Eduardo Pondé de Sena

Relapse in patients with schizophrenia: a comparison between risperidone and haloperidol

OBJECTIVES To compare rates of rehospitalization and time to relapse in risperidone vs. haloperidol-treated schizophrenic patients discharged from the hospital. METHODS Randomized controlled trial comparing risperidone and haloperidol regarding relapse in patients with schizophrenia treated with flexible doses during one year. RESULTS Twenty patients were assigned to risperidone and 13 to haloperidol. One patient from each group withdrew consent and one patient in the risperidone group was lost for follow-up. Six (30.0%) patients in the risperidone group and 3 (23.1%) in the haloperidol group relapsed (p=1.00). However, time to relapse was shorter in the later (logrank =4.2; p=.04). When rehospitalized, patients in the risperidone group stayed 34.5 days (median) at hospital as compared to the haloperidol group (median of 61 days) (p=.61). CONCLUSION The proportion of schizophrenic patients who relapsed was similar in both groups; However, time to relapse was shorter in the haloperidol-treated patients.

Haloperidol blood levels and clinical outcome: a meta‐analysis of studies relevant to testing the therapeutic window hypothesis

Haloperidol, the most studied antipsychotic drug, is the only one about which reliable statements on the relationship between blood levels and clinical outcome can be made. A systematic overview was undertaken to determine whether there was an optimum blood concentration range for clinical efficacy. Eighteen published studies which provided individual patient data in tables or graphs were reviewed. Clinical benefits tended to decline when the haloperidol blood concentration was increased above 26 ng/ml. Our data support the existence of a therapeutic window between 4 and 26 ng/ml for haloperidol in the treatment of schizophrenic, schizoaffective and schizophreniform disorders.

Safety and tolerability of antipsychotics: focus on amisulpride

The introduction of the atypical antipsychotic drugs represents an important advance in the treatment of schizophrenia, because the therapeutic efficacy, tolerability, and safety profiles of these agents seem to be superior to that of the classical neuroleptics. As would be predicted from the pharmacologic profile of a pure D2/D3 receptor blocker, amisulpride is an atypical antipsychotic agent, effective for positive and negative symptoms, which can bring about additional improvement in the social functioning and quality of life of patients with schizophrenia. Amisulpride is effective in acute schizophrenia as determined by Clinical Global Impression scores. The major concern regarding the safety of the atypical antipsychotics is related to their propensity to induce weight gain and alter glucose and lipid metabolism. Amisulpride has one of the lowest potentials for weight gain of all the antipsychotic agents, and is associated with clearly lower use of antiparkinsonian medication and with fewer dropouts due to adverse events than conventional antipsychotics. Amisulpride is well tolerated with regard to anxiety and insomnia, and not notably different from placebo. Amisulpride has a pronounced prolactin-elevating effect which appears to be independent of dosage and duration of administration. Hyperprolactinemia rapidly reverses following amisulpride discontinuation. Amisulpride benefits patients with negative symptoms, and is the only antipsychotic to demonstrate efficacy in patients with predominantly negative symptoms. Amisulpride maintains its efficacy when used for medium/long-term treatment, as demonstrated in studies of up to 12 months. In terms of relevance of the effects, superiority is observed for quality of life, social adaptation, and functioning, as measured by the Quality of Life and Functional Status Questionnaire scales. In conclusion, amisulpride is an antipsychotic agent with proven efficacy and good tolerability. Moreover, this drug can help people with schizophrenia to attain social reinsertion.

A Randomized, Double-Blind, Sham-Controlled Trial of Transcranial Direct Current Stimulation in Attention-Deficit/Hyperactivity Disorder

Background Current standardized treatments for cognitive impairment in attention-deficit/hyperactivity disorder remain limited and their efficacy restricted. Transcranial direct current stimulation (tDCS) is a promising tool for enhancing cognitive performance in several neuropsychiatric disorders. Nevertheless, the effects of tDCS in reducing cognitive impairment in patients with attention-deficit/hyperactivity disorder (ADHD) have not yet been investigated. Methods A parallel, randomized, double-blind, sham-controlled trial was conducted to examine the efficacy of tDCS on the modulation of inhibitory control in adults with ADHD. Thirty patients were randomly allocated to each group and performed a go/no-go task before and after a single session of either anodal stimulation (1 mA) over the left dorsolateral prefrontal cortex or sham stimulation. Results A nonparametric two-sample Wilcoxon rank-sum (Mann-Whitney) test revealed no significant differences between the two groups of individuals with ADHD (tDCS vs. sham) in regard to behavioral performance in the go/no go tasks. Furthermore, the effect sizes of group differences after treatment for the primary outcome measures—correct responses, impulsivity and omission errors—were small. No adverse events resulting from stimulation were reported. Conclusion According to these findings, there is no evidence in support of the use of anodal stimulation over the left dorsolateral prefrontal cortex as an approach for improving inhibitory control in ADHD patients. To the best of our knowledge, this is the first clinical study to assess the cognitive effects of tDCS in individuals with ADHD. Further research is needed to assess the clinical efficacy of tDCS in this population. Trial Registration ClinicalTrials.gov NCT01968512

Is there a relationship between antipsychotic blood levels and their clinical efficacy? An analysis of studies design and methodology

Summary— There are now more than 50 studies concerning neuroleptic blood levels and clinical outcome relationships. Haloperidol, the most studied, is the only antipsychotic permitting some conclusions. A number of authors suggest that the striking lack of agreement between different studies results from heterogeneity of their quality. Here, we have used a scoring system for assessing the quality of those studies. According to this system, none (0/14) of the studies having a score <0.60 was able to show a therapeutic window, as compared to 53% (10/19) of those having a score ≥0.60 (p = 0.002, Fisher exact test). Also, the studies able to identify the presence of a therapeutic window during haloperidol treatment were those having sample sizes >20 (p = 0.06) and those whose patients were treated with fixed doses (p = 0.02). The diagnosis of schizophrenia in the studies seems not to be an exclusive condition, as compared with those also including schizophreniform and schizoaffective disorders (p = 0.12). Our qualitative analysis of haloperidol blood level publications seem to indicate that an upper limit may exist for haloperidol efficacy; values above this limit seem not to provide any supplementary clinical improvement and may even reduce therapeutic effect.

Aripiprazole for Patients with Schizophrenia and Schizoaffective Disorder: An Open-Label, Randomized, Study Versus Haloperidol

INTRODUCTION Aripiprazole, a dopamine D2 receptor partial agonist, has also partial agonist activity at serotonin (5-HT)1A receptors and antagonist activity at 5-HT2A receptors. METHODS In this 8-week, multicenter, randomized, parallel-group, open-label, flexible-dose study, patients diagnosed with schizophrenia or schizoaffective disorder were randomized to aripiprazole 15-30 mg/day or haloperidol 10-15 mg/day. RESULTS Patients treated with both aripiprazole and haloperidol improved from baseline in Positive and Negative Syndrome Scale total, positive, and negative scores as well as in Clinical Global Impressions scores (all P<.001). At the end of the study, the percentage of patients classified as responders--according to >or=40% reduction in the Positive and Negative Syndrome Scale negative subscale score--was significantly higher in the aripiprazole group (20%) than in the haloperidol group (0%) (P<.05). Additionally, a higher number of patients receiving haloperidol required more anticholinergic medications (P<.001) than aripiprazole-treated patients, whereas more aripiprazole (45.5%) than haloperidol-treated patients (12.9%) required benzodiazepines (P=.002). At endpoint, rates of preference of medication were higher in the aripiprazole group (63.2%) than in the haloperidol group (21.7%), as expressed by patients and caregivers (P=.001). CONCLUSION Aripiprazole and haloperidol had similar efficacy in terms of reduction of overall psychopathology. Although aripiprazole has been demonstrated to be superior concerning negative symptoms and in terms of tolerability (extrapyramidal symptoms) and preferred by patients and caregivers than haloperidol, significantly more aripiprazole-treated patients required benzodiazepines.

Spreading Effect of tDCS in Individuals with Attention-Deficit/Hyperactivity Disorder as Shown by Functional Cortical Networks: A Randomized, Double-Blind, Sham-Controlled Trial

Background Transcranial direct current stimulation (tDCS) is known to modulate spontaneous neural network excitability. The cognitive improvement observed in previous trials raises the potential of this technique as a possible therapeutic tool for use in attention-deficit/hyperactivity disorder (ADHD) population. However, to explore the potential of this technique as a treatment approach, the functional parameters of brain connectivity and the extent of its effects need to be more fully investigated. Objective The aim of this study was to investigate a functional cortical network (FCN) model based on electroencephalographic activity for studying the dynamic patterns of brain connectivity modulated by tDCS and the distribution of its effects in individuals with ADHD. Methods Sixty ADHD patients participated in a parallel, randomized, double-blind, sham-controlled trial. Individuals underwent a single session of sham or anodal tDCS at 1 mA of current intensity over the left dorsolateral prefrontal cortex for 20 min. The acute effects of stimulation on brain connectivity were assessed using the FCN model based on electroencephalography activity. Results Comparing the weighted node degree within groups prior to and following the intervention, a statistically significant difference was found in the electrodes located on the target and correlated areas in the active group (p < 0.05), while no statistically significant results were found in the sham group (p ≥ 0.05; paired-sample Wilcoxon signed-rank test). Conclusion Anodal tDCS increased functional brain connectivity in individuals with ADHD compared to data recorded in the baseline resting state. In addition, although some studies have suggested that the effects of tDCS are selective, the present findings show that its modulatory activity spreads. Further studies need to be performed to investigate the dynamic patterns and physiological mechanisms underlying the modulatory effects of tDCS. Trial Registration ClinicalTrials.gov NCT01968512.

Review of the efficacy of placebo in comparative clinical trials between typical and atypical antipsychotics

Objectives: to review the efficacy of placebo in comparison with typical antipsychotics (TAs) and atypical antipsychotics (AAs) for the treatment of schizophrenia and schizoaffective disorder and to evaluate the pertinence of using placebo in clinical trials with antipsychotics. Methods: Trials in which the AAs were compared with TAs and placebo were included. A search was conducted using the terms amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone and zotepine. Main efficacy parameters were calculated using the proportion of “events” (defined as a deterioration or lack of improvement by at least 20% in PANSS or BPRS) and the pooled relative risk with random effects, with their respective 95% confidence intervals. We also calculated the necessary sample sizes in studies in which the study drug is compared to a TA or placebo. Results: The pooled efficacy rates observed were 40.8%, 34.9% and 21.3% for the AAs, TAs and placebo, respectively. One hundred and sixty six patients would have to be included when a new drug is compared with placebo if calculation is based on a difference of 20% found between the AA and placebo and 2,054 if the difference sought were that found between the AA and the TA, i.e. 6%. The estimated therapeutic failures would be 115 of the 166 patients when the study drug is compared with placebo, and 1,274 failures in the 2,054 patients when the study drug is compared to the TA. Conclusion: Placebo controlled studies may reduce the number of individuals exposed to the harmful effects of ineffective drugs.

Use of transcranial direct current stimulation for the treatment of auditory hallucinations of schizophrenia – a systematic review

Introduction Auditory hallucinations are defined as experiences of auditory perceptions in the absence of a provoking external stimulus. They are the most prevalent symptoms of schizophrenia with high capacity for chronicity and refractoriness during the course of disease. The transcranial direct current stimulation (tDCS) – a safe, portable, and inexpensive neuromodulation technique – has emerged as a promising treatment for the management of auditory hallucinations. Objective The aim of this study is to analyze the level of evidence in the literature available for the use of tDCS as a treatment for auditory hallucinations in schizophrenia. Methods A systematic review was performed, searching in the main electronic databases including the Cochrane Library and MEDLINE/PubMed. The searches were performed by combining descriptors, applying terms of the Medical Subject Headings (MeSH) of Descriptors of Health Sciences and descriptors contractions. PRISMA protocol was used as a guide and the terms used were the clinical outcomes (“Schizophrenia” OR “Auditory Hallucinations” OR “Auditory Verbal Hallucinations” OR “Psychosis”) searched together (“AND”) with interventions (“transcranial Direct Current Stimulation” OR “tDCS” OR “Brain Polarization”). Results Six randomized controlled trials that evaluated the effects of tDCS on the severity of auditory hallucinations in schizophrenic patients were selected. Analysis of the clinical results of these studies pointed toward incongruence in the information with regard to the therapeutic use of tDCS with a view to reducing the severity of auditory hallucinations in schizophrenia. Only three studies revealed a therapeutic benefit, manifested by reductions in severity and frequency of auditory verbal hallucinations in schizophrenic patients. Conclusion Although tDCS has shown promising results in reducing the severity of auditory hallucinations in schizophrenic patients, this technique cannot yet be used as a therapeutic alternative due to lack of studies with large sample sizes that portray the positive effects that have been described.

Antipsychotic agents: efficacy and safety in schizophrenia

Antipsychotics have provided a great improvement in the management of people with schizophrenia. The first generation antipsychotics could establish the possibility of managing many psychotic subjects in an outpatient setting. With the advent of the second (SGA) and third generation antipsychotics (TGA), other psychiatric disorders such as bipolar depression, bipolar mania, autism, and major depressive disorder have now been approved for the use of these drugs for their treatment. Also, the administration of more specific assessment tools has allowed for better delineation of the repercussions of these drugs on symptoms and the quality of life of patients who use antipsychotic agents. In general, the SGA share similar mechanisms of action to achieve these results: dopamine-2 receptor antagonism plus serotonin-2A receptor antagonism. The TGA (eg, aripiprazole) have partial agonist activity at the dopamine-2 receptor site, and are also called dopaminergic stabilizers. The pharmacological profile of SGA and TGA may provide better efficacy against negative symptoms, and are less likely to produce extrapyramidal symptoms; however, the SGA and TGA are associated with many other adverse events. The clinician has to balance the risks and benefits of these medications when choosing an antipsychotic for an individual patient.