K Sweers

Body weight and metabolic adverse effects of asenapine, iloperidone, lurasidone and paliperidone in the treatment of schizophrenia and bipolar disorder: a systematic review and exploratory meta-analysis

AbstractBackground: The introduction of second-generation antipsychotics (SGAs) over the past 2 decades generated considerable optimism that better anti-psychotic treatments for schizophrenia and bipolar disorder were possible. SGAs offer several tolerability benefits over first-generation antipsychotics (FGAs), particularly with respect to extrapyramidal symptoms. However, SGAs can induce serious metabolic dysregulations, especially in drug-naive, first-episode, and child and adolescent populations, with olanzapine and clozapine having the highest propensity to cause these abnormalities. In this context, newer SGAs were developed to further improve the adverse effect burden of available agents. However, until now, the metabolic risk profile of the newly approved SGAs — asenapine, iloperidone, lurasidone and paliperidone (paliperidone extended release and paliperidone palmitate) — has not been compared. Objective: The objective of this systematic review and exploratory meta-analysis was to assess the effects of asenapine, iloperidone, lurasidone and paliperidone on body weight and other metabolic parameters (cholesterol, triglycerides and glucose), as this information is relevant to guide clinical decision making. Method: A systematic literature search (1966–March 2012), using the Cochrane Central Register of Controlled Trials and MEDLINE, CINAHL and EMBASE databases, was conducted for randomized, placebo-controlled and head-to-head clinical trials of asenapine, iloperidone, lurasidone and paliperidone. Published and unpublished data on changes in body weight and glucose and lipid metabolism parameters were extracted. For placebo-controlled, short-term (≤12 weeks) and longer-term (>12 weeks) trials with available data on ≥7% weight increase compared with pre-treatment weight, or mean weight change with standard deviation, a formal meta-analysis was performed, estimating the pooled effect size (represented as relative risk [RR], numbers-needed-to-harm [NNH] and weighted mean difference [WMD]). An exploratory meta-analysis was also performed for the other metabolic variables (cholesterol, triglycerides and glucose). Data from active- and placebo-controlled studies were used for a pooled comparison of simple mean changes in weight, cholesterol, triglyceride and glucose levels. Results: Fifty-six trials (n = 21691) in schizophrenia (N = 49, n= 19 299) or bipolar disorder (N = 7, n = 2392) were identified (asenapine: N = 9, iloperidone: N=11, lurasidone: N = 8, paliperidone: N = 28). Most of the trials (64.3%) were of ≤12 weeks’ duration. In the short-term trials, compared with placebo, a ≥7% weight increase was statistically significantly (p < 0.05) most prevalent for asenapine (5 trials, n = 1360, RR = 4.09, 95% confidence interval [CI] 2.25, 7.43, NNH = 17), followed by iloperidone (4 trials, n = 1931, RR = 3.13, 95% CI 2.08, 4.70, NNH = 11) and paliperidone (12 trials, n = 4087, RR = 2.17, 95% CI 1.64, 2.86, NNH = 20). The effect of lurasidone on body weight (6 trials, n = 1793, RR = 1.42, 95% CI 0.87, 2.29) was not statistically significant. Short-term weight gain was statistically significantly (p < 0.001) greater than placebo with iloperidone (1 trial, n = 300, +2.50 kg, 95% CI 1.92, 3.08), paliperidone (15 trials, n = 3552, +1.24 kg, 95% CI 0.91, 1.57), asenapine (3 trials, n = 751, +1.16 kg, 95% CI 0.83, 1.49), as well as with lurasidone (5 trials, n = 999, +0.49 kg, 95% CI 0.17, 0.81, p < 0.01). Sufficient meta-analysable, longer-term, weight change data were only available for asenapine and paliperidone, showing statistically significantly (p < 0.001) greater weight gain versus placebo for both drugs (asenapine, 3 trials, n = 311, +1.30 kg, 95% CI 0.62, 1.98; paliperidone, 6 trials, n = 1174, +0.50 kg, 95% CI 0.22, 0.78). Although statistically significant, in general, no clinically meaningful differences were observed between the four newly approved SGAs and placebo regarding the mean change from baseline to endpoint in cholesterol levels in short-term trials, with the exception of iloperidone for total cholesterol (1 trial, n = 300, +11.60 mg/dL, 95% CI 4.98, 18.22, p ≤ 0.001), high-density cholesterol (1 trial, n = 300, +3.6 mg/dL, 95% CI 1.58, 5.62, ps < 0.001) and low-density cholesterol (1 trial, n = 300, +10.30 mg/dL, 95% CI 4.94, 15.66, p < 0.001) and with the exception of lurasidone for high-density cholesterol (5 trials, n = 1004, +1.50 mg/dL, 95% CI 0.56, 2.44, p < 0.01). Asenapine increased total cholesterol statistically significantly (p < 0.05) during longer-term treatment (1 trial, n = 194, +6.53 mg/dL, 95% CI 1.17, 11.89). Regarding triglycerides, only short-term (3 trials, n = 1152, +1.78 mg/dL, 95% CI 0.40, 3.17, p < 0.01) and longer-term treatment with paliperidone (4 trials, n = 791, −0.20 mg/dL, 95% CI −0.40, −0.01, p < 0.05) had a statistically, but not clinically, significant effect. Statistically significant changes in glucose levels were noticed during short-term treatment with asenapine (2 trials, n = 379, −3.95 mg/dL, 95% CI −7.37, −0.53, p < 0.05) and iloperidone (1 trial, n =300, +6.90 mg/dL, 95% CI 2.48, 11.32, p < 0.01), and during long-term treatment with paliperidone (6 trials, n = 1022, +3.39 mg/dL, 95% CI 0.42, 6.36, p < 0.05). Conclusion: While preliminary data suggest the lowest weight gain potential with lurasidone and potentially relevant short-term metabolic effects for asenapine and iloperidone, data are still too sparse to comprehensively evaluate the metabolic safety of the newly approved SGAs. Therefore, there is a clear need for further controlled studies to evaluate whether these agents are less problematic regarding treatment-emergent weight gain and metabolic disturbances than other currently available antipsychotics.

Relationships between obesity, functional exercise capacity, physical activity participation and physical self-perception in people with schizophrenia

Vancampfort D, Probst M, Sweers K, Maurissen K, Knapen J, De Hert M. Relationships between obesity, functional exercise capacity, physical activity participation and physical self‐perception in people with schizophrenia.

Lack of physical activity during leisure time contributes to an impaired health related quality of life in patients with schizophrenia

OBJECTIVE The aim of the present study was to identify if lack of physical activity participation and an impaired functional exercise capacity compared with healthy controls contributed to an impaired health related quality of life (HRQL). We also evaluated whether the presence of metabolic syndrome (MetS) could explain the variability in HRQL in patients. METHOD Patients with DSM-IV schizophrenia (n=60) and age- and gender-matched healthy controls (n=40) completed the SF-36 quality of life scale and the Baecke Physical Activity Questionnaire and performed a 6 minute walk test (6MWT). Patients also received a fasting metabolic laboratory screening. Linear multiple regression analysis was used to assess the associations between demographical and clinical variables and HRQL outcomes. RESULTS Physical and mental HRQL and the Baecke and 6MWT-scores were significantly lower in patients with schizophrenia compared with matched healthy controls. When in schizophrenia patients all individual HRQL-predictors were included in a regression model, only BMI and lack of PA during leisure time remained significant predictors for physical HRQL while for mental HRQL no significant predictor remained. The impaired functional exercise capacity and the presence of MetS did not additionally explain the variance in HRQL. CONCLUSIONS Physical HRQL in patients with schizophrenia is not only related to increased BMI but also to lack of leisure time physical activity. A reduced physical HRQL in patients with MetS appears to be related to their greater BMI, rather than to MetS per se. Present findings provide further support for routinely incorporating physical activity within rehabilitation programs and clinical assessments.

Relationships between physical fitness, physical activity, smoking and metabolic and mental health parameters in people with schizophrenia

Low physical fitness has been recognised as a prominent behavioural risk factor for cardiovascular diseases (CVD) and metabolic syndrome (MetS), and as an independent risk factor for all-cause mortality. No studies have systematically assessed physical fitness compared with a matched health control group in patients with schizophrenia. Eighty patients with schizophrenia and 40 age-, gender- and body mass index (BMI)-matched healthy volunteers were included. All participants performed an Eurofit test battery and filled out the International Physical Activity Questionnaire. Patients additionally had a fasting metabolic laboratory screening and were assessed for psychiatric symptoms. Patients with schizophrenia demonstrated significant differences from controls in whole body balance, explosive leg muscle strength, abdominal muscular endurance, and running speed. Inactive patients scored worse on most Eurofit items than patients walking for at least 30min per day. Low physical fitness was associated with illness duration, smoking, the presence of MetS and more severe negative, depressive and cognitive symptoms. Less physically active patients who smoke and suffer from high levels of negative, depressive and/or cognitive symptoms might benefit from specific rehabilitation interventions aimed at increasing physical fitness.

Effects of cannabis use on age at onset in schizophrenia and bipolar disorder

BACKGROUND Cannabis use may decrease age at onset in both schizophrenia and bipolar disorder, given the evidence for substantial phenotypic and genetic overlap between both disorders. METHODS 766 patients, aged 16 to 65 years, were assessed with the Composite International Diagnostic Interview (CIDI) for substance abuse/use. 676 subjects were diagnosed with schizophrenia and 90 subjects with bipolar disorder. The influence of cannabis use on age at onset in both schizophrenia and bipolar disorder was examined using regression analysis. RESULTS Cannabis and other substance use was more frequent in patients with schizophrenia compared to the bipolar group. Both cannabis use and a schizophrenia diagnosis predicted earlier age at onset. There was a significant interaction between cannabis use and diagnosis, cannabis having a greater effect in bipolar patients. Age at onset in users of cannabis was comparable in both diagnostic groups whereas bipolar non-users were significantly older than schizophrenia non-users at onset. CONCLUSION Cannabis use may decrease age at onset in both schizophrenia and bipolar patients and reduce the effect of diagnosis. This is consistent with the view that cannabis use may unmask a pre-existing genetic liability that is partly shared between patients with schizophrenia and bipolar disorder.

Prevalence and severity of antipsychotic related constipation in patients with schizophrenia: a retrospective descriptive study

BackgroundAntipsychotic are the cornerstone in the treatment of schizophrenia. They also have a number of side-effects. Constipation is thought to be common, and a potential serious side-effect, which has received little attention in recent literature.MethodWe performed a retrospective study in consecutively admitted patients, between 2007 and 2009 and treated with antipsychotic medication, linking different electronic patient data to evaluate the prevalence and severity of constipation in patients with schizophrenia under routine treatment conditions.ResultsOver a period of 22 months 36.3% of patients (99) received at least once a pharmacological treatment for constipation. On average medication for constipation was prescribed for 273 days. Severe cases (N = 50), non-responsive to initial treatment, got a plain x-ray of the abdomen. In 68.4% fecal impaction was found.ConclusionA high prevalence of constipation, often severe and needing medical interventions, was confirmed during the study period. Early detection, monitoring over treatment and early intervention of constipation could prevent serious consequences such as ileus.

Reliability, minimal detectable changes, practice effects and correlates of the 6-min walk test in patients with schizophrenia

We examined the reproducibility of the 6-min walk test (6 MWT) in patients with schizophrenia. Secondary aims were to assess minimal detectable changes and practice effects of the 6 MWT and the presence of clinical conditions that might interfere. From 71 patients with schizophrenia two trials of the 6 MWT, administered within 3 days, were analysed. The intraclass correlation coefficient between the two tests was 0.96. The minimal detectable change was 56.2m for men and 50.2m for women. Body mass index, daily antipsychotic dose, negative and depressive symptoms, resting heart rate, age, smoking behavior and different musculoskeletal complaints were all significantly associated with the distance walked. The 6 MWT can be recommended for evaluating the functional exercise capacity in patients with schizophrenia. Some practice effect could however not be excluded.

Association of the metabolic syndrome with physical activity performance in patients with schizophrenia

AIM The primary aim of this study was to determine whether the presence of the metabolic syndrome (MetS) limits physical activity (PA) in patients with schizophrenia. A secondary aim was to investigate cross-sectional associations of leisure-time PA, sports participation and PA performance with MetS parameters. METHODS Patients with schizophrenia who had MetS (n=37) were compared with those without MetS (n=69). Patients were assessed for PA performance using a 6-minute walk test (6MWT) and PA participation using the Baecke PA questionnaire, as well as for antipsychotic medication dose (expressed in chlorpromazine equivalents), negative symptoms and smoking behaviour. RESULTS The two patient groups were similar in age, gender, mean antipsychotic medication dose, negative symptomatology and smoking behaviour. Distance achieved on the 6MWT was 13.7% shorter (P<0.001) in patients with versus patients without MetS (527.6±108.9 m vs 610.0±93.7 m, respectively). Patients with MetS were also significantly less involved in sports activities (P=0.001) and less physically active during leisure time (P=0.002). Also, the distance of the 6MWT was moderately correlated with body mass index (r=-0.44, P<0.001), waist circumference (r=-0.43, P<0.001), sports participation (r=0.60, P<0.001) and leisure-time PA (r=0.42, P<0.001). CONCLUSION MetS is associated with poorer PA performance in patients with schizophrenia. The additional burden of MetS places patients with schizophrenia at even greater risk for physical and functional limitations in daily life.

Eurofit test battery in patients with schizophrenia or schizoaffective disorder: reliability and clinical correlates

OBJECTIVE To investigate the reproducibility of the Eurofit physical fitness test battery in patients with schizophrenia or schizoaffective disorder. Secondary aims were to assess clinical and demographic characteristics that correlate with the performance on the Eurofit and evaluation of the feasibility of the test. METHODS Fifty patients with schizophrenia or schizoaffective disorder (mean age of 32.9±9.5 years) with a mean body mass index (BMI) of 26.1±6.0 kg/m(2) performed two Eurofit tests administered within 3 days. RESULTS All Eurofit items showed good reproducibility with intraclass correlation coefficients ranging from 0.72 for flamingo balance to 0.98 for standing broad jump test. All participants could perform five of the seven test items without problems. The whole body balance and abdominal muscle endurance test could be executed by 74 and 90%, respectively. Significant correlations were found with age, BMI, waist circumference, dose of antipsychotic medication and extrapyramidal, negative and cognitive symptoms. CONCLUSIONS The Eurofit test showed good reproducibility and can be recommended for evaluating physical fitness parameters in patients with schizophrenia or schizoaffective disorder. Physical fitness measures were related to both physical and mental health parameters.

Metaphor interpretation and use : a window into semantics in schizophrenia

The nature of putative semantic anomalies in schizophrenia is controversial. Metaphor interpretation and use provide a useful methodology with which to probe semantics since metaphors are critical in reasoning processes and in how conceptual knowledge is organized. The first study examined free speech for figurative language. The second study explored whether emotional versus non-emotional metaphorical language interpretation elicits differences in the tendencies to produce idiosyncratic (bizarre) or literal interpretations or use of other metaphors to describe the meaning of a metaphor. The third study examined the interpretation of time metaphors. We expected the time perspective in ambiguous sentences to be differentially influenced by previously presented unambiguous sentences of a specific perspective, either events moving relative to a stationary observer (moving-time) or an observer moving relative to a stationary event (moving-ego). First, we found that patients used a similar amount of figurative language as control participants. Second, we did not find any difference between the groups in terms of idiosyncratic interpretations, although patients did interpret more metaphors literally and controls utilized more figurative language. Third, we did not find evidence of a difference between the groups in terms of time perspectives influencing ambiguous target sentences differentially. As operationalized here, the interpretation and use of metaphors is similar in patients with schizophrenia to that of healthy control participants. To the extent that metaphors recruit semantic processes this area of cognition is generally intact in schizophrenia.