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.     

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.     

Double-blind placebo-controlled pilot study of sertraline in military veterans with posttraumatic stress disorder

The efficacy of sertraline in the treatment of civilian posttraumatic stress disorder (PTSD) has been established by two large placebo-controlled trials. The purpose of the current pilot study was to obtain preliminary evidence of the efficacy of sertraline in military veterans suffering from PTSD. Outpatient Israeli military veterans with a DSM-III-R diagnosis of PTSD were randomized to 10 weeks of double-blind treatment with sertraline (50-200 mg/day; N = 23, 83% male, mean age = 41 years) or placebo (N = 19, 95% male, mean age = 38 years). Efficacy was evaluated by the Clinician-Administered PTSD Scale (CAPS-2) and by Clinical Global Impression Scale-Severity (CGI-S) and -Improvement (CGI-I) ratings. Consensus responder criteria consisted of a 30% or greater reduction in the CAPS-2 total severity score and a CGI-I rating of "much" or "very much" improved. The baseline CAPS-2 total severity score was 94.3 +/- 12.9 for sertraline patients, which is notably higher than that reported for most studies of civilian PTSD. On an intent-to-treat endpoint analysis, sertraline showed a numeric but not statistically significant advantage compared with placebo on the CAPS-2 total severity and symptom cluster scores. In the study completer analysis, the mean CGI-I score was 2.4 +/- 0.3 for sertraline and 3.4 +/- 0.3 for placebo (t = 2.55, df = 30, p = 0.016), CGI-I responder rates were 53% for sertraline and 20% for placebo (chi2 = 3.62, df = 1, p = 0.057), and combined CGI-I and CAPS-2 responder rates (>or=30% reduction in baseline CAPS-2 score) were 41% for sertraline and 20% for placebo (chi2 = 1.39, df = 1, p = 0.238). Sertraline treatment was well tolerated, with a 13% discontinuation rate as a result of adverse events. This pilot study suggests that sertraline may be an effective treatment in patients with predominantly combat-induced PTSD, although the effect size seems to be somewhat smaller than what has been reported in civilian PTSD studies. Adequately powered studies are needed to confirm these results and to assess whether continued treatment maintains or further improves response.     

A placebo-controlled trial of guanfacine for the treatment of posttraumatic stress disorder in veterans

Preclinical and clinical studies demonstrate a hyperactivity of the norepinephrine system in patients with posttraumatic stress disorder (PTSD). a(2) adrenergic agonists have been shown to ameliorate symptoms of PTSD, likely because of their ability to dampen noradrenergic tone. This study tests the ability of the a(2) adrenergic agonist, guanfacine, to reduce the symptoms of PTSD. Experimental Design: Patients with chronic PTSD were randomized (1:1) to an 8-week double-blind, placebo-controlled treatment of guanfacine followed by a 2 month open label extension phase. Patients were maintained on their stable doses of allowed antidepressants during the trial. Efficacy was measured by the following assessment scales: Clinician Administered PTSD Scale (CAPS), Montgomery Asberg Depression Rating Scale (MADRS), Clinical Global Impression-Severity (CGI-S), Clinical Global Impression-Improvement (CGI-I), and Davidson Trauma Scale (DTS, self-report). Principal Observations: There were no significant differences in the drug versus placebo responses for the clinician-administered or patient self-report outcome measures in this small sample of predominantly male combat veterans with PTSD. However, the medication was well tolerated. Similar to previous findings, this small pilot study failed to show differences in the response to guanfacine versus placebo in a small sample of predominantly male combat veterans with PTSD.     

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.     

The atypical antipsychotics olanzapine and risperidone in the treatment of posttraumatic stress disorder: a meta-analysis of randomized, double-blind, placebo-controlled clinical trials

Posttraumatic stress disorder (PTSD) is a prevalent and disabling mental illness. Small studies found atypical antipsychotics (AAs) to be beneficial in the treatment of patients with PTSD regardless of psychotic symptoms who are unresponsive to conventional pharmacological treatments such as serotonin selective reuptake inhibitors. This study reports the results of a meta-analysis of existing randomized, double-blind, placebo-controlled clinical trials (RCTs) of AAs as a monotherapy or augmentation therapy for the treatment of patients with PTSD. Seven RCTs were identified through extensive scans of databases, which included PubMed, MedLine, the National PTSD Center Pilots database, PsycINFO, Cochrane Central Register of Controlled Trials, and the Abstracts Library of the American Psychiatric Association with predefined inclusion criteria. Dichotomous and continuous measures were performed using a fixed effects model, heterogeneity was assessed, and subgroup analyses were done. Data from seven RCTs involving a total of 192 PTSD patients (102 randomized to AAs and 90 randomized to placebo) were analyzed. The results show that AAs may have a beneficial effect in the treatment of PTSD, as indicated by the changes from baseline in Clinician Administered PTSD Scale total scores [standardized mean difference (SMD)=-0.45, 95% confidence interval (CI) (-0.75, -0.14), P=0.004]. In addition, the overall SMD of the mean changes in the three Clinician Administered PTSD Scale subscores was statistically significant (P=0.007) between AAs and placebo groups, favoring AAs over placebo (SMD=-0.27, 95% CI=-0.47, -0.07). In particular, the symptom of 'intrusion' was mainly responsible for this significance. Clinical significance of the results, however, should be carefully interpreted and translated into clinical practice, given that the quality and availability of currently existing RCTs included in the analysis.     

Enteric-release glyceryl trinitrate in active Crohn's disease: a randomized, double-blind, placebo-controlled trial

BACKGROUND: Mucosal ischaemia may contribute to the pathogenesis of Crohn's disease. Microvascular abnormalities have been found in colonic resection specimens, and mucosal levels of constitutive nitric oxide synthase are reduced. AIM: To assess the efficacy of a novel, enteric-release formulation of the nitric oxide donor, glyceryl trinitrate, aimed at increasing the mucosal circulation and relaxing smooth muscle in the affected bowel. METHODS: The trial was randomized, double-blind and placebo-controlled. Baseline disease activity was assessed by a structured symptom diary, with blood tests and a quality of life assessment. Patients with a Crohn's disease activity index of > or = 150 and < 450 were randomized to receive 12 weeks of either glyceryl trinitrate (initially 6 mg twice daily, increasing to 9 mg twice daily after 6 weeks) or an identical placebo. Assessments were repeated at 6 and 12 weeks. RESULTS: Seventy patients (22 male) entered the study; 34 were given glyceryl trinitrate and 36 placebo. At 12 weeks, there were no differences between the treatment groups in terms of Crohn's disease activity index, pain, stool frequency, inflammatory markers or quality of life scores. CONCLUSIONS: Enteric-release glyceryl trinitrate did not benefit patients with mild to moderately active Crohn's disease. Whilst ischaemia may contribute to the pathogenesis of Crohn's disease, our results fail to provide supportive evidence for this hypothesis.     

Efficacy and tolerability of mirtazapine and sertraline in Korean veterans with posttraumatic stress disorder: a randomized open label trial

BACKGROUND: The aim of this study was to investigate the potential use of mirtazapine in Korean veterans diagnosed with PTSD, by comparing it with sertraline, a drug approved for use in PTSD in the USA. METHODS: Efficacy was evaluated by the clinician administered PTSD scale (CAPS-2), the Hamilton rating scale for depression (HAMD-17) and the clinical global impression scale (CGI), at baseline and at weeks 1, 2 and 6. A response was defined as a > or = 30 % decrease in CAPS-2 total severity, a > or = 50 % decrease in total HAMD-17 score, and a CGI-I score < 3. RESULTS: 51 patients on mirtazapine (mean age/duration of illness: 59.1/33.5 years) and 49 on sertraline (mean age/duration of illness: 60.6/35.6 years) completed the study. The mean daily dosage was 34.1 mg for mirtazapine and 101.5 mg for sertraline. On the CAPS-2 total score more patients responded in the mirtazapine group at week 1 (13 vs 2 %) and week 2 (51 vs 31 %). At week 6 this difference was statistically significant (88 % vs 69 %, p = 0.039) on the CAPS-2 total score. The HAMD-17 total score and CGI-I score decreased in both groups, with no significant differences between th groups on all time points. The main side effects for the mirtazapine group were: dry mouth (19.6 %), constipation (19.6 %), somnolence (15.7 %) and weight gain (1.96 %); and for the sertraline group: indigestion (14.3 %), palpitation (6.1 %), agitation (2.0 %), epigastric soreness (2.0 %), insomnia (2.0 %) and sexual dysfunction (2.0 %). CONCLUSION: Mirtazapine appeared to be an effective and well-tolerated treatment for PTSD in Korean veterans.     

In a double-blind,randomized and placebo-controlled trial,adjuvant allopurinol improved symptoms of mania in in-patients suffering from bipolar disorder

Allopurinol is a drug used primarily to treat hyperuricemia. In patients suffering from acute mania, increased levels of uric acid are observed, and symptom improvements are associated with decreased levels of uric acid. Accordingly, a purinergic dysfunction is plausibly a causative factor in the pathophysiology of mania. The aim of the present study was therefore to investigating whether allopurinol has benefits for patients treated with sodium valproate during acute mania. (Background) A double-blind, placebo-controlled study lasting 4 weeks was performed. The intention-to-treatment population included 57 patients; 50 concluded the study per protocol. Patients suffering from BPD and during acute mania were randomly assigned either to a treatment (sodium valproate 15–20 mg/kg+300 mg allopurinol twice a day) or to a control condition (sodium valproate 15–20 mg/kg+placebo). Experts rated illness severity and illness improvements (Clinical Global impression), and extent of mania via the Young Mania Rating scale. Uric acid levels were assessed at the beginning and end of the study. (Experimental procedures) Compared to the control group, symptoms of mania decreased significantly over time in the treatment group. Uric acid levels declined significantly in the treatment as compared to the control group. Probability of remission after 4 weeks was 23 times higher in the treatment than the control group. Lower uric acid levels after 4 weeks were associated with symptom improvements. (Results) The pattern of results from this double-blind, randomized and placebo-controlled study indicates that adjuvant allopurinol leads to significant improvements in patients suffering from acute mania (Conclusion).     

Granisetron adjunct to fluvoxamine for moderate to severe obsessive-compulsive disorder: a randomized, double-blind, placebo-controlled trial

Background: Several small studies have shown beneficial effects of ondansetron, a serotonin 5-HT(3) receptor antagonist, in the treatment of obsessive-compulsive disorder (OCD). The efficacy of other 5-HT(3) receptor antagonists in patients with OCD is still unclear. Granisetron does not alter cytochrome P450 activity and might have a lower risk of drug interactions, a longer duration of action and a better tolerability profile than other 5-HT(3) receptor antagonists. Objective: The objective of this study was to assess the efficacy and tolerability of granisetron augmentation of fluvoxamine in patients with OCD. Study Design: This was a two-centre, randomized, double-blind, placebo-controlled, parallel-group study conducted from November 2011 to March 2012. Study Setting: The study setting was outpatient clinics of two large referral centres. Patients: Study participants were men and women, aged 18-60 years, who met the diagnostic criteria of OCD based on the DSM-IV-TR and who had a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of at least 21. Interventions: Participants were randomly assigned to granisetron (Kytril?; SmithKline Beecham, Philadelphia, PA, USA) 1?mg every 12 hours or placebo every 12 hours in addition to fluvoxamine for 8 weeks. Main Outcome Measure: Patients were assessed using the Y-BOCS at baseline, second, fourth, sixth and eighth weeks. The primary outcome measure was the difference in the score change of Y-BOCS total score from baseline to week 8 between the two groups. We also compared changes in the obsession and compulsion subscales of the Y-BOCS, and frequencies of partial response (≥25% reduction in Y-BOCS score), complete response (≥35% reduction in Y-BOCS score) and remission (Y-BOCS score ≤16) between the two groups. Results: Of the 42 included patients, 39 (20 in the placebo group, 19 in the granisetron group) completed the study. Significant time X treatment interaction was observed for total Y-BOCS (F [2.097, 79.678]?=?4.941, p?=?0.009), obsession (F [2.337, 88.799]?=?4.938, p?=?0.006) and compulsion (F [2.050, 77.899]?=?4.674, p?=?0.012) subscales. By week 8, complete response and remission were achieved by 20 (100%) and 18 (90%) patients in the granisetron group and by 7 (35%) patients in the placebo group (p-value of Fisher's exact test <0.001, risk ratio (RR) [95% CI]?=?3.857 [2.039, 7.297]). There was no significant difference in the tolerability between the two regimens. Conclusion: Granisetron is an efficacious adjunct for the short-term treatment of patients with moderate to severe OCD and is well tolerated. Clinical Trial Registration Number: IRCT201202041556N32.     

Tiagabine for posttraumatic stress disorder: effects of open-label and double-blind discontinuation treatment

Rationale Preliminary results suggest a potential benefit of agents that enhance gamma-aminobutyric acid (GABA) neurotransmission in treating posttraumatic stress disorder (PTSD). Objectives It is the aim of this study to evaluate the effect of a selective GABA reuptake inhibitor (SGRI), tiagabine, in patients with PTSD. Methods Twenty-nine adult outpatients with PTSD were treated with open-label tiagabine for 12 weeks. Those who responded to treatment (i.e., demonstrated at least minimal clinical improvement) were randomly assigned to double-blind treatment with either tiagabine or matching placebo. Efficacy assessments included measures of PTSD, anxiety, depression, sleep quality, resilience, and disability. Safety evaluation included changes in vital signs and weight and treatment-emergent adverse events. Results In subjects completing open-label treatment (n=19), significant improvement was observed on all outcome measures (P<0.05) and the treatment was well tolerated. Eighteen subjects responded and were randomized into the double-blind phase. Following randomization, benefits of treatment were generally upheld, but there was no greater incidence of relapse in the placebo group. However, continued treatment with tiagabine was associated with a greater trend toward likelihood of remission than if one was switched to placebo (P<0.08). Conclusions These findings suggest a possible role for the SGRI tiagabine in the treatment of PTSD. As the role of GABAergic drugs in PTSD is poorly defined, larger, randomized, double-blind, placebo-controlled trials are needed.     

Comparison of the effects of ketamine and memantine on prolactin and cortisol release in men. a randomized, double-blind, placebo-controlled trial.

N-methyl D-aspartate (NMDA)-antagonists decrease neurotoxicity by inhibiting Ca2+ influx which is of interest for the treatment of acute cerebrovascular insults and chronic neurodegenerative disorders. Currently, there is no surrogate marker for quantification of NMDA-receptor-mediated drug effects, which hampers dose-finding clinical studies. As prolactin and cortisol liberation is in part influenced through NMDA-receptors we investigated whether the elevation of prolactin or cortisol plasma levels is a class effect of NMDA-antagonists and might be an appropriate marker for studying NMDA-antagonistic potency. Fifteen healthy male volunteers participated in this placebo-controlled, randomized, three-way crossover trial. Ketamine (0.5mg/kg), memantine (0.16 mg/kg; i.e., a well tolerated standard dose) or placebo were infused over 60 min. Ketamine increased serum prolactin and cortisol levels (p < 0.001), whereas memantine and placebo did not affect hormone levels. Further studies are needed to define whether higher doses of memantine or other NMDA antagonists can induce hormone release.     

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.

     

Intranasal desmopressin as an adjunct to risperidone for negative symptoms of schizophrenia: A randomized,double-blind,placebo-controlled,clinical trial

Considering the role of neurohypophyseal peptides in normal development and function of higher cortical processes along with their proven abnormalities in schizophrenic patients, these pathways have recently attracted greater attention as treatment targets for schizophrenia. Desmopressin (DDAVP) is a synthetic analog of vasopressin. This study aimed to evaluate the efficacy and safety of DDAVP nasal spray as an adjunct to risperidone in improving negative symptoms of schizophrenia. In this randomized double-blind placebo-controlled clinical trial, forty patients aged 18–50 years with a DSM IV-TR diagnosis of chronic schizophrenia and a minimum score of 60 on positive and negative syndrome scale (PANSS) were equally randomized to receive DDAVP nasal spray (20 mcg/day) or placebo in addition to risperidone for 8 weeks. Patients were partially stabilized and treated with a stable dose of risperidone (5 or 6 mg/day) for at least four weeks prior to entry. Participants were rated by PANSS every two weeks and decrease in the PANSS negative subscale score was considered as our primary outcome. By the study endpoint, DDAVP-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=0.005 and P=0.003; respectively) compared to the placebo group. Treatment group was the strongest predictor of changes in negative symptoms (β=−0.48, t=−3.67, P=001). No serious adverse event or fluid/electrolyte imbalance was reported in this trial. In conclusion, DDAVP nasal spray showed to be an effective and safe medication for improving negative symptoms in patients with chronic schizophrenia.     

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.