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.

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.

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.

Definitions of REM latency: some comparisons with particular reference to depression.

Unlike sleep stages, which are assessed by standardized criteria, an informal survey by us showed that the definition of REM latency is relatively idiosyncratic. Differences in definition arise for two reasons: Differences in the definition of sleep onset, and the inclusion or exclusion of wakefulness that may occur prior to the first REM period. Seven definitions are identified. Each was applied to 70 records taken from 14 depressed patients, 5 remitted depressives, and 5 normal subjects. In all three samples, REM latencies calculated on the basis of the different definitions differed significantly. Reasons for adopting a common definition are discussed. It is suggested that, if established, the reliability and validity (concurrent and predictive) of the available measures would provide an empirical basis for selection.

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.

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.

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.

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.

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.

Sex differences in the cognitive effects of unilateral brain damage.

One hundred subjects (50 men, 50 women), of whom 80 had suffered a unilateral cerebrovascular accident (40 left, 40 right), were tested on the WAIS. In the case of left hemisphere damage the male patients showed lower Verbal than Performance Scale IQ scores; for the right brain damaged men Performance Scale scores were Lower than their scores on the Verbal Scale. Women with unilateral brain damage showed no such reliable discrepancies between their Verbal and Performance Scale scores. This difference in the patterning of WAIS IQs in male and female stroke patients persisted even after the scores of those few patients with any significant degree of expressive aphasia had been excluded from consideration.

Sex differences in the cognitive effects of unilateral brain damage: comparison of stroke patients and normal control subjects.

Our original paper on the influence of the sex of the patients on the cognitive effects of unilateral brain damage mainly described the differences found between the various lesion groups (left/right, male/female) and said little about comparisons between these groups and our control subjects. Such comparisons are examined here; they confirm that the major sex differences after such brain damage appear in tasks intended to involve nonverbal processing. This evidence supports the hypothesis that women, to a greater extent than men, may employ verbal, left hemisphere processing to solve ostensibly nonverbal problems.

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.

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.

REM latency and depression: computer simulations based on the results of phase delay of sleep in normal subjects.

A phase advance of the circadian rhythm of rapid eye movement (REM) sleep propensity relative to the sleep-wake cycle has been hypothesized to account for the abnormalities of REM sleep in depression. One implication of this hypothesis is that an acute phase delay of sleep in normal subjects should produce the same abnormalities of REM sleep. A further implication is that changes in REM sleep that occur in normal subjects with delay shifts of sleep of progressively greater magnitude describe those that occur during the course of a depressive episode. This hypothesis was tested by computer simulation using two equations which, given the data derived from normal subjects experiencing phase delays of sleep, generated the REM latencies expected during successive stages of a depressive episode. For severely depressed patients, the computer-generated data matched those found empirically. The known correlation between severity of depression and REM latency, and the REM latencies of recovered patients, are consistent with the hypothesis.

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.

Dose-response effects of ethanol on the sleep of young women.

In healthy young women, rapid eye movement sleep decreased, slow-wave sleep increased, sleep-onset latency decreased and late-night disturbance of sleep increased with increasing doses of alcohol.

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.