Effects of risperidone on glucose metabolism in Chinese patients with schizophrenia: a prospective study

Background

While most of the second generation antipsychotic agents are associated with abnormal glucose metabolism, previous studies have shown that risperidone has relatively little effect upon blood glucose levels. This study aimed to explore the effect of risperidone on the glucose-regulating mechanism of patients with schizophrenia by using the oral glucose tolerance test (OGTT), measuring insulin and C-peptide levels.

Methods

Thirty inpatients with schizophrenia taking risperidone were studied. All the patients were given a simplified OGTT at baseline and six weeks after treatment. Plasma glucose, insulin, and C-peptide concentrations were measured at fasting, then 1 and 2 h after OGTT respectively. Other data, including demographic characteristics and plasma drug concentrations, were also recorded.

Results

(1) There was no significant increase in the proportion of patients demonstrating abnormal plasma glucose levels compared with baseline (p = 1.000, McNemar test); (2) risperidone was associated with elevated insulin concentrations (p = 0.013), C-peptide levels (p = 0.020), insulin/glucose ratio (p = 0.020) and BMI (p < 0.01); (3) no sex differences in glucose-related measures were observed.

Conclusion

Risperidone treatment may be associated with alterations in glucose-regulating mechanisms in patients with schizophrenia.     

The prevalence of dental anxiety across previous distressing experiences

Aims

To compare the prevalence of high dental anxiety across a variety of past distressing experiences with a previously reported Dutch sample.

Method

University students from the UK (N = 1024) completed an online survey containing; the Modified Dental Anxiety Scale, and the Level of Exposure-Dental Experiences Questionnaire (LOE-DEQ). Adjusted odds ratios (OR) were calculated to assess the association of self-reported distressing experiences and dental anxiety.

Results

The percentage of respondents with high dental anxiety (HDA) (total MDAS score ≥ 19) was 11.2%. Significant prevalence of HDA across several distressing experiences was shown in both UK and Dutch samples notably: extreme helplessness during dental treatment, lack of understanding of the dentist and extreme embarrassment during dental treatment. There were little or no effects of non-dental trauma, with the exception of sexual abuse in the UK sample.

Conclusions

Trauma from various past experiences may be implicated in an increased risk of high dental anxiety.     

A randomized, placebo-controlled trial of risperidone augmentation for patients with difficult-to-treat unipolar, non-psychotic major depression

Objective

Patients (30-50%) with non-psychotic major depression will not respond despite an adequate trial of antidepressant medication. This study evaluated risperidone as an augmenting agent for patients who failed or only partially responded to an adequate trial of an antidepressant medication.

Method

Ninety-seven patients with unipolar non-psychotic major depression who were not responsive to antidepressant monotherapy were randomized to risperidone (0.5-3 mg/day) or placebo augmentation in a four-week, double-blind, placebo controlled treatment trial. The primary outcome measure was remission defined by a score of ?10 on the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes measures were the Hamilton Rating Scale for Depression, the Clinician Global Impression of Severity scale and the overall satisfaction item of the Quality of Life and Enjoyment Questionnaire.

Results

Subjects in both treatment groups improved significantly over time. The odds of remitting were significantly better for patients in the risperidone vs. placebo arm (OR = 3.33, p = .011). At the end of 4 weeks of treatment 52% of the risperidone augmentation group remitted (MADRS ? 10) compared to 24% of the placebo augmentation group (CMH(1) = 6.48, p = .011), but the two groups were converging. Patients in the risperidone group also reported significantly more improvement in quality-of-life than patients in the placebo group. There were no between-group differences in the number of adverse events reported, however, weight gain was significantly higher in the group receiving risperidone.

Conclusion

Augmentation of an antidepressant with risperidone for patients with difficult-to-treat depression leads to more rapid response and a higher remission rate and better quality-of-life.     

Short duration repetitive transcranial magnetic stimulation for tinnitus treatment: a prospective Asian study

Background

Tinnitus is a subjective auditory perception of sounds or noise not triggered by external auditory stimuli. To date, treatment in severe cases is generally unsatisfactory. Characteristic functional brain imaging changes associated with tinnitus include hyperactivity encompassing both the primary auditory cortex (AC) and the secondary or associative cortex. Brief repetitive transcranial magnetic stimulation (rTMS) trains applied to the scalp overlying the hyperactive left AC is known to produce moderate tinnitus attenuation.

Objective

Although Western studies have documented the value of rTMS in tinnitus treatment, we evaluate the efficacy of a short duration rTMS protocol for the first time in the Asian setting.

Method

Consecutive patients were recruited at our tinnitus clinic. Detailed history, examination, audiogram and baseline tinnitus scales were recorded. RTMS consisted of 1000 pulses/day at 1 Hz and 110% of the motor threshold, for five consecutive days over the left temporoparietal cortex. Tinnitus ratings were determined weekly for 4 weeks after rTMS.

Result

Fifteen patients completed the trial; none experienced significant side effects. Repeated measures ANOVA showed significant linear decrease in Tinnitus Handicap Inventory (THI) scores over the time period (F_(1,14) = 4.7, p = 0.04). However, none of the other parameters (severity, annoyance, effect on lifestyle and overall impression: visual analogue scale) showed beneficial outcomes.

Conclusions

Our findings point to a positive effect of short duration rTMS in tinnitus treatment using the THI. However, no significant benefits were demonstrated for other subjective patient ratings. Although well tolerated and convenient, short duration rTMS may prove inadequate for modulating maladaptive plastic changes at the cortical level, and our results suggest the need for delivery of more stimuli. Future studies will utilize at least 2000 pulses/day, in line with previous experience in Western settings.     

Association of elevated NTproBNP with recurrent thromboembolic events after acute pulmonary embolism

Introduction

N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) is a predictor of adverse short-term clinical outcomes in patients with acute pulmonary embolism (APE), but its long-term prognostic value remains largely undefined. The aim of this study was to assess the value of plasma NTproBNP with regard to recurrent venous thromboembolism (VTE).

Materials and Methods

NTproBNP levels were measured in 224 consecutive patients with the first episode of acute pulmonary embolism occurring from January 2005 through October 2010. Patients were categorized into two groups by NTproBNP reference range. Follow-ups were performed at 3, 6, and 12 months and yearly thereafter. The primary end point was symptomatic, recurrent fatal or nonfatal VTE.

Results

NTproBNP was elevated in 158 (70.5%) patients and not elevated in 66 (29.5%) patients. After a mean follow-up period of 31.0 ± 19.4 months, patients with elevated NTproBNP showed an increased risk of recurrent VTE (20 patients, 12.7%) compared to those without elevated NTproBNP (only 1 patient, 1.5%) (P = 0.009). Of the 7 deaths related to pulmonary embolism, 6 occurred in patients with elevated NTproBNP compared to patients with normal NTproBNP (1 of 7 deaths). In a multivariate analysis stratified by oral anticoagulant treatment duration, elevated NTproBNP was an independent predictor of recurrent VTE (hazard ratio, 9.32; P = 0.02).

Conclusions

Elevated NTproBNP is associated with recurrent VTE in acute pulmonary embolism patients.     

Poor creativity in frontotemporal dementia: A window into the neural bases of the creative mind

Background

The prefrontal cortex (PFC) supports functions critical for creative thinking. Damage to the PFC is expected to impair creativity. Yet, previous works suggested the emergence of artistic talent in patients with frontotemporal lobar degeneration (FTLD), which was interpreted as increased creativity.

Objective

We designed a study in patients with frontal variant (fv) of FTLD in order to verify whether: (1) creativity is impaired after frontal degeneration, (2) poor creativity is associated with frontal dysfunctions, and (3) poor creativity is related to hypoperfusion in specific PFC regions.

Materials and methods

Three groups of subjects were enrolled in the study: fvFTLD patients (n = 17), non-demented Parkinson's disease (PD) patients (n = 12) and healthy controls (n = 17). Participants performed a standardized test of creativity, the Torrance Test of Creative Thinking (TTCT) and tests assessing frontal functions. Brain perfusion was correlated to fvFTLD patients’ performance in the TTCT.

Results

Patients with fvFTLD were strongly impaired in all dimensions of the TTCT, compared to PD patients and controls. Disinhibited and perseverative responses were observed only in fvFTLD patients, leading to “pseudo-creative” responses. Poor creativity was positively correlated with several frontal tests. Poor creativity was also correlated with prefrontal hypoperfusion, particularly in the frontal pole.

Conclusions

Poor creativity is associated with fvFTLD. The results also suggest that the integrity of the PFC (in particular frontopolar) is strongly associated with creative thinking. The emergence of artistic talent in patients with fvFTLD is explained by the release of involuntary behaviors, rather than by the development of creative thinking.     

Outcome in delusional depression comparing trimipramine monotherapy with a combination of amitriptyline and haloperidol - A double-blind multicenter trial

Background

Patients with delusional depression are difficult to treat. The atypical antidepressant trimipramine was effective in a previous 4-week open label pilot study in patients with this disorder. The major neurobiological effect of trimipramine is the inhibition of the hypothalamic-pituitary-adrenocortical (HPA) system. In delusional depression HPA overactivity is more distinct than in other subtypes of depression. HPA suppression is thought to contribute to the action of trimipramine.

Methods

In a double-blind, randomized, placebo controlled multicenter trial we compared the effects of trimipramine monotherapy versus a combination of amitriptyline and haloperidol. Dosage was increased stepwise from 100 mg up to 400 mg trimipramine and from 100 mg up to 200 mg amitriptyline combined with 2 mg up to 7.5 mg haloperidol. The average dose of trimipramine was higher than that of amitriptyline throughout the trial. During sixth week mean dosage (±standard deviation) were 356.1 ± 61.2 mg trimipramine, 184.0 ± 23.6 mg amitriptyline and 6.3 ± 1.8 mg haloperidol. During six weeks psychometric assessments were performed weekly. For HPA monitoring a dexamethasone/corticotropin-releasing hormone (Dex/CRH) test was performed before active medication and at the end of treatment. Additionally tolerability was monitored by ECG, EEG assessment of extrapyramidal symptoms and akathisia, clinical laboratory routine and recording of blood pressure and heart rate. Adverse events were documented.

Results

94 patients were enclosed into the study. The per protocol sample consisted of 33 patients of the trimipramine group and of 24 patients of the amitriptyline/haloperidol group. The decrease of the Hamilton depression (HAMD) score (24 items) showed non-inferiority of trimipramine compared to amitriptyline/haloperidol. Twenty-eight patients (84.84%) in the trimipramine arm and 17 patients (70.83%) in the amitriptyline/haloperidol arm were responders (HAMD ? 50%). Remission (HAMD < 8) was found in 18 (54.55%) patients after trimipramine and in 11 (45.83%) patients after amitriptyline/haloperidol. No significant differences were found concerning response and remission. The cortisol and ACTH response in the Dex/CRH test decreased between days 1 and 42 in both groups. Serious side effects were not reported.

Conclusion

In all, trimipramine monotherapy appears to be an effective treatment in delusional depression.     

Social anxiety disorder women easily recognize fearfull, sad and happy faces: The influence of gender

Background

It has been suggested that individuals with social anxiety disorder (SAD) are exaggeratedly concerned about approval and disapproval by others. Therefore, we assessed the recognition of facial expressions by individuals with SAD, in an attempt to overcome the limitations of previous studies.

Methods

The sample was formed by 231 individuals (78 SAD patients and 153 healthy controls). All individuals were treatment naïve, aged 18-30 years and with similar socioeconomic level. Participants judged which emotion (happiness, sadness, disgust, anger, fear, and surprise) was presented in the facial expression of stimuli displayed on a computer screen. The stimuli were manipulated in order to depict different emotional intensities, with the initial image being a neutral face (0%) and, as the individual moved on across images, the expressions increased their emotional intensity until reaching the total emotion (100%). The time, accuracy, and intensity necessary to perform judgments were evaluated.

Results

The groups did not show statistically significant differences in respect to the number of correct judgments or to the time necessary to respond. However, women with SAD required less emotional intensity to recognize faces displaying fear (p = 0.002), sadness (p = 0.033) and happiness (p = 0.002), with no significant differences for the other emotions or men with SAD.

Conclusions

The findings suggest that women with SAD are hypersensitive to threat-related and approval-related social cues. Future studies investigating the neural basis of the impaired processing of facial emotion in SAD using functional neuroimaging would be desirable and opportune.     

Different effects of enoxaparin and unfractionated heparin on some thrombogenesis markers during hemodialysis: a cross-over study

Background

Unfractionated heparin (UFH) and low molecular weight heparin constitute fundamental anticoagulants during hemodialysis (HD). We aimed to investigate the effect of UFH and enoxaparin on plasma levels of prothrombin fragment 1 + 2 (PF 1 + 2) and thrombin/antithrombin complex (TAT) as markers of intravascular thrombogenesis during HD.

Methods

We enrolled 22 chronic HD patients, who were randomly assigned to either iv enoxaparin (n = 11) or UFH (n = 11) anticoagulation, and followed prospectively for 12 weeks before crossing over to the alternate therapy for further 12 weeks. Plasma levels of PF 1 + 2 and TAT were measured by immunoassay at the start, at 10 and 180 min of HD session after each period of evaluation.

Results

The baseline PF 1 + 2 and TAT levels were comparable under enoxaparin and UFH treatment. PF 1 + 2 significantly decreased during both UFH (χ² ANOVA = 9.82, P = 0.007) and enoxaparin (χ² ANOVA = 29.40, P < 10^− 6) anticoagulated HD, while over-HD TAT levels changes differed depending on the type of heparin. The switch from enoxaparin to UFH treatment was connected with a significantly higher PF 1 + 2 after 10 and 180 min as well as higher TAT concentration after 180 min of HD. Only during enoxaparin anticoagulated HD 34% PF 1 + 2 decrease and TAT levels after 180 min of HD was closely associated with heparin dosage.

Conclusion

Single bolus of enoxaparin ensures efficient and convenient anti-thrombotic protection during HD procedure. Enoxaparin mean dose of 0.67 mg/kg, which is generally lower than manufacturer's instructions, can be recommended for over-dialytic regular use.     

Effects of microbubbles on transcranial Doppler ultrasound-assisted intracranial urokinase thrombolysis

Introduction

To evaluate the efficacy of microbubbles in transcranial Doppler ultrasound (TCD)-assisted urokinase thrombolysis.

Materials and Methods

Male New Zealand white rabbits (N = 32) were randomly divided into 2 groups, a urokinase group and a combined urokinase plus microbubble group. The middle cerebral artery (MCA) was occluded by injecting autologous blood clots through the carotid artery. In the urokinase plus microbubble group, sulfur hexafluoride (SonoVue) microbubbles were injected intravenously immediately after intravenous injection of urokinase. The 2 groups were monitored by TCD from before until 2 h after thrombolysis, and the hemodynamic changes and infarct size were recorded.

Results

The urokinase alone group had 1 case of complete recanalization and 4 cases of partial recanalization (recanalization rate, 31.3%). The urokinase plus microbubble group had 3 cases of complete recanalization and 6 cases of partial recanalization (recanalization rate, 56.3%). The average size of the infarction foci was 13.9% in the urokinase group and 9.1% in the urokinase plus microbubble group (P = 0.025). Pathological examination revealed no cerebral hemorrhage in either group.

Conclusions

The addition of microbubbles enhanced the effects of transcranial Doppler ultrasound-assisted urokinase thrombolysis.     

Pharmacotherapy impacts functional connectivity among affective circuits during response inhibition in pediatric mania

Objective

The aim of the current study was to determine the influence of implicated affective circuitry disturbance in pediatric bipolar disorder (PBD) on behavioral inhibition. The differential influence of an antipsychotic and an anti-epileptic medication on the functional connectivity across affective and cognitive neural operations in PBD was examined.

Methods

This was a six-week double blind randomized fMRI trial of risperidone plus placebo vs. divalproex plus placebo for patients with mania (n = 22; 13.6 ± 2.5 years). Healthy controls (HC; n = 14, 14.5 ± 2.8 years) were also scanned for normative comparison. Participants performed a response inhibition fMRI task where a motor response, already ‘on the way’ to execution, had to be voluntarily inhibited on trials where a stop signal was presented. Independent component analysis was used to map functional connectivity across the whole brain.

Results

While there were no behavioral differences between the groups at pre- or post-drug trial, there was significant improvement on manic symptoms in the patient groups. All participants engaged an evaluative affective circuit (EAC: bilateral inferior frontal gyrus, middle frontal gyrus, anterior cingulate cortex (ACC), middle temporal gyrus, insulae, caudate and putamen) and a reactive affective circuit (RAC: bilateral occipital cortex, amygdala, medial frontal gyrus and insula) during task performance. Within the EAC, post-treatment and relative to HC, greater engagement was seen in left insula in risperidone group and left subgenual ACC in divalproex group. Within the RAC, greater baseline amygdala connectivity in patients did not alter with treatment.

Conclusion

EAC and RAC are two key circuits that moderate emotional influence on response inhibition in PBD. Risperidone and divalproex differentially engage the EAC. Limited change in amygdala activity with treatment in all patients indicates a likely trait deficit in PBD.     

Differences in findings of nocturnal polysomnography and multiple sleep latency test between narcolepsy and idiopathic hypersomnia

Objectives

To compare differences in nocturnal and daytime polysomnographic findings between narcolepsy (NA) with and without cataplexy (CA) and idiopathic hypersomnia without long sleep time (IHS w/o LST).

Methods

Nocturnal polysomnography (n-PSG) and multiple sleep latency test (MSLT) findings were compared among subjects with NA with CA (n = 52), NA without CA (n = 62), and IHS w/o LST (n = 50).

Results

The NA with CA group had significantly more disrupted and shallower nocturnal sleep than the other groups. On MSLT, the IHS w/o LST group had significantly longer sleep latency (SL) compared with the two NA groups. The latter two groups did not show statistical differences in diurnal variation of SL.

Conclusions

The IHS w/o LST group had milder objective daytime sleepiness compared with the NA groups. In patients with NA, nocturnal sleep disturbances appeared only in cases with CA, despite a similar trend in diurnal changes in sleep propensity between the two NA groups.

Significance

Objective nocturnal sleep disturbances are specific to NA patients with CA, whereas diurnal variations of sleep propensity are observed irrespective of the presence of CA among NA patients. These findings could be helpful for choosing optimal treatment plans for patients with these disorders.     

Efficacy and bleeding risk of antithrombin supplementation in septic disseminated intravascular coagulation: A prospective multicenter survey

Introduction

Although supplementation with antithrombin (AT) concentrates has been widely accepted for the treatment of disseminated intravascular coagulation (DIC) in Japan, the effects and adverse effects have not been investigated.

Materials and Methods

We conducted a nonrandomized multi-institutional survey. A total of 729 septic DIC patients with AT activity levels of 70% or lower, who had undergone AT substitution at either 1500 IU/day or 3000 IU/day for consecutive 3 days were analyzed. Of these, 650 and 79 patients had received 1500 IU/day (AT1500 group) and 3000 IU/day (AT3000 group), respectively.

Results

Bleeding events were observed in 6.52% of patients (severe bleeding, 1.71%). A significant decrease in initial AT level (below 50%) was observed in 69.6% of patients in AT3000 group and 48.2% in AT1500 group, and this difference was significant (P < 0.01). A logistic-regression analysis conducted using age, gender, body weight, initial AT activity, and supplemented AT dose, revealed that higher initial AT activity (odds ratio (OR), 1.032; P < 0.001), AT dose of 3000 IU/day (OR, 1.912; P = 0.026), and age (OR, 0.985; P = 0.023) were significant factors for improved survival.

Conclusion

The risk of severe bleeding is less than 2%, and concomitant administration of heparin did not increase the risk. The survival in AT1500 group was 65.2%, while that in AT3000 group was 74.7%.     

The interplay of cannabinoid and NMDA glutamate receptor systems in humans: preliminary evidence of interactive effects of cannabidiol and ketamine in healthy human subjects

Background

Interactions between glutamatergic and endocannabinoid systems may contribute to schizophrenia, dissociative states, and other psychiatric conditions. Cannabidiol (CBD), a cannabinoid-1/2 (CB1/2) receptor weak partial agonist or antagonist, may play a role in the treatment of schizophrenia.

Objective

This study tested the hypothesis that CBD would attenuate the behavioral effects of the NMDA receptor antagonist, ketamine, in healthy human subjects.

Methods

Ten male healthy volunteers were evaluated twice in a randomized order. In both sessions they received ketamine (bolus of 0.26 mg/kg/1 min followed by IV infusion of 0.25 mg/kg over 30 min) preceded by either CBD (600 mg) or placebo. Psychopathology was assessed using the Brief Psychiatric Rating Scale (BPRS) and the CADSS (Clinician Administered Dissociative States Scale) at regular intervals from 30 min before to 90 min after ketamine administration.

Results

CBD significantly augmented the activating effects of ketamine, as measured by the activation subscales of the BPRS. However, CBD also showed a non-significant trend to reduce ketamine-induced depersonalization, as measured by the CADSS.

Conclusion

These data describe a complex pattern of psychopharmacologic interactions between CBD and ketamine at the doses of each agent studied in this experiment.     

Effect of pramipexole on cutaneous-silent-period parameters in patients with restless legs syndrome

Objective

The aim of this study was to investigate cutaneous-silent-period (CSP) parameters in patients with restless legs syndrome (RLS) and examine the effects of treatment on CSP which, to our knowledge, have not been investigated till date.

Methods

A total of 25 patients with RLS and 25 healthy volunteers were studied. CSP latency and duration in the upper and lower extremities were examined in the two groups. In RLS patients, the variables were examined before and after pramipexole treatment.

Results

Lower-extremity CSP latency was longer (106.22 ± 11.69 ms vs. 91.67 ± 8.53 ms; p < 0.001) and CSP duration was shorter (35.50 ± 10.91 ms vs. 49.47 ± 6.43 ms; p < 0.001) in patients, compared with controls. In the patient group, CSP durations in the upper (40.88 ± 7.95 ms vs. 46.84 ± 10.22 ms; p = 0.006) and lower extremities (35.50 ± 10.91 ms vs. 44.91 ± 6.43 ms; p = 0.005) were prolonged after treatment, compared with pre-treatment values.

Conclusions

Small-fibre neuropathy may exist in RLS. In addition, we suggest that pramipexole may regulate cortical and spinal inhibitory mechanisms.

Significance

The use of CSP may aid in the diagnosis of RLS and may be used as a measure of treatment effectiveness.     

Anterior cingulate proton spectroscopy glutamate levels differ as a function of smoking cessation outcome

Background

Cigarette smoking is the leading preventable cause of death. Unfortunately, the majority of smokers who attempt to quit smoking relapse within weeks. Abnormal dorsal anterior cingulate cortex (dACC) function may contribute to tobacco smoking relapse vulnerability. Growing evidence suggests that glutamate neurotransmission is involved in mediating nicotine dependence. We hypothesized that prior to a cessation attempt, dACC glutamate levels would be lower in relapse vulnerable smokers.

Methods

Proton magnetic resonance spectra (MRS) were obtained from dACC and a control region, the parieto-occipital cortex (POC), using two-dimensional J-resolved MRS at 4 T and analyzed using LCModel. Nine nicotine-dependent women were scanned prior to making a quit attempt. Subjects then were divided into two groups; those able to maintain subsequent abstinence aided by nicotine replacement therapy (NRT) and those who slipped while on NRT (smoked any part of a cigarette after attaining at least 24 h of abstinence).

Results

Slip subjects exhibited significantly reduced dACC MRS glutamate (Glu/Cr) levels (p < 0.03) compared to abstinent subjects. This effect was not observed in the POC control region.

Conclusions

Our preliminary findings suggest that dACC Glu levels as measured with MRS may help identify and/or be a biomarker for relapse vulnerable smokers. Future research following up on these findings may help clarify the role of dACC Glu in smoking dependence that may lead to new treatment strategies.