Analysis of clinical symptomatology, extrapyramidal symptoms and neurocognitive dysfunction following dehydroepiandrosterone (DHEA) administration in olanzapine treated schizophrenia patients: a randomized, double-blind placebo controlled trial

Several studies have demonstrated the effective use of dehydroepiandrosterone (DHEA) in the management of mood, however studies of its use in psychosis remain limited. The aim of this study was to investigate for the first time efficacy of DHEA augmentation with standardized antipsychotic medication (olanzapine) and to explore effects of DHEA augmentation on side-effect profiles including weight gain, glucose tolerance, aggression, quality of life and neurocognitive function. Finally, we aimed to analyze any relationship between plasma levels and clinical response to DHEA administration. Forty patients with chronic schizophrenia stabilized on olanzapine were randomized in double-blind fashion to receive either DHEA (titrated up to 150mg) or placebo augmentation for a period of 12-weeks. Blood samples were collected at baseline, mid-study and study completion. Results indicated improvement of negative symptoms (SANS scale) even when baseline scores were controlled as a covariate. Some improvement in Parkinsonism and akathisia compared to baseline was seen in patients receiving DHEA. No change in psychosis as reflected by the PANSS was noted. Patients receiving DHEA appeared to demonstrate relatively stable glucose levels compared to controls at the end of the study. An improvement in cognitive performance (most notably memory), which did not reach significance due to low sample number, was observed following DHEA administration. Results further suggest preliminary evidence of involvement of the neurosteroid system in schizophrenia pathophysiology, and confirm initial "cautious" findings identifying an agent capable of improving negative symptoms and certain features of extrapyramidal side effects.     

A double-blind, randomized, crossover trial of pemoline in fatigue associated with multiple sclerosis.

Fatigue occurs in a majority of patients with MS and is generally independent of measurable neurologic disability. Few options for treatment are available. We conducted a double-blind, placebo-controlled, crossover trial for each of two 4-week treatment periods. Forty-six eligible patients entered and five dropped out due to concurrent exacerbations. Nineteen patients (46.3%) experienced excellent or good relief of fatigue with pemoline, and eight patients (19.5%) with placebo (p = 0.06, Fisher's exact test). One-fourth of patients did not tolerate the drug well, and 7% had to discontinue pemoline during the study due to side effects. The most common side effects were anorexia, irritability, and insomnia. Pemoline may be an effective short-term treatment for fatigue associated with MS, but its adverse effects are not well tolerated by many patients.     

Lovastatin for the adjunctive treatment of schizophrenia: A preliminary randomized double-blind placebo-controlled trial

While statins target many of the pathways to neuroprogression in schizophrenia, the safety and efficacy of statins for treating schizophrenia has never been examined. This is an 8-week randomized double blind controlled clinical trial examining the efficacy and safety of adjunctive lovastatin (20 mg/day) treatment or placebo for people with schizophrenia. The baseline characteristics of the two groups were not different. Endpoint changes in Positive and Negative Syndrome Scale (PANSS) total and subscale scores did not differ between the two groups. However there was a significant difference between the doses of risperidone used in the two groups. The mean dose in the lovastatin and placebo groups were 4.8(1.8) and 3.4(1.4) mg/day, respectively (P<.03). No serious adverse events were reported. Slowness of movements, muscle rigidity, increased appetite, and decreased energy were the most common adverse effects, and these rates did not differ between the two groups. This study failed to demonstrate a benefit of lovastatin on symptoms of schizophrenia. This combination was well tolerated. However, a higher dosage of risperidone was used for treating the disorder in those taking concomitant lovastatin compared to placebo.     

Pregnenolone as an adjunct to risperidone for treatment of women with schizophrenia: A randomized double-blind placebo-controlled clinical trial

There have been few studies of pregnenolone therapy in schizophrenia and those that exist have been subject to several critical limitations, thus yielding inconsistent results. We attempted to assess the therapeutic effect of pregnenolone in a patient sample as homogeneous as possible. In this randomized double-blind clinical trial, 82 female inpatients with chronic schizophrenia, who had discontinued their antipsychotic medications for at least one week in case of any oral antipsychotic medication or a month for any depot antipsychotic medication, received risperidone plus either pregnenolone (50 mg/day) or placebo for 8 weeks. Inclusion criteria were acute illness with a baseline Positive and Negative Syndrome Scale (PANSS) negative subscale score of ≥20. Exclusion criteria were the presence of severe depression or other concomitant psychiatric disorders. Primary outcome was defined as the difference in the PANSS total score change from baseline to week 8 in the pregnenolone group compared to the placebo group. No significant difference was found in the PANSS total score changes between the two arms (mean difference (CI 95%) = −9.41 (−20.24 to 1.41); p = 0.087). Significant differences were initially found for PANSS negative change scores (mean difference (CI 95%) = −2.61 (−5.03 to −0.19); p = 0.035) and general psychopathology change scores (mean difference (CI 95%) = −5.93 (−11.37 to −0.48); p = 0.033). However, these findings did not survive Bonferroni correction for multiple testing. While this trial may suggest a potential effect of pregnenolone on schizophrenia symptoms, further studies are warranted.     

Neurocognitive effects of adjunctive levetiracetam in children with partial-onset seizures: A randomized, double-blind, placebo-controlled, noninferiority trial

Purpose : Evaluate potential neurocognitive effects of adjunctive levetiracetam in children with inadequately controlled partial‐onset seizures (POS). Methods : Randomized, double‐blind, placebo‐controlled, noninferiority safety study. Children (4–16 years; IQ ≥65) with ≥1 POS during 4 weeks before screening despite taking 1–2 antiepileptic drugs (AEDs) were randomized (2:1) to levetiracetam (20–60 mg/kg/day) or placebo for 12 weeks. Results : Ninety‐nine patients were randomized with 98 (levetiracetam 64, placebo 34) in intent‐to‐treat (ITT) and 73 (levetiracetam 46, placebo 27) in per protocol (PP) populations. Primary cognitive assessment was the Leiter International Performance Scale–Revised Attention and Memory Battery with the memory screen composite score change from baseline as the primary endpoint. PP Least Square Mean [LSM (standard error)] were 5.36 (1.78) for levetiracetam; 5.17 (2.33) for placebo; difference [two‐sided 90% confidence interval (CI)] 0.19 (?4.69, 5.08). Levetiracetam was noninferior to placebo because the 90% CI lower bound was greater than the defined noninferiority margin (?9.0). There were no statistically significant differences between groups in Wide Range Assessment of Memory and Learning‐2 indexes and Leiter‐R Examiner’s Rating Scale scores. Median reductions from baseline in weekly POS frequency were 91.5% versus 26.5% for levetiracetam versus placebo; ≥50% responder rates: 62.5% versus 41.2%; seizure freedom rates: 46.9% versus 8.8% (ITT). Adverse events were reported by 89.1% levetiracetam‐treated and 85.3% placebo‐treated patients; those reported by ≥10% levetiracetam patients and more often with levetiracetam were headache, nasopharyngitis, fatigue, vomiting, somnolence, and aggression. Discussion : Neurocognitive effects were no different in pediatric patients with POS treated with adjunctive levetiracetam or placebo. Levetiracetam was effective and well tolerated.     

米诺环素辅助治疗早期精神分裂症阴性症状的双盲、随机、对照研究

目的探讨米诺环素辅助治疗精神分裂症患者阴性症状的效果及耐受性。方法将92例符合《精神疾病诊断与统计手册》(DSM-IV)诊断标准、以阴性症状为主且单一利培酮治疗的精神分裂症患者随机分为米诺环素组(n=46)和安慰剂对照组(n=46),治疗周期为16周。于入组及出组时以阴性症状评定量表(SANS)、阳性和阴性症状量表(PANSS)评定疗效,使用静坐不能量表(Barnes)和锥体外系副反应量表(SAS)评定不良反应。结果米诺环素组在SANS分、PANSS阴性症状分、PANSS总分较安慰剂组相比,减分差异有统计学意义(P0.01);两组间在副反应发生率及脱落率比较差异无统计学意义(P0.05)。结论米诺环素可能有助于改善精神分裂症的阴性症状,且耐受性良好。     

A 12-week, double-blind, placebo-controlled trial of donepezil adjunctive treatment to risperidone in chronic and stable schizophrenia

There is considerable incentive to develop new treatment strategies that effectively target cognitive deficits in schizophrenia. One of the theoretically promising novel treatment candidates is acetylcholinesterase inhibitors that increase the synaptic levels of cholinergic, nicotinic, and muscarinic receptor activity. The purpose of this study was to assess the efficacy of donepezil as an adjuvant agent in the treatment of chronic schizophrenia in particular for cognitive impairments. This investigation was a 12-week, double-blind study of parallel groups of patients with stable chronic schizophrenia. Thirty patients were recruited from inpatient and outpatient departments, age ranging from 22 to 44 years. All participants met DSM-IV-TR. diagnostic criteria for schizophrenia. To be eligible, patients were required to have been treated with a stable dose of risperidone as their primary antipsychotic treatment for a minimum period of 8 weeks. The subjects were randomized to receive donepezil (10 mg/day) or placebo, in addition to risperidone (4–6 mg/day). Clinical psychopathology was assessed with Positive and Negative Syndrome Scale (PANSS). Cognition was measured by a cognitive battery. Patients were assessed by a psychiatrist at baseline and after 8, and 12 weeks after the medication started. The PANSS scores and cognitive performance were used as the outcome measures. The donepezil group had significantly greater improvement in the negative symptoms over the 12-week trial. There were no differences between the donepezil and placebo groups on any neurocognitive assessments at endpoint (week 12). The present study indicates donepezil as a potential adjunctive treatment strategy for negative symptoms of chronic schizophrenia.     

米诺环素辅助治疗精神分裂症阴性症状的效果及对免疫因子的影响

目的探讨米诺环素辅助治疗精神分裂症阴性症状的效果及免疫学机制。方法将92例符合美国《精神疾病诊断与统计手册(第4版)》(DSM-IV)诊断标准、以阴性症状为主且单一利培酮治疗的精神分裂症患者随机分为米诺环素组(n=46)或安慰剂对照组(n=46),治疗周期为16周。于入组及出组时以阴性症状评定量表(SANS)、阳性和阴性症状量表(PANSS)评定疗效,测定治疗前后白介素1-β(IL-1β)、肿瘤坏死因子-α(TNF-α)、一氧化氮(NO)浓度变化。结果 PANSS阴性症状评分和总评分与安慰剂组相比,减分差异有统计学意义(P0.01);两组治疗前后除NO外其余两个因子的浓度变化均无统计学意义(P0.05)。结论米诺环素辅助治疗精神分裂症的阴性症状有效,但作用机制仍不明,是否通过抑制NO浓度的变化尚需进一步的研究。     

A randomised, double-blind, placebo-controlled trial of tropisetron in patients with schizophrenia

Background

Cognitive deficits in schizophrenia are associated with psychosocial deficits that are primarily responsible for the poor long-term outcome of this disease. Auditory sensory gating P50 deficits are correlated with neuropsychological deficits in attention, one of the principal cognitive disturbances in schizophrenia. Our studies suggest that the α7 nicotinic acetylcholine receptor (α7 nAChR) agonist tropisetron might be a potential therapeutic drug for cognitive deficits in schizophrenia. Therefore, it is of particular interest to investigate the effects of tropisetron on the cognitive deficits in patients with schizophrenia.

Methods

A randomised, placebo-controlled trial of tropisetron in patients with schizophrenia was performed. A total of 40 patients with chronic schizophrenia who had taken risperidone (2 to 6 mg/day) were enrolled. Subjects were randomly assigned to a fixed titration of tropisetron (n = 20, 10 mg/day) or placebo (n = 20) in an 8-week double-blind trial. Auditory sensory gating P50 deficits and Quality of Life Scale (QLS), Cambridge Neuropsychological Test Automated Battery (CANTAB), and Positive and Negative Syndrome Scale (PANSS) scores were measured.

Results

In all, 33 patients completed the trial. Tropisetron was well tolerated. Administration of tropisetron, but not placebo, significantly improved auditory sensory gating P50 deficits in non-smoking patients with schizophrenia. The score on the rapid visual information processing (sustained visual attention) task of CANTAB was significantly improved by tropisetron treatment. Total and subscale scores of PANSS were not changed by this trial. QLS scores in the all patients, but not non-smoking patients, were significantly improved by tropisetron trial.

Conclusions

This first randomised, double-blind, placebo-controlled trial supports the safety and efficacy of adjunctive tropisetron for treatment of cognitive deficits in schizophrenia.     

Efficacy of Bach-flower remedies in test anxiety: a double-blind, placebo-controlled, randomized trial with partial crossover

Bach-flower remedies are a type of alternative medication used increasingly for over-the-counter self-help purposes. We studied the efficacy of a combination of Bach-flower remedies in subjects with test anxiety in a randomized, placebo-controlled, blinded parallel group design, with crossing over the placebo group to remedies after the first phase. Anxiety was measured by a standardized, validated test anxiety questionnaire (the German version of the Test Anxiety Inventory, TAI-G). Fifty-five of 61 subjects with self-reported test anxiety gave valid data. There was no significant difference between the groups, but a significant decrease of test anxiety in all groups was present. We conclude that Bach-flower remedies are an effective placebo for test anxiety and do not have a specific effect.     

Fatigue in progressive multiple sclerosis: results of a randomized, double-blind, placebo-controlled, crossover trial of oral 4-aminopyridine.

Previous studies suggest that aminopyridine may play a role in the symptomatic treatment of fatigue in multiple sclerosis. Although the mechanism underlying the beneficial effect on fatigue remains unclear, it has been proposed that aminopyridines may help to improve conduction in demyelinated central pathways, implicating both axonal and synaptic mechanisms. The objective of the present study is to determine whether 4-AP decreases daily-living fatigue in progressive multiple sclerosis. The effect of 4-AP on other neurophysiological and neuropsychological parameters was also considered. A 'double-blind', randomized, 'placebo-controlled', crossover trial was conducted on 54 patients with progressive multiple sclerosis. All patients received treatment with placebo and 32 mg per day of 4-AP, each for 6 months. The main outcome measure was the Fatigue Severity Scale. Secondary measures were EDSS, cognitive functions and neurophysiological parameters. Forty-nine patients (91%) completed the study. Changes in fatigue scores, EDSS and cognitive functions were not significantly different between 4-AP and placebo. However, when patients treated with 4-AP were divided into two groups according to the serum level of 4-AP, a significant effect on fatigue compared with placebo was observed in the 'high level' (>30 ng/ml) group (P=0.05). Synchronization of motor evoked potentials improved during 4-AP with respect to placebo (P=0.019) and this correlated positively with fatigue reduction (P=0.010). No relevant side effects were observed.     

Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial

OBJECTIVE: The authors evaluated the efficacy and safety of augmenting clozapine with risperidone in patients with treatment-resistant schizophrenia. METHOD: In a randomized, double-blind, placebo-controlled 12-week trial, 40 patients unresponsive or partially responsive to clozapine monotherapy received a steady dose of clozapine combined with either placebo (N=20) or up to 6 mg/day of risperidone (N=20). Patient psychopathology was assessed at 2-week intervals with the Brief Psychiatric Rating Scale (BPRS) and the Scale for the Assessment of Negative Symptoms (SANS), among other measures. Movement disorders were assessed with the Simpson-Angus Rating Scale. RESULTS: From baseline to week 6 and week 12, mean BPRS total and positive symptom subscale scores were reduced significantly in both groups, but the reductions were significantly greater with clozapine/risperidone treatment. Reductions in SANS scores were also significantly greater with clozapine/risperidone treatment than with clozapine/placebo. The adverse event profile for clozapine/risperidone treatment was similar to that for clozapine/placebo. Simpson-Angus Rating Scale scores were lower with clozapine/risperidone treatment throughout the trial but increased to approach those of clozapine/placebo treatment at week 12. Clozapine/risperidone treatment did not induce additional weight gain, agranulocytosis, or seizures compared with clozapine/placebo treatment. CONCLUSIONS: In patients with a suboptimal response to clozapine, the addition of risperidone improved overall symptoms and positive and negative symptoms of schizophrenia. The combination appears to be safe and well tolerated. Augmentation of clozapine with risperidone may provide additional clinical benefit for patients who are nonresponsive or only partially responsive to clozapine alone.     

Adjunctive sarcosine plus benzoate improved cognitive function in chronic schizophrenia patients with constant clinical symptoms: A randomised,double-blind,placebo-controlled trial

Objectives Hypofunction of NMDA receptor is implicated in the pathophysiology, particularly cognitive impairment, of schizophrenia. Sarcosine, a glycine transporter I (GlyT-1) inhibitor, and sodium benzoate, a d-amino acid oxidase (DAAO) inhibitor, can both enhance NMDA receptor-mediated neurotransmission. We proposed simultaneously inhibiting DAAO and GlyT-1 may be more effective than inhibition of either in improving the cognitive and global functioning of schizophrenia patients. Methods This study compared add-on sarcosine (2?g/day) plus benzoate (1?g/day) vs. sarcosine (2?g/day) for the clinical symptoms, as well as the cognitive and global functioning, of chronic schizophrenia patients in a 12-week, double-blind, randomised, placebo-controlled trial. Participants were measured with the Positive and Negative Syndrome Scale and the Global Assessment of Functioning Scale every 3 weeks. Seven cognitive domains, recommended by the Measurement and Treatment Research to Improve Cognition in Schizophrenia Committee, were measured at weeks 0 and 12. Results Adjunctive sarcosine plus benzoate, but not sarcosine alone, improved the cognitive and global functioning of patients with schizophrenia, even when their clinical symptoms had not improved. Conclusions This finding suggests N-methyl-d-aspartate receptor-enhancement therapy can improve the cognitive function of patients with schizophrenia, further indicating this pro-cognitive effect can be primary without improvement in clinical symptoms.     

Amisulpride augmentation in patients with schizophrenia partially responsive or unresponsive to clozapine. A randomized, double-blind, placebo-controlled trial

INTRODUCTION: Only limited data are available on the effectiveness of augmented antipsychotics to clozapine therapy in chronic schizophrenia. We conducted a randomized, double-blind, placebo-controlled pilot study to evaluate the efficacy and safety of augmentation with the atypical neuroleptic amisulpride to clozapine in a small sample group of patients. METHODS: 16 patients with the DSM-IV diagnosis of chronic schizophrenia and partially responsive to clozapine participated in this pilot study. Patients on a steady dose of clozapine randomly received either clozapine and amisulpride 400 mg/day (n=7) or clozapine and amisulpride 600 mg/day (n=6) or clozapine and placebo for 6 weeks (n=3). Efficacy measures were BPRS, CGI, GAF and MADRS score. Side effects and prolactin levels were obtained. Primary outcome measure were BPRS score changes. RESULTS: The beneficial effect of augmented amisulpride at a daily dose of 600 mg was observed in the mean scores of secondary outcome measures, as assessed by GAF, CGI and MADRS. Measures of primary objectives failed to improve significantly. No reduction in BPRS total score was achieved due to lack of power of the study, whereas the BPRS subscore "activity" had a tendency to improve. Amisulpride was more beneficial in a higher than a lower dose. No severe side-effects occurred, but tremor, bradykinesia, akathisia and elevated prolactin levels were recorded. DISCUSSION: Augmented amisulpride improved the global outcome of patients suffering from chronic schizophrenia in this pilot study and tended to be a helpful treatment option in cases of partial or non-responsiveness to clozapine. Limitations emerge from the small sample size and lack of power. Further investigation requires a larger number of patients to be included.     

A randomized, double-blind placebo-controlled trial of moclobemide in patients with chronic fatigue syndrome

BACKGROUND: Chronic fatigue syndrome is characterized by prolonged and disabling fatigue and a range of neuropsychiatric symptoms including depressed and/or irritable mood. To date, no medical or psychotropic therapies have provided clear symptomatic benefit. METHOD: Ninety patients with chronic fatigue syndrome, diagnosed with our system that approximates CDC criteria, participated in a randomized, placebo-controlled, double-blind trial of 450 to 600 mg/day of moclobemide, a novel reversible inhibitor of monoamine oxidase-A. RESULTS: Fifty-one percent (24/47) of patients receiving moclobemide improved compared with 33% (14/43) of patients receiving placebo (odds ratio = 2.16, 95% confidence interval [CI] = 0.9 to 5.1). Drug response was best characterized symptomatically by an increase in the subjective sense of vigor and energy rather than a reduction in depressed mood. The effect of moclobemide on subjective energy was detectable within the first 2 weeks of treatment and increased across the course of the study. The greatest reduction in clinician-rated disability was in patients with concurrent immunologic dysfunction (mean difference in standardized units of improvement = 0.8, 95% CI = 0.03 to 1.6). CONCLUSION: Moclobemide produces some improvement in key symptoms experienced by patients with chronic fatigue syndrome. This effect is not dependent on the presence of concurrent psychological distress and is likely to be shared with other monoamine oxidase inhibitors.     

A placebo-controlled, double-blind, randomized, two-center, pilot trial of Cop 1 in chronic progressive multiple sclerosis

We found Cop 1 to be effective and relatively safe in a previous (exacerbating-remitting) clinical trial. This current trial involves 106 chronic-progressive patients. The major end point, confirmed progression of 1.0 or 1.5 units (depending on baseline disability) on the Kurtzke Expanded Disability Status Scale, was observed in nine (17.6%) treated and 14 (25.5%) control patients. The differences between the overall survival curves were not significant. Progression rates at 12 and 24 months were higher for the placebo group (p = 0.088) with 2-year probabilities of progressing of 20.4% for Cop 1 and 29.5% for placebo. We found a significant difference at 24 months between placebo and Cop 1 at one but not the other center. Two-year progression rates for two secondary end points, unconfirmed progression, and progression of 0.5 EDSS units, (p = 0.03) are significant.     

银杏叶提取物结合氟哌啶醇治疗慢性精神分裂症的双盲对照研究

目的探讨银杏叶提取物结合氟哌啶醇对慢性精神分裂症的治疗作用。方法采用随机、双盲、空白对照法，用银杏叶提取物３６０ｍｇ／ｄ结合氟哌啶醇（０２５ｍｇ／ｋｇ）对１１２例慢性精神分裂症患者进行治疗１２周，在治疗前后评定ＢＰＲＳ、ＳＡＰＳ、ＳＡＮＳ和ＴＥＳＳ量表。结果银杏叶提取物结合氟哌啶醇治疗慢性精神分裂症的疗效比单用氟哌啶醇要好，前者ＢＰＲＳ、ＳＡＰＳ和ＳＡＮＳ量表总分明显降低，而后者仅ＢＰＲＳ量表总分明显降低；同时前者治疗后ＳＡＰＳ量表评分显著低于后者；银杏叶提取物具有减轻氟哌啶醇锥体外系和行为毒性副反应的作用。结论银杏叶提取物可提高抗精神病药治疗慢性精神分裂症的疗效，并减轻抗精神病药副作用。     

A randomized, double-blind, placebo-controlled trial of donepezil to improve memory in epilepsy

PURPOSE: To determine whether an acetylcholinesterase inhibitor, such as donepezil, would improve memory or other cognitive/psychological functions in epilepsy patients with subjective memory complaints. METHODS: Twenty-three epilepsy patients with subjective memory difficulty were randomized to either 3 months of donepezil (10 mg/day) or 3 months of placebo treatment, and then crossed over to the other treatment arm. Patients and physicians were blinded to treatment phase throughout data acquisition. Assessment of memory and other cognitive functions, subjective memory, mood, and self-rated quality of life (QOL) and social functioning was performed at baseline and following completion of both treatment phases. Seizure frequency and severity as well as treatment emergent adverse effects were also monitored. RESULTS: Donepezil treatment was not associated with improvement in memory or other cognitive functions, mood, social functioning or QOL. Comparable increases in self-rated memory functioning relative to baseline were evident during donepezil and placebo phases. Donepezil treatment was not associated with increased seizure frequency or severity. Similar to group results, analysis of change within individual patients as a function of treatment phase also showed neither significant benefit nor detriment associated with donepezil. CONCLUSION: This study found no benefit on memory or other cognitive/psychological functions in a heterogeneous group of epilepsy patients with subjective memory difficulty. Further investigation would be required to determine whether individual patients, or those with particular epilepsy syndromes, might benefit from donepezil or other acetylcholinesterase inhibitors, or if a higher dosage might be effective.