Divalproex in the treatment of posttraumatic stress disorder: a randomized, double-blind, placebo-controlled trial in a veteran population

OBJECTIVE: To evaluate the efficacy of divalproex for the treatment of posttraumatic stress disorder (PTSD) hyperarousal symptom cluster. METHOD: Under double-blind conditions, 85 US military veterans with PTSD were randomized to treatment with divalproex or placebo for 8 weeks. All patients who received at least 1 dose of medication and 1 postbaseline assessment (n = 82) were included in the efficacy population. The primary outcome measure was the hyperarousal subscale of the Clinician-Administered PTSD Scale. RESULT: There were no significant intergroup differences in primary or secondary end points. The final mean (SD) divalproex dose and serum valproic acid level were 2309 +/- 507 mg/d and 82 +/- 30 mg/L, respectively. CONCLUSIONS: Divalproex monotherapy was not effective in the treatment of chronic PTSD in predominantly older male combat veterans. Further study is needed to determine the efficacy of divalproex in the management of PTSD in women or civilians or in combination with antidepressants.     

Adjunctive risperidone in the treatment of generalized anxiety disorder: a double-blind, prospective, placebo-controlled, randomized trial

Background:Residual symptoms despite treatment are common in generalized anxiety disorders (GAD). The Patient-Rated Troubling Symptoms for Anxiety (PaRTS-A) is a newly created and validated instrument that measures the symptoms most troublesome to each individual patient and was used to test the hypothesis that adjunctive risperidone improves residual GAD symptoms. Methods: Primary care and psychiatry clinicians enrolled adults (n = 417) with GAD and a Clinical Global Impressions of Severity rating >/=4 despite >/=8 weeks of anxiolytic treatment. Subjects were randomized to adjunctive risperidone or placebo. The primary endpoint was change from baseline to week 4 endpoint in PaRTS-A. Results: Improvement from baseline to week 4 endpoint in PaRTS-A total score (mean +/-SE) was similar between treatment groups (-8.54 [0.63] and -7.61 [0.64] for adjunctive risperidone and placebo, respectively; P = .265). Patients in each treatment group exhibited significant improvements from baseline in nearly all patient- and clinician-rated measures. A post-hoc analysis of PaRTS-A symptoms of moderate to severe severity at baseline suggested greater improvement with risperidone than placebo (P = .04). Headache, weight increase, and increased appetite were the most frequently reported adverse events in both groups. Conclusions: Residual GAD symptoms assessed by the PaRTS-A improved with either adjunctive risperidone or placebo. Alternative analyses or scoring approaches may improve the ability of the PaRTS-A to provide clinically meaningful information on patient-rated symptoms. Further exploration of the benefits of risperidone in patients with more severe GAD may be indicated.     

Celecoxib as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial

Rational

Autism is associated with activation of the inflammatory response system.

Objective

This study aims to assess the efficacy of a cyclooxygenase-2 inhibitor, celecoxib, as adjunctive therapy in the treatment of autism

Methods

In a 10-week randomized double-blind placebo-controlled study, 40 outpatient children with a Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision clinical diagnosis of autism were randomly allocated to celecoxib plus risperidone or placebo plus risperidone. The dose of risperidone and celecoxib were titrated up to 3 and 300 mg/day, respectively. Patients were assessed at baseline and after 2, 4, 6, and 10 weeks of starting medication using the Aberrant Behavior Checklist-Community (ABC-C) Rating Scale. Primary outcome measure was the change in irritability subscale of ABC-C.

Results

Significant time?×?treatment interaction was observed for Irritability (F (1.658, 63.021)?=?13.580, P?<?0.001), Lethargy/Social Withdrawal (F (1.948, 74.032)?=?16.811, P?<?0.001), and Stereotypic Behavior (F(1.742, 66.198)?=?12.104, P?<?0.001), but not for Hyperactivity/Noncompliance (F (2.564, 97.424)?=?1.469, P?=?0.232), and Inappropriate Speech subscales (F (1.607, 61.075)?=?0.173, P?=?0.794). By week 10, patients in the celecoxib group showed significantly greater improvement in the Irritability (P?<?0.001), Lethargy/Social Withdrawal (P?<?0.001), and Stereotypic Behavior (P?<?0.00) but not in Hyperactivity/Noncompliance (P?=?0.202) and Inappropriate Speech (P?=?0.802) subscales than the placebo group. Complete response was achieved by four (20 %) patients in the placebo group and 11 (55 %) patients in the celecoxib group (χ ² (1)?=?5.227, P?=?0.022). Frequency of side effects was similar between the two groups.

Conclusions

Combination of risperidone and celecoxib was superior to risperidone alone in treating irritability, social withdrawal, and stereotypy of children with autism. (Registration, www.irct.ir; IRCT138711091556N2)     

A randomized, double-blind, placebo-controlled trial of augmentation topiramate for chronic combat-related posttraumatic stress disorder

BACKGROUND: Topiramate, a novel anticonvulsant, has been reported to rapidly reduce symptoms of posttraumatic stress disorder (PTSD) in an open-label trial. The present study was designed as a test of topiramate's efficacy as adjunctive therapy in a 7-week, randomized, double-blind, placebo-controlled trial. METHODS: Forty male veterans with PTSD in a residential treatment program were randomized to flexible-dose topiramate or placebo augmentation. The primary outcome measures were PTSD symptom severity and global symptom improvement. RESULTS: Baseline Clinician-Administered PTSD Scale scores were 62.1 +/- 13.9 for placebo and 61.0 +/- 22.2 for topiramate. There was a high dropout rate from the study (55% topiramate; 25% placebo), with 40% of topiramate and 10% of placebo dropping because of adverse events (AEs). No significant treatment effects of topiramate versus placebo were observed for the primary treatment outcomes. Subjects reporting central nervous system-related AEs and with higher baseline severity of depression were more likely to discontinue because of AEs. CONCLUSIONS: Primary outcome measures failed to demonstrate a significant effect for topiramate over placebo; however, high dropout rate in the treatment group prohibits definitive conclusions about the efficacy of topiramate in this population.     

Changes in cognitive functioning with risperidone and olanzapine treatment: a large-scale,double-blind,randomized study

Objective The effects of risperidone and olanzapine on cognitive functioning in patients with schizophrenia were compared in a randomized, double-blind trial. Method Three hundred and seventy-seven patients were randomly assigned to receive 2–6 mg/day of risperidone or 5–20 mg/day of olanzapine for 8 weeks. Cognitive function was assessed with a focused cognitive assessment battery; in addition, extrapyramidal symptoms were assessed using the extrapyramidal symptom rating scale (ESRS), and the positive and negative syndrome scale (PANSS) was rated for all patients. Results Treatment with these two atypical antipsychotic medications was associated with improved performance on the Wisconsin card sorting test, the trail-making test, the California verbal learning test, the continuous performance test, and some aspects of verbal fluency and spatial working memory. No differences in the effects of the drugs on any of the cognitive tests were noted. Correcting for the effects of anticholinergic treatment did not alter the magnitude of cognitive effects. Conclusions Atypical antipsychotic treatment is associated with wide-ranging benefits on cognitive functioning. Previous reports of greater benefits of olanzapine over risperidone in a small-sample pilot study were not substantiated. These results are not due in general to changes in clinical symptoms or movement disorders, suggesting a direct effect of atypical antipsychotic medications on cognitive deficits in schizophrenia.     

Adjunctive azapirone for schizophrenia: A meta-analysis of randomized,double-blind,placebo-controlled trials

Azapirones, which are serotonin_1A (5-HT_1A) receptor partial agonists, have been used as an adjunctive treatment for schizophrenia with mixed results. This is a meta-analysis of the efficacy and tolerability of azapirones for schizophrenia based on randomized, double-blind, placebo-controlled trials (RCTs). English and Chinese databases were systematically and independently searched by two investigators. Data were extracted and analyzed using the RevMan software (version 5.3). Seven RCTs (n = 368) of azapirones (buspirone in 6 RCTs and tandospirone in 1 RCT) were identified and analyzed. Only adjunctive buspirone outperformed placebo regarding total psychopathology [standardized mean difference: ?1.03 (95% confidence interval (CI): ?1.91, ?0.15), P = 0.02; I² = 92%], but the significance disappeared in sensitivity analysis after removing two outlying studies, and in 10 of the 12 subgroup analyses. In 5 RCTs examining neurocognitive function of azapirones, only 2 RCTs found the superiority of buspirone in improving attention/speeded motor performance, verbal and performance intelligence. Adjunctive buspirone outperformed placebo regarding extrapyramidal symptoms [SMD:-0.51, (95%CI: ?0.99, ?0.02), P = 0.04; I² = 0%]. Similar rates of discontinuation [risk ratio:1.06 (95%CI:0.54, 2.07), P = 0.86, I² = 0%] and adverse drug reactions were found between both groups. Adjunctive buspirone and tandospirone failed to show efficacy for psychotic symptoms, but adjunctive buspirone may be associated with improvement in extrapyramidal symptoms and cognitive deficits in schizophrenia. Due to the preliminary nature of this meta-analysis, larger sample size and higher quality RCTs are needed to confirm these finding.     

Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: a double-blind,randomized, placebo-controlled multi-center clinical trial

This study tested the efficacy of repeated intravenous ketamine doses to reduce symptoms of posttraumatic stress disorder (PTSD). Veterans and service members with PTSD (n = 158) who failed previous antidepressant treatment were randomized to 8 infusions administered twice weekly of intravenous placebo (n = 54), low dose (0.2 mg/kg; n = 53) or standard dose (0.5 mg/kg; n = 51) ketamine. Participants were assessed at baseline, during treatment, and for 4 weeks after their last infusion. Primary analyses used mixed effects models. The primary outcome measure was the self-report PTSD Checklist for DSM-5 (PCL-5), and secondary outcome measures were the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and the Montgomery Åsberg Depression Rating Scale (MADRS). There were no significant group-by-time interactions for PTSD symptoms measured by the PCL-5 or CAPS-5. The standard ketamine dose ameliorated depression measured by the MADRS significantly more than placebo. Ketamine produced dose-related dissociative and psychotomimetic effects, which returned to baseline within 2 h and were less pronounced with repeated administration. There was no evidence of differential treatment discontinuation by ketamine dose, consistent with good tolerability. This clinical trial failed to find a significant dose-related effect of ketamine on PTSD symptoms. Secondary analyses suggested that the standard dose exerted rapid antidepressant effects. Further studies are needed to determine the role of ketamine in PTSD treatment. ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT02655692","term_id":"NCT02655692"}}NCT02655692.Subject terms: Drug development, Trauma     

Low-dose risperidone augmentation of fluvoxamine treatment in obsessive-compulsive disorder: a double-blind, placebo-controlled study.

According to previous data, the addition of risperidone in obsessive-compulsive patients refractory to serotonin reuptake inhibitors (SRIs) is shown to be a safe and effective treatment strategy. The aims of our study were to evaluate the efficacy of risperidone addition, in comparison to placebo, in fluvoxamine-refractory obsessive-compulsive patients and to investigate whether risperidone could boost the efficacy of fluvoxamine in fluvoxamine-responder patients. Subjects were 45 obsessive-compulsive inpatients, consecutively recruited at the Department of Neurosciences at the San Raffaele Hospital, Milan. Thirty-nine patients completed the study. All patients received 12 weeks of a standardized open-label fluvoxamine monotherapy and then continued for 6 weeks with placebo or risperidone in a double-blind design. Results showed a significant effect of risperidone addition, at the end of the double-blind phase (18th week), only for fluvoxamine-refractory patients. Five patients on risperidone (50%) and two (20%) on placebo became responders, with a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) decrease > or =35%. Risperidone was generally well tolerated, except for a mild transient sedation and a mild increase in appetite. This preliminary study suggests that even very low (0.5 mg) risperidone doses are effective in OC patients who were nonresponders to a standardized treatment with fluvoxamine.     

Efficacy of olanzapine and risperidone in schizophrenia: a randomized double-blind crossover design

This article compares the efficacy of olanzapine and risperidone for positive and negative symptoms using an 18-week, randomized, double-blind, crossover design. The hypotheses were that olanzapine would be more efficacious for treating negative symptoms, and that risperidone would be superior in treating positive symptoms. Positive and negative symptoms scores improved throughout treatment, regardless of medication type. Differences between the medications were found for negative and general psychopathology rating scales. Overall, olanzapine led to greater improvements in negative symptoms than did risperidone. When each scale was analyzed individually, greater improvements were found for olanzapine on Positive and Negative Symptoms Scale (PANSS) General,PANSS total, and Scale for the Assessment of Negative Symptoms (SANS)attention. A nearly significant trend favoring olanzapine was found for the Calgary Depression Scale. Several negative symptom subscales followed a nonsignificant trend toward olanzapine being more efficacious than risperidone.Thus, there was a very consistent pattern of greater efficacy for olanzapine, particularly for negative symptoms. Despite the small number of subjects, this study shows the potential of a within-subject design to elucidate differences in efficacy.     

Effects of the atypical antipsychotics olanzapine and risperidone on plasma prolactin levels in male rats: a comparison with clinical data

Rationale Hyperprolactinaemia is a common side effect of antipsychotic treatment and the clinical consequences associated with this, e.g. sexual dysfunction, can have a negative impact on patient compliance. Objectives The aim of this study was to investigate the effect of the atypical antipsychotics olanzapine and risperidone on prolactin levels in rats using different treatment regimes and to compare these data with those reported clinically. Methods: All experiments were carried out in male CD rats. In separate studies, the effects of acute, sub-chronic (7 days) and chronic (28 days) olanzapine and risperidone administration on prolactin levels were determined. Further studies investigated the time course of the prolactin response following olanzapine and risperidone treatment over 24 h. Results Both drugs significantly increased prolactin levels in a similar manner following acute administration, in keeping with clinically reported data. However, this elevation was still present following sub-chronic and chronic treatment, contrasting with clinical data with respect to olanzapine but not risperidone. Over 24 h, olanzapine demonstrated a more transient elevation of prolactin levels, whereas risperidone caused a robust and persistent increase in prolactin up to 24 h post-dose, closely mimicking clinical results. Conclusions The present study has demonstrated that olanzapine and risperidone display similar effects on prolactin levels in the rat following acute and chronic administration but differ in their prolactin response over a 24-h period. In conclusion, prolactin levels in rats following atypical antipsychotic treatment may not be fully predictive of the clinical situation.     

A double-blind,randomized, placebo-controlled,multi-center study of brofaromine in the treatment of post-traumatic stress disorder

A large multi-center, double-blind, parallel trial to assess the efficacy of brofaromine in the treatment of post traumatic stress disorder (PTSD) failed to show a significant difference between the brofaromine and placebo treatment groups. The placebo response rate in this study was higher than that in previously published double-blind, placebo-controlled studies of PTSD.     

Differential rates of treatment discontinuation in clinical trials as a measure of treatment effectiveness for olanzapine and comparator atypical antipsychotics for schizophrenia

Antipsychotic treatment discontinuation can be used to measure overall treatment effectiveness. Our goal was to investigate differential treatment discontinuation comparing olanzapine with other atypical antipsychotics. A post hoc pooled analysis of 4 randomized, double-blind, 24- to 28-week schizophrenia clinical trials included 822 olanzapine-treated and 805 risperidone-, quetiapine-, or ziprasidone-treated patients. A checklist was used to record the reason for discontinuation. Treatment differences were assessed between olanzapine and the other 3 antipsychotics combined. Poor response/symptom worsening was the primary reason for discontinuation, regardless of medication. The rate of discontinuation due to poor response/symptom worsening significantly varied by treatment (olanzapine, 14.23%, vs. other atypical antipsychotics, 24.60%; P < 0.0001). The rate of discontinuation due to intolerability of medication did not significantly vary by treatment (olanzapine, 5.60%, vs. other atypical antipsychotics, 7.45%; P = 0.13). Consequent to the differential rates of discontinuation due to poor response/symptom worsening, the olanzapine-treated patients experienced a significantly greater likelihood of overall treatment completion (53.9% vs. 39.3%; P < 0.001) and a significantly longer duration of treatment (19.1 vs. 16.1 weeks; P < 0.0001) than other atypical-treated patients. The predominant reason for the significantly lower discontinuation rate of treatment for patients taking olanzapine compared with that of patients taking other atypical antipsychotics was the significantly higher dropout rates in other atypical antipsychotics because of poor response/symptom worsening.     

The efficacy of selective serotonin reuptake inhibitors in adult social anxiety disorder: a meta-analysis of double-blind, placebo-controlled trials

Social anxiety disorder is associated with impairment in social and occupational functioning, significant personal distress and a possible economic burden, resulting in a reduction in quality of life. To understand better the efficacy of selective serotonin reuptake inhibitors in social anxiety disorder, randomized, double-blind, placebo-controlled trials were evaluated. Pubmed and PsychINFO electronic databases were searched for social anxiety disorder, social phobia, selective serotonin reuptake inhibitors, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline. Fifteen published, randomized, double-blind, placebo-controlled trials of selective serotonin reuptake inhibitors in social anxiety disorder were identified. Design, subject number, drug and dose, trial length, rating instruments, and baseline and end point data were extracted and then verified independently by a second investigator. Effect sizes were calculated from mean changes in drug and placebo groups in the Liebowitz Social Anxiety Scale and the Sheehan Disability Scale, as well as from other scales where available. For the binary data of the Clinical Global Impression of Change scores, Theta log-odds ratios (the effect-size measure appropriate for binary data) were calculated from proportion changes. Effect sizes for the Liebowitz Social Anxiety Scale ranged from -0.029 to 1.214. Effect sizes for the Sheehan Disability Scale ranged from 0.203 to 0.480 for work, 0.237 to 0.786 for social function, and 0.118 to 0.445 for family function. The Theta log-odds ratios for Clinical Global Impression of Change scores ranged from 0.644 to 3.267. Consistent with previous studies, selective serotonin reuptake inhibitors appear more effective than placebo for social anxiety disorder, with improvement extending into social and occupational function.     

Selective serotonin reuptake inhibitors in the treatment of post-traumatic stress disorder: a meta-analysis of randomized controlled trials

Advances in the neurobiology of post-traumatic stress disorder (PTSD) and the availability of modern psychotropics have led to renewed interest in the pharmacotherapy of this disorder. In this paper we focus on trials of the selective serotonin reuptake inhibitors (SSRIs) in PTSD. Studies of the pharmacotherapy of PTSD were identified using methods developed by the Cochrane collaboration. Although a range of open trials of different SSRIs in PTSD show promise, there are few controlled pharmacotherapy studies in this disorder. Nevertheless, pharmacotherapy for PTSD appears to have reasonably robust effects, with odds ratios for responder status, defined as 'much improved' or 'very much improved' on the Clinical Global Impression Scale (CGI), on drug versus placebo varying from 2.2 to 5.6 in randomized controlled trials of different agents. The SSRIs appear both safe and effective for this indication. Additional research with these agents is necessary to clarify many questions, including predictors of response, duration of treatment, comparison with other agents, and integration with psychotherapy. In the interim, however, the SSRIs can be recommended as a first-line medication for the treatment of PTSD.     

Fluvoxamine treatment of generalized social anxiety disorder in Japan: a randomized double-blind, placebo-controlled study

The efficacy of selective serotonin reuptake inhibitors (SSRIs) for the treatment of social anxiety disorder (SAD) has been reported in the USA and Europe. However, no clinical investigation has been done with SSRIs in Japanese patients with SAD. This study was performed to determine the effectiveness and safety of fluvoxamine for generalized SAD (GSAD) in Japanese patients. In this double-blind study, patients meeting DSM-IV criteria for GSAD were randomized to receive treatment with fluvoxamine or placebo for 10 wk. Fluvoxamine treatment was initiated at 50 mg/d, and increased by 50 mg weekly to a maximum of 150 or 300 mg/d. The primary efficacy outcome was mean change from baseline on the Liebowitz Social Anxiety Scale - Japanese Version (LSAS-J) total score. The secondary outcomes were response according to the Clinical Global Impressions - Global Improvement (CGI-I) score and three domains of the Sheehan Disability Scale (SDS; used to assess psychosocial impairment). A total of 176 fluvoxamine-treated patients and 89 placebo-treated patients were eligible for the efficacy analysis. At week 10, the fluvoxamine-treated patients had a significantly greater reduction in the LSAS-J total score compared with placebo-treated patients (p=0.0197), with significantly more fluvoxamine recipients being at least much improved on the CGI-I scale compared with placebo-treated patients (p=0.024). Fluvoxamine-treated patients also had better responses on the SDS compared with placebo-treated patients (p=0.0208). Fluvoxamine was safe and well tolerated. These results suggest that fluvoxamine is effective for the treatment of Japanese patients with GSAD.     

Nitazoxanide in the treatment of viral gastroenteritis: a randomized double-blind placebo-controlled clinical trial

Summary

Background

Enteric viruses including noroviruses and rotavirus are leading causes of diarrhoeal disease and gastroenteritis worldwide, and there is no effective treatment.

Aim

To evaluate nitazoxanide, a thiazolide anti‐infective agent, in treating viral gastroenteritis in adults and adolescents.

Methods

50 out‐patients at least 12 years of age (mean 33.5 years) presenting with diarrhoea and stool‐positive by enzyme‐linked immunosorbent assay for norovirus, rotavirus or adenovirus were enrolled in a double‐blind, placebo‐controlled clinical trial. Patients were randomly assigned either nitazoxanide 500 mg or placebo twice daily for 3 days. The primary end point was time from first dose to resolution of symptoms. Analysis was modified intent‐to‐treat for 45 patients, excluding five patients with other identified enteropathogens at baseline.

Results

The median time from first dose to resolution of symptoms was 1.5 days (IQR: 0.5–2.5) for nitazoxanide‐treated patients and 2.5 days (IQR: 1.5–4.5) for the placebo group. Significant reductions in time to resolution of symptoms were observed for all patients analysed (P < 0.0001) and for subsets of patients with rotavirus (P = 0.0052) and norovirus (P = 0.0295). The number of patients with adenovirus (n = 5) was too small to draw any conclusion. No significant adverse events were reported.

Conclusions

Nitazoxanide may play an important role in managing viral gastroenteritis in adults.

     

Mentha longifolia syrup in secondary amenorrhea: a double-blind,placebo-controlled,randomized trials

Background

Amenorrhea is defined as the cessation of menses. Hormone therapy is the most common treatment. Due to the contraindications and side effects of it and the increasing demand for alternative medicine substitutes, Mentha longifolia L. was used in this study. Mentha longifolia L. is a known medication in Iranian traditional medicine to induce menstrual bleeding in women with secondary amenorrhea and oligomenorrhea.

Methods

A double-blind, randomized, placebo-controlled, multicenter study was conducted in 120 women with secondary amenorrhea and oligomenorrhea. Treatment consisted of sequential oral syrup, 45 ml (15 ml three times a day) for 2 weeks. If the patients did not have menstruation after 2 weeks of taking the medication, we would wait for two more weeks. If the patients had menstruation at each stage of using the drug, we started it one week after the end of menstruation. But if the patients had not menstruate after four weeks (two-week using of drug and waiting for two more weeks), the previous steps were repeated. The drug and placebo were repeated in three cycles of menstruation. Bleeding was documented by the patient on diary cards. The primary outcome variable was the occurrence (yes/no) of bleeding during the first treatment cycle. The secondary efficacy outcome was the regularity of bleeding pattern during the three cycles of the study.

Results

The number of women with bleeding during the first cycle were higher in the drug group as in the placebo group (68.3% vs. 13.6%; p < 0.001). The regularity of bleeding throughout the study was markedly better in the drug group compared with those given placebo (33.3% vs. 3.3%; p < 0.001). No notable complication or side effect was reported in relation to Mentha longifolia L. syrup.

Conclusion

In conclusion, Mentha longifolia L. syrup is a safe, well-tolerated, and effective choice in inducing bleeding and maintaining regular bleeding in women with secondary amenorrhea and oligomenorrhea.