Treatment resistance constitutes the highest burden of disease within schizophrenia. We hypothesized that the synergistic activity of Lu AF35700 at dopamine D1 and D2 receptors might provide superior ...antipsychotic effects versus first-line antipsychotic therapy in patients with treatment resistant schizophrenia (TRS), with a benign tolerability profile.
This was a randomized, double-blind, active-controlled clinical trial (NCT02717195) followed by a one year open-label safety extension (NCT02892422). Following prospective confirmation of treatment resistance, patients were randomized (1:1:1) to 10 weeks double-blind treatment with Lu AF35700 10 mg or 20 mg, or active comparator (risperidone or olanzapine).
1628 patients were screened for TRS, of which 1092 entered the prospective confirmation period. Of these, 697 were randomized (Lu AF35700 10 mg n = 235, 20 mg n = 232, comparator n = 230) and 395 discontinued before randomization, including 264 (24 %) who responded to treatment. 586 patients completed the double-blind phase, of which 524 entered the open-label extension and 318 completed 1-year of open-label treatment. At the end of the double-blind phase, the mean ± SE change in positive and negative syndrome scale (PANSS) total score was −10.1 ± 0.96 for Lu AF35700 10 mg, −8.22 ± 0.98 for Lu AF35700 20 mg, and − 9.90 ± 0.97 for the comparator group. Treatment differences 95 % CI versus comparator treatment were non-significant (−0.12 −2.37; 2.13 and 1.67 −0.59; 3.94, respectively). The most common adverse events with Lu AF35700 were increased weight and headache. Prolactin values decreased by ≥50 % in both sexes treated with Lu AF35700.
Despite evidence of antipsychotic efficacy, treatment with Lu AF35700 failed to differentiate from conventional antipsychotic treatment for patients with TRS.
Abstract
Aims
Two post-authorisation studies assessed the safety and persistence of patients’ use of nalmefene.
Methods
The START study (EUPAS5678) was a non-interventional, multi-country, ...prospective, 18-month (8 follow-up visits) cohort study including outpatients initiating nalmefene for the first time. The multi-database retrospective cohort study (MDRC, EUPAS14083) included baseline and follow-up data from German, Swedish and UK healthcare databases. Both studies permitted ‘all comers’ without explicit exclusion criteria; predefined subgroups of interest included the elderly (≥65 years) as well as patients with significant psychiatric and/or somatic comorbidities.
Results
START study: Overall, the mean duration of nalmefene treatment was 10.3 ± 7.3 months (N = 1348), with 49.0% of patients treated for ≥1 year; frequent reasons for treatment discontinuation were ‘goal reached’ and ‘drug cost’. The most frequently reported adverse drug reactions (ADRs) were nausea (4.7%), dizziness (3.2%) and insomnia (2.0%). ADR rates appeared higher in the elderly subpopulation (18.6% reported ≥1 ADR vs. 12.0% in the total population) but were not higher in the other predefined subgroups.
MDRC study: The database follow-up analysis followed 2892 patients over 18 months for whom the duration of nalmefene treatment was between 2 and 3 months and <5% of patients used nalmefene for ≥1 year.
Conclusions
Despite the inclusion of a wider patient population (e.g. elderly patients and those with relevant co-morbidities), the safety and tolerability profile of nalmefene given in routine practice was consistent with previous clinical studies. The differing rates of persistence beyond 1 year likely reflect the different methodologies and highlight the relevance of psychosocial support at follow-up visits.
Short Summary: Two studies were used to evaluate the safety and persistence of nalmefene in the routine management of alcohol dependence in Europe as part of the overall risk management plan. Although adverse events appeared more common in over 65-year olds, there were no major differences in safety outcomes between the total population, and those with psychiatric and somatic comorbidities or those with a history of seizures. Findings were in line with those from previous clinical studies. The differing rates of persistence beyond 1 year (49% in the prospective study and < 5% in the multi-database retrospective cohort study) likely reflect the different study methodologies and serve to highlight the relevance of follow-up support.
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.
This study assessed the safety and tolerability of sertindole in the long-term treatment of schizophrenia. An open-label, noncomparative, flexible-dose study was carried out in 11 European countries. ...Upon completion of an 8-week, haloperidol-referenced randomized clinical trial with sertindole, patients were offered sertindole maintenance treatment up to 18 months. In total, 294 patients were enrolled, of whom 237 (81%) had received sertindole and 57 (19%) had received haloperidol in the lead-in trial. The modal dose during the maintenance period was 16 mg/day. Patients showed therapeutic improvement indicated by significant decreases in the Positive And Negative Syndrome Scale and Clinical Global Impression ‘severity-of-illness’ scores. An adverse event was the primary reason for withdrawal in 13% of patients. The most common adverse events were fatigue and weight gain, both with incidences of 14%. The incidence of extrapyramidal symptoms was 18%, and 11% of the patients required anticholinergic medication. No statistically significant changes were observed in laboratory values or vital signs, but the mean serum prolactin levels decreased. The mean change in weight from baseline to the last assessment was 2.7 kg. The largest weight increase was observed in patients who were underweight at baseline. Long-term treatment with sertindole was safe and well tolerated, and patients showed clinical improvement beyond acute treatment.
In a European, multicenter, double-blind study, 244 adolescents, 13 to 18 years old, with major depression were randomized to treatment with citalopram (n = 124) or placebo (n = 120). One third of ...the patients in both groups withdrew from the study. No significant differences in improvement of scores from baseline to week 12 between citalopram and placebo were found. The response rate was 59% to 61% in both groups according to the Schedule for Affective Disorders and Schizophrenia for school-aged children-Present episode version (Kiddie-SADS-P) (depression and anhedonia scores < or =2) and Montgomery Asberg Depression Rating Scale (MADRS) (> or =50% reduction). Remission (MADRS score < or =12) was achieved by 51% of patients with citalopram and 53% with placebo. A post hoc analysis revealed that more than two thirds of all patients received psychotherapy during this study. For those patients not receiving psychotherapy, there was a higher percentage of Kiddie-SADS-P responders with citalopram (41%) versus placebo (25%) and a significantly higher percentage of MADRS responders and remitters with citalopram (52% and 45%, respectively) versus placebo (22% and 19%, respectively). Mild to moderate treatment-emergent adverse events were reported in 75% citalopram and 71% of placebo patients, most commonly headache, nausea, and insomnia. Serious adverse events occurred in 14% to 15% in both groups. Suicide attempts, including suicidal thoughts and tendencies, were reported by 5 patients in the placebo group and by 14 patients in the citalopram group (not significant) with no pattern with respect to duration of treatment, time of onset, or dosage. In contrast, the suicidal ideation (Kiddie-SADS-P) single item showed worsening more frequently in the placebo (18%) than in the citalopram group (8%).
The enormous interindividual variation in the plasma concentrations of the atherogenic lipoprotein(a) Lp(a) is almost entirely controlled by the apo(a) locus on chromosome 6q26-q27. A variable number ...of transcribed kringle4 repeats (K4-VNTR) in the gene explains a large fraction of this variation, whereas the rest is presently unexplained. We here have analyzed the effect of the K4-VNTR and of a pentanucleotide repeat polymorphism (TTTTA)n (n = 6-11) in the 5' control region of the apo(a) gene on plasma Lp(a) levels in unrelated healthy Tyroleans (n = 130), Danes (n = 154), and Black South Africans (n = 112). The K4-VNTR had a significant effect on plasma Lp(a) levels in Caucasians and explained 41 and 45% of the variation in Lp(a) plasma concentration in Tyroleans and Danes, respectively. Both, the pentanucleotide repeat (PNR) allele frequencies and their effects on Lp(a) concentrations were heterogeneous among populations. A significant negative correlation between the number of pentanucleotide repeats and the plasma Lp(a) concentration was observed in Tyroleans and Danes. The effect of the 5' PNRP on plasma Lp(a) concentrations was independent from the K4-VNTR and explained from 10 to 14% of the variation in Lp(a) concentrations in Caucasians. No significant effect of the PNRP was present in Black Africans. This suggests allelic association between PNR alleles and sequences affecting Lp(a) levels in Caucasians. Thus, in Caucasians but not in Blacks, concentrations of the atherogenic Lp(a) particle are strongly associated with two repeat polymorphisms in the apo(a) gene.
The objective of the present study was to examine the possible associations between low molecular weight (LMW) apolipoprotein(a) (apo(a)) isoforms (F,B,S1,S2) and coronary heart disease (CHD). We ...conducted a nested case-control (prospective) study of five cohorts of white men: The 1936 cohort (baseline 1976, n=548) and four cohorts from MONICA I born in 1923 (n=463), 1933 (n=491), 1943 (n=504) and 1953 (n=448) studied at baseline in 1983. At follow up in 1991, 52 subjects had developed a first myocardial infarction and 22 had been hospitalized with angina pectoris. Plasma samples obtained at baseline were stored frozen until 1993–94, when case samples (n=74) were analyzed together with samples from matched (disease free) controls (n=190). In a statistical model (conditional logistic regression) including all age groups, cholesterol (or apo B) level (P<0.01), systolic blood pressure (P=0.05) and smoking (P=0.02) predicted CHD. In the statistical model Lp(a) interacted significantly with age (OR=5.7; 95% CI: 1.4–23.6; P=0.016), and high Lp(a) (over 45 mg/dl) was associated with significantly increased risk in subjects under 60 years (OR=3.82; 95% CI: 1.47–9.96), but not in older men (OR=0.67; 95% CI: 0.235–1.89). Therefore, we studied the impact of Lp(a)/apo(a) and other variables in subjects who had been under 60 years when they became cases. Among the younger subjects the presence of LMW apo(a) isoforms significantly predicted the development of CHD (OR=3.83; 95% CI: 1.18–12.4). The increased risk pertained to high Lp(a) (above versus below 45 mg/dl: OR=3.68; 95% CI: 1.03–13.10), and to Lp(a) concentrations when entered into the model as a continuous variable (P=0.04). Cholesterol or apo B (P<0.01), smoking (P=0.02), systolic blood pressure (P=0.05) and low alcohol consumption (under nine drinks/week) (P=0.04) were also significant predictors of CHD. We conclude that LMW apo(a) isoforms are significantly associated with increased risk of CHD in men under 60 years.
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