The authors evaluated the autonomic and cardiovascular side effects of citalopram with particular emphasis on their relation to the age of treated patients. The data that formed the basis for the U.S. Food and Drug Administration approval of citalopram were provided by Lundbeck (Copenhagen, Denmark). This database included placebo-controlled short- and long-term studies in major depressed patients. The list of side effects comprised all "heart rate and rhythm disorders" as well as "autonomic nervous system disorders" that had been reported by at least 5% more than that reported for the placebo group of subjects. The database encompassed 1344 subjects treated with citalopram (20-60 mg/day) for a period of no less than 6 weeks. Statistically significant age-related distribution was found for five side effects: bradycardia, nausea, diarrhea, sweating and headache. Bradycardia was more prevalent in elderly (>65 years) patients as compared to the younger population (2.4% vs. 0.2%, P
PURPOSE: To study the association between alopecia and selective serotonin reuptake inhibitors (SSRIs) by estimating reporting rates and by making association comparisons within databases of adverse drug reactions (ADRs). METHODS: All reports of alopecia with marketed SSRIs until the end of 2004 were identified in SWEDIS, the national Swedish database for spontaneously reported ADRs, and in Vigibase, the international ADR database of the World Health Organization. Total SSRI sales volumes in Sweden until the end of 2004 were obtained from the National Corporation of Swedish Pharmacies. The Bayes' Confidence Propagation Neural Network (BCPNN) method was used to estimate associations between alopecia and each of the SSRIs within the two databases. RESULTS: A total of 27 reports of alopecia were identified in SWEDIS. As two reports concerned the use of two SSRIs, there was a total of 29 drug-ADR combinations. All except three reports concerned women (88.9%). The reporting rate of alopecia in Sweden was significantly higher with sertraline compared with citalopram; 20.1 (95%CI 10.7-34.4) reports per million patient-years versus 4.5 (95%CI 1.8-9.3) reports per million patient-years. No significant differences in reporting rates were noted for the remaining SSRIs. Sertraline also showed a statistically significant association with alopecia in both SWEDIS and Vigibase. Citalopram was significantly associated with alopecia in Vigibase, but not in SWEDIS. No statistically significant associations were found for any of the other SSRIs. CONCLUSIONS: Alopecia appears to be a rare ADR to SSRIs. The risk of alopecia seems to vary between the different SSRIs, and might be higher in women than in men.
This double-blind, multicenter trial, carried out in general practice in Denmark, comprised 221 women and 70 men, aged 58 to 97 years, with major depression (with or without mild cognitive dysfunction) or dysthymia (DSM-III-R). Patients had a total score > or =13 on the 17-item Hamilton Depression Rating Scale (HDRS) and a score > or =20 on the Mini Mental State Examination scale. The efficacy and tolerability of citalopram (20-40 mg daily) and amitriptyline (50-100 mg daily) were compared over 12 weeks. The participating general practitioners were trained at corating sessions in the use of the HDRS and Melancholia Scale (MES) prior to and during the study. The inter-observer reliability was assessed to investigate if general practitioners were able to use scales that measure the severity of depression. The two treatments were considered equally effective; the 90% confidence interval for the difference between the treatment groups in change from baseline to end-point in HDRS total score (-0.84 to +1.23) was within the predefined interval (-4 to +4). Significantly more patients on citalopram (50%) than on amitriptyline (31%) reported no adverse events at all (P = .001). Moreover, patients on amitriptyline reported adverse events significantly earlier and more frequently than patients on citalopram. The inter-observer reliability was highly satisfactory, with intra-class correlation coefficients (ICC-U) of .83 for the HDRS and .82 for the MES; however, the ICC-U for the Clinical Global Impressions was .54, indicating a poorer consensus in the investigators clinical judgment. Training in the use of the HDRS and MES scales improved the inter-observer reliability.
AIM: To describe spontaneously reported cases of torsades de pointes (TdP) in Sweden and to investigate if this adverse drug reaction (ADR) was labelled in the summary of product characteristics (SPC) for the drugs implicated. METHODS: Reported cases of TdP 1991-2006 were identified and evaluated with regard to drug use and other possible risk factor. RESULTS: Among a total of 61 788 ADRs, 88 cases of TdP were identified. In these cases, 27 different suspected drugs were implicated. Cardiac drugs were involved in most reports (74%; 65/88), with sotalol being the most frequently suspected drug (57%, 58/88). In addition to drug treatment two or more established risk factors were present in 85% of the cases (75/88). Heart disease (90%; 79/88) was the most common risk factor followed by age over 65 years (72%; 63/88) and female gender (70%; 62/88). TdP or QT prolongation were labelled in the SPC for 33% (9/27) of the drugs implicated in the 88 cases. However, supporting evidence for an association was found elsewhere in 56% (15/27) for the different drugs implicated in the reports. Although citalopram was the third most common suspected drug in the reports (10%; 9/88), TdP was not listed in the SPC. CONCLUSION: TdP is a rarely reported ADR. Several risk factors are often present. In two thirds of the drugs implicated in the reports neither TdP nor QT prolongation was labelled in the SPC. Further investigations are needed regarding the association between citalopram and TdP.
We aimed to compare the antidepressant and anxiolytic effects, tolerability and effects on quality of life of mirtazapine and citalopram in a randomized, double-blind, multicentre, 8-week study. Patients with a Major Depressive Episode (DSM-IV) and a baseline score of > or = 22 on the Montgomery-Asberg Depression Rating Scale (MADRS) were randomized to 8 weeks treatment with either mirtazapine (n = 137, 15-60 mg/day) or citalopram (n = 133, 20-60 mg/day). Efficacy was evaluated by the MADRS, Hamilton Anxiety Scale (HAM-A), Clinical Global Impression scales (CGI), the Leeds Sleep Evaluation Questionnaire (LSEQ) and Quality of Life Enjoyment and Satisfaction Questionnaire (QLESQ). The efficacy analyses were performed on the Intent-To-Treat Group using the Last Observation Carried Forward method. Vital signs and laboratory variables are measured and adverse events recorded at each weekly visit. The magnitude of reduction from baseline in group mean MADRS scores was large in both groups, reaching after 8 weeks of treatment mean scores of 9.1 in the mirtazapine group and 8.9 in the citalopram group. Both treatments also resulted in a substantial improvement in anxiety symptoms, sleep disturbances and quality of life, and high percentage of responders. However, at day 14, statistically significantly larger magnitudes of change favouring mirtazapine were present in the group mean MADRS, HAM-A and CGI-Severity of illness and Quality of life scores. A difference of 2.3 points on MADRS favouring mirtazapine is considered indicative for a clinically relevant superiority between two proven antidepressants. Mirtazapine treatment was also related to faster improvement of sleep, quality of sleep and improved alertness following awakening, as shown by statistically significant differences on the self-rating LSEQ at various time points. There were no differences between two treatment groups on self-rating QLSEQ. Both drugs were well tolerated, with a low number of patients in either group prematurely terminating the study due to adverse events (mirtazapine: 3.6%, citalopram, 3.0%). Sweating and nausea were statistically significantly more frequent in the citalopram group and increased appetite and complaints of weight increase in the mirtazapine group. There were no clinically relevant changes in laboratory parameters and vital sign variables with either treatment, except for clinically relevant increase in body weight, occurring more frequently in mirtazapine patients. In this study, mirtazapine and citalopram were equally effective in reducing symptoms of depression and anxiety, and well tolerated. However, mirtazapine was significantly more effective than citalopram after 2 weeks of treatment on the MADRS, HAM-A and CGI Severity of illness and Quality of life scales. This finding, consistently present at all major efficacy variables, suggests potentially faster onset of efficacy of mirtazapine over citalopram.
Lundbeck and Forest have developed and launched escitalopram, the therapeutically active (S)-enantiomer of citalopram, as an improved follow-up compound for the potential treatment of depression. In December 2001, Lundbeck received Swedish approval for the treatment of depression and panic disorder , and in January 2002, the product was approved in Switzerland for the treatment of depression . By May 2002 it had been approved in Belgium, Denmark, the UK, France, Iceland, Luxembourg, Norway and Austria, as a result of the European Mutual Recognition Procedure. Independently, regulatory authorities in Lithuania had also approved the drug for the treatment of depression. Launch in these countries will begin immediately after price and reimbursement negotiations are completed . By June 2002, it had been launched in Switzerland, Sweden and the UK . Based on the approvals in the EU, national applications are being submitted in several Central and Eastern European countries, where review and the first approvals were expected in the second half of 2002. At this time, the approval of escitalopram in Australia and Canada was expected in the second half of 2002 and the first half of 2003, respectively . It became evident in May 2002, that Portugal, Greece, Italy, Spain, Finland and Germany did not intend to approve escitalopram for marketing within the 90-day timeframe, and, at this time, Lundbeck, in accordance with the advice of the reference country, Sweden, chose to withdraw the registration applications from these six countries. At this time, the company still expected escitalopram to be approved in these countries . In the US, Forest submitted an NDA in March 2001  and in January 2002, Forest received an approvable letter from the FDA for escitalopram; at this time, US launch was expected in mid-2002 , . By March 2002, Lundbeck had started to supply escitalopram to Forest . Lundbeck and Morchida entered a Japanese development and marketing agreement in May 2002, replacing a collaboration with Mitsui .
OBJECTIVE: The incidence of sexual dysfunction due to antidepressant drugs reported in pre-marketing clinical efficacy trials is often several times lower than in subsequent clinical experiences and independent reports. Although it is commonly believed that the reason for this discrepancy is that the nonleading questions employed in conventional clinical trials underestimate sexual dysfunction while the direct questioning used in independent trials provides more accurate data, few studies have actually compared these 2 methods. METHOD: In this study, 119 patients with a DSM-IV-defined major depressive episode (82 women and 37 men) who had been treated with but not responded to a selective serotonin reuptake inhibitor (SSRI; either citalopram or paroxetine) were assessed regarding sexual functioning by means of open-ended questions and direct questioning at baseline (after SSRI treatment only) and after 4 weeks of SSRI treatment plus buspirone or placebo. RESULTS: More patients reported sexual dysfunction in response to direct questioning (41%) as compared with spontaneous report (6%) (p
This open-label multicentre semi-naturalistic study in Finland assessed the impact of educational information on efficacy of 16-week treatment with escitalopram (5-20 mg/day) in a patient population suffering from depression. Patients were randomized single blind to receive educational information (n=79) or no information (n=78) in addition to open-label escitalopram treatment. Patients were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression - Severity and - Improvement (CGI-S and CGI-I), Patient Global Evaluation (PGE), and Hopkins Symptom Checklist (SCL-90) scales. Tolerability was assessed by the incidence of adverse events (AEs). A total of 132 (84%) out of 157 patients completed the study, with similar completer rates in both groups. There was no statistically significant effect of educational information on the efficacy of escitalopram treatment, as measured by MADRS, CGI and PGE. Mean MADRS total score was 25.3 at baseline, corresponding to moderate to severe depression, and decreased to 7.9 at the end of the treatment for both groups. The response rate (> or = 50% reduction in MADRS total score from baseline) was 80% at the end of treatment for both groups. The clinical relevance of the improvement was seen in CGI-I and PGE scores and there was a strong correlation between the two scales, indicating agreement by both patients and investigators. AEs were mostly mild and transient and 11 patients (7.0%) dropped out of the study due to AEs, with similar incidence in both groups. Escitalopram was effective and well tolerated in the treatment of depression over a 16-week period in a semi-naturalistic setting, and an additional effect of educational information could not be shown, possibly due to the high response to treatment.
PURPOSE: The objective of the present study was to explore the available evidence in a regulatory agency on the safety and efficacy of two types of psychotropic medicine frequently prescribed to children and adolescents. METHODS: We analysed the documentation in registration files, renewal registration files, summaries of product characteristics and scientific assessment reports in the Danish Medicines Agency for two psychotropic medications prescribed for children: methylphenidate and citalopram to discover what data pertaining to the pediatric population are available to the regulatory agency. RESULTS: The licensing of methylphenidate for treating attention-deficit hyperactivity disorders (ADHD) in children from the age of six was based on a single-dose crossover study and, a 2-week double blind, parallel group clinical trial in 100 patients from ages 6 to 12 and published literature. Citalopram is not licensed for pediatric use in Denmark. Citalopram was being investigated in three ongoing clinical trials lasting 8-24 weeks in 423 patients aged 7-18 years. The registration files contained no data on the long-term efficacy and safety of citalopram in pediatric use. Registration material also contained information on planned clinical trials with methylphenidate and citalopram among children/adolescents. CONCLUSIONS: Evidence on the efficacy and safety of methylphenidate and citalopram for pediatric use in the Danish Medicine Agency is limited and supports the need for further clinical trials. Medicine prescription for the pediatric population should be monitored in order to identify risks that were not identified at the time of licensing. The results of clinical trials already conducted should be made publicly available.
Although case reports and open studies have reported augmentation with buspirone to be beneficial in the treatment of depression refractory to treatment with a selective serotonin reuptake inhibitor (SSRI), a recently published randomized, placebo-controlled, double-blind study failed to show superiority of buspirone over placebo in this respect.
One hundred two outpatients who fulfilled DSM-IV criteria for a major depressive episode and who had failed to respond to a minimum of 6 weeks of treatment with either fluoxetine or citalopram were included in this double-blind, randomized, placebo-controlled study. After a single-blind placebo wash-in period of 2 weeks while continuing their SSRI, the patients were randomly assigned to adjunctive treatment with either buspirone, 10 to 30 mg b.i.d., or placebo for 6 weeks. Patients were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impressions scale (CGI), and visual analogue scales.
After the first week of double-blind treatment, there was a significantly greater reduction in MADRS score (p = .034) in the buspirone group as compared with placebo. At endpoint, there was no significant difference between treatment groups as a whole, although patients with initially high MADRS scores (> 30) showed a significantly greater reduction in MADRS score (p = .026) in the buspirone group as compared with placebo.
Patients with severe depressive symptoms may benefit from augmentation with buspirone. It cannot be excluded that augmentation with buspirone may speed up the antidepressive response of patients refractory to treatment with fluoxetine or citalopram.