A double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes.

Evidence of the antidepressant efficacy of lamotrigine is increasing, although there are no placebo-controlled trials of lamotrigine augmentation in depression. The aim of this study was to assess if augmentation with lamotrigine was superior to placebo in patients who were receiving fluoxetine for resistant major depressive episodes.

Efficacy of mirtazapine add on therapy to haloperidol in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled study.

The negative symptoms of schizophrenia remain a major clinical challenge. Mirtazapine is an antidepressant with antagonist properties at 5-HT2A, 5-HT3 and alpha 2 receptors as well as indirect 5-HT1a agonist effects. Many of these pharmacological actions have clinical or preclinical evidence of efficacy in schizophrenia. This study was a 6-week randomized placebo-controlled trial of mirtzepine or placebo add on to haloperidol 5 mg in the treatment of 30 patients with DSM-IV schizophrenia. The primary finding of the trial was a 42% reduction in Positive and Negative Syndrome Scale (PANSS) negative symptom scores in the mirtazapine group compared to placebo at the end of 6 weeks (mirtazapine 13.9, SD 1.56; placebo 23.9, SD 1.56; P = 0.000, F = 20.31, d.f. = 1). The PANNS total scores, Clinical Global Impression severity and improvement scales in addition showed superiority of mirtazapine over placebo. There was no difference between the groups on the Hamilton depression scale at endpoint, suggesting that the improvement in negative symptoms was not an artifact of mood improvement. These results suggest a potential role for mirtazapine in the negative symptoms of schizophrenia.

Efficacy of nefazodone in the treatment of neuroleptic induced extrapyramidal side effects: a double-blind randomised parallel group placebo-controlled trial.

Many atypical antipsychotics show antagonism at both serotonergic and dopaminergic neurones and show fewer extrapyramidal side effects (EPS). Nefazodone blocks postsynaptic 5HT2A receptors and weakly inhibits serotonin reuptake. This study aimed to elucidate the role of nefazodone in the treatment of antipsychotic-induced EPS. The trial was a double-blind, randomised, placebo-controlled trial of patients requiring antipsychotic treatment with haloperidol 10mg daily; from which a subgroup of patients who developed EPS were selected for the study. Patients were randomised to add-on therapy with either placebo (n=24) or nefazodone (n=25) 100mg bd. EPS were measured on days 0, 3 and 7 using the Simpson Angus, Barnes akathisia, abnormal involuntary movement and Chouinard scales. Nefazodone significantly reduced EPS as measured by both the Simpson Angus scale and CGI (p=0.007 and 0.0247, respectively). Akathisia and tardive dyskinesia did not differ between the two groups (p=0.601; p=0.507, respectively). These results suggest the role of 5HT2 antagonism in the mechanism of action of atypical antipsychotics with respect to lowering rates of drug-induced EPS. In addition, a therapeutic role for nefazodone is suggested in the treatment of antipsychotic-induced EPS.

Reboxetine add on therapy to haloperidol in the treatment of schizophrenia: a preliminary double-blind randomized placebo-controlled study.

The negative symptoms of schizophrenia remain a major clinical challenge. Reboxetine is an antidepressant whose major mechanism of action is as a noradrenergic reuptake inhibitor. This study was a 6-week randomized placebo-controlled trial of reboxetine or placebo add on to haloperidol 5 mg in the treatment of 30 patients with DSM-IV schizophrenia. The trial failed to demonstrate any significant difference between the placebo and reboxetine groups on any of the outcome measures. This trial does not suggest that increased noradreneregic drive mediated by reuptake inhibition in patients taking dopamine antagonists is of therapeutic value in schizophrenia.

Fluoxetine treatment of acral lick dermatitis in dogs: a placebo-controlled randomized double blind trial.

The aim of the study was to assess the efficacy and tolerability of fluoxetine treatment of acral lick dermatitis (ALD) in dogs and to investigate ALD as an animal model of obsessive-compulsive disorder (OCD). Sixty-three dogs with ALD were treated with fluoxetine 20 mg daily, or placebo, for 6 weeks. In the fluoxetine group, owners rated both appearance of the lesion (t = 10.2, df = 29, P < 0.0001) and licking behavior (t = 10.2, df = 29, P < 0.0001) as significantly improved by the end of the trial. Veterinarian-rated pre- and post-treatment photographs showed statistically significant improvement in the fluoxetine group (mean = 2.55). There were no significant changes in the placebo group as rated by owners and veterinarians. These results demonstrate the efficacy of fluoxetine in the treatment of ALD and lend further support to ALD as an animal model of OCD.

Effects of a multivitamin, mineral and herbal supplement on cognition and blood biomarkers in older men: a randomised, placebo-controlled trial

OBJECTIVE: Nutritional and vitamin status may be related to cognitive function and decline in older adults. The aim of this study was to investigate the effects of nutritional supplementation on cognition in older men. METHOD: The current study was an 8-week, placebo-controlled, double-blind investigation into the effects of a multivitamin, mineral and herbal supplement (Swisse Men's Ultivite®, Swisse Vitamins Pty Ltd, Melbourne, Australia) on cognitive performance in older men. Participants were 51 male individuals aged between 50 and 74 years, with a sedentary lifestyle. Cognitive performance was assessed at baseline and post-treatment using a computerised battery of cognitive tasks, enabling the measurement of a range of attentional and memory processes. Blood measures of vitamin B(12) , folate and homocysteine were collected prior to and after supplementation. RESULTS: The results of this study revealed that contextual recognition memory performance was significantly improved following multivitamin supplementation (p < 0.05). Performance on other cognitive tasks did not change. Levels of vitamin B(12) and folate were significantly increased with a concomitant decrease in homocysteine, indicating that relatively short-term supplementation with a multivitamin can benefit these risk factors for cognitive decline. CONCLUSION: Findings from this study indicate that daily multivitamin supplementation may improve episodic memory in older men at risk of cognitive decline.

Nocebo effects in the treatment of major depression: results from an individual study participant-level meta-analysis of the placebo arm of duloxetine clinical trials

BACKGROUND: The nocebo effect, when a harmless substance creates harmful effects in a person who takes it, is a clinically salient yet seldom studied phenomenon that may be associated with poorer treatment outcomes, perceived adverse events, and treatment discontinuation. The covert presence of nocebo responders in clinical trials may contribute to outcome variance in both placebo and active treatment arms for important primary and secondary endpoints. Nocebo effects are thought to be driven by expectancy and conditioning. METHOD: This study analyzed pooled clinical trial data in the placebo arms of controlled trials of antidepressant medications to investigate variables associated with the emergence of adverse outcomes in placebo-treated participants (N = 2,457). Specifically, we examined treatment-emergent adverse events (TEAEs) and discontinuation in placebo-treated individuals. Trials were commenced between 1993 and 2010 as studies of duloxetine versus active comparator and/or placebo. RESULTS: TEAEs were reported by 1,569 placebo-treated participants (63.9%), with 115 (4.7%) discontinuing from the studies due to TEAEs and 274 (11.2%) showing worsening of Hamilton Depression Rating Scale total score during placebo treatment. There was specifically no evidence to support the expectancy hypothesis, that reported TEAEs were influenced by adverse effects described in the clinical trials participant information and consent forms, or the conditioning hypothesis, that reported TEAEs would be influenced by adverse effect profiles of previous antidepressant medications used by these study participants. There was some evidence to suggest that people who had previously used complementary medications were more likely to report TEAEs. Variables specific to individual studies were the strongest predictors of TEAEs. DISCUSSION: In this study, TEAEs were very common among placebo-treated clinical trial participants. Unexpectedly, there was no evidence to associate TEAEs with adverse clinical outcomes, nor were the conditioning or expectancy hypotheses supported by these data. CONCLUSIONS: The nocebo effect is a common, covert, and poorly understood driver of clinical outcomes that requires further investigation.

N-Acetyl Cysteine (NAC) in the treatment of obsessive-compulsive disorder: a 16-week, double-blind, randomised, placebo-controlled study

BACKGROUND: Obsessive-compulsive disorder (OCD) is a disabling mental illness for which pharmacological and psychosocial interventions are all too often inadequate. Recent preclinical and clinical studies have implicated dysfunction of glutamatergic neurotransmission in the pathophysiology of OCD. The amino acid-based nutraceutical N-acetyl cysteine (NAC) is a safe and readily available agent that has been found to modify the synaptic release of glutamate in subcortical brain regions via modulation of the cysteine-glutamate antiporter. OBJECTIVE: The aim of this study was to assess the efficacy and safety of NAC in treating OCD. METHODS: A 16-week, double-blind, placebo-controlled, randomised trial using 3 g/day of NAC (1.5 g twice daily) in 44 participants (aged 18-70 years) with Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)-diagnosed OCD, during 2013-2015. The primary outcome measure was the Yale-Brown Obsessive Compulsive Scale (YBOCS), conducted every 4 weeks. RESULTS: Analysis of the full sample (intention-to-treat) with repeated measures mixed linear modelling revealed a nonsignificant time × treatment interaction for the YBOCS scale total score (p = 0.39). A per-protocol analysis removing protocol violators also failed to show a significant time × treatment interaction for YBOCS total score (p = 0.15). However, a significant time × treatment interaction was observed for the YBOCS 'Compulsions' subscale in favour of NAC (p = 0.013), with a significant reduction observed at week 12 (dissipating at week 16). At 16 weeks, only four (20 %) participants were considered 'responders' (YBOCS ≥35 % reduction at endpoint) versus four (27 %) in the placebo group. The NAC was well-tolerated, aside from more cases of heartburn occurring compared with placebo (p = 0.045). CONCLUSION: Further research involving NAC for OCD may require larger samples to detect moderate or small effect sizes, involve dosage or formulation differences, use in concert with exposure therapy, or an additional post-study observational period to mitigate study withdrawal. TRIAL REGISTRATION: ACTRN12613000310763.

Youth Depression Alleviation-Augmentation with an anti-inflammatory agent (YoDA-A): protocol and rationale for a placebo-controlled randomized trial of rosuvastatin and aspirin

AIM: There is growing support for the role of inflammation and oxidative stress in the pathophysiology of major depressive disorder (MDD). This has led to the development of novel strategies targeting inflammation in the treatment of depression. Rosuvastatin and aspirin have well-documented, anti-inflammatory and antioxidant properties. The aim of the Youth Depression Alleviation: Augmentation with an anti-inflammatory agent (YoDA-A) study is to determine whether individuals receiving adjunctive anti-inflammatory agents, aspirin and rosuvastatin experience a reduction in the severity of MDD compared with individuals receiving placebo. METHODS: YoDA-A is a 12-week triple-blind, randomized controlled trial funded by the National Health and Medical Research Council, Australia. Participants aged 15-25, with moderate-to-severe MDD, are allocated to receive either 10 mg/day rosuvastatin, 100 mg/day aspirin, or placebo, in addition to treatment as usual. Participants are assessed at baseline and at weeks 4, 8, 12 and 26. The primary outcome is change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 12. RESULTS: The study is planned to be completed in 2017. At date of publication, 85 participants have been recruited. CONCLUSION: Timely and targeted intervention for youth MDD is crucial. Given the paucity of new agents to treat youth MDD, adjunctive trials are not only pragmatic and 'real-world', but additionally aim to target shortfalls in conventional medications. This study has the potential to first provide two new adjunctive treatment options for youth MDD; aspirin and rosuvastatin. Second, this study will serve as proof of principle of the role of inflammation in MDD.

Confiança, comprometimento e efeito chicote na gestão da cadeia de suprimentos automotiva

Dissertação apresentada ao Programa de Mestrado em Administração da Universidade Municipal de São Caetano do Sul - USCS