Matthew J. Byerly

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.

A comparison of electronic monitoring vs. clinician rating of antipsychotic adherence in outpatients with schizophrenia

Antipsychotic non-adherence rates of outpatients with schizophrenia or schizoaffective disorder was assessed by electronic monitoring and clinician rating. Antipsychotic adherence was determined monthly over 3 consecutive months with (1) the Medication Event Monitoring System (MEMS) cap and (2) the Clinician Rating Scale. Non-adherence was defined as daily adherence of <70% during any one of three monthly evaluations for MEMS and ratings of <or=4 (scale of 1-7) on the Clinician Rating Scale. Non-adherence was detected in 12 of 25 patients (48%) by MEMS and 0% by the Clinician Rating Scale. Clinician assessment dramatically underestimated antipsychotic non-adherence.

Clinical implications of antipsychotic-induced hyperprolactinemia in patients with schizophrenia spectrum or bipolar spectrum disorders: recent developments and current perspectives.

Hyperprolactinemia is increasingly studied as a frequent and potentially important consequence of antipsychotic medication treatment. Some individuals presenting with hyperprolactinemia remain asymptomatic, but others may exhibit a wide range of clinical symptoms resulting from either the direct effects of prolactin on body tissues (galactorrhea, gynecomastia) or endocrine-related secondary effects (sexual and reproductive dysfunction in the short term, and possibly the risk of tumorigenesis and osteoporosis in the longer term). Short-term side effects may negatively impact medication compliance, and long-term effects have the potential for serious health consequences. Antipsychotic medications have differing propensities to cause prolactin elevation. The first-generation antipsychotics, as well as the second-generation antipsychotic risperidone and its active metabolite paliperidone, have been shown to cause marked and sustained elevations in prolactin levels, whereas others of the second-generation antipsychotics appear to have little or no effect on prolactin levels or may decrease prolactin. A comprehensive overview of antipsychotics and hyperprolactinemia is presented together with a review of emerging evidence about the short- and long-term health risks of hyperprolactinemia.

Effectiveness of Switching From Antipsychotic Polypharmacy to Monotherapy

OBJECTIVE This randomized trial addressed the risks and benefits of staying on antipsychotic polypharmacy or switching to monotherapy. METHOD Adult outpatients with schizophrenia taking two antipsychotics (127 participants across 19 sites) were randomly assigned to stay on polypharmacy or switch to monotherapy by discontinuing one antipsychotic. The trial lasted 6 months, with a 6-month naturalistic follow-up. Kaplan-Meier and Cox regression analyses examined time to discontinuation of assigned antipsychotic treatment, and random regression models examined additional outcomes over time. RESULTS Patients assigned to switch to monotherapy had shorter times to all-cause treatment discontinuation than those assigned to stay on polypharmacy. By month 6, 86% (N=48) of those assigned to stay on polypharmacy were still taking both medications, whereas 69% (N=40) of those assigned to switch to monotherapy were still taking the same medication. Most monotherapy discontinuations entailed returning to the original polypharmacy. The two groups did not differ with respect to psychiatric symptoms or hospitalizations. On average, the monotherapy group lost weight, whereas the polypharmacy group gained weight. CONCLUSIONS Discontinuing one of two antipsychotics was followed by treatment discontinuation more often and more quickly than when both antipsychotics were continued. However, two-thirds of participants successfully switched, the groups did not differ with respect to symptom control, and switching to monotherapy resulted in weight loss. These results support the reasonableness of prescribing guidelines encouraging trials of antipsychotic monotherapy for individuals receiving antipsychotic polypharmacy, with the caveat that patients should be free to return to polypharmacy if an adequate trial on antipsychotic monotherapy proves unsatisfactory.

Obsessive compulsive symptoms in schizophrenia: Frequency and clinical features

OBJECTIVE Prior studies have evaluated the occurrence and clinical effects of obsessive-compulsive (OC) symptoms in schizophrenia with varied results. This study systematically assessed the frequency and clinical impact of OC symptoms among outpatients with schizophrenia and schizoaffective disorder. METHOD One hundred subjects with schizophrenia or schizoaffective disorder were evaluated with a 20-question detailed screen for the presence of OC symptoms. The severity of OC symptoms was assessed with the Yale Brown Obsessive-Compulsive Scale (Y-BOCS). Fifty-eight patients participated in subsequent assessments comparing schizophrenia severity (Positive and Negative Syndrome Scale) functional status (Social and Occupational Functioning Scale) and resource utilization (psychiatric hospitalization) of OC (N=21) and non-OC (N=37) patients. RESULTS Thirty percent of patients exhibited two or more OC symptoms, and 19% had at least moderate OC symptoms (Y-BOCS score >or= 16). Twenty-three percent met full DSM-IV criteria for OCD. There were no differences observed between the OC and non-OC groups on any of the clinical outcomes. OC symptoms were developed prior to the onset of schizophrenia in only 28% of patients. CONCLUSIONS Nearly one-third of patients exhibited clinically significant OC symptoms in this systematic, cross-sectional assessment. However, OC symptoms did not appear to impact the clinical outcome of patients. In most cases, OC symptoms began concurrently with or after the onset of the psychotic disorder. Studies are needed to define the relevance and pathological basis for the co-occurrence of OC symptoms in persons with schizophrenia.

Validity of Electronically Monitored Medication Adherence and Conventional Adherence Measures in Schizophrenia

OBJECTIVE This study evaluated the validity of prescriber, patient, and research assistant ratings of adherence to prescribed oral antipsychotic medication among outpatients with schizophrenia or schizoaffective disorder in comparison with electronic monitoring. METHODS Adult outpatients with schizophrenia (N=35) or schizoaffective disorder (N=26) received adherence assessments via electronically monitored medication vial caps as well as by monthly prescriber, patient, and research assistant report for up to six months. RESULTS Electronic monitoring detected greater nonadherence rates (57%) than either prescribers (7%) or patients (5%), though the research assistant ratings were 54%. No directional bias was found between electronic monitoring and assignment of adherence by research assistants, although disagreement occurred in 36% of cases. CONCLUSIONS Both patients and prescribers grossly overestimated medication adherence, which may interfere with or reduce the effectiveness of diligent medication management.

The Brief Adherence Rating Scale (BARS) validated against electronic monitoring in assessing the antipsychotic medication adherence of outpatients with schizophrenia and schizoaffective disorder

Among outpatients with schizophrenia, antipsychotic non-adherence is common, grossly under-detected by patients and their prescribers, and is associated with poor clinical outcomes. Using electronic monitoring (EM) as the reference standard we evaluated the reliability and validity as well as the sensitivity and specificity of a recently developed, brief, pencil-paper, clinician-administered adherence instrument [the Brief Adherence Rating Scale (BARS)] to assess the oral antipsychotic medication adherence of outpatients with schizophrenia and schizoaffective disorder. EM and BARS adherence and symptom severity ratings were gathered at baseline and prospectively at 6 monthly visits in 61 participants (n=35 with schizophrenia; n=26 with schizoaffective disorder). A significant positive relationship was found between mean BARS and EM adherence (beta=0.98; rs=0.59, p<0.0001). Cronbachs coefficient alpha revealed very high internal reliability for the BARS (alpha=0.92). A moderate-to-strong degree of test-retest reliability was also found for the BARS (beta ranged from 0.53 to 0.92 and rs ranged from 0.46 to 0.86). Regarding concurrent validity of the BARS, greater mean BARS adherence was significantly related to lower mean PANSS total scores (beta=-0.40; rs=-0.39, p=0.002) and to lower mean Positive symptom sub-scale scores (beta=-0.08, p=.007; rs=-0.28, p=.02). An initial 3-month monitoring period with the BARS also demonstrated good sensitivity (73%) and specificity (74%) in identifying non-adherent outpatients (defined as <70% mean EM adherence). Relative to EM, the BARS appears to provide valid, reliable, sensitive, and specific estimates of antipsychotic medication adherence of outpatients with schizophrenia and schizoaffective disorder. The BARS appears to be a promising candidate as a brief adherence assessment instrument for feasible use in community-based settings.

Antipsychotic medications and the elderly: effects on cognition and implications for use.

Despite being frequently prescribed in the elderly, antipsychotic medications are commonly associated with adverse effects in this population, including sedative, orthostatic and extrapyramidal adverse effects. Growing evidence suggests that antipsychotics can also cause deleterious cognitive effects in some elderly patients. Preclinical and growing clinical evidence indicates that inhibitory effects on dopaminergic, cholinergic and histaminergic neurochemical systems may account for antipsychotic-associated cognitive impairment in the elderly.A review of published reports of the cognitive effects of antipsychotics in the elderly suggests that newer antipsychotic medications may possess a more favourable cognitive profile than that of traditional agents in this population. The cognitive effect that a specific antipsychotic will have in the elderly, however, is likely better predicted by considering the pharmacodynamic action of an individual agent in combination with the pathophysiology of the condition being treated. Agents with relatively weak dopamine inhibiting effects (e.g. clozapine and quetiapine), for example, would theoretically have a cognitive profile superior to that of agents with higher degrees of dopaminergic inhibition (all traditional agents, risperidone, olanzapine and ziprasidone) when used for conditions associated with diminished dopamine function (e.g. idiopathic Parkinson’s disease). Drugs with weak anticholinergic effects (high-potency traditional agents, risperidone, quetiapine and ziprasidone) would theoretically be less likely to cause cognitive impairment than agents with high degrees of cholinergic receptor blocking actions (clozapine and olanzapine) when treating patients with impaired cholinergic function (e.g. Alzheimer’s disease). Cholinergic agonist effects of clozapine and olanzapine may, however, mitigate potential adverse cognitive effects associated with the cholinergic blocking actions of these agents.Large, rigorous trials comparing the cognitive effects of antipsychotics with diverse pharmacodynamic actions are lacking in the elderly and are needed.

Effectiveness of Paliperidone Palmitate vs Haloperidol Decanoate for Maintenance Treatment of Schizophrenia: A Randomized Clinical Trial

IMPORTANCE Long-acting injectable antipsychotics are used to reduce medication nonadherence and relapse in schizophrenia-spectrum disorders. The relative effectiveness of long-acting injectable versions of second-generation and older antipsychotics has not been assessed. OBJECTIVE To compare the effectiveness of the second-generation long-acting injectable antipsychotic paliperidone palmitate with the older long-acting injectable antipsychotic haloperidol decanoate. DESIGN, SETTING, AND PARTICIPANTS Multisite, double-blind, randomized clinical trial conducted from March 2011 to July 2013 at 22 US clinical research sites. Randomized patients (n = 311) were adults diagnosed with schizophrenia or schizoaffective disorder who were clinically assessed to be at risk of relapse and likely to benefit from a long-acting injectable antipsychotic. INTERVENTIONS Intramuscular injections of haloperidol decanoate 25 to 200 mg or paliperidone palmitate 39 to 234 mg every month for as long as 24 months. MAIN OUTCOME MEASURES Efficacy failure, defined as a psychiatric hospitalization, a need for crisis stabilization, a substantial increase in frequency of outpatient visits, a clinicians decision that oral antipsychotic could not be discontinued within 8 weeks after starting the long-acting injectable antipsychotics, or a clinicians decision to discontinue the assigned long-acting injectable due to inadequate therapeutic benefit. Key secondary outcomes were common adverse effects of antipsychotic medications. RESULTS There was no statistically significant difference in the rate of efficacy failure for paliperidone palmitate compared with haloperidol decanoate (adjusted hazard ratio, 0.98; 95% CI, 0.65-1.47). The number of participants who experienced efficacy failure was 49 (33.8%) in the paliperidone palmitate group and 47 (32.4%) in the haloperidol decanoate group. On average, participants in the paliperidone palmitate group gained weight and those in the haloperidol decanoate group lost weight; after 6 months, the least-squares mean weight change for those taking paliperidone palmitate was increased by 2.17 kg (95% CI, 1.25-3.09) and was decreased for those taking haloperidol decanoate (-0.96 kg; 95% CI, -1.88 to -0.04). Patients taking paliperidone palmitate had significantly higher maximum mean levels of serum prolactin (men, 34.56 µg/L [95% CI, 29.75-39.37] vs 15.41 µg/L [95% CI, 10.73-20.08]; P <.001, and for women, 75.19 [95% CI, 63.03-87.36] vs 26.84 [95% CI, 13.29-40.40]; P<.001). Patients taking haloperidol decanoate had significantly larger increases in global ratings of akathisia (0.73 [95% CI, 0.59-0.87] vs 0.45 [95% CI, 0.31-0.59]; P=.006). CONCLUSIONS AND RELEVANCE In adults with schizophrenia or schizoaffective disorder, use of paliperidone palmitate vs haloperidol decanoate did not result in a statistically significant difference in efficacy failure, but was associated with more weight gain and greater increases in serum prolactin, whereas haloperidol decanoate was associated with more akathisia. However, the CIs do not rule out the possibility of a clinically meaningful advantage with paliperidone palmitate. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01136772.

Metformin for Weight Loss and Metabolic Control in Overweight Outpatients With Schizophrenia and Schizoaffective Disorder

OBJECTIVE The purpose of this study was to determine whether metformin promotes weight loss in overweight outpatients with chronic schizophrenia or schizoaffective disorder. METHOD In a double-blind study, 148 clinically stable, overweight (body mass index [BMI] ≥27) outpatients with chronic schizophrenia or schizoaffective disorder were randomly assigned to receive 16 weeks of metformin or placebo. Metformin was titrated up to 1,000 mg twice daily, as tolerated. All patients continued to receive their prestudy medications, and all received weekly diet and exercise counseling. The primary outcome measure was change in body weight from baseline to week 16. RESULTS Fifty-eight (77.3%) patients who received metformin and 58 (81.7%) who received placebo completed 16 weeks of treatment. Mean change in body weight was -3.0 kg (95% CI=-4.0 to -2.0) for the metformin group and -1.0 kg (95% CI=-2.0 to 0.0) for the placebo group, with a between-group difference of -2.0 kg (95% CI=-3.4 to -0.6). Metformin also demonstrated a significant between-group advantage for BMI (-0.7; 95% CI=-1.1 to -0.2), triglyceride level (-20.2 mg/dL; 95% CI=-39.2 to -1.3), and hemoglobin A1c level (-0.07%; 95% CI=-0.14 to -0.004). Metformin-associated side effects were mostly gastrointestinal and generally transient, and they rarely led to treatment discontinuation. CONCLUSIONS Metformin was modestly effective in reducing weight and other risk factors for cardiovascular disease in clinically stable, overweight outpatients with chronic schizophrenia or schizoaffective disorder over 16 weeks. A significant time-by-treatment interaction suggests that benefits of metformin may continue to accrue with longer treatment. Metformin may have an important role in diminishing the adverse consequences of obesity and metabolic impairments in patients with schizophrenia.