The selective serotonin reuptake inhibitors (SSRIs) are believed to have a more benign cardiovascular safety profile than do the tricyclic antidepressants. The effects of the SSRI citalopram on ...cardiac conduction and repolarization have been extensively evaluated, both in prospective studies in volunteers and patients and in retrospective evaluations of all electrocardiographic (ECG) data from all clinical trials conducted from 1978 through 1996 (a total of 40 studies). A randomized, double-blind, placebo-controlled study was conducted in healthy volunteers (N = 23) to assess intraindividual variability of the QTc interval, as well as possible changes during treatment with placebo or citalopram, and its correlation to plasma drug levels. To document any dose-related changes, ECGs were performed at baseline and at the end of study in three randomized, double-blind, placebo- or active-controlled, fixed-dose trials in adult and elderly patients (N = 1,460) with major depression and/or dementia. Finally, more than 6,000 ECGs (N = 1,789 citalopram-treated patients) collected from all clinical trials conducted from 1978 through 1996 were reassessed in a standardized manner to identify any effects of citalopram on ECG parameters. Results of both prospective and retrospective analyses showed that the only effect of citalopram on ECG findings is a small reduction in heart rate (< or = 8 beats per minute). There were no significant effects on PQ, QRS, or QTc intervals, indicating that citalopram has no effect on cardiac conduction and repolarization during short- or long-term treatment.
The relationship between the metabolism of the selective serotonin reuptake inhibitor citalopram and the sparteine and mephenytoin oxidation polymorphisms was studied in 24 healthy male volunteers, ...constituting panels of extensive metabolizers of sparteine and mephenytoin (n = 10), poor metabolizers of sparteine (n = 8), and poor metabolizers of mephenytoin (n = 6). Each subject was given 40 mg/day citalopram for 10 days and citalopram, and its des- and didesmethylmetabolites were assayed in serum and urine. Using a nonenantioselective analytical method (high-performance liquid chromatography), it was shown that the citalopram elimination partially depends on the mephenytoin oxygenase, since steady-state serum concentration, half-life, and area under the serum concentration/time curve for citalopram were significantly higher in poor metabolizers of mephenytoin than in extensive metabolizers of mephenytoin. Both citalopram total clearance and demethylation clearance (formation of desmethylcitalopram) were significantly lower in poor metabolizers of mephenytoin compared to extensive metabolizers (median 15.2 vs. 27.3 and 2.6 vs. 5.9 L/h, respectively). It was further indicated that the demethylation of desmethylcitalopram to didesmethylcitalopram depends on the sparteine oxygenase CYP2D6. Didesmethylcitalopram could virtually not be detected in any poor metabolizers of sparteine, contrasting measurable serum levels in all sparteine/mephenytoin extensive metabolizers. The demethylation clearance of desmethylcitalopram was significantly lower in sparteine poor metabolizers compared to extensive metabolizers (0.3 vs. 2.4 L/h, respectively). During administration of citalopram, there was a modest increase in sparteine metabolic ratio from median 0.31 to 0.80 in extensive metabolizers of sparteine, whereas the mephenytoin S/R ratio was unaltered during citalopram treatment. Both the sparteine and the mephenytoin oxidation polymorphism thus appear to contribute partially to the total pharmacokinetic variability of citalopram.
Bech P, Tanghøj P, Andreasson K, Overø KF. Dose–response relationship of sertindole and haloperidol using the pharmacopsychometric triangle.
Objective: Renewed insight into dose‐related effects of ...sertindole and haloperidol was sought by re‐analysing published data for antipsychotic effect, extrapyramidal effect, and patient wellbeing – i.e., the important pharmacopsychometric triangle domains.
Method: Selected Positive and Negative Syndrome Scale (PANSS) subscales and the Simpson–Angus scale were tested for validity. Standardized effect sizes last observation carried forward (LOCF) at endpoint were calculated.
Results: The scales were found to be valid instruments. The PANSS11 psychotic subscale showed clinically significant effect sizes for all doses of sertindole (12, 20, and 24 mg) and haloperidol (4, 8, and 16 mg). Extrapyramidal effects were evident for all doses of haloperidol, but absent for the lower doses of sertindole. The PANSS6 depression subscale, a proxy measure of quality of life, showed a clinically significant effect for sertindole 20 mg and no effect for haloperidol.
Conclusion: This re‐analysis confirmed the antipsychotic effect and absence of extrapyramidal effects for sertindole and, in addition, showed a clinically significant antidepressant effect. A profile for bipolar states emerged.
Citalopram, the most selective serotonin reuptake inhibitor (SSRI), is a bicyclic phthalane derivative with a chemical structure that is unrelated to that of other SSRIs and available ...antidepressants. The drug is approved for use in 69 countries. This 6-week, fixed-dose, placebo-controlled, parallel-arm, multicenter trial was performed to confirm its efficacy and safety in treatment of outpatients with major depression in the United States.
Six hundred and fifty adult outpatients with moderate-to-severe major depression (DSM-III-R) were randomly assigned to receive citalopram at doses of 10 mg (N = 131), 20 mg (N = 130), 40 mg (N = 131), or 60 mg (N = 129) or placebo (N = 129) once daily. Outcome assessments were the 21-item Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions scale.
Between-group comparisons of the change from baseline to endpoint revealed significantly greater improvement in the citalopram patients relative to the placebo patients on all 3 efficacy measures. Patients randomly assigned to 40 mg/day and 60 mg/day of citalopram showed significantly greater improvement than placebo on all efficacy measures, as well as on the HAM-D symptom clusters measuring depressed mood, melancholia, cognitive disturbance, and psychomotor retardation. Patients who received 10 mg/day and 20 mg/day of citalopram also showed consistent improvement relative to placebo on all efficacy ratings, with statistical significance demonstrated in the MADRS response rate, the HAM-D depressed mood item, and the HAM-D melancholia subscale. Citalopram was well tolerated, with only 15% of patients discontinuing for adverse events. The side effects most commonly associated with citalopram treatment were nausea, dry mouth, somnolence, insomnia, and increased sweating.
Citalopram was significantly more effective than placebo in the treatment of moderate-to-severe major depression, especially symptoms of depressed mood and melancholia, with particularly robust effects shown at doses of 40 and 60 mg/day. Citalopram was well tolerated in spite of forced upward titration to fixed-dose levels, with a low incidence of anxiety, agitation, and nervousness.
Among the many problems in interpreting dose-response studies with antidepressants are the psychometric problems in the identification of true antidepressive effect versus true adverse drug effect.
...This study is a re-examination of a dose-response trial with citalopram in order to examine the explanatory ability of using strict psychometric dimensions to measure the wanted and unwanted drug effects of different doses compared to placebo.
The antidepressive response was measured after 2 and 6 weeks of therapy with the depression subscales of the HAM-D and on the Montgomery-Asberg Depression Scale (MADRS). The patient-reported Symptom Checklist (SCL) sub-scales for depression and anxiety were also examined. Subjective side-effects were measured on serotonin-specific items of the SCL. Effect size statistics were used to measure the antidepressive effect (an effect size of 0.30 equals a drug superiority over placebo of 15-20%). Side effects were statistically analysed using baseline-adjusted scores of the individual symptoms.
The psychometric analysis of the outcome scales showed that the full HAM-D(17), the SCL-56 and the SCL side-effect subscale were multidimensional scales, while the HAM-D and MADRS subscales as well as the SCL-anxiety subscale were most homogeneous, indicating that their total scores are sufficient statistics. When the scales were used as well as the individual serotonin-specific SCL side-effect symptoms, the results showed that after 2 weeks of therapy a clinical response (effect side over 0.30) was only seen for the SCL-anxiety subscale in the citalopram doses of 40 mg and 60 mg daily. After 6 weeks of therapy response to even 10 mg and 20 mg was seen in the HAM-D and MADRS subscales and in the SCL-anxiety subscale, however, with lower effect sizes than found for 40 mg and 60 mg citalopram daily. The dose of 20 mg citalopram induced side-effects comparable with those seen for 40 mg and 60 mg, while 10 mg was not different from placebo. This was further confirmed by the fact that more patients dropped out on 20 mg than on 10 mg citalopram daily, due to adverse events.
This psychometric re-examination of a citalopram dose-response trial has shown that the pure antidepressive or antianxiety effects can be observed after 6 weeks of therapy even in a dose of 10 mg daily. However, both 10 mg and 20 mg daily had lower effect sizes than 40 mg and 60 mg daily. At a dose level of 20 mg daily, side effects are more pronounced initially than at 10 mg daily; this should be taken into account clinically when evaluating the overall benefit of the drug. For a highly serotonin-specific drug such as citalopram, both wanted and unwanted effects are dose-related.
The pharmacokinetic interactions between the selective serotonin reuptake inhibitor citalopram, given as an oral dose of 40 mg/day for 10 days, and (1) levomepromazine (50 mg single oral dose), (2) ...imipramine (100 mg single oral dose), and (3) lithium (30 mmol/day orally for 5 days) were examined in three panels each of 8 healthy young male volunteers (age 20-31). All volunteers were classified as extensive metabolizers of sparteine and mephenytoin. Each subject completed three study phases--one with citalopram alone, one with one of the three other drugs, alone, and one with citalopram combined with the corresponding other drug. For citalopram and its metabolites, a non-enantioselective analytical method (high-performance liquid chromatography) was used. Only two statistically significant interactions were indicated. First, levomepromazine caused a 10-20% increase from the initial steady-state levels of the primary citalopram metabolite, desmethylcitalopram. Second, citalopram caused approximately 50% increase in the single-dose area under the serum concentration/time curve of desipramine (primary metabolite or imipramine) and a corresponding reduction in the level of the subsequently formed metabolite 2-hydroxydesipramine. These findings are in agreement with the recent observations that (1) the demethylation of desmethylcitalopram (to didesmethylcytalopram) is partly mediated via the sparteine/debrisoquine oxygenase (CYP2D6) and that levomepromazine is a potent inhibitor of CYP2D6, and (2) that desmethylcitalopram has a somewhat stronger affinity for CYP2D6 than desipramine, and therefore may inhibit the hydroxylation of desipramine, which is also a substrate of CYP2D6.
The effect of chronic administration of citalopram on the single oral dose pharmacokinetics of digoxin was evaluated in 11 healthy adult subjects in an open, one-way crossover study. Subjects ...received 1 mg digoxin on day 1. Serial blood samples and total urine were collected over 192 hours, followed by an 11-day washout period. On days 22 through 50, subjects received 40 mg citalopram once daily. On day 43, a single dose of 1 mg digoxin was coadministered; again, serial blood samples and total urine were collected over 192 hours after the digoxin dose. There were no statistically significant differences in any of the digoxin pharmacokinetic parameters (AUC(0-->24), AUC(0-->infinity), Cmax, tmax, t(1/2), CL/F, CLrenal, and Ae(0-->infinity)), and the 90% confidence intervals for treatment differences for the parameters (except for tmax) were all within 80% to 125%. Concomitant digoxin administration did not significantly affect citalopram pharmacokinetics. The treatment was well tolerated by all subjects; no serious adverse events and no clinically significant ECG changes were observed. These data suggest that it is unlikely that concomitantly administered citalopram would have any significant effect on serum digoxin concentrations in patients who are receiving chronic digoxin therapy.
Three dose levels (5, 25, and 50 mg once daily) of the selective serotonin uptake inhibitor citalopram were compared in a four-week, double-blind trial in depressed patients. Serum levels of ...citalopram and desmethylcitalopram, and the inhibitory effect of serum on serotonin uptake by fresh platelets, were assessed once weekly during the trial. The serum concentrations of citalopram were highly correlated with inhibition of serotonin uptake. Less of the metabolite was found, it being detected only in the higher dose groups. Steady state levels of citalopram, attained after 1 week, were linearly related to dose. The relationship between improvement (percentage reduction in total score on the Montgomery-Asberg Depression Rating Scale) and serum level of citalopram indicated a lower limit of effect in endogenous depression at about 100 nM, corresponding to an average dose of 15 mg. Marked improvement was seen in ten patients with steady state levels in the range 70 to 335 nM. The ten nonendogenously depressed patients had steady state levels from 15 to 620 nM; complete remission was seen in the three with the lowest levels (15-25 nM). No significant correlation was found between serum drug level and the few reported side effects.
The aim of the present study was to compare cardiovascular and/or cardiotoxic effects of eight anti-depressants (imipramine, chlorimipramine, amitriptyline, nortriptyline , doxepin, maprotiline, ...mianserin and citalopram) in anaesthetized cats after oral dosing and in conscious rabbits after intravenous infusion. In the cats drug plasma levels were determined as well. When estimated from ECG recordings, citalopram and chlorimipramine in particular, but also mianserin, appeared less cardiotoxic than the other drugs tested. The cardiovascular effects seen in the cats were with few exceptions identical for all the drugs tested but not seen at the same dose (concentration). Safety margins were defined as minimal doses or plasma levels when ECG changes (conduction or rhythm) or cardiovascular effects (+/- 10% change of initial value in a series of parameters) occurred in experimental animals divided by maximal therapeutic dose or mean plasma levels in patients. From comparisons of the safety margins it is concluded that except for citalopram and mianserin (safety margins 80 and 18 respectively in cats and greater than 15 in rabbits) all the other drugs tested (safety margins less than or equal to 9) have a cardiotoxic potential. The probability that cardiovascular side effects may occur is less pronounced for citalopram (safety margins 10-32) than for all the other drugs tested (safety margins ranging from 0.1 to less than 5).
