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THE EFFICACY AND TOLERABILITY OF ONCE-DAILY EXTENDED RELEASE QUETIAPINE FUMARATE IN HOSPITALIZED PATIENTS WITH ACUTE SCHIZOPHRENIA: A 6-WEEK RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY
Jean-Pierre Lindenmayer, MD, David Brown, MD,  Sherry Liu, PhD, Martin Brecher, MD, and Didier Meulien, MD,  on behalf of the Study 41 investigators

ABSTRACT
Objectives: This study aimed to demonstrate efficacy of once-daily extended release quetiapine fumarate (quetiapine XR) versus placebo in patients with acute schizophrenia.
Methods: In this 6-week, randomized, double-blind study (5077IL/0041) patients were randomized to receive quetiapine XR (300, 600, or 800mg/day), quetiapine fumarate immediate release (quetiapine IR) [300 or 600mg/day], or placebo.  Primary endpoint was change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score at Day 42.  Secondary variables included PANSS response rate at Day 42 (≥30% decrease in PANSS total score from baseline) and Clinical Global Impressions Severity (CGI S) and Improvement (CGI-I) ratings.  Safety assessments included adverse event (AE) reporting and laboratory measures.
Results: Of 532 patients randomized, 222 (41.7%) completed the study.  Improvements in PANSS total scores from baseline to Day 42 across treatment groups were: quetiapine XR 300mg/day  5.01, 600mg/day -13.01 and 800mg/day -11.17, quetiapine IR 300mg/day -9.42 and 600mg/day -6.97, and placebo -5.19; the difference in change was statistically significant only for quetiapine XR 600mg/day (p=0.033).  There were no statistically significant differences between active treatment groups and placebo for PANSS response rates.  Several post hoc analyses were conducted to explain the study efficacy outcome but these were inconclusive.  Quetiapine XR was generally well tolerated with the majority of AEs being mild or moderate in intensity and no unexpected AEs.
Conclusions: Superior efficacy of quetiapine XR versus placebo in patients with schizophrenia was demonstrated for quetiapine XR 600mg/day.  The safety and tolerability profile of quetiapine XR was similar to that of quetiapine IR.



A MAJOR CHANGE OF PRESCRIBING PATTERN IN ABSENCE OF ADEQUATE EVIDENCE: BENZODIAZEPINES VERSUS NEWER ANTIDEPRESSANTS IN ANXIETY DISORDERS
Patricia BERNEY, MD, Demian HALPERIN, MD, Rodrigo TANGO, MD, Isabelle DAENIKER-DAYER, MD, and
Pierre SCHULZ, MD

ABSTRACT

We performed a systematic review of controlled trials on anxiety disorders treatment (generalized anxiety disorder, panic disorder, social phobia and post-traumatic stress disorder) published from 1980 to 2006, and identified trials comparing the efficacy of benzodiazepines (BZD) with that of antidepressants, in particular comparisons between BZD and newer antidepressants.  Among 969 publications, 274 double-blind randomized controlled studies remained after using our exclusion criteria.  These studies comprised altogether 439 comparisons.  There were in total 23 comparisons of antidepressants versus BZD.  Among these, 22 compared the efficacy of older antidepressants versus BZD, whereas only 1 concerned the comparison of a newer antidepressant versus BZD.  It showed comparable efficacy between venlafaxine and diazepam in the treatment of generalized anxiety disorder.  Our study shows that the major change of prescribing pattern from BZD to newer antidepressants in anxiety disorders has occurred in absence of comparative data of high level of proof.



Developing and Testing Adaptive Treatment Strategies Using Substance-Induced Psychosis as an Example
Short Title:  Strategies for Substance-Induced Psychosis
Ree Dawson, Ph.D., Alan I. Green, M.D., Robert E. Drake, M.D., Ph.D. Thomas H. McGlashan, M.D., Bella Schanzer, M.D. and Philip W. Lavori, Ph.D.

Abstract

Decisions concerning treatment changes pervade the management of chronic psychiatric disorders that resist definitive cure, yet empirical evidence for the comparative clinical effectiveness of treatment strategies remains underdeveloped.  In this paper we exploit the example of psychosis following substance use to illustrate some new developments in clinical trials design that can provide the most solid evidence base for defining successful strategies.  The intent is to explore the strengths and limitations of the methodological approach through a meaningful clinical example, with an emphasis on concepts and issues.  Both methodology and clinical science are overviewed.



Cocaine is a major Risk Factor for Antipsychotic Induced Akathisia, Parkinsonism and Dyskinesia
Arija Maat, MD,1 Annemarie Fouwels, MD, and Lieuwe de Haan, MD, PhD

Abstract

Objective: To assess the relative contribution of different drugs of abuse to extrapyramidal side effects (EPS) of antipsychotic drugs.
Method: 106 consecutively contacted or admitted male patients in the Psychiatric Center of Surinam (PCS) with schizophrenia or a related disorder were included. Prevalence and severity of EPS were measured with the Unified Parkinson’s Disease Rating Scale (UPDRS), the Abnormal Involuntary Movement rating Scale (AIMS), the Barnes Akathisia Rating Scale (BARS) and the Dystonia rating scale. Recent use of cigarettes, cannabis, alcohol, and cocaine were assessed. Standard multiple regression analyses were used to evaluate the relative contribution of above-mentioned drugs of abuse controlled for milligrams haloperidol equivalent a day and use of anticholinergic medication.
Results: Recent cocaine use was significantly associated with severity of dyskinesia (p = 0.001), parkinsonism (p = 0.007), and akathisia (p < 0.001) (n = 106).
Conclusions: Recent cocaine use is a major risk factor for antipsychotic induced EPS.



Psychometric Evaluation of a Patient-Rated Most Troubling Symptom Scale for Generalized Anxiety Disorder Clinical Trials
Gahan J. Pandina, Dennis A. Revicki, Leah Kleinman, Ibrahim Turkoz, Jasmanda Wu, Ramy Mahmoud, and Georges M. Gharabawi

ABSTRACT
Background: The majority of clinical outcome assessments developed for generalized anxiety disorder (GAD) may not efficiently and sensitively reflect heterogeneous symptom clusters from a patient perspective.  The Patient-Rated Troubling Symptoms Scale for Anxiety (PaRTS-A) was developed to provide an individualized assessment of patient relevant GAD symptoms. 
Objective: The objective of this analysis was to evaluate the psychometric characteristics of the PaRTS-A. 
Methods:  Data were taken from a 6-week clinical trial evaluating the efficacy of adjunctive risperidone therapy in GAD patients undergoing standard treatment.  Patients completed the PaRTS-A, the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) and the Sheehan Disability Scale (SDS) as well as impressions of improvement. Physicians completed the HAM-A.  PaRTS-A instrument characteristics were assessed through statistical tests of reliability, reproducibility, construct and discriminant validity, and responsiveness.
Results: In the item response theory (IRT) analysis, the PaRTS-A items fit into a single construct of anxiety.  Internal consistency reliability exceeded 0.70. The PaRTS-A total score was moderately correlated with the Q-LES-Q and the SDS. The PaRTS-A distinguished between patients with high and low HAM-A scores (p <0.001).   The PaRTS-A was responsive to changes in clinical status and the minimal important difference was identified. 
Conclusion: The PaRTS-A provides a unique patient-rated assessment of anxiety symptoms.  The instrument may provide clinicians with useful information regarding patient’s self-rated anxiety disorder symptoms and the hierarchy of symptoms that they considered most troubling. Our analysis suggests that the PaRTS-A is an internally consistent, valid and responsive instrument that may be a beneficial adjunct to other instruments in clinical trials.  



PLACEBO RESPONSE IN DEPRESSION:  A PERSPECTIVE FOR CLINICAL PRACTICE
Arif Khan, MD, and Shirin Khan, BS

Conclusions

It is important to note that acute head to head comparison of antidepressants to placebo is difficult test for most depression treatments to pass.  In fact, antidepressant trials using the long-term withdrawal model may reflect a more reasonable therapeutic index for depression treatments.  However, eliminating the high bar of placebo may allow ineffective depression treatments to become acceptable. 

Of the two recent publications, the paper from Dr. Turner and his colleagues reinforce the idea that there is a publication bias, worth paying attention to.  On the other hand, the paper from Dr. Kirsch and his colleagues appears to be mired in weak methodology, internal inconsistencies and contradictions in what their analysis shows to what they conclude and finally potential partisan bias.  At best, this can be taken as a publication bias of these investigators, as highlighted by Dr. Turner and his colleagues, this being a common problem (caveat emptor).  We strongly urge Dr. Kirsch and his colleagues to conduct an analysis evaluating the efficacy/effectiveness of psychotherapy that is not affected by publication bias. 

For the practicing clinician, the best available data suggest that clinically depressed patients warrant treatment and the most robust body of data would favor use of antidepressants.  We do wish we will have soon have antidepressant with a better risk/benefit ratio. 

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