Martha Sajatovic

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.

Subjective and expressive emotional responses in depression

Twenty-four depressed and twenty-three nondepressed male patients rated pleasantness of slides varying in hedonic content. Depressed patients rated positive slides as less pleasant and less arousing but did not differ from nondepressed patients in subjective response to normatively unpleasant images. Analysis of videotapes of facial expressions while watching the slide images showed that depressives exhibited more negative expressions than nondepressives to negative slides. Groups did not differ in facial expression to positive stimuli, but neither group displayed much affect to those stimuli. These data suggest a possible dissociation between self-reported and observable responsivity to emotional stimuli in depression and that diminished subjective emotional response in depression is restricted to hedonically positive stimuli and does not reflect generalized diminished emotional responsivity. These results also imply that clinical assessment of emotional responsivity in depression should be made using modalities in addition to observer evaluation of expressed emotion.

Predictors of nonadherence among individuals with bipolar disorder receiving treatment in a community mental health clinic.

BACKGROUND Subjective experience of illness is a critical component of treatment adherence in populations with bipolar disorder (BPD). This cross-sectional analysis examined clinical and subjective variables in relation to adherence in 140 individuals with BPD receiving treatment with mood-stabilizing medication. METHODS Nonadherence was defined as missing 30% or more of medication on the Tablets Routine Questionnaire, a self-reported measure of medication treatment adherence. Adherent and nonadherent groups were compared on measures of attitudes toward illness and treatment including the Attitudes toward Mood Stabilizers Questionnaire, the Insight and Treatment Attitudes Questionnaire, the Rating of Medication Influences, and the Multidimensional Health Locus of Control Scale. RESULTS Except for substance abuse comorbidity, adherent individuals (n = 113, 80.7%) did not differ from nonadherent individuals (n = 27, 19.3%) on clinical variables. However, nonadherent individuals had reduced insight into illness, more negative attitudes toward medications, fewer reasons for adherence, and more perceived reasons for nonadherence compared with adherent individuals. The strongest attitudinal predictors for nonadherence were difficulties with medication routines (odds ratio = 2.2) and negative attitudes toward drugs in general (odds ratio = 2.3). LIMITATIONS Results interpretation is limited by cross-sectional design, self-report methodology, and sample size. CONCLUSIONS Comorbid substance abuse, negative attitudes toward mood-stabilizing medication, and difficulty managing to take medication in the context of ones daily schedule are primary determinants of medication treatment adherence. A patient-centered collaborative model of care that addresses negative attitudes toward medication and difficulty coping with medication routines may be ideally suited to address individual adherence challenges.

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)

Rapidly progressive Alzheimer's disease features distinct structures of amyloid-β.

Genetic and environmental factors that increase the risk of late-onset Alzheimer disease are now well recognized but the cause of variable progression rates and phenotypes of sporadic Alzheimers disease is largely unknown. We aimed to investigate the relationship between diverse structural assemblies of amyloid-β and rates of clinical decline in Alzheimers disease. Using novel biophysical methods, we analysed levels, particle size, and conformational characteristics of amyloid-β in the posterior cingulate cortex, hippocampus and cerebellum of 48 cases of Alzheimers disease with distinctly different disease durations, and correlated the data with APOE gene polymorphism. In both hippocampus and posterior cingulate cortex we identified an extensive array of distinct amyloid-β42 particles that differ in size, display of N-terminal and C-terminal domains, and conformational stability. In contrast, amyloid-β40 present at low levels did not form a major particle with discernible size, and both N-terminal and C- terminal domains were largely exposed. Rapidly progressive Alzheimers disease that is associated with a low frequency of APOE e4 allele demonstrates considerably expanded conformational heterogeneity of amyloid-β42, with higher levels of distinctly structured amyloid-β42 particles composed of 30-100 monomers, and fewer particles composed of < 30 monomers. The link between rapid clinical decline and levels of amyloid-β42 with distinct structural characteristics suggests that different conformers may play an important role in the pathogenesis of distinct Alzheimers disease phenotypes. These findings indicate that Alzheimers disease exhibits a wide spectrum of amyloid-β42 structural states and imply the existence of prion-like conformational strains.

Medical and psychiatric comorbidities among elderly individuals with bipolar disorder: a literature review.

Introduction: The common comorbid conditions that accompany late-life bipolar disorder (BD) have not been well studied. This is a literature review on psychiatric and medical comorbidities among elderly individuals with BD. Methods: A focused literature review searched PubMed. Inclusion criteria were original research reports, in English, until June 2009, specifically focused on medical and psychiatric comorbidities in BD individuals over the age of 50. Results: A limited number of studies were identified. Most involved small samples (n < 100). Metabolic syndrome, respiratory and cardiovascular conditions, and endocrine abnormalities are common, with patients having an average of 3 to 4 medical comorbid conditions. Approximately 4.5% to 19% of elderly individuals with BD have dementia. Rates of psychiatric comorbidity appear lower than in younger BD populations, with the most common concurrent psychiatric illnesses being anxiety and substance use disorders. Rates of comorbid medical conditions appear similar to rates among geriatric patients without BD. Conclusions: Elderly individuals with BD are burdened by multiple concomitant medical disorders. In contrast to the elevated rates of medical comorbidity, rates of psychiatric comorbidity appear lower in elderly individuals with BD than in younger populations with BD. Greater awareness of concurrent medical conditions might help inform coordinated care that considers both mental and physical health among geriatric patients with BD.

Factors associated with prospective long-term treatment adherence among individuals with bipolar disorder.

OBJECTIVE Clinical characteristics, adverse effects of medication, and treatment attitudes have been associated with adherence in bipolar populations in cross-sectional studies. The aim of this secondary analysis from a larger study was to identify the association between baseline variables and average treatment adherence over a subsequent three-year period. METHODS Veterans with bipolar disorder were evaluated on self-reported adherence status at baseline and every six months over a three-year period. The sample was dichotomized into two clinically relevant categories: those who were primarily adherent and those who were primarily nonadherent. Demographic and clinical variables were examined for the two groups of patients in relation to their average adherence over the three-year period. RESULTS The study recruited a sample of 306 persons with severe bipolar disorder. The sample was predominantly male (278 men, or 91%), with a mean+/-SD age of 46.6+/-10.1 years. A total of 240 individuals (78%) were largely adherent to treatment, and 37 individuals (12%) were largely nonadherent to treatment. Nonadherent individuals were less likely to be on intensive somatotherapy regimens (p=.001); experienced more barriers to care, including lack of telephone access (p<.05) and life obligations and commitments (p<.05); and had more prior suicide attempts (p=.003). CONCLUSIONS Nonadherent individuals with bipolar disorder received less intensive pharmacologic treatments, had more suicide attempts, and experienced more barriers to care than adherent individuals. Nonadherence may have system as well as patient components. Consideration of nonadherence as a function of both patient factors and system factors will enhance our ability to understand nonadherence and intervene more effectively.

A report on older‐age bipolar disorder from the International Society for Bipolar Disorders Task Force

In the coming generation, older adults with bipolar disorder (BD) will increase in absolute numbers as well as proportion of the general population. This is the first report of the International Society for Bipolar Disorder (ISBD) Task Force on Older‐Age Bipolar Disorder (OABD).

Illness experience and reasons for nonadherence among individuals with bipolar disorder who are poorly adherent with medication

AIM Nonadherent individuals are the most likely to avoid participating in research studies, thus limiting potential opportunities to develop evidence-based approaches for adherence enhancement. This mixed-method analysis evaluated factors related to adherence among 20 poorly adherent community mental health clinic patients with bipolar disorder (BD). METHODS Illness experience was evaluated with qualitative interview. Quantitative assessments measured symptoms (Hamilton Depression Rating Scale, Young Mania Rating Scale, Brief Psychiatric Rating Scale), adherence behavior, and treatment attitudes. Poor adherence was defined as missing 30% or more of medication. RESULTS Minorities (80%), unmarried individuals (95%), and those with substance abuse (65%) predominated in this nonadherent group of patients with BD. Individuals were substantially depressed (mean Hamilton Depression Rating Scale, 19.2), had at least some manic symptoms (mean Young Mania Rating Scale, 13.6), and had moderate psychopathology (mean Brief Psychiatric Rating Scale, 41.2). Rates of missed medications were 41% to 43%. Forgetting to take medications was the top reason for nonadherence (55%), followed by side effects (20%). Disorganized home environments (30%), concern regarding having to take long-term medications (25%) or fear of side effects (25%), and insufficient information regarding BD (35%) were relatively common. Almost one third of patients had individuals in their core social network who specifically advised against medication. Access problems included difficulty paying for medications among more than half of patients. Interestingly, patients reported good relationships with their providers. CONCLUSIONS Forgetting to take medication and problems with side effects are primary drivers of nonadherence. Lack of medication routines, unsupportive social networks, insufficient illness knowledge, and treatment access problems may likewise affect overall adherence. Complementary quantitative and qualitative data collection can identify reasons for nonadherence and may inform specific clinical approaches to enhance adherence.

Maintenance treatment outcomes in older patients with bipolar I disorder.

OBJECTIVE The efficacy and tolerability of mood stabilizers in older adults with bipolar disorder remains understudied. Authors retrospectively examined response to lamotrigine, lithium, and placebo in older (>or=age 55) adults with Bipolar I disorder (DSM-IV) who participated in two mixed-age, maintenance studies examining time to intervention for an emerging mood episode (manic/hypomanic/mixed or depressed) and drug tolerability. METHODS In all, 588 patients received double-blind lamotrigine (LTG, 100 mg-400 mg/day), lithium (Li, 0.8 mEq/L-1.1 mEq/L), or placebo (PBO); data from 98 older adults (LTG: 33, Li: 34, PBO: 31) were examined. Mean modal total daily doses were LTG 240 mg and Li 750 mg. RESULTS LTG significantly delayed time to intervention for any mood episode and for a depressive episode, compared with placebo. Li significantly delayed time to intervention for mania/hypomania/mixed compared with placebo. Back pain and headache were the most common adverse events during LTG treatment; rash: LTG, 3%; Li, 6%; and PBO, 0; no serious rash was reported. The most common adverse events (>10%) during lithium treatment were dyspraxia, tremor, xerostomia, headache, infection, amnesia, dizziness, diarrhea, nausea, and fatigue. CONCLUSION Lamotrigine and lithium may be effective and well-tolerated maintenance therapies for older adults with Bipolar I depression.