Antipsychotic polypharmacy: is there evidence for its use?

Antipsychotic polypharmacy occurs frequently in clinical practice; however, there is a lack of controlled clinical studies testing the efficacy of the combinations used. The purpose of this literature review was to examine studies and other reports that have assessed the incremental benefits and deficits of combination antipsychotic therapy versus monotherapy. A PUBMED search covering a 26-year period from 1976 to 2002 was conducted. The search was limited to clinical trials, case series, and reports. Fifty-two reports were identified that systematically assessed the efficacy of combination therapy as opposed to monotherapy: 4 double-blind studies, 13 open-label clinical trials, and 35 case reports. Only one open-label trial and 2 case reports met the design criteria of having trials of each medication and the combination in the same patients and using some type of standardized assessment to evaluate outcome. The most frequent combination was clozapine-risperidone. Of the clinical trials, 75% (3/4) of the double-blind studies and 69% (9/13) of the open-label trials found that combination therapy was effective in reducing symptoms, while 37% (13/35) of case reports documented an overall positive outcome. Currently, the clinical practice of antipsychotic polypharmacy is not evidence-based; however, there is also no evidence against its use. Expanded systematic research to assess this clinical practice is needed.     

The adaptive response of skeletal muscle: What is the evidence?

Adult skeletal muscle is capable of adapting its properties in response to changing functional demands. This now sounds like a statement of the obvious, and many people assume it has always been this way. A mere 40 years ago, however, the picture was entirely different. In this Review and personal memoir, I outline the scientific context in which the theory was generated, the objections to it from entrenched opinion, and the way those objections were progressively met. The material should be of some historical interest, but, more importantly, it collects together the full range of evidence on which the current paradigm is based. Muscle Nerve 57 : 531–541, 2018     

Childhood trauma and psychosis - what is the evidence?

In the last decade, a substantial number of population-based studies have suggested that childhood trauma is a risk factor for psychosis. In several studies, the effects held after adjusting for a wide range of potentially confounding variables, including genetic liability for psychosis. Less is known about the mechanisms underlying the association between childhood trauma and psychosis. Possible pathways include relationships between negative perceptions of the self, negative affect, and psychotic symptoms, as well as biological mechanisms such as dysregulated cortisol and increased sensitivity to stress. Psychotic patients with a history of childhood trauma tend to present with a variety of additional problems, including post-traumatic stress disorder, greater substance abuse, higher levels of depression and anxiety, and more frequent suicide attempts. Initial studies suggest that trauma-specific treatments are as beneficial for these patients as for other diagnostic groups.     

CTOs: what is the state of the evidence?

Purpose

Community Treatment Orders (CTOs) require outpatients to adhere to treatment and permit rapid hospitalisation when necessary. They have become a clinical and policy solution to repeated hospital readmissions despite some strong opposition and the contested nature of published evidence. In this article, we appraise the current literature on CTOs from the viewpoint of Evidence-Based Medicine and discuss the way forward for using and researching CTOs.

Results

Non-randomised outcome studies show conflicting results, but their lack of standardisation of methods and measures makes it difficult to draw conclusions. In contrast, all three randomised controlled trials (RCTs) conducted concur in their findings that CTOs do not impact on hospital outcomes. No systematic review or meta-analysis has identified any clear clinical advantage to CTOs.

Conclusion

The evidence-base does not support the use of CTOs in their current form. Involuntary clinical interventions must conform to the highest standard of evidence-based care. To enable clinicians to take an evidence-based approach and to settle remaining uncertainties about the current evidence, high-quality RCTs should be designed and undertaken, using standardised outcome measures.     

Slow cortical potential neurofeedback in attention deficit hyperactivity disorder: is there neurophysiological evidence for specific effects?

This study compared changes in quantitative EEG (QEEG) and CNV (contingent negative variation) of children suffering from ADHD treated by SCP (slow cortical potential) neurofeedback (NF) with the effects of group therapy (GT) to separate specific from non-specific neurophysiological effects of NF. Twenty-six children (age: 11.1 ± 1.15 years) diagnosed as having ADHD were assigned to NF (N = 14) or GT (N = 12) training groups. QEEG measures at rest, CNV and behavioral ratings were acquired before and after the trainings and statistically analyzed. For children with ADHD-combined type in the NF group, treatment effects indicated a tendency toward improvement of selected QEEG markers. We could not find the expected improvement of CNV, but CNV reduction was less pronounced in good NF performers. QEEG changes were associated with some behavioral scales. Analyses of subgroups suggested specific influences of SCP training on brain functions. To conclude, SCP neurofeedback improves only selected attentional brain functions as measurable with QEEG at rest or CNV mapping. Effects of neurofeedback including the advantage of NF over GT seem mediated by both specific and non-specific factors. M. Doehnert and D. Brandeis have contributed equally to this paper.     

Is there evidence for negative effects of antidepressants on suicidality in depressive patients?

The role of antidepressants in suicide prevention is a major public health question given the high prevalence of both depression and depression-related suicidality. Therefore all available means should be utilised to clarify the influence of antidepressants on suicidality, especially in view of the ongoing intensive debate about possible suicidality-inducing effects of antidepressants that may outweigh their traditionally hypothesised beneficial effects. This paper gives a systematic and comprehensive review of the empirical data which might indicate that antidepressants have negative effects on suicidality. First, principal methodological issues related to this research question are discussed. Thereafter, the results of controlled trials and epidemiological and cohort studies are presented. Altogether, there seems to be only a small amount of evidence from different research approaches that antidepressants, not only serotonin reuptake inhibitors (SSRIs), might induce, aggravate or increase the risk of suicidal ideation and suicide attempts. As to suicide, there are no hints in this direction. TCAs have a higher risk of fatal outcome in overdose compared to SSRIs, which, in case of mono-intoxication, carry almost no risk of lethal consequences. The ongoing discussion about suicidality-inducing effects should not prevent physicians from prescribing SSRIs and other antidepressants to their patients if they are clinically indicated. However, they should take into account potential risks and manage them by good clinical practice.     

Antidepressant effects of exercise: evidence for an adult-neurogenesis hypothesis?

It has been hypothesized that a decrease in the synthesis of new neurons in the adult hippocampus might be linked to major depressive disorder (MDD). This hypothesis arose after it was discovered that antidepressant medications increased the synthesis of new neurons in the brain, and it was noted that the therapeutic effects of antidepressants occurred over a time span that approximates the time taken for the new neurons to become functional. Like antidepressants, exercise also increases the synthesis of new neurons in the adult brain: a 2-3-fold increase in hippocampal neurogenesis has been observed in rats with regular access to a running wheel when they are compared with control animals. We hypothesized, based on the adult-neurogenesis hypothesis of MDD, that exercise should alleviate the symptoms of MDD and that potential mechanisms should exist to explain this therapeutic effect. Accordingly, we evaluated studies that suggest that exercise is an effective treatment for MDD, and we explored potential mechanisms that could link adult neurogenesis, exercise and MDD. We conclude that there is evidence to support the hypothesis that exercise alleviates MDD and that several mechanisms exist that could mediate this effect through adult neurogenesis.     

Why do we yawn? The importance of evidence for specific yawn-induced effects

Gallup (this issue) believes that our recent review on the function of yawning (Guggisberg et al., 2010) is unbalanced and that it ignores evidence for his thermoregulation hypothesis. Here we address these criticisms and show them to be untenable. While we never claimed that the social hypothesis of yawning has “definite experimental support”, we emphasize the importance of experimental evidence for specific effects of yawns when considering why we yawn. The only specific effect of yawning that could be demonstrated so far is its contagiousness in humans, some non-human primates, and possibly dogs, whereas all studies investigating physiological consequences of yawns were unable to observe specific yawn-induced effects in the individual of any species. The argument that from an evolutionary perspective, yawns must have a “primitive” physiological function arises from imprecise reasoning.     

Carbamazepine augmentation for schizophrenia: how good is the evidence?

BACKGROUND: Augmentation strategies in schizophrenia treatment remain an important issue because despite the introduction of several new antipsychotics, many patients remain treatment resistant. The aim of this study was to undertake a systematic review and meta-analysis of the safety and efficacy of one frequently used adjunctive compound: carbamazepine. DATA SOURCES AND STUDY SELECTION: Randomized controlled trials comparing carbamazepine (as a sole or as an adjunctive compound) with placebo or no intervention in participants with schizophrenia or schizoaffective disorder were searched for by accessing 7 electronic databases, cross-referencing publications cited in pertinent studies, and contacting drug companies that manufacture carbamazepine. METHOD: The identified studies were independently inspected and their quality assessed by 2 reviewers. Because the study results were generally incompletely reported, original patient data were requested from the authors; data were received for 8 of the 10 randomized controlled trials included in the present analysis, allowing for a reanalysis of the primary data. Dichotomous variables were analyzed using the Mantel-Haenszel odds ratio and continuous data were analyzed using standardized mean differences, both specified with 95% confidence intervals. RESULTS: Ten studies (total N = 283 subjects) were included. Carbamazepine was not effective in preventing relapse in the only randomized controlled trial that compared carbamazepine monotherapy with placebo. Carbamazepine tended to be less effective than perphenazine in the only trial comparing carbamazepine with an antipsychotic. Although there was a trend indicating a benefit from carbamazepine as an adjunct to antipsychotics, this trend did not reach statistical significance. CONCLUSION: At present, this augmentation strategy cannot be recommended for routine use. The most promising targets for future trials are patients with excitement, aggression, and schizoaffective disorder bipolar type.     

The story of the serpin plasminogen activator inhibitor 1: is there any need for another mutant?

The importance of obtaining insight in the structure/function relationship in the serpin plasminogen activator inhibitor type-1 can be understood from the major role PAI-1 plays in different (patho)physiological processes, mainly because of its involvement in the plasminogen/plasmin system. Moreover, during the past years, studies indicated a contribution of PAI-1 to the development of cardiovascular disease in common syndromes such as atherosclerosis, diabetes and hypertension. Furthermore, PAI-1 also inhibits u-PA, attributing a role in phenomena such as cell migration and tissue remodelling. Considering the role of PAI-1 in such various pathogenic path-ways, detailed insight into the structure/function relationship in PAI-1 might provide a means of interfering with a given pathological situation without disturbing other physiological processes. Therefore, since the discovery of PAI-1 and the cloning of its cDNA 20 years ago, over 600 PAI-1 variants have been constructed, elucidating the most important structural features of PAI-1. This review gives an overview of the contribution of the different PAI-1 variants to the understanding of the structure/function relationship in PAI-1, based on the different functional features of PAI-1.     

The role of excitotoxicity in ALS – what is the evidence?

It is well accepted that excitotoxic mechanisms contribute to the pathogenesis of acute neuronal death in stroke, epilepsy, or brain trauma. It is less widely acknowledged that excitotoxic mechanisms play a role in the pathogenesis of chronic neurological disorders, in particular neurodegenerative diseases. However, evidence is accumulating that this mechanism is indeed part of the pathogenesis of late-onset neurodegenerative diseases. One of the clinical examples may be amyotrophic lateral sclerosis, a disease in which antiexcitotoxic strategies have neuroprotective effects in both, an established animal model and in man. In addition, there is accumulating neuropathological, pathobiochemical and pathophysiological evidence which indicates that excitotoxic mechanisms are part of the pathogenesis of the human disease and consequently part of the mechanisms explaining selective vulnerability (“pathoclisis”) in the human motor system.

     

Supported employment outcomes across a decade: is there evidence of improvement in the quality of implementation?

There is little question that the strategies used to improve supported employment outcomes, namely higher wages and higher levels of integration, have changed since the mid-1980s. Innovations of natural supports and employer leadership have helped increase the capacity of provider agencies and the business community to include people with disabilities in the workforce. This report is the sixth in a series that focuses on features of natural supports and its relationship to outcomes. Our purpose in this paper is to describe an analysis designed to investigate the features of employment, wage, and integration outcomes of jobs acquired by people with disabilities early in the development of supported employment compared to more recent years.     

The role of neurotensin in central nervous system pathophysiology: what is the evidence?

The peptide neurotensin has been studied for more than 30 years. Although it is widely distributed in the central and peripheral nervous systems, neurotensin has been more intensely studied with regard to its interactions with the central dopamine system. A number of claims have been made regarding its possible implication in many diseases of the central nervous system, including schizophrenia. In this review, we describe briefly the basic biology of this neuropeptide, and then we consider the strengths and the weaknesses of the data that suggest a role for neurotensin in schizophrenia, drug abuse, Parkinson's disease, pain, central control of blood pressure, eating disorders, cancer, neurodegenerative disorders and inflammation.     

The crossover approach to switching antipsychotics: what is the evidence?

Clinicians frequently use a crossover approach in switching antipsychotics, although historically there has been a lack of data addressing the question of switch strategies. To establish if there is now empiric evidence that may guide clinicians in this regard, a MEDLINE search to April 2004 was carried out to identify published, randomized and controlled trials that have addressed this topic. A total of 404 articles were identified in the search, which resulted in the identification of four reports meeting the criteria. The four studies evaluated switching strategies to one of three atypical antipsychotics: aripiprazole, olanzapine (two reports), and ziprasidone. The switching process itself could be subdivided as follows: discontinuation (abrupt vs. gradual); and, replacement (abrupt vs. gradual). Meta-analyses confirmed a lack of difference in outcome, regardless of approach. While a crossover approach does not appear to increase adverse events, the available empiric evidence does not support its clinical superiority on various outcome measures. The existing data therefore argue against the position that a crossover approach in switching antipsychotics represents a 'safer' means of preventing clinical deterioration during the switch.