e.g., maprotiline, mianserin [not commercially available in the US]) than in those receiving selective serotonin-reuptake inhibitors (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline).236,240,340 However, further studies are needed to confirm these findings.348

Extrapyramidal reactions1,65,262 associated with citalopram, which are uncommon, appear to be a class effect of selective serotonin-reuptake inhibitors and dose related.65,245,246,247,248,249,262 Reactions occurring early during therapy with the drug may be secondary to preexisting parkinsonian syndrome and/or concomitant therapy.247 Although a causal relationship to citalopram has not been established,1,65 extrapyramidal symptoms reported in at least 0.1% of patients receiving the drug include tremor,1 hypokinesia,1 and dystonia.1 Choreoathetosis1 also has been reported rarely.1 Pending further clinical experience, some clinicians recommend that extrapyramidal reactions developing in patients receiving selective serotonin-reuptake inhibitors be managed by reducing the dosage or discontinuing the drug; if necessary, the symptoms appear to respond to the same treatment as antipsychotic-induced extrapyramidal reactions.262

Adverse nervous system effects reported in less than 0.1% of patients receiving citalopram include abnormal coordination,1 hyperesthesia,1 melancholia,1 catatonic reaction,1 and stupor.1 Although a causal relationship to the drug has not been established, serotonin syndrome also has been reported in patients receiving citalopram, other selective serotonin-reuptake inhibitors (SSRIs), and selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs).1,316,317,399 (See Cautions: Precautions and Contraindications, Drug Interactions: Serotonergic Drugs, and see also Acute Toxicity.)

Withdrawal Reactions

Withdrawal symptoms, including dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures, have been reported upon discontinuance of citalopram, other SSRIs, and SNRIs, particularly when discontinuance of these drugs is abrupt.223,231,232,234,399 While these reactions are generally self-limiting, there have been reports of serious discontinuance symptoms.399 Therefore, patients should be monitored for such symptoms when discontinuing citalopram therapy.399 A gradual reduction in the dosage rather than abrupt cessation is recommended whenever possible.399 (See Dosage and Administration: Dosage.)

Withdrawal reactions have been reported rarely in citalopram-treated patients following discontinuance of the drug.223,231,232,234,399 Data from a controlled study evaluating citalopram in preventing depression relapse suggest that the symptoms associated with abrupt discontinuance of therapy generally are mild and transient.223 Overall clinical experience to date suggests that the risk of withdrawal effects may be somewhat lower with citalopram, fluoxetine, and sertraline compared with paroxetine.65,231,232,233 These differences may be due at least in part to the prolonged elimination half-lives of the parent drugs and/or their active metabolites.218,219,220,225,226,229,233,235 In addition, drug dependence399 has been reported in at least 0.1% of patients receiving citalopram, although a causal relationship to the drug remains to be established.399 (See Chronic Toxicity.)

Suicidality

Suicide and suicide attempts have been reported in less than 1% of depressed adults receiving citalopram.1,65,255,256,257 The US Food and Drug Administration (FDA) has determined that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders.1,370,371 Patients, therefore, should be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of citalopram therapy (i.e., the first few months) and during periods of dosage adjustments.1,370,371,376 (See Cautions: Precautions and Contraindications, see Cautions: Pediatric Precautions, and see also Acute Toxicity.)

GI Effects

Like other selective serotonin-reuptake inhibitors (e.g., escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline),65,205,244,252,340 citalopram therapy is associated with a relatively high incidence of GI disturbances, principally nausea, dry mouth, diarrhea, dyspepsia, anorexia, vomiting, and abdominal pain.1,65 The most frequent adverse GI effect associated with citalopram therapy is nausea,1,65 which occurred in about 21% of patients receiving the drug in controlled clinical trials.1 Nausea generally is mild to moderate in severity.65 In clinical trials, nausea required discontinuance of citalopram in about 4% of patients and was the most frequent adverse effect requiring discontinuance of the drug.1 While the mechanism(s) of citalopram-induced GI effects has not been fully elucidated, such effects appear to arise at least in part because of increased serotonergic activity in the GI tract (which may result in stimulation of small intestine motility and inhibition of gastric and large intestine motility) and possibly because of the drug's effect on central serotonergic type 3 (5-HT₃) receptors.115,258,259

Dry mouth1,65 occurred in about 20%,1 diarrhea1,65 in about 8%,1 and dyspepsia in about 5%1 of patients receiving citalopram in short-term controlled clinical trials.1 Other adverse GI effects associated with citalopram therapy include vomiting1 and anorexia,1 which both occurred in 4% of patients,1 and abdominal pain,1 which occurred in about 3% of patients1 receiving the drug in short-term controlled clinical trials.1 Vomiting and dry mouth each resulted in discontinuance of citalopram in about 1% of patients.1 Constipation1 was reported in at least 2% of citalopram-treated patients in clinical trials.1

As with some other selective serotonin-reuptake inhibitors, bruxism (involuntary clenching or grinding of the teeth)1,260,261 has been reported in at least 0.1% of patients receiving citalopram.1,260,261 The cases of bruxism reported to date with citalopram and other serotonin-reuptake inhibitors suggest that bruxism may be dose dependent and that buspirone therapy may be helpful in relieving this symptom.260

Although a causal relationship to citalopram has not been established, increased salivation1 and flatulence1 have been reported in at least 1% of patients receiving the drug.1 Gastritis,1 gastroenteritis,1 stomatitis,1 eructation,1 hemorrhoids,1 dysphagia,1 gingivitis,1 and esophagitis1 have been reported in at least 0.1% of patients receiving citalopram.1 However, a causal relationship to the drug has not been established for these effects.1

Epidemiologic case-control and cohort design studies have suggested that selective serotonin-reuptake inhibitors may increase the risk of upper GI bleeding.1,54,55,377,378 Although the precise mechanism for this increased risk remains to be clearly established, serotonin release by platelets is known to play an important role in hemostasis, and selective serotonin-reuptake inhibitors decrease serotonin uptake from the blood by platelets thereby decreasing the amount of serotonin in platelets. 1,54,378 In addition, concurrent use of aspirin or other nonsteroidal anti-inflammatory agents was found to substantially increase the risk of GI bleeding in patients receiving selective serotonin-reuptake inhibitors in 2 of these studies.1,54,55,377 Although these studies focused on upper GI bleeding, there is some evidence suggesting that bleeding at other sites may be similarly potentiated.1 Further clinical studies are needed to determine the clinical importance of these findings.54,378 (See Cautions: Hematologic Effects and see also Drug Interactions: Drugs Affecting Hemostasis.)

Colitis,1 gastric ulcer,1 duodenal ulcer,1 cholecystitis,1 cholelithiasis,1 gastroesophageal reflux,1 glossitis,1 diverticulitis,1 and rectal hemorrhage1 have been reported in less than 0.1% of patients receiving citalopram.1 However, these adverse effects have not been definitely attributed to the drug.1

Dermatologic and Sensitivity Reactions

Increased sweating,1 which appears to be dose related, occurred in approximately 11% of patients receiving citalopram in short-term clinical studies.1 Rash1,65 and pruritus1 have been reported in at least 1% of patients receiving citalopram;1 however, these adverse effects have not been definitely attributed to the drug.1

Photosensitivity reaction,1 urticaria,1 acne,1 skin discoloration,1 eczema,1 alopecia,1 dermatitis,1 dry skin,1 and psoriasis1 have been reported in less than 1% of patients receiving citalopram; however, these adverse effects have not been definitely attributed to the drug.1

Hypertrichosis,1 decreased sweating,1 melanosis,1 keratitis,1 cellulitis,1 pruritus ani,1 hay fever,1 and facial edema1 have occurred in less than 0.1% of citalopram-treated patients, although a causal relationship to the drug has not been established.1 Allergic reactions,1 anaphylaxis,1 and angioedema also have been reported in patients receiving citalopram, although a causal relationship to the drug has not been established.1

Severe adverse dermatologic effects such as erythema multiforme1 and epidermal necrolysis1 have occurred rarely in patients receiving citalopram.1 In addition, a case of extensive papular and purpuric erythema with keratinocytes, necrosis, and dermal leukocytoclastic vasculitis has been reported in a patient receiving citalopram; improvement occurred slowly following discontinuance of the drug.263

Metabolic and Endocrine Effects

Weight loss1 and weight gain1,50 each occurred in at least 1% of patients receiving citalopram in controlled clinical trials;1 obesity has occurred rarely.1 Increased appetite1 also has been reported in at least 1% of patients receiving the drug, although a causal relationship has not been established.1 While clinically important weight loss may occur in some patients receiving citalopram, only minimal weight loss (averaging 0.5 kg) generally occurred in patients receiving the drug in controlled clinical trials.1 In addition, while decreased appetite was reported in about 4% of patients receiving citalopram in short-term clinical trials,1 the drug, unlike fluoxetine, does not appear to exhibit clinically important anorectic effects1,49,50,51 nor to produce clinically important long-term weight changes.1 In addition, short-term citalopram therapy did not produce substantial weight loss in severely obese individuals in one study.51

Taste perversion1 has occurred in more than 1% of patients, and thirst1 and abnormal glucose tolerance1 have been reported in less than 1% of citalopram-treated patients, although a causal relationship to the drug has not been established.1 Taste loss has been reported rarely.1 Adverse metabolic and endocrine effects reported in less than 0.1% of patients receiving the drug include hypoglycemia, hypothyroidism,1 and goiter.1

Ocular and Otic Effects

Vision abnormalities1 occurred in about 2% and abnormality of accommodation1 in at least 1% of patients receiving citalopram in short-term controlled clinical trials.1 Ocular dryness,1 conjunctivitis,1 and ocular pain1 have been reported in less than 1% of citalopram-treated patients, although a causal relationship to the drug has not been established.1 Mydriasis,1 photophobia,1 diplopia,1 ptosis,1 abnormal lacrimation,1 and cataract1 have been reported in less than 0.1% of patients receiving the drug;1 these adverse effects have not been definitely attributed to the drug.1 Angle-closure glaucoma (narrow-angle glaucoma) also has been reported in citalopram-treated patients.399 (See Cautions: Precautions and Contraindications.)

Tinnitus occurred in less than 1% of patients receiving citalopram;1 this adverse effect has not been definitely attributed to the drug.1

Cardiovascular Effects

Citalopram does not exhibit clinically important anticholinergic activity,52,399 and current evidence suggests that the drug generally is less cardiotoxic than many older antidepressants (e.g., tricyclic antidepressants, monoamine oxidase inhibitors) at the usual recommended dosages.62,65,68,69,71,399

No clinically important changes in vital signs (systolic and diastolic blood pressure and heart rate) were observed in patients receiving citalopram in controlled trials.1,68,69

Citalopram causes dose-dependent prolongation of the corrected QT (QT_c) interval, an ECG abnormality that has been associated with torsades de pointes, ventricular tachycardia, and sudden death, all of which have been reported in postmarketing experience in patients receiving the drug.399,416,417,418,419,420,421,424 In a study of the effects of citalopram on the QT interval, use of the drug was associated with a dose-dependent increase in the corrected QT_c interval.399 In this placebo-controlled study, a change from baseline in QT_cF (Fridericia's formula) greater than 60 msec occurred in 1.9% of patients receiving citalopram compared with 1.2% of patients receiving placebo.399 None of the patients receiving placebo had a post-dose QT_cF greater than 500 msec compared with 0.5% of patients receiving citalopram.399 The incidence of tachycardic and bradycardic outliers was 0.5 and 0.9% in the citalopram group, respectively, and 0.4% in the placebo group.399 Individually corrected QT_c (QT_cNi) interval was evaluated in a randomized, double-blind, placebo- and active-controlled, crossover study in healthy individuals.399,416 In this study, the maximum mean differences from placebo were 8.5 and 18.5 msec for daily dosages of 20 and 60 mg of citalopram, respectively.399,416 Based on these results, the predicted QT_cNi for citalopram 40 mg daily is 12.6 msec.399,416 ECG changes, including QT-interval prolongation, also have been reported in individuals receiving overdosages of the drug (more than 400-600 mg).1,70,256,347,422,423 (See Dosage and Administration: Dosage, Cautions: Precautions and Contraindications, and see also Acute Toxicity.)

Palpitation1 was reported in at least 2% of citalopram-treated patients in clinical trials, although a causal relationship to the drug remains to be established.1 A comparison of supine and standing vital signs in depressed patients receiving citalopram indicated that the drug generally does not produce orthostatic changes such as hypotension.1,62,65,68,69 Although postural hypotension1 and hypotension1 occurred in at least 1% of patients receiving citalopram in short-term controlled clinical trials, a causal relationship to the drug has not been established.1

Tachycardia,1 hypertension,1 bradycardia,1 peripheral edema,1 syncope,1 angina pectoris,1 extrasystoles,1 cardiac failure,1 flushing1 and hot flushes,1 myocardial infarction,1 cerebrovascular accident,1 myocardial ischemia,1 transient ischemic attack,1 phlebitis,1 atrial fibrillation,1 ventricular arrhythmia,1 cardiac arrest,1 and bundle branch block1,211 have been reported in premarketing studies of citalopram or during postmarketing surveillance; these adverse effects have not been definitely attributed to the drug.1

Musculoskeletal Effects

Arthralgia1 and myalgia1 each occurred in about 2% of patients receiving citalopram in short-term controlled clinical trials.1 In addition, back pain1 was reported in at least 2% of citalopram-treated patients in clinical trials, although a causal relationship to the drug remains to be established.1

Arthritis,1 muscle weakness,1 leg cramps,1 and skeletal pain1 have been reported in at least 0.1% of citalopram-treated patients; these adverse effects have not been definitely attributed to the drug.1 Bursitis1 and osteoporosis1 have been reported in less than 0.1% of patients receiving citalopram, although a causal relationship has not been established.1

Hematologic Effects

Purpura,1 anemia,1 leukocytosis,1 and leukopenia1 have been reported in at least 0.1% of patients receiving citalopram, although a causal relationship to the drug has not been established.1

Adverse hematologic effects reported in less than 0.1% of patients receiving citalopram include pulmonary embolism,1 granulocytopenia,1 lymphocytosis,1 lymphopenia,1 hypochromic anemia,1 coagulation disorders,1 and gingival bleeding;1 however, a causal relationship to the drug has not been established.1 In addition, thrombocytopenia1 has been reported.1

Bleeding complications (e.g., ecchymosis, purpura, menorrhagia, rectal bleeding) have been reported infrequently in patients receiving citalopram and other selective serotonin-reuptake inhibitors.1,54,55,205,283,284,285,287 Although the precise mechanism for these reactions has not been established,283,284,285,286,287 it has been suggested that impaired platelet aggregation and prolonged bleeding time may be due at least in part to inhibition of serotonin reuptake into platelets and/or that increased capillary fragility and vascular tone may contribute to these cases.1,283,284,285,286,287 (See Cautions: GI Effects and see also Drug Interactions: Drugs Affecting Hemostasis.)

Respiratory Effects

Respiratory disorders have been reported in patients receiving citalopram in short-term controlled clinical trials.1 Upper respiratory tract infections1 and rhinitis1 both have been reported in about 5% of citalopram-treated patients1 and sinusitis has occurred in about 3% of patients receiving the drug.1 Yawning1 and pharyngitis1 each occurred in about 2% of patients receiving citalopram.1 In addition, coughing1 has been reported in at least 1% of citalopram-treated patients.1

Adverse respiratory effects reported in at least 0.1% of patients receiving citalopram in controlled trials include bronchitis,1 dyspnea,1 epistaxis,1 and pneumonia;1 however, a causal relationship to the drug remains to 1 be established. Other adverse effects reported in less than 0.1% of citalopram-treated patients include asthma,1 laryngitis,1 bronchospasm,1 pneumonitis,1 and increased sputum;1 these adverse effects have not been definitely attributed to the drug.1

Renal, Electrolyte, and Genitourinary Effects

Sexual Dysfunction

Like other selective serotonin-reuptake inhibitors, adverse effects on sexual function have been reported in both men and women receiving citalopram.1,24,65,205,265,266,267,268,269,270,271,272,273,274,275,277 Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they also may occur as the result of pharmacologic therapy.1,205,265,270,277 It is difficult to determine the true incidence and severity of adverse effects on sexual function during citalopram therapy, in part because patients and clinicians may be reluctant to discuss these effects.1,205,274,277 Therefore, incidence data reported in product labeling and earlier studies are most likely underestimates of the true incidence of adverse sexual effects.1,205,265,270,274 Recent reports indicate that up to 50%265 of patients receiving selective serotonin-reuptake inhibitors describe some form of sexual dysfunction during treatment and the actual incidence may be even higher.265,274

Ejaculatory disturbances (principally ejaculatory delay)1,65,273,274,277 are the most common adverse urogenital effects associated with citalopram in males, occurring in about 6% of male patients receiving the drug compared with 1% of depressed patients receiving placebo in controlled clinical studies.1 However, the adverse effect of ejaculatory delay associated with serotonin-reuptake inhibitors has been used for therapeutic benefit in the treatment of premature ejaculation.273 (See Uses: Premature Ejaculation.) Results of some (but not all) studies in men and women suggest that paroxetine may be associated with a higher incidence of sexual dysfunction than some other currently available selective serotonin-reuptake inhibitors, including citalopram and sertraline.273,274,277 Since it is difficult to know the precise risk of sexual dysfunction associated with citalopram and other serotonin-reuptake inhibitors, clinicians should routinely inquire about such possible adverse effects in patients receiving these drugs.1,275,277

Decreased libido1,34,275,277 was reported in about 4% of depressed male patients receiving citalopram in short-term placebo-controlled studies compared with less than 1% of patients receiving placebo.1 In these studies, impotence, which appears to be dose related,1 was reported in about 3% of male patients receiving citalopram compared with less than 1% of males receiving placebo.1 In female patients receiving citalopram in controlled clinical studies for the treatment of depression, decreased libido1,277 and anorgasmia1 were reported in about 1% of those receiving citalopram.1 Increased libido1,277 has been reported in up to 1% of patients receiving citalopram.1 Priapism also has been reported during postmarketing surveillance in male patients,1,271 and clitoral priapism272 has been reported in at least 3 female patients receiving the drug.272

The long-term effects of selective serotonin-reuptake inhibitors on sexual function have not been fully determined to date.277 In a double-blind study evaluating 6 months of citalopram or sertraline therapy in depressed patients, sexual desire and overall sexual functioning (as measured on the UKU Side Effect Scale) substantially improved in women and sexual desire improved in men.277 In men, no change in orgasmic dysfunction, erectile dysfunction, or overall sexual functioning was reported after 6 months of therapy with citalopram or sertraline, although there was a trend toward worsening of ejaculatory dysfunction.277 However, in the subgroups of women and men reporting no sexual problems at baseline, approximately 12% of women reported decreased sexual desire and 14% reported orgasmic dysfunction after 6 months of citalopram therapy; the corresponding figures in the same subgroup of men were approximately 17 and 19%, respectively, and as many as 25% experienced ejaculatory dysfunction after 6 months.277 No substantial differences between citalopram and sertraline were reported in this study.277

Management of sexual dysfunction caused by selective serotonin-reuptake inhibitor therapy includes waiting for tolerance to develop; using a lower dosage of the drug; using drug holidays; delaying administration of the drug until after coitus; or changing to another antidepressant.270 Although further study is needed, there is some evidence that adverse sexual effects of the selective serotonin-reuptake inhibitors may be reversed by concomitant use of certain drugs, including buspirone,276 5-hydroxytryptamine-2 (5-HT₂) receptor antagonists (e.g., nefazodone), 5-HT₃ receptor inhibitors (e.g., granisetron), or α₂-adrenergic receptor antagonists (e.g., yohimbine), selective phosphodiesterase (PDE) inhibitors (e.g., sildenafil), or dopamine receptor agonists (e.g., amantadine, dextroamphetamine, pemoline [no longer commercially available in the US], methylphenidate).270,276 In most patients, sexual dysfunction is fully reversed 1-3 days after discontinuance of the antidepressant.270

Other Renal, Electrolyte, and Genitourinary Effects

Treatment with SSRIs, including citalopram, or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) may result in hyponatremia.1,206,207,208,344,363,399 In many cases, this hyponatremia appeared to be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and was reversible when citalopram was discontinued.207,399 Cases with serum sodium concentrations lower than 110 mmol/L have been reported.399 Prolonged coma caused by hyponatremia has been reported in a patient with multiple sclerosis receiving citalopram therapy.207 Severe postoperative hyponatremia has been reported in an elderly female patient receiving the drug.363 Hyponatremia and SIADH usually develop an average of 2 weeks after initiating therapy (range: 3-120 days).8,9,192,193,194,195,196,197,198,199,200,201,202,203,204,205,207,209,210 Geriatric individuals and patients receiving diuretics or who are otherwise volume depleted may be at greater risk of developing hyponatremia during therapy with SSRIs or SNRIs.201,202,203,204,205,208,209,210,344,363,399 Discontinuance of citalopram should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.399 Because geriatric patients may be at increased risk for hyponatremia associated with these drugs, clinicians prescribing citalopram in such patients should be aware of the possibility that such reactions may occur.207,208,209,344,399 In addition, periodic monitoring of serum sodium concentrations (particularly during the first several months) in geriatric patients receiving selective serotonin-reuptake inhibitors has been recommended by some clinicians.207,208,209,348,349

Hypokalemia1 and dehydration1 have occurred in less than 0.1% of patients receiving citalopram;1 these adverse effects have not been definitely attributed to the drug.1

Urinary disorders (e.g., micturition disorders) have been reported in at least 2% of patients receiving citalopram in short-term controlled trials.1 In addition, polyuria has been reported in at least 1% of patients receiving the drug.1 Although a definite causal relationship to citalopram has not been established, urinary frequency,1 urinary incontinence,1 urinary retention,1 and dysuria1 have been reported in at least 0.1% of patients receiving the drug.1 Other adverse urologic effects reported in less than 0.1% of citalopram-treated patients include hematuria,1 oliguria,1 pyelonephritis,1 renal calculus,1 and renal pain;1 these adverse effects have not been definitely attributed to the drug.1

Dysmenorrhea1 has been reported in at least 3% of female patients receiving citalopram in short-term controlled trials.1 In addition, amenorrhea1 has been reported in at least 1% of patients receiving the drug.1 Galactorrhea,1 breast pain,1 breast enlargement,1 and vaginal hemorrhage1 have been reported in less than 1% of patients receiving citalopram,1 and spontaneous abortion1 has been reported rarely;1 however, these adverse effects have not been definitely attributed to the drug.1 Breast enlargement also has been reported in some women receiving chronic therapy with other selective serotonin-reuptake inhibitors.1,93 In one study, approximately 40% of patients receiving selective serotonin-reuptake inhibitors (e.g., fluoxetine, paroxetine, sertraline) or venlafaxine reported some degree of breast enlargement; most patients with breast enlargement also experienced weight gain.93 In addition, serum prolactin concentrations were increased in the women receiving other selective serotonin-reuptake inhibitors in this study.93 Gynecomastia1 has been reported rarely.1

Hepatic Effects

Abnormal liver function test results, including elevations in serum hepatic enzyme concentrations,1 and increased serum alkaline phosphatase concentrations1 have been reported in at least 0.1% of patients receiving citalopram.1 Hepatitis,1 jaundice,1 and hyperbilirubinemia1 have been reported in less than 0.1% of patients receiving citalopram;1 however, these adverse effects have not been definitely attributed to the drug.1 Hepatic necrosis has also been reported during postmarketing surveillance in citalopram-treated patients.1

Other Adverse Effects

Fever1 occurred in about 2% of patients receiving citalopram in short-term controlled clinical trials.1 Rigors,1 alcohol intolerance,1 lymphadenopathy,1 and influenza-like symptoms1 have been reported in less than 1% of patients receiving citalopram; however, these adverse effects have not been definitely attributed to the drug.1 Pancreatitis1 also has occurred in association with citalopram, although a causal relationship to the drug has not been clearly established.1

Precautions and Contraindications

Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric (see Cautions: Pediatric Precautions) patients with major depressive disorder or other psychiatric disorders, whether or not they are taking antidepressants.1,370,371,376,398 This risk may persist until clinically important remission occurs.1,370,371 Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.1,370,371,376 However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.1,370 Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders.1,370,371 An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age and a reduced risk was observed in adults 65 years of age or older.1,370,371 It currently is unknown whether the suicidality risk extends to longer-term use (i.e., beyond several months); however, there is substantial evidence from placebo-controlled maintenance trials in adults with major depressive disorder that antidepressants can delay the recurrence of depression.1,370,371

The US Food and Drug Administration (FDA) recommends that all patients being treated with antidepressants for any indication be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.1,370,371,376 Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, also should be advised to monitor patients on a daily basis for the emergence of agitation, irritability, or unusual changes in behavior as well as the emergence of suicidality, and to report such symptoms immediately to a health-care provider.1,370,376 (See Suicidality under Cautions: Nervous System Effects, in Paroxetine 28:16.04.20.)

Although a causal relationship between the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.1,370,376 Consequently, consideration should be given to changing the therapeutic regimen or discontinuing therapy in patients whose depression is persistently worse or in patients experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if such manifestations are severe, abrupt in onset, or were not part of the patient's presenting symptoms.1,370 If a decision is made to discontinue therapy, citalopram dosage should be tapered as rapidly as is feasible but with recognition of the risks of abrupt discontinuance.1,370 (See Dosage and Administration: Dosage.) FDA also recommends that the drugs be prescribed in the smallest quantity consistent with good patient management, in order to reduce the risk of overdosage.1,370

Citalopram causes dose-dependent QT_c-interval prolongation, an ECG abnormality that has been associated with torsades de pointes, ventricular tachycardia, and sudden death, all of which have been reported in postmarketing experience in patients receiving the drug.399,416,417,418,419,420,421,424 On August 24, 2011, the US Food and Drug Administration (FDA) notified healthcare professionals that citalopram should no longer be used at dosages exceeding 40 mg daily due to the risk of QT-interval prolongation and torsades de pointes ; previously, the prescribing information for the drug stated that certain patients may require a dosage of 60 mg daily.399,416,417,424 On March 28, 2012, the FDA provided the following revised recommendations for citalopram use related to the potential risk of abnormal heart rhythms associated with higher dosages of the drug.399,424 The FDA advised that citalopram therapy is not recommended in patients with congenital long QT syndrome, bradycardia, hypokalemia or hypomagnesemia, recent acute myocardial infarction, or uncompensated heart failure.399,424 The FDA also stated that citalopram should not be used in patients receiving other drugs known to prolong the QT_c interval.399,424 Such drugs include class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents, certain antipsychotic agents (e.g., chlorpromazine, thioridazine), some anti-infective agents (e.g., gatifloxacin, moxifloxacin), and other drugs (e.g., pentamidine, levomethadyl acetate, methadone).399,424 In addition, the maximum dosage of citalopram should be limited to 20 mg once daily in patients who are poor metabolizers of the cytochrome P-450 (CYP) isoenzyme 2C19; patients receiving cimetidine or another CYP2C19 inhibitor; patients with hepatic impairment; and in patients older than 60 years of a higher citalopram exposures in such patients increase the risk of QT-interval prolongation and torsades de pointes.399,424 Furthermore, electrolyte and/or ECG monitoring is recommended in certain situations.399,424 Patients being considered for citalopram therapy who are at risk for clinically important electrolyte disturbances should have baseline measurements of serum potassium and magnesium concentrations with subsequent periodic monitoring.399,424 Because hypokalemia and/or hypomagnesemia may increase the risk of QT_c-interval prolongation and arrhythmias, hypokalemia and hypomagnesemia should be corrected prior to citalopram administration and serum concentrations of these electrolytes should be periodically monitored.399,416 In addition, ECG monitoring is recommended in patients for whom citalopram use is not recommended but nevertheless considered essential, including those with the above-mentioned cardiovascular conditions (e.g., congenital long QT syndrome, bradycardia, recent acute myocardial infarction, uncompensated heart failure) and those concurrently receiving other drugs that may prolong the QT_c interval.399,424 Citalopram should be discontinued in any patient who has persistent QT_c measurements exceeding 500 msec.399,424 Patients receiving citalopram should be informed of the possible symptoms of QT-interval prolongation and torsades de pointes (e.g., chest pain, irregular heartbeat, shortness of breath, dizziness or fainting) and advised to seek immediate medical attention should such symptoms occur.399,416,424 If a citalopram-treated patient experiences such symptoms, further evaluation should be initiated, including cardiac monitoring.399,424

It is generally believed (though not established in controlled trials) that treating a major depressive episode with an antidepressant alone may increase the likelihood of precipitating a mixed or manic episode in patients at risk for bipolar disorder.1,370 Therefore, patients should be adequately screened for bipolar disorder prior to initiating treatment with an antidepressant; such screening should include a detailed psychiatric history (e.g., family history of suicide, bipolar disorder, and depression).1,370

Potentially life-threatening serotonin syndrome has been reported with SSRIs, including citalopram, and selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) when used alone, but particularly with concurrent use of other serotonergic drugs (including serotonin [5-hydroxytryptamine; 5-HT] type 1 receptor agonists [“triptans”], tricyclic antidepressants, buspirone, fentanyl, lithium, tramadol, tryptophan, and St. John's wort [ Hypericum perforatum ]) and with drugs that impair the metabolism of serotonin (particularly monoamine oxidase [MAO] inhibitors, both those used to treat psychiatric disorders and others, such as linezolid and methylene blue).316,317,386,399,400 Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or GI symptoms (e.g., nausea, vomiting, diarrhea).316,317,386,399,400 Patients receiving citalopram should be monitored for the development of serotonin syndrome.399

Concomitant use of citalopram and MAO inhibitors intended to treat psychiatric disorders is contraindicated.399 Citalopram also should not be initiated in patients who are being treated with other MAO inhibitors such as linezolid or IV methylene blue.399 In patients who require more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered.399 Citalopram may be started 24 hours after the last dose of linezolid or IV methylene blue.399

If concurrent therapy with citalopram and other serotonergic drugs is clinically warranted, the patient should be made aware of the potential increased risk for serotonin syndrome, particularly during initiation of therapy or when dosage is increased.386,399 If manifestations of serotonin syndrome occur, treatment with citalopram and any concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.399 (See Drug Interactions: Serotonergic Drugs.) For further information on serotonin syndrome, including manifestations and treatment, see Drug Interactions: Serotonergic Drugs, in Fluoxetine Hydrochloride 28:16.04.20.

The pupillary dilation (mydriasis) that occurs following the use of many antidepressant agents, including citalopram, may trigger an acute attack of angle-closure glaucoma (narrow-angle glaucoma) in patients with anatomically narrow angles who do not have a patent iridectomy.399 Possible symptoms of angle-closure glaucoma include eye pain, vision changes, and swelling or redness in or around the eye.399 Preexisting glaucoma is almost always open-angle glaucoma since angle-closure glaucoma can be treated definitively with iridectomy when diagnosed; open-angle glaucoma is not a risk factor for angle-closure glaucoma.399 Patients should be advised that citalopram can cause mild pupillary dilation, which can lead to an episode of angle-closure glaucoma in susceptible individuals.399 In addition, patients may wish to be examined to determine whether they are susceptible to angle-closure glaucoma and have a prophylactic procedure (e.g., iridectomy) if they are susceptible.399

Citalopram should be used with caution and a lower maximum dosage (20 mg once daily) is recommended in patients with hepatic impairment, since decreased clearance and increased plasma concentrations of the drug may occur in such patients.399,424 (See Dosage and Administration: Dosage in Hepatic and Renal Impairment and see also Pharmacokinetics: Elimination.)

Because citalopram is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination.1 Severe renal failure did not markedly affect the pharmacokinetics of citalopram in one study, suggesting that dosage adjustment may not be necessary in patients with severe renal impairment.88 However, until long-term citalopram therapy has been more fully evaluated in such patients, citalopram should be used with caution in patients with severe renal impairment.1 (See Dosage and Administration: Dosage in Hepatic and Renal Impairment and see also Pharmacokinetics: Elimination.)

Because of the potential for adverse drug interactions, patients receiving citalopram should be advised to notify their clinician if they are taking or plan to take nonprescription (over-the-counter) or prescription medications.1 Although citalopram has not been shown to potentiate the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while receiving the drug.1

Citalopram generally is less sedating than many other currently available antidepressants and does not appear to produce substantial impairment of cognitive or psychomotor function nor to potentiate psychomotor impairment induced by other CNS depressants (e.g., alcohol).1,65,66,67 However, patients should be cautioned that citalopram may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle) and to avoid such activities until they gain experience with the drug's effects.1

Patients receiving citalopram should be advised that while they may notice improvement within 1-4 weeks after starting therapy, they should continue therapy with the drug as directed by their clinician.1

Although anticonvulsant effects have been observed in animal studies with citalopram,1,191 the drug has not been systematically evaluated in patients with a seizure disorder.1,62 In addition, patients with seizure disorders were excluded from premarketing clinical trials with the drug.1 In clinical studies of citalopram, seizures occurred in 0.3% of patients receiving citalopram and in 0.5% of patients receiving placebo; a causal relationship to the drug remains to be established.1,62 However, as with other antidepressants, citalopram should be initiated and used with caution in patients with a history of seizures.1

Activation of mania and hypomania have occurred in patients receiving therapeutic dosages of citalopram.1,236,237,327 The drug should be used with caution in patients with a history of mania.1 (See Cautions: Nervous System Effects.)

Treatment with SSRIs, including citalopram, or SNRIs may result in hyponatremia.1,206,207,208,344,363,399 In many cases, this hyponatremia appears to be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and was reversible when the SSRI or SNRI was discontinued.207,399 Geriatric individuals and patients receiving diuretics or who are otherwise volume depleted may be at greater risk of developing hyponatremia during therapy with SSRIs or SNRIs.201,202,203,204,205,208,209,210,344,363,399 Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls; more severe and/or acute cases have been associated with hallucinations, syncope, seizures, coma, respiratory arrest, and death.399 Discontinuance of citalopram should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.399 (See Cautions: Renal, Electrolyte, and Genitourinary Effects and see also see Cautions: Geriatric Precautions.)

Because of similarity in spelling of Celexa^® (citalopram hydrobromide), Celebrex^® (celecoxib), and Cerebyx^® (fosphenytoin sodium), extra care should be exercised in ensuring the accuracy of prescriptions for these drugs.346

Use of citalopram is contraindicated in patients who are currently receiving or have recently (i.e., within 2 weeks) received therapy with an MAO inhibitor intended to treat psychiatric disorders because of an increased risk of serotonin syndrome.399 Conversely, use of an MAO inhibitor intended to treat psychiatric disorders is contraindicated within 2 weeks of citalopram discontinuance.399 (See Drug Interactions: Serotonergic Drugs.)

Initiation of citalopram therapy in patients receiving MAO inhibitors such as linezolid or IV methylene blue also is contraindicated because of an increased risk of serotonin syndrome.399 (See Drug Interactions: Serotonergic Drugs.)

Concurrent use of citalopram in patients receiving pimozide is contraindicated.1,399 (See Drug Interactions: Pimozide.)

Citalopram is contraindicated in patients who are hypersensitive to the drug, escitalopram, or any ingredient in the formulation.1,348,349

Pediatric Precautions

Safety and efficacy of citalopram in pediatric patients have not been established.1 Two placebo-controlled trials involving 407 children and adolescents with major depressive disorder have been conducted with citalopram; the results of these trials were not sufficient to support a claim of efficacy for use of the drug in pediatric patients with this condition.1,379 (See Pediatric Considerations under Uses: Major Depressive Disorder.)

Decreased appetite and weight loss have been observed in patients receiving SSRIs.399 Therefore, regular monitoring of weight and growth should be performed in children and adolescents receiving citalopram therapy.399

FDA warns that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders.1,370,371,376 The risk of suicidality for these drugs was identified in a pooled analysis of data from a total of 24 short-term (4-16 weeks), placebo-controlled studies of 9 antidepressants (i.e., citalopram, bupropion, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, venlafaxine) in over 4400 children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders.1,370,371,306,372 The analysis revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in pediatric patients receiving antidepressants than in those receiving placebo.1,370,371 However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients younger than 19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation.398 No suicides occurred in these pediatric trials.1,370,371,398

The risk of suicidality in the FDA's pooled analysis differed across the different psychiatric indications, with the highest incidence observed in the major depressive disorder studies.1,370,371 In addition, although there was considerable variation in risk among the antidepressants, a tendency toward an increase in suicidality risk in younger patients was found for almost all drugs studied.1,370,371 It currently is unknown whether the suicidality risk in pediatric patients extends to longer-term use (i.e., beyond several months).1,370 (See Suicidality under Cautions: Nervous System Effects, in Paroxetine 28:16.04.20.)

As a result of this analysis and public discussion of the issue, FDA has directed manufacturers of all antidepressants to add a boxed warning to the labeling of their products to alert clinicians of this suicidality risk in children and adolescents and to recommend appropriate monitoring and close observation of patients receiving these agents.1,370,371 (See Cautions: Precautions and Contraindications.) The drugs that are the focus of the revised labeling are all drugs included in the general class of antidepressants, including those that have not been studied in controlled clinical trials in pediatric patients, since the available data are not adequate to exclude any single antidepressant from an increased risk.1,370,371,374 In addition to the boxed warning and other information in professional labeling on antidepressants, FDA currently recommends that a patient medication guide explaining the risks associated with the drugs be provided to the patient each time the drugs are dispensed.1,370,371,376 Caregivers of pediatric patients whose depression is persistently worse or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality during antidepressant therapy should consult their clinician regarding the best course of action (e.g., whether the therapeutic regimen should be changed or the drug discontinued).1,370,371,376 Patients should not discontinue use of selective serotonin-reuptake inhibitors without first consulting their clinician; it is very important that the drugs not be abruptly discontinued, as withdrawal effects may occur. 1,370,371,376 (See Dosage and Administration: Dosage.)

Anyone considering the use of citalopram in a child or adolescent for any clinical use must balance the potential risk of therapy with the clinical need.1,370,376,398

Geriatric Precautions

While safety and efficacy of citalopram in geriatric patients have not been established specifically, approximately 31% of patients receiving the drug for depression in clinical trials were 60 years of age or older, approximately 23% were 65 years of age or older, and approximately 10% were 75 years of age or older.1

Although no overall differences in the efficacy or adverse effect profile of citalopram were observed between geriatric and younger patients and other clinical experience revealed no evidence of age-related differences in response, pharmacokinetic studies in healthy geriatric individuals and depressed patients 60 years of age or older have revealed higher areas under the plasma concentration-time curve (AUC) values and longer elimination half-lives compared with those in younger individuals.83,85,399 (See Pharmacokinetics: Absorption and Elimination.) Therefore, the manufacturer and some clinicians recommend a maximum citalopram dosage of 20 mg once daily for geriatric patients older than 60 years of age with major depressive disorder.118,338,399,416 (See Dosage and Administration: Dosage in Geriatric Patients.)

In pooled data analyses, a reduced risk of suicidality was observed in adults 65 years of age or older with antidepressant therapy compared with placebo.1,370,371 (See Cautions: Precautions and Contraindications.)

Limited evidence suggests that geriatric patients also may be more likely than younger patients to develop citalopram-induced hyponatremia and transient syndrome of inappropriate secretion of antidiuretic hormone (SIADH).201,202,203,204,205,208,209,210,344,399 Therefore, clinicians prescribing citalopram in geriatric patients should be aware of the possibility that such reactions may occur.207,208,209,344 In addition, periodic monitoring (especially during the first several months) of serum sodium concentrations in geriatric patients receiving selective serotonin-reuptake inhibitors has been recommended by some clinicians.207,208,209,344,348,349

In a double-blind, multicenter trial, citalopram (20 or 40 mg daily) was found to be as effective as and better tolerated than amitriptyline in depressed geriatric patients.130 In a small study comparing citalopram and nortriptyline in depressed geriatric patients, citalopram was found to be somewhat less effective but better tolerated than nortriptyline.78

In a controlled study comparing citalopram and placebo in elderly patients with dementia†, citalopram (20-30 mg daily) was found to improve depression as well as cognitive and emotional functioning more than placebo.157 In an open study in a limited number of patients with dementia and behavioral disturbances†, citalopram was found to improve the behavioral complications associated with dementia†.156

As with other psychotropic drugs, geriatric patients receiving antidepressants appear to have an increased risk of hip fracture.73,407 Despite the decreased incidence of cardiovascular and anticholinergic effects associated with selective serotonin-reuptake inhibitors, these drugs did not show any advantage over tricyclic antidepressants with regard to hip fracture in a case-control study.73 In addition, there was little difference in the rates of falls between nursing home residents receiving selective serotonin-reuptake inhibitors and those receiving tricyclic antidepressants in a retrospective study.74 Therefore, all geriatric individuals receiving either type of antidepressant should be considered at increased risk of falls, and appropriate measures should be taken.73,74,407

Mutagenicity and Carcinogenicity

Citalopram was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 out of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation.1 In the in vitro Chinese hamster lung cell assay for chromosomal aberrations, citalopram was clastogenic in the presence and absence of metabolic activation.1 The drug was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in a coupled in vitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver.1 Citalopram was not found to be clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in 2 in vivo mouse micronucleus assays.1

Studies to determine the carcinogenic potential of citalopram were performed in mice receiving oral dosages of up to 240 mg/kg daily for 18 months and in rats receiving 8 or 24 mg/kg daily for 24 months.1 These dosages were approximately 20 times the maximum recommended human daily dosage of 60 mg on a surface area (mg/m²) basis in mice and approximately 1.3 and 4 times the maximum recommended human daily dosage on a mg/m² basis in rats, respectively.1 No evidence of carcinogenicity was found in the mice.1 In rats receiving 8 or 24 mg/kg daily of citalopram, an increased incidence of small intestine carcinoma was reported.1 The manufacturer states that a no-effect dosage for this finding was not established; the relevance of this finding to humans is not known.1

Pregnancy, Fertility, and Lactation

Pregnancy

Some neonates exposed to citalopram and other selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) late in the third trimester of pregnancy have developed complications that have sometimes been severe and required prolonged hospitalization, respiratory support, enteral nutrition, and other forms of supportive care in special-care nurseries.1,212,213,380,381,382,383 Such complications can arise immediately upon delivery and usually last several days or up to 2-4 weeks.1,380,381,382 Clinical findings reported to date in the neonates have included respiratory distress, cyanosis, apnea, seizures, temperature instability or fever, feeding difficulty, dehydration, excessive weight loss, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, reduced or lack of reaction to pain stimuli, and constant crying.1,212,213,380,381,382,383 These clinical features appear to be consistent with either a direct toxic effect of the SSRI or SNRI or, possibly, a drug withdrawal syndrome.1,212,213,380,381,382,383 It should be noted that, in some cases, the clinical picture was consistent with serotonin syndrome (see Drug Interactions: Serotonergic Drugs).1,381

Infants exposed to SSRIs in late pregnancy may have an increased risk of persistent pulmonary hypertension of the newborn (PPHN).399,600,601,602,603,610 PPHN is a rare heart and lung condition occurring in an estimated 1-2 infants per 1000 live births in the general population;399,600,601,602,603 it occurs when a neonate does not adapt to breathing outside the womb.600 Some experts have suggested that respiratory distress in neonates exposed to SSRIs may occur along a spectrum of seriousness in association with maternal use of SSRIs, with PPHN among the most serious consequences.602,608 Neonates with PPHN may require intensive care support, including mechanical ventilation; in severe cases, multiple organ damage, including brain damage, and even death may occur.600 Although several epidemiologic studies have suggested an increased risk of PPHN with SSRI use during pregnancy,399,600,601,602,603,610 other studies did not demonstrate a statistically significant association.399,600,601,604,605,606 Thus, the FDA states that it is currently unclear whether use of SSRIs, including citalopram, during pregnancy can cause PPHN and recommends that clinicians not alter their current clinical practice of treating depression during pregnancy.600

Clinicians should consider that in a prospective longitudinal study of 201 women with a history of recurrent major depression who were euthymic in the context of antidepressant therapy at the beginning of pregnancy, women who discontinued their antidepressant medication (SSRIs, tricyclic antidepressants, or others) during pregnancy were found to be substantially more likely to have a relapse of depression than were women who continued to receive their antidepressant therapy while pregnant.399,601,607,609 When treating a pregnant woman with citalopram, the clinician should carefully consider the potential risks of taking an SSRI along with the established benefits of treating depression with an antidepressant; this decision can only be made on a case-by-case basis.399,600,601 (See Dosage and Administration: Treatment of Pregnant Women during the Third Trimester.)

For additional information on the management of depression in women prior to conception and during pregnancy, including treatment algorithms, the FDA advises clinicians to consult the joint American Psychiatric Association and American College of Obstetricians and Gynecologists guidelines (at [Web]).600,608

Most epidemiologic studies of pregnancy outcome following first-trimester exposure to SSRIs, including citalopram, conducted to date have not revealed evidence of an increased risk of major congenital malformations.95,214,215,384,385 Analysis of data collected in 531 Swedish women who received SSRIs during early pregnancy (citalopram accounted for 375 of these exposures) found that no increase in congenital abnormalities was observed during the neonatal period compared with the general population.214 In a prospective, controlled, multicenter study, maternal use of several SSRIs (fluvoxamine, paroxetine, sertraline) did not appear to increase the risk of congenital malformation, miscarriage, stillbirth, or premature delivery when used during pregnancy at recommended dosages.215 Birth weight and gestational age in neonates exposed to the drugs were similar to those in the control group.215 In another small study based on medical records review, the incidence of congenital anomalies reported in infants born to women who were treated with several other SSRIs (fluoxetine, paroxetine, sertraline) during pregnancy was comparable to that observed in the general population.384,385

Citalopram and its metabolites have been shown to cross the placenta in humans.95,362,401 In 11 women who received 20-40 mg of citalopram daily during pregnancy, trough plasma citalopram, demethylcitalopram, and didemethylcitalopram concentrations in the infants at the time of delivery were found to be 64, 66, and 68%, respectively, of maternal concentrations.95 No significant difference in pregnancy outcome was observed between the group of women who received citalopram during pregnancy and a similar control group of pregnant women who did not receive the drug.95 In addition, the body weight and neurologic status of the infants in both groups were all assessed as normal after 12 months.95 However, the results of epidemiologic studies indicate that exposure to paroxetine during the first trimester of pregnancy may increase the risk for congenital malformations, particularly cardiovascular malformations.384,391,392,602 (See Pregnancy, under Cautions: Pregnancy, Fertility, and Lactation, in Paroxetine 28:16.04.20.) Additional epidemiologic studies are needed to more thoroughly evaluate the relative safety of citalopram and other SSRIs during pregnancy, including their potential teratogenic risks and possible effects on neurobehavioral development. 95,362,384,392,602

There are no adequate and well-controlled studies to date using citalopram in pregnant women and the drug should be used during pregnancy only when the potential benefits justify the potential risks to the fetus.399 Women should be advised to notify their clinician if they become pregnant or plan to become pregnant during therapy with the drug.399,600 FDA states that women who are pregnant or thinking about becoming pregnant should not discontinue any antidepressant, including citalopram, without first consulting their clinician.600,607 The decision whether or not to continue antidepressant therapy should be made only after careful consideration of the potential benefits and risks of antidepressant therapy for each individual pregnant patient.600,602,607 If a decision is made to discontinue treatment with citalopram or other SSRIs before or during pregnancy, discontinuance of therapy should be done in consultation with the clinician in accordance with the prescribing information for the antidepressant, and the patient should be closely monitored for possible relapse of depression.607

The effect of citalopram on labor and delivery is not known.1

In animal reproduction studies, citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects, when administered at dosages that exceeded the recommended human dosage.1 Teratogenic effects were observed in rats receiving dosages of citalopram that were toxic to the dams but were not observed in rabbits.1 In 2 rat embryo/fetal development studies, oral administration of citalopram dosages of 32, 56, or 112 mg/kg daily to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidence of fetal abnormalities, including cardiovascular and skeletal defects, at the highest dosage (equivalent to approximately 18 times the maximum recommended human daily dosage on a mg/m² basis).1 This dosage also was associated with maternal toxicity.1 The developmental no-effect dosage was 56 mg/kg daily, which is approximately 9 times the maximum recommended human daily dosage on a mg/m² basis.1 No adverse effects on embryo/fetal development were observed in rabbits receiving citalopram dosages of up to 16 mg/kg daily (equivalent to approximately 5 times the maximum recommended human dosage on a mg/m² basis).1

In female rats receiving citalopram dosages of 4.8, 12.8, or 32 mg/kg daily from late gestation through weaning, increased offspring mortality during the first 4 days following birth and persistent offspring growth retardation were observed at the highest dosage, which is equivalent to approximately 5 times the maximum recommended human dosage on a mg/m² basis.1 The no-effect dosage of 12.8 mg/kg daily is approximately 2 times the maximum recommended human dosage on a mg/m² basis.1 Similar effects on offspring mortality and growth were seen when dams were treated with the drug throughout gestation and early lactation at daily dosages of 24 mg/kg or more (approximately 4 or more times the maximum recommended human dosage on a mg/m² basis).1 A no-effect dosage was not determined in this study.1

Fertility

In reproduction studies in male and female rats receiving oral citalopram dosages of 16/24 (males/females), 32, 48, and 72 mg/kg daily, decreased mating was observed at all dosages.1 Fertility was decreased at daily dosages of 32 mg/kg or more (approximately 5 times the maximum recommended human dosage on a mg/m² basis).1 Gestation duration was increased in rats receiving 48 mg/kg daily of the drug, which is equivalent to approximately 8 times the maximum recommended human dosage.1

Lactation

Like other SSRIs, citalopram and its principal metabolite, demethylcitalopram, are distributed into milk.1,5,6,90,91,92,95,96,362 (See Pharmacokinetics: Distribution.) Limited data indicate that milk-to-plasma ratios of citalopram and demethylcitalopram range from 1.7-3.5,91,92,95 Available data indicate that citalopram and fluoxetine are the serotonin-reuptake inhibitors with the highest relative exposure for breast-fed infants.6,92,95,96,362 Excessive somnolence, decreased feeding, and weight loss were reported in 2 nursing infants whose mothers received citalopram.1 In one of these cases, the infant reportedly recovered completely upon discontinuance of citalopram by its mother, and in the second case, no follow-up information is available.1 Disturbed sleep has been reported in another breast-feeding infant whose mother was receiving citalopram 40 mg daily.92 The infant's sleep normalized once the citalopram dosage was reduced and 2 breast-feedings were replaced with artificial nutrition.92

Women should be advised to notify their clinician if they plan to breast-feed.1 Because of the potential for adverse reactions to citalopram in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1 If a decision is made to continue citalopram therapy in a nursing woman, some clinicians recommend that the lowest effective dosage of citalopram be used and that breast-feeding during the period of drug absorption be avoided.5,90,92,362

Drugs that Prolong the QT Interval

Citalopram use is not recommended in patients concurrently receiving other drugs known to prolong the QT_c interval, including class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents, certain antipsychotic agents (e.g., chlorpromazine, thioridazine), some anti-infective agents (e.g., gatifloxacin, moxifloxacin), and other drugs (e.g., pentamidine, levomethadyl acetate, methadone).399,424 However, if citalopram therapy is considered essential in such patients, ECG monitoring is recommended.399,424 (See Cautions: Cardiovascular Effects and see Drug Interactions: Pimozide.)

Serotonergic Drugs

Use of selective serotonin-reuptake inhibitors (SSRIs) such as citalopram concurrently or in close succession with other drugs that affect serotonergic neurotransmission may result in potentially life-threatening serotonin syndrome.205,291,292,293,294,295,296,297,312,314,315,316,317,386,399 Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or GI symptoms (e.g., nausea, vomiting, diarrhea).386,399 The precise mechanism of serotonin syndrome is not fully understood; however, it appears to result from excessive serotonergic activity in the CNS, probably mediated by activation of serotonin 5-HT_1A receptors.296,300,301,386 The possible involvement of dopamine and 5-HT₂ receptors also has been suggested, although their roles remain unclear.296

Serotonin syndrome most commonly occurs when 2 or more drugs that affect serotonergic neurotransmission are administered either concurrently or in close succession.294,295,296,300,301,386,399 Serotonergic agents include those that increase serotonin synthesis (e.g., the serotonin precursor tryptophan),244,294,295,296,299,399 stimulate synaptic serotonin release (e.g., some amphetamines, dexfenfluramine [no longer commercially available in the US], fenfluramine [no longer commercially available in the US]),294,295,302 inhibit the reuptake of serotonin after release (e.g., SSRIs, selective serotonin- and norepinephrine-reuptake inhibitors [SNRIs], tricyclic antidepressants, trazodone, dextromethorphan, meperidine, tramadol),294,295,296,303,386,399 decrease the metabolism of serotonin (e.g., monoamine oxidase [MAO] inhibitors),291,294,295,296,316,317,399 have direct serotonin postsynaptic receptor activity (e.g., buspirone),294,295 or nonspecifically induce increases in serotonergic neuronal activity (e.g., lithium salts).294,295,296,399 Selective agonists of serotonin (5-hydroxytryptamine; 5-HT) type 1 (5-HT₁) receptors (“triptans”) and dihydroergotamine, agents with serotonergic activity used in the management of migraine headache, and St. John's wort ( Hypericum perforatum ) also have been implicated in cases of serotonin syndrome.205,304,386,399

The combination of SSRIs and MAO inhibitors may result in serotonin syndrome.291,294,296,300,301,305,306,307,308,309,310,311,312,313,316,317,399 Such reactions also have been reported in patients receiving SSRIs concomitantly with tryptophan, lithium, dextromethorphan, sumatriptan, or dihydroergotamine.205,294,296,301,304,386,399,408 In rare cases, serotonin syndrome reportedly has occurred in patients receiving the recommended dosage of a single serotonergic agent (e.g., clomipramine)294,296 or during accidental overdosage (e.g., sertraline intoxication in a child).294,296 Some other drugs that have been implicated in precipitating symptoms suggestive of serotonin syndrome include buspirone, bromocriptine, dextropropoxyphene, linezolid, methylene blue, methylenedioxymethamphetamine (MDMA; “ecstasy”), selegiline (a selective MAO-B inhibitor), and sibutramine (an SNRI used for the management of obesity [no longer commercially available in the US]).296,303,327,386,390,396,399,400,405,408,409,411,412,413,414,415 Other drugs that have been associated with the syndrome but for which less convincing data are available include carbamazepine, fentanyl, and pentazocine.296,399

Clinicians should be aware of the potential for serious, possibly fatal reactions associated with serotonin syndrome in patients receiving 2 or more drugs that affect serotonergic neurotransmission, even if no such interactions with the specific drugs have been reported to date in the medical literature.299,300,304,386,399 Such patients should be monitored for the emergence of serotonin syndrome.399 Serotonin syndrome may be more likely to occur when initiating therapy, increasing the dosage, or following the addition of another serotonergic drug.386,399 Some clinicians state that patients who have experienced serotonin syndrome may be at higher risk for recurrence of the syndrome upon reinitiation of serotonergic drugs.294 Pending further experience in such cases, some clinicians recommend that therapy with serotonergic agents be limited following recovery.294 If concomitant use of citalopram and other serotonergic drugs is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases.399 If manifestations of serotonin syndrome occur, treatment with citalopram and any concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.399

For further information on serotonin syndrome, including manifestations and treatment, see Drug Interactions: Serotonergic Drugs, in Fluoxetine Hydrochloride 28:16.04.20.

Monoamine Oxidase Inhibitors

Concomitant use of citalopram and MAO inhibitors, both those used to treat psychiatric disorders and others such as linezolid and methylene blue, is associated with a risk of potentially life-threatening serotonin syndrome.399 Such reactions also have been reported in patients who recently have discontinued an SSRI and have initiated therapy with an MAO inhibitor.205,291,297,399

Because of the potential risk of serotonin syndrome, concomitant use of citalopram and MAO inhibitors intended to treat psychiatric disorders is contraindicated.399 At least 2 weeks should elapse between discontinuance of MAO inhibitors intended to treat psychiatric disorders and initiation of citalopram therapy and vice versa.399

Linezolid

Linezolid, an anti-infective agent that is a nonselective and reversible MAO inhibitor, has been associated with drug interactions resulting in serotonin syndrome, including some associated with SSRIs.399,611,612 Because of this potential risk, linezolid generally should not be used in patients receiving citalopram.611 However, certain life-threatening or urgent situations may necessitate immediate linezolid treatment in a patient receiving a serotonergic drug, including citalopram.399,611 In such emergency situations, the availability of acceptable alternative anti-infectives should be considered and the benefits of linezolid should be weighed against the risk of serotonin syndrome.399,611 If linezolid is indicated in such emergency situations, citalopram must be immediately discontinued and the patient monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last linezolid dose, whichever comes first.399,611 Treatment with citalopram may be resumed 24 hours after the last linezolid dose.399,611

If nonemergency use of linezolid is being planned for a patient receiving citalopram, citalopram should be withheld for at least 2 weeks prior to initiating linezolid.611

Initiation of citalopram in a patient receiving linezolid is contraindicated; when necessary, citalopram may be started 24 hours after the last linezolid dose.399,611 (See Drug Interactions: Serotonergic Drugs, in Linezolid 8:12.28.24.)

Methylene Blue

Methylene blue, a potent and reversible inhibitor of MAO-A, has been associated with drug interactions resulting in serotonin syndrome, including some associated with SSRIs.399,613,614 All of the reports of serotonin syndrome with methylene blue that provided information on the route of administration involved IV administration of doses of 1-8 mg/kg (e.g., when used as a diagnostic [visualizing] dye† during parathyroid surgery); none of the reports to date involved administration of methylene blue by other routes (such as oral tablets or by local tissue injection) or at lower doses.399,613,614 Because of this potential risk, methylene blue generally should not be used in patients receiving citalopram.613 However, certain life-threatening or urgent situations may necessitate immediate IV methylene blue administration in a patient receiving a serotonergic drug, including citalopram.399,613 In such emergency situations, the availability of acceptable alternatives to methylene blue should be considered and the benefits of IV methylene blue should be weighed against the risk of serotonin syndrome.399,613 If methylene blue is indicated in such emergency situations, citalopram must be immediately discontinued and the patient monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last methylene blue dose, whichever comes first.399,613 Treatment with citalopram may be resumed 24 hours after the last methylene blue dose.399,613

If nonemergency use of methylene blue is being planned for a patient receiving citalopram, citalopram should be withheld for at least 2 weeks prior to initiating methylene blue treatment.613

Initiation of citalopram in a patient receiving IV methylene blue is contraindicated; when necessary, citalopram may be started 24 hours after the last IV methylene blue dose.399,613

Moclobemide

Moclobemide (not commercially available in the US), a selective and reversible MAO-A inhibitor, has been associated with serotonin syndrome, and such reactions have been fatal in several cases in which the drug was given in combination with citalopram or with clomipramine.174,296,312,314,315,316,317 Pending further experience with such combinations, some clinicians recommend that concurrent therapy with moclobemide and a selective serotonin-reuptake inhibitor be used only with extreme caution and serotonin-reuptake inhibitors should have been discontinued for some time (depending on the elimination half-lives of the drug and its active metabolites) before initiating moclobemide therapy.314

Selegiline

Selegiline, a selective MAO-B inhibitor used in the management of parkinsonian syndrome, has been reported to cause serotonin syndrome when given concurrently with selective serotonin-reuptake inhibitors (e.g., fluoxetine, paroxetine, sertraline).294,296,319 Although selegiline is a selective MAO-B inhibitor at therapeutic dosages, the drug appears to lose its selectivity for the MAO-B enzyme at higher dosages (e.g., those exceeding 10 mg/kg), thereby increasing the risk of serotonin syndrome in patients receiving higher dosages of the drug either alone or in combination with other serotonergic agents.293,296,303

In a double-blind, placebo-controlled study in healthy individuals receiving citalopram and selegiline concurrently, no clinically important differences in vital signs or in the frequency of adverse events between the study groups were reported.318 In addition, no evidence of a clinically relevant pharmacokinetic interaction between the 2 drugs was found.318 Pending further accumulation of data, the manufacturer of selegiline recommends avoiding concurrent selegiline and selective serotonin-reuptake inhibitor therapy.303,319 In addition, the manufacturer of selegiline recommends that at least 2 weeks elapse between discontinuance of selegiline and initiation of selective serotonin-reuptake inhibitor therapy.303,319

Isoniazid

Isoniazid, an antituberculosis agent, appears to have some MAO-inhibiting activity.320 In addition, iproniazid (not commercially available in the US), another antituberculosis agent structurally related to isoniazid that also possesses MAO-inhibiting activity, reportedly has resulted in serotonin syndrome in at least 2 patients when given in combination with meperidine.296 Pending further experience, clinicians should be aware of the potential for serotonin syndrome when isoniazid is given in conjunction with selective serotonin-reuptake inhibitor therapy (such as citalopram) or other serotonergic agents.320

Tryptophan

An interaction between paroxetine (another SSRI) and tryptophan (a serotonin precursor) has been reported during concurrent use.1,205 Adverse reactions reported to date during combined therapy with these drugs resemble serotonin syndrome and have consisted principally of headache, nausea, sweating, and dizziness.1,205 If concomitant use of citalopram and tryptophan is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases.399 If serotonin syndrome manifestations occur, treatment with citalopram, tryptophan, and any other concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.399 (See Cautions: Precautions and Contraindications.)

5-HT1 Receptor Agonists (“Triptans”)

Weakness, hyperreflexia, and incoordination have been reported rarely during postmarketing surveillance in patients receiving sumatriptan concomitantly with an SSRI (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline); these reactions resembled serotonin syndrome.1,205,294,304,386 Oral or subcutaneous sumatriptan and SSRIs were used concomitantly in some clinical studies without unusual adverse effects.321,322,323 However, an increase in the frequency of migraine attacks and a decrease in the effectiveness of sumatriptan in relieving migraine headache have been reported in a patient receiving subcutaneous injections of sumatriptan intermittently while undergoing fluoxetine therapy.324

Clinicians prescribing triptans, SSRIs, and SNRIs should consider that triptans often are used intermittently and that either the triptan, SSRI, or SNRI may be prescribed by a different clinician.1,386 Clinicians also should weigh the potential risk of serotonin syndrome with the expected benefit of using a triptan concurrently with SSRI or SNRI therapy.1,386,399 If concomitant treatment with a triptan and citalopram is clinically warranted, patients should be advised of the increased risk of serotonin syndrome, particularly during treatment initiation and dosage increases.399 If serotonin syndrome manifestations occur, treatment with citalopram, the triptan, and any other concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.399 (See Cautions: Precautions and Contraindications.)

Other Selective Serotonin-reuptake Inhibitors and Selective Serotonin- and Norepinephrine-reuptake Inhibitors

Concomitant use of citalopram and other SSRIs or SNRIs potentially may result in serotonin syndrome.399 If concomitant use of citalopram and other SSRIs or SNRIs is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases.399 If serotonin syndrome manifestations occur, treatment with citalopram, the other SSRI or SNRI, and any other concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.399 (See Cautions: Precautions and Contraindications.)

Clinical experience regarding the optimal timing of switching from other SSRIs to citalopram therapy is limited.348,349 Therefore, care and prudent medical judgment should be exercised when switching from other SSRIs to citalopram, particularly from long-acting agents (e.g., fluoxetine).348,349 Because some adverse reactions resembling serotonin syndrome have developed when fluoxetine therapy has been abruptly discontinued and therapy with another SSRI (sertraline) was initiated immediately afterward, a washout period may be advisable when transferring a patient from fluoxetine to another SSRI.144,330,331,332,333 However, the appropriate duration of the washout period when switching from other SSRIs to citalopram has not been clearly established.348,349 Pending further experience in patients being transferred from therapy with another SSRI to citalopram and as the clinical situation permits, it generally is recommended that the previous antidepressant be discontinued according to the recommended guidelines for the specific SSRI prior to initiation of citalopram therapy.229,332,334

Drugs Undergoing Hepatic Metabolism or Affecting Hepatic Microsomal Enzymes

In vitro enzyme inhibition data did not reveal an inhibitory effect of citalopram on cytochrome P-450 (CYP) isoenzyme 3A4, 2C9, or 2E1 but did suggest that it is a weak inhibitor of 1A2, 2D6, and 2C19.1,170,278 Citalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these isoenzymes.1,278 However, in vivo data to address this question are very limited.1

In vitro studies have indicated that CYP3A4 and CYP2C19 are the principal isoenzymes involved in the metabolism of citalopram.278,399 Therefore, it is expected that potent inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, macrolide antibiotics) and potent inhibitors of CYP2C19 (e.g., omeprazole) might decrease the clearance of citalopram.399 However, concurrent administration of citalopram and ketoconazole, a potent inhibitor of CYP3A4, did not substantially affect the pharmacokinetics of citalopram.399 (See Ketoconazole under Drug Interactions: Drugs Undergoing Hepatic Metabolism or Affecting Hepatic Microsomal Enzymes.)

Steady-state plasma citalopram concentrations were not substantially different in healthy individuals with poor or extensive CYP2D6 metabolizer phenotypes following multiple-dose administration of citalopram, suggesting that coadministration of citalopram with a drug that inhibits CYP2D6 is unlikely to have clinically important effects on citalopram metabolism.278,399

Carbamazepine

Concurrent administration of citalopram (40 mg daily for 14 days) and carbamazepine (titrated up to 400 mg daily for a total of 35 days) in healthy individuals did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate.1,316,335 Trough plasma citalopram concentrations were unaffected in this study, which suggests that the initiation of citalopram therapy in patients stabilized on carbamazepine should not produce clinically important changes in plasma carbamazepine concentrations.1,316,335 However, in an open study in depressed patients, the addition of carbamazepine to citalopram therapy resulted in a decrease in the plasma concentrations of escitalopram, the active enantiomer with the 1-( S ) absolute configuration.337 In addition, 2 cases of increased plasma citalopram concentrations and altered antidepressant response have been reported when carbamazepine was discontinued.336 Because of the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of citalopram should be considered if the 2 drugs are administered concomitantly or if carbamazepine therapy is initiated or discontinued in a patient receiving citalopram.1,336,337,348,349

CYP2C19 Inhibitors

Cimetidine is known to inhibit many CYP oxidative enzymes, including CYP2C19, and can affect the pharmacokinetics of citalopram.7,399 In a study in which oral citalopram (40 mg daily) was given for 3 weeks, the area under the plasma concentration-time curve (AUC) and peak plasma concentrations of citalopram were increased by approximately 43 and 39%, respectively, during concomitant use of oral cimetidine (400 mg daily) for the final 8 days.1,7 The possible effects of citalopram on the pharmacokinetics of cimetidine have not been studied.349

Because of the potential risk of QT-interval prolongation and torsades de pointes, the maximum recommended dosage of citalopram is 20 mg once daily in patients concomitantly receiving citalopram and cimetidine or other CYP2C19 inhibitors.399,416,424

Ketoconazole

In a randomized, double-blind study, concurrent administration of single doses of citalopram (40 mg) and ketoconazole (200 mg), a potent inhibitor of CYP3A4, in healthy individuals decreased the peak plasma ketoconazole concentrations and AUC by 21 and 10%, respectively.1,325 The pharmacokinetics of citalopram and demethylcitalopram were not substantially affected during concomitant administration of these two drugs in this study.1,325 Therefore, citalopram dosage adjustment is unlikely to be necessary in patients receiving ketoconazole concurrently.325

Triazolam

Concurrent administration of citalopram (titrated to 40 mg daily for 28 days) and a single dose of triazolam (0.25 mg), a CYP3A4 substrate, in healthy individuals did not substantially affect the pharmacokinetics of either drug.1,316,328 However, triazolam appeared to be absorbed slightly more quickly during citalopram coadministration.328

Tricyclic and Other Antidepressants

The extent to which selective serotonin-reuptake inhibitor interactions with tricyclic antidepressants may pose clinical problems depends on the degree of inhibition and the pharmacokinetics of the serotonin-reuptake inhibitor involved.170,229,252,278 In vitro studies suggest that citalopram is a relatively weak inhibitor of CYP2D6 and CYP2C19.1,170,278,316 In one study in healthy adults receiving citalopram (40 mg once daily for 10 days), concurrent administration of a single 100-mg dose of imipramine hydrochloride, a CYP2D6 and CYP2C19 substrate, did not substantially affect the plasma concentrations of either citalopram or imipramine.1,170 However, the plasma concentration of the principal imipramine metabolite, desipramine, increased by approximately 50%; the clinical importance of this change is not known.1,170 The manufacturer of citalopram recommends that caution be exercised during concurrent use of tricyclic antidepressants with citalopram.1

In addition, concomitant use of citalopram and tricyclic antidepressants potentially may result in serotonin syndrome.399 If concomitant use of citalopram and a tricyclic antidepressant is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases.399 If serotonin syndrome manifestations occur, treatment with citalopram, the tricyclic antidepressant, and any concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.399 (See Cautions: Precautions and Contraindications and also see Drug Interactions: Serotonergic Drugs.)

Clinical experience regarding the optimal timing of switching from other antidepressants to citalopram therapy is limited.348,349 Therefore, care and prudent medical judgment should be exercised when switching from other antidepressants to citalopram.348,349 Pending further experience in patients being transferred from therapy with another antidepressant to citalopram and as the clinical situation permits, it generally is recommended that the previous antidepressant be discontinued according to the recommended guidelines for the specific antidepressant prior to initiation of citalopram therapy.229,332,334

Alcohol

Citalopram has not been shown to potentiate the impairment of mental and motor skills caused by alcohol.1,65 However, the drug's ability to reduce alcohol consumption in animals and humans suggests that there may be a serotonergically mediated, pharmacodynamic interaction between citalopram and alcohol within the CNS.20,34,35,36,37,38,39,40,44,45,46,47 (See Pharmacology: Effects on Alcohol Intake, and also see Uses: Alcohol Dependence.) The manufacturer recommends that patients be advised to avoid alcohol while receiving citalopram.1

Lithium

The manufacturer states that coadministration of lithium and citalopram did not substantially affect the pharmacokinetics of either drug in healthy individuals.1,170 In a placebo-controlled trial in depressed patients refractory to citalopram therapy alone, there also was no evidence of a pharmacokinetic interaction when lithium therapy (800 mg daily) was added; the combination was found to be well tolerated.168 However, pending further accumulation of data, the manufacturer of citalopram recommends that plasma lithium concentrations be monitored in patients receiving citalopram concurrently and that the lithium dosage be adjusted accordingly.1 Lithium also may enhance the serotonergic effects of citalopram, potentially resulting in serotonin syndrome.1,169,399 Caution should be exercised in patients receiving these two drugs concomitantly.399 (See Drug Interactions: Serotonergic Drugs.)

Drugs Affecting Hemostasis

Warfarin

The administration of a single, 25-mg dose of warfarin, a CYP3A4 substrate, in healthy individuals receiving citalopram 40 mg daily for 15 days did not affect the pharmacokinetics of warfarin.1,190 However, the prothrombin time increased by an average of 5% compared with baseline.1,190 The clinical importance, if any, of these findings is not known.1,190

Other Drugs that Interfere with Hemostasis

Epidemiologic case-control and cohort design studies that have demonstrated an association between selective serotonin-reuptake inhibitor therapy and an increased risk of upper GI bleeding also have shown that concurrent use of aspirin or other nonsteroidal anti-inflammatory agents substantially increases the risk of GI bleeding.1,54,55,377,378 Although these studies focused on upper GI bleeding, there is some evidence suggesting that bleeding at other sites may be similarly potentiated.1 The precise mechanism for this increased risk remains to be clearly established; however, serotonin release by platelets is known to play an important role in hemostasis, and selective serotonin-reuptake inhibitors decrease serotonin uptake from the blood by platelets, thereby decreasing the amount of serotonin in platelets.1,54,378 Patients receiving citalopram should be cautioned about the concomitant use of drugs that interfere with hemostasis, including aspirin and other nonsteroidal anti-inflammatory agents.1

Pimozide

In a controlled study, concurrent administration of a single 2-mg dose of pimozide in individuals receiving citalopram (40 mg once daily for 11 days) was associated with mean increases in the QT_c interval of approximately 10 msec compared with pimozide given alone.1 Citalopram did not substantially affect the mean AUC or peak plasma concentrations of pimozide.1 The mechanism for this potential pharmacodynamic interaction is not known.1 In addition, concomitant use of citalopram and pimozide rarely may result in potentially serious, sometimes fatal serotonin syndrome.408

The manufacturers of citalopram hydrobromide state that concurrent administration of citalopram and pimozide is contraindicated.399,615

Other CNS-active Agents

The manufacturers state that, given the primary CNS effects of citalopram, caution should be used when it is given concurrently with other centrally acting drugs.399,615

Digoxin

In healthy adults who received citalopram (40 mg daily for 3 weeks), the concurrent administration of a single, 1-mg dose of digoxin did not significantly affect the pharmacokinetics of citalopram or digoxin.1,188 Concurrent administration of the 2 drugs was well tolerated, with no serious adverse events and no clinically important ECG changes reported.188 These data suggest that concomitantly administered citalopram is unlikely to substantially affect serum digoxin concentrations in patients who are receiving chronic digoxin therapy.188

Diuretics

Concomitant use of citalopram and diuretics may increase the risk of hyponatremia.399 (See Other Renal, Electrolyte, and Genitourinary Effects under Cautions: Renal, Electrolyte, and Genitourinary Effects.)

Electroconvulsive Therapy

The manufacturer states that there are no clinical studies on the concurrent use of citalopram and electroconvulsive therapy (ECT).1 In a limited number of depressed women given either citalopram 20 mg or placebo before their third and fourth ECT sessions, no adverse effects were reported after citalopram administration and the length of the electrically induced seizures and neurohormonal responses did not substantially differ between the 2 groups.171 However, additional studies are needed to confirm the safety and efficacy of ECT in patients receiving citalopram.171,348,349

Metoprolol

Administration of citalopram 40 mg daily for 22 days resulted in a twofold increase in the plasma concentrations of metoprolol in one study.1 Increased plasma concentrations of metoprolol have been associated with decreased cardioselectivity.1 Concurrent administration of citalopram and metoprolol had no clinically important effects on blood pressure or heart rate.1

Theophylline

In an open, multiple-dose study, concurrent administration of citalopram (40 mg daily) for 21 days and theophylline (single, 300-mg dose), a CYP1A2 substrate, in healthy individuals did not substantially affect the pharmacokinetics of theophylline.1,329 Therefore, some clinicians state that dosage adjustment of theophylline may not be necessary in patients receiving citalopram concurrently.329 The effect of theophylline on the pharmacokinetics of citalopram was not evaluated.1,329

Cyclosporine

Limited evidence suggests that citalopram does not substantially affect the pharmacokinetics of cyclosporine; further study is needed to confirm these preliminary findings.326

Acute Toxicity

Limited information is available on the acute toxicity of citalopram.1,70,211,255,256,257,399

Pathogenesis

The acute lethal dose of citalopram in humans is not known.349 The manufacturer states that no fatalities were reported among patients taking overdosages of up to 2 g during clinical trials.1 However, postmarketing reports of citalopram overdosage have included ingestions of up to 6 g; as with other selective serotonin-reuptake inhibitors, fatalities have been reported rarely following citalopram overdosage.1,70,255,257,315,317

Manifestations

In general, overdosage of citalopram may be expected to produce effects that are extensions of the drug's pharmacologic and adverse effects.1,357 Case reports in humans indicate that the possible effects of citalopram overdosage (either alone or in combination with other drugs and/or alcohol) include dizziness,1 sweating,1 nausea,1 vomiting,1 tremor,1 somnolence,1 and sinus tachycardia.1 In rare cases, observed symptoms have included amnesia,1 confusion,1 coma,1 seizures,1,70,347 hyperventilation,1 cyanosis,1 and rhabdomyolysis.1,347

ECG changes, including QT_c prolongation,1,70,256,347,422 sinus bradycardia,256 nodal rhythm,1 ventricular arrhythmias,1 left bundle branch block,211 and torsades de pointes,1,264,422 have been reported rarely in citalopram overdosage.1,70,256,264,422 In a young, healthy female who ingested 400 mg of citalopram, QT_c prolongation was reported.70 In most cases of pure citalopram overdosage at doses exceeding 600 mg, ECG changes, including QT prolongation and sinus bradycardia, gradually resolved 12-24 hours following the intoxication.70,256,347 However, severe sinus bradycardia developed within about 4 hours following ingestion of 800 mg of citalopram alone in one female patient and lasted up to 6 days during intensive care unit (ICU) treatment; hypotension and syncope also occurred but no QT-interval prolongation was observed.256 A temporary pacemaker was necessary for treatment of this patient.256 In another case, a woman developed life-threatening cardiac toxicity, including torsades de pointes with cardiac arrest, approximately 32 hours following ingestion of 1 g of citalopram; her corrected QT interval remained abnormal for 24 hours after presentation.422

Manifestations resembling serotonin syndrome also have been reported following citalopram overdosage either alone or in combination with other serotonergic drugs (e.g., moclobemide [not commercially available in the US]).253,254,315,317,347,399 (See Cautions: Precautions and Contraindications and also see Drug Interactions: Serotonergic Drugs.)

In one fatal case involving a 47-year-old man who ingested an unknown amount of citalopram in combination with other drugs, postmortem citalopram concentrations were 0.88 mg/L in femoral blood, 1.16 mg/L in heart blood, and 0.9 mg/L in urine.255 In another fatal case involving a 53-year-old woman who ingested an unknown amount of citalopram and trimipramine, postmortem analysis revealed a citalopram concentration of 4.81 mg/L and a trimipramine concentration of 2.33 mg/L in femoral blood.257 The citalopram to demethylcitalopram ratios were 1.96 and 2.02 in femoral blood and hepatic tissue, respectively.257

Treatment

Because fatalities and severe toxicity have been reported following overdosage of citalopram and other selective serotonin-reuptake inhibitors, particularly in large overdosage and when taken with other drugs or alcohol, some clinicians recommend that any overdosage involving these drugs be managed aggressively.70,255,256,315,347,357,359 Because suicidal ingestion often involves more than one drug, clinicians treating citalopram overdosage should be alert to possible manifestations caused by drugs other than citalopram.1,255,357

Clinicians also should consider the possibility of serotonin syndrome in patients presenting with similar clinical features and a recent history of citalopram ingestion and/or ingestion of other serotonergic agents.253,254,315,317,399,408 (See Cautions: Precautions and Contraindications and also see Drug Interactions: Serotonergic Drugs.)

Management of citalopram overdosage generally requires symptomatic and supportive care.1,347 A patent airway should be established and maintained, and adequate oxygenation and ventilation should be ensured.1 An ECG should be obtained and monitoring of cardiac function instituted.1,70,256,347 Frequent vital sign monitoring and close observation of the patient is necessary.1 Clinicians should consider that development of cardiac toxicity following citalopram overdosage may be delayed.422 There is no specific antidote for citalopram intoxication.1

Following recent (i.e., within 4 hours) ingestion of a potentially toxic amount of citalopram and in the absence of signs and symptoms of cardiac toxicity, the stomach should be emptied immediately by inducing emesis or by gastric lavage.1,21 However, some clinicians recommend avoidance of emesis in patients who have ingested overdoses of selective serotonin-reuptake inhibitors because of the potential for unexpected changes in mental status.216 If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents.349 However, some clinicians note that gastric lavage generally is not necessary because of the low incidence of fatalities associated with selective serotonin-reuptake inhibitor overdoses.216 In one study, activated charcoal alone or gastric lavage followed by activated charcoal demonstrated similar efficacy in preventing the absorption of citalopram.94 In another study, single-dose activated charcoal administration given an average of 2.1 hours after citalopram ingestion was found to be effective in reducing the risk of QT-interval prolongation associated with overdosage of the drug.423 Since administration of activated charcoal (which may be used in conjunction with sorbitol) may be as or more effective than induction of emesis or gastric lavage, its use has been recommended either in the initial management of selective serotonin-reuptake inhibitor overdosage or following induction of emesis or gastric lavage in patients who have ingested a potentially toxic quantity of these drugs.94,205,423

Because of the large volume of distribution of citalopram, hemodialysis, peritoneal dialysis, forced diuresis, hemoperfusion, and/or exchange transfusion are unlikely to be effective in removing substantial amounts of citalopram from the body.1,88,347,349

Clinicians should consult a poison control center for additional information on the management of citalopram overdosage.1

Chronic Toxicity

The results of animal studies suggest that the abuse potential for citalopram is low.1 Citalopram has not been studied systematically in humans to determine whether therapy with the drug is associated with abuse, tolerance, or physical dependence.1

The premarketing clinical experience with citalopram did not reveal any drug-seeking behavior.1 However, these observations were not systematic, and it is not possible to accurately predict from the limited data currently available the extent to which a CNS-active drug like citalopram will be misused, diverted, and/or abused.1

Experience with citalopram, other selective serotonin-reuptake inhibitors (SSRIs), and selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) suggests that a withdrawal syndrome may occur within several days following discontinuance of these drugs, particularly when abrupt.17,218,219,220,221,223,224,225,226,227,228,229,231,232,233,234,235,399 The most commonly observed manifestations are those that resemble influenza, such as fatigue, lethargy, GI complaints (e.g., nausea), dizziness or lightheadedness, impaired sleep, tremor, anxiety, insomnia, chills, sweating, and incoordination.17,212,225,226,227,229,230,231,232 Other reported manifestations include dysphoric mood, irritability, emotional lability, hypomania, memory impairment, sensory disturbances (such as paresthesias, including electric shock-like sensations), confusion, headache, palpitations, agitation, and aggression.17,219,221,225,226,227,229,230,399 Although the mechanism(s) for such withdrawal reactions is not fully understood, it has been suggested that they may be caused by a sudden decrease in serotonin availability at the synapse or cholinergic rebound; other neurotransmitters (e.g., dopamine, norepinephrine, GABA) also may be involved.228,229 These manifestations may in some cases be mistaken for physical illness or relapse into depression.17,219,224,226,227 While these reactions generally appear to be self-limiting and improve over one to several weeks,17,205,225,229,230,232,399 there have been reports of serious discontinuance symptoms.399 Manifestations of withdrawal also may be improved by restarting therapy with citalopram or another antidepressant with a similar pharmacologic profile.220,225,227,229,232

Withdrawal reactions have been reported rarely in citalopram-treated patients.223,231,232,234,399 Data from a controlled study evaluating citalopram in preventing depression relapse indicate that the symptoms associated with abrupt discontinuance of therapy generally are mild and transient.223 Overall clinical experience to date suggests that the risk of withdrawal effects may be somewhat lower with citalopram, fluoxetine, and sertraline compared with paroxetine.65,231,232,233 These differences may be due at least in part to the prolonged elimination half-lives of the parent drugs and/or their active metabolites.218,219,220,225,226,229,233,235 The manufacturer399 and some clinicians recommend that citalopram, like other SSRIs, be discontinued gradually (e.g., over a period of several weeks) rather than abruptly whenever possible to prevent the possible development of withdrawal reactions.13,14,17,348,349,399

As with other CNS-active drugs, clinicians should carefully evaluate patients for a history of substance abuse prior to initiating citalopram therapy.1 If citalopram therapy is initiated in patients with a history of substance abuse, such patients should be monitored closely for signs of misuse or abuse of the drug (e.g., development of tolerance, use of increasing doses, drug-seeking behavior).1

Pharmacology

The pharmacology of citalopram is complex and in many ways resembles that of other antidepressant agents, particularly those agents (e.g., escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, clomipramine, trazodone) that predominantly potentiate the pharmacologic effects of serotonin (5-hydroxytryptamine [5-HT]).1,18,20,26,52,340 Like other selective serotonin-reuptake inhibitors (SSRIs), citalopram is a potent and highly selective inhibitor of serotonin reuptake and has little or no effect on other neurotransmitters.1,18,20,21,26,52

Nervous System Effects

The precise mechanism of antidepressant action of citalopram is unclear, but the drug has been shown to selectively inhibit the reuptake of serotonin at the presynaptic neuronal membrane.1,20,22,23,26,52 Citalopram-induced inhibition of serotonin reuptake causes increased synaptic concentrations of serotonin in the CNS, resulting in numerous functional changes associated with enhanced serotonergic neurotransmission.1,20,22,23,26 Like other selective serotonin-reuptake inhibitors (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline), citalopram appears to have only very weak effects on the reuptake of norepinephrine or dopamine1,18,20,26,52 and does not exhibit clinically important anticholinergic, antihistaminic, or adrenergic (α₁, α₂, β) blocking activity at usual therapeutic dosages.1,18,20,26

Although the mechanism of antidepressant action of antidepressant agents may involve inhibition of the reuptake of various neurotransmitters (e.g., serotonin, norepinephrine) at the presynaptic neuronal membrane,1,20 it has been suggested that postsynaptic receptor modification is mainly responsible for the antidepressant action observed during long-term administration of antidepressant agents.20 During long-term therapy with most antidepressants (e.g., tricyclic antidepressants, monoamine oxidase [MAO] inhibitors), these adaptive changes mainly consist of subsensitivity of the noradrenergic adenylate cyclase system in association with a decrease in the number of β-adrenergic receptors; such effects on noradrenergic receptor function are commonly referred to as “down regulation.”20 However, selective serotonin-reuptake inhibitors have not consistently demonstrated the ability to downregulate β-adrenergic receptors despite being effective antidepressant agents clinically.20,24,25,26 Thus, downregulation of β-adrenergic receptors does not appear to be an absolute prerequisite for antidepressant action.20,26 Long-term administration of desipramine but not citalopram substantially decreased β-adrenergically mediated cyclic adenosine monophosphate accumulation.20,25 In addition, some antidepressants (e.g., amitriptyline) reportedly decreased the number of serotonergic binding sites following chronic administration.27

The exact mechanism of action of citalopram in panic disorder has not been fully elucidated but appears to involve at least in part changes in serotonergic neurotransmission.28,29,30,288

The precise mechanism of action that is responsible for the efficacy of citalopram in the treatment of obsessive-compulsive disorder is unclear.24,31,32,33,173,177 However, because of the potency of clomipramine and other selective serotonin-reuptake inhibitors (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) in inhibiting serotonin reuptake and their efficacy in the treatment of obsessive-compulsive disorder, a serotonin hypothesis has been developed to explain the pathogenesis of the condition.24,31,32,33,173,177 The hypothesis postulates that a dysregulation of serotonin is responsible for obsessive-compulsive disorder and that citalopram and these other agents are effective because they correct this imbalance.24,31,32,33,177 Although considerable evidence supports the serotonergic hypothesis of obsessive-compulsive disorder, additional studies are necessary to confirm this hypothesis.31,32,33,177 Regardless of the precise pathogenesis of obsessive-compulsive disorder, the clinical efficacy of long-term therapy with selective serotonin-reuptake inhibitors such as citalopram appears to be due at least in part to alterations in serotonergic neurotransmission.32,33,173,177

Serotonergic mechanisms also appear to be involved at least in part in a number of other pharmacologic effects associated with selective serotonin-reuptake inhibitors, including citalopram, such as decreased alcohol intake20,34,35,36,37,38,39,40,43,45,46 and regulation of food intake.48,49,50

Serotonergic Effects

Citalopram is a highly selective inhibitor of serotonin reuptake at the presynaptic neuronal membrane.1,18,20,21,22,23,26,52 Citalopram-induced inhibition of serotonin reuptake causes increased synaptic concentrations of the neurotransmitter, resulting in numerous functional changes associated with enhanced serotonergic neurotransmission.1,20,22,23

Based on in vitro studies, the relative potency of citalopram as an inhibitor of serotonin reuptake compared with norepinephrine and dopamine reuptake inhibition is 3400 and 22,000, respectively, making the drug the most selective serotonin-reuptake inhibitor currently available.18,20,21,26,52 These findings have been confirmed by the results of in vivo and ex vivo studies demonstrating that citalopram inhibits the uptake of serotonin without appreciably inhibiting the uptake of norepinephrine or dopamine.18,26,52 In an initial study in rats, tolerance to the serotonin-reuptake inhibiting effect was not induced following long-term (14 days) citalopram administration.1,20

Citalopram occurs as a racemic mixture and data from in vitro and in vivo studies indicate that the serotonin-reuptake blocking activity of citalopram is principally due to escitalopram, the (+)-enantiomer with the 1-( S ) absolute configuration.1,18,20,97 Escitalopram is at least 100-fold more potent as an inhibitor of the reuptake of serotonin at the presynaptic membranes and the 5-HT neuronal firing rate than the R -enantiomer and is twice as potent as the racemic mixture.217,340,345 However, further studies are needed to determine whether these differences result in any clinical superiority of escitalopram.217,348 For additional information on escitalopram, see Escitalopram Oxalate 28:16.04.20.

Unlike some other serotonin-reuptake inhibitors, the demethylated metabolites of citalopram, demethylcitalopram and didemethylcitalopram, are substantially less active than the parent compound as inhibitors of serotonin reuptake and have negligible affinity for various neurotransmitter receptor-binding sites.1,18,26,52,97 In vitro studies have shown that citalopram is at least 8 times more potent than its metabolites in inhibiting serotonin reuptake;1 therefore, the drug's metabolites are unlikely to contribute to the clinical activity of the drug.1,18,97

At therapeutic dosages in humans, citalopram has been shown to inhibit the reuptake of serotonin into platelets.52,53

Like other selective serotonin-reuptake inhibitors, in vitro data have demonstrated that citalopram has no or very low affinity for serotonergic receptor subtypes (5-HT_1A and 5-HT_2A receptors).1,20

Effects on Other Neurotransmitters

The results of in vitro and in vivo studies indicate that citalopram has little effect on the neuronal reuptake of norepinephrine and dopamine.1,18,20,26,52 In addition, in vivo and in vitro data suggest that citalopram does not substantially inhibit MAO.18,52,56,57 However, citalopram has demonstrated some inhibitory activity towards MAO-A and MAO-B, with clear selectivity for MAO-B, in one in vivo study.58

Unlike tricyclic and some other antidepressants, citalopram does not exhibit clinically important anticholinergic, α- or β-adrenergic blocking, or antihistaminic activity at usual therapeutic dosages.1,52 As a result, the incidence of adverse effects commonly associated with blockade of muscarinic cholinergic receptors (e.g., dry mouth, blurred vision, urinary retention, constipation, confusion), α-adrenergic receptors (e.g., orthostatic hypotension), and histamine H₁- and H₂-receptors (e.g., sedation) is lower in citalopram-treated patients.1,20,52 In vitro studies have demonstrated that citalopram possesses no or very low affinity for α₁- or α₂-adrenergic,1,20,52β-adrenergic,1,20 histaminergic (H₁),1,20,52 GABA,1,52 muscarinic,1,20,52 benzodiazepine,1,20,52 dopamine D₁ and D₂,1,20,52 or opiate receptors.52

Effects on Sleep

Like tricyclic and most other antidepressants, citalopram suppresses rapid eye movement (REM) sleep.52,59,60,61,62 In animals, citalopram has been shown to suppress REM sleep and increase deep slow wave sleep.61,62 In one study in humans, single doses of the drug suppressed REM sleep in a dose-dependent manner while chronic therapy produced more sustained REM sleep inhibition.59 Single doses of citalopram resulted in only minor changes in non-REM sleep as well as in non-REM EEG power spectral density in this study.59 However, chronic administration of the drug resulted in a major shift from slow-wave sleep stage 2 to slow-wave sleep stage 1.59 In another study, citalopram prolonged REM latency and increased non-REM stage 2 sleep.60

Although not clearly established, there is some evidence that the REM-suppressing effects of antidepressant agents may contribute to the antidepressant activity of these drugs.52,59,60 Although the precise mechanism has not been fully elucidated, available data suggest that citalopram's effects on REM sleep may be serotonergically mediated.59,61,62

Effects on EEG

Limited data currently are available regarding the effects of citalopram on the EEG.62,63,64,66 In animals, EEG studies have revealed an activating effect associated with behavioral arousal.63 In healthy individuals receiving single 20- and 40-mg doses, citalopram decreased slow-wave EEG activity in one study.66 However, the overall EEG changes were considered minimal in this study, particularly following repeated doses of the drug.66 EEG changes in healthy individuals receiving single, 10- to 50-mg oral doses of citalopram were dose-related and similar to those produced by desipramine, protriptyline, and fluvoxamine in another study.62,64

Effects on Psychomotor Function

Citalopram generally does not appear to cause clinically important sedation and generally does not adversely affect psychomotor performance.1,65,66,67 In studies in healthy individuals, citalopram did not produce impairment of psychomotor function or intellectual function when given in doses of 40 mg daily.1 In one controlled study, improved psychomotor responses to sensory stimuli and sustained attention, with substantial decreases in movement times of the choice reaction time test and an increase in critical flicker fusion threshold, were reported in healthy individuals receiving single doses of the drug.67

Cardiovascular Effects

No clinically important changes in vital signs (systolic and diastolic blood pressure and heart rate) were observed in patients receiving citalopram in controlled trials.1,68,69 In addition, a comparison of supine and standing vital signs in depressed patients receiving citalopram indicated that the drug generally does not produce orthostatic changes.1,62,65,68,69 Adverse cardiovascular effects, including QT-interval prolongation and torsades de pointes, have occasionally been reported in healthy individuals and in depressed patients receiving citalopram.399,416,417,418,419,420,421 (See Cautions: Cardiovascular Effects and see also Cautions: Precautions and Contraindications.)

In a thorough QT study, citalopram was associated with a dose-dependent increase in the corrected QT (QT_c) interval.399 In a placebo-controlled study, a change from baseline in QT_cF (Fridericia's formula) greater than 60 msec occurred in 1.9% of patients receiving citalopram compared with 1.2% of patients receiving placebo.399 None of the patients receiving placebo had a post-dose QT_cF greater than 500 msec compared with 0.5% of patients receiving citalopram.399 The incidence of tachycardic and bradycardic outliers was 0.5 and 0.9% in the citalopram group, respectively, and 0.4% in the placebo group.399 ECG changes also have been reported in individuals receiving overdosages of the drug.1,70,211,256,264,422,423 (See Acute Toxicity.)

Citalopram did not induce any substantial change in cardiovascular autonomic function tests (such as heart rate variability) in a limited number of healthy individuals receiving the drug.71

Effects on Appetite and Body Weight

Citalopram appears to possess some anorexigenic activity, although to a lesser degree than certain other serotonergic agents (e.g., fenfluramine [no longer commercially available in the US], fluoxetine, sertraline, zimelidine [not commercially available in the US]).1,49,50,51 Although the precise mechanism has not been clearly established, results from animal studies indicate that the appetite-inhibiting action of these drugs may result at least in part from serotonin-reuptake blockade and enhancement of serotonin release thereby increasing serotonin availability at the neuronal synapse.48,49

Only minimal weight loss (averaging 0.5 kg) generally occurred in patients receiving citalopram in controlled clinical trials.1 In addition, while decreased appetite was reported in about 4% of patients receiving citalopram in short-term clinical trials,1 the drug, unlike fluoxetine, does not appear to exhibit clinically important anorectic effects49,50,51 nor to produce clinically important long-term weight changes.1 Short-term citalopram therapy did not produce substantial weight loss in severely obese individuals in one study.51 Paradoxical weight gain and obesity also have been reported in some patients receiving the drug.1,50

Effects on Alcohol Intake

Like some other serotonergic agents, citalopram produces a substantial decrease in voluntary alcohol intake in animals;37,38,39,40,44 however, development of tolerance to this effect has been reported.40 Like some other serotonin-reuptake inhibitors (fluoxetine, zimelidine), citalopram also has been shown to reduce alcohol consumption in alcohol-dependent, nondepressed drinkers receiving short-term therapy with 40 mg of the drug daily.40,43,45,46,47 Because serotonin appears to be involved in the regulation of alcohol intake, it has been suggested that selective serotonin-reuptake inhibitors may attenuate alcohol consumption via enhanced serotonergic neurotransmission.37,38,39,40,43,44,45,46 (See Uses: Alcohol Dependence and see Drug Interactions: Alcohol.)

Neuroendocrine Effects

Limited data currently are available regarding the effects of citalopram on the neuroendocrine system.62,75,76,318 In a controlled study in healthy individuals, plasma prolactin concentrations reportedly were increased by 40% following 10 days of treatment with citalopram 20 mg daily.318 In addition, in healthy individuals receiving low-dose IV citalopram (parenteral dosage form not commercially available in the US), plasma prolactin and cortisol concentrations increased in a dose-dependent manner.75,76

Other Effects

Like some other antidepressants that are amphiphilic cationic compounds, citalopram has been found to cause a generalized lipidosis in animal studies.62,79 Lipidosis-like changes in lymph nodes, adrenal cortex and medulla, kidney, lung, and sympathetic ganglia have been noted in animals receiving 140 mg/kg daily of the drug for 7 weeks; however, the clinical importance of these findings remains to be established.62,79

Limited data in animals suggest that citalopram may possess anticonvulsant activity during chronic administration.191

Pharmacokinetics

In all human studies described in the Pharmacokinetics section, citalopram was administered as the hydrobromide salt; dosages and concentrations are expressed in terms of citalopram.1,80,83

A concentration of 1 nmol/L of citalopram is approximately equivalent to 0.32 ng/mL.349

Absorption

Like other selective serotonin-reuptake inhibitors, citalopram is a highly lipophilic compound that appears to be rapidly and well absorbed from the GI tract following oral administration.1,18,62,80,82,97,100,101,339 Following a single 40-mg oral dose of citalopram as a tablet, the manufacturer states that peak plasma concentrations averaging approximately 44 ng/mL occur at about 4 hours.1,349

The absolute bioavailability of citalopram is approximately 80% relative to an IV dose.1,4 The oral tablets and solution of citalopram reportedly are bioequivalent.615 Food does not substantially affect the absorption of citalopram.1

The single- and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in a dosage range of 10-60 mg daily.1,62,80,81,82,339 With once-daily dosing, steady-state plasma concentrations are achieved within approximately 1 week.1,80 In one study, the steady-state plasma concentrations ranged from about 30-230 ng/mL in depressed patients receiving dosages of 30-60 mg daily and agreed well with predicted values.82 The mean plasma concentration was approximately 80 ng/mL at the usual dosage of 40 mg daily.82 At steady state, the extent of accumulation of citalopram in plasma, based on the half-life, is expected to be about 2.5 times higher than the plasma concentrations observed after a single dose of the drug.1,80,82

In depressed patients receiving 20-60 mg daily of citalopram, steady-state plasma concentrations of racemic citalopram and demethylcitalopram, a principal metabolite, ranged from 9-200 ng/mL and 10-105 ng/mL, respectively.97,99 When using a stereoselective analysis method, plasma concentrations ranged from 9-106 ng/mL for escitalopram ( S -citalopram), 20-186 ng/mL for R -citalopram, 4-38 ng/mL for S -demethylcitalopram, and 3-75 ng/mL for R -demethylcitalopram in depressed patients receiving citalopram therapy (20-80 mg daily).97,98 The mean ratio between R -citalopram and escitalopram was 0.56 (range: 0.32-0.97).97,98

The effect of age on the pharmacokinetics of citalopram has not been fully elucidated.83,84,85,399 Studies in healthy individuals and depressed patients 60 years of age or older have found higher areas under the plasma concentration-time curves (AUC) and longer elimination half-lives compared with those in younger individuals.83,85,399 (See Pharmacokinetics: Elimination.) In healthy individuals 60 years of age or older, the AUC of citalopram was increased by an average of approximately 30% in a single-dose study and by an average of approximately 23% in a multiple-dose study.399 Steady-state plasma citalopram concentrations were up to 4 times higher in geriatric patients receiving 20 mg of the drug once daily in one multiple-dose study than expected based on data in younger patients and healthy individuals.85 (See Dosage and Administration: Dosage in Geriatric Patients and see Cautions: Geriatric Precautions.)

The effect of gender on the pharmacokinetics of citalopram has not been fully elucidated to date.1 The manufacturer states that in 3 pharmacokinetic studies, the AUC of citalopram in women was 1.5-2 times higher than that found in men; however, this difference was not observed in 5 other pharmacokinetic studies performed with the drug.1 In clinical studies, no differences in steady-state plasma citalopram concentrations were observed between men and women.1 In addition, there were no gender differences in the pharmacokinetics of the principal metabolites of citalopram, demethylcitalopram and didemethylcitalopram.1 Therefore, the manufacturer states that no adjustment of citalopram dosage on the basis of gender is necessary.1

The onset of antidepressant activity following oral administration of citalopram hydrobromide usually occurs within 1-4 weeks.1,174

As with other selective serotonin-reuptake inhibitors, the relationship between plasma citalopram concentrations and the therapeutic and/or toxic effects of the drug has not been clearly established.53,62,97,99 Since citalopram is administered as a racemic mixture with the pharmacologic effect of the drug associated mainly with escitalopram, the S -enantiomer, it may be important to take the stereoselective metabolism of the drug into account when evaluating the relationship between the clinical effect of the drug and plasma concentrations of citalopram.97,98

Distribution

Distribution of citalopram and its metabolites into human body tissues and fluids has not been fully characterized.1,62,80,82 However, limited pharmacokinetic data suggest that the drug, which is highly lipophilic, is widely distributed in body tissues.18,62,80,82,97,339

The volume of distribution of citalopram is approximately 12 L/kg.1,82,339 The drug crosses the blood-brain barrier in humans and animals.62,86,87

The binding of citalopram, demethylcitalopram, and didemethylcitalopram to human plasma proteins in vitro is about 80%.1,349

Citalopram and demethylcitalopram are distributed into milk1,5,90,91,92,95,362 and also cross the placenta.95,362,401 In a study involving 7 lactating women who received median oral citalopram doses of 0.36 mg/kg daily for the treatment of depression, mean milk-to-plasma AUC values of 1.8 were calculated for both citalopram and demethylcitalopram.91 Depending on the method of calculation, mean infant exposure was estimated to be 3.2 or 3.7% for citalopram and 1.2 or 1.4% for demethylcitalopram in this study.91 In 9 lactating women receiving 20-40 mg daily of citalopram in another study, maternal milk-to-plasma ratios of the drug ranged from approximately 2-3; however, plasma citalopram concentrations in the neonates were found to be very low or below the limit of detection.95 In a lactating woman receiving 40 mg daily of citalopram, concentrations of the drug in milk and serum were about 205 ng/mL and 99 ng/mL, respectively, and the drug concentration in the infant's serum was about 13 ng/mL.92 In another lactating woman receiving 20 mg daily of citalopram, peak milk concentrations of the drug occurred 3-9 hours following maternal drug intake; the milk-to-serum concentration ratio was approximately 3 for both citalopram and demethylcitalopram.5 Accordingly, the infant received approximately 5% of the mother's dose when adjusted for weight.5 (See Cautions: Pregnancy, Fertility, and Lactation.)

Elimination

The elimination half-life of citalopram averages approximately 35 hours in adults with normal renal and hepatic function.1,4,62,80,82,339

The exact metabolic fate of citalopram has not been fully elucidated; however, metabolism of citalopram is mainly hepatic and involves N -demethylation.1,3,62,97,100 Citalopram is metabolized to demethylcitalopram, didemethylcitalopram, citalopram- N -oxide, and a deaminated propionic acid derivative.1 In vitro studies have indicated that cytochrome P-450 (CYP) 3A4 and 2C19 isoenzymes are the principal enzymes involved in the N -demethylation of citalopram to demethylcitalopram and that demethylcitalopram is further N -demethylated to didemethylcitalopram by CYP2D6.1,77,97,278 Because citalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme is unlikely to appreciably decrease the clearance of citalopram.1,97,316 Unlike some other selective serotonin-reuptake inhibitors, the demethylated metabolites of citalopram, demethylcitalopram and didemethylcitalopram, are substantially less active than the parent compound as inhibitors of serotonin reuptake.1,18,26,52,62,97 Thus, citalopram's metabolites are unlikely to contribute to the antidepressant and other clinical actions of the drug.1,18,62,97

In humans, unchanged citalopram is the predominant compound in plasma.1,3 At steady state, the concentrations of demethylcitalopram and didemethylcitalopram in plasma are approximately one-half and one-tenth, respectively, that of the parent drug.1,62,80 Following IV (parenteral dosage form not commercially available in the US) administration of citalopram, the fraction of drug recovered in urine as citalopram and demethylcitalopram was about 10 and 5%, respectively.1

Following oral administration of a single, radiolabeled dose of citalopram in healthy individuals, approximately 75% of the dose was excreted in urine and approximately 10% was eliminated in feces within 17 days.100 An analysis of the urinary composition showed that besides the known metabolites of citalopram, 3 glucuronides were present.100 The relative amounts of citalopram, demethylcitalopram, didemethylcitalopram, and the N -oxide metabolite present in urine collected for 7 days were 26, 19, 9, and 7%, respectively, with glucuronidated metabolites accounting for the remainder.100

Following IV administration, the mean systemic clearance of citalopram is approximately 330 mL/minute, with approximately 20% of that due to renal clearance.1,339,349

The effect of age on the elimination of citalopram has not been fully elucidated.1,62,83,338 Studies in healthy geriatric individuals and depressed geriatric patients have found higher AUC values and longer elimination half-lives compared with younger individuals.62,83,399 (See Pharmacokinetics: Absorption.) In healthy individuals 60 years of age or older, the elimination half-life of citalopram was increased by 50% in a single-dose study and by 30% in a multiple-dose study.83,399 It has been suggested that these differences in pharmacokinetic parameters may reflect declining liver and kidney function.62,83 In addition, the stereoselective metabolism of the enantiomers for citalopram and demethylcitalopram in older individuals appears to differ from that reported in younger patients, suggesting possible age-associated changes in CYP2C19 activities.84 (See Dosage and Administration: Dosage in Geriatric Patients and see Cautions: Geriatric Precautions.)

Because citalopram is extensively metabolized in the liver, hepatic impairment can affect the elimination of the drug.1,3,4,62,97,100,338 Following oral administration, the clearance of citalopram in patients with impaired hepatic function was reduced by 37% and the elimination half-life was increased twofold compared with that in healthy individuals.1,4 Therefore, the manufacturer recommends that in depressed patients with hepatic impairment, the maximum recommended dosage of citalopram is 20 mg once daily due to the risk of QT-interval prolongation.399 (See Dosage and Administration: Dosage in Hepatic and Renal Impairment and see Cautions: Precautions and Contraindications.)

In poor metabolizers of CYP2C19, steady-state peak concentrations and AUC values of citalopram increased by 68 and 107%, respectively.399 Therefore, the manufacturer recommends that in poor metabolizers of CYP2C19, the maximum recommended dosage of citalopram is 20 mg once daily due to the risk of QT-interval prolongation.399 (See Dosage and Administration: Dosage in Poor CYP2C19 Metabolizers or Patients Receiving CYP2C19 Inhibitors and see Cautions: Precautions and Contraindications.) Steady-state plasma citalopram concentrations were not substantially different in healthy individuals with poor or extensive CYP2D6 metabolizer phenotypes following multiple-dose administration of the drug.278,399

The effect of renal impairment on the pharmacokinetics of citalopram has not been fully evaluated to date.1,4,88 In patients with moderate renal impairment, the renal clearance of citalopram and its 2 principal metabolites was reduced and the elimination half-life of citalopram was slightly prolonged to an average of about 50 hours.4 In a study comparing the pharmacokinetics of citalopram in a limited number of patients with severe renal failure undergoing hemodialysis and in healthy individuals, no substantial differences were found between the 2 groups in any of the pharmacokinetic parameters, with the exception of the renal clearance of citalopram, which was significantly lower in the renal failure group than in the control group (1.7 mL/minute versus 66 mL/minute).88 Therefore, moderate to severe renal failure does not appear to markedly affect the pharmacokinetics of citalopram suggesting that dosage adjustment in such patients may not be necessary.1,4,88 Additional studies evaluating long-term citalopram therapy in patients with severe renal impairment are necessary to confirm these findings.1 (See Dosage and Administration: Dosage in Hepatic and Renal Impairment.)

Limited data indicate that citalopram and demethylcitalopram are not appreciably removed by hemodialysis.88 In a limited number of patients, hemodialysis cleared only about 1% of an oral dose of citalopram as the parent drug and 1% as demethylcitalopram.88 Because of the large volume of distribution of citalopram, hemodialysis, peritoneal dialysis, forced diuresis, hemoperfusion, and/or exchange transfusion also are unlikely to be effective in removing substantial amounts of citalopram from the body.1,88,347,349

Chemistry and Stability

Chemistry

Citalopram hydrobromide, a selective serotonin-reuptake inhibitor (SSRI), is a bicyclic phthalane-derivative antidepressant.1,18,26,52,340 The drug differs structurally from most other selective serotonin-reuptake inhibitors (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) and also differs structurally and pharmacologically from tricyclic and tetracyclic antidepressants.1 The commercially available drug is a 50:50 racemic mixture of the R - and S -enantiomers.1,340 The inhibition of serotonin reuptake by citalopram is principally due to the S -enantiomer, escitalopram (see Escitalopram Oxalate 28:16.04.20).1,18,20,26,97,101

Citalopram hydrobromide occurs as a fine white to off-white powder that is sparingly soluble in water and soluble in ethanol.1 The drug has a pK_a of 9.5.349

Citalopram hydrobromide is commercially available for oral administration as tablets and as an oral solution.1,615 Commercially available citalopram hydrobromide oral solution is a clear, colorless solution with a peppermint flavor and contains 10 mg of citalopram per 5 mL.615,616 Citalopram hydrobromide oral solution contains methylparabens and propylparabens as preservatives.615 Citalopram also is commercially available in some countries as an IV injection†; however, this dosage form currently is not available in the US.1,162

Stability

Citalopram hydrobromide tablets should be stored at a temperature of 25°C but may be exposed to temperatures ranging from 15-30°C.1,19 When stored as directed, the tablets have an expiration date of 2 years following the date of manufacture.1,19,349

Citalopram hydrobromide oral solution should be stored at 20-25°C but may be exposed to temperatures ranging from 15-30°C.615

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