Government initiatives in autism clinical trials

Randomized clinical trials remain the most valid method of testing the efficacy and safety of treatments. While efforts to elucidate the genetic and neurodevelopmental bases of autism are underway, clinicians and families are in need of scientifically valid information on how to best treat patients with autism. The effectiveness of many interventions currently used in communities has not been adequately tested. Given the high public health relevance of autism treatment research and the low interest of the pharmaceutical industry in autism, the role of the National Institutes of Health in supporting this research is paramount. Among recently launched initiatives in autism clinical trials, there are the Research Units on Pediatric Psychopharmacology Autism Network and the network of centers for Studies to Advance Autism Research and Treatment. These and other government activities in the area of autism clinical trials are here briefly reviewed.     

Outcome measures for clinical drug trials in autism

This paper identifies instruments and measures that may be appropriate for randomized clinical trials in participants with autism spectrum disorders (ASDs). The Clinical Global Impressions scale was recommended for all randomized clinical trials. At this point, however, there is no "perfect" choice of outcome measure for core features of autism, although we will discuss five measures of potential utility. Several communication instruments are recommended, based in part on suitability across the age range. In trials where the intention is to alter core features of ASDs, adaptive behavior scales are also worthy of consideration. Several "behavior complexes" common to ASDs are identified, and instruments are recommended for assessment of these. Given the prevalence of cognitive impairment in ASDs, it is important to assess any cognitive effects, although cognitive data from ASD randomized clinical trials, thus far, are minimal. Guidance from trials in related pharmacologic areas and behavioral pharmacology may be helpful. We recommend routine elicitation of side effects, height and weight, vital signs, and (in the case of antipsychotics) extrapyramidal side-effects assessment. It is often appropriate to include laboratory tests and assessments for continence and sleep pattern.     

Identity: recent findings and clinical implications

After a review of foundational contributions to the concept of identity, including Erikson's, the author discusses the research methods and findings of the Personality Disorders Institute of the Joan and Sanford I. Weill Medical College of Cornell University regarding the concepts of normal identity and identity diffusion, toward an elucidation of the psychopathology of personality disorders--their etiology, diagnosis, and treatment. The application of an object relations theory model to analyze the development of identity clarifies the relationship of individual identity with the social and cultural frame that influences identity formation and may amplify the effects of pathological identity development. Detailed excerpts are presented from a diagnostic structural interview at the Personality Disorders Institute.     

Neurobiological correlates of autism: a review of recent research.

This review paper integrates recent structural and functional imaging, postmortem, animal lesion, and neurochemical research about the pathophysiology of autism. An understanding of the neurobiological correlates of autism is becoming increasingly important as more children are diagnosed with the condition and funding for well-targeted interventions increases. Converging evidence suggests that autism involves abnormalities in brain volume, neurotransmitter systems, and neuronal growth. In addition, evidence firmly links autism with abnormalities in the cerebellum, the medial temporal lobe, and the frontal lobe. Potential implications of these findings and suggestions for future research are reviewed.     

The empirical status of empirically supported psychotherapies: assumptions, findings, and reporting in controlled clinical trials

This article provides a critical review of the assumptions and findings of studies used to establish psychotherapies as empirically supported. The attempt to identify empirically supported therapies (ESTs) imposes particular assumptions on the use of randomized controlled trial (RCT) methodology that appear to be valid for some disorders and treatments (notably exposure-based treatments of specific anxiety symptoms) but substantially violated for others. Meta-analytic studies support a more nuanced view of treatment efficacy than implied by a dichotomous judgment of supported versus unsupported. The authors recommend changes in reporting practices to maximize the clinical utility of RCTs, describe alternative methodologies that may be useful when the assumptions underlying EST methodology are violated, and suggest a shift from validating treatment packages to testing intervention strategies and theories of change that clinicians can integrate into empirically informed therapies.     

Evaluation of drug toxicity in clinical trials

An increasing number of drugs removed from the market because of unacceptable toxicity raises concerns regarding preapproval testing of drug safety. In the present paper it is postulated that the non-inferiority type of trial should be abandoned in favor of the superiority trial with active controls and less stringent (p<0.1, both for efficacy and toxicity) statistics. This approach will increase sensitivity of detection of drug-induced adverse effects at the expense of increasing false positive results regarding the difference in efficacy between the tested and reference drug. Such a move will increase the protection of future patients. In addition, the proposed design is far more acceptable from the clinical (e.g. no need to specify the statistically expected “unimportant” number of deaths) and ethical points of view, as well as being favored by the strong incentive of involved parties. In the second part of this paper arguments are presented in favor of the hypothesis that placebo (still used in some superiority trials) does not induce adverse effects. The assertion that placebo may induce adverse effects is probably biased by the nature of the clinical experiment. Such a conclusion is supported by studies indicating that placebo-induced adverse effects are disease — and treatment — specific. The modification of clinical trials according to the proposed changes may increase the trials’ sensitivity at detecting adverse effects of drugs. A lecture on the subject of this paper was presented at the 6th International Bioethics Conference on the subject of ‘The Responsible Conduct of Basic and Clinical Research’, held in Warsaw, Poland, 3–4 June 2005.     

An analysis of recent meditation research and suggestions for future directions

Abstract

Meditation offers a rich and complex field of study. Over the past 40 years, several hundred research studies have demonstrated numerous significant findings including changes in psychological, physiological, and transpersonal realms. This paper attempts to summarize these findings, and to review more recent meditation research. We then suggest directions for future research, emphasizing the necessity to continue to expand the paradigm from which meditation research is conducted, from a predominantly re‐ductionistic, biomedical model to one which includes subjective and transpersonal domains and an integral perspective.     

The longitudinal study of personality disorders: history, design considerations, and initial findings

The Longitudinal Study of Personality Disorders (LSPD) began in 1990 and it is the first NIMH-funded prospective multiwave longitudinal study of all DSM-defined personality disorders (PDs). The LSPD, now in its 16th year, has focused on several major issues including: (a) the epidemiology of the PDs; (b) the stability of individual differences and mean levels of PD features over time; (c); patterns of individual growth in PD features over time; (d) the development of a neurobehavioral model that links personality and personality disorder; (e) specification of those neurobehavioral systems predicting change in borderline personality disorder; and (f) illumination of simultaneous growth processes in neurobehavioral systems and PD. The LSPD possesses a number of methodological enhancements designed to increase the validity of the longitudinal findings such as a prospective multiwave design, use of a validated structured interview and well-known self-report instrument for Axis II assessments, double measurement of all major constructs under study, use of blinded interviewers for all interview Axis II assessments, and use of a community sample. The history and context in which the LSPD was developed is reviewed, methodological issues related to the study of PDs are discussed, primary LSPD findings to date are summarized, and future directions of the LSPD are introduced.     

The impact of HIV infection on society's perception of clinical trials

All international codes of research ethics and virtually all national legislation and regulation in the field of research involving human subjects project an attitude of protectionism. Written with the aim of avoiding a repetition of atrocities like those committed by the Nazi physician-researchers, calamities like the thalidomide experience, or ethical violations like those of the Tuskegee syphilis study, their dominant concerns are the protection of individuals from injury and from exploitation. In recent years, however, society's perception of clinical research has shifted dramatically. Now, largely as a consequence of the efforts of the AIDS activists, clinical research is widely perceived as benign and beneficial. Although this shift in attitude has resulted in some important improvements in research policies and practices, this new perception is just as wrong-headed as was the earlier excessive protectionism. It is necessary to maintain a balanced perspective; our policies should encourage the conduct of ethical research while maintaining the vigilance necessary to safeguard the rights and welfare of the subjects.     

The study of autism as a distributed disorder

Past autism research has often been dedicated to tracing the causes of the disorder to a localized neurological abnormality, a single functional network, or a single cognitive-behavioral domain. In this review, I argue that autism is a "distributed disorder" on various levels of study (genetic, neuroanatomical, neurofunctional, behavioral). "Localizing" models are therefore not promising. The large array of potential genetic risk factors suggests that multiple (or all) emerging functional brain networks are affected during early development. This is supported by widespread growth abnormalities throughout the brain. Interactions during development between affected functional networks and atypical experiential effects (associated with atypical behavior) in children with autism further complicate the neurological bases of the disorder, resulting in an "exponentially distributed" profile. Promising approaches to a better characterization of neural endophenotypes in autism are provided by techniques investigating white matter and connectivity, such as MR spectroscopy, diffusion-tensor imaging (DTI), and functional connectivity MRI. According to a recent hypothesis, the autistic brain is generally characterized by "underconnectivity." However, not all findings are consistent with this view. The concepts and methodology of functional connectivity need to be refined and results need to be corroborated by anatomical studies (such as DTI tractography) before definitive conclusions can be drawn.     

The CIOMS view on the use of placebo in clinical trials

Based on worldwide consultations with experts in science and ethics the revised CIOMS 2002 International Ethical Guidelines for Biomedical Research Involving Human Subjects provide guidance on when the use of placebo as a comparator in clinical research is ethically acceptable. The article reviews the main points of the CIOMS Guidelines and commentaries including the use of placebo in situations where the best current method is available and the relation of placebo to established effective intervention. It discusses the use of placebo in externally sponsored research in low-resource countries and requirements for informed consent related to placebo studies. An earlier version of this paper was presented at an international conference, “Placebo: Its Action and Place in Health Research Today,” held in Warsaw, Poland on 12–13 April, 2003.     

Impact of age-relevant goals on future thinking in younger and older adults

This study investigated how personal goals influence age differences in episodic future thinking. Research suggests that personal goals change with age and like autobiographical memory, future thinking is thought to be organised and impacted by personal goals. It was hypothesised that cueing older adults with age-relevant goals should modulate age differences in episodic details and may also influence phenomenological characteristics of imagined scenarios. Healthy younger and older adults completed the Future Thinking Interview [Addis, D. R., Wong, A. T., & Schacter, D. L. (2008). Age-related changes in the episodic simulation of future events. Psychological Science, 19(1), 33–41. doi:10.1111/j.1467-9280.2008.02043.x] adapted to activate age-appropriate goals. Narratives were scored with an established protocol to obtain objective measures of episodic and semantic details. Subjective features such as emotionality and personal significance showed age differences as a function of goal domain while other features (e.g., vividness) were unaffected. However, consistent with prior reports, older adults produced fewer episodic details than younger adults and this was not modulated by goal domain. The results do not indicate that goal activation affects level of episodic detail. With respect to phenomenological aspects of future thinking, however, younger adults show more sensitivity to goal activation, compared with older adults.