Human models as tools in the development of psychotropic drugs

Despite the growing means devoted to research and development (R α D) and refinements in the preclinical stages, the efficiency of central nervous system (CMS) drug development is disappointing. Many drugs reach patient studies with an erroneous therapeutic indication andlor in incorrect doses. Apart from the first clinical studies, which are conducted in healthy volunteers and focus only on safety, iolerability, and pharmacokinetics, drug development mostly relies on patient studies. Psychiatric disorders are characterized by heterogeneity and a high rate of comorbidity. It is becoming increasingly difficult to recruit patients for clinical trials and there are many confounding factors in this population, for example, those related to treatments. In order to keep patient exposure and financial expenditure to a minimum, it is important to avoid ill-designed and inconclusive studies. This risk could be minimized by gathering pharmacodynamic data earlier in development and considering that the goal of a phase 1 plan is to reach patient studies with clear ideas about the compound's pharmacodynamic profile, its efficacy in the putative indication (proof of concept), and pharmacokinetic/pharmacodynamic relationships, in addition to safety, tolerability, and pharmacokinetics. Human models in healthy volunteers may be useful tools for this purpose, but their use necessitates a global adaptation of the phase scheme, favoring pharmacodynamic assessments without neglecting safety. We are engaged in an R α D program aimed to adapt existing models and develop new paradigms suitable for early proof of concept substantiation.     

Quality of life and related concepts in Parkinson's disease: a systematic review.

Several studies have investigated the quality of life (QOL) of patients with Parkinson's disease (PD). The purpose of this study was to review the conceptual and methodological quality of quality of life (QOL) studies among patients with PD and to identify factors associated with poor (HR)QOL. Computerized bibliographic databases were screened for publications from 1960 to January 2007. According to a list of predefined criteria, the methodological quality of the 61 studies, was moderate. The term 'QOL' was often used inappropriately. In fact, almost all studies in this review actually assessed health status (HS) instead of QOL. The functioning of patients with PD on physical, social, and emotional domains is affected by PD. Their HS seems to be lower when compared to healthy persons or patients with other chronic diseases. HS studies augment the insight in self-perceived functioning. Therefore, HS is conceived as a valuable construct. However, QOL is also an important factor in health care. Attention towards QOL is needed in order to draw valid conclusions regarding a person's subjective experience of well-being in a broad sense. In order to accomplish this, future studies should apply the QOL concept with more rigor, should use an adequate operational definition, and should employ sound measures.     

Apathy and depression scales in Parkinson's disease: are they good enough?

The choice of a scale has important implications for the results of clinical research, including epidemiological and treatment studies. In addition to the requirements for any clinical scale, evaluation of rating scales for depression and apathy in Parkinson's disease (PD) faces additional challenges, reflecting the overlap of syndromes, controversies on the concept particularly of apathy, fluctuations related to medication, and difficulties in assessment. However, a number of rating scales are available which have been assessed for use in patients with PD, and the evidence for the use of these scales is discussed. A number of scales fulfil the basic requirements but further studies on their properties are required. Scales for screening need to have different properties than scales for rating severity. Overall, there is no perfect scale, but the choice of scale needs to take into account clinimetric properties, validity in the sample examined, content and purpose.     

The Logical and Clinical Argument for the Concept of Meta-Schema in Cognitive Therapy

The role of client’s belief systems in therapy is the central concept in cognitive therapy. In our therapeutic work with clients, we focus on their cognitive schemas surrounding a particular problem. These schemas, however, are embedded in a hierarchy of much larger schemas which strongly influence the content of the particular sub-schemas being investigated. The purpose of this article is to introduce the concept of “meta-schema,” from a theoretical perspective, and then offer clinical case examples to illustrate this concept.     

Neuroethics, Gender and the Response to Difference

This paper examines how the new field of neuroethics is responding to the old problem of difference, particularly to those ideas of biological difference emerging from neuroimaging research that purports to further delineate our understanding of sex and/or gender differences in the brain. As the field develops, it is important to ask what is new about neuroethics compared to bioethics in this regard, and whether the concept of difference is being problematized within broader contexts of power and representation. As a feminist science studies scholar trained in the neurosciences, it seems logical to me that, as a growing field, neuroethics should reach out to the rich bodies of scholarship on the history of medicine, feminist theory and feminist bioethics while attempting to approach discussions of sex, gender and sexuality differences in the brain. What is also clear to me is that feminist scholars need to learn how to engage with neuroimaging studies on sex, gender and sexuality not just to critique, but also to productively contribute to neuroscientific research. The field of neuroethics can potentially provide the appropriate forum for this interdisciplinary engagement and create opportunities for shared perplexity. I suggest three possible points of departure for creating this shared perplexity, namely (i) is difference being measured in the study for the purpose of understanding difference in and of itself, or for the purpose of division?; (ii) is there an appreciation for biological complexity?; and (iii) is it assumed that structural differences can be conveniently translated into functional differences?     

Update on "expressed emotions"

The present article is meant to sum up the current state of scientific knowledge with regard to the concept of "Emotional Expression" and its very implementation in the clinical and therapeutical field which are well-known in anglo-saxon countries but very little applied and known in France. "Emotional Expression" (EE), which came out of research and studies undertaken by Brown (1959) and later on, Vaughn and Leff (1976), defines interaction between a schizophrenic patient and his close environment according to 3 criterium: judgmental comments and criticism, hostility, emotional over-involvement. Family surroundings are characterized by strong EE or weak EE according to the frequency and the quantity of the measures during a typical standard family-interview: the Camberwell Family Interview (CFI). A strong EE is considered as being a non-specific factor. "Emotional Expression" proves to be a predictable indication for relapse in terms of psychiatric affluence (positive symptoms), hospitalization rate and psycho-social adjustment process. The possibilities of forecasting do not concern specifically schizophrenia as the relation between family climate and relapse can be observed in other mental pathology as well. The psycho-educational approach which is induced by this research trend is based on a concept of a partnership between the patients's family and the patient. The purpose in fact is to bring about changes within the relationship of the patient and his environment so as to reduce judgmental criticism, hostility and emotional over-involvement (information programs concerning etiology, therapeutical strategies in view of improving understanding of the illness and to reorganize proper family relationship). The advantage of such a concept which is well-known lies in the fact that it helps to find out those family surroundings with strong EE who represent factors of relapse for psychiatric patients and to suggest therefore therapeutical treatment, the purpose of which should be defined together with all those concerned namely, the patient, the family, the therapeutist so as to intervene during the evolution of the illness. The literary bibliographical review which we have made lead us to find the existence of a wide field of research with results showing clearly the predictable aspects of EE in the illness process. In this way, new approaches in the "intake" of schizophrenic patients and their families are clearly defined.     

Referater

The borderline project in Umeå started 5 years ago. The purpose of the project is to study the validity of the borderline concept in terms of diagnostic specificity and long-term course and outcome under various conditions. A diagnostic battery including Kernberg's structural interview, Gunderson's DIB and DSM-III, along with the Defense Mechanism Test and Benjamin's SASB constitutes the common denominator of different studies. Another common denominator of the different studies is a time span of 3-5 years between initial and follow-up assessments. One study concerns the outcome of normal psychiatric care for a group of 50 unselected inpatients. Other studies include individual psychotherapy and milieu treatment for schizophrenic patients and group therapy for borderline patients. The completed studies so far include comparisons between different diagnostic methods and contrasts between suicided and non-suicided borderline patients.     

Capacity to consent to participate in research – a recontextualization

Capacity to consent is an important concept when working with people with learning disabilities. The current concept of consent is based on a dichotomous categorization: people either have or do not have capacity to consent. Several research studies have focused on the assessment of capacity to consent and these studies report a range from 0 to 65% of people with learning disabilities identified as having capacity to consent. Findings from these studies reflect several limitations with the current concept of consent. A recontextualization is needed in order to address these limitations. This should include the concept of risk and benefit assessment, i.e. the seriousness of the consequences involved determines the level of capacity needed for a specific decision. Moreover, the emergence of participatory research paradigms in the field of learning disabilities further challenges the validity of such concepts of consent. Therefore, it is proposed that it is more helpful to present the concept of capacity to consent within a broader contextual framework rather than as a unitary dichotomous categorization.     

Scientific and consumer models of recovery in schizophrenia: concordance, contrasts, and implications

Schizophrenia has traditionally been viewed as a chronic condition with a very pessimistic outlook, but that assumption may not be valid. There has been a growing consumer movement among people with schizophrenia that has challenged both the traditional perspective on the course of illness and the associated assumptions about the possibility of people with the illness living a productive and satisfying life. This new conception of the illness is supported by long-term studies that suggest that as much as 50% of people with the illness have good outcomes. There has also been a change in political and public health perspectives of the illness, stimulated in part by the President''s New Freedom Commission on Mental Health. The purpose of this article is to provide an overview of some key themes about the recovery concept, as applied to schizophrenia. The article will address 3 questions: (1) What is recovery? (2) Is recovery possible? and (3) What are the implications of a recovery model for a scientific approach to treatment (ie, the use of evidence-based practices)? Scientific and consumer models of recovery are described, and commonalities and differences are discussed. Priorities for future research are suggested.     

Ethnicity as a variable in mental disorder research

Despite voluminous research on mental disorders conducted on several levels with numerous variables. other potentially significant variables often are implied but seldom investigated. Most non-organically oriented studies have dealt with psychological variables. Research investigating socio-cultural variables has paid particular attention to social status. This paper suggests that investigations of socio-economic aspects of mental disorders — especially when directed toward etiology — are implicitly concerned with value systems, a related concept. But since value systems are more abstract than socio-economic status, a more easily operationalized intermediate variable — yet one more closely representing value systems — may be useful. Ethnicity is suggested for this purpose.     

Misuse of the Mood Disorders Questionnaire as a case-finding measure and a critique of the concept of using a screening scale for bipolar disorder in psychiatric practice

Zimmerman M. Misuse of the Mood Disorders Questionnaire as a case‐finding measure and a critique of the concept of using a screening scale for bipolar disorder in psychiatric practice. Bipolar Disord 2012: 14: 127–134. © 2012 The Author. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: Under‐recognition of bipolar disorder (BD) is common and incurs significant costs for individuals and society. Clinicians are often encouraged to use screening instruments to help them identify patients with the disorder. The Mood Disorder Questionnaire (MDQ) is the most widely studied measure for this purpose. Some studies, however, have used the MDQ as a case‐finding instrument rather than a screening scale. Such inappropriate use of screening scales risks distorting perceptions about many facets of BD, from its prevalence to its consequences. Methods: Studies using the MDQ were reviewed to identify those reports that have used the scale as a case‐finding measure rather than a screening scale. Results: Multiple studies were identified in the BD literature that used the MDQ as a diagnostic proxy. The findings of these studies were misinterpreted because of the failure to make the distinction between screening and case‐finding. Conclusions: Inappropriate conclusions have been drawn regarding the prevalence, morbidity, and diagnostic under‐recognition of BD in studies that rely on the MDQ as a diagnostic proxy. A conceptual critique is offered against the use of self‐administered screening questionnaires for the detection of BD in psychiatric settings.     

Is vitamin D hypothesis for schizophrenia valid? Independent segregation of psychosis in a family with vitamin-D-dependent rickets type IIA

The vitamin D hypothesis of schizophrenia is a recent concept bringing together old observations on environmental risk factors and new findings on the neurodevelopmental effects of vitamin D. Candidate genes related to the vitamin D endocrine system have not yet been fully explored for this purpose. The coexistence of vitamin-D-dependent-rickets type II with alopecia (VDDR IIA) and different forms of psychosis in the same inbred family has provided us with an opportunity to investigate the presumed relationship between vitamin D deficiency and psychosis. Psychiatric examination and molecular genetic studies were performed in this family overloaded with psychotic disorders and VDDR IIA. Forty members were evaluated in order to describe their phenotypic features. The family was tested for a linkage to the chromosome 12q12-q14 region where the vitamin D receptor (VDR) gene is located. Psychosis was the common phenotype in the 18 psychiatrically affected members. Pedigree analysis did not show a cosegregation of psychosis and rickets. Lod scores were not significant to prove a linkage between psychosis and VDR locus. The authors concluded that (1) the neurodevelopmental consequences of vitamin D deficiency do not play a causative role in psychotic disorders, (2) these two syndromes are inherited independently, and (3) vitamin D deficiency does not act as a risk factor in subjects susceptible to psychosis.     

A study of the psychoanalytic concept of castration anxiety in symbolically castrated amputees

Summary The purpose of this study was to investigate the concept of castration anxiety and syntactically related postulates of Freudian psychosexual theory. The importance of the study lies in the fact that castration anxiety is a central concept in Freudian theory, resulting in the subsidence of the Oedipal phase, the formation of the super-ego, ego development, and identification and preparation for the latency period. A group of symbolically castrated subjects (amputees) were compared with normal controls on certain castration anxiety indices of the Blacky Pictures. Within certain limitations involving the extrapolation of infantile phenomena to adulthood, presumptive evidence validating the castration anxiety concept was obtained. Presumptive validity was also demonstrated for the use of the Blacky Pictures in investigating psychoanalytic concepts.This study is adapted from an investigation conducted in 1956 under the auspices of the Prosthetic Devices Study of New York University, where the authors were then research associates. The authors wish to express their gratitude to Dr. Marvin L. Aronson, Postgraduate Center for Psychotherapy, for making available the data on normal subjects used in this study.     

Comments on the Reiss Screen for Maladaptive Behaviour and its factor structure

Sturmey's factor analysis of the Reiss Screen for Maladaptive Behaviour is based upon several significant errors, some of which are of general interest because misuse of factor analysis is common (Ford et al. 1986). In this commentary, the author discusses: the concept of factor robustness; appropriate samples for evaluating the factor structure of a dual diagnosis instrument; the differences between exploratory and confirmatory analyses; and how the Reiss Screen was intended to fulfill its purpose. In the Sturmey study, the Reiss Screen may have actually performed well under adverse conditions. The criteria for conducting valid factor analytic studies of dual diagnosis instruments are identified in order to encourage future research evaluating the Reiss Screen and other instruments.     

Meta-Consent in Research on Decisional Capacity: A “Catch-22”?

Empirical studies of ethical issues, which have increased in number and scope in recent years, may themselves raise both practical and ethical issues. One example of such an issue is the question of who may be legitimately enrolled in studies of decision-making capacity; must all participants in studies of consent capacity have capacity to consent? This question may pose a “Catch-22”: For example, if some of the participants in a study of consent capacity are deemed by a particular standard to be incapable of consent. In weighing the risks and benefits of studies of consent capacity, how should reviewers consider the context of actual versus hypothetical trials for which the participant''s consent is being sought? Here, we explore these “meta-consent” issues by describing the dimensions of the issue and potential solutions, centering around the concept of “active assent” (requiring expressed understanding of the purpose of the study and its voluntary nature, as well as expression of a choice to participate).     

A population-based survey of childhood epilepsy in Okayama Prefecture, Japan: reclassification by a newly proposed diagnostic scheme of epilepsies in 2001

The purpose of this study is to clarify the usefulness and problems of the newly proposed classification of epilepsies (International League Against Epilepsy: ILAE, 2001) in the epidemiological studies of epilepsy. We previously conducted an epidemiological study in Okayama Prefecture, Japan, in 1999, using the ILAE 1989 classification. Among 250,997 children under 13 years of age, 2220 epileptic patients were ascertained. In this study, we reclassified them according to the ILAE 2001 classification, focusing on axes 2 (seizure types) and 3 (syndromes). We were able to classify 1803 (95.0%) seizure types out of 1899 with detailed clinical information. In focal seizures, the most common were secondarily generalized seizures (88.6%), which generally do not represent a unique anatomic substrate. In generalized seizures, topic-clonic seizures (40.7%) and spasms (21.0%) were the most common. We identified only 269 (12.1%) patients with specific epilepsy syndromes out of the 2220. We classified 1761 patients without specific syndromic diagnoses only by axis 2, but the new concept of epileptic seizure types, representing a unique pathophysiologic mechanism and anatomic substrate, was not very meaningful in most cases, even in those with focal seizures.     

Competing Definitions of Schizophrenia: What Can Be Learned From Polydiagnostic Studies?

The contemporary diagnoses of schizophrenia (sz)-Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition(DSM-IV) and International Classification of Diseases, 10th Revision(ICD-10)-are widely considered as important scientific achievements. However, these algorithms were not a product of explicit conceptual analyses and empirical studies but defined through consensus with the purpose of improving reliability. The validity status of current definitions and of their predecessors remains unclear. The so-called "polydiagnostic approach" applies different definitions of a disorder to the same patient sample in order to compare these definitions on potential validity indicators. We reviewed 92 polydiagnostic sz studies published since the early 1970s. Different sz definitions show a considerable variation concerning frequency, concordance, reliability, outcome, and other validity measures. The DSM-IV and the ICD-10 show moderate reliability but both definitions appear weak in terms of concurrent validity, eg, with respect to an aggregation of a priori important features. The first-rank symptoms of Schneider are not associated with family history of sz or with prediction of poor outcome. The introduction of long duration criteria and exclusion of affective syndromes tend to restrict the diagnosis to chronic stable patients. Patients fulfilling the majority of definitions (core sz patients) do not seem to constitute a strongly valid subgroup but rather a severely ill subgroup. Paradoxically, it seems that a century after the introduction of the sz concept, research is still badly needed, concerning conceptual and construct validity of sz, its essential psychopathological features, and phenotypic boundaries.