Faculty Bibliography

OBJECTIVE: To examine the impact of medication nonadherence on treatment outcome in schizophrenia and potential risk factors for nonadherence. METHOD: A post hoc analysis of a randomized, double-blind, 8-week, fixed-dose study comparing olanzapine 10, 20, and 40 mg/day for patients with schizophrenia or schizoaffective disorder (DSM-IV criteria) with suboptimal response to current treatment (N = 599) was conducted between September 12, 2003, and November 3, 2005, at 55 study centers in the United States. Nonadherence was defined as not taking medication as prescribed based on daily pill counts. Because there was no significant difference in nonadherence between dose groups, effects of nonadherence on efficacy and safety outcomes were examined using all 3 groups combined. Baseline demographics and symptom severity were investigated as potential risk factors for nonadherence. RESULTS: During the 8-week study, 34.5% of patients were nonadherent at least once. Nonadherent patients had significantly less improvement compared to adherent patients as measured by change in Positive and Negative Syndrome Scale total score (-22.57 vs. -26.84, p = .002). Longer duration of nonadherence was associated with reduced likelihood of treatment response (odds ratio = 0.94, 95% CI = 0.90 to 0.99, p = .008). The early treatment discontinuation rate was higher in nonadherent compared to adherent patients (40.8% vs. 24.5%, p < .001). Adherent and nonadherent patients had comparable outcomes in most safety measures, except for weight change, for which adherent patients had greater weight gain than nonadherent patients (2.63 kg vs. 1.96 kg, p = .02). Greater depression severity at baseline (p = .01) and greater hostility level during the study were significant risk factors for nonadherence (p = .02). CONCLUSIONS: Medication nonadherence had a significantly negative impact on treatment response, highlighting the importance of adherence to achieve satisfactory treatment outcome. Findings may also help clinicians identify patients at risk for nonadherence and utilize interventions to improve adherence. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00100776

Impulsive and aggressive behaviors are important clinical challenges in the treatment of patients with schizophrenia. They occur both in the acute phase as well as in the chronic phase of the disorder and call for differentiated treatment interventions. It is important to always first consider behavioral and nonpharmacological interventions. High levels of structure and organization together with a nonconfrontational approach may be very successful interventions. In terms of acute pharmacological interventions, clinicians now have a broad spectrum of intramuscular antipsychotic compounds available with rapid onset of action and relatively little sedation. There is a need for new compounds with a more acceptable tolerability profile for the long-term treatment of these important syndromes

Paliperidone palmitate is an investigational, injectable atypical antipsychotic. The safety and tolerability of initiating treatment with paliperidone palmitate via deltoid versus gluteal injections given once monthly, and of switching injection sites, in adults with stable schizophrenia were assessed. In this crossover trial, stable outpatients (N=252) were randomly assigned 1:1:1 to 3 dose groups (paliperidone palmitate 50, 75, or 100 mg eq.) and 2 treatment sequences (blinded to dose): deltoid muscle (period 1 [13 weeks]) followed by gluteal muscle (period 2 [12 weeks]) or the reverse. The intent-to-treat analysis set had 249 patients: mean age=43 (SD: 12.8) years; 57% men, 81% white, baseline mean Positive and Negative Syndrome Scale (PANSS) total score=56 (SD: 11.5). A total of 170 (68%) patients completed the study, with a similar proportion completing each treatment sequence. The incidence of systemic treatment-emergent adverse events (TEAEs) was similar between the 2 injection sites across doses during period 1 (deltoid [D]: 61% to 67%; gluteus [G]: 58% to 65%), and during the last 8 weeks of the 2 study periods (DG: 32% to 45% [period 1], 29% to 42% [period 2]; GD: 31% to 40% [period 1], 30% to 41% [period 2]). During the first treatment week, median plasma paliperidone concentrations were higher with treatment initiation in the deltoid muscle compared with the gluteal muscle. At apparent steady state, there was little difference in plasma paliperidone concentrations between the deltoid and gluteus sites for a given dose. Local tolerability was slightly better with gluteal injections. Patient preference for injection sites differed between geographical regions, e.g. patients from the US preferred deltoid to gluteal sites. The most common (>or=5% overall) TEAEs were: (period 1) insomnia, anxiety, headache, and agitation; and (period 2) insomnia, psychotic disorder, weight increased, and tachycardia. Paliperidone palmitate treatment was tolerated, irrespective of injection site, and thus could offer the choice of administration into either the deltoid or gluteal muscle to meet patient and physician preference

OBJECTIVE: N-Desmethylclozapine (NDMC), one of clozapine's major metabolites, has become a recent focus of study for both its antipsychotic and metabolic effects. The aim of this review is to examine NDMC's biological activity in the context of the pathophysiology of schizophrenia and to critically evaluate the few recent preclinical and clinical studies of NDMC's potential antipsychotic effects to predict its therapeutic potential. RESULTS: We review the complex interaction between clozapine and NDMC at relevant receptor sites, notably at M1 sites where NDMC acts as an agonist and clozapine acts as an antagonist, and at D2 and D3 receptor sites, where NDMC acts as a partial agonist and clozapine as an inverse agonist. In terms of its antipsychotic potential, there is some support that higher NDMC/clozapine concentration ratios may be associated with symptom improvement; however, there are little data on NDMC alone as having specific potential antipsychotic effects. At best, NDMC shows efficacy only at very high doses in preclinical studies, particularly based on its muscarinic M1 agonism with a potential as a procognitive compound. Regarding metabolic effects, it seems that NDMC may be associated with more metabolic side effects than the parent compound clozapine, which may therefore reduce its overall tolerability profile. CONCLUSION: Although there is some suggestion based on animal data that NDMC may have a somewhat different biological profile than clozapine, clinical data on its antipsychotic efficacy are scant at this point. This makes it necessary to test NDMC alone compared with established antipsychotic compounds in clinical trials to elucidate its effects on schizophrenia symptoms, clinical outcome, and physiologic/metabolic side effects

BACKGROUND: Comparisons of diabetic potential, glucose related metabolic levels, and insulin resistance between olanzapine and risperidone have produced variable results in cross-sectional and epidemiologic studies. Randomized prospective studies of metabolic effects during treatment with these drugs may provide results that are more informative. METHOD: Hospitalized patients with chronic schizophrenia (DSM-IV), most of whom had been treated with multiple antipsychotics in the past, were randomly assigned to treatment with a single antipsychotic, olanzapine or risperidone, for a period of 5 months. At baseline and every treatment month thereafter, fasting glucose, insulin, insulin-related metabolic measures, and prolactin were assessed, and an oral glucose tolerance test (OGTT) was performed during baseline and months 1, 2, and 5 of treatment. Weight was assessed monthly, and waist and hip measures were taken at baseline and month 5. Data were analyzed on 23 patients randomly assigned to risperidone and 23 patients randomly assigned to olanzapine. The study was conducted from February 2003 to August 2007. RESULTS: Most patients were overweight or obese at baseline (mean body mass index [BMI] = 29.4), but there were no differential drug effects on weight change and no differences between drug groups at the 5-month time point. There were no overall drug treatment differences in fasting glucose or glycohemoglobin or 2-hour glucose levels in OGTT and no differences between the two drug groups at the 5-month time point. There were no consistent drug treatment differences in the number of patients who developed borderline or diabetic glucose levels. Olanzapine-treated patients showed a significantly greater increase than risperidone-treated patients in a fasting measure of insulin resistance (P = .041), and olanzapine patients showed greater decreases in insulin sensitivity during OGTT (P = .023) compared to risperidone-treated patients. Olanzapine-treated patients had a significantly greater increase in 1-hour glucose and insulin levels during OGTT in subsequent months compared to baseline and greater increase in glucose and insulin area under the curve over time than the risperdone-treated patients. Prolactin levels decreased in olanzapine patients and increased in risperidone patients (P values approximately .02). There were no significant drug treatment differences in C-peptide levels or 2 indices proposed as measures of insulin secretion or beta-cell function (homeostasis model assessment of beta-cell function [HOMA-B], BIGTT-acute insulin response surrogate measure [BIGTT-AIR]). Changes in insulin resistance over time were not strongly related to changes in BMI or waist circumference during study drug treatment. CONCLUSIONS: The increase in insulin levels during olanzapine treatment may compensate for the increase in insulin resistance and serve to reduce fasting and postprandial glucose levels. This may contribute to the lack of differences between olanzapine and risperidone in indices of diabetic or prediabetic glucose levels or glycohemoglobin. How many years this compensatory mechanism will persist needs further investigation. Periodic OGTT tests measuring glucose and insulin levels would be helpful in assessing the status of beta-cell insulin reserve in patients treated with olanzapine and other second-generation antipsychotics and assessing an individual patient's risk for conversion to type 2 diabetes. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT00287820

OBJECTIVE: Neuroleptic malignant syndrome (NMS) is a severe iatrogenic complication of treatment with antipsychotic medication. The purpose of this report is to examine the published cases of NMS in children and adolescents receiving atypical antipsychotic medication and review early warning symptoms, risk factors, and treatment in this population. METHOD: An extensive review of the literature from 1990 to 2008 was conducted via computerized searches (PubMed and Ovid) to identify case reports. Descriptive statistics were employed to describe our findings. RESULTS: There were 23 episodes in 20 subjects, with ages ranging from 11 to 18 years. Increased creatine phosphokinase (CPK) was the most common finding (100%), followed by fever (78%), tachycardia (74%), rigidity (70%), and altered mental status (61%). The number of NMS symptoms ranged from 1 to 11 (mean 4.7 +/- 2.4) and positive laboratory findings ranged from 1 to 4 (2.2 +/- 1). The duration of NMS (mean 6.1 +/- 6.4 days) was one third of the duration associated with typical antipsychotics. Patients treated with bromocriptine had a shorter duration of illness, whereas the same was not true for those receiving dantrolene. In all cases, the NMS symptoms eventually resolved and there were no reported deaths or permanent sequelae. CONCLUSIONS: NMS is a serious condition. Symptom presentation related to atypical agents differs from that seen with older antipsychotic medications