Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned.

Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls and >1 M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were (a) gene-based tests suggesting roles for adenylate cyclase 3 (ADCY3, 2p23.3) and galanin (GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C (P=0.020, odds ratio=1.10); and (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies (P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD.

Nonpharmacologic group treatment of insomnia: a preliminary study with cancer survivors.

This study describes, and examines the initial efficacy of, a sleep therapy programme developed for cancer patients with insomnia. The six-session group programme included stimulus control therapy, relaxation training, and other strategies aimed at consolidating sleep and reducing cognitive-emotional arousal. The 12 final participants were patients of a regional cancer centre; mean age was 54.7 years (S.D. 10.4); median time from cancer diagnosis was 33.6 months; all had high performance status. Participants kept sleep diaries and rated their sleep quality, mood and functioning at baseline, week 4 and week 8. Significant improvement over baseline was observed at weeks 4 and 8 in the number of awakenings, time awake after sleep onset, sleep efficiency, sleep quality ratings, and scores on European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 role functioning and insomnia. Total sleep time and fatigue were significantly improved at week 8. The sleep therapy programme was associated with improved sleep, reduced fatigue and enhanced ability to perform activities in relatively well individuals attending a cancer centre. This is preliminary evidence of the efficacy of the programme. Further research is required to examine the programme's effectiveness and suitability for a wider range of people with cancer. Options for providing cancer patients with access to nonpharmacologic treatments for insomnia are discussed.

How do prolonged wakefulness and alcohol compare in the decrements they produce on a simulated driving task?

The effects of alcohol ingestion were compared with those of prolonged wakefulness on a simulated driving task. Eighteen healthy, male subjects aged between 19 and 35 years drove for 30 min on a simulated driving task at blood alcohol concentrations of 0.00, 0.05 and 0.08%. Subjective sleepiness was assessed before and after the driving task. Driving performance was measured in terms of the mean and standard deviation (S.D.) of lane position (tracking); the mean and S.D. of speed deviation (the difference between the actual speed and the posted speed limit); and the number of off-road occurrences. Ratings of sleepiness increased with increasing blood alcohol concentration, and were higher following the driving task. With increasing blood alcohol concentration, tracking variability, speed variability, and off-road events increased, while speed deviation decreased, the result of subjects driving faster. The results were compared with a previous study examining simulated driving performance during one night of prolonged wakefulness [Arnedt, J.T., MacLean A.W., 1996. Effects of sleep loss on urban and motorway driving stimulation performance. Presented at the Drive Alert... Arrive Alive International Forum, Washington DC], using an approach adopted by Dawson and Reid [Dawson, D., Reid, K., 1997. Fatigue, alcohol and performance impairment. Nature 388, 23]. For mean tracking, tracking variability, and speed variability 18.5 and 21 h of wakefulness produced changes of the same magnitude as 0.05 and 0.08% blood alcohol concentration, respectively. Alcohol consumption produced changes in speed deviation and off-road occurrences of greater magnitude than the corresponding levels of prolonged wakefulness. While limited to situations in which there is no other traffic present, the findings suggest that impairments in simulated driving are evident even at relatively modest blood alcohol levels, and that wakefulness prolonged by as little as 3 h can produce decrements in the ability to maintain speed and road position as serious as those found at the legal limits of alcohol consumption.

Simulated driving performance following prolonged wakefulness and alcohol consumption: separate and combined contributions to impairment.

The separate and combined effects of prolonged wakefulness and alcohol were compared on measures of subjective sleepiness, simulated driving performance and drivers' ability to judge impairment. Twenty-two males aged between 19 and 35 years were tested on four occasions. Subjects drove for 30 min on a simulated driving task under conditions determined by the factorial combination of 16 and 20 h of wakefulness and blood alcohol concentrations of 0.00 and 0.08%. The simulated driving session took place 30 min postingestion; subjects in the two alcohol conditions participated in a second 30-min driving session 90-min postingestion. Subjects made simultaneous ratings of their impairment while driving and retrospective ratings at the end of each test session. Subjective sleepiness measures were completed before and after each driving session. The combination of 20 h of prolonged wakefulness and alcohol produced significantly lower ratings of subjective sleepiness and driving performance that was worse, but not significantly so, than would be expected from the additive effects of each condition alone. Driving performance was always worse in the second driving session, during the elimination phase of alcohol metabolism, despite blood alcohol concentrations being lower than during the first driving session. There was a modest association between perceived and actual impairments in driving performance following prolonged wakefulness and alcohol. The findings suggest that the combination of prolonged wakefulness and alcohol consumption produced greater decrements in simulated driving performance than each condition alone and that drivers have only a modest ability to appreciate the magnitude of their impairment.

The effects of bright light treatment on the symptoms of fibromyalgia.

OBJECTIVE: To investigate the effects of bright light treatment on the symptoms of pain, mood, and sleep in patients with fibromyalgia (FM) reporting seasonality of symptoms on the Seasonal Pattern Assessment Questionnaire (SPAQ). METHODS: A randomized 10 week crossover study compared the effects of 4 weeks of "visible electromagnetic fields" (EMF) (light condition; mean 4750 lux, SD 2337 lux) to 4 weeks of "nonvisible EMF" (no light condition) in 14 patients with FM having a minimum SPAQ score of 11. The light visor system (Bio-Brite) was fitted with an opaque filter for the "nonvisible EMF" control condition. RESULTS: No significant differences were found between treatment conditions on tenderness measured with dolorimetry, self-ratings of sleep, pain, mood, and global measures. Mood was not related to pain or sleep. There was significant reduction in depression scores and subjective pain, but increased tenderness and nocturnal awakenings related to time. CONCLUSION: The were no significant differences between the light and no light conditions on pain, mood, or sleep in patients with FM reporting seasonality of symptoms. No relationship was found between mood and the symptoms of FM (i.e., pain, sleep, and fatigue).

Recombination patterns around the breakpoints of a balanced 1;11 autosomal translocation associated with major mental illness.

The frequency and extent of pairing failure around human translocations are unknown. We have examined the pattern of recombination around the breakpoints of a balanced autosomal translocation t(1;11) (q43;q21) associated with major mental illness. DNA was available from 17 carriers and 10 non-translocation carriers with meioses involving four generations. The derivative 1 and 11 chromosomes were also isolated in somatic cell hybrids and used to confirm phase. We have genotyped pedigree members using 20 polymorphic markers within 10 cM on either side of both chromosome 1 and 11 breakpoints. We find no significant reduction of recombination in the vicinity of either breakpoint. However we estimate that there are insufficient meioses even in this large family to make a meaningful interpretation and suggest that sperm typing alone can answer these interesting questions.

Sleep-related violence.

We hypothesized that sleep-related violent behavior associated with parasomnias occurs as the result of a diathesis and is precipitated by stressors and mediated by disturbed nonrapid eye movement (NREM) sleep physiology. Sixty-four consecutive adult patients (mean age 30 years) who were investigated for sleepwalking or sleep terrors were categorized according to clinical history into three groups: serious violence during sleep to other people or to property or self (n = 26); harmful, but not destructive behavior (n = 12); and nonviolent behavior (n = 26). Log linear analysis showed that a diathesis (childhood parasomnia and/or family history of parasomnia) and a stressor (psychologic distress, substance abuse and sleep schedule disorder) predicted the presence of sleepwalking or night terror. Serious violent acts were more likely to occur with males (p < 0.004) who showed sleep schedule disorder (p < 0.03). Both harmful and serious violent sleep behavior occurred with drug abuse (p < 0.009). In comparison to all other groups, those who were violent to other people were males who experienced more stressors (p < 0.02), drank excessive caffeinated beverages, abused drugs (p < 0.03) and showed less stage 4 sleep (p < 0.02) and less alpha (7.5-11 Hz) electroencephalogram NREM sleep (p < 0.02) on polysomnography. Being male and having < 2% stage 4 sleep provided 89% sensitivity, 80% specificity and 81% diagnostic accuracy for individuals who were violent to others. The forensic implications of these findings are discussed.

The reliability of visual scoring of alpha EEG activity during sleep.

The reliability of visual scoring of alpha electroencephalogram activity in nonrapid eye movement sleep was evaluated. Three trained scorers independently, on two occasions, assessed one record from each of 10 patients. In addition to standard sleep staging of the records, alpha activity was scored using three methods: a) while the record was being scored, an assessment of alpha activity during the preceding stage was made at each stage change; b) after the record was scored a single global rating of alpha was made; and c) each 20-second epoch of the record was rated on the amount of alpha present. Relative and absolute generalizability coefficients in excess of 0.810 and 0.698, respectively, were obtained. However, the results also indicated that careful attention to methodological factors is critical in ensuring satisfactory standards of reliability.

Alleviating sleep-related discontinuance symptoms associated with benzodiazepine withdrawal: a new approach.

There is limited information on the time course of recovery of sleep architecture in patients withdrawn from benzodiazepines (BDZ). This study examined the effects of substituting a new class of hypnotic drugs, namely the cyclopyrrolones, for current BDZs in patients presenting with BDZ dependence. The results indicated a clear improvement in a variety of sleep parameters after commencing with a cyclopyrrolone (zopiclone). These changes remained to some extent after zopiclone was discontinued. Also, the absence of certain withdrawal effects (i.e. rebound insomnia) upon discontinuation of zopiclone allows for patients to be carried through a potentially difficult period after stopping BDZs, while expediting the eventual discontinuation of all hypnotic medication.

Changes in paraspinal electromyographic spectral analysis with exercise: Two studies.

It has been suggested, but not substantiated, that electromyographic (EMG) power spectrum (PS) analysis of the paraspinal muscles could be a useful method of evaluating low back pain treatment outcome. The use of PS analysis to measure paraspinal muscle adaptations was investigated in two studies: Study 1, involving previously sedentary healthy women who participated in a 12-week fitness class program, and Study 2, involving low back pain sufferers who participated in a 10-week back-care exercise program. All subjects underwent assessments of physical fitness (aerobic capacity, back strength, and flexibility) and EMG PS analysis of the multifidus and iliocostalis muscles (during a constant force contraction), before and after the experimental period. The results in both studies indicated that the EMG PS measures were sensitive to adaptive changes, with findings of (a) decreases in multifidus initial median frequency (IMF) and fatigue (FTG) of the fitness class participants and (b) an increase in multifidus IMF and decreases in multifidus and iliocostalis FTG of the back-care participants. The results are discussed with regard to possible links between spectral changes and alterations in muscle fiber characteristics and functioning, and the need for further research to substantiate such links.

Rapid eye movement latency and mood following a delay of bedtime in healthy subjects: do the effects mimic changes in depressive illness?

The phase advance hypothesis proposes that a phase advance of certain circadian rhythms (such as rapid eye movement (REM) sleep propensity) relative to the sleep-wake cycle is implicated in the pathophysiology and pathogenesis of depression. In an earlier study, we reported that a 6-h delay of sleep in normals produced REM changes that resembled the depressive pattern. Mood change was generally modest, although 2 of the 10 subjects became noticeably depressed. This study assessed the replicability of these results, and introduced a phase advance control condition. Predicted changes were observed in REM parameters. Modest but reliable mood change was confined to the first night of the phase delay, and was attributed to sleep loss. These results suggest that the effects of the phase shift were relatively benign, except in a minority of cases. Such individuals may have a susceptibility to depression that manifests itself under certain conductive physiological conditions.

Sleep physiology and psychological aspects of the fibrositis (fibromyalgia) syndrome.

Fibrositis (fibromyalgia) patients were compared with normal controls in terms of electrophysiology (EEG), self-report indicants of awakening, quality of sleep, behaviourally signalled awakenings, and Symptom Check List 90R (SCL-90R) scores. The results differentiated fibrositis patients from normal controls in terms of SCL-90R scores, with fibrositis patients showing significantly more psychopathology. Fibrositis patients had more alpha EEG sleep and less REM and Stage 1 sleep. They were better able to recall their behaviourally signalled awakenings the following morning and reported qualitatively less satisfying sleep than the normal controls. The alpha EEG sleep anomaly may reflect a vigilant arousal state during nocturnal sleep and result in the daytime experience of unrefreshing sleep, psychologic distress, that re-enforces the perpetuation of the sleep-related symptoms.

Age-related changes in sleep in depressed and healthy subjects. A meta-analysis.

In this article we demonstrate that the difference in sleep between depressives and healthy controls varies systematically as a function of the mean age of the sample studied. The data were taken from 27 studies that had compared the sleep of drug-free depressed patients and age-matched healthy controls. In all, the studies give data for 822 patients (in 41 samples) and 621 healthy controls (in 37 samples). The mean age of the samples varied between 9 and 72 years. For total sleep time, minutes awake, sleep efficiency, minutes of slow-wave sleep, and REM latency, there are reliable age-related trends in both sets of samples. These trends follow a progressively diverging course such that, within studies, the mean difference and the standardized mean difference (d) between patients and controls increases as a linear function of the mean age of the former (i.e., the older the patients, the greater the difference). Possible reasons for the interaction are discussed.

Variation in process S: effects on sleep continuity and architecture.

Given the two-process model of sleep regulation, and the hypothesis that the sleep disorder in depressive illness is a consequence of a deficient Process S, it was predicted that relatively high levels of S would result in enhanced sleep continuity, increased slow-wave sleep (SWS), prolonged rapid-eye-movement (REM) latency, and less REM sleep. These predictions were tested in two studies. In Study 1, the level of Process S (at 0900 h prior to a 3-h sleep episode) was varied by altering the time and duration of prior nocturnal sleep (2400-0300 h, 0300-0600 h, 2400-0600 h). In Study 2, the leve of Process S (at 2400 h prior to an 8-h sleep episode) was varied by studying subjects when they had not napped or had taken 2-h naps beginning at either 1000 or 1900 h. As predicted by the model, SWS varied reliably depending on the level of S at bedrest, as did indices of sleep continuity at night. Contrary to prediction, however, REM sleep was either increased (Study 1) or did not change reliably (Study 2). It is suggested that, contrary to the other aspects of sleep, REM sleep is strongly influenced by circadian and homeostatic processes and that Process S plays a relatively minor role in its regulation.

The time course of 'process S': comparison of visually scored slow wave sleep and power spectral analysis.

The sleep of 4 groups (N = 8) of young healthy subjects was recorded during naps at either 09.00, 14.00, 19.00 or 24.00 h. For the first hour of sleep, conventionally scored slow wave sleep (SWS) and computed EEG power density (0-25 Hz) were found to increase exponentially as a function of prior wakefulness (range 3-18 h). The equations based on SWS and spectral analysis of the sleep EEG gave values for r' (the growth rate of the function) that were similar to each other (0.038 and 0.039, respectively) and to that reported by Daan et al. (1984; 0.055). These data are consistent with the proposal that process S, 1 of 2 processes believed to regulate sleep and wakefulness, increases exponentially during the waking day (Daan et al. 1984). In addition, they indicate that in this context SWS and spectral analysis provide measures of slow wave activity that are equally sensitive to changes in prior wakefulness.

Sleep in the premenstrual phase: a self-report study of PMS patients and normal controls.

Sleep disturbances commonly occur in the premenstruum in both Premenstrual Syndrome (PMS) patients and in women from the general population. Reports on the Post-Sleep Inventory were obtained from a clinic sample of PMS patients and samples from the general population dichotomized into a non-clinic group with and without premenstrual disturbance on the basis of their scores on the Premenstrual Tension Syndrome Self Rating Scale. The patients reported degrees of disturbance that were consistently higher than either or both the other two groups. PMS patients reported unpleasant dreams, awakenings, failure to wake at the expected time and tiredness in the morning, and heightened mental activity during the night and upon awakening. The three groups could be reliably discriminated on this basis with an overall accuracy of 82%. Sleep disturbances form an important component of premenstrual disturbance and merit specific clinical intervention and more detailed investigation.

The influence of prior wakefulness on REM sleep.

Data from studies of naps and of shifted sleep were used to determine the relationship between two measures of rapid eye movement (REM) sleep (percentage of REM in the first 2 hr of sleep and REM latency) and prior wakefulness. For each sample, we calculated the difference between the observed value and that predicted by a cosine function that estimated the circadian rhythm of REM sleep propensity. The difference values were found to correlate reliably with hours and log hours of prior wakefulness. We conclude that while REM sleep is regulated in part by an endogenous circadian oscillator, it is also influenced by the duration of prior wakefulness.

REM sleep and depression: further use of computer simulation to test the phase-advance hypothesis.

A phase advance of the circadian rhythm of rapid eye movement (REM) sleep propensity relative to the sleep-wake cycle has been proposed to account for the abnormalities of REM sleep commonly found in depressed patients. One implication of this hypothesis is that a phase delay of sleep in normal subjects should produce the same abnormalities of REM sleep. The hypothesis was tested by computer simulation using equations based on data derived from normal subjects who had experienced phase shifts of their bedtime. At phase delays of between 4 and 6 hours (an estimate of the putative phase advance in depressed patients), the mean REM latency and the mean duration of the first REM period predicted by the equations did not differ significantly from those observed in depressed patients. The findings with respect to the distribution of REM latency were more equivocal.

The sleep of remitted bipolar depressives: comparison with sex and age-matched controls.

The sleep of 10 bipolar patients was recorded for five consecutive nights following their recovery from a depressive episode. In all respects except the number of arousals, their sleep did not differ reliably from that of 10 sex and age-matched control subjects. We conclude that sleep measures are unlikely to be useful as trait markers of a depressive diathesis in bipolar disorder.

Slow-wave sleep in daytime and nocturnal sleep: an estimate of the time course of "Process S".

Daan et al. (1984) have proposed that sleep and wakefulness are regulated, in part, by a "Process S" that increases during wakefulness and declines during sleep. Data derived from several studies were taken to determine the time course of Process S during both wakefulness and sleep. As required by the model, slow-wave-sleep (SWS; an index of Process S) was found to increase exponentially as a function of prior wake time (equation 1) and to decline exponentially as a function of time asleep (equation 2). The equations accounted for 91% and 96% of the variance, respectively. In addition, equation 1 accurately predicted the amount the amount of SWS in the first hour of nocturnal sleep.