M. Lynn Crismon

Aripiprazole: A comprehensive review of its pharmacology, clinical efficacy, and tolerability

BACKGROUND Recently approved for the treatment of schizophrenia, aripiprazole represents the sixth second-generation antipsychotic (SGA) introduced to the US market. Aripiprazole is considered a partial dopaminergic agonist, acting on both postsynaptic dopamine(2) receptors and presynaptic autoreceptors, in addition to displaying partial agonism at serotonin(1A) receptors and antagonism at serotonin(2A) receptors. OBJECTIVE The aim of this study was to comprehensively review all available literature regarding the mechanism of action, pharmacokinetics, clinical efficacy, and adverse effects of aripiprazole. METHODS Relevant data were collected using MEDLINE and International Pharmaceutical Abstracts searches with the terms aripiprazole and OPC-14597 and with no limitations on year. Abstracts and posters presented at national and international scientific meetings were also reviewed. RESULTS Aripiprazole exhibits linear pharmacokinetics and is administered once daily. In multiple clinical trials, aripiprazole was effective in significantly reducing symptomatology associated with schizophrenia-related disorders compared with placebo (P < 0.05). Dosages > or =15 mg/d more consistently produced significant reductions from baseline of Positive and Negative Syndrome Scale total scores (P < 0.05) and were more likely to elicit a response than smaller dosages. Effects observed were comparable to those seen with risperidone and haloperidol, which were also significantly more effective than placebo (P < or = 0.05). Aripiprazole exhibited a favorable safety and tolerability profile, with a low propensity to cause extrapyramidal symptoms, weight gain, cardiovascular abnormalities, hyperprolactinemia, hypercholesterolemia, or glucose dysregulation. CONCLUSIONS Aripiprazole represents a well-tolerated and effective addition to the antipsychotic armamentarium. However, definitive advantages associated with dopamine partial agonism have yet to be determined. Long-term, head-to-head comparisons with other SGAs are needed to establish the effects of chronic administration and the relative safety and efficacy of aripiprazole.

Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY). Part I: a review

OBJECTIVES To review the evidence for the safety and efficacy of nonpharmacological and pharmacological treatments for aggression in children and adolescents. METHOD and searches (1990-present) were conducted for double-blind, placebo-controlled studies of atypical antipsychotics for aggression and for literature on the use of other pharmacological agents and psychosocial interventions for aggression. Case reports and adult literature regarding the safety of atypical antipsychotics were used where controlled data for youth were lacking. RESULTS Controlled data on the treatment of aggression in youth is scarce. Psychosocial interventions may be effective alone or in combination with pharmacological treatments. Psychotropic agents (e.g., stimulants, mood stabilizers, beta-blockers) have also been shown to have limited efficacy in reducing aggression. Antipsychotics, particularly the atypical antipsychotics, show substantial efficacy in the treatment of aggression in selected pediatric populations. Atypical antipsychotics are generally associated with fewer extrapyramidal symptoms than are typical antipsychotics. CONCLUSIONS Psychosocial interventions and atypical antipsychotics are promising treatments for aggression in youth. Double-blind studies should examine the safety and efficacy of atypical antipsychotics compared to each other and to medications from other classes, the efficacy of specific medications for different subtypes of aggression, combining various psychotropic medications, optimal dosages, and long-term safety.

The Texas Children's Medication Algorithm Project : Report of the Texas Consensus Conference Panel on Medication Treatment of Childhood Attention-Deficit/Hyperactivity Disorder. Part II : Tactics

OBJECTIVES Expert consensus methodology was used to develop a medication treatment algorithm for attention-deficit/hyperactivity disorder (ADHD). The algorithm broadly outlined the choice of medication for ADHD and some of its most common comorbid conditions. Specific tactical recommendations were developed with regard to medication dosage, assessment of drug response, management of side effects, and long-term medication management. METHOD The consensus conference of academic clinicians and researchers, practicing clinicians, administrators, consumers, and families developed evidence-based tactics for the pharmacotherapy of childhood ADHD and its common comorbid disorders. The panel discussed specifics of treatment of ADHD and its comorbid conditions with stimulants, antidepressants, mood stabilizers, alpha-agonists, and (when appropriate) antipsychotics. RESULTS Specific tactics for the use of each of the above agents are outlined. The tactics are designed to be practical for implementation in the public mental health sector, but they may have utility in many practice settings, including the private practice environment. CONCLUSIONS Tactics for psychopharmacological management of ADHD can be developed with consensus.

Quantitative analysis of sponsorship bias in economic studies of antidepressants

BACKGROUND Concern is widespread about potential sponsorship influence on research, especially in pharmacoeconomic studies. Quantitative analysis of possible bias in such studies is limited. AIMS To determine whether there is an association between sponsorship and quantitative outcomes in pharmacoeconomic studies of antidepressants. METHOD Using all identifiable articles with original comparative quantitative cost or cost-effectiveness outcomes for antidepressants, we performed contingency table analyses of study sponsorship and design v. study outcome. RESULTS Studies sponsored by selective serotonin reuptake inhibitor (SSRI) manufacturers favoured SSRIs over tricyclic antidepressants more than non-industry-sponsored studies. Studies sponsored by manufacturers of newer antidepressants favoured these drugs more than did non-industry-sponsored studies. Among industry-sponsored studies, modelling studies favoured the sponsors drug more than did administrative studies. Industry-sponsored modelling studies were more favourable to industry than were non-industry-sponsored ones. CONCLUSIONS Pharmacoeconomic studies of antidepressants reveal clear associations of study sponsorship with quantitative outcome.

The Texas children's medication algorithm project: Report of the Texas consensus conference panel on medication treatment of childhood major depressive disorder

OBJECTIVES To develop consensus guidelines for medication treatment algorithms for childhood major depressive disorder (MDD) based on scientific evidence and clinical opinion when science is lacking. The ultimate goal of this approach is to synthesize research and clinical experience for the practitioner and to increase the uniformity of preferred treatment for childhood MDD. A final goal is to develop an approach that can be tested as to whether it improves clinical outcomes for children and adolescents with MDD. METHOD A consensus conference was held. Participants included academic clinicians and researchers, practicing clinicians, administrators, consumers, and families. The focus was to review and use clinical evidence to recommend specific pharmacological approaches for treatment of MDD in children and adolescents. After a series of presentations of current research evidence and panel discussion, the consensus panel met, agreed on assumptions, and drafted the algorithms. The process initially addressed strategies of treatment and then tactics to implement the strategies. RESULTS Consensually agreed-upon algorithms for major depressions (with and without psychosis) and comorbid attention deficit disorders were developed. Treatment strategies emphasized the use of selective serotonin reuptake inhibitors. The algorithm consists of systematic strategies for treatment interventions and recommended tactics for implementation of the strategies, including medication augmentation and medication combinations. Participants recommended prospective evaluation of the algorithms in various public sector settings, and many volunteered as sites for such an evaluation. CONCLUSIONS Using scientific and clinical experience, consensus-derived algorithms for children and adolescents with MDD can be developed.

Evaluating the Impact of Pharmacists in Mental Health: A Systematic Review

Efforts to improve the outcomes of patients with mental illness often have involved incorporating the skills of a variety of health care professionals into collaborative care models. For over 30 years, clinical pharmacists have contributed to these care models in capacities ranging from educator to consultant to provider. This systematic review evaluates the quantity and quality of medical literature examining the impact of pharmacists in mental health from 1972–2003. Although we identified approximately 35 publications describing the roles of clinical pharmacists in this regard, only 16 were of sufficient scientific rigor to permit evaluation and comparison. The 16 studies were divided equally between inpatient and outpatient settings and were conducted in a variety of health care organizations (e.g., Veterans Administration, health maintenance organizations, community mental health clinics, and nursing homes). Nine of the studies examined the role of pharmacists in providing treatment recommendations and patient education, five featured pharmacists as providers (with prescriptive authority), and the remaining two described the impact pharmacists have in delivering education to the psychiatric staff. Six of the 16 studies were prospective, but only three of these incorporated a randomization procedure for patients or facilities. Collectively, the results of the 16 studies were positive, demonstrating improvements in outcomes, prescribing practices, patient satisfaction, and resource use. Unfortunately, most of the investigations were small, and significant limitations in study design limited further comparison. Given the long history and anecdotal success of pharmacists in mental health care settings, additional multicenter cost‐effectiveness trials are warranted to further support the role of the psychiatric pharmacist.

Assessment of Adherence Measures with Different Stimulants Among Children and Adolescents

Study Objective. To examine adherence measures with different stimulants in children and adolescents.

Brief Psychiatric Rating Scale Expanded Version: How do new items affect factor structure?

Our goal was to suggest a factor structure for the Brief Psychiatric Rating Scale Expanded Version (BPRS-E) based upon a large and diverse sample and to determine which of the new items improved the factors derived from the 18-item version of the scale that have been used in clinical research for decades. We investigated the consistency of our proposed model over time and across demographic groups. As part of the Texas Medication Algorithm Project, the BPRS-E was administered to a total of 1440 psychiatric outpatients in three different diagnostic groups on multiple occasions. The sample was randomly split so that exploratory factor analysis could be done with the first half, and the model could be confirmed on the second half. A four-factor structure including factors assessing depression/anxiety, psychosis, negative symptoms, and activation was found. For each factor, we specify items in the expanded version that added to the breadth of the commonly used clinical factors while improving or maintaining goodness of fit and reliability. The final model proposed was consistent over time and across diagnosis, phase of illness, age, gender, ethnicity, and level of education. The BPRS-E has a stable four-factor structure, making it useful as a clinical outcome measure.

Olanzapine-induced glucose dysregulation

OBJECTIVE: To report a patient who developed severe exacerbation of type 2 diabetes mellitus after the initiation of olanzapine therapy. CASE SUMMARY: A 54-year-old African-American woman developed severe glucose dysregulation 12 days after the initiation of olanzapine. Prior to starting olanzapine therapy, the patients diabetes was controlled by diet modification with a glycosylated hemoglobin of 6.5%. During olanzapine therapy, blood glucose concentrations could not be regulated despite use of antidiabetic agents, insulin, and dietary interventions. The patient also gained a total of 13 kg. Two weeks after discontinuation of all antipsychotic medications (olanzapine, quetiapine), the patients blood glucose concentrations became better regulated and remained better controlled until discharge. DISCUSSION: All atypical antipsychotics are associated with weight gain. Obesity is a well-documented risk factor for developing type 2 diabetes mellitus. Currently there are only six published reports that implicate olanzapine as being associated with glucose dysregulation. The exact cause of glucose dysregulation with olanzapine is unclear, but weight gain does not seem to be the sole etiology. It has been hypothesized that serotonin (5-HT1A) antagonism may decrease the responsiveness of the pancreatic β-cells. This would then result in inappropriately low insulin secretion and, therefore, hyperglycemia. Based on the Naranjo probability scale, the likelihood that olanzapine caused the glucose dysregulation in our patient was possible. CONCLUSIONS: Although olanzapine has shown greater clinical efficacy and is associated with fewer extrapyramidal side effects than typical antipsychotics, it may produce exacerbation or new emergence of diabetes mellitus. Further examination of the incidence and etiology of glucose dysregulation after the initiation of olanzapine therapy is necessary.

Tacrine: First Drug Approved for Alzheimer's Disease

OBJECTIVE: To review the pharmacology, biopharmaceutics/pharmacokinetics, clinical efficacy, adverse effects, and therapeutic considerations regarding the use of tacrine in patients with Alzheimers disease. DATA SOURCES: Data from the scientific and professional literature were analyzed, interpreted, and summarized. Citations were obtained by performing a MEDLINE search using the following indexing terms: tacrine, tetrahydroaminoacridine, and Alzheimers drug therapy. Data also were obtained from a summary of the New Drug Application (Summary Basis of Approval of Cognex) and from the approved product labeling. STUDY SELECTION: Studies in Alzheimers disease have been plagued by methodologic inconsistencies and deficiencies. Only efficacy studies subsequent to the Food and Drug Administrations (FDA) issuance of recommendations for studies in Alzheimers disease (1991) were used. Therefore, only double-blind, placebo-controlled, parallel design studies of at least three-months duration using the Alzheimers Disease Assessment Scale-Cognitive Subscale and the Clinical Interview-Based Impression of Change as efficacy parameters were included. DATA EXTRACTION: Trials were assessed according to the criteria listed above. Results were evaluated on the basis of both completed patients and last observation carried forward models. DATA SYNTHESIS: Tacrine is a cholinesterase inhibitor that increases the availability of acetylcholine in muscarinic neurons. It has a mean bioavailability after oral administration of about 17 percent and an elimination half-life of approximately three hours. Although drug interactions are poorly studied, tacrine is metabolized by isoenzyme P-450IA2 and may interact with other drugs metabolized by this isoenzyme. Tacrine has been shown to have efficacy in mildly to moderately impaired Alzheimers patients on both psychometric testing and a clinicians structured interview. Although efficacious, its effects are not dramatic, and it does not affect the ultimate course of the disease. Adverse effects are frequent, and significantly elevated hepatic transaminase concentrations may occur in approximately 25 percent of patients. CONCLUSIONS: Tacrine is the first drug approved by the FDA for treatment of Alzheimers disease. Although it may improve psychometric test scores in mild to moderately impaired patients, it is not a panacea and does not affect the course of the disease. Patients must be monitored closely for elevated transaminase, cholinergic adverse effects, and interactions with drugs metabolized through P-450IA2.