Michael D. Jibson

A Comparison of the Relative Safety, Efficacy, and Tolerability of Quetiapine and Risperidone in Outpatients with Schizophrenia and Other Psychotic Disorders: The Quetiapine Experience with Safety and Tolerability (QUEST) Study

BACKGROUND The few published direct comparative studies of the tolerability and efficacy of atypical antipsychotic agents were performed in relatively homogeneous populations that may not be typical of patients seen in clinical practice. OBJECTIVE The Quetiapine Experience with Safety and Tolerability (QUEST) study compared the relative safety, tolerability, and efficacy of quetiapine and risperidone in outpatients with a broad range of psychotic symptoms. METHODS This was a multicenter, 4-month, open-label, randomized clinical trial. Patients were randomized in a 3:1 ratio to receive quetiapine or risperidone. Doses were adjusted to maximize efficacy and to minimize adverse events. Extrapyramidal symptoms (EPS) were assessed with an EPS checklist; adverse events were recorded. Efficacy was assessed using the Clinical Global Impression (CGI) scale, Positive and Negative Symptom Scale (PANSS), and Hamilton Rating Scale for Depression (HAM-D). RESULTS A total of 728 patients were randomized, 553 to quetiapine and 175 to risperidone. Mean prescribed doses over the study period were 253.9 mg/d quetiapine and 4.4 mg/d risperidone. At the end of 4 months, EPS declined in both treatment groups, but quetiapine-treated patients were significantly less likely to require dose adjustment or concurrent anti-EPS medication (P < 0.001). The most common adverse events in the quetiapine and risperidone groups were somnolence (31.3% and 15.4%, respectively), dry mouth (14.5% and 6.9%), and dizziness (12.7% and 6.9%). Overall, tolerance to side effects with the 2 drugs, measured by dropout rates, was comparable. At each visit, a higher percentage of quetiapine-treated patients showed improvement on the CGI scale, but there were no significant between-group differences on the PANSS. At end point, quetiapine-treated patients had significantly lower HAM-D scores (P = 0.028). CONCLUSIONS The results of this study suggest that quetiapine is as effective as risperidone for the treatment of psychotic symptoms, is more effective for depressive symptoms, may have a more favorable EPS profile, and has comparable overall tolerability.

Extrapyramidal Side Effects of Antipsychotic Treatment: Scope of Problem and Impact on Outcome

Abstractclinicians worked with antipsychotic drugs (conventional or typical) that almost invariably caused extrapyramidal symptoms (EPS) at clinically effective doses. This led to the false impression that all antipsychotics were the same, and that EPS were an unavoidable consequence of effective antipsychotic therapy. EPS adversely impact several aspects of antipsychotic efficacy and tolerability, thereby worsening outcome of afflicted individuals. EPS reduce beneficial effects of antipsychotic treatment on the negative, cognitive, and mood symptom domains, while increasing the risk of tardive dyskinesia and reducing compliance. By definition, the newer generation of “atypical” antipsychotic agents are significantly better than conventional agents with regard to EPS (i.e., they are clinically effective at doses at which they do not cause EPS). Pharmacologically, this difference is expressed in the greater degree of separation between respective dose response curves for antipsychotic and EPS effects observed for “atypical” in contrast to conventional agents. Clinically, this EPS advantage of atypical antipsychotics translates into several important benefits, including better negative symptom efficacy, less dysphoria, less impaired cognition, a lower risk of TD, and better overall outcome.

Phasic and enduring negative symptoms in schizophrenia: biological markers and relationship to outcome.

Negative symptoms have been associated with poor response to neuroleptics, enlarged ventricles, cognitive impairment, and poor outcome in schizophrenia. These associations appear, however, to be dependent on the phase of study, suggesting that acute-phase (phasic) negative symptoms may be pathophysiologically distinct from enduring negative symptoms that persist through the residual phase. To compare correlates of enduring and phasic negative symptoms, we studied 60 drug-free schizophrenic patients (DSM-III-R and SADS/RDC) at baseline, 4 weeks after neuroleptic treatment, and assessed the 1 year outcome. We rated positive and negative symptoms at baseline and 4 weeks after treatment. At baseline, premorbid function, neuropsychological function, ventricle-brain ratio (VBR) and symptom response to an anticholinergic agent were assessed, and a two-night sleep EEG and 1mg dexamethasone suppression test (DST) were conducted. Phasic negative symptoms were defined as the change in negative symptoms (baseline to 4 weeks) and enduring negative symptoms as severity of negative symptoms at 4 weeks. Patients had varying proportions of phasic and enduring symptoms; the two did not define distinct subgroups. Phasic negative symptoms were significantly correlated with global treatment response, positive symptom treatment response, response to anticholinergic agent, baseline post-dexamethasone cortisol, and shortened REM latency. Enduring negative symptoms were significantly correlated with residual positive symptoms and global psychopathology, VBR, poor performance on neuropsychological testing, decreased slow-wave sleep, poor premorbid function, and poor 1 year outcome. These data suggest that phasic negative symptoms and enduring negative symptoms may be caused by different pathophysiological mechanisms.

The American Psychiatric Association Practice Guideline on the Use of Antipsychotics to Treat Agitation or Psychosis in Patients With Dementia.

anagement of behavioral disturbances Mand psychosis associated with dementia is a clinical and, in some cases, a medicolegal and ethical challenge for clinicians, caregivers, and health care settings. These medications are associated with multiple adverse outcomes, including serious adverse effects, such as increased risk for cerebrovascular events and mortality. At the same time, clinicians feel pressure from caregivers, acute inpatient staff, and long-term care settings to safely manage psychotic and aggressive behaviors in this population. The incidence and prevalence of dementia and associated behavioral disturbances in the adult population is on the rise. There is a lack of consistent practices and guidance to manage these behaviors as well as an upto-date review of the existing effectiveness literature, and these are much needed. Thus, the recent publication of the American Psychiatric Associations (APAs) practice guidelines on the use of antipsychotics to treat agitation or psychosis in patients with dementia comes at a most opportune time. Practice guidelines are unique in that they have the potential to positively impact behavior of practicing clinicians. They are also likely to be used as standard of care by insurance companies and in lawsuits or other litigation. It is thus important that practice guidelines provide a thorough, balanced, accurate, and current review of available treatments based on medical and scientific literature. The APAs most recent practice guideline on antipsychotic treatment in patients with dementia appears to have done just that. The practice guideline is organized into two main sections. The first section is broken up into four main categories: an introduction and overview of the guidelines, the guidelines themselves and how they were implemented based on current evidence in literature, quality measurement considerations, and the guideline development process. The second section is an appendix that provides a comprehensive review of available evidence and the results of expert opinion survey data. The authors also included a list of acronyms and abbreviations used in the guidelines, glossary of terms, list

POSITIVE AND NEGATIVE SYMPTOMS COVARY DURING CLOZAPINE TREATMENT IN SCHIZOPHRENIA

Summary-Although negative symptoms were traditionally considered to be unresponsive to neuroleptic medication, recent studies have demonstrated that negative symptoms do improve during neuroleptic treatment and that such improvement tends to occur concurrently with improvement in positive symptoms. Clozapine is an atypical neuroleptic that is effective in a significant proportion of otherwise neuroleptic-nonresponsive schizophrenic patients; in contrast to conventional neuroleptics, clozapine is also purported to possess unique efficacy in the amelioration of negative symptoms. How clozapine-associated reduction in negative symptoms relates to change in positive symptoms is not clear. To study the relationship between change in positive and negative symptoms during clozapine treatment, we monitored symptomatology in 40 DSM-III-R schizophrenic patients before and about 8 weeks after a trial of clozapine. Both positive and negative symptoms improved significantly. There was a significant correlation (r = .63, p c.01) between change in positive symptoms and change in negative symptoms; as with conventional neuroleptics, negative symptoms improved concomitantly with positive symptoms during clozapine treatment. Clozapine’s apparent greater efficacy on negative symptoms may be related to its greater efficacy on positive symptoms in otherwise neuroleptic-refractory patients and its lesser propensity to cause extrapyramidal sideeffects.

The Cholinergic System in Schizophrenia Reconsidered: Anticholinergic Modulation of Sleep and Symptom Profiles

The role of the cholinergic system in schizophrenia remains controversial. A series of investigations are reviewed that describe the effects of pharmacological manipulation of the cholinergic system on schizophrenia symptomatology and whether putative measures of the cholinergic system are altered in schizophrenia. The effects of biperiden (an anticholinergic agent) on positive and negative symptoms of schizophrenia and on rapid eye movement (REM) latency and other sleep measures were assessed. Biperiden produced a significant increase in positive symptoms and a decrease in negative symptoms. REM latency was significantly shorter in schizophrenic patients and increased in both groups following biperiden. REM density decreased in a dose-dependent manner following biperiden in schizophrenic patients, but not in normal controls. The slope of REM density plotted against biperiden dose was inversely related to plasma homovanillic acid (HVA), an index of dopamine (DA) activity, in schizophrenic patients. These results further implicate the cholinergic system in schizophrenia pathophysiology and suggest a role for DA-acetylcholine (ACh) interactions in the production of sleep abnormalities and expression of positive and negative symptoms in schizophrenia.

Biological predictors of suicidality in schizophrenia

The objective of this study was to determine whether polysomnographic rapid eye movement (REM) sleep abnormalities and Cortisol response to the dexamethasone suppression test (DST) differentiate between schizophrenic patients with and without a history of suicidal behaviour. We assessed a sample of 96 schizophrenic in‐patients at the end of a 2‐week medication‐free period with the DST, polysomnography, and an extensive clinical assessment battery. Patients exhibiting suicidal behaviour were significantly more likely to have increased total REM time and increased total REM activity. We found no significant relationship between suicidal behaviour and DST non‐suppression. This study confirms a previous finding suggesting an association between REM sleep abnormalities and suicidal behaviour in schizophrenia. It is postulated that this observed association may be related to serotonergic dysfunction in schizophrenia.

Clinician-Educator Tracks for Residents: Three Pilot Programs

ObjectiveOver the past 30 years, clinician-educators have become a prominent component of medical school faculties, yet few of these individuals received formal training for this role and their professional development lags behind other faculty. This article reviews three residency tracks designed to build skills in teaching, curriculum development and assessment, education research, and career development to meet this need.MethodsThe residency clinician educator tracks at University of Michigan, Baylor College of Medicine, and University of California Davis are described in detail, with particular attention to their common elements, unique features, resource needs, and graduate outcomes.ResultsCommon elements in the tracks are faculty mentorship, formal didactics, teaching opportunities, and an expectation of scholarly productivity. Essential resources include motivated faculty, departmental support, and a modest budget. Favorable outcomes include a high percentage of graduates in clinical faculty positions, teaching programs created by the residents, positive effects on recruitment, and enhancement of faculty identity as clinician educators.ConclusionClinician-educator tracks in residency present a viable means to address the training needs of clinical track faculty. The programs described in this article provide a model to assist other departments in developing similar programs.

Symptom correlates of global measures of severity in schizophrenia

There is an increasing need for practical instruments that can rapidly and accurately assess the effectiveness of treatments for mental illness in clinical settings. Symptom rating scales used in clinical research are too complex and time-consuming to be useful in these settings. In contrast, single-item global measures of severity such as the Clinical Global Impression-severity scale (CGI) and the Global Assessment of Function scale (GAF) are brief and easy to complete, but little is known about their relationship with the specific symptoms of severe mental illnesses. In this study, we examine the extent to which CGI and GAF scores reflect the severity and the change in severity of positive, negative, depressive, and agitation symptoms in a sample of 102 schizophrenia inpatients at the University of Michigan Medical Center. At admission, positive symptoms were the strongest correlates of both CGI and GAF scores, followed by negative symptoms, and agitation. Depressive symptoms did not correlate significantly with either global measure. The three symptom scores together explained 58% of the variation in CGI and 39% of the variation in GAF. A similar pattern of association was found for the scores measured at discharge and for the relationships between the change in global measures and change in specific symptom clusters. Thus, by demonstrating that single-item global measures, particularly the CGI, can be reasonably good indicators of psychopathology, this study suggests that these measures may be practical tools for routine monitoring of the effectiveness of treatments for severe mental illness in community settings.

Comparing efficacy of first-line atypical antipsychotics: No evidence of differential efficacy between risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole

Objective To evaluate the comparative efficacy of the first-line atypical antipsychotics risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. Methods We reviewed published short-term, randomised, controlled clinical trials of first-line atypical antipsychotics in the treatment of schizophrenia or schizoaffective disorder that used the Positive and Negative Syndrome Scale to assess efficacy. We used a combined overview analysis to compare the extent of improvement in global symptoms and positive and negative symptoms. We did not analyse adverse event data. Results Although we found considerable variation in the degree of improvement with a particular atypical antipsychotic across different studies, the range and average improvement were similar among all first-line atypicals for all efficacy parameters considered. Dosage was a critical determinant of efficacy, although the most effective dose of each agent varied across studies. There were insufficient data for ziprasidone and aripiprazole to allow their inclusion in the formal overview comparison. Conclusion Despite confounding and methodological limitations, the data we reviewed do not support assertions of differential efficacy between the first-line atypical antipsychotics. Additional controlled comparative studies of the atypical antipsychotics should be of particular interest.