Long-term neurocognitive effects of antipsychotics in schizophrenia: a network meta-analysis

Purpose

Most schizophrenic patients have mild to moderate cognitive impairment in the early stages of schizophrenia. The aim was to compare the long-term effects of various antipsychotic drugs on overall cognition and on specific cognitive domains in patients with schizophrenia or related disorders.

Methods

We searched MEDLINE and EMBASE for randomized controlled trials in which oral formulations of second-generation antipsychotic drugs were compared head-to-head or against placebo or against haloperidol. Trials had to be of at least 6 months duration to be included. We used a network meta-analysis to combine direct and indirect comparisons of the cognitive effects between antipsychotics.

Results

Nine studies were eligible. The median trial duration was 52 weeks. Quetiapine, olanzapine and risperidone had better effects on global cognitive score than amisulpride (p?<?0.05) and haloperidol (p?<?0.05). When memory tasks were considered, ziprasidone had better effect than amisulpride (0.28 [0.02–0.54]) and haloperidol (0.32 [0.09–0.55]). Quetiapine was better than other drugs (p?<?0.001) on attention and processing speed tasks, followed by ziprasidone (p?<?0.05) and olanzapine (p?<?0.05). The effects of quetiapine, risperidone and olanzapine were better than those of amisulpride (p?<?0.05) on executive functions.

Conclusions

Our results suggest differences between antipsychotics in their effect on the overall cognitive score in schizophrenia. Quetiapine and olanzapine had the most positive effects, followed by risperidone, ziprasidone, amisulpride and haloperidol in that order. Significant differences were also observed according to specific cognitive tasks.     

Decreased levels of serum brain-derived neurotrophic factor in drug-naïve first-episode schizophrenia: relationship to clinical phenotypes

Objective

There is accumulating evidence that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of patients with schizophrenia. Clinical studies show reductions in BDNF in schizophrenic patients treated with first generation antipsychotics or second generation antipsychotics. However, there have been few systematic studies to examine the relationship between BDNF levels and psychopathology in first-episode and drug-naïve patients with schizophrenia.

Materials and methods

Serum BDNF levels were determined using enzyme-linked-immunosorbent assay (ELISA) in the serum of 88 never-medicated first-episode and 90 healthy controls subjects matched for age and gender. The schizophrenia symptomatology and the depressive symptoms were assessed by the positive and negative syndrome scale (PANSS) and the Hamilton rating (HAMD) scale for depression.

Results

The results showed that BDNF levels were significantly lower in first-episode patients with schizophrenia than in healthy control subjects (9.0?±?4.2 ng/ml vs 12.1?±?2.2 ng/ml; F?=?37.6; df?=?1, 176; p?<?0.0001). A significant positive correlation between BDNF levels and PANSS positive subscore was observed (r?=?0.29; df?=?88; p?=?0.008). Furthermore, higher BDNF levels were observed in patients with paranoid subtype of schizophrenia. However, no significant correlation between BDNF and HAMD total score was found.

Conclusion

Low BDNF levels at the onset of psychosis suggest that it may contribute to the pathogenesis of schizophrenia and perhaps, could be a candidate biological marker for positive symptoms.     

A study of antioxidant activity in patients with schizophrenia taking atypical antipsychotics

Introduction

Atypical antipsychotics have significantly improved the quality of life for schizophrenic patients. Despite their beneficial effects, these antipsychotics induce weight gain, diabetes, and dyslipidemia. The aims of this study were to investigate the antioxidative activity of paraoxonase and assess lipid profile as a cardiovascular risk factor in patients with schizophrenia under long-term clozapine or risperidone treatment.

Methods

The study included 66 patients with schizophrenia under clozapine or risperidone treatment and 19 healthy control subjects. Serum paraoxonase activities against paraoxon (PON(PO)), phenylacetate (PON(PA)), dihydrocoumarin (PON(DHC)), serum Trolox equivalent antioxidant activity (TEAC), antioxidant gap (GAP), and lipid profile were determined.

Results

PON(DHC) activity was reduced in both antipsychotic drug-treated groups (clozapine 43.46?±?1.06 U/ml, p?p?Conclusions In patients with schizophrenia, clozapine or risperidone treatment had different effects on various paraoxonase activities. The results of the present study suggest that patients with schizophrenia might be at increased risk for metabolic and cardiovascular disease related to reduced PON(DHC), TEAC, and GAP.     

The effect of reboxetine co-administration with olanzapine on metabolic and endocrine profile in schizophrenia patients

Rationale

We previously demonstrated that the addition of the selective norepinephrine reuptake inhibitor reboxetine attenuates olanzapine-induced weight gain. Using the same study sample, we also sought to determine whether reboxetine’s weight-attenuating effect was accompanied by a beneficial effect on metabolic and endocrine parameters relevant to antipsychotic-induced weight gain and obesity.

Method

Blood samples at baseline and at the end of the 6-week trial were available for 54 participants who participated in previous double-blind, placebo-controlled studies of reboxetine (4 mg BID) addition to olanzapine-treated schizophrenia patients. Fasting glucose, lipid profile, insulin, leptin, cortisol, dehydroepiandrosterone (DHEA), prolactin, and thyroid-stimulating hormone (TSH) were analyzed.

Results

In contrast to the olanzapine/placebo group, the olanzapine/reboxetine group exhibited a reduction in blood triglyceride (p?<?0.05) and leptin (p?<?0.05) levels, and elevation in cortisol (p?<?0.05) and DHEA (p?<?0.008) levels. No significant between-group differences were detected in the changes in cholesterol, glucose, insulin, TSH, and prolactin.

Conclusions

Reboxetine addition resulted in meaningful improvement of some metabolic and endocrine measures associated with olanzapine-induced weight gain. The potential role of reboxetine in the prevention of olanzapine-induced weight gain and cardio–metabolic morbidity merits further large-scale, long-term investigation.     

Low BDNF is associated with cognitive impairment in chronic patients with schizophrenia

Objective

Several lines of evidence suggest that brain-derived neurotrophic factor (BDNF) plays a critical role in activity-dependent neuroplasticity underlying learning and memory in the hippocampus. Schizophrenia has a range of cognitive deficits that may evolve from decreased BDNF, and this study examines this association of BDNF with cognitive deficits in schizophrenia.

Materials and methods

We recruited 251 chronic schizophrenic patients and 206 healthy control subjects and examined the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and serum BDNF in both groups. Schizophrenic symptoms were assessed using the Positive and Negative Syndrome Scale.

Results

BDNF levels were significantly lower in patients than controls (p?p?p?>?0.05) were significantly lower in schizophrenic patients than normal controls. For the patients, BDNF was positively associated with immediate memory in schizophrenia.

Conclusion

Our findings suggest that BDNF may be involved in the pathophysiology of schizophrenia, and its associated cognitive impairment, especially immediate memory.     

A placebo-controlled study of tropisetron added to risperidone for the treatment of negative symptoms in chronic and stable schizophrenia

Rational

A growing body of evidence illustrates that 5-HT3 receptor antagonist drugs may be of benefit in the treatment of negative symptoms in schizophrenia.

Objective

The objective of this study was to assess the efficacy and tolerability of tropisetron add-on to risperidone on negative symptoms in patients with chronic stable schizophrenia.

Methods

In a double-blind, placebo-controlled 8-week trial, 40 patients with chronic schizophrenia who were stabilized on risperidone were randomized into tropisetron or placebo add-on groups. Psychotic symptoms were measured using the Positive and Negative Syndrome Scale (PANSS) every 2 weeks. Furthermore, extrapyramidal and depressive symptoms as well as side effects were assessed. The primary outcome measure was the difference in change from baseline of negative subscale scores between the two groups at week 8.

Results

Tropisetron resulted in greater improvement of the total PANSS scores [F(1.860,70.699)?=?37.366, p?<?0.001] as well as negative scores [F(2.439,92.675)?=?16.623, p?<?0.001] and general psychopathology [F(1.767,67.158)?=?4.602, p?=?0.017], but not positive subscale scores [F(1.348, 51.218)?=?0.048, p?=?0.893] compared to placebo. In a multiple regression analysis controlling for positive, extrapyramidal, and depressive symptoms, treatment group (standardized β?=??0.640) significantly predicted changes in primary negative symptoms. The side effect profile did not differ significantly between the two groups.

Conclusion

Tropisetron add-on to risperidone improves the primary negative symptoms of patients with chronic stable schizophrenia.     

Changes in pro-inflammatory cytokines and body weight during 6-month risperidone treatment in drug naïve, first-episode schizophrenia

Objective

The present study aimed to examine the changes in pro-inflammatory cytokines and body weight during 6-month risperidone treatment in drug naïve, first-episode schizophrenia.

Methods

Sixty-two drug naïve, first-episode schizophrenia (SZ group) and 60 healthy individuals (control group) were enrolled in the study. Serum interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) levels, and body weight were measured at baseline for both groups, and repeated for the SZ group at five different time points during 6-month risperidone treatment.

Results

At baseline, serum IL-1β, IL-6, and TNF-α levels in the SZ group (53.28?±?12.62, 33.98?±?14.13, 50.08?±?12.86 pg/mL, respectively) were significantly higher than those in the control group (23.49?±?15.27, 15.53?±?7.16, 32.12?±?15.23 pg/mL, respectively) (p's?<?0.001). Within the SZ group, serum IL-1β levels decreased significantly at 2 weeks (48.02?±?16.00 pg/mL, p?<?0.01) and 1 month (44.70?±?16.63 pg/mL, p?<?0.001), but then gradually increased at 2 months (48.49?±?18.87 pg/mL), 3 months (50.59?±?18.48 pg/mL) and 6 months (53.64?±?16.22 pg/mL) to the levels comparable to baseline; serum IL-6 levels changed significantly over the course of treatment (p?=?0.001), but reached the levels comparable to baseline at 6 months (37.13?±?13.23 pg/mL); serum levels of TNF-α increased significantly at 3 months (55.02?±?16.69 pg/mL, p?<?0.01) and 6 months (58.69?±?13.57 pg/mL, p?<?0.001); steady and significant weight gain was observed at each follow-up time point (p's?<?0.001), from 56.71?±?9.25 kg at baseline to 62.72?±?9.53 kg at 6 months.

Conclusions

Risperidone treatment is associated with changes in serum pro-inflammatory cytokines levels and weight. There is an initial anti-inflammatory effect that reduces with treatment, potentially due to its weight gain side effect.     

Effects of risperidone, amisulpride and nicotine on eye movement control and their modulation by schizotypy

Rationale

The increasing demand to develop more efficient compounds to treat cognitive impairments in schizophrenia has led to the development of experimental model systems. One such model system combines the study of surrogate populations expressing high levels of schizotypy with oculomotor biomarkers.

Objectives

We aimed (1) to replicate oculomotor deficits in a psychometric schizotypy sample and (2) to investigate whether the expected deficits can be remedied by compounds shown to ameliorate impairments in schizophrenia.

Methods

In this randomized double-blind, placebo-controlled study 233 healthy participants performed prosaccade (PS), antisaccade (AS) and smooth pursuit eye movement (SPEM) tasks after being randomly assigned to one of four drug groups (nicotine, risperidone, amisulpride, placebo). Participants were classified into medium- and high-schizotypy groups based on their scores on the Schizotypal Personality Questionnaire (SPQ, Raine (Schizophr Bull 17:555–564, 1991)).

Results

AS error rate showed a main effect of Drug (p?<?0.01), with nicotine improving performance, and a Drug by Schizotypy interaction (p?=?0.04), indicating higher error rates in medium schizotypes (p?=?0.01) but not high schizotypes under risperidone compared to placebo. High schizotypes had higher error rates than medium schizotypes under placebo (p?=?0.03). There was a main effect of Drug for saccadic peak velocity and SPEM velocity gain (both p?≤?0.01) indicating impaired performance with risperidone.

Conclusions

We replicate the observation of AS impairments in high schizotypy under placebo and show that nicotine enhances performance irrespective of group status. Caution should be exerted in applying this model as no beneficial effects of antipsychotics were seen in high schizotypes.     

Treatment of first-episode non-affective psychosis: a randomized comparison of aripiprazole, quetiapine and ziprasidone over 1 year

Rationale

Discontinuation of antipsychotic treatment at early phases increases the risk of poor adherence to maintenance drug therapy. Differences among antipsychotics in terms of effectiveness may determine a good adherence to treatment.

Objectives

The aim of this study is to compare the clinical effectiveness of aripiprazole, ziprasidone and quetiapine in the treatment of first-episode schizophrenia spectrum disorders at 1 year.

Method

From October 2005 to January 2011 a prospective, randomized, open-label study was undertaken. Two hundred two first-episode drug-naïve patients were randomly assigned to aripiprazole (N?=?78), ziprasidone (N?=?62), or quetiapine (N?=?62) and followed up for 1 year. The primary effectiveness measure was all-cause of treatment discontinuation. In addition, an analysis based on intention-to-treat principle was conducted in the analysis for clinical efficacy.

Results

The overall dropout rate at 1 year was 13.37 %. The treatment discontinuation rate differed significantly between treatment groups (aripiprazole?=?43.6 %, ziprasidone?=?66.1 % and quetiapine?=?82.3 %) (χ ²?=?22.545; p?<?0.001). Insufficient efficacy in the group of quetiapine is the most important reason for differences in discontinuation rates between agents (χ ²?=?19.436; p?<?0.001). The mean time to all-cause discontinuation was significantly different between groups (LogRank?=?30.732 p?<?0.001). The profile of extrapyramidal symptoms varies between treatments. Patients on ziprasidone were more likely to be prescribed antidepressants.

Conclusions

First episode patients treated with quetiapine have a higher risk of treatment discontinuation at midterm due to insufficient efficacy. Establishing differences between SGAs may help clinicians on prescribing decision for treatment of individuals presenting with first-episode non-affective psychosis.     

A double-blind, placebo controlled, randomized trial of riluzole as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia

Rationale

Several recent studies have focused on glutamate modulating agents for symptoms relief in schizophrenia, especially negative symptoms which are resistant to conventional therapies.

Objectives

We aimed to assess the efficacy and tolerability of riluzole, an anti-glutamate agent with neuroprotective properties, as an adjunct to risperidone in improving negative symptoms of schizophrenia.

Methods

In this randomized double-blind placebo-controlled parallel-group study, 50 patients with chronic schizophrenia and a score of ≥20 on the negative subscale of positive and negative syndrome scale (PANSS) were enrolled in the active phase of their illness. Participants were equally randomized to receive riluzole (100 mg/day) or placebo in addition to risperidone (up to 6 mg/day) for 8 weeks. Participants were rated by PANSS every 2 weeks. The primary outcome of this study was the difference in the decrease of PANSS negative subscale score from baseline to the study endpoint between the two groups.

Results

By the study endpoint, riluzole-treated patients showed significantly greater improvement in the negative symptoms (P?<?0.001) as well as the PANSS total and general psychopathology subscale scores (P?=?0.001 and P?<?0.001; respectively) compared to the placebo group. Treatment group was the only significant predictor of changes in negative symptom in this trial (β?=??0.56, P?<?0.001). No significant difference was observed between two groups in the frequency of side effects.

Conclusion

These preliminary findings suggest that riluzole may be a safe and effective medication for the treatment of negative symptoms in patients with chronic schizophrenia. Further research and replication of study findings is warranted.

Clinical trial registry name and registration number

Iranian registry of clinical trials www.irct.ir, IRCT201107281556N26     

Low BDNF is associated with cognitive deficits in patients with type 2 diabetes

Objective

Studies suggest that brain-derived neurotrophic factor (BDNF) plays an essential role in regulating memory-related neuroplasticity in the hippocampus. Type 2 diabetes (T2DM) is associated with impairment in many domains of cognitive function which may result from reduced BDNF; however, the correlation of BDNF with cognitive impairment in T2DM has not been investigated.

Materials and methods

We compared 208 patients with T2DM to 212 normal controls on serum BDNF and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

Results

Serum BDNF levels were significantly decreased in T2DM patients compared to normal controls (p?<?0.001). The total score and nearly all indexes (all p?<?0.01) except for attention and visuospatial/constructional indexes (all p?>?0.05) of RBANS were markedly lower in T2DM than controls. There was a positive relationship between serum BDNF and delayed memory in patients with T2DM.

Conclusion

Our results suggest that BDNF may play a role in the pathophysiology of cognitive deficits, especially delayed memory in T2DM.     

Glutamate,N-acetyl aspartate and psychotic symptoms in chronic ketamine users

Rationale

Ketamine, a non-competitive NMDA receptor antagonist, induces acute effects resembling the positive, negative and cognitive symptoms of schizophrenia. Chronic use has been suggested to lead to persistent schizophrenia-like neurobiological changes.

Objectives

This study aims to test the hypothesis that chronic ketamine users have changes in brain neurochemistry and increased subthreshold psychotic symptoms compared to matched poly-drug users.

Methods

Fifteen ketamine users and 13 poly-drug users were included in the study. Psychopathology was assessed using the Comprehensive Assessment of At-Risk Mental State. Creatine-scaled glutamate (Glu/Cr), glutamate?+?glutamine (Glu?+?Gln/Cr) and N-acetyl aspartate (NAA/Cr) were measured in three brain regions—anterior cingulate, left thalamus and left medial temporal cortex using proton magnetic resonance spectroscopy.

Results

Chronic ketamine users had higher levels of subthreshold psychotic symptoms (p?<?0.005, Cohen’s d?=?1.48) and lower thalamic NAA/Cr (p?<?0.01, d?=?1.17) compared to non-users. There were no differences in medial temporal cortex or anterior cingulate NAA/Cr or in Glu/Cr or Glu?+?Gln/Cr in any brain region between the two groups. In chronic ketamine users, CAARMS severity of abnormal perceptions was directly correlated with anterior cingulate Glu/Cr (p?<?0.05, r?=?0.61—uncorrected), but NAA/Cr was not related to any measures of psychopathology.

Conclusions

The finding of lower thalamic NAA/Cr in chronic ketamine users may be secondary to the effects of ketamine use compared to other drugs of abuse and resembles previous reports in individuals at genetic or clinical risk of schizophrenia.     

Comparison of metabolic effects of ziprasidone versus olanzapine treatment in patients with first-episode schizophrenia

Objective

The objective of the study was to compare metabolic effects of ziprasidone versus olanzapine treatment in patients with first-episode schizophrenia.

Methods

In this 6-week, multicenter, open-label trial, 260 patients were randomly assigned to receive ziprasidone or olanzapine treatment (130 per group). Primary metabolic measures were changes in weight and body mass index (BMI). Secondary metabolic measures were changes in glucose, insulin, lipids, and blood pressure. Efficacy and safety were also measured additionally.

Results

A total number of 230 patients completed the study. The mean daily dosages were 138.2(28.6) mg for ziprasidone and 19.0(2.3) mg for olanzapine. After 6-week treatment, there were significant between-group differences in change scores on weight [4.22(3.49) kg versus ?0.84(2.04) kg, p < 0.001] and BMI [1.59(1.37) versus ?0.30(0.74), p < 0.001]. In addition, there were significant between-group differences in change scores on fasting plasma glucose, insulin, homeostasis model assessment 2-insulin resistance, low-density lipoprotein, total cholesterol, and triglycerides (p < 0.001); all the changes were clinically in favor of ziprasidone treatment. Both medications were effective in improving schizophrenia symptoms, but the decreases in Positive and Negative Syndrome Scale total scores of the olanzapine group were significantly greater than that of the ziprasidone group (p < 0.05). Compared with olanzapine, ziprasidone also induced more prolonging of corrected QT interval and extrapyramidal side effects (p < 0.05). Both medications were well tolerated, and no serious adverse events were observed in either group.

Conclusions

Compared with olanzapine, ziprasidone treatment was associated with less adverse effects on glucose and lipid metabolism in patients with first-episode schizophrenia.     

Decreased vancomycin clearance in patients with congestive heart failure

Purpose

Congestive heart failure (CHF) alters the pharmacokinetics of various drugs, including cardiovascular agents, due to decreased cardiac output and decreased renal blood flow. The purpose of this study was to evaluate the influence of CHF on the clearance of vancomycin, a glycopeptide antibacterial agent.

Methods

After reviewing more than 1,500 clinical charts of patients who received vancomycin therapy and whose serum vancomycin level was monitored, we identified 101 patients who also had the left ventricular ejection fraction (LVEF) assessed at that time. The fluorescence polarization immunoassay method was used to measure vancomycin serum concentrations in these patients 1 h after the end of vancomycin infusion and just before the next administration. Using these two measurements, we calculated the pharmacokinetic parameters using the Bayesian estimator.

Results

Patients with an LVEF of?<40 % (16 patients) or those with an LVEF of ≥ 40 %? and <60 % (40 %?≤?LVEF?<?60 % ; 32 patients) had a significantly lower vancomycin clearance than patients with LVEF of?≥60 % (53 patients) (2.29?±?0.95 or 2.79?±?0.99 vs. 3.50?±?1.04 L/h; p?<?0.001 or p?<?0.01, respectively). Vancomycin clearance was strongly correlated not only with estimated creatinine clearance (CLcr) in patients with an LVEF of?<40 % (r?=?0.828) and 40 %?≤?LVEF?<?60 % (r?=?0.773), but also with an LVEF in patients with a CLcr of?<60 mL/min (r?=?0.646). Consistent with these findings, multiple regression analysis revealed that CLcr, LVEF and body weight were important independent variables for vancomycin clearance (r ²?=?0.649).

Conclusions

Vancomycin clearance decreased with decreasing cardiac function (LVEF) and decreasing CLcr. This finding suggests that vancomycin clearance is affected by cardiac function and would be predicted not only CLcr but also by LVEF.     

Patient- and physician-related risk factors for hyperkalaemia in potassium-increasing drug–drug interactions

Purpose

Hyperkalaemia due to potassium-increasing drug–drug interactions (DDIs) is a clinically important adverse drug event. The purpose of this study was to identify patient- and physician-related risk factors for the development of hyperkalaemia.

Methods

The risk for adult patients hospitalised in the University Hospital Zurich between 1 December 2009 and 31 December 2011 of developing hyperkalaemia was correlated with patient characteristics, number, type and duration of potassium-increasing DDIs and frequency of serum potassium monitoring.

Results

The 76,467 patients included in this study were prescribed 8,413 potentially severe potassium-increasing DDIs. Patient-related characteristics associated with the development of hyperkalaemia were pulmonary allograft [relative risk (RR) 5.1; p?<?0.0001), impaired renal function (RR 2.7; p?<?0.0001), diabetes mellitus (RR 1.6; p?=?0.002) and female gender (RR 1.5; p?=?0.007). Risk factors associated with medication were number of concurrently administered potassium-increasing drugs (RR 3.3 per additional drug; p?<?0.0001) and longer duration of the DDI (RR 4.9 for duration ≥6 days; p?<?0.0001). Physician-related factors associated with the development of hyperkalaemia were undetermined or elevated serum potassium level before treatment initiation (RR 2.2; p?<?0.001) and infrequent monitoring of serum potassium during a DDI (interval >48 h: RR 1.6; p?<?0.01).

Conclusion

Strategies for reducing the risk of hyperkalaemia during potassium-increasing DDIs should consider both patient- and physician-related risk factors.     

Effects of caffeine and alcohol on mood and performance changes following consumption of lager

Rationale

The present study examined whether caffeine would modify the behavioural effects of alcohol.

Objectives

The aim of the study was to determine whether caffeine modifies the effects of alcohol on mood and psychomotor performance and to identify possible dose–response and temporal relationships.

Methods

A double-blind study examined the effects of three successive lager drinks (330 ml each) in the early afternoon on mood and psychomotor performance assessed at 30-min intervals over a 2-h period. Participants carried out a baseline session and were then randomly assigned to one of six conditions formed by combining three different doses of caffeine (0, 62.5 and 125 mg per drink) with either no alcohol or 4.3 % alcohol. One hundred and forty-six young adults (65 male, 81 female; age range 18–30 years) participated in the study. Mood (alertness, hedonic tone and anxiety) was assessed before and after performing simple reaction time and choice reaction time tasks.

Results

Alcohol was associated with higher hedonic tone (p?<?0.005), reduced anxiety (p?<?0.05) and reduced alertness (p?<?0.005). Caffeine had no modifying effect on hedonic tone or anxiety. However, the highest dose of caffeine did remove the effect of alcohol on alertness (p?<?0.05). Effects of alcohol and caffeine were found on the performance tasks (all p values?<?0.05) but these were independent effects.

Conclusions

The results from the present study confirm that caffeine does not remove the negative effects of alcohol on performance although high doses counteract the drop in subjective alertness produced by alcohol.     

Risperidone, QTc interval prolongation, and torsade de pointes: a systematic review of case reports

Rationale

A recent publication asserted that even low-dose risperidone may induce corrected QT (QTc) interval prolongation up to 500 ms without drug-induced I_Kr blockade. We seek to better understand the complexity of any link between risperidone-induced/associated QTc interval prolongation and torsade de pointes (TdP).

Objectives

The objective of this study is to systematically analyze all available case reports of risperidone, QTc interval prolongation, and/or TdP.

Method

We identify case reports using PubMed, Medline, EMBASE, and Cochrane.

Results

Of the 15 cases found, nine were adult women (ages 31, 33, 34, 37, 47, “elderly”, 77, 84, and 87 years) and one was a teenager. There were four men (ages 28, 29, 29, and 46 years) and one preadolescent boy. Besides risperidone administration or overdose, traditional risk factors for QTc interval prolongation and TdP included female sex (n?=?10), older age (n?=?4), heart disease (n?=?3), hypokalemia (n?=?2), bradycardia (n?=?1), liver disease (n?=?1), QTc interval prolonging drugs other than risperidone (n?=?8), and metabolic inhibitors (n?=?2). TdP occurred in four cases. Six patients died, and three deaths were probably related to TdP.

Conclusion

Risperidone (when properly prescribed in patients free of other risk factors for QTc interval prolongation and TdP) is a relatively safe drug. Conventional statistics can neither predict the individual patient who will experience TdP nor determine the relationship of drug dose to QTc interval prolongation and TdP. Narrative medicine using a case report format appears to be an alternative and valuable additional approach to advance our understanding of this relationship and to reduce risks.     

Docosahexaenoic acid-concentrated fish oil supplementation in subjects with mild cognitive impairment (MCI): a 12-month randomised, double-blind, placebo-controlled trial

Rationale

Epidemiological studies have suggested a beneficial effect of fish oil supplementation in halting the initial progression of Alzheimer’s disease. However, it remains unclear whether fish oil affects cognitive function in older people with mild cognitive impairment (MCI).

Objectives

This study investigated the effects of fish oil supplementation on cognitive function in elderly person with MCI.

Methods

This was a 12-month, randomised, double-blind, placebo-controlled study using fish oil supplementation with concentrated docosahexaenoic acid (DHA). Thirty six low-socioeconomic-status elderly subjects with MCI were randomly assigned to receive either concentrated DHA fish oil (n?=?18) or placebo (n?=?18) capsules. The changes of memory, psychomotor speed, executive function and attention, and visual-constructive skills were assessed using cognitive tests. Secondary outcomes were safety and tolerability of the DHA concentrate.

Results

The fish oil group showed significant improvement in short-term and working memory (F?=?9.890; ηp ²?=?0.254; p?<?0.0001), immediate verbal memory (F?=?3.715; ηp ²?=?0.114; p?<?0.05) and delayed recall capability (F?=?3.986; ηp ²?=?0.121; p?<?0.05). The 12-month change in memory (p?<?0.01) was significantly better in the fish oil group. Fish oil consumption was well tolerated, and the side effects were minimal and self-limiting.

Conclusions

This study suggested the potential role of fish oil to improve memory function in MCI subjects. Studies with larger sample sizes, longer intervention periods, different fish oil dosages and genetic determinations should be investigated before definite recommendations can be made.     

Association of genetic variants of the histamine H1 and muscarinic M3 receptors with BMI and HbA1c values in patients on antipsychotic medication

Rationale

Antipsychotic affinity for the histamine H1 receptor and the muscarinic M3 receptor have been associated with the side effects weight gain, and development of diabetes, respectively.

Objectives

We investigated polymorphisms of the histamine H1 (HRH1) and muscarinic acetylcholine receptor M3 (CHRM3) receptor genes for an association with body mass index (BMI) and glycated hemoglobin (HbA1c).

Methods

We included 430 Caucasian patients with a non-affective psychotic disorder using antipsychotics for at least 3?months. Primary endpoints of the study were cross-sectionally measured BMI and HbA1c; secondary endpoints were obesity and hyperglycaemia. Two single-nucleotide polymorphisms (SNPs) in the HRH1 gene, rs346074 and rs346070, and one SNP in the CHRM3 gene, rs3738435, were genotyped. Our primary hypothesis in this study was an interaction between genotype on BMI and antipsychotic affinity for the H1 and M3 receptor.

Results

A significant association of interaction between haplotype rs346074?Crs346070 and BMI (p value 0.025) and obesity (p value 0.005) in patients using high-H1 affinity antipsychotics versus patients using low-H1 affinity antipsychotics was found. There was no association of CHRM3 gene variant rs3738435 with BMI, and we observed no association with HbA1c or hyperglycaemia in any of the variants.

Conclusions

This study, for the first time, demonstrates a significant association between HRH1 variants and BMI in patients with a psychotic disorder using antipsychotics. In future, genotyping of HRH1 variants may help predicting weight gain in patients using antipsychotics.