Circadian rhythms in cognitive functioning among patients with schizophrenia: impact on signal detection in clinical trials of potential pro-cognitive therapies.

OBJECTIVE: Cognition is affected by circadian rhythms over the course of a day. Circadian rhythms in cognitive functioning are driven by a variety of both endogenous and exogenous factors. Patients with schizophrenia are known to have disturbed circadian rhythms that can affect their cognitive functioning. We examined the impact of time of day on cognitive test scores from subjects participating in clinical trials of potential pro-cognitive therapies for schizophrenia and then explored how this diurnal variation affected signal detection. METHOD: Baseline data from 8 separate schizophrenia clinical trials using the MATRICS Consensus Cognitive Battery (MCCB) were aggregated (Total N=2032). The MCCB assessments were divided into five 2-hour time intervals based on the start-time of the assessments (varying from 8:00 am to 5:59 pm) and then analyzed for differences by time interval. Next, data from two Phase 2 schizophrenia clinical trials of potential pro-cognitive therapies were analyzed to explore the impact of this diurnal variation on placebo separation. RESULTS: Time of day exerted a significant effect on baseline composite MCCB scores (p=.002). Follow-up comparisons revealed significant differences among multiple temporal epochs. In both Phase 2 clinical trials, subjects whose cognitive functioning was assessed at consistent times of day between their baseline and endpoint visits showed a more robust treatment response as compared to subjects assessed at inconsistent times of day. CONCLUSION: Cognitive functioning ebbs and flows over the course of the day. Maintaining consistency in the time of day of cognitive test administrations between visits can help to reduce the noise introduced by circadian rhythms, thereby enhancing signal detection in clinical trials of potential pro-cognitive therapies.

Effect of milnacipran on body weight in patients with fibromyalgia.

BACKGROUND: The purpose of this study was to evaluate the effects of milnacipran on body weight in patients with fibromyalgia. METHODS: ANALYSES WERE CONDUCTED IN THE FOLLOWING GROUPS: patients from three double-blind, placebo-controlled milnacipran trials (3 months, n = 2096; 6 months, n = 1008); 354 patients receiving milnacipran in placebo-controlled trials and double-blind extension studies (total ≥ 12 months of treatment); and 1227 patients in a long-term (up to 3.25 years) open-label milnacipran study. RESULTS: In placebo-controlled trials, 77% of patients were overweight or obese at baseline (body mass index ≥ 25 kg/m(2)). Mean weight loss was found with milnacipran at 3 months (100 mg/day, -1.14 kg; 200 mg/day, -0.97 kg; placebo, -0.06 kg; P < 0.001) and 6 months (100 mg/day, -1.01 kg; 200 mg/day, -0.71 kg; placebo, -0.04 kg; P < 0.05). Approximately twice as many milnacipran-treated patients had ≥5% weight loss from baseline compared with placebo (3 and 6 months, P < 0.01). In extension studies, mean weight loss in patients receiving ≥12 months of milnacipran was -1.06 kg. In patients receiving ≥3 years of treatment in the open-label study, mean changes at 12, 24, 30, and 36-38 months were -1.16, -0.76, -0.19, and +0.11 kg, respectively. Among milnacipran-treated patients, rates of nausea (the most common adverse event) were lower among patients who lost weight than among those who did not (3 months, P = 0.02). CONCLUSION: The majority of patients with fibromyalgia in the milnacipran studies were overweight or obese. Milnacipran was associated with mean weight loss at 3 and 6 months (P < 0.05 versus placebo) and at 12 and 24 months of treatment, with mean changes drifting back to baseline at 30 months (-0.19 kg) and 36-38 months (+0.11 kg, no placebo comparison).

Ecological momentary assessment.

Assessment in clinical psychology typically relies on global retrospective self-reports collected at research or clinic visits, which are limited by recall bias and are not well suited to address how behavior changes over time and across contexts. Ecological momentary assessment (EMA) involves repeated sampling of subjects' current behaviors and experiences in real time, in subjects' natural environments. EMA aims to minimize recall bias, maximize ecological validity, and allow study of microprocesses that influence behavior in real-world contexts. EMA studies assess particular events in subjects' lives or assess subjects at periodic intervals, often by random time sampling, using technologies ranging from written diaries and telephones to electronic diaries and physiological sensors. We discuss the rationale for EMA, EMA designs, methodological and practical issues, and comparisons of EMA and recall data. EMA holds unique promise to advance the science and practice of clinical psychology by shedding light on the dynamics of behavior in real-world settings.

Nonnormality and divergence in posttreatment alcohol use: reexamining the Project MATCH data "another way.".

Alcohol lapses are the modal outcome following treatment for alcohol use disorders, yet many alcohol researchers have encountered limited success in the prediction and prevention of relapse. One hypothesis is that lapses are unpredictable, but another possibility is the complexity of the relapse process is not captured by traditional statistical methods. Data from Project Matching Alcohol Treatments to Client Heterogeneity (Project MATCH), a multisite alcohol treatment study, were reanalyzed with 2 statistical methodologies: catastrophe and 2-part growth mixture modeling. Drawing on previous investigations of self-efficacy as a dynamic predictor of relapse, the current study revisits the self-efficacy matching hypothesis, which was not statistically supported in Project MATCH. Results from both the catastrophe and growth mixture analyses demonstrated a dynamic relationship between self-efficacy and drinking outcomes. The growth mixture analyses provided evidence in support of the original matching hypothesis: Individuals with lower self-efficacy who received cognitive behavior therapy drank far less frequently than did those with low self-efficacy who received motivational therapy. These results highlight the dynamical nature of the relapse process and the importance of the use of methodologies that accommodate this complexity when evaluating treatment outcomes.

Assessing clients in their natural environments with electronic diaries: rationale, benefits, limitations, and barriers.

Increasingly, mobile technologies are used to gather diary data in basic research and clinical studies. This article considers issues relevant to the integration of electronic diary (ED) methods in clinical assessment. EDs can be used to gather rich information regarding clients' day-to-day experiences, aiding diagnosis, treatment planning, treatment implementation, and treatment evaluation. The authors review the benefits of using diary methods in addition to retrospective assessments, and they review studies assessing whether EDs yield higher quality data than conventional, less expensive paper-pencil diaries. Practical considerations--including what platforms can be used to implement EDs, what features they should have, and considerations in designing diary protocols for sampling different types of clinical phenomena--are described. The authors briefly illustrate with examples some ways in which ED data could be summarized for clinical use. Finally, the authors consider barriers to clinical adoption of EDs. EDs are likely to become increasingly popular tools in routine clinical assessment as clinicians become more familiar with the logic of diary designs; as software packages evolve to meet the needs of clinicians; and as mobile technologies become ubiquitous, robust, and inexpensive.

Characterization and consequences of pain variability in individuals with fibromyalgia.

OBJECTIVE: A growing body of evidence suggests that real-time electronic assessments of pain are preferable to traditional paper-and-pencil measures. We used electronic assessment data derived from a study of patients with fibromyalgia (FM) to examine variability of pain over time and to investigate the implications of pain fluctuation in the context of a clinical trial. METHODS: The study group comprised 125 patients with FM who were enrolled in a randomized, placebo-controlled trial of milnacipran. Pain intensity levels were captured in real time by participants using electronic diaries. Variability in pain was assessed as the standard deviation of pain entries over time (pain variability index [PVI]). RESULTS: Substantial between-subject differences in pain variability were observed (mean +/- SD PVI 1.61 +/- 0.656 [range 0.27-4.05]). The fluctuation in pain report was constant over time within individuals (r = 0.664, P < 0.001). Individuals with greater variability were more likely to be classified as responders in a drug trial (odds ratio 6.14, P = 0.006); however, this association was primarily attributable to a greater change in pain scores in individuals receiving placebo (r = 0.460, P = 0.02) rather than active drug (r = 0.09, P > 0.10). CONCLUSION: Among individuals with FM, there were large between-subject differences in real-time pain reports. Pain variability was relatively constant over time within individuals. Perhaps the most important finding is that individuals with larger pain fluctuations were more likely to respond to placebo. It is not clear whether these findings are applicable only to patients with FM or whether they may also be seen in patients with other chronic pain conditions.

Assessing motivation to change among problem drinkers with and without co-occurring major depression.

The University of Rhode Island Change Assessment Scale (URICA) is a widely used measure of readiness to change. To evaluate the URICA's ability to discriminate among alcohol abusers with and without co-occurring major depression, the authors administered it to 193 outpatients court-referred for alcohol treatment. Estimates of internal consistency suggest that scoring the URICA using its traditional factors, as well as using the newer Readiness to Change index, produced variable yet adequately reliable scores. Further, the URICA detected statistically significant differences in motivation to change an alcohol problem between an alcohol use disorder group (AD; n = 131) and an alcohol use disorder with co-occurring depression group (AD/D; n = 62) with the AD/D group showing greater readiness to change. For the AD/D group, separate URICAs were given for alcohol use and depressed mood. Confirming previous findings, results suggest the URICA may lack sensitivity to discriminate among two simultaneously occurring psychological disorders.

Pain assessment in patients with fibromyalgia syndrome: a consideration of methods for clinical trials.

OBJECTIVE: This study was designed to compare 3 commonly used methodologies for assessing clinical pain during trials involving patients diagnosed with fibromyalgia syndrome. Baseline characteristics, characteristics over time, and compliance were evaluated for each of the methods. METHODS: Fourteen patients diagnosed with fibromyalgia syndrome were asked to monitor their symptoms of pain using 3 different strategies over a 12-week period: 1) real-time pain reports were collected on an electronic diary using randomly-scheduled audible prompts; 2) end-of-week reports asked patients to rate their mean pain over the past week on the electronic diary; and 3) monthly in-clinic reports asked patients to rate their mean pain for the week using a traditional paper and pencil diary. RESULTS: Significantly different baseline values were obtained for the 3 methods. Paper and pencil produced the highest values, and real-time pain reports produced the lowest baseline values. Pain ratings were more likely to reflect decreases in the 2 methods relying on recall than the real-time strategy. The average adherence with pain monitoring using the electronic diary was 85%, which was superior to the adherence for the recall measures completed during the clinic visits. CONCLUSION: Pain assessment methods relying on recall might contribute to an apparent improvement in clinical trials in the absence of an intervention; such an effect has been considered a "placebo response." Future clinical trials might consider using a real-time approach to pain assessment, which in this study appeared to mitigate against seeing improvement in the absence of an intervention and demonstrated higher levels of patient adherence.

Signaling does not adequately improve diary compliance.

HYPOTHESIS: Compliance with a paper diary protocol would be improved by using auditory signaling. BACKGROUND: Prior research has demonstrated that compliance with the reporting schedule in paper diary protocols is poor. METHODS: Adults with chronic pain (N = 27) were recruited from the community to participate in a 24-day experience sampling protocol of 3 pain assessments per day (10:00 a.m., 4:00 p.m., 8:00 p.m.). Diaries were instrumented to record openings and closings, thereby permitting determination of date and time when the participant could have made diary entries. Participants were signaled with a programmed wristwatch at the onset of each 30-min assessment window. Two compliance windows were defined: -/+ 15 min and -/+ 45 min of the targeted assessment time. RESULTS: Self-reported compliance based on participants' paper diaries was 85% and 91% for the 30- and 90-min windows. Verified compliance was 29% and 39% for the two windows. Signaling produced a significant increment in verified compliance when compared with an identical trial without signaling. A significant eroding of verified compliance was observed across the 3 weeks of the study. CONCLUSIONS: Self-report dating of diary entries may be misleading investigators about compliance with diary protocols. Although auditory signaling enhances compliance, the result is still unsatisfactory.

Measuring clinical pain in chronic widespread pain: selected methodological issues.

Assessing clinical pain is an important task in clinical practice and research. A large empirical literature has documented that patients' pain reports can be systematically biased by a number of methodological factors. This chapter reviews a selection of methodological issues that can affect pain ratings, including: the impact of recall bias, the use of paper and electronic diaries to assess pain experiences, ecological momentary assessment methods as a way of capturing real-time pain data in the real world, and pain scaling and data analysis considerations. Data from a recent study that implemented an electronic diary for capturing real-time pain data are presented and reviewed in the context of the methodological factors reviewed above. It is concluded that methodological factors can greatly affect our understanding of patients' pain experiences.

Relapse as a nonlinear dynamic system: application to patients with alcohol use disorders.

Understanding the relapse process is one of the most important issues in addictive behaviors research. To date, most studies have taken a linear approach toward predicting relapse based on risk factors. Nonlinear dynamical systems theory can be used to describe processes that are not adequately modeled using a linear approach. In particular, the authors propose that catastrophe theory, a subset of nonlinear dynamical systems theory, can be used to describe the relapse process in addictive behaviors. Two small prospective studies using 6-month follow-ups of patients with alcohol use disorders (inpatient, n = 51; outpatient, n = 43) illustrate how cusp catastrophe theory may be used to predict relapse. Results from these preliminary studies indicate that a cusp catastrophe model has more predictive utility than traditional linear models.

Patient compliance with paper and electronic diaries.

Paper diaries are commonly used in health care and clinical research to assess patient experiences. There is concern that patients do not comply with diary protocols, possibly invalidating the benefit of diary data. Compliance with paper diaries was examined with a paper diary and with an electronic diary that incorporated compliance-enhancing features. Participants were chronic pain patients and they were assigned to use either a paper diary instrumented to track diary use or an electronic diary that time-stamped entries. Participants were instructed to make three pain entries per day at predetermined times for 21 consecutive days. Primary outcome measures were reported vs actual compliance with paper diaries and actual compliance with paper diaries (defined by comparing the written times and the electronically-recorded times of diary use). Actual compliance was recorded by the electronic diary. Participants submitted diary cards corresponding to 90% of assigned times (+/-15 min). However, electronic records indicated that actual compliance was only 11%, indicating a high level of faked compliance. On 32% of all study days the paper diary binder was not opened, yet reported compliance for these days exceeded 90%. For the electronic diary, the actual compliance rate was 94%. In summary, participants with chronic pain enrolled in a study for research were not compliant with paper diaries but were compliant with an electronic diary with enhanced compliance features. The findings call into question the use of paper diaries and suggest that electronic diaries with compliance-enhancing features are a more effective way of collecting diary information.

Reactivity to ecological momentary assessment: an example using undergraduate problem drinkers.

A. A. Stone and S. Shiffman (1994) defined ecological momentary assessment (EMA) as monitoring or sampling strategies that assess phenomena at the moment they occur in natural settings, thus maximizing ecological validity while avoiding retrospective recall. To address the extent to which EMA affects the behaviors and cognitions under observation, the authors examined behavioral and motivational reactivity to EMA among male and female undergraduate problem drinkers (n = 33). Participants completed a 2-week monitoring protocol using palmtop computers as well as pre- and postmonitoring measures of their drinking behavior and motivation for change. The findings suggest that the magnitude of reactivity to EMA is small. Suggestions for future research are presented.

Methodological issues affecting the value of patient-reported outcomes data.

The validity and value of patient-reported outcomes data are heavily dependent on the methods used to collect the data. This review examines the impact of a variety of methodological issues on the value of patient-reported outcome data. In particular, when patients are asked to self-monitor their experiences, disease episodes and healthcare utilization over time, a variety of methodological issues must be addressed if the data are to be considered a reliable and valid reflection of their daily lives. Ecological momentary assessment, a set of methods for collecting real-time data from patients in their natural environments, holds considerable promise as a way to enhance the value of certain types of patient-reported outcome data.