To provide a concise focus on medication trials in the N-of-1 study (which is properly described as a single-patient open trial (SPOT), we have re-titled our manuscript and extensively revised it. The following sections were cut, reorganized, and amended:
- Introduction and Methods were removed from superfluous patient histories
- Table 1 (drug trial description) was moved to Methods to Results
- To justify and address study design decisions regarding medication blinding and washout periods, and cross-overs, Text was added to Methods & Limitations
- Discussion was removed from suggestions for future directions
To simplify the text, the auxiliary follow-up study of mild sleep disorder was moved to the Supplementary Material. We chose to keep this work available rather than removing it completely.
- It shows the reproducibility of the subject’s basic, no-drug sleep structure 6 months after the medication trials.
- This report reveals the effects of a clinical intervention to mild sleep apnea.
Abstract
A growing number of people are interested in personalized and preventive medicine that involves patient engagement. This includes initiatives such as the one initiated by participants in the quantified self movement. Many self-assessments are not grounded in scientific principles, such as using controls, dose escalation strategies and multiple endpoint monitoring. Individual monitoring and health assessments are very useful in areas such as sleep and behavior. There are many sleep-related and behavioral conditions that can be difficult to treat and are not easily treated without personalization. Winter depression, also known as seasonal affective disorder (SAD), is a severe, recurrent, and atypical depressive disorder that impacts millions of people every year. To prevent SAD recurring each year, antidepressant drugs can be used as a prophylactic treatment. These antidepressant drugs can also affect sleep patterns and further exacerbate the condition. This is why it may be possible to prescribe unique combinations or ‘polypharmaceutical” interventions that involve sleep aids. Unfortunately, there has not been much research on the long-term effects of polypharmacy on sleep quality for those who have been treated. We used wireless monitoring to study the effects of polypharmacy on sleep patterns, and to determine the best course of treatment for a patient being treated for SAD using duloxetine (Cymbalta), and temazepam.
Introduction
Seasonal affective disorder (SAD), also known as winter depression, is a depressive disorder that usually begins in the fall or winter and remissions in the spring or summer. The U.S. has approximately 5-10% of the population with SAD. In the United States, approximately 5-10 percent of people experience SAD. Although full syndromal symptoms of SAD are not possible every year (which is often dependent on external stressors), subsyndromal symptoms can still be observed . There are many symptoms that can be seen, including hypersomnia, carbohydrate craving, and jet-lagged mental and physical states (also known as “brain fog”), which lead to fatigue and irritability. SAD is thought to be caused by an annual shortening in the photoperiod. However, seasonal mammals have shown evolutionary conservation down to lower forms – . This suggests that SAD could be caused by a variety of basic physiologic mechanisms. SAD is complex and has both neurobiological and chronobiological underpinnings 7-11. Some cases may even start in utero 12 16.
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Participant
A post-menopausal, 58-year old female was studied. She had been treated for SAD since 2001. Due to her long dissatisfaction regarding available treatments, insufficient insight into her multiple conditions and her complex treatment history, the subject was interested both in self-monitoring as well as an N-of-1 study. The subject was a regular user of benzodiazepine for sleep and antidepressant use. According to the Basic Language Morningness Scale (BALM), the subject is classified as either evening prone or delayed sleeping phase disorder. It uses a 6-item scale . She reported in summer 2012 that she felt fatigued even when she was indoors in low light conditions. The subject was on 60 mg Cymbalta and 30 mg temazepam to sleep. Sumatriptan 100 mg as needed for morning headaches. A SPOT study (N-of-1) was conducted to examine how her medications affected her sleep. It was done in the context of her winter depression (SAD), evening chronotype and delayed sleep phase, morning headaches, restless legs/PLMs, and her diagnosed winter depression (SAD).
Ethics
VLM was the author of this study. The Helsinki Declaration is not applicable in this instance, so an institutional review board was not required to approve the ethical approval.
Wireless devices and measures
Sleep and activity monitoring. To assess sleep patterns a Zeo Sleep Monitor ( http://www.myzeo.com, model number ZEO 301) was used, which was worn nightly after entering bed per manufacturer instructions. The Zeo wirelessly records the stages of sleep at 5-minute intervals. It has been tested against laboratory polysomnography HTML3_. A companion iPAD application, Zeo Sleep Manager v1.9.0, recorded the number of awakenings after sleep onset, percent time in light, deep, REM, and wake and gave an assessment. The Zeo online application offered nightly monitoring of sleep stages, and tools to evaluate trends. It was available until the manufacturer went bankrupt. Additionally, the Zeo online application offered educational materials to remind users of good sleep hygiene practices as well as journaling and counseling options. The Zeo monitor’s data was recorded on an iPad. Zeo graphic data from the device can be obtained from the authors. An Actiwatch Spectrum, manufactured by Philips Respironics, was also used to record data at 15 second intervals. It was worn daily to track light exposure and sleep. The Zeo monitor was synced to it on the nights that it was worn. Actiwatch uses movement to determine wake and sleep. Actiwatch software version 04.00 tends to underestimate sleep time and overestimate sleep time. The PAM-RL, also manufactured by Philips Respironics, measured leg movements and was scored using default settings (PAMRL version 7.6.2). Finally, the Fitbit Ultra actigraphic monitor ( http://www.fitbit.com) was worn daily to track walking or “step” activity. From the beginning of her day until the end of the night, the subject wore her Fitbit around her waist. The Fitbit is a device that monitors sleep activity. However, it can overestimate sleep time because it tracks movement. (Fitbit app version 1.8.2).
Procedures
Pharmacotherapy: Effect on Sleep. The following schedule was created to evaluate the effects of Cymbalta and temazepam on this subject. From 12-30 2012 to 07-05 2013, 14 trials were performed. The Results include a description of each trial and the number of nights, as well as complete data. The subject was given Cymbalta or temazepam in pre-specified times, with pre-specified doses being administered on weekends. To try to phase-shift the subject, Nature Made 3 mg chocolate melts used melatonin. However, several periods were conducted to examine the effect of melatonin upon phase. Consistent with a SPOT design by definition and rationale, the study was pursued without randomization in a real-time, real-life setting, similar to a clinical practice drug de-escalation/withdrawal, and no medication blinding was utilized. Due to the strong side effects of the medication on the subject, any placebo would not have been detected. A “no treatment interruption” period between treatments was also not possible or used. This is due to two reasons. First, it was not desirable to disrupt the biological effects. Second, and most importantly, Cymbalta withdrawal can cause undesirable side-effects such as “brain-zaps”, which last several months. The duration of these cannot be predicted.
The subject entered the start and end times manually into the Zeo iPAD app. Based on Zeo graphic histogram output, which showed the first REM sleep bar, the time to REM was manually calculated. The Zeo device provided the percentages of REM, light, deep, and wake sleep, as well as the number of awakenings. Due to the presence of PLMs in our subject’s sleep (clinically confirmed via videotape), we did not use the Zeo sleep latency parameter Time to Z.
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Statistical analysis of general nature
All analyses were performed using R version 3.1.3 ( http://www.R-project.org). The data was used for the sleep analysis. It contained data for 188 consecutive nights, December 30, 2012 through July 5, 2013. 21 nights had missing data due to lost records. These nights were therefore treated as missing at random. The following response variables were used to assess sleep quality: number of wakes (time to first REM), percent time spent in deep sleep, percentage time in light sleep, percent sleep time, and percent time awake. Linear models that included an autoregressive moving mean (ARMA), serial correlation structure, were used to account for the serial correlation among the nightly data. Different assumptions regarding the degree of serial correlation were tested. There was not much evidence to support strong serial correlation. Therefore, simple univariate linear regressions were performed for all response variables using the lm function. Predictors variables that are significant at p0.05 were retained. Analyses of model residuals were used to evaluate goodness-of-fit, satisfaction with linear model criteria.
Mathematics
For example, a perstage t model was created. It follows the same scheme as above, but with additional variables that leverage similar models.
perstage t = m 0 + b cym30 * cym30 + b cym60 * cym60 + b mel3 * mel3 + b cym30 mel3 * cym30 mel3 + b cym30 mel6 * cym30 mel6 + b cym60 mel3 * cym60 mel3 + b cym60 mel6 * cym60 mel6 + b cym60 tem15 * cym60 tem15 + b cym60 tem30 * cym60 tem30 + t
where m0 is a term that is not a yintercept term; b terms are regression coefficients and t is an error term with zero mean and variance s2. The model also includes terms that correspond to drugs being evaluated. These are: Cymbalta (30 mg) and Cymbalta (60 mg) Cymbalta and Melatonin 30 mg each (cym30mel3) Cymbalta and Melatonin 60 mg each (cym60mel6) Cymbalta and Melatonin 60 mg (cym60mel6) Cymbalta and Cymbalta 60mg and Temazepam (15 mg, cym60tem15); Cym60tem30 mg of Cym60tem30 and Cym60tem30 mg; Cymbalta60tem30 mg; Cymbalta and Temazepam 60m60tem30 and Cym60tem30; Cymbalta60tem30; Cymbalta60tem30; Cymbalta ta60tem30); Cymbalta60tem30; Cym60tem30; 60 mg; Significative terms (i.e. p 0.05 based upon the t-test for the coefficient value and its standard error; Cymbalta 60 mg and Temazepam 15 mg (cym60tem15); Cymbalta 60 mg and Temazepam 30 Mg (cym60tem30).
