How representative are insomnia clinical trials?

OBJECTIVES: To address the question of how representative subjects studied in hypnotic clinical trials are of the broader insomnia population, this study assessed initial contact rates and reasons for inclusion and exclusion during recruitment to an efficacy trial and to a safety trial of Food & Drug Administration (FDA) approved hypnotics. METHODS: Otherwise heathy persons meeting Diagnostic Statistical Manual, Fourth Edition, Revised (DSM-IVR) criteria for insomnia were recruited. In one study, persons 32-65 yrs, were invited to a 12 month trial of nightly use of zolpidem or placebo. In the other, persons 21-64 yrs with driver's licenses were recruited to test the effects of a hypnotic on live on-the-road driving ability. In both studies screening was conducted through an initial telephone interview followed by a clinic visit. RESULTS: In the United States (US) study 13% (n = 410) of 3180 initial contacts and in the Netherlands (NL) study 67% (n = 53) of the 79 initial contacts proceeded to the clinic visit. Of those at clinic 25% of US and 37% of NL participants failed to meet additional insomnia criteria. Mental health exclusions accounted for 24% of US and 23% of NL participants and medical problems accounted for 23% of US and 9% NL exclusions. Finally 20% of US and 26% of NL participants were excluded for drug use/abuse histories. After all screening 4% of the initial US contacts and 0% of the NL contacts entered the study. CONCLUSIONS: These data suggest persons entering insomnia hypnotic clinical trials are a highly selected sample that is unlikely to be representative of the broad insomnia population or the population of potential medication users.

Hyperarousal in insomnia and hypnotic dose escalation.

BACKGROUND: Given concerns about the abuse liability of hypnotics, this study assessed hyperarousal in people with insomnia and its relation to hypnotic self-administration over 12 months of nightly hypnotic use. METHODS: Ninety-five subjects with insomnia (age 32-64 years) underwent screening nocturnal polysomnogram (NPSG) and Multiple Sleep Latency Test (MSLT) the following day and, then, were randomized to receive zolpidem 10 mg or placebo nightly for 12 months. NPSGs and MSLTs were conducted and urine was collected (0700-1500 h) and analyzed for norepinephrine (NE) levels during months one and eight on study medication. A subset (n = 54) underwent hypnotic self-administration assessments in months one, four, and 12. RESULTS: Mean daily sleep latency on screening MSLT was distributed across the full range of MSLT latencies (2-20 min). The highest screening MSLT latencies were detected in subjects with higher NE levels, compared to those with the lowest MSLT latencies. In the subset undergoing self-administration assessment, those with the highest MSLT latencies chose more capsules (placebo and zolpidem) and increased the number of capsules chosen in months four relative to month one, compared to those with the lowest MSLT latencies. CONCLUSIONS: These data show that some insomniacs are hyperaroused with high MSLT/NE levels and, compared to low MSLT/NE insomniacs, they increase the number of capsules (zolpidem and placebo) self-administered on months four and 12 relative to Month one.

The status of sleep abnormalities as a diagnostic test for major depressive disorder.

BACKGROUND: Psychiatry lags other fields in development of diagnostic tests. METHODS: A literature review and meta-analysis was conducted to ascertain if polysomnographic abnormalities (REM density, REM latency, sleep efficiency, slow wave sleep, stage 1 and stage 2 sleep) warrant additional effort to develop them into a clinical diagnostic test for major depressive disorder (MDD). The 31 publications meeting inclusion criteria were then classified into one of three progressive steps using guidelines for evaluating the clinical usefulness of a diagnostic test. RESULTS: Most of the abnormalities found in MDD patients, when compared to healthy controls, occurred in the expected direction with moderate effect sizes but with substantial publication bias and heterogeneity. Eleven studies compared abnormalities in MDD to other psychiatric disorders (step 2a), and four studies provided data on the sensitivity or specificity of the findings in differentiating among the psychiatric disorders that frequently appear on the same differential diagnostic list as MDD (step 2b). No multicenter trial has been conducted prospectively to test the clinical utility of the diagnostic test (step 3). LIMITATIONS: Only published articles in the English language were used. CONCLUSIONS: Sleep studies for the detection of MDD appear replicable with a moderate effect size. However, additional step 1 studies are needed to define the sensitivity and specificity. The heterogeneity of sleep recording, scoring techniques, and MDD must also be addressed.

Medical comorbidity affects antidepressant treatment response in patients with melancholic depression.

BACKGROUND: This study aimed at the impact of medical comorbidity (MC) on response to antidepressant treatment over 6 weeks in diagnostic subtypes of patients with major depressive episode (MDE). METHODS: In a clinical sample of 241 admitted patients with MDE, MC was assessed by medical specialists and weekly response to antidepressant treatment was assessed with the Hamilton Depression Scale (HAM-D 21). RESULTS: Over 6 weeks of treatment, patients with melancholic depression and MC had poorer treatment response on the HAM-D scale and a worse functional outcome (GAF) as opposed to their counterparts without MC, which was first detected after 4 weeks of treatment (p = 0.02). More specifically, subjects with melancholic depression and cardiovascular or endocrinological MC showed significantly poorer treatment response over 6 weeks. Interestingly, these effects were not related to various antidepressant treatment regimens. CONCLUSIONS: MC has a negative impact on treatment response in patients with melancholic depression.

Serotonin receptor 1A-1019C/G variant: impact on antidepressant pharmacoresponse in melancholic depression?

Previous studies on the effects of serotonin receptor 1A (5-HT1A) gene variation on treatment response in depression revealed inconsistent results with studies pointing towards a detrimental influence of the 5-HT1A-1019G allele on antidepressant treatment response, while others did not discern any involvement of 5-HT1A variants. In order to further delineate the impact of 5-HT1A gene variation on pharmacoresponse in depression over 6 weeks of antidepressant treatment, the influence of the 5-HT1A-1019C/G (rs6295) polymorphism was investigated in 340 Caucasian patients with a Major Depressive Episode (DSM-IV) with particular attention to the subtype of depression (major depression and melancholic depression). Antidepressant treatment response across 5-HT1A-1019C/G genotype groups showed no differences in either Major Depressive Episode or major depression between genotype groups, whereas stratification for the melancholic subtype of depression revealed a significantly worse treatment response as conferred by the -1019CC genotype (p=0.02). The poorer treatment response in melancholic depression could first be detected in week 2 (p=0.03), continuing until week 6 and showing a maximum effect in week 3 (p=0.01). The present study adds to the clarification of the role of 5-HT1A variation in treatment response in major depression by providing preliminary support for poor treatment response mediated by the 5-HT1A-1019C allele repressing 5-HT1A activity specifically in the melancholic subtype of depression.

Sleep, sleepiness, and alcohol use.

The study of alcohol's effects on sleep dates back to the late 1930s. Since then, an extensive literature has described alcohol's effects on the sleep of healthy, nonalcoholic people. For example, studies found that in nonalcoholics who occasionally use alcohol, both high and low doses of alcohol initially improve sleep, although high alcohol doses can result in sleep disturbances during the second half of the nocturnal sleep period. Furthermore, people can rapidly develop tolerance to the sedative effects of alcohol. Researchers have investigated the interactive effects of alcohol with other determinants of daytime sleepiness. Such studies indicate that alcohol interacts with sleep deprivation and sleep restriction to exacerbate daytime sleepiness and alcohol-induced performance impairments. Alcohol's effects on other physiological functions during sleep have yet to be documented thoroughly and unequivocally.

Effects of zaleplon or triazolam with or without ethanol on human performance.

Objectives and background: Given that non-selective gamma-aminobutyric acid (GABA) agonist hypnotics impair performance and potentiate the disruptive effects of ethanol, this study was done to determine the performance-impairing and ethanol-potentiating effects of zaleplon, a new selective GABA agonist hypnotic.Methods: Eighteen healthy men (12) and women (six), 31.5+/-5.6 years old, were studied. Each underwent six treatments of 2 days in duration, presented in a Latin square design with 2-12 recovery days between. The treatments were: placebo-placebo; placebo-ethanol; triazolam-placebo; triazolam-ethanol; zaleplon-placebo; and zaleplon-ethanol; with triazolam (0.25 mg) or placebo administered at 08:30 h, zaleplon (10 mg) or placebo at 09:00 h, and ethanol (0.75 g/kg) or placebo consumed from 09:30 h. Performance tests were completed each day at 10:30, 12:00 and 14:30 h.Results: Breath ethanol concentration (BrEC), tested 0.5, 2.0, 4.5 and 6 h post consumption, did not differ among treatments and peaked at 0.052%, declining to 0.037, 0.009 and 0.001%. Triazolam with and without ethanol impaired digit symbol substitution, symbol copying, simple and complex reaction times and divided attention performance relative to placebo-placebo treatment. It did so consistently at 10:30 and 12:00 h, and less consistently at 14:30 h. Zaleplon without ethanol impaired only digit symbol substitution and divided attention tracking, and only at 10:30 h. Zaleplon with ethanol impaired most measures at 10:30 and 12:00 h, but not at 14:30 h. Zaleplon without ethanol consistently differed from triazolam without ethanol in the extent of performance impairment. Zaleplon with ethanol began to differ from triazolam with ethanol in performance impairment on the 12:00 and 14:30 h test sessions. Ethanol itself impaired most measures at 10:30 h, fewer at 12:00 h and none at 14:30 h. All active drug treatments increased self-rated sleepiness compared with placebo-placebo. Triazolam without ethanol produced greater self-rated sleepiness than zaleplon without ethanol. The addition of ethanol to both drugs generally produced comparable levels of self-rated sleepiness.Conclusions: In an absolute sense, zaleplon produced less performance impairment and a shorter period of ethanol potentiation than triazolam.

Treatment regimen and hypnotic self-administration.

RATIONALE AND OBJECTIVES: Previous studies have shown that insomniacs self-administer hypnotics at high nightly rates. This study determined whether prior experience with different treatment regimens (i.e., instructions and capsule availability) would alter the previously observed high hypnotic self-administration rates. METHODS: Sixty-four healthy men and women with (n = 32) and without (n = 32) insomnia, 21-55 years, self administered placebo or triazolam (0.25 mg) after different prior treatment regimens. They received one of three different treatment regimens enforced for 11 nights: a capsule each night, a capsule as needed, or a capsule every third night. On 14 subsequent nights they choose to self-administer a capsule or not, placebo during 1 week and triazolam (0.25 mg) the other (counterbalanced in order). RESULTS: Insomniacs self-administered more capsules than normals and triazolam was self-administered more than placebo. For both groups, treatment regimen had a minimal effect on capsule self-administration. During the treatment phase, triazolam improved self-ratings of sleep relative to placebo. During the choice phase, nightly variations in self-rated sleep predicted self-administration of a capsule on the following night, regardless of whether the capsule was active drug or placebo. CONCLUSIONS: The data of this study are consistent with the view that hypnotic self-administration by insomniacs is therapy-seeking behavior and not drug abuse.

Alexithymia and polysomnographic measures of sleep in healthy adults.

OBJECTIVE: This study examined associations between alexithymia and objective characteristics of sleep (latencies, stages, and amount and patterning of REM sleep) that may contribute to subjective reports of poor sleep quality and impaired dream recall among alexithymic people. METHODS: Fifty healthy, normally sleeping adults from the community completed the 20-item Toronto Alexithymia Scale and slept uninterrupted for one night in the laboratory while polysomnography was conducted. Various measures of sleep latency, sleep stages, and REM sleep-related variables were obtained, and analyses correlated these sleep measures with alexithymia, controlling for age, sex, and level of depressed affect. RESULTS: Higher alexithymia scores were significantly related to increased stage 1 (light) sleep and decreased stage 3/4 (deep) sleep. Alexithymia was unrelated to overall sleep efficiency or percentage of stage 2 sleep. Alexithymia was related to more frequent REM episodes and more stage 1 sleep during and immediately after REM episodes but was unrelated to the absolute amount of REM sleep. Alexithymia was also related to an earlier onset of the first REM episode. CONCLUSIONS: Alexithymia is associated with more light sleep and less deep sleep, which may contribute to subjective reports of poor sleep and increased sleepiness, fatigue, and somatic symptoms. Although alexithymia is not associated with an overall reduction of REM sleep, the increased frequency of episodes of REM that are interrupted and followed by light sleep rather than complete awakenings may contribute to limited dream recall.

Effects of rapid versus slow accumulation of eight hours of sleep loss.

The present study assessed alertness, memory, and performance following three schedules of approximately 8 hr of sleep loss (slow, intermediate, and rapid accumulation) in comparison to an 8-hr time in bed (TIB) sleep schedule. Twelve healthy individuals aged 21-35 completed each of four conditions according to a Latin Square design: no sleep loss (8-hr TIB for 4 nights; 2300-0700), slow (6-hr TIB for 4 nights; 0100-0700), intermediate (4-hr TIB for 2 nights; 0300-0700), and rapid (0-hr TIB for 1 night) sleep loss. On each day, participants completed a multiple sleep latency test (MSLT), a probed-recall memory task, a psychomotor vigilance task, a divided attention task, and the Profile of Mood States. "Rapid" sleep loss produced significantly more impairment on tests of alertness, memory, and performance compared to the "slow" accumulation of a comparable amount of sleep loss. The impairing effects of sleep loss vary as a function of rate, suggesting the presence of a compensatory adaptive mechanism operating in conjunction with the accumulation of a sleep debt.

Scoring reliability of the multiple sleep latency test in a clinical population.

STUDY OBJECTIVES: To determine intrarater and interrater scoring reliability of the multiple sleep latency test (MSLT) in a population of sleep clinic patients. DESIGN: N/A. SETTING: Urban sleep center. PATIENTS: 200 consecutive sleep center patients (diagnoses included: obstructive sleep apnea, narcolepsy, periodic-limb-movement, and individuals with no diagnosis). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: MSLTs were recorded and scored according to standard clinical procedures. One of four clinical polysomnographers and one of seven polysomnographic technologists scored each MSLT. All MSLTs were then rescored by the same polysomnographer. The intrarater reliability coefficient for mean MSLT score was .87 and interrater reliability was .90. Coefficients for the mean number of REM onsets during the MSLT were .81 for intrarater and .88 for interrater reliability. Intrarater and interrater agreement (kappa coefficients) for the presence of at least one REM onset during the MSLT was .78 and .86, respectively. For the presence of greater than one REM onset, a kappa of .78 was obtained for intrarater agreement and .91 for interrater agreement. CONCLUSIONS: The clinical MSLT displays excellent interrater and intrarater reliability estimates for both sleep latency and REM onset scores in a sleep-disordered population.

Effects of sleep loss on waking actigraphy.

STUDY OBJECTIVES: To assess the effect of sleep loss and the effect of a sedating drug on waking actigraphy DESIGN: N/A SETTING: N/A PARTICIPANTS: Seventeen healthy volunteers, aged 19-35 yrs INTERVENTIONS: Four night-day treatments presented in a Latin Square Design: placebo-8 hr time-in-bed (TIB), placebo-4 hr TIB, placebo-0 hr TIB, and diphenhydramine 50 mg-8 hr TIB. MEASUREMENTS AND RESULTS: After the appropriate TIB, medication was administered at 09:00 hr, the Multiple Sleep Latency Test at 09:30, 11:30, 13:30, 15:30, and 17:30 hr, and a 45 min performance battery at 10:30, 14:30, and 16:30 hr. Each day the volunteers wore actigraphs from 0700-1800 hrs. Decreasing TIB was associated with decreased daily mean sleep latency on the MSLT with 4 and 0 hrs differing from 8 hrs and each other. Daytime activity also was reduced by the reduced prior TIB. Increased inactivity relative to the 8 hr TIB developed between the 4 hr and 0 hr TIBs, with 4 hrs differing from 0 hrs, but not 8 hrs. Diphenhydramine 50 mg reduced mean daily sleep latency and increased percent inactive time relative to placebo. On the MSLT diphenhydramine was intermediate to 4 hr and 0 hr TIB and on actigraphy it was similar to 0 hr TIB. CONCLUSIONS: The difference in the effect of diphenhydramine on these actigraphy and MSLT may reflect the different sensitivities of the measures.

Sleep physiology and pathophysiology.

Sleep is a complex, highly organized state that is fundamental to life. And yet, many functions of sleep remain to be discovered and understood. The past 50 years of modern sleep research clearly indicate what sleep is not--simply a resting brain, as popular notions and behavioral observations might suggest. This review will describe normal sleep physiology and its regulation as well as the major disorders of sleep and their underlying pathophysiology.

Sleep-wake state and memory function.

Facility of memory formation and retrieval is affected by sleep-wake state. This paper discusses memory function while individuals are awake, but sleepy, at the transitions in state (i.e., wake to sleep and sleep to wake), and in REM and NREM sleep. The basal state of arousal at the time of memory function seems to be critical and the sleepy state, state transitions, and NREM sleep seem to define a continuum of arousal with respect to memory function. While different memory systems have been described, the effect of sleep-wake state on memory systems appears to be non-specific. Finally there is a shift in neurobiology from the NREM to REM state and memory function also appears to change in REM sleep.

Effects of sleep deprivation on daytime sleepiness in primary insomnia.

STUDY OBJECTIVES: This study investigated changes in MSLT scores and recovery sleep following total sleep deprivation in subjects with insomnia as compared to normal sleepers. DESIGN: Matched-groups design. SETTING: A sleep disorders center in a large medical center. PARTICIPANTS: Ten individuals with psychophysiological insomnia and ten age- and sex-matched normal sleepers served as subjects. INTERVENTIONS: Subjects underwent total sleep deprivation after baseline polysomnography and MSLT. A post-deprivation MSLT was obtained, as well as polysomnography on the recovery night and an MSLT after the recovery night. MEASUREMENTS AND RESULTS: Both groups showed significant decreases in MSLT scores following total sleep deprivation, as compared to baseline. Both groups had significantly shorter scores on a nighttime MSLT compared to a daytime MSLT. The insomnia group also showed a significant increase in total sleep time on the recovery night compared to baseline. CONCLUSIONS: The MSLT is sensitive to changes in sleepiness associated with total sleep deprivation in individuals with primary insomnia.

Sleep organization and regulation.

Sleep is a vital, complex state with as yet unknown functions. It is active and highly organized and is regulated by homeostatic, circadian, and ultradian processes. It consists of two distinct sleep states, rapid eye movement (REM) and non-rapid eye movement (NREM), both of which have a dramatic impact on many aspects of physiology and behavior. The significance and consequences of the REM-NREM organization of sleep are not known. On the other hand, the sleep state and its organization are quite fragile and dynamic. Any number of factors can disrupt sleep and its expression, and its nature changes over the life span. What is certain is that any reduction and/or disruption of sleep hinders an organism's ability to navigate through the waking state.

Effects of an experimentally induced rhinovirus cold on sleep, performance, and daytime alertness.

STUDY OBJECTIVES: There is accumulating evidence that the common cold produces impairments in psychomotor vigilance. This has led some investigators to hypothesize that such illnesses may also have disruptive effects on sleep. While several self-report studies suggest that viral illness may influence sleep parameters, no studies have assessed polysomnographically recorded sleep following viral infections. DESIGN: Parallel control group comparison. SETTING: Sleep laboratory in a large urban medical center. PARTICIPANTS: Twenty-one men and women with susceptibility to the rhinovirus type 23. INTERVENTIONS: Nasal inoculation with rhinovirus type 23. MEASUREMENTS: Polysomnographically recorded sleep for five nights (2300-0700 h) post-viral inoculation. Twice daily (1030 and 1430 h) performance assessment during each experimental day using auditory vigilance and divided attention tasks. A multiple sleep latency test (MSLT) was performed daily for the duration of the study. RESULTS: In symptomatic individuals, total sleep time decreased an average of 23 min, consolidated sleep decreased an average of 36 min, and sleep efficiency was reduced by an average of 5% during the active viral period (experimental days/nights 3-5) compared with the incubation period. Psychomotor performance was impaired. These changes were significantly greater than those observed in asymptomatic individuals. CONCLUSIONS: The common cold can have detrimental effects on sleep and psychomotor performance in symptomatic individuals during the initial active phase of the illness.

The effects of cocaine on mood and sleep in cocaine-dependent males.

The effects of cocaine use and withdrawal on mood and sleep were examined. Three cocaine-dependent men lived in an inpatient facility for approximately 4 weeks, which included an initial abstinence phase (8-10 days), a cocaine administration phase (5 days), and a 2nd abstinence phase (14-16 days). During the 2nd phase, cocaine was administered intranasally a few hours before bedtime. During the day, mood and daytime sleepiness were measured, and sleep was monitored each night. Cocaine produced typical changes in mood and blood pressure, and sleep was severely disrupted. Following Phase 2, there were no changes in mood that was indicative of an abstinence syndrome, although, initially, daytime sleepiness increased. After 2 weeks, sleep architecture remained different from age-matched controls. This study is the first to measure changes in sleep architecture polysomnographically following a period of controlled cocaine use.

Repeated nocturnal sleep latencies in narcoleptic, sleepy and alert subjects.

OBJECTIVES: The purpose of this study was to assess nocturnal sleep latencies among narcoleptics. METHODS: Thirteen narcoleptics and matched sleepy and alert controls participated in this study. Subjects were awakened three times on each of two experimental nights. The latencies to sleep and rapid eye movement sleep were evaluated at the beginning of the night and following each experimental awakening. RESULTS: The alert group (AG) had a significantly longer mean nocturnal sleep latency than the narcoleptic (NG) and sleepy groups (SG). The sleep latencies at 23:00 and 01:10 h were significantly longer than the latencies at 03:10 and 05:10 h. The interaction between group and time of night demonstrated longer latencies at 23:00 and 03:10 h for the AG when compared to the SG and the NG. At 01:10 and 05:10 h all groups had comparable latencies. The number of subjects in the NG who had multiple sleep onset REM periods (SOREMPs) was significantly higher than in either the AG or the SG. CONCLUSIONS: Narcoleptics were found to have a heightened propensity to fall asleep and increased number of SOREMPs during nocturnal sleep opportunities. These characteristics are consistent with the daytime polysomnographic findings known in this patient population.