Aaron S. Kemp

What Is Causing the Reduced Drug-Placebo Difference in Recent Schizophrenia Clinical Trials and What Can be Done About It?

On September 18, 2007, a collaborative session between the International Society for CNS Clinical Trials and Methodology and the International Society for CNS Drug Development was held in Brussels, Belgium. Both groups, with membership from industry, academia, and governmental and nongovernmental agencies, have been formed to address scientific, clinical, regulatory, and methodological challenges in the development of central nervous system therapeutic agents. The focus of this joint session was the apparent diminution of drug-placebo differences in recent multicenter trials of antipsychotic medications for schizophrenia. To characterize the nature of the problem, some presenters reported data from several recent trials that indicated higher rates of placebo response and lower rates of drug response (even to previously established, comparator drugs), when compared with earlier trials. As a means to identify the possible causes of the problem, discussions covered a range of methodological factors such as participant characteristics, trial designs, site characteristics, clinical setting (inpatient vs outpatient), inclusion/exclusion criteria, and diagnostic specificity. Finally, possible solutions were discussed, such as improving precision of participant selection criteria, improving assessment instruments and/or assessment methodology to increase reliability of outcome measures, innovative methods to encourage greater subject adherence and investigator involvement, improved rater training and accountability metrics at clinical sites to increase quality assurance, and advanced methods of pharmacokinetic/pharmacodynamic modeling to optimize dosing prior to initiating large phase 3 trials. The session closed with a roundtable discussion and recommendations for data sharing to further explore potential causes and viable solutions to be applied in future trials.

Alpha EEG guided TMS in schizophrenia

BACKGROUND Alpha EEG guided Transcranial Magnetic Stimulation (αTMS) of the dorsolateral prefrontal cortex (DLPFC) has shown promising efficacy for treating the negative symptoms of schizophrenia. OBJECTIVE/ HYPOTHESIS: The purpose of the current investigation was to test (1) the therapeutic effect in other domains of symptoms of schizophrenia and (2) the specificity of stimulus location. The hypothesis to be tested was that global alpha EEG normalization after αTMS would help improve the clinical symptoms of schizophrenia, regardless of the site of stimulation. METHOD Seventy-eight patients with schizophrenia were enrolled in a randomized, double-blind, sham-controlled study with four study groups: frontal αTMS, parietal αTMS, frontal sham, and parietal sham. Patients received daily treatment for 10 days and clinical evaluations at day 5 and 10. The stimulus rate and intensity were determined by individuals characteristic alpha frequency and motor threshold (80%). RESULTS Positive and general psychotic symptoms improved significantly after αTMS (P < 0.02). Frontal and parietal αTMS had similar effects (P = 0.48). (3) αTMS with concomitant typical neuroleptics treatment had greater efficacy than atypical neuroleptics (P < 0.04). Degree of EEG normalization as measured by increase in Q factor was highly associated with the improvement in all three domains of symptoms of schizophrenia (P < 0.04). CONCLUSIONS Alpha EEG normalization after treatment with αTMS may directly subserve the processes underlying clinical improvements in schizophrenia. Nonetheless, given the confound of possible unblinding of participants because of an inactive sham control, the current results should be considered preliminary until replicated further.

Increased temporal patterns in choice responding and altered cognitive processes in schizophrenia and mania.

RationaleThe THEME method for measuring time-determined patterns (T-patterns) in behavior has been suggested as a new, more objective method for assessing cognitive disturbances in schizophrenia.ObjectivesTHEME was used to compare responses of schizophrenic patients with those having mood, schizoaffective, or severe anxiety disorders, and with healthy control subjects.MethodsA two-choice, button-pressing task was used to elicit T-patterns among responses, with knowledge-of-results (K) rewards and coin reinforcements (RF) as reinforcers. Subjects were compared by diagnosis, drug treatment, and gender.ResultsSchizophrenic and manic patients showed excessive numbers of, and more complex T-patterns than controls. Schizophrenic and manic patients frequently demonstrated repetitive (stereotyped) responding, an effect never seen in healthy controls. Although clozapine (CLZ) reduced both excessive T-pattern structure and stereotyped responding, it also reduced growth of responding to the coin RF.ConclusionsSignificant T-pattern increases may represent a common, time-related symptom of schizophrenia and mania. CLZ’s effect on T-pattern production suggests that receptor effects other than the DAD2 antagonism of “typical” neuroleptics’ may be relevant to these findings.

Opioid Antagonists May Reverse Endogenous Opiate “Dependence” in the Treatment of Self-Injurious Behavior

Self-injurious behavior (SIB) is a primary reason that individuals with neurodevelopmental disabilities (NDD) are either retained in restrictive environments or are administered psychotropic medication. There are no known causes and no universally accepted treatments for this complex behavior among individuals with NDD. There is developing evidence, however, that individuals exhibiting SIB have a disturbance of the opiate-mediated pain and pleasure system. One hypothesis is that SIB reflects insensitivity to pain and general sensory depression (hypoalgesia), perhaps related to chronic elevation of endogenous opiates. For instance, many self-injurious individuals do not exhibit the usual signs of pain after their “injurious” behavior. Moreover, for some individuals the addictive properties of elevated endogenous opiates (euphoria) may be responsible for maintaining their SIB. In this perspective, SIB may be viewed as an addiction because it supplies the “fix” for tolerant, down-regulated opiate receptors. Reports that levels of endogenous opiates at rest and after SIB episodes predict positive responses to opiate blockers (e.g., naltrexone) provide further support for opiate-mediated SIB and form the basis for a rational treatment strategy. Although the long term effects of opiate blockers on SIB are unknown, reduction in SIB following acute treatment provides support that a specific biological system may be dysregulated in a subgroup of patients. It is concluded that naltrexone produces a clinically significant reduction in the serious and life-threatening behavior of self injury for individuals who have not been responsive to any other type of treatment. Several suggestions and cautions are provided for regimens of naltrexone treatment of SIB.

Consumer and provider responses to a computerized version of the Illness Management and Recovery Program.

OBJECTIVE To explore mental health consumer and provider responses to a computerized version of the Illness Management and Recovery (IMR) program. METHOD Semistructured interviews were conducted to gather data from 6 providers and 12 consumers who participated in a computerized prototype of the IMR program. An inductive-consensus-based approach was used to analyze the interview responses. RESULTS Qualitative analysis revealed consumers perceived various personal benefits and ease of use afforded by the new technology platform. Consumers also highly valued provider assistance and offered several suggestions to improve the program. The largest perceived barriers to future implementation were lack of computer skills and access to computers. Similarly, IMR providers commented on its ease and convenience, and the reduction of time intensive material preparation. Providers also expressed that the use of technology creates more options for the consumer to access treatment. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE The technology was acceptable, easy to use, and well-liked by consumers and providers. Clinician assistance with technology was viewed as helpful to get clients started with the program, as lack of computer skills and access to computers was a concern. Access to materials between sessions appears to be desired; however, given perceived barriers of computer skills and computer access, additional supports may be needed for consumers to achieve full benefits of a computerized version of IMR.

Gating of a novel brain potential is associated with perceptual anomalies in bipolar disorder.

Patterson JV, Sandman CA, Jin Y, Kemp AS, Potkin SG, Bunney WE Jr. Gating of a novel brain potential is associated with perceptual anomalies in bipolar disorder. 
Bipolar Disord 2013: 00: 000–000.

The role of self‐injury in the organisation of behaviour

BACKGROUND Self-injuring acts are among the most dramatic behaviours exhibited by human beings. There is no known single cause and there is no universally agreed upon treatment. Sophisticated sequential and temporal analysis of behaviour has provided alternative descriptions of self-injury that provide new insights into its initiation and maintenance. METHOD Forty hours of observations for each of 32 participants were collected in a contiguous 2-week period. Twenty categories of behavioural and environmental events were recorded electronically that captured the precise time each observation occurred. Temporal behavioural/environmental patterns associated with self-injurious events were revealed with a method (t-patterns; THEME) for detecting non-linear, real-time patterns. RESULTS Results indicated that acts of self-injury contributed both to more patterns and to more complex patterns. Moreover, self-injury left its imprint on the organisation of behaviour even when counts of self-injury were expelled from the continuous record. CONCLUSIONS Behaviour of participants was organised in a more diverse array of patterns when self-injurious behaviour was present. Self-injuring acts may function as singular points, increasing coherence within self-organising patterns of behaviour.

Psychometric Comparison of Standard and Computerized Administration of the Alzheimers Disease Assessment Scale – Cognitive Subscale (ADASCog)

BACKGROUND The Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) has become the de facto gold standard for assessing the efficacy of anti-dementia treatments. However, manual administration of the ADAS-Cog is subject to procedural inconsistencies, including scoring and transcription errors, which can introduce unwanted variance and compromise data quality within and across sites and trials. To address such concerns, a computerized version was developed that integrates, rather than replaces, the examiner, standardizes administration, and uses electronic data capture at the point of patient contact. The examiner can control administration and pacing, pause or repeat digitized instructions, score verbal report and overt behavioral performance, and freely interact with the subject. PURPOSE To conduct psychometric comparisons of traditional, paper-based administration of the standard ADAS-Cog (sADAS) with examiner- assisted administration of the computerized ADAS-Cog (cADAS). METHODS Eighty-eight patients (39M; 49F) with mild to moderate Alzheimer’s disease were tested on three occasions with each version over a period of one year with one month between paired visits. RESULTS Intraclass Correlation Coefficients (ICC) comparisons between sADAS and cADAS were significant for total score (ICC=0.96) and all subscores (ICCs ranged 0.78-0.93), with no significant differences on paired t-tests. The mean ICCs across cADAS scores for test-retest reliability for short-term (mean ICC=0.96) and long-term (mean ICC=0.91) comparisons were significantly higher than across sADAS scores (mean ICCs were 0.87 and 0.84, respectively). CONCLUSIONS These results indicate that examiner-assisted, computerized administration is equivalent to traditional, paper-based administration, and shows significantly greater test-retest reliability.

Trial Designs Likely to Meet Valid Long-Term Alzheimer's Disease Progression Effects: Learning from the Past, Preparing for the Future

The International Society for CNS Clinical Trials and Methodology (ISCTM) held its 4th Annual Autumn Conference in Toronto, Ontario, October 6-7, 2008. The purpose of the present report is to provide an overview of one of the sessions at the conference which focused on the designs and methodologies to be applied in clinical trials of new treatments for Alzheimers disease (AD) with purported “disease-modifying” effects. The session began with a discussion of how neuroimaging has been applied in multiple sclerosis clinical trials (another condition for which disease modification claims have been achieved). The next two lectures provided a pharmaceutical industry perspective on some of the specific challenges and possible solutions for designing trials to measure disease progression and/or modification. The final lecture provided an academic viewpoint and the closing discussion included additional academic and regulatory perspectives on trial designs, methodologies, and statistical issues relevant to the disease modification concept.

Summary of the 1st Schizophrenia International Research Society Conference oral sessions, Venice, Italy, June 21-25, 2008: The rapporteur reports

The Schizophrenia International Research Society held its first scientific conference in Venice, Italy, June 21 to 25th, 2008. A wide range of controversial topics were presented in overlapping and plenary oral sessions. These included new genetic studies, controversies about early detection of schizophrenia and the prodrome, treatment issues, clinical characteristics, cognition, neuropathology and neurophysiology, other etiological considerations, substance abuse co-morbidity, and animal models for investigating disease etiology and for use as targets in drug studies. Young investigators in the field were awarded travel grants to participate in the congress and one of their roles was to summarize the oral sessions and subsequent discussions. The reports that follow are the culmination of this work produced by 30 young investigators who attended the congress. It is hoped that these summaries will be useful synopses of what actually occurred at the congress for those who did not attend each session or were unable to be present. The abstracts of all presentations, as submitted by the authors a few months prior, were previously published as supplement 2 to volume 102/1-3, June 2008.