Ole Lemming

Citalopram 20 mg, 40 mg and 60 mg are all effective and well tolerated compared with placebo in obsessive-compulsive disorder

Serotonin reuptake inhibitors appear to be uniquely effective treatments for obsessive-compulsive disorder (OCD). This double-blind, placebo-controlled study was the first trial to assess the efficacy of the most selective of the serotonin reuptake inhibitors, citalopram, in OCD. A total of 401 patients were randomized to receive citalopram 20, 40 or 60 mg/day or placebo for 12 weeks. All three doses of citalopram were significantly more effective than placebo measured on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) change score (P < 0.01). The highest response rate, defined as 25% improvement in Y-BOCS entry score, was observed in the 60 mg group (65%). This compared with 52% and 57.4% in the 40 mg and 20 mg groups. Response rate on placebo was 36.6% (P < 0.05 for all three doses of citalopram compared to placebo). There was no significant difference between the individual doses of citalopram. An advantage was seen for citalopram on the Sheehan Disability Scale compared with placebo (P < 0.05 on all three citalopram groups versus placebo for both the work situation and the family life and home responsibilities and P < 0.05 on citalopram 60 mg and 20 mg versus placebo for the social life and home activities). Citalopram was well tolerated; only 4 to 6 patients in each dose group discontinued the study prematurely due to adverse events.

Escitalopram prevents relapse of obsessive-compulsive disorder

To examine the efficacy and tolerability of escitalopram in the prevention of relapse in patients with OCD, 468 patients with OCD were treated with open label escitalopram (10 mg or 20 mg) for 16 weeks, after which the 320 responders (Y-BOCS total score decrease > or =25%) were randomised to placebo or escitalopram (at the assigned dose) for 24 weeks double-blind treatment. The primary analysis (time to relapse) showed a significant advantage for escitalopram (p<0.001, log-rank test). The proportion of patients who relapsed was statistically significantly higher in the placebo group (52%) than in the escitalopram group (23%) (p<0.001, chi(2)-test). The risk of relapse was 2.74 times higher for placebo compared to escitalopram. Escitalopram was well tolerated and improvements in obsessive-compulsive symptoms reported during the open label period were sustained during the double-blind extension of treatment with active drug. These results demonstrate that escitalopram is effective for long-term treatment and relapse prevention in OCD.

Memantine in patients with Alzheimer's disease receiving donepezil: new analyses of efficacy and safety for combination therapy

IntroductionMemantine and cholinesterase inhibitors potentially offer additional benefits in Alzheimers disease (AD) when used together. This study assessed the efficacy and safety of combination treatment with memantine added to stable donepezil in patients with moderate to severe AD, and in a subset with moderate AD.MethodsPost hoc meta-analyses of data combined from two 24-week, randomised, double-blind, placebo-controlled trials of memantine 20 mg/day versus placebo, added to a stable cholinesterase inhibitor, were conducted. Data were included for all patients receiving donepezil 10 mg/day with Mini-Mental State Examination (MMSE) scores < 20 (n = 510). Efficacy was assessed using measures of cognition, function, and global status. Furthermore, marked clinical worsening, defined as concurrent deterioration from baseline in the three main efficacy domains, and safety, measured by treatment-emergent adverse events, were assessed. Analyses were performed for patients with moderate to severe AD (MMSE 5-19; MOD-SEV subgroup), and also for patients with moderate AD (MMSE 10-19; MOD subgroup; n = 367).ResultsAt week 24, in the MOD-SEV subgroup, patients receiving memantine added to donepezil significantly outperformed those receiving placebo added to donepezil in measures of cognition (P < 0.0001), function (P = 0.02), and global status (P = 0.010), with standardised mean differences (SMDs) of 0.36, 0.21, and 0.23, respectively (all last observation carried forward). Similarly, in the MOD subgroup, significant benefits were observed for cognition (P = 0.008), function (P = 0.04) and global status (P = 0.008), with SMDs of 0.28, 0.21, and 0.28, respectively. Significantly fewer patients receiving memantine added to donepezil showed marked clinical worsening than those receiving placebo added to donepezil, in both subgroups (MOD-SEV: 8.7% versus 20.4%, P = 0.0002; MOD: 5.9% versus 15.0%, P = 0.006). The incidence of adverse events was similar between treatment groups.ConclusionsThese results support and extend previous evidence that combination treatment with memantine added to stable donepezil in patients with moderate AD, and in those with moderate to severe AD, is associated with significant benefits in reducing 24-week decline in cognition, function and global status. Combination treatment produces substantially reduced rates of marked clinical worsening, has good safety and tolerability, and generates effect sizes that are both statistically significant and clinically meaningful.

Citalopram and Fluoxetine in Major Depression

SummaryTwo studies carried out in France compared citalopram with fluoxetine 20mg daily in the treatment of major depression (DSM-III-R). One of the studies was carried out in a psychiatrist setting (citalopram 40mg daily) and the other in a general practice setting (citalopram 20mg daily). Both studies showed a significant improvement in the mean primary and secondary efficacy variables (MADRS and HDRS) without any difference between the two treatment groups. In the general practice study, the onset of recovery was greater in the citalopram group after 2 weeks. In this population, citalopram was superior to fluoxetine in patients not receiving concomitant anxiolytics/hypnotics. The incidence of adverse events was comparable in both groups. A higher frequency of vomiting was observed at initiation of the 40mg citalopram treatment, but disappeared afterwards.

Memantine and brain atrophy in Alzheimer's disease: a 1-year randomized controlled trial.

The primary objective of this study was to evaluate the rate of total brain atrophy (TBA) with serial magnetic resonance imaging (MRI), using the Brain Boundary Shift Integral (BBSI), in patients with probable Alzheimers disease (AD) over the course of 52 weeks of treatment with memantine or placebo. This was a multi-national, randomized, double-blind, placebo-controlled, fixed-dose 1-year study. Patients were randomized (1 : 1) to treatment with placebo or memantine. Patients randomized to memantine were up-titrated to the target dose of 20 mg/day over 4 weeks. MRI scans were collected at screening and at Weeks 4, 42, and 52. Secondary efficacy assessments included several cognitive and behavioral scales. 518 patients were screened, 278 patients were randomized, and 217 patients completed the study. In the primary efficacy analysis, the differences in TBA rates between memantine (15.2 mL/year) and placebo (15.3 mL/year) were not statistically significant (-0.04 mL/year [(95% CI: -2.60, 2.52), p = 0.98]). There was a statistically significant correlation between change in TBA and change in most cognitive and behavioral scale scores. Patients who were not treated with acetyl cholinesterase inhibitors (AChEIs) showed a significantly lower TBA rate than patients treated with AChEIs. Memantine had a placebo-level incidence of adverse events. There were no statistically significant differences between memantine and placebo in total brain or hippocampal atrophy rates in patients with probable AD treated for 1 year. The biological relevance of cerebral atrophy was supported by a significant correlation between rate of atrophy and decline in cognitive and behavioral outcomes.

Escitalopram in the Long-Term Treatment of Major Depressive Disorder in Elderly Patients

Aim: The primary aim was to investigate the long-term safety and tolerability of escitalopram (10 or 20 mg/day) treatment of elderly patients suffering from major depressive disorder. The secondary aim was to examine response to treatment, as measured by change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from study entry to each visit, using observed cases. Method: This extension trial included 225 patients who had completed an 8-week, double blind, placebo-controlled lead-in study, which was performed in outpatients in primary care and in specialist clinics. The intent-to-treat population comprised 223 patients. Results: The overall withdrawal rate was 24%. The most common reason for withdrawal was adverse events (9%). The 5 most common adverse events were accidental injury, rhinitis, weight increase, arthralgia and coughing, with an incidence ranging from 8 to 13%. No new types of adverse events were reported in this extension study compared to the 8-week lead-in study. The mean weight increased from 69.7 kg at study entry to 70.3 kg at endpoint. The percentage of patients in remission (MADRS total score ≤12) increased from 48% at study entry to 72% by week 52. Conclusion: Escitalopram demonstrated a favourable tolerability profile during 52 weeks of open-label treatment of elderly patients, with further improvement in depressive symptoms.

Measuring therapeutic efficacy in patients with Alzheimer's disease: role of instruments.

Background/Aims: Global cognitive scales and meta-analyses thereof are used to appraise therapeutic efficacy over a broad range of disease severity. Clinically, however, different aspects of cognition change in different stages of disease. Methods: Calculation of effect sizes for single cognitive functions on treatment as assessed by the Alzheimer’s Disease Assessment Scale (ADAS-cog), the Mini-Mental-Status Examination (MMSE), and the Severe Impairment Battery (SIB). In these scales, subdomains of ‘cognition’, e.g. memory and language, are represented in different proportions. To exemplify the analysis of ‘cognition’, we used original data of previously published clinical studies with memantine. Results: Depending on dementia severity and on the scale used, the effect size for memory varies between –0.44 and +0.34 and for language between –0.40 and +0.26. Conclusion: Beyond interstudy variance, effect sizes for treatment with antidementia drugs are subject to disease stage, instruments used, and interaction thereof. Therefore, clinical interpretation is necessary to appraise therapeutic efficacy in clinical studies and meta-analyses thereof when patients with different severity are included or different instruments are used. Alternatively, severity-adapted endpoints should be used for appraisal and meta-analysis of therapeutic efficacy.

Pharmacokinetics and Safety of Vortioxetine in Pediatric Patients

Abstract Objective: The primary objectives of this study were to evaluate the pharmacokinetics (PK) and tolerability of single and multiple doses of vortioxetine in children and adolescents with a depressive or anxiety disorder and to provide supportive information for appropriate dosing regimens for pediatric clinical trials. Methods: This prospective, open-label, multinational, multisite, multiple-dose trial enrolled 48 patients (children and adolescents; 1:1 ratio) divided into 8 cohorts (4 adolescent and 4 child), with each cohort including 6 patients. The cohorts in each age group were assigned to receive one of four dosing regimens: vortioxetine 5, 10, 15, or 20 mg q.d. for 14 days. The total treatment period lasted 14–20 days with patients in the higher dose cohorts uptitrated over 2–6 days. Plasma samples for PK analysis were obtained on the first and last days of dosing. Results: Among children and adolescents, respectively, 62% and 92% had depression and 58% and 33% had anxiety disorder. Comorbid attention-deficit/hyperactivity disorder (ADHD) was present in 50% of children and 38% of adolescents. After 14 days q.d. at the target dose, the PK of vortioxetine concentrations was generally proportional to the dose in both age groups. Exposure, as assessed by maximum plasma concentrations and area under the plasma concentration–time curve from time 0 to 24 hours, was 30%–40% lower in adolescents than in children. There was no significant relationship between sex, height, or ADHD diagnosis and PK parameters. Most adverse events were mild in severity and consistent with those seen in adults. Conclusion: The results suggest that the dosages of vortioxetine evaluated (5–20 mg q.d.; approved for treatment in adults) and the uptitration schedule used are appropriate for pediatric efficacy and safety trials.

A 6-Month Open-Label Extension Study of Vortioxetine in Pediatric Patients with Depressive or Anxiety Disorders

Abstract Objectives: In this 6-month open-label extension (OLE) of NCT01491035 (a 14-day, open-label, pharmacokinetic/safety lead-in study), the long-term safety and tolerability of vortioxetine (5–20 mg/day) were investigated in children and adolescents with a DSM-IV-TR™ diagnosis of depressive or anxiety disorder in the United States or Germany. The study also was designed to provide data to inform dose selection and titration in future pediatric studies with vortioxetine. Methods: Safety evaluations included spontaneously reported adverse events (AEs), the Columbia Suicide Severity Rating Scale (C-SSRS), and the Pediatric Adverse Events Rating Scale (PAERS; clinician administered). Clinical effectiveness was determined by Clinical Global Impressions. Comorbid attention-deficit/hyperactivity disorder was permitted, including concomitant use of stimulant medication (US sites only). Results: Of the 47 patients who completed the lead-in period, 41 continued into the OLE. Most patients (n = 39 [95%]) continued their previous dose regimen. Twenty-one patients (51%) withdrew during the OLE; the most common primary reasons were administrative [n = 8], AEs [n = 4], and lack of efficacy [n = 3]. Thirty-five patients (85%) had ≥1 AE, 86% of which were mild or moderate in severity. Five patients (12%) reported a severe AE, none of which was considered related to study medication. The most common AEs (≥10%) were headache (27%), nausea (20%), dysmenorrhea (females; 19%), and vomiting (15%), with no relationship between AE intensity and age or dose. Five patients reported instances of suicidal ideation during the OLE, one of whom also reported this during the lead-in period. Two patients had nonsuicidal self-injurious behavior; one had a nonfatal suicide attempt. Throughout the study, there was a decrease over time in the incidence and intensity of AEs collected using the PAERS. Effectiveness assessment indicated a trend toward improvement based on numeric results. Conclusion: This OLE confirms the findings from the lead-in study, which concluded that a dosing strategy of 5–20 mg/day is safe, well tolerated, and suitable for future clinical studies of vortioxetine in pediatric patients.