Peter J. Weiden

Obesity as a risk factor for antipsychotic noncompliance

Abstract Objective: Weight gain is a common side effect of antipsychotic medications and is of particular concern with most of the newer “atypical” antipsychotics. It is, therefore, increasingly important to understand the impact of obesity and perceived weight problems on compliance with these medications. Methods: A survey of treatment and health issues was mailed to local chapters of the National Alliance for the Mentally Ill (NAMI) and National Mental Health Association (NMHA), who distributed them to people with schizophrenia. Noncompliance was defined as a self-report of missing any antipsychotic medication in the previous month. The primary independent variables were (1) body mass index (BMI; weight [kg]/height [m2])—categorized as normal ( 30, n=100)—and (2) subjective distress over weight gain. Other independent variables included demographics, medication attitudes, and treatment satisfaction. Result: BMI status and subjective distress from weight gain were predictors of noncompliance. Obese individuals were more than twice as likely as those with a normal BMI to report missing their medication (OR=2.5; CI 1.1–5.5). A comprehensive model suggested that the primary mediator of noncompliance was distress over weight gain. Conclusions: There appears to be a significant, positive association between obesity and subjective distress from weight gain and medication noncompliance, even when accounting for other possible confounding factors.

The expert consensus guideline series

Abstract Over the past decade, many new epilepsy treatments have been approved in the United States, promising better quality of life for many with epilepsy. However, clinicians must now choose among a growing number of treatment options and possible combinations. Randomized clinical trials (RCTs) form the basis for evidence-based decision making about best treatment options, but they rarely compare active therapies, making decisions difficult. When medical literature is lacking, expert opinion is helpful, but may contain potential biases. The expert consensus method is a new approach for statistically analyzing pooled opinion to minimize biases inherent in other systems of summarizing expert opinion. We used this method to analyze expert opinion on treatment of three epilepsy syndromes (idiopathic generalized epilepsy, symptomatic localization-related epilepsy, and symptomatic generalized epilepsy) and status epilepticus. For all three syndromes, the experts recommended the same general treatment strategy. As a first step, they recommend monotherapy. If this fails, a second monotherapy should be tried. Following this, the experts are split between additional trials of monotherapy and a combination of two therapies. If this fails, most agree the next step should be additional trials of two therapies, with less agreement as to the next best step after this. One exception to these recommendations is that the experts recommend an evaluation for epilepsy surgery after the third failed step for symptomatic localization-related epilepsies. The results of the expert survey were used to develop user-friendly treatment guidelines concerning overall treatment strategies and choice of specific medications for different syndromes and for status epilepticus.

Improvement in indices of health status in outpatients with schizophrenia switched to ziprasidone.

Side effect and health status changes were measured in 3 studies in which outpatients experiencing suboptimal efficacy or tolerability with their current antipsychotic were switched to 6 weeks of open-label ziprasidone. The studies differed only in the patient’s prior antipsychotic; 1 study group was on olanzapine (n = 104), a second on risperidone (n = 58), and third on a conventional antipsychotic (n = 108). Baseline and end point health status measures included weight and height, nonfasting cholesterol, and triglyceride levels, prolactin levels, and extrapyramidal side effects. Improvements in health indices and side effects were seen among all 3 groups, but the specific benefits depended on the preswitch antipsychotic. For example, patients switched from olanzapine experienced a mean weight loss of 1.76 kg (P < 0.0001), those switched from risperidone had a lesser reduction in weight (−0.86 kg; P = 0.015), and those switched from conventionals had a nonsignificant increase (+0.27 kg; P = 0.3). Prolactin levels decreased among those switched from risperidone (P < 0.0001) or conventionals (P = 0.05), but not for patients switched from olanzapine. EPS improved among those switched from conventionals (P < 0.0001) and to a lesser extent among those switched from risperidone (P < 0.01), but not in those changed from olanzapine (NS). Thus, in these studies, switching to ziprasidone in patients with continuing symptoms or side effects on their current medication was often associated with improved health status indices, lowered prolactin levels, or less EPS, with the magnitude benefit consistent with the known side-effect profile of the preswitch antipsychotic.

A Randomized Controlled Trial of Long-Acting Injectable Risperidone vs Continuation on Oral Atypical Antipsychotics for First-Episode Schizophrenia Patients: Initial Adherence Outcome

OBJECTIVE Nonadherence for first-episode schizophrenia is a major unsolved challenge. The long-acting injectable route is an appealing strategy, but there are concerns about acceptability. We report on acceptance and initial adherence outcomes with risperidone long-acting injection (RLAI) in first-episode schizophrenia patients. METHOD We conducted a prospective randomized controlled trial in which we enrolled patients defined by appropriate Structured Clinical Interview for DSM-IV diagnosis and < or = 16 weeks of lifetime antipsychotic exposure. Participants were randomly assigned (2:1 ratio) to a recommendation of changing to RLAI versus continuing on oral therapy (ORAL). Nonadherence behavior was defined as a medication gap > or = 14 days. Adherence attitudes were determined by the Rating of Medication Influences (ROMI) scale. A priori analysis defined treatment groups as intent-to-treat (ITT) and as-actually-treated (AAT) for the first 12 weeks after initial randomization. Participants were enrolled from December 2004 to March 2007. RESULTS Of 46 eligible patients, 37 were randomly assigned, 11 to ORAL and 26 to RLAI. Nineteen of 26 patients (73%) accepted the RLAI recommendation. There were no differences in adherence behavior at 12 weeks based on initial randomization (Kaplan-Meier survival for ITT: 76% [95% CI, 35%-90%] adherent for RLAI vs 72% [95% CI, 55%-89%] for ORAL; log-rank P = .78), but patients accepting RLAI were significantly more likely to be adherent than patients staying on ORAL (AAT: 89% [95% CI, 64%-97%] adherent for RLAI vs 59% [95% CI, 32%-78%] for ORAL; log-rank P = .035). There were no ROMI attitude differences between either treatment group comparison at 12 weeks. CONCLUSIONS Most first-episode patients taking oral antipsychotics will accept a recommendation of RLAI therapy. On the basis of initial randomization status, an RLAI recommendation did not affect adherence behavior at 12 weeks. However, acceptance of RLAI was associated with significantly better adherence. Regardless of whether RLAI is recommended or accepted, there is no adverse impact on subsequent medication attitudes at 12 weeks. These results support the feasibility and acceptability of introducing RLAI as a treatment option for first-episode schizophrenia patients. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00220714.

Four-week, Double-blind, Placebo- and Ziprasidone-controlled Trial of Iloperidone in Patients With Acute Exacerbations of Schizophrenia

Abstract Iloperidone is a mixed D2/5-HT2 antagonist in development for treatment of schizophrenia. This trial aimed to evaluate the efficacy and safety of a fixed dose of iloperidone in patients with acute exacerbations of schizophrenia. This randomized, placebo-controlled, multicenter study comprised a 1-week titration period and a 3-week double-blind maintenance period. Eligible patients (n = 593) were randomized to iloperidone 24 mg/d, ziprasidone 160 mg/d as an active control, or placebo. Primary efficacy variable was change from baseline in the Positive and Negative Syndrome Scale Total (PANSS-T) score, using a mixed-effects model repeated measures analysis. Iloperidone demonstrated significant reduction versus placebo on the PANSS-T score (P< 0.01). Significant improvement versus placebo was also demonstrated with ziprasidone (P < 0.05). Compared with ziprasidone, iloperidone was associated with lower rates of many adverse events (AEs) that are particularly troublesome with antipsychotics, including sedation, somnolence, extrapyramidal symptoms, akathisia, agitation, and restlessness; iloperidone was associated with higher rates of weight gain, tachycardia, orthostatic hypotension, dizziness, and nasal congestion as reported as an AE. Most AEs were mild to moderate. A similar amount of QT prolongation was observed with both active treatments, although no patient had a treatment-emergent postbaseline corrected QT interval of 500 msec or greater. The incidence of clinically relevant changes in laboratory parameters was comparable between iloperidone and ziprasidone. Iloperidone was associated with a low incidence of extrapyramidal symptoms. Overall, there was improvement in akathisia with iloperidone treatment. Iloperidone treatment was effective, safe, and well tolerated in patients with acute exacerbation of schizophrenia.

Which side effects really matter? Screening for common and distressing side effects of antipsychotic medications.

As a class, the newer antipsychotics are less likely to cause EPS but continue to have a range of other, non-EPS, side effects. Most standardized scales for side effects of antipsychotics emphasize the physical findings of the motor abnormalities of extrapyramidal symptoms (EPS). There is a need for screening instruments that include both EPS and non-EPS side effects. This article discusses the development of a screening instrument called the Approaches to Schizophrenia Communication (ASC). Initially derived from other subjective screening measures, the ASC was specifically designed to address the following issues pertaining to side effect evaluation of antipsychotics: 1) to cover all common and distressing side effects from antipsychotics, not just EPS, and 2) to screen for perceived distress, rather than the objective severity of the side effect. These two characteristics of the ASC make it possible for it to be given directly to the patient (the ASC Self-Report Version) or to be administered by mental health clinicians who do not have to be extensively trained in side-effect assessments (the ASC Clinician Interview version).

Assessment of adherence problems in patients with serious and persistent mental illness: recommendations from the Expert Consensus Guidelines.

Poor adherence to medication treatment can have devastating consequences for patients with serious mental illness. The literature review and recommendations in this article concerning assessment of adherence are reprinted from The Expert Consensus Guideline Series: Adherence Problems in Patients with Serious and Persistent Mental Illness, published in 2009. The expert consensus survey contained 39 questions (521 options) that asked about defining nonadherence, extent of adherence problems in schizophrenia and bipolar disorder, risk factors for nonadherence, assessment methods, and interventions for specific types of adherence problems. The survey was completed by 41 (85%) of the 48 experts to whom it was sent. When evaluating adherence, the experts considered it important to assess both behavior and attitude, although they considered actual behavior most important. They also noted the importance of distinguishing patients who are not willing to take medication from those who are willing but not able to take their medication as prescribed due to forgetfulness, misunderstanding of instructions, or financial or environmental problems, since this will affect the type of intervention needed. Although self- and physician report are most commonly used to clinically assess adherence, they are often inaccurate and may underestimate nonadherence. The experts believe that more accurate information will be obtained by asking about any problems patients are having or anticipate having taking medication rather than if they have been taking their medication; They also recommended speaking with family or caregivers, if the patient gives permission, as well as using more objective measures (e.g., pill counts, pharmacy records, smart pill containers if available, and, when appropriate, medication plasma levels). Use of a validated self-report scale may also help improve accuracy. For patients who appear adherent to medication, the experts recommended monthly assessments for adherence, with additional assessments if there is a noticeable symptomatic change. If there is concern about adherence, they recommended more frequent (e.g., weekly) assessments. The article concludes with suggestions for clinical interview techniques for assessing adherence. (Journal of Psychiatric Practice 2010;16:34–45)

Safety profile of iloperidone: a pooled analysis of 6-week acute-phase pivotal trials.

Iloperidone, a mixed D2/5-HT2 antagonist, is currently in clinical development for the treatment of schizophrenia. This article assesses the short-term safety of iloperidone using a pooled analysis of 3 phase 2, short-term acute schizophrenia studies conducted between 1998 and 2002 (N = 1943). Patients exposed to 3 dose ranges of iloperidone, another antipsychotic, or placebo were compared on rates of serious adverse events (SAEs), adverse events (AEs), extrapyramidal symptoms, akathisia, prolactin, weight and metabolic parameters, QTc, and other standard safety parameters. The most common treatment-related AEs observed with iloperidone were dizziness, headache, dry mouth, nausea, and insomnia. Discontinuation due to AEs was 4.8% for iloperidone, 7.6% for haloperidol, 6.2% for risperidone, and 4.8% for placebo. Iloperidone groups showed better overall performance on the Extrapyramidal Symptom Rating Scale and Barnes Akathisia Scale than risperidone or haloperidol groups. Patients taking iloperidone experienced a mild weight increase (range, 1.5-2.1 kg) similar to that of risperidone (1.5 kg), whereas those on haloperidol and placebo showed mean weight loss (−0.1 kg and −0.3 kg, respectively). QTc interval significantly increased across all iloperidone groups (least squares mean change from baseline to end point, 2.9-9.1 msec) and for haloperidol (5.0 msec). No significant QTc changes occurred in the risperidone or placebo groups. Iloperidone was associated with no change from baseline in total cholesterol, mild elevation in serum glucose, and slight decrease in triglycerides. Prolactin levels decreased with iloperidone and increased significantly with risperidone and haloperidol. These short-term trials suggest that iloperidone has a reassuring safety profile in many of the areas that are of potential concern, including relatively low dropout rates because of AEs, low extrapyramidal symptoms, akathisia, and prolactin elevation, and a modest short-term effect on weight gain.

Relationships between medication treatments and neuropsychological test performance in schizophrenia

Few investigations have assessed the neuropsychological effects of psychotropic medications on schizophrenic patients. In this study, 44 clinically stable schizophrenic inpatients were administered a battery of neuropsychological tests, and their performance was correlated with dosage of neuroleptic medication and benztropine. Neuroleptic dose was correlated with poorer performance on tests of psychomotor speed and attention, and with the number of perserverative errors on the Wisconsin Card Sort. Anticholinergic dose was associated with poorer verbal learning, verbal fluency, and motor speed. Both medication dosages were associated with poorer verbal recognition memory, but this association was strongly influenced by the performance of individuals on the highest medication doses. The findings, which were independent of clinical state and intelligence, indicate that higher doses of neuroleptic and anticholinergic medications are associated with poorer neuropsychological functioning in schizophrenia.

Long-term changes in weight and plasma lipids during maintenance treatment with ziprasidone.

To measure the long-term changes in weight and plasma lipids after switching antipsychotic treatment to ziprasidone, three 52-week, open-label extension studies of ziprasidone in outpatients (N=185) with schizophrenia or schizoaffective disorder successfully completing one of three, 6-week switch studies were carried out. Pre-switch treatment consisted of risperidone (n=43), olanzapine (n=71), or conventional antipsychotic agents (n=71). The maximum length of exposure to ziprasidone was 58 weeks. Nonfasting total cholesterol and triglyceride levels were obtained at baseline and at weeks 6, 19, 32, 45, and 58. Weight was measured at baseline and during each follow-up visit; height was recorded at baseline for the purpose of body mass index (BMI) calculation. Efficacy measures included the Positive and Negative Syndrome Scale and Clinical Global Impression—Severity scale which were obtained at baseline and major follow-up points. Clinically significant sustained improvements in weight, BMI, total cholesterol, and triglyceride levels were observed among patients switched to ziprasidone from risperidone or olanzapine. Switching from conventional antipsychotics was not associated with significant changes in weight and lipid parameters. Mean reductions in weight from baseline to study endpoint were 9.8 kg (p<0.001) and 6.9 kg (p<0.005) for patients previously treated with olanzapine and risperidone, respectively. These findings demonstrate that switching from risperidone or olanzapine to ziprasidone is associated with sustained, clinically significant improvements in weight and plasma lipids.