Meta-analysis and the science of schizophrenia: variant evidence or evidence of variants?

Quantification (meta-analysis) of the neuroscience evidence on schizophrenia shows very modest average differences between patient and control distributions across a great variety of measures and literatures. The strongest findings involve cognitive and psychophysiological measures. Several possible explanations for this situation are reviewed including technical immaturity, methodological variability, dimensional and multiple illness models and the nature of cognitive measurement. An argument is developed that biological subtypes and endophenotypes within the broad diagnostic category of schizophrenia underpin the meta-analytic evidence. Considerations in the use of this evidence to identify illness variants are described and four candidate subtypes are proposed. Schizophrenia is a disease that will resist biological definition until its variants are isolated and extracted from the generic patient population.     

Does case management work? The evidence and the abuse of evidence-based medicine

OBJECTIVES: This study reviews typologies of psychiatric case management and then discusses the efficacy, effectiveness and cost effectiveness of psychiatric case management, with particular focus on evidence from Australia and the UK. Subsequently, it aims to examine the way such evidence has been interpreted in the context of UK psychiatric research and services. Finally it examines the ways in which, by the selective reviewing or editorializing of evidence, case management has been brought into disrepute in the UK. METHOD: This study reviews literature of the recent evidence for case management, and asks three questions of case management: has it been shown to be efficacious in controlled research, is it effective in applied settings, and is it cost effective? An examination is then made of the concurrent representations of the UK evidence in both the academic literature and the media. RESULTS: There is strong evidence for the efficacy effectiveness and cost-effectiveness of case management in psychiatry, the closer it conforms to active and assertive community treatment models. It appears, however, that studies and evidence-based reviews of case management have possibly been misused and misrepresented in a highly charged atmosphere of professional media debate. The potential for this abuse is not limited to psychiatry and remains a challenge for all evidence-based practice. CONCLUSION: On the evidence, assertive community treatment case management is one of the most effective interventions in psychiatry today. Despite improving the evidence base for practice (e.g. as has occurred for case-management in psychiatry), evidence-based medicine (EBM) is still susceptible to compromise and misrepresentation, due to unexamined or undeclared bias. Unless this potential for abuse is recognized and checked, EBM in psychiatry is in danger of being discredited at the hand of some of its own proponents. There is a need for more rigorous pursuit of evidence-based psychiatry, including more systematic declaration of bias in all research, whether quantitative or qualitative in design.     

Cerebellum and cognition—Viewed from philosophy of mind

Traditionally, it is believed, that the primary function of the cerebellum is to coordinate movement. During the past three decades, it has been controversially discussed, whether the cerebellum may also contribute to cognition and mental states like emotions. In this paper, no position relating to this controversy will be taken. Instead, the hypothesis of non-motor functions of the cerebellum will be viewed from the position of the philosophy of mind. The remarkably uniform microscopic structure and neuronal networks of the cerebellum have led to computer analogies by several authors. The main idea of functionalism, i.e., a theory within the philosophy of mind, is that the mental relates to the physical as computer software does to hardware. This raises the question, whether a cerebellar contribution to cognition and mental states would support functionalism in the philosophy of mind. No support of functionalism could be found in this study, investigating the classical philosophical arguments pro and con functionalism such as those of multiple realizability, the Chinese room and the explanatory gap, while taking the results of cerebellar research into account. On the other hand, philosophical reflection suggests a careful use of the phrases “cognitive dysmetria” (Andreasen et al. Proc Natl Acad Sci USA. 1996;93:9985–90) in the context of mental illness and of “dysmetria of thought” (Schmahmann Arch Neurol. 1991;48:1178–87). According to the argument of the explanatory gap there is at present little support for the assumption that the phenomenal experiencing of an altered emotion can be reduced to the dysmetria of movement.     

Are animal studies of antipsychotics appropriately dosed? Lessons from the bedside to the bench.

Animal models are crucial for understanding the mechanism of action of antipsychotics. However, the dose of an antipsychotic in animal studies is often arbitrarily chosen, with haloperidol 1 mg/kg being a rather common standard. Recent clinical positron emission tomography (PET) studies in patients show all antipsychotics to block dopamine D2 receptors, and most are effective at doses that lead to 60% to 80% D2 occupancy. When occupancy exceeds 80%, the incidence of side effects rises sharply. To use this "bedside" information to inform the "bench," we measured D2 occupancy in rats using a method similar in principle to the [11C]-raclopride PET method in humans. We found that: 1) as in humans, haloperidol is effective in animal models of antipsychotic action when D2 occupancy > 70% and leads to effects in models of extrapyramidal side effects when D2 occupancy is > 80%; 2) very low doses, 0.06 mg/kg/sc, cause acute D2 occupancy of 75%; 3) and even doses that acutely saturate D2 receptors give little D2 occupancy after 24 hours due to the very short half-life of haloperidol in rats (2.5 hours versus 24 hours in humans). We conclude that most previous animal studies of antipsychotics have used doses giving rise to inappropriately high acute D2 occupancy and inappropriately low D2 occupancy between doses. We exemplify how this dosing confounder could lead to inappropriate conclusions. Data from the bedside translated to the bench--using D2 occupancy as a mediating variable--will lead to more valid animal models.     

Can the brain be protected through exercise? Lessons from an animal model of parkinsonism

Evidence suggests that following injury the brain has the capacity for self-repair and that this can be promoted through a variety of experiences including motor activity. In their article, D?br?ssy and Dunnett have provided further evidence that this is the case in an animal model in which an excitotoxin is applied to the neostriatum. Under standard conditions, such a toxin would cause considerable damage to the GABAergic cells of this region and produce behavioral deficits. This model has been used to explore certain aspects of Huntington's disease, which also involves the loss of these neurons. However, D?br?ssy and Dunnett show that the damage can be reduced by prior motor training. We have been exploring the neuroprotective effects of motor exercise in a different model, one involving 6-hydroxydopamine, which normally destroys dopamine neurons. Our results indicate that forced exercise can reduce the vulnerability of dopamine neurons to 6-hydroxydopamine. The results further suggest that this protection is due in part to an increase in the availability of the trophic factor GDNF, which can in turn stimulate certain signaling cascades, including one that activates ERK. Our results, together with those of D?br?ssy and Dunnett and others, raise the possibility that exercise will protect against a variety of neurodegenerative conditions.     

Emotional behavior in aquatic organisms? Lessons from crayfish and zebrafish

Experimental animal models are a valuable tool to study the neurobiology of emotional behavior and mechanisms underlying human affective disorders. Mounting evidence suggests that various aquatic organisms, including both vertebrate (e.g., zebrafish) and invertebrate (e.g., crayfish) species, may be relevant to study animal emotional response and its deficits. Ideally, model organisms of disease should possess considerable genetic and physiological homology to mammals, display robust behavioral and physiological responses to stress, and should be sensitive to a wide range of drugs known to modulate stress and affective behaviors. Here, we summarize recent findings in the field of zebrafish- and crayfish-based tests of stress, anxiety, aggressiveness and social preference, and discuss further perspectives of using these novel model organisms in translational biological psychiatry. Outlining the remaining questions in this field, we also emphasize the need in further development and a wider use of crayfish and zebrafish models to study the pathogenesis of affective disorders.     

Peer support working: a question of ontology and epistemology?

There is increasing attention to the impacts of stigma and discrimination related to mental health on quality of life and access to and quality of healthcare. Effective strategies for stigma reduction exist, but most evidence comes from high-income settings. Recent reviews of stigma research have identified gaps in the field, including limited cultural and contextual adaptation of interventions, a lack of contextual psychometric information on evaluation tools, and, most notably, a lack of multi-level strategies for stigma reduction. The Indigo Partnership research programme will address these knowledge gaps through a multi-country, multi-site collaboration for anti-stigma interventions in low- and middle-income countries (LMICs) (China, Ethiopia, India, Nepal, and Tunisia). The Indigo Partnership aims to: (1) carry out research to strengthen the understanding of mechanisms of stigma processes and reduce stigma and discrimination against people with mental health conditions in LMICs; and (2) establish a strong collaborative research consortium through the conduct of this programme. Specifically, the Indigo Partnership involves developing and pilot testing anti-stigma interventions at the community, primary care, and mental health specialist care levels, with a systematic approach to cultural and contextual adaptation across the sites. This work also involves transcultural translation and adaptation of stigma and discrimination measurement tools. The Indigo Partnership operates with the key principle of partnering with people with lived experience of mental health conditions for the development and implementation of the pilot interventions, as well as capacity building and cross-site learning to actively develop a more globally representative and equitable mental health research community. This work is envisioned to have a long-lasting impact, both in terms of the capacity building provided to participating institutions and researchers, and the foundation it provides for future research to extend the evidence base of what works to reduce and ultimately end stigma and discrimination in mental health.     

The place of race and racism in cultural competence: what can we learn from the English experience about the narratives of evidence and argument?

This paper outlines the history of workforce strategies for providing mental health care to "black and ethnic minorities" in England. Universal mental health policies failed to deliver equity in care, and thus specific policies were launched to address ethnic inequalities in care experiences and outcomes. The emphasis on race equality rather than cultural complexity led to widespread acceptance of the need for change. The policy implementation was delivered in accord with multiple regional and national narratives of how to reduce inequalities. As changes in clinical practice and services were encouraged, resistance emerged in various forms from clinicians and policy leaders. In the absence of commitment and then dispute about forms of evidence, divergent policy and clinical narratives fuelled a shift of attention away from services to silence issues of race equality. The process itself represents a defence against the pain of acknowledging systemic inequities whilst rebutting perceived criticism. We draw on historical, psychoanalytic, and learning theory in order to understand these processes and the multiple narratives that compete for dominance. The place of race, ethnicity, and culture in history and their representation in unconscious and conscious thought are investigated to reveal why cultural competence training is not simply an educational intervention. Tackling inequities requires personal development and the emergence and containment of primitive anxieties, hostilities, and fears. In this paper we describe the experience in England of moving from narratives of cultural sensitivity and cultural competence, to race equality and cultural capability, and ultimately to cultural consultation as a process. Given the need to apprehend narratives in care practice, especially at times of disputed evidence, cultural consultation processes may be an appropriate paradigm to address intersectional inequalities.     

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.     

Motor deficits and schizophrenia: the evidence from neuroleptic-na?ve patients and populations at risk.

Patients with schizophrenia and high-risk populations have elevated rates of eye movement abnormalities. However, it is not known whether these abnormalities are specific to eye movements or whether they are also found in more traditional domains of motor control. Most studies examining the motor function of patients with schizophrenia have involved patients treated with medication; abnormalities in motor function could be a result of treatment rather than the disease itself. If motor abnormalities are related to schizophrenia, they should also be found in neuroleptic-naïve patients and possibly in high-risk populations in whom eye movement abnormalities are also observed. We reviewed relevant empirical papers published in the last 35 years. Results suggest that approximately one-fifth of neuroleptic-naïve patients with schizophrenia have increased rates of parkinsonism and neurological soft signs. In high-risk populations, replicated findings include delayed motor development in preschizophrenia subjects, and poor motor skills in the offspring of patients with schizophrenia. In first-degree relatives, increased rates of neurological soft signs were reported. These findings suggest that motor abnormalities are not limited to eye movements and may constitute markers of vulnerability. The literature has several weaknesses that should be addressed in future studies.     

Are the available apathy measures reliable and valid? A review of the psychometric evidence

Objective

Apathy is highly prevalent among neuropsychiatric populations and is associated with greater morbidity and worse functional outcomes. Despite this, it remains understudied and poorly understood, primarily due to lack of consensus definition and clear diagnostic criteria for apathy. Without a gold standard for defining and measuring apathy, the availability of empirically sound measures is imperative. This paper provides a psychometric review of the most commonly used apathy measures and provides recommendations for use and further research.

Methods

Pertinent literature databases were searched to identify all available assessment tools for apathy in adults aged 18 and older. Evidence of the reliability and validity of the scales were examined. Alternate variations of scales (e.g., non-English versions) were also evaluated if the validating articles were written in English.

Results

Fifteen apathy scales or subscales were examined. The most psychometrically robust measures for assessing apathy across any disease population appear to be the Apathy Evaluation Scale and the apathy subscale of the Neuropsychiatric Inventory based on the criteria set in this review. For assessment in specific populations, the Dementia Apathy Interview and Rating for patients with Alzheimer's dementia, the Positive and Negative Symptom Scale for schizophrenia populations, and the Frontal System Behavior Scale for patients with frontotemporal deficits are reliable and valid measures.

Conclusion

Clinicians and researchers have numerous apathy scales for use in broad and disease-specific neuropsychiatric populations. Our understanding of apathy would be advanced by research that helps build a consensus as to the definition and diagnosis of apathy and further refine the psychometric properties of all apathy assessment tools.     

Pushing the Margins of Responsibility: Lessons from Parks’ Somnambulistic Killing

David Shoemaker has claimed that a binary approach to moral responsibility leaves out something important, namely instances of marginal agency, cases where agents seem to be eligible for some responsibility responses but not others. In this paper we endorse and extend Shoemaker’s approach by presenting and discussing one more case of marginal agency not yet covered by Shoemaker or in the other literature on moral responsibility. Our case is that of Kenneth Parks, a Canadian man who drove a long way to his mother-in-law’s and killed her in a state of somnambulism. We support our claim about Parks’ marginal responsibility in three steps: we first deny that Parks acts involuntarily as traditionally claimed in the legal literature; we then propose to extend Shoemaker’s analysis of marginal responsibility based on quality of will so as to include two other dimensions: the moral status of the agent and the actual causal effects of their actions; finally, we distinguish Parks’ marginal responsibility from four other existing concepts: “tracing” (drunken cases), diminished responsibility (minor mental disorders), causal responsibility (Williams’ unlucky lorry driver), and moral disapproval without responsibility (bad actions by small children, animals, or machines).