An Overview of Current Statistical Methods for Implementing Quality Tolerance Limits.

BACKGROUND: In 2016, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use updated its efficacy guideline for good clinical practice and introduced predefined quality tolerance limits (QTLs) as a quality control in clinical trials. QTLs are complementary to Quality by Design (QbD) principles (ICH-E8) and are one of the components of the risk-based clinical trial quality management system. METHODS: Currently the framework for QTLs process is well established, extensively describing the operational aspects of Defining, Monitoring and Reporting, but a single source of commonly used methods to establish QTLs and secondary limits is lacking. This paper will primarily focus on closing this gap and include applications of statistical process control and Bayesian methods on commonly used study level quality parameters such as premature treatment discontinuation, study discontinuation and significant protocol deviations as examples. CONCLUSIONS: Application of quality tolerance limits to parameters that correspond to critical to quality factors help identify systematic errors. Some situations pose special challenges to implementing QTLs and not all methods are optimal in every scenario. Early warning signals, in addition to QTL, are necessary to trigger actions to further minimize the possibility of an end-of-study excursion.

Temporal lobe epilepsy following maintenance electroconvulsive therapy-Electrical kindling in the human brain?

Maintenance electroconvulsive therapy (ECT) is sometimes prescribed for refractory psychiatric conditions. We describe five patients who received maintenance ECT and developed florid temporal epileptiform abnormalities on electroencephalography (EEG) despite no history of epilepsy and normal neuroimaging. All patients had received regular ECT for at least 8 months. Three patients had clinical events consistent with epileptic seizures, and video-EEG monitoring captured electrographic seizures in two patients. After cessation of ECT the EEGs normalized in all patients, and no further clinical seizures occurred. Maintenance ECT may predispose to epilepsy with a seizure focus in the temporal lobe.

Are consumers on community treatment orders informed of their legal and human rights? a West Australian study.

The human and legal rights under the Western Australian Mental Health Act (1996) of involuntary patients on community treatment orders (CTOs) include being provided with information by clinicians about the treatment expectations of the order, the procedure for review of status by the Mental Health Review Board, access to the Council of Official Visitors, and the opportunity for a second opinion about their psychiatric condition. To date, there has been no specific research in this area. This paper presents the findings of a study conducted in Western Australia where consumers on CTOs were asked to provide feedback as to whether they were informed of these legal rights. A questionnaire was distributed which asked eight questions related to being informed of these rights. The results indicated that from the consumer's perspective, the process of providing them with information about their rights was only partially met. Most consumers were informed about first appointments, their right to a review by the Mental Health Review Board, and provided with the appropriate legal form. However, in relation to what it means to be on a CTO, access to the Council of Official Visitors and the right to a second opinion, information was not being provided to the majority of consumers. The findings suggest that mental health clinicians need to make significant improvements in providing information to consumers. This level of consumer engagement could have beneficial results for the development of therapeutic relationships which in turn may lead to improved compliance with the CTO and better health outcomes for the consumer.

The effects of cannabis on information-processing speed.

Despite extensive research on the effects of cannabis on cognitive and motor performance, studies administering computerised cognitive batteries and pencil-and-paper tests have not provided consistent results. Contributing factors are the broad range of tests used, together with a lack of sensitivity for assessing specific cognitive processes. This study for the first time assesses a very early cognitive process, information processing, that is sufficiently fundamental as to be immune from higher cognitive, motivational, and social processes. Information processes are thought to represent the basic building blocks of higher order cognitive processes. The inspection time (IT) task was used to investigate the effects of acute and subacute cannabis use on information processing in 22 heavy users, compared to 22 noncannabis-using controls. Findings indicate that users in the subacute state display significantly slowed information-processing speeds (longer ITs) compared to controls. Paradoxically, this deficit appears to be normalised whilst users are in the acute state. These results may be explained as a withdrawal effect, but may also be due to tolerance development as a result of long-term cannabis use. Furthermore, these results may assist in providing an explanation for the development of dependence with chronic cannabis users.

Depressive, positive, negative and parkinsonian symptomsin schizophrenia.

OBJECTIVE: Depressive symptoms are common in schizophrenia but their relationship to the positive and negative symptoms of the disorder and to extrapyramidal side-effects remains unclear. Considerable overlap exists between these symptom clusters when rated with traditional clinical rating scales. The aim of this study was to investigate the relationship of depressive to positive, negative and parkinsonian symptoms using the recent adaptation of the Positive and Negative Syndrome Scale (PANSS). METHOD: The study involved the cross-sectional measurement of symptoms in a sample of community-treated and hospitalized patients with schizophrenia. Structured assessment included thePANSS, Montgomery-Asberg Depression Rating Scale (MADRS) and the Extrapyramidal Side Effects Rating Scale (ESRS). RESULTS: Depressive symptoms were common and correlated with positive and negative symptoms. These correlations were of a similar magnitude using either the original PANSS factor structure or the newer pentagonal model. The overlap between depressive and negative symptoms was limited to certain items in the rating scales and there was a clear separation between these symptom clusters and the other items. Parkinsonian symptoms also correlated with negative symptoms rated with either PANSS model. CONCLUSION: Use of the pentagonal PANSS model does not improve its capacity to distinguish between depressive and negative symptoms. Positive, negative, parkinsonian and depressive symptoms overlap using common rating scales but there appears to be some separation between these symptom domains when rated with individual scale items rather than total scale scores.