The optimal dosing regimen for citalopram-a meta-analysis of nine placebo-controlled studies

Montgomery, Stuart; Pedersen, Vilhelm Møller; Tanghøj, Per; Rasmussen, Cathy A.; Rioux, Patrice

doi:10.1097/00004850-199403001-00006

Cited by 56 publications

(23 citation statements)

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“…Such a finding is not unexpected among psychotropics, although some (Montgomery, 1995;Montgomery et al, 1994) have reported a dose-response relationship. Few caveats that prevent full generalization of this finding are warranted.…”

Section: Discussionmentioning

confidence: 77%

Frequency of Positive Studies Among Fixed and Flexible Dose Antidepressant Clinical Trials: An Analysis of the Food and Drug Administraton Summary Basis of Approval Reports

Khan

Walens

et al. 2002

Neuropsychopharmacol

149

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The assumption that the design of an antidepressant clinical trial affects the outcome of that trial is based on sparse data. We sought to examine if the dosing schedule, either a fixed dose or a flexible dose type, in an antidepressant clinical trial affects the frequency with which antidepressants show statistical superiority over placebo. Randomized, placebo-controlled clinical trials of nine antidepressants approved by the Food and Drug Administration between 1985 and 2000 were reviewed. These trials comprised 9313 depressed patients who participated in 51 antidepressant clinical trials consisting of 92 treatment arms with eventual approved doses. In the flexible dose trials, 59.6% (34/57) of the antidepressant treatment arms were statistically significant compared to placebo, whereas in the fixed dose trials only 31.4% (11/35) of the antidepressant treatment arms were statistically significant compared to placebo (w 2 ¼ 6.9, df ¼ 1, po0.01). These data suggest that the antidepressant dose schedule may influence trial outcome due in part to a significantly lower magnitude of symptom reduction with placebo in flexible dose trials (F ¼ 4.08, df ¼ 1, 48, po0.05) compared to fixed dose trials. Symptom reduction was similar with antidepressants in the flexible and fixed dose trials. Further, the primary function of finding a doseresponse relationship was not found among the fixed dose studies.

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Section: Discussionmentioning

confidence: 77%

Frequency of Positive Studies Among Fixed and Flexible Dose Antidepressant Clinical Trials: An Analysis of the Food and Drug Administraton Summary Basis of Approval Reports

Khan

Walens

et al. 2002

Neuropsychopharmacol

149

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“…FLUV-CIT could be a type of potent "serotoninergic cocktail" as would be the case with the addition of FLUV to clomipramine which induces an elevation of clomipramine associated with a decrease of the metabolites (Bertschy et al 1991;Conus et al 1996). According to the results of a recently published meta-analysis, a treatment period for at least 3-4 weeks is needed to assess the efficacy of different doses (Montgomery et al 1994). Therefore, in the present study, it may not be excluded that both a longer period of treatment with 40 mg/day CIT or an increase of its dose would have led to the same response rate.…”

Section: Discussionmentioning

confidence: 99%

“…Citalopram (CIT) is the most selective SSRI (Hyttel et al 1995). Its minimal effective dose is 20 mg / day, but in patients suffering from severe or recurrent depression, a better therapeutic result may be obtained with 40 mg/day (Montgomery et al 1994). Independently of the class of compound, TCAs or SSRIs, about 30 % of depressive patients are non-responders to a first treatment.…”

Section: Introductionmentioning

confidence: 99%

Non-response to citalopram in depressive patients: pharmacokinetic and clinical consequences of a fluvoxamine augmentation

et al. 1996

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The effect of comedication with fluvoxamine on the plasma concentrations of the enantiomers of citalopram and its metabolites in dextromethorphan/mephenytoin phenotyped patients pretreated with citalopram (CIT) was studied: seven female patients (45.1 +/- 13.9 years) suffering from a major depressive episode [ICD-10: F32.2 (n = 3 patients), F33.2 (n = 2), F32.10 (n = 1) or F32.11 (n = 1)], who were non-responders to a 3-week treatment with 40 mg/day CIT (From day-21 to day 0) (day 0: MADRS score > or = 12), were co-medicated for another 3 weeks with fluvoxamine (50 mg/day from day 1-7, 100 mg/day from day 14-21). All patients were extensive metabolizers of mephenytoin (CYP2C19) and dextromethorphan (CYP2D6), except one patient, who had a genetic deficiency of CYP2D6. There was a significant increase of the plasma concentrations of S- and R-citalopram from day 0 (27 +/- 14 micrograms/l and 55 +/- 23 micrograms/l, respectively) to day 21 (83 +/- 38 micrograms/l and 98 +/- 44 micrograms/l, respectively), after addition of fluvoxamine (P < 0.02, for each comparison), and the mean ratio S/R-citalopram increased from 0.48 to 0.84. S-Citalopram inhibits more potently 5-HT uptake than R-citalopram: therefore, fluvoxamine increases the pharmacologically more active S-citalopram with some stereoselectivity. According to a previous in vitro study, this pharmacokinetic interaction occurs on the level of CYP2C19, but also of CYP2D6 and CYP3A4 which, in contrast to CYP1A2, contribute to the N-demethylation of citalopram and which are stereoselectively inhibited by fluvoxamine. All but one patient showed clinical improvement by a decrease of the MADRS score by at least 50% and a final score < or = 13 (mean +/- SD: day 0:30.6 +/- 9.2; day 21:11.0 +/- 6.5). Some patients showed minor symptoms, such as nausea and tremor, but the combined treatment was generally well tolerated.

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“…This finding is in accordance with the fact that 20 mg is an effective dose in the majority of patients. Recently a metaanalysis of nine placebo-controlled studies on the assessment of the antidepressant efficacy of different doses of citalopram, including a great number of patients, was published (Montgomery et al, 1994). This study demonstrated a tendency for patients suffering from severe or recurrent depression to achieve better therapeutic results with 40 mg than with 20 mg citalopram daily.…”

Section: Discussionmentioning

confidence: 99%

?-CIT SPECT demonstrates blockade of 5HT-uptake sites by citalopram in the human brain in vivo

Pirker¹,

Asenbaum²,

Kasper

et al. 1995

J. Neural Transmission

123

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The cocaine analogue 2-beta-carbomethoxy-3-beta-(4-iodophenyl)-tropane (beta-CIT) is a potent ligand for both dopamine- and serotonin uptake sites which in its 123I labeled form can be used for single photon emission computerized tomography (SPECT). It was demonstrated previously by SPECT-studies in non-human primates that 123I-beta-CIT binds to dopamine transporters in the striatum and to serotonin transporters in hypothalamus and midbrain. The aim of the present study was to compare 123I-beta-CIT binding in the brain stem of normal controls and a group of subjects under treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram. 123I-beta-CIT-SPECT was performed in 12 depressed patients under 20 mg (n = 5), 40 mg (n = 6) and 60 mg (n = 1) citalopram daily, in one untreated depressed patient and in 11 controls at regular time intervals up till 24 hours p.inj. A highly significant reduction of beta-CIT binding was found in an area including mesial thalamus, hypothalamus, midbrain and pons in patients under citalopram compared to controls (44.1 +/- 14.4 vs. 82.3 +/- 18.6cpm's/mCi x kg body weight; specific binding 4 hrs p.inj.; p = 0.0001). No differences were seen between the high and low dose group and no changes were found in the striatum. 123I-beta-CIT binding in the brain stem and striatum in one untreated depressed patient fell within the range of control values. To our knowledge this is the first report directly demonstrating the effect of a selective serotonin uptake inhibitor in the brain in humans in vivo. SPECT measurements of serotonin uptake sites in patients with depression and other psychiatric disorders might provide better insights into the pathophysiology of these disorders and into mechanisms of drug action.

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The optimal dosing regimen for citalopram-a meta-analysis of nine placebo-controlled studies

Cited by 56 publications

References 0 publications

Frequency of Positive Studies Among Fixed and Flexible Dose Antidepressant Clinical Trials: An Analysis of the Food and Drug Administraton Summary Basis of Approval Reports

Frequency of Positive Studies Among Fixed and Flexible Dose Antidepressant Clinical Trials: An Analysis of the Food and Drug Administraton Summary Basis of Approval Reports

Non-response to citalopram in depressive patients: pharmacokinetic and clinical consequences of a fluvoxamine augmentation

?-CIT SPECT demonstrates blockade of 5HT-uptake sites by citalopram in the human brain in vivo

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